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d5872a55029aa615abc671dd5b3acbe3885e51c1	nice	Weight management: lifestyle services for overweight or obese adults	Weight management: lifestyle services for overweight or obese adults This guideline covers multi-component lifestyle weight management services including programmes, courses, clubs or groups provided by the public, private and voluntary sector. The aim is to help people lose weight and become more physically active to reduce the risk of diseases associated with obesity. This includes coronary heart disease, stroke, type 2 diabetes and various cancers. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The aim of this guideline to help meet a range of public health goals. These include helping reduce the risk of the main diseases associated with obesity, for example: coronary heart disease, stroke, hypertension, osteoarthritis, type 2 diabetes and various cancers (endometrial, breast, kidney and colon). The focus is on lifestyle weight management programmes that: accept self-referrals or referrals from health or social care practitioners are provided by the public, private or voluntary sector are based in the community, workplaces, primary care or online. Usually known as 'tier 2' services (see Tiers of weight management services), these programmes are just 1 part of a comprehensive approach to preventing and treating obesity. Clinical judgement will be needed to determine whether they are suitable for people with conditions that increase the risk of, or are associated with, obesity or who have complex needs. This guideline replaces section 1.1.7 of NICE's guideline on obesity prevention. It gives recommendations on lifestyle weight management services for overweight and obese adults aged 18 and over. The recommendations should be considered alongside NICE's other guidance on obesity. # Recommendation 1 Adopt an integrated approach to preventing and managing obesity Local authorities, working with other local service providers, clinical commissioning groups and health and wellbeing boards, should: Ensure there is an integrated approach to preventing and managing obesity and its associated conditions (see recommendation 1 in NICE's guideline on obesity: working with local communities. Systems should be in place to allow people to be referred to, or receive support from (or across) the different service tiers of an obesity pathway, as necessary. This includes referrals to and from lifestyle weight management programmes. All the options in the local obesity pathway should be made clear to both professionals and the public. Identify local services, facilities or groups that could be included in the local obesity pathway, meet the needs of different groups and address the wider determinants of health. Examples include community walking groups or gardening schemes. Ensure staff in local health services are aware of, and make referrals to, the lifestyle weight management service. This includes staff working in: GP teams, pharmacies, health visiting, the NHS Health Check programme and services for smoking cessation, fertility or type 2 diabetes. Ensure lifestyle weight management services for adults meet local needs as identified by the joint strategic needs assessment (JSNA) and other local data. # Recommendation 2 Ensure services cause no harm Public Health England, health and social care professionals, health and wellbeing boards, commissioners of health and social care services and providers of lifestyle weight management services (see Who should take action?) should: Be aware of the effort needed to lose weight, prevent weight regain or avoid any further weight gain. Also be aware of the stigma that adults who are overweight or obese may feel or experience. Ensure the tone and content of all communications is respectful and non-judgemental (see recommendation 5 in NICE's guideline on obesity: working with local communities). In addition, the terminology used to describe someone's condition should respect how they like to be described. Ensure equipment and facilities meet the needs of most adults who are overweight or obese. For example, referrers to, and providers of, lifestyle weight management services should ensure there are large blood pressure cuffs and suitably sized chairs without arms. Any new scales purchased should be able to accurately weigh the heaviest patients seen by the service. Be aware that people may feel anxious about being weighed and measured. For example, respect someone's preference for privacy at the weekly weigh-in. (Note, although people may find a waist circumference measurement helpful for self-monitoring, it does not help to assess people with a BMI greater than 35 kg/m2.) # Recommendation 3 Raise awareness of local weight management issues among commissioners Local authorities and Public Health England should ensure all those commissioning lifestyle weight management services are aware of: the number of adults who are overweight or obese locally, including any variations in rates between different groups the effect of the local environment and the wider determinants of health on the prevention and management of obesity the local obesity pathway and the role of lifestyle weight management services in the local strategic approach to the prevention and management of obesity the range of lifestyle weight management programmes that could be commissioned locally (see recommendation 12) continuing professional development or training opportunities on weight management (see recommendation 14). # Recommendation 4 Raise awareness of lifestyle weight management services among health and social care professionals Clinical commissioning groups, health and wellbeing boards, hospital and community trusts, local authorities, NHS England and Public Health England should: Ensure health and social care professionals in contact with adults who are overweight or obese are made aware of: the local obesity pathway and the local strategic approach to preventing and managing obesity the range of local lifestyle weight management services available national sources of accurate information and advice, such as NHS information on losing weight and healthier families continuing professional development or training opportunities on weight management (see recommendation 14). # Recommendation 5 Raise awareness of lifestyle weight management services among the local population Local authorities and Public Health England should: Ensure sources of information and advice about local lifestyle weight management services are included in any communications about being overweight or obese. This includes information provided by health and social care professionals working with adults (such as GPs, practice nurses, health visitors and pharmacists). Public Health England, local authorities, health and wellbeing boards and clinical commissioning groups should ensure the local adult population is aware of: The health benefits for adults who are overweight or obese of losing even a relatively small amount of weight and keeping it off in the long term (or avoiding any further weight gain). (See recommendation 7.) The range of lifestyle weight management services available locally. Local sources of information and advice such as GPs, practice nurses, health visitors and pharmacists. National sources of accurate information and advice such NHS information on losing weight and healthier families. # Recommendation 6 Refer overweight and obese adults to a lifestyle weight management programme GP practices and other health or social care professionals who give advice about, or refer people to, lifestyle weight management programmes (see Who should take action?) should: Raise the issue of weight loss in a respectful and non-judgemental way. Recognise that this may have been raised on numerous occasions and respect someone's choice not to discuss it further on this occasion. Identify people eligible for referral to lifestyle weight management services by measuring their body mass index (BMI). Also measure waist circumference for those with a BMI less than 35 kg/m2. Consider any other locally agreed risk factors. For funded referrals, note that: programmes may particularly benefit adults who are obese (that is, with a BMI over 30 kg/m2, or lower for those from black and minority ethnic groups) or with other risk factors (comorbidities such as type 2 diabetes) where there is capacity, access for adults who are overweight should not be restricted (that is, for people with a BMI between 25 to 30 kg/m2, or lower for those from black and minority ethnic groups) or with other risk factors (comorbidities such as type 2 diabetes) there should be no upper BMI or upper age limit for referral. Provide information on programmes available locally, where possible, taking people's preferences and previous experiences into account. Be clear that no programme holds the 'magic bullet' or can guarantee long-term success. Refer people to a group rather than an individual programme if they express no preference because, on average, group programmes tend to be more cost effective. Ensure people who are overweight or obese who are not referred (for whatever reason) have an opportunity to discuss and reconsider attending a programme in the future. Discuss making a follow-up appointment at an agreed date (for example, in 3 to 6 months). Provide them with sources of information about how to make gradual, long-term changes to their dietary habits and physical activity levels (for example, NHS Live Well). Give people the opportunity for a re-referral, as necessary, because weight management is a long-term process. Use clinical judgement, taking into account the person's circumstances, previous experiences of weight management and commitment to change. # Recommendation 7 Address the expectations and information needs of adults thinking about joining a lifestyle weight management programme GPs and other health or social care professionals advising or referring adults to lifestyle weight management programmes, and providers advising people who are thinking about joining programmes (see Who should take action?) should: Discuss the importance and wider benefits of adults who are overweight or obese making gradual, long-term changes to their dietary habits and physical activity levels. Discuss what the programme does and does not involve. Discuss realistic weight-loss goals. People should be aware that: The more weight they lose, the greater the health benefits, particularly if someone loses more than 5% of their body weight and maintains this for life. On average, people attending a lifestyle weight management programme lose around 3% of their body weight, but this varies a lot. Preventing future weight gain and maintaining a lower weight trajectory leads to health benefits. Discuss the effort and commitment needed to lose weight and prevent weight regain, and the benefit of receiving long-term support. Discuss sources of long term support, such as from the practice nurse, pharmacist, local support group or weight management programme, online groups or networks, and friends or family. Providers of lifestyle weight management services (see Who should take action?) should: Discuss any previous or ongoing weight management strategies (acknowledge what the person has already achieved); any positive or negative experiences of weight management programmes; any concerns or barriers they may have about joining the programme; the process of change and meeting their personal goals. Discuss other local services that may provide additional support (for example, local walking or gardening groups). Discuss any financial costs (including any costs once a funded referral period has ended). # Recommendation 8 Improve programme uptake, adherence and outcomes Providers of lifestyle weight management services (see Who should take action?) should: At the outset, discuss with adults considering a lifestyle weight management programme: what the programme does and does not involve realistic goals they might hope or expect to achieve and the wider benefits of the programme -ther local services that may provide additional support (for example, local walking or gardening groups) any financial costs (including any costs once a funded referral has ended). Explore with participants any issues that may affect their likelihood of benefiting from the programme. Discussions should take place at the outset and at other times, if someone is having difficulty attending or participating in the programme. Discussions may include: any previous or ongoing strategies to manage their weight (acknowledge what the person has already achieved) any positive or negative experiences of weight management programmes any concerns they may have, or barriers they may face, in relation to joining the programme, the process of change or meeting their personal goals. Agree with each person whether the programme is suitable for them at this time. Use the regular weigh-in as an opportunity to monitor and review progress toward individual goals. If it has not been possible to resolve someone's difficulties with the programme (for example, their attendance or participation), agree what should happen next. For example, they could be referred to another service, leave the programme at an agreed time, or think about being re-referred at a future date. # Recommendation 9 Commission programmes that include the core components for effective weight loss Commissioners of lifestyle weight management services (see Who should take action?) should commission or recommend lifestyle weight management programmes that: Are multi-component that is, they address dietary intake, physical activity levels and behaviour change. Are developed by a multidisciplinary team. This includes input from a registered dietitian, registered practitioner psychologist and a qualified physical activity instructor. Ensure staff are trained to deliver them and they receive regular professional development sessions. Focus on life-long lifestyle change and the prevention of future weight gain. Last at least 3 months, and that sessions are offered at least weekly or fortnightly and include a 'weigh-in' at each session. Ensure achievable goals for weight loss are agreed for different stages – including within the first few weeks, for the end of the programme or referral period (as appropriate) and for 1 year (see recommendation 8). Ensure specific dietary targets are agreed (for example, for a clear energy intake or for a specific reduction in energy intake) tailored to individual needs and goals. Note: it is preferable not to 'ban' specific foods or food groups – and the price of any recommended dietary approaches should not be prohibitive. Individual advice from a registered dietitian may be beneficial, but is not essential. Ensure discussions take place about how to reduce sedentary behaviour and the type of physical activities that can easily be integrated into everyday life and maintained in the long term (for example, walking). Ensure any supervised physical activity sessions are led by an appropriately qualified physical activity instructor and take into account any medical conditions people may have. Instructors should be on the Register of Exercise Professionals (or equivalent) at level 3 or above. Use a variety of behaviour-change methods. These should address: problem solving; goal setting; how to carry out a particular task or activity; planning to provide social support or make changes to the social environment; self-monitoring of weight and behaviours that can affect weight; and feedback on performance. Tailor programmes to support the needs of different groups. For example, programmes should provide men- or women-only sessions as necessary; provide sessions at a range of times and in venues with good transport links or used by a particular community; and consider providing childcare for attendees. Monitor weight, indicators of behaviour change and participants' personal goals throughout the programme. Adopt a respectful, non-judgemental approach (see recommendation 2). # Recommendation 10 Commission programmes that include the core components to prevent weight regain Commissioners should: Commission or recommend lifestyle weight management programmes that address the prevention of weight regain by: Fostering independence and self-management (including self-monitoring). Discussing opportunities for ongoing support once the programme or referral period has ended. Sources of ongoing support may include the programme itself, online resources or support groups, other local services or activities, and family or friends. Stressing the importance of maintaining new dietary habits and increased physical activity levels in the long term to prevent weight re‑gain and discussing strategies to overcome any difficulties in maintaining the new behaviours. Encouraging dietary habits that will support weight maintenance and are sustainable in the long term. For example, programmes should emphasise how following national advice on healthy eating can support weight management. (For example, see NHS Eat Well.) Promoting ways of being more physically active and less sedentary that are sustainable in the long term (for example, walking). The wider benefits of physical activity should also be emphasised. # Recommendation 11 Provide lifestyle weight management programmes based on the core components for effective weight loss and to prevent weight regain Providers of lifestyle weight management programmes should: ensure programmes are based on the core components for effective weight loss (see recommendation 9) ensure programmes are based on the core components to prevent weight regain (see recommendation 10). # Recommendation 12 Provide a national source of information on effective lifestyle weight management programmes Public Health England and other national agencies with an interest in the effectiveness of lifestyle weight management programmes should: Work together to establish a national source of information on programmes suitable for commissioning. Any national database should be regularly updated. Work with providers and commissioners of lifestyle weight management programmes to agree a standard format and process for providing robust, consistent and regularly updated information on programmes. Providers of lifestyle weight management programmes (public, private or voluntary organisations) should demonstrate that their programmes: Are effective at 12 months or beyond. (The following programmes currently available in the UK have been shown to be effective at 12 to 18 months: Rosemary Conley, Slimming World and Weight Watchers.) Meet best practice criteria for commissioning (see recommendation 13). Meet the core components for weight loss and the prevention of weight regain (see recommendations 9 and 10). # Recommendation 13 Ensure contracts for lifestyle weight management programmes include specific outcomes and address local needs Clinical commissioning groups, health and wellbeing boards and local authorities should: Commission a range of lifestyle weight management programmes. For example, both group and individual programmes might be needed to meet the needs and preferences of different groups). Use the Department of Health's nest practice guidance for weight management services. In particular, commission programmes that: at least 60% of participants are likely to complete are likely to lead to an average weight loss of at least 3%, with at least 30% of participants losing at least 5% of their initial weight. Ensure contracts clearly specify: The geographic areas and population groups that the programme should cover. Adequate provision should be made for disadvantaged groups, such as those on a lower income. The additional efforts that may be needed to get specific groups involved (based on discussions with providers and referrers). Who will undertake routine evaluation and what measures will be collected. (Adherence to data protection and information governance requirements should not stop services from providing this data – see recommendations 16 and 17.) Ensure monitoring takes place 12 months after the programme is completed. This may involve working with providers of lifestyle weight management programmes or commissioning an additional service. Consider commissioning additional services to prevent weight regain. For example, consider providing support to establish or expand local support groups or networks that may encourage self-management. Ensure lifestyle weight management programmes are complemented by a range of activities or services that address the wider determinants of health. This includes, for example, providing safe cycle and walking routes or restrictions in planning permission for takeaways and other food and drink outlets in specific areas. Review programmes that do not meet agreed uptake, provision or outcome targets. Amend or de-commission programmes as appropriate. # Recommendation 14 Provide continuing professional development on lifestyle weight management for health and social care professionals Those responsible for setting competences and continuing professional development programmes for health professionals (see Who should take action?) should: Ensure professional development training on weight management is available for health and social care professionals. (Also see recommendation 13 in NICE's guideline on obesity: working with local communities.) Train GPs and other health and social care professionals to identify when to raise weight management with someone and to do so confidently, but with empathy. They should understand why many adults have difficulty managing their weight and the experiences they may face in relation to it. This includes considering the effect of their attitudes to, and any concerns about, their own weight. (Also see recommendations 9 and 13 in NICE's guideline on obesity: working with local communities.) Train GPs and other health and social care professionals to accurately measure and record height and weight, determine body mass index (BMI) and accurately measure waist circumference. Train GPs and other health and social care professionals to understand the practical skills and behaviours that can help someone lose or maintain their weight and how to provide ongoing support and encouragement. This includes encouraging people to self-manage and self-monitor their weight and any associated behaviours over the long term. Train GPs and other health and social care professionals to discuss the likely benefits of a lifestyle weight management programme with service users, taking into account someone's personal circumstances. For example, they should take into account any associated medical conditions or personal factors, such as someone's commitment to change. Train GPs and other health and social care professionals in how to help people make an informed decision about the best weight management option for them. They should also be able to refer people to the most appropriate weight management service. This includes identifying people with more complex needs and referring them to appropriate services (such as mental health, psychological or alcohol services). Train GPs and other health and social care professionals to identify when someone may benefit from re-referral to a lifestyle weight management programme. # Recommendation 15 Provide training and continuing professional development for lifestyle weight management programme staff Lifestyle weight management services, professional bodies and training organisations (see Who should take action?) should: Develop training for lifestyle weight management programme staff with qualified professionals such as registered practitioner psychologists, registered dietitians and qualified physical activity specialists. Ensure this training addresses staff attitudes to, and any concerns about, their own weight. Train staff to communicate effectively with, and generally adopt a respectful and non-judgemental approach to, participants. They should work collaboratively with them. This means they should understand the complexity of weight management and the reasons why many people have difficulty managing their weight, the experiences they may face in relation to their weight, and the fact that they may feel anxious about attending the programme. They should also be clear and open about what the programme involves, so that participants can make an informed choice about whether or not to join. Train staff to deliver multicomponent programmes that cover weight management, dietary habits, safe physical activity and behaviour-change strategies. This should include the ability to: tailor interventions to individual needs (considering, for example, any specific language or literacy needs) review progress and provide constructive feedback to both participants and referrers identify possible reasons for relapse and use problem-solving techniques to address these collect information about people's weight, eating habits and physical activity to support monitoring in line with the Department of Health's information governance and data protection requirements (for example, see the Public Health Services Contract 2014/15: guidance on the non-mandatory contract for public health services.) Train staff to accurately measure and record height and weight to determine body mass index (BMI) and to accurately measure waist circumference. They should also be sensitive to how people feel about being measured and able to identify when it is practical, relevant and appropriate to measure someone. Ensure staff are aware of the common medical and psychological problems associated with being overweight or obese. Ensure staff are aware of evidence on the effect of dietary habits and physical activity on weight gain, loss and maintenance. Ensure staff are aware of the practical skills and behaviours that can help someone lose or maintain their weight. This includes, for example, shopping and cooking skills, understanding food labels and knowing what constitutes an appropriate portion of food. It also includes being able to identify opportunities to be less sedentary and more physically active. Train staff to identify when a participant should be referred to their GP for potential onward referral to other services (for example, specialist weight management or other specialist services, such as alcohol counselling). Ensure staff leading supervised physical activity sessions are qualified and insured (for example, they should be trained to at least level 3 on the register of exercise professionals or equivalent). Train staff to identify any gaps in their own knowledge, confidence or skills and ensure they know how to get these gaps addressed through further training. # Recommendation 16 Improve information sharing on people who attend a lifestyle weight management programme Commissioners of lifestyle weight management services should work with all referrers and providers to put systems in place to share any relevant information, in confidence, about people referred to lifestyle weight management programmes. (Examples of relevant information include details of someone's weight at baseline, programme end and at 12 months.) This should be in line with the Department of Health's information governance and data protection requirements (for example, see Public Health Services Contract 2014/15: guidance on the non-mandatory contract for public health services). Referrers to, and providers of, lifestyle weight management programmes should seek the consent of participants to share between them any relevant information (see above) on the participant's progress. Explain that this information will be used to help monitor and evaluate the service. # Recommendation 17: Monitor and evaluate programmes Commissioners and providers of lifestyle weight management programmes, professionals who make referrals, services that help prevent weight regain, and monitoring services (see Who should take action?) should: Use the standard evaluation framework for weight management programmes and validated tools to monitor interventions. Ensure the scales used for monitoring people's weight are regularly calibrated (see recommendation 2). As a minimum, collect and assess the following information on participants at the end of the programme, in line with the Department of Health's Department of Health's best practice criteria for weight management services: Weight – to calculate total and percent weight change. Do not rely on self-reported measures of height or weight. Percent of participants losing more than 3% of their baseline weight. Percent of participants losing more than 5% of their baseline weight. Percent adherence to the programme. Age, gender, ethnicity and socioeconomic status (for example, as indicated by the postcode of participants), so that the effect on health inequalities can be assessed. Collect details on how each participant's weight has changed 12 months after the programme is completed (see recommendation 16). Consider collecting and assessing other outcomes, for example: changes in other measures of body fatness, such as waist circumference changes in dietary habits, physical activity and sedentary behaviour changes in self-esteem, depression or anxiety changes in health outcomes, such as blood pressure the views and experience of participants who completed the programme the views and experience of participants who did not complete the programme, and any changes in their weight the views of staff delivering the programme and of those referring participants to it. # Recommendation 18 Monitor and evaluate local provision Commissioners of lifestyle weight management services, health and wellbeing boards and local authorities should: Regularly review lifestyle weight management services for adults to ensure they meet local needs (as identified by the joint strategic needs assessment), any gaps in provision should be identified and adherence and outcomes should be reported to agreed standards. Monitor awareness of the programmes among health and social care professionals and potential users (see recommendations 4 and 5). Collect data on referral routes to identify geographical areas where awareness of available programmes is low and where referral rates might be increased. Collate the results of routine monitoring and programme expenditure. Analyse these results in relation to the characteristics of the local population (for example, urban versus rural groups and between the general population and minority ethnic groups). Amend, improve or decommission programmes based on these findings. See also recommendation 10 in NICE's guideline on obesity: working with local communities.# Who should take action? # Introduction The guideline is for: commissioners and providers of lifestyle weight management programmes and health and social care professionals who advise or refer people these programmes. It may also be of interest to adults who are overweight or obese, their families and other members of the public. Who should take action Recommendation Clinical commissioning groups Commissioners of health and social care services Commissioners of lifestyle weight management programmes GPs and other health and social care professionals Health and wellbeing boards Hospital and community trusts Local authorities Local education and training boards or councils and others responsible for setting competences and designing continuing professional development programmes for health professionals Local service providers National agencies with an interest in the effectiveness of lifestyle weight management programmes NHS England Professional bodies Providers of lifestyle weight management services Providers of monitoring services Public Health England # Who should take action in detail ## Recommendation 1 Local authorities, working with other local service providers, clinical commissioning groups and health and wellbeing boards ## Recommendation 2 Public Health England; GPs and other health and social care professionals; health and wellbeing boards; local authorities and other commissioners of health and social care services; providers (designers, developers or deliverers) of lifestyle weight management programmes in private, public or voluntary sector organisations working in the community or in (or via) primary care settings ## Recommendation 3 Local authorities, Public Health England, NHS England, clinical commissioning groups and health and wellbeing boards ## Recommendation 4 Clinical commissioning groups, health and wellbeing boards, hospital and community trusts, local authorities, NHS England and Public Health England ## Recommendation 5 Public Health England, local authorities, health and wellbeing boards and clinical commissioning groups ## Recommendation 6 General practice teams and other health or social care professionals who give advice about, or refer people to, lifestyle weight management programmes. This includes professionals working in: cardiac rehabilitation, diabetes, disability, fertility, postnatal, rheumatology and smoking services ## Recommendation 7 GPs and other health or social care professionals advising or referring adults to lifestyle weight management programmes; providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings ## Recommendation 8 Providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings ## Recommendation 9 Commissioners of lifestyle weight management services, such as public health teams within local authorities or other health and social care commissioners ## Recommendation 10 Commissioners of lifestyle weight management programmes, such as public health teams within local authorities or other health and social care commissioners ## Recommendation 11 Providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings ## Recommendation 12 Public Health England; national agencies with an interest in the effectiveness of lifestyle weight management programmes; commissioners; providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings ## Recommendation 13 Clinical commissioning groups; health and wellbeing boards; local authorities ## Recommendation 14 Local education and training boards; local education and training councils; professional bodies; those responsible for setting competences and designing continuing professional development programmes for health professionals ## Recommendation 15 Providers of, and staff working for, lifestyle weight management services (designers, developers or deliverers in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings; professional bodies; training organisations ## Recommendation 16 Commissioners of lifestyle weight management services, such as public health teams within local authorities or other health and social care commissioners; providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings; health and social care professionals advising or referring service users; providers of monitoring services ## Recommendation 17 Commissioners of lifestyle weight management programmes, such as public health teams within local authorities or other health and social care commissioners; providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings; health and social care professionals who refer people to lifestyle weight management programmes; providers of services to support the prevention of weight regain; providers of programme monitoring services ## Recommendation 18 Commissioners of lifestyle weight management services, such as public health teams within local authorities or other health and social care commissioners; health and wellbeing boards; local authorities# Context In 2012, around a quarter of adults in England (24% of men and 25% of women aged 16 or older) were classified as obese (body mass index 30 kg/m2 or more). A further 42% of men and 32% of women were overweight (BMI 25 to 30 kg/m2) (Health and Social Care Information Centre statistics on obesity, physical activity and diet: England 2014). Although there are people in all population groups who are overweight or obese, obesity is related to social disadvantage (Marmot review fair society, healthy lives: strategic review of health inequalities in England post-2010). Prevalence varies by population characteristics. For women, obesity prevalence increases with greater levels of deprivation, regardless of the measure used. For men, only occupation-based and qualification-based measures show differences in obesity rates by levels of deprivation. For both men and women, obesity prevalence decreases with increasing levels of educational attainment. Around 30% of men and 33% of women with no qualifications are obese compared to 21% of men and 17% of women with a degree or equivalent (Health and Social Care Information Centre statistics on obesity, physical activity and diet: England 2010). Obesity is also linked to ethnicity: it is most prevalent among black African women (38%) and least prevalent among Chinese and Bangladeshi men (6%) (The NHS Information Centre statistics on obesity, physical activity and diet: England, 2006). Being overweight or obese can lead to both chronic and severe medical conditions (Government office for Science's tackling obesities: future choices – project report). It is estimated that life expectancy is reduced by an average of 2 to 4 years for those with a BMI of 30 to 35 kg/m2, and 8 to 10 years for those with a BMI of 40 to 50 kg/m2 (National Obesity Observatory Briefing note: obesity and life expectancy 2010). Women who are obese are estimated to be around 13 times more likely to develop type 2 diabetes and 4 times more likely to develop hypertension than women who are not obese. Men who are obese are estimated to be around 5 times more likely to develop type 2 diabetes and 2.5 times more likely to develop hypertension than men who are not obese (Health and Social Care Information Centre statistics on obesity, physical activity and diet: England, 2011; National Audit Office tackling obesity in England 2001). People who are obese may also experience mental health problems as a result of stigma and bullying or discrimination in the workplace (Puhl and Heuer 2009). The cost to society and the economy of people being overweight or obese was estimated at almost £16 billion in 2007 (more than 1% of gross domestic product). It could rise to just under £50 billion in 2050 (based on 2007 prices), if obesity rates continue to rise unchecked (Department of Health's healthy lives, healthy people: a call to action on obesity in England). The government's obesity strategy 'Healthy lives: a call to action on obesity in England' aimed to reduce, 'the level of excess weight averaged across all adults by 2020'. It advocated a range of local interventions that both prevent obesity and treat those who are already obese or overweight. In many areas, public, private or voluntary organisations are commissioned to provide individual or group lifestyle weight management services. People can also self-refer to commercial or voluntary programmes, for example, by attending a local class or 'club' or joining an online programme. Local policies vary but generally, funded referrals to a lifestyle weight management programme (in tier 2 services) lasts for around 12 weeks or 12 sessions. There has been uncertainty about which weight management programmes are effective and constitute good value for money. Evidence published since 2006 (such as Loveman 2011) provides an opportunity to refine and clarify best practice (for both self-help and referral schemes) and provide guidance on the commissioning of such programmes.# Considerations This section describes the factors and issues the Programme Development Group (PDG) considered when developing the recommendations. Please note: this section does not contain the recommendations. # Protecting people's mental and physical wellbeing The PDG considered that the overarching approach to lifestyle weight management should be to do no harm. Generally, the more weight an adult loses as part of a lifestyle weight management programme, the more health benefits they are likely to gain. (For example, they could benefit from reducing their blood pressure or improving control of blood glucose levels.) A commonly stated 'realistic' goal is to lose around 5–10% of baseline weight. The evidence reviews for this guideline estimated that the mean percentage weight loss from participating in a lifestyle weight management programme was somewhat lower, with an average of around 3% of baseline weight. However, the PDG noted that even losing this relatively small amount of weight is likely to lead to health benefits (particularly if the weight loss is maintained for many years). Observed weight losses from multicomponent lifestyle weight management programmes (as identified in the evidence review) are unlikely to be associated with unintended or adverse effects. (For example, musculoskeletal injuries or increased anxiety.) But the PDG noted that any unintended or adverse effects were not actively investigated, or systematically reported, in the majority of trials reviewed. The PDG heard that people who are obese may perceive or experience stigma on a daily basis, and that any failure to lose weight (or regaining weight following weight loss) may have a negative psychological effect. Although this should not be a reason to avoid managing weight, it does highlight the importance of adopting a respectful, non-judgemental approach. It also highlights the importance of providing long-term support. The PDG noted that it is vital people are enabled to make informed choices about if, when and how they manage their weight. Training and continuing professional development is, members believe, particularly important in both these contexts. The Group also noted that the type and level of training for weight management programmes varies substantially. In particular, healthcare professionals have reported concerns about their lack of training or confidence in raising the issue of weight management. # Evidence The PDG considered a substantial body of evidence, including 29 randomised controlled trials of lifestyle weight management programmes lasting at least 12 months. Seven of the 29 trials reported outcomes at 3 years or longer. But no studies were identified with outcomes beyond 5 years. Maintaining weight loss is known to be difficult and, as a result, extrapolating longer term outcomes from short term studies may be misleading. Modelling showed that even a small amount of weight loss is cost effective, but only if it is maintained long term on a lower weight trajectory. The PDG concluded that multicomponent lifestyle weight management programmes that address dietary habits, physical activity and behaviour change techniques can help adults lose weight and maintain that weight loss for at least 12 to 18 months. However, it was difficult to draw conclusions about why some programmes were more effective than others, or about the effect of specific components. (Examples of the latter include: the setting, face-to-face versus remote contact and the effect of the length or intensity of a programme.) Few studies reported outcomes for specific groups and it was unclear what any reported 'tailoring' meant in practice. The PDG noted that obese adults may attempt to lose weight many times throughout their lives. The point at which they may be successful (and the number of times this translates into a referral to services) was unclear. In addition, the effect (both positive and negative) on their psychological or physical health remains unclear. The PDG agreed that people who are obese need as many opportunities as possible to lose weight. Members also agreed that this should be an ongoing area for research. The PDG was unable to consider the relative effectiveness of alternative approaches to weight management – such as focusing on a healthy lifestyle and the prevention of weight gain rather than weight loss – because of a lack of trials that met the review inclusion criteria. The PDG noted the lack of longer term follow-up of a range of approaches to weight management and the lack of standard evaluation of trials. This includes standard reporting of weight outcomes and strategies for dealing with missing data for different groups to judge the effect on inequalities in health. It has made a research recommendation on this to improve the evidence base. # Wider context The guideline focused on multicomponent lifestyle weight management services and excluded other routes for managing obesity, such as drugs or surgery. Evidence that focused only on populations with linked conditions (such as type 2 diabetes) was excluded, as was evidence on people with more complex needs (such as those who are obese and also have alcohol or mental health problems). The relative effectiveness of, for example, specific dietary approaches or the effect of wider behaviours that have been linked to weight gain (such as shift working or sleep) was not considered. Therefore it is important to read this guideline in the context of broader NICE guidance on obesity. The PDG noted that local services or activities that address the wider determinants of health may also help people to change their dietary habits or physical activity levels and manage their weight. # Commissioning The PDG was concerned that people who have attended weight management services may not have enough sources of support to prevent them regaining the weight they have lost. Members recognised the importance of commissioned services addressing the prevention of weight regain. The evidence reviewed suggests that commercial multicomponent lifestyle weight management programmes available in the UK are likely to be effective, at least up to 12 to 18 months. However, this finding is based on a relatively small number of trials and no head-to-head comparisons of the relative effectiveness of programmes were available. The evidence reviewed also suggests that primary care-led services may be less effective than commercial programmes, but it is unclear why. The PDG noted that local authority services may be established to support people living in particular geographic areas, or from lower income groups. This is particularly the case if their needs are not being met by commercial programmes. The PDG discussed the importance of ensuring commissioners have access to robust, regularly updated information on effective lifestyle weight management programmes. Members noted how time consuming and potentially difficult it would be otherwise for each local area to decide which programmes may be most effective and cost effective. It was noted that programme range, content and evidence of effectiveness may be subject to change. They agreed that a national source of information on programmes shown to be effective – based on robust and consistent data – would be helpful. The PDG's conclusions were informed by the randomised controlled trials of programmes included in the evidence reviews. Members noted that it was unclear what impact any subsequent changes made to the format or content of programmes would have on effectiveness. The PDG noted that the ability to review, improve or decommission programmes at a local level is dependent on monitoring processes being built into the programme from the outset. Members also agreed that establishing systems for information sharing between referrers and providers (such as weight outcomes at programme end or at 12 months) was key. The PDG was concerned that people from lower income groups may struggle to attend programmes once their referral period is over. This is a particular concern if participants wishing to continue the programme beyond the referral period have to pay for it. The PDG noted the importance of an integrated approach to weight management to ensure referrals can easily be made within and across different tiers of weight management services. In addition, because some people who are obese may have other health issues, it noted the importance of local links between a variety of services. (This includes, for example, weight management, smoking cessation, mental health services, substance misuse and alcohol counselling services.) The PDG noted that the recommendations in this guideline apply equally to all types of lifestyle weight management programme. # Cost effectiveness The economic model estimated that a 12-week programme costing £100 or less will be cost-effective for adults who are overweight or obese under 2 conditions. First, the weight loss, compared with what it would have been without the intervention, must be maintained for life. Second, at least 1 kg of weight is lost and this weight difference is maintained for life (that is, the person's lifetime weight trajectory is lowered by at least 1 kg). A 24-week programme costing £200 or less was estimated to be cost effective under the same conditions. However, there were not enough data to populate the model for adults with an initial body mass index (BMI) of more than 40 kg/m2. So it was unclear whether or not it would be cost effective for this group. For programmes costing £500 per head to be cost effective, it is estimated that an average 2 kg weight differential must be maintained for life. A 3 kg loss must be maintained for life for programmes costing £1000 or more per head. The model estimated that programmes costing £100 or more per head are not cost effective if, on average, participants regain the weight lost within 2 to 3 years or less. This is regardless of the average initial weight loss. The key variable is thus the speed with which weight is regained. However, the PDG noted that evidence based on long term follow up of participants was limited. The length of time that someone's weight trajectory must be below the 'without-intervention' trajectory and still remain cost effective is reduced by the following 4 factors: a higher initial weight loss the person being older (for a given BMI group) the person having a higher BMI (for a given age group) a lower cost per head of the intervention. In relation to age, the model implies that the recommendations will generate better value for money for people older than 50 – even if they only maintain a lower weight trajectory for 3 to 10 years. This is because older people will gain the health benefits sooner (not because older people lose more weight than younger people). Trials suggest average weight loss is similar for all ages and BMI groups. For people aged 20–39, weight loss may need to be maintained for up to 40 years before the intervention is worth undertaking. In relation to weight, the model implies that implementation of the recommendations will generate better value for money when used with adults who are obese (rather than overweight) (see adults who are overweight or obese). As a result, the PDG felt that people with a BMI between 30 and 40 kg/m2 should be made a priority for funded referrals to lifestyle weight management programmes. But members also agreed that people who are overweight (BMI 25 to 30 kg/m2) should not be excluded from funded referrals if there is enough capacity. There were insufficient data to make a judgement on this for people whose BMI is above 40 kg/m2. The modelling data relate to population cohorts of a given age, sex and BMI category – not to every individual in each cohort, because weight loss and gain vary greatly between people in each cohort. Effective interventions for a particular cohort will usually be cost effective for people who have lost at least the average amount of weight, or who have regained weight at an average or slower than average rate.# Recommendations for research The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects. All the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity. Findings should be published in peer reviewed journals. How effective are lifestyle weight management programmes available in the UK, when directly compared using high-quality trials? In particular, what effect do specific components of a multicomponent lifestyle weight management programme have on adherence, effectiveness and cost effectiveness? This includes: components, or combinations of components, that support weight loss or the prevention of weight regain the effect of programme length, intensity, setting and means of delivery (examples of the latter include group, individual and remote support) specific behaviour change techniques (using a recognised taxonomy) the effect of new technologies the effect of additional support services, such as self-help groups and networks approaches to commissioning processes for collecting long-term follow-up data. How effective and cost effective are lifestyle weight management programmes available in the UK over at least at least 3 to 5 years, and ideally beyond 10 years. Specifically: Do short-term (12-week) interventions provide adults with the self-management skills they need to maintain weight loss in the long term? Are alternative approaches to weight management (such as approaches that focus on a healthy lifestyle, behaviour change and the prevention of weight gain rather than weight loss) effective and cost effective in the long term? How effective and cost effective are programmes for people of different ages, gender, sexuality or from different ethnic or socioeconomic groups? How effective and cost effective are programmes for specific population groups, such as adults with depression or with disabilities? What is the effect of lifestyle weight management programmes available in the UK on: Changes to dietary habits and choices, physical activity level and sedentary behaviour? Wider lifestyle factors, such as sleeping patterns or stress management? Psychological issues, such as body confidence or attitude, depression, anxiety or self-esteem? Health conditions, such as changes to blood pressure or lipids? Unintended outcomes such as musculoskeletal injuries, symptoms of an eating disorder; increased anxiety or depression? User adherence and satisfaction? Quality of life? How can referrals to other services after involvement in a lifestyle weight management service be as effective and cost effective as possible? This includes: re-referrals to a lifestyle weight management service, referrals to other tiers of weight management services or referrals to other specialist services (such as alcohol or substance misuse). In particular: How long should people wait before being re-referred to a programme? Does re-referral to the same (or a similar programme) influence adherence, effectiveness or cost effectiveness? In what circumstances should participants not be re-referred to the same (or a similar programme)? Who is best placed to provide ongoing support after the programme, and does this differ according to whether someone completed the programme or met their weight loss goal? Are there any unintended or adverse effects from repeated attempts to lose weight? What effect does lifestyle weight management training for health professionals and lifestyle weight management staff have on: The referral process, including patient satisfaction? Programme outcomes (weight loss and prevention of weight regain), adherence to the programme and participants' satisfaction with it? Staff confidence in discussing weight issues and any concerns about their own weight? Staff ability to deliver the programme? General approach of staff (that is, whether they adopt a 'respectful and non-judgemental' approach as a result)? More detail identified during development of this guideline is provided in Gaps in the evidence.# Glossary # Adults who are overweight or obese Adults are assessed to see if they are overweight or obese using their body mass index (BMI). The following are the cut-off points for a healthy weight or being overweight or obese: Healthy weight, BMI (kg/m2) 18.5–24.9 Overweight, BMI 25–29.9 Obesity I, BMI 30–34.9 Obesity II, BMI 35–39.9 Obesity III, BMI 40 or more. BMI is a less accurate indicator of adiposity in adults who are highly muscular, so it should be interpreted with caution in this group. Waist circumference can also be used to assess whether someone is at risk of health problems because they are overweight or obese (up to a BMI of 35, see recommendation 1.2.2.9 in NICE's guideline on obesity prevention). For men, a waist circumference of less than 94 cm is low risk, 94–102 cm is high and more than 102 cm is very high risk. For women, a waist circumference of less than 80 cm is low risk, 80–88 cm is high and more than 88 cm is very high risk. The use of lower BMI thresholds to trigger action to reduce the risk of conditions such as type 2 diabetes has been recommended for black African, African–Caribbean and Asian groups. The lower thresholds are 23 kg/m2 to indicate increased risk and 27.5 kg/m2 to indicate high risk. (See recommendations on BMI and waist circumference for Black, Asian and minority ethnic groups in NICE's guideline on obesity identification, assessment and management.) # Behaviour change techniques A collection of techniques that aim to help people change their behaviour to improve their health. The techniques are based on an established theory or rationale (see NICE guidance on behaviour change). # Body mass index Body mass index (BMI) is commonly used to measure whether or not adults are a healthy weight or underweight, overweight or obese. It is defined as weight in kilograms divided by the square of height in metres (kg/m2). # Complex needs 'Complex needs' refers to issues that affect a person's health and wellbeing. They might include: a behavioural issue such as substance misuse specific conditions such as those limiting mobility or learning, mental health conditions, substantive or life-threatening comorbidities or dietary needs personal social circumstances, such as homelessness. # Dietary habits This includes a range of factors including the food and drink (including alcoholic drinks) consumed, energy and nutrient intake, portion size and the pattern and timing of eating. Population advice on food and nutrition is available on the NHS Choices website. # Lifestyle weight management programmes Lifestyle weight management programmes for overweight or obese adults are multi-component programmes that aim to reduce a person's energy intake and help them to be more physically active by changing their behaviour. They may include weight management programmes, courses or clubs that: accept adults through self-referral or referral from a health or social care practitioner are provided by the public, private or voluntary sector are based in the community, workplaces, primary care or online. Although local definitions vary, these are usually called tier 2 services and are just one part of a comprehensive approach to preventing and treating obesity. # Physical activity The full range of human movement, from competitive sport and exercise to active hobbies, walking, cycling and the other physical activities involved in daily living. # Physical activity instructor A qualified physical activity instructor meets the fitness industry's agreed qualification standards and undertakes continued professional development. Instructors working with people referred from a GP or another health professional should hold level 3 membership of the Register of Exercise Professionals (or equivalent). # Stigma Stigma in relation to someone's weight may take the form of bullying, teasing, harsh comments, discrimination or prejudice based on a person's body size. # Tiers of weight management services Different tiers of weight management services cover different activities. Definitions vary locally but usually tier 1 covers universal services (such as health promotion or primary care); tier 2 covers lifestyle interventions; tier 3 covers specialist weight management services; and tier 4 covers bariatric surgery. # Weight loss In this guideline, weight loss refers to the amount of weight lost through a lifestyle weight management programme. # Weight maintenance The maintenance of a specific weight (whether or not weight has been lost). # Weight regain In this guideline, weight regain means regaining some or all of the weight that was lost during a lifestyle weight management programme. The prevention of weight regain refers to keeping to a lower weight than the person would have been if they had not lost weight in the first place. This is also referred to as being on a lower weight trajectory. # Weight trajectory A weight trajectory refers to a general pattern of weight gain or weight loss over many years. Many adults gradually put on weight as they get older. This gradual increase in weight will be lower for someone who has lost weight during a lifestyle weight management programme, if they have not regained any of that lost weight.# References Golubic R, Ekelund U, Wijndaele K et al. (2013). Rate of weight gain predicts change in physical activity levels: a longitudinal analysis of the EPIC-Norfolk cohort. International Journal of Obesity 37: 404–9 Loveman E, Frampton GK, Shepherd J et al. (2011) The clinical effectiveness and cost-effectiveness of long-term weight management schemes for adults: a systematic review. Health Technology Assessment 15 (2) Puhl RM, Heuer CA (2009). The stigma of obesity: a review and update. Obesity 17: 941–64# Summary of the methods used to develop this guideline # Introduction The reviews, commissioned report and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations. # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching question was: how effective and cost effective are multi-component lifestyle weight management programmes for adults? The subsidiary questions were: . How does effectiveness and cost effectiveness vary for different population groups (for example, men, black and minority ethnic or low-income groups)? . What are the best practice principles for multi-component lifestyle weight management programmes for adults? . What are the most effective and cost effective behavioural or psychological components of a lifestyle weight management programme for adults – and who might best deliver them? . What are the views, perceptions and beliefs of adults in relation to lifestyle weight management programmes (whether or not they use such programmes)? How can overweight and obese adults from a diverse range of backgrounds be encouraged to join, and adhere to, these programmes? . How can lifestyle changes and weight loss be sustained once the weight management programme has ended? . What barriers and facilitators affect the delivery of effective weight-management programmes for adults and how do they vary for different population groups? . What are the best practice principles for primary care when referring people to commercial, voluntary or community sector or self-help lifestyle weight management programmes? . What are the best practice principles for commissioners of lifestyle weight management services for adults? . What training is needed for professionals involved directly or indirectly with lifestyle weight management programmes for adults? . How should lifestyle weight management programmes be monitored and evaluated locally? These questions were made more specific for each review (see reviews for further details). # Reviewing the evidence ## Effectiveness reviews One review of effectiveness was conducted, split into 3 sections: Review 1a 'The clinical effectiveness of long-term weight management schemes for adults'. Review 1b 'How components of behavioural weight management programmes affect weight change'. Review 1c 'Weight regain after behavioural weight management programmes'. Identifying the evidence The review updated and expanded on an existing review (Loveman 2011) and uses similar methods. Ten electronic databases were systematically searched in October 2012 for randomised controlled trials of multi-component behavioural weight management programmes. See review 1 for details of the databases searched. Reference lists were also screened and references submitted to NICE in a call for evidence. Selection criteria Studies were included in the effectiveness review if they: were multi-component interventions addressing physical activity, dietary intake and behaviour change were randomised controlled trials. included at least 12 months follow-up included a measure for weight loss (for example, weight or body mass index ) included adults aged 18 and older who were overweight or obese were undertaken in OECD (Organisation for Economic Co-operation and Development) countries were published in English. Studies were excluded if they: included children and pregnant women included people with eating disorders -nly included people with specific pre-existing medical condition such as diabetes, heart failure, uncontrolled hypertension or angina focused on pharmacological or surgical interventions. See review 1 for details of the inclusion and exclusion criteria. ## Other reviews One review of barriers and facilitators, referral, commissioning and training issues in relation to lifestyle weight management was conducted: Review 2: Managing overweight and obese adults. Identifying the evidence Several databases and websites were searched in April 2013 for qualitative evidence, grey literature and best practice guidelines. See above for details. ## Selection criteria Studies were included in the review if they: addressed questions included in the scope (except questions of effectiveness). focused on adults aged 18 and older who were overweight or obese were undertaken in the UK. Studies were excluded if they: included children and pregnant women included people with eating disorders focused on pharmacological or surgical interventions -nly included people with a specific pre-existing medical condition such as diabetes, heart failure, uncontrolled hypertension or angina focused on pharmacological or surgical interventions. ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in Methods for the development of NICE public health guidance. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution. Included studies were not evaluated on the basis of blinding. Study quality: internal validity ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled, or not adequately described, are unlikely to alter the conclusions. − Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. This was based on: randomisation and allocation procedures evidence of selective reporting attrition (at 12 months or at the closest point reported after 12 months, as appropriate). Study quality: external validity As above, external validity was rated '++', '+' or '−' based on whether: participants were representative of the general population the intervention needed any extraordinary efforts to implement in the UK (for example, the implementation of a particular infrastructure). ## Summarising the evidence and making evidence statements The review data were summarised in evidence tables (see the reviews in Supporting evidence). The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see 'Supporting evidence'). The statements reflect their judgment of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope. # Commissioned report A questionnaire covering practical and process issues was sent to known weight management providers operating in England. Responses to the survey were compiled by an independent researcher: Practical and process issues in the provision of lifestyle weight management services for adults. # Cost effectiveness There was a review of economic evaluations and an economic modelling exercise. See Managing overweight and obesity among adults: report on economic modelling and cost consequence analysis. ## Review of economic evaluations The review of economic evaluations was an extension of the effectiveness review (review 1). Studies were considered if they had been undertaken in an OECD country and included a cost effectiveness analysis. For a description of the search strategy and the inclusion, exclusion and quality criteria used, see review 1. ## Economic modelling An economic model was constructed to incorporate data from review 1. The results are reported in: Managing overweight and obesity among adults: report on economic modelling and cost consequence analysis. # How the PDG formulated the recommendations At its meetings in 2013, the Programme Development Group (PDG) considered the evidence, expert testimony, commissioned report and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgment where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guideline. The PDG developed draft recommendations through informal consensus, based on the following criteria: Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential effect on the target population's health. Effect on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgments. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. The PDG noted that effectiveness can vary according to whether interventions are delivered to a group or on a one-to-one basis. Where possible, recommendations were linked to an evidence statement(s) (see The evidence for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).# The evidence The evidence statements from 2 reviews are provided by external contractors. This section lists how the evidence statements and expert papers link to the recommendations and sets out a brief summary of findings from the economic analysis. # How the evidence and expert papers link to the recommendations The evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. Evidence statement number 1.2 indicates that the linked statement is numbered 1.2 in review 1. Evidence statement number 2.2 indicates that the statement is numbered 2.2 in review 2. EP1 indicates that expert paper 1 is linked to a recommendation. CR indicates that the commissioned report is linked to a recommendation. EM indicates that the economic modelling report is linked to a recommendation. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: EP2, EP4; IDE Recommendation 2: evidence statement 1.9; EP1, EP2, EP3; IDE Recommendation 3: evidence statements 2.8, 2.9, 2.10; EP2, EP4; CR; IDE Recommendation 4: evidence statements 2.8, 2.9, 2.10; EP2, EP4; CR; IDE Recommendation 5: evidence statement 2.1; EP2, EP4; CR; IDE Recommendation 6: evidence statements 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.10, 1.12, 2.1, 2.2, 2.3, 2.4, 2.5, 2.7, 2.8, 2.9, 2.11; EP1; EP2; CR, EM Recommendation 7: evidence statements 1.1, 1.3, 1.23, 2.1, 2.7, 2.8, 2.9; EP1, EP2, EP3, EP4; EM Recommendation 8: evidence statements 2.1, 2.2, 2.4, 2.5, 2.7, 2.8, 2.11; EP2, CR. Recommendation 9: evidence statements 1.2, 1.8, 1.9, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.22, 2.5, 2.6, 2.14; EP1, EP2, EP3; CR; EM Recommendation 10: evidence statements 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 2.5; EP2, EP3; EM Recommendation 11: evidence statements 1.2, 1.8, 1.9, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 2.5, 2.6, 2.14; EP1, EP2, EP3; CR; EM Recommendation 12: evidence statements 1.3, 2.13 Recommendation 13: evidence statements 1.3, 1.4, 1.5, 1.6, 1.7, 1.10, 1.20, 1.23, 2.12, 2.13; EP2, EP4; CR Recommendation 14: evidence statements 2.9, 2.10, 2.11, 2.14; EP1, EP2, EP3 Recommendation 15: evidence statements 2.9, 2.10, 2.11, 2.14; EP1, EP2, EP3 Recommendation 16: evidence statement 2.8; EP4; CR Recommendation 17: evidence statements 2.8, 2.9, 2.11, 2.12, 2.13 Recommendation 18: evidence statements 2.9, 2.10, 2.14; EP4 ## Expert papers and commissioned report Expert papers 1–4 Commissioned report # Economic modelling Overall, the modelling showed that lifestyle weight management interventions that help people lose weight and then maintain the weight loss in the long term would be cost effective, if they can be identified. The economic model considered cohorts of (virtual) adults of different ages and with a body mass index (BMI) of 25, 30, 35 and 40 kg/m2. The model tested the effect of a 12-week lifestyle weight management programme. All cohorts were followed for the whole of their lives and they contract diseases and conditions at different rates, depending on their BMI. From a public sector perspective, the modelling showed that if the original weight loss achieved by attending a lifestyle weight management programme were to be maintained for life, most of these interventions would be cost effective. That is, provided they cost less than £500 per person and on average, participants lost more than 1 kg in weight. This is true for all age groups and both sexes. However, if they were to regain the lost weight within 2 to 3 years, the modelling indicates that few, if any, of these interventions would be cost effective. To be cost effective, they would need to cost less than £100 per person and the average weight lost would need to be in excess of 5 kg. More detail (including any observed differences by age and gender) is given in the modelling report: Managing overweight and obesity among adults: report on economic modelling and cost consequence analysis.# Gaps in the evidence The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence. These gaps are set out below. . There is a lack of long-term (that is, 3 years or longer) trials of lifestyle weight management programmes to determine cost effectiveness. (Source: evidence reviews 1a and 1c; economic modelling) . There is a lack of trials directly comparing lifestyle weight management programmes in the UK. (Source: evidence reviews 1a, 1b and 1c) . There is a lack of evidence on whether there are any adverse or unintended effects associated with long-term weight management programmes. There is also a lack of evidence on 'weight cycling' (repeated attempts to lose weight) in relation to these programmes. (Source: evidence reviews 1a, 1b and 1c; expert paper 1) . There is a general lack of evidence on which specific components of a lifestyle weight management programme ensure effectiveness. In particular, it is unclear what effect programme length and intensity has on effectiveness. (Source: evidence reviews 1a and 1b) . There is a lack of evidence on the effect of sexual orientation, disability, religion, place of residence, occupation, education, socioeconomic position or social capital on the effectiveness of lifestyle weight management programmes. There is also a lack of analysis of participants by age and gender. (Source: evidence review 1a) . The existing evidence base is limited by studies characterised by: short-term follow up, small sample sizes, the collection of data at only a limited number of time points (usually 2), demographic samples that limit the ability to generalise and non-reporting of reasons for people dropping out. (Source: evidence reviews 1a and 1b) . There is a lack of evidence on whether any particular approach to commissioning leads to better outcomes for participants in lifestyle weight management programmes. (Source: evidence review 2) . There is a lack of evidence as to whether any particular type of training for practitioners leads to more effective programmes. (Source: evidence review 2) The Committee made 5 recommendations for research into areas that it believes will be a priority for developing future guidance.# About this guideline # What evidence is the guideline based on? The evidence that the PDG considered included: Evidence reviews: Review 1 was divided into 3 sections and was carried out by the University of Oxford. The principal authors were: Paul Aveyard, Jamie Hartmann-Boyce and David Johns. Review 1a, 'The clinical effectiveness of long-term weight management schemes for adults'. Review 1b, 'How components of behavioural weight management programmes affect weight change'. Review 1c, 'Weight regain after behavioural weight management programmes'. Review 2: 'Managing overweight and obese adults' was carried out by the University of Oxford. The principal authors were: Paul Aveyard, Jamie Hartmann-Boyce and David Johns. Economic modelling: 'Economic modelling and cost consequence analysis' was carried out by the UK Health Forum and the University of East Anglia. The authors were: Martin Brown, Tim Marsh, Lise Retat, Ric Fordham, Marc Suhrcke, David Turner, Richard Little and Oyebanji Filani. Commissioned report: 'Practical and process issues in the provision of lifestyle weight management services for adults' was carried out by GK research. The principal author was Graham Kelly. Expert papers: Expert paper 1 'Weight bias and stigma and the effectiveness of weight management programmes' by Jane Ogden, Professor in Health Psychology, University of Surrey. Expert paper 2 'Experience from practice – psychological issues' by Rachel Holt, Consultant Clinical Psychologist/Service Lead at Derbyshire Tier 3 Weight Reduction Service. Expert paper 3 'Weight bias and the impact of weight stigma on emotional and physical health' by Dr Rebecca Puhl, Director of Research and Weight Stigma Initiatives at the Rudd Center for Food Policy and Obesity, Yale University. Expert paper 4 'Commissioning and working with health and wellbeing boards' by Stephen Watkins, Director of Public Health, Stockport. Note: the views expressed in the expert papers above are the views of the authors and not those of NICE. In some cases the evidence was insufficient and the PDG has made recommendations for future research, see Gaps in the evidence.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe aim of this guideline to help meet a range of public health goals. These include helping reduce the risk of the main diseases associated with obesity, for example: coronary heart disease, stroke, hypertension, osteoarthritis, type 2 diabetes and various cancers (endometrial, breast, kidney and colon).\n\nThe focus is on lifestyle weight management programmes that:\n\naccept self-referrals or referrals from health or social care practitioners\n\nare provided by the public, private or voluntary sector\n\nare based in the community, workplaces, primary care or online.\n\nUsually known as 'tier 2' services (see Tiers of weight management services), these programmes are just 1 part of a comprehensive approach to preventing and treating obesity. Clinical judgement will be needed to determine whether they are suitable for people with conditions that increase the risk of, or are associated with, obesity or who have complex needs.\n\nThis guideline replaces section 1.1.7 of NICE's guideline on obesity prevention. It gives recommendations on lifestyle weight management services for overweight and obese adults aged 18 and over.\n\nThe recommendations should be considered alongside NICE's other guidance on obesity.\n\n# Recommendation 1 Adopt an integrated approach to preventing and managing obesity\n\nLocal authorities, working with other local service providers, clinical commissioning groups and health and wellbeing boards, should:\n\nEnsure there is an integrated approach to preventing and managing obesity and its associated conditions (see recommendation 1 in NICE's guideline on obesity: working with local communities. Systems should be in place to allow people to be referred to, or receive support from (or across) the different service tiers of an obesity pathway, as necessary. This includes referrals to and from lifestyle weight management programmes. All the options in the local obesity pathway should be made clear to both professionals and the public.\n\nIdentify local services, facilities or groups that could be included in the local obesity pathway, meet the needs of different groups and address the wider determinants of health. Examples include community walking groups or gardening schemes.\n\nEnsure staff in local health services are aware of, and make referrals to, the lifestyle weight management service. This includes staff working in: GP teams, pharmacies, health visiting, the NHS Health Check programme and services for smoking cessation, fertility or type 2 diabetes.\n\nEnsure lifestyle weight management services for adults meet local needs as identified by the joint strategic needs assessment (JSNA) and other local data.\n\n# Recommendation 2 Ensure services cause no harm\n\nPublic Health England, health and social care professionals, health and wellbeing boards, commissioners of health and social care services and providers of lifestyle weight management services (see Who should take action?) should:\n\nBe aware of the effort needed to lose weight, prevent weight regain or avoid any further weight gain. Also be aware of the stigma that adults who are overweight or obese may feel or experience. Ensure the tone and content of all communications is respectful and non-judgemental (see recommendation 5 in NICE's guideline on obesity: working with local communities). In addition, the terminology used to describe someone's condition should respect how they like to be described.\n\nEnsure equipment and facilities meet the needs of most adults who are overweight or obese. For example, referrers to, and providers of, lifestyle weight management services should ensure there are large blood pressure cuffs and suitably sized chairs without arms. Any new scales purchased should be able to accurately weigh the heaviest patients seen by the service.\n\nBe aware that people may feel anxious about being weighed and measured. For example, respect someone's preference for privacy at the weekly weigh-in. (Note, although people may find a waist circumference measurement helpful for self-monitoring, it does not help to assess people with a BMI greater than 35\xa0kg/m2.)\n\n# Recommendation 3 Raise awareness of local weight management issues among commissioners\n\nLocal authorities and Public Health England should ensure all those commissioning lifestyle weight management services are aware of:\n\nthe number of adults who are overweight or obese locally, including any variations in rates between different groups\n\nthe effect of the local environment and the wider determinants of health on the prevention and management of obesity\n\nthe local obesity pathway and the role of lifestyle weight management services in the local strategic approach to the prevention and management of obesity\n\nthe range of lifestyle weight management programmes that could be commissioned locally (see recommendation 12)\n\ncontinuing professional development or training opportunities on weight management (see recommendation 14).\n\n# Recommendation 4 Raise awareness of lifestyle weight management services among health and social care professionals\n\nClinical commissioning groups, health and wellbeing boards, hospital and community trusts, local authorities, NHS England and Public Health England should:\n\nEnsure health and social care professionals in contact with adults who are overweight or obese are made aware of:\n\n\n\nthe local obesity pathway and the local strategic approach to preventing and managing obesity\n\nthe range of local lifestyle weight management services available\n\nnational sources of accurate information and advice, such as NHS information on losing weight and healthier families\n\ncontinuing professional development or training opportunities on weight management (see recommendation 14).\n\n\n\n# Recommendation 5 Raise awareness of lifestyle weight management services among the local population\n\nLocal authorities and Public Health England should:\n\nEnsure sources of information and advice about local lifestyle weight management services are included in any communications about being overweight or obese. This includes information provided by health and social care professionals working with adults (such as GPs, practice nurses, health visitors and pharmacists).\n\nPublic Health England, local authorities, health and wellbeing boards and clinical commissioning groups should ensure the local adult population is aware of:\n\nThe health benefits for adults who are overweight or obese of losing even a relatively small amount of weight and keeping it off in the long term (or avoiding any further weight gain). (See recommendation 7.)\n\nThe range of lifestyle weight management services available locally.\n\nLocal sources of information and advice such as GPs, practice nurses, health visitors and pharmacists.\n\nNational sources of accurate information and advice such NHS information on losing weight and healthier families.\n\n# Recommendation 6 Refer overweight and obese adults to a lifestyle weight management programme\n\nGP practices and other health or social care professionals who give advice about, or refer people to, lifestyle weight management programmes (see Who should take action?) should:\n\nRaise the issue of weight loss in a respectful and non-judgemental way. Recognise that this may have been raised on numerous occasions and respect someone's choice not to discuss it further on this occasion.\n\nIdentify people eligible for referral to lifestyle weight management services by measuring their body mass index (BMI). Also measure waist circumference for those with a BMI less than 35\xa0kg/m2. Consider any other locally agreed risk factors.\n\nFor funded referrals, note that:\n\n\n\nprogrammes may particularly benefit adults who are obese (that is, with a BMI over 30\xa0kg/m2, or lower for those from black and minority ethnic groups) or with other risk factors (comorbidities such as type 2 diabetes)\n\nwhere there is capacity, access for adults who are overweight should not be restricted (that is, for people with a BMI between 25 to 30\xa0kg/m2, or lower for those from black and minority ethnic groups) or with other risk factors (comorbidities such as type 2 diabetes)\n\nthere should be no upper BMI or upper age limit for referral.\n\n\n\nProvide information on programmes available locally, where possible, taking people's preferences and previous experiences into account. Be clear that no programme holds the 'magic bullet' or can guarantee long-term success.\n\nRefer people to a group rather than an individual programme if they express no preference because, on average, group programmes tend to be more cost effective.\n\nEnsure people who are overweight or obese who are not referred (for whatever reason) have an opportunity to discuss and reconsider attending a programme in the future. Discuss making a follow-up appointment at an agreed date (for example, in 3 to 6\xa0months). Provide them with sources of information about how to make gradual, long-term changes to their dietary habits and physical activity levels (for example, NHS Live Well).\n\nGive people the opportunity for a re-referral, as necessary, because weight management is a long-term process. Use clinical judgement, taking into account the person's circumstances, previous experiences of weight management and commitment to change.\n\n# Recommendation 7 Address the expectations and information needs of adults thinking about joining a lifestyle weight management programme\n\nGPs and other health or social care professionals advising or referring adults to lifestyle weight management programmes, and providers advising people who are thinking about joining programmes (see Who should take action?) should:\n\nDiscuss the importance and wider benefits of adults who are overweight or obese making gradual, long-term changes to their dietary habits and physical activity levels.\n\nDiscuss what the programme does and does not involve.\n\nDiscuss realistic weight-loss goals. People should be aware that:\n\n\n\nThe more weight they lose, the greater the health benefits, particularly if someone loses more than 5% of their body weight and maintains this for life.\n\nOn average, people attending a lifestyle weight management programme lose around 3% of their body weight, but this varies a lot.\n\nPreventing future weight gain and maintaining a lower weight trajectory leads to health benefits.\n\n\n\nDiscuss the effort and commitment needed to lose weight and prevent weight regain, and the benefit of receiving long-term support. Discuss sources of long term support, such as from the practice nurse, pharmacist, local support group or weight management programme, online groups or networks, and friends or family.\n\nProviders of lifestyle weight management services (see Who should take action?) should:\n\nDiscuss any previous or ongoing weight management strategies (acknowledge what the person has already achieved); any positive or negative experiences of weight management programmes; any concerns or barriers they may have about joining the programme; the process of change and meeting their personal goals.\n\nDiscuss other local services that may provide additional support (for example, local walking or gardening groups).\n\nDiscuss any financial costs (including any costs once a funded referral period has ended).\n\n# Recommendation 8 Improve programme uptake, adherence and outcomes\n\nProviders of lifestyle weight management services (see Who should take action?) should:\n\nAt the outset, discuss with adults considering a lifestyle weight management programme:\n\n\n\nwhat the programme does and does not involve\n\nrealistic goals they might hope or expect to achieve and the wider benefits of the programme\n\nother local services that may provide additional support (for example, local walking or gardening groups)\n\nany financial costs (including any costs once a funded referral has ended).\n\n\n\nExplore with participants any issues that may affect their likelihood of benefiting from the programme. Discussions should take place at the outset and at other times, if someone is having difficulty attending or participating in the programme. Discussions may include:\n\n\n\nany previous or ongoing strategies to manage their weight (acknowledge what the person has already achieved)\n\nany positive or negative experiences of weight management programmes\n\nany concerns they may have, or barriers they may face, in relation to joining the programme, the process of change or meeting their personal goals.\n\n\n\nAgree with each person whether the programme is suitable for them at this time.\n\nUse the regular weigh-in as an opportunity to monitor and review progress toward individual goals.\n\nIf it has not been possible to resolve someone's difficulties with the programme (for example, their attendance or participation), agree what should happen next. For example, they could be referred to another service, leave the programme at an agreed time, or think about being re-referred at a future date.\n\n# Recommendation 9 Commission programmes that include the core components for effective weight loss\n\nCommissioners of lifestyle weight management services (see Who should take action?) should commission or recommend lifestyle weight management programmes that:\n\nAre multi-component that is, they address dietary intake, physical activity levels and behaviour change.\n\nAre developed by a multidisciplinary team. This includes input from a registered dietitian, registered practitioner psychologist and a qualified physical activity instructor.\n\nEnsure staff are trained to deliver them and they receive regular professional development sessions.\n\nFocus on life-long lifestyle change and the prevention of future weight gain.\n\nLast at least 3\xa0months, and that sessions are offered at least weekly or fortnightly and include a 'weigh-in' at each session.\n\nEnsure achievable goals for weight loss are agreed for different stages – including within the first few weeks, for the end of the programme or referral period (as appropriate) and for 1\xa0year (see recommendation 8).\n\nEnsure specific dietary targets are agreed (for example, for a clear energy [calorie] intake or for a specific reduction in energy intake) tailored to individual needs and goals. Note: it is preferable not to 'ban' specific foods or food groups – and the price of any recommended dietary approaches should not be prohibitive. Individual advice from a registered dietitian may be beneficial, but is not essential.\n\nEnsure discussions take place about how to reduce sedentary behaviour and the type of physical activities that can easily be integrated into everyday life and maintained in the long term (for example, walking).\n\nEnsure any supervised physical activity sessions are led by an appropriately qualified physical activity instructor and take into account any medical conditions people may have. Instructors should be on the Register of Exercise Professionals (or equivalent) at level 3 or above.\n\nUse a variety of behaviour-change methods. These should address: problem solving; goal setting; how to carry out a particular task or activity; planning to provide social support or make changes to the social environment; self-monitoring of weight and behaviours that can affect weight; and feedback on performance.\n\nTailor programmes to support the needs of different groups. For example, programmes should provide men- or women-only sessions as necessary; provide sessions at a range of times and in venues with good transport links or used by a particular community; and consider providing childcare for attendees.\n\nMonitor weight, indicators of behaviour change and participants' personal goals throughout the programme.\n\nAdopt a respectful, non-judgemental approach (see recommendation 2).\n\n# Recommendation 10 Commission programmes that include the core components to prevent weight regain\n\nCommissioners should:\n\nCommission or recommend lifestyle weight management programmes that address the prevention of weight regain by:\n\n\n\nFostering independence and self-management (including self-monitoring).\n\nDiscussing opportunities for ongoing support once the programme or referral period has ended. Sources of ongoing support may include the programme itself, online resources or support groups, other local services or activities, and family or friends.\n\nStressing the importance of maintaining new dietary habits and increased physical activity levels in the long term to prevent weight re‑gain and discussing strategies to overcome any difficulties in maintaining the new behaviours.\n\nEncouraging dietary habits that will support weight maintenance and are sustainable in the long term. For example, programmes should emphasise how following national advice on healthy eating can support weight management. (For example, see NHS Eat Well.)\n\nPromoting ways of being more physically active and less sedentary that are sustainable in the long term (for example, walking). The wider benefits of physical activity should also be emphasised.\n\n\n\n# Recommendation 11 Provide lifestyle weight management programmes based on the core components for effective weight loss and to prevent weight regain\n\nProviders of lifestyle weight management programmes should:\n\nensure programmes are based on the core components for effective weight loss (see recommendation 9)\n\nensure programmes are based on the core components to prevent weight regain (see recommendation 10).\n\n# Recommendation 12 Provide a national source of information on effective lifestyle weight management programmes\n\nPublic Health England and other national agencies with an interest in the effectiveness of lifestyle weight management programmes should:\n\nWork together to establish a national source of information on programmes suitable for commissioning. Any national database should be regularly updated.\n\nWork with providers and commissioners of lifestyle weight management programmes to agree a standard format and process for providing robust, consistent and regularly updated information on programmes.\n\nProviders of lifestyle weight management programmes (public, private or voluntary organisations) should demonstrate that their programmes:\n\nAre effective at 12 months or beyond. (The following programmes currently available in the UK have been shown to be effective at 12 to 18 months: [in alphabetical order] Rosemary Conley, Slimming World and Weight Watchers.)\n\nMeet best practice criteria for commissioning (see recommendation 13).\n\nMeet the core components for weight loss and the prevention of weight regain (see recommendations 9 and 10).\n\n# Recommendation 13 Ensure contracts for lifestyle weight management programmes include specific outcomes and address local needs\n\nClinical commissioning groups, health and wellbeing boards and local authorities should:\n\nCommission a range of lifestyle weight management programmes. For example, both group and individual programmes might be needed to meet the needs and preferences of different groups).\n\nUse the Department of Health's nest practice guidance for weight management services. In particular, commission programmes that:\n\n\n\nat least 60% of participants are likely to complete\n\nare likely to lead to an average weight loss of at least 3%, with at least 30% of participants losing at least 5% of their initial weight.\n\n\n\nEnsure contracts clearly specify:\n\n\n\nThe geographic areas and population groups that the programme should cover. Adequate provision should be made for disadvantaged groups, such as those on a lower income.\n\nThe additional efforts that may be needed to get specific groups involved (based on discussions with providers and referrers).\n\nWho will undertake routine evaluation and what measures will be collected. (Adherence to data protection and information governance requirements should not stop services from providing this data – see recommendations 16 and 17.)\n\n\n\nEnsure monitoring takes place 12\xa0months after the programme is completed. This may involve working with providers of lifestyle weight management programmes or commissioning an additional service.\n\nConsider commissioning additional services to prevent weight regain. For example, consider providing support to establish or expand local support groups or networks that may encourage self-management.\n\nEnsure lifestyle weight management programmes are complemented by a range of activities or services that address the wider determinants of health. This includes, for example, providing safe cycle and walking routes or restrictions in planning permission for takeaways and other food and drink outlets in specific areas.\n\nReview programmes that do not meet agreed uptake, provision or outcome targets. Amend or de-commission programmes as appropriate.\n\n# Recommendation 14 Provide continuing professional development on lifestyle weight management for health and social care professionals\n\nThose responsible for setting competences and continuing professional development programmes for health professionals (see Who should take action?) should:\n\nEnsure professional development training on weight management is available for health and social care professionals. (Also see recommendation 13 in NICE's guideline on obesity: working with local communities.)\n\nTrain GPs and other health and social care professionals to identify when to raise weight management with someone and to do so confidently, but with empathy. They should understand why many adults have difficulty managing their weight and the experiences they may face in relation to it. This includes considering the effect of their attitudes to, and any concerns about, their own weight. (Also see recommendations 9 and 13 in NICE's guideline on obesity: working with local communities.)\n\nTrain GPs and other health and social care professionals to accurately measure and record height and weight, determine body mass index (BMI) and accurately measure waist circumference.\n\nTrain GPs and other health and social care professionals to understand the practical skills and behaviours that can help someone lose or maintain their weight and how to provide ongoing support and encouragement. This includes encouraging people to self-manage and self-monitor their weight and any associated behaviours over the long term.\n\nTrain GPs and other health and social care professionals to discuss the likely benefits of a lifestyle weight management programme with service users, taking into account someone's personal circumstances. For example, they should take into account any associated medical conditions or personal factors, such as someone's commitment to change.\n\nTrain GPs and other health and social care professionals in how to help people make an informed decision about the best weight management option for them. They should also be able to refer people to the most appropriate weight management service. This includes identifying people with more complex needs and referring them to appropriate services (such as mental health, psychological or alcohol services).\n\nTrain GPs and other health and social care professionals to identify when someone may benefit from re-referral to a lifestyle weight management programme.\n\n# Recommendation 15 Provide training and continuing professional development for lifestyle weight management programme staff\n\nLifestyle weight management services, professional bodies and training organisations (see Who should take action?) should:\n\nDevelop training for lifestyle weight management programme staff with qualified professionals such as registered practitioner psychologists, registered dietitians and qualified physical activity specialists. Ensure this training addresses staff attitudes to, and any concerns about, their own weight.\n\nTrain staff to communicate effectively with, and generally adopt a respectful and non-judgemental approach to, participants. They should work collaboratively with them. This means they should understand the complexity of weight management and the reasons why many people have difficulty managing their weight, the experiences they may face in relation to their weight, and the fact that they may feel anxious about attending the programme. They should also be clear and open about what the programme involves, so that participants can make an informed choice about whether or not to join.\n\nTrain staff to deliver multicomponent programmes that cover weight management, dietary habits, safe physical activity and behaviour-change strategies. This should include the ability to:\n\n\n\ntailor interventions to individual needs (considering, for example, any specific language or literacy needs)\n\nreview progress and provide constructive feedback to both participants and referrers\n\nidentify possible reasons for relapse and use problem-solving techniques to address these\n\ncollect information about people's weight, eating habits and physical activity to support monitoring in line with the Department of Health's information governance and data protection requirements (for example, see the Public Health Services Contract 2014/15: guidance on the non-mandatory contract for public health services.)\n\n\n\nTrain staff to accurately measure and record height and weight to determine body mass index (BMI) and to accurately measure waist circumference. They should also be sensitive to how people feel about being measured and able to identify when it is practical, relevant and appropriate to measure someone.\n\nEnsure staff are aware of the common medical and psychological problems associated with being overweight or obese.\n\nEnsure staff are aware of evidence on the effect of dietary habits and physical activity on weight gain, loss and maintenance.\n\nEnsure staff are aware of the practical skills and behaviours that can help someone lose or maintain their weight. This includes, for example, shopping and cooking skills, understanding food labels and knowing what constitutes an appropriate portion of food. It also includes being able to identify opportunities to be less sedentary and more physically active.\n\nTrain staff to identify when a participant should be referred to their GP for potential onward referral to other services (for example, specialist weight management or other specialist services, such as alcohol counselling).\n\nEnsure staff leading supervised physical activity sessions are qualified and insured (for example, they should be trained to at least level\xa03 on the register of exercise professionals or equivalent).\n\nTrain staff to identify any gaps in their own knowledge, confidence or skills and ensure they know how to get these gaps addressed through further training.\n\n# Recommendation 16 Improve information sharing on people who attend a lifestyle weight management programme\n\nCommissioners of lifestyle weight management services should work with all referrers and providers to put systems in place to share any relevant information, in confidence, about people referred to lifestyle weight management programmes. (Examples of relevant information include details of someone's weight at baseline, programme end and at 12\xa0months.) This should be in line with the Department of Health's information governance and data protection requirements (for example, see Public Health Services Contract 2014/15: guidance on the non-mandatory contract for public health services).\n\nReferrers to, and providers of, lifestyle weight management programmes should seek the consent of participants to share between them any relevant information (see above) on the participant's progress. Explain that this information will be used to help monitor and evaluate the service.\n\n# Recommendation 17: Monitor and evaluate programmes\n\nCommissioners and providers of lifestyle weight management programmes, professionals who make referrals, services that help prevent weight regain, and monitoring services (see Who should take action?) should:\n\nUse the standard evaluation framework for weight management programmes and validated tools to monitor interventions.\n\nEnsure the scales used for monitoring people's weight are regularly calibrated (see recommendation 2).\n\nAs a minimum, collect and assess the following information on participants at the end of the programme, in line with the Department of Health's Department of Health's best practice criteria for weight management services:\n\n\n\nWeight – to calculate total and percent weight change. Do not rely on self-reported measures of height or weight.\n\nPercent of participants losing more than 3% of their baseline weight.\n\nPercent of participants losing more than 5% of their baseline weight.\n\nPercent adherence to the programme.\n\nAge, gender, ethnicity and socioeconomic status (for example, as indicated by the postcode of participants), so that the effect on health inequalities can be assessed.\n\n\n\nCollect details on how each participant's weight has changed 12\xa0months after the programme is completed (see recommendation 16).\n\nConsider collecting and assessing other outcomes, for example:\n\n\n\nchanges in other measures of body fatness, such as waist circumference\n\nchanges in dietary habits, physical activity and sedentary behaviour\n\nchanges in self-esteem, depression or anxiety\n\nchanges in health outcomes, such as blood pressure\n\nthe views and experience of participants who completed the programme\n\nthe views and experience of participants who did not complete the programme, and any changes in their weight\n\nthe views of staff delivering the programme and of those referring participants to it.\n\n\n\n# Recommendation 18 Monitor and evaluate local provision\n\nCommissioners of lifestyle weight management services, health and wellbeing boards and local authorities should:\n\nRegularly review lifestyle weight management services for adults to ensure they meet local needs (as identified by the joint strategic needs assessment), any gaps in provision should be identified and adherence and outcomes should be reported to agreed standards.\n\nMonitor awareness of the programmes among health and social care professionals and potential users (see recommendations 4 and 5).\n\nCollect data on referral routes to identify geographical areas where awareness of available programmes is low and where referral rates might be increased.\n\nCollate the results of routine monitoring and programme expenditure. Analyse these results in relation to the characteristics of the local population (for example, urban versus rural groups and between the general population and minority ethnic groups).\n\nAmend, improve or decommission programmes based on these findings.\n\nSee also recommendation 10 in NICE's guideline on obesity: working with local communities.", 'Who should take action?': '# Introduction\n\nThe guideline is for: commissioners and providers of lifestyle weight management programmes and health and social care professionals who advise or refer people these programmes. It may also be of interest to adults who are overweight or obese, their families and other members of the public.\n\nWho should take action\n\nRecommendation\n\nClinical commissioning groups\n\n, 3, 4, 5,13\n\nCommissioners of health and social care services\n\n\n\nCommissioners of lifestyle weight management programmes\n\n, 10, 16, 17, 18\n\nGPs and other health and social care professionals\n\n, 6, 7, 16, 17\n\nHealth and wellbeing boards\n\n, 2, 3, 4, 5, 13, 18\n\nHospital and community trusts\n\n, 16\n\nLocal authorities\n\n, 2, 3, 4, 5, 13, 18\n\nLocal education and training boards or councils and others responsible for setting competences and designing continuing professional development programmes for health professionals\n\n, 15\n\nLocal service providers\n\n, 8\n\nNational agencies with an interest in the effectiveness of lifestyle weight management programmes\n\n\n\nNHS England\n\n, 4\n\nProfessional bodies\n\n, 15\n\nProviders of lifestyle weight management services\n\n, 7, 9, 10, 11, 12,15, 16, 17\n\nProviders of monitoring services\n\n, 17\n\nPublic Health England\n\n, 3, 4, 5, 12\n\n# Who should take action in detail\n\n## Recommendation 1\n\nLocal authorities, working with other local service providers, clinical commissioning groups and health and wellbeing boards\n\n## Recommendation 2\n\nPublic Health England; GPs and other health and social care professionals; health and wellbeing boards; local authorities and other commissioners of health and social care services; providers (designers, developers or deliverers) of lifestyle weight management programmes in private, public or voluntary sector organisations working in the community or in (or via) primary care settings\n\n## Recommendation 3\n\nLocal authorities, Public Health England, NHS England, clinical commissioning groups and health and wellbeing boards\n\n## Recommendation 4\n\nClinical commissioning groups, health and wellbeing boards, hospital and community trusts, local authorities, NHS England and Public Health England\n\n## Recommendation 5\n\nPublic Health England, local authorities, health and wellbeing boards and clinical commissioning groups\n\n## Recommendation 6\n\nGeneral practice teams and other health or social care professionals who give advice about, or refer people to, lifestyle weight management programmes. This includes professionals working in: cardiac rehabilitation, diabetes, disability, fertility, postnatal, rheumatology and smoking services\n\n## Recommendation 7\n\nGPs and other health or social care professionals advising or referring adults to lifestyle weight management programmes; providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings\n\n## Recommendation 8\n\nProviders (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings\n\n## Recommendation 9\n\nCommissioners of lifestyle weight management services, such as public health teams within local authorities or other health and social care commissioners\n\n## Recommendation 10\n\nCommissioners of lifestyle weight management programmes, such as public health teams within local authorities or other health and social care commissioners\n\n## Recommendation 11\n\nProviders (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings\n\n## Recommendation 12\n\nPublic Health England; national agencies with an interest in the effectiveness of lifestyle weight management programmes; commissioners; providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings\n\n## Recommendation 13\n\nClinical commissioning groups; health and wellbeing boards; local authorities\n\n## Recommendation 14\n\nLocal education and training boards; local education and training councils; professional bodies; those responsible for setting competences and designing continuing professional development programmes for health professionals\n\n## Recommendation 15\n\nProviders of, and staff working for, lifestyle weight management services (designers, developers or deliverers in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings; professional bodies; training organisations\n\n## Recommendation 16\n\nCommissioners of lifestyle weight management services, such as public health teams within local authorities or other health and social care commissioners; providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings; health and social care professionals advising or referring service users; providers of monitoring services\n\n## Recommendation 17\n\nCommissioners of lifestyle weight management programmes, such as public health teams within local authorities or other health and social care commissioners; providers (designers, developers or deliverers of lifestyle weight management programmes in private, public or voluntary sector organisations) working in the community or in (or via) primary care settings; health and social care professionals who refer people to lifestyle weight management programmes; providers of services to support the prevention of weight regain; providers of programme monitoring services\n\n## Recommendation 18\n\nCommissioners of lifestyle weight management services, such as public health teams within local authorities or other health and social care commissioners; health and wellbeing boards; local authorities', 'Context': "In 2012, around a quarter of adults in England (24% of men and 25% of women aged 16 or older) were classified as obese (body mass index [BMI] 30\xa0kg/m2 or more). A further 42% of men and 32% of women were overweight (BMI 25 to 30\xa0kg/m2) (Health and Social Care Information Centre statistics on obesity, physical activity and diet: England 2014).\n\nAlthough there are people in all population groups who are overweight or obese, obesity is related to social disadvantage (Marmot review fair society, healthy lives: strategic review of health inequalities in England post-2010).\n\nPrevalence varies by population characteristics. For women, obesity prevalence increases with greater levels of deprivation, regardless of the measure used. For men, only occupation-based and qualification-based measures show differences in obesity rates by levels of deprivation.\n\nFor both men and women, obesity prevalence decreases with increasing levels of educational attainment. Around 30% of men and 33% of women with no qualifications are obese compared to 21% of men and 17% of women with a degree or equivalent (Health and Social Care Information Centre statistics on obesity, physical activity and diet: England 2010).\n\nObesity is also linked to ethnicity: it is most prevalent among black African women (38%) and least prevalent among Chinese and Bangladeshi men (6%) (The NHS Information Centre statistics on obesity, physical activity and diet: England, 2006).\n\nBeing overweight or obese can lead to both chronic and severe medical conditions (Government office for Science's tackling obesities: future choices – project report). It is estimated that life expectancy is reduced by an average of 2 to 4\xa0years for those with a BMI of 30 to 35\xa0kg/m2, and 8 to 10\xa0years for those with a BMI of 40 to 50\xa0kg/m2 (National Obesity Observatory Briefing note: obesity and life expectancy 2010).\n\nWomen who are obese are estimated to be around 13 times more likely to develop type 2 diabetes and 4 times more likely to develop hypertension than women who are not obese. Men who are obese are estimated to be around 5 times more likely to develop type 2 diabetes and 2.5 times more likely to develop hypertension than men who are not obese (Health and Social Care Information Centre statistics on obesity, physical activity and diet: England, 2011; National Audit Office tackling obesity in England 2001). People who are obese may also experience mental health problems as a result of stigma and bullying or discrimination in the workplace (Puhl and Heuer 2009).\n\nThe cost to society and the economy of people being overweight or obese was estimated at almost £16\xa0billion in 2007 (more than 1% of gross domestic product). It could rise to just under £50\xa0billion in 2050 (based on 2007 prices), if obesity rates continue to rise unchecked (Department of Health's healthy lives, healthy people: a call to action on obesity in England).\n\nThe government's obesity strategy 'Healthy lives: a call to action on obesity in England' aimed to reduce, 'the level of excess weight averaged across all adults by 2020'. It advocated a range of local interventions that both prevent obesity and treat those who are already obese or overweight.\n\nIn many areas, public, private or voluntary organisations are commissioned to provide individual or group lifestyle weight management services. People can also self-refer to commercial or voluntary programmes, for example, by attending a local class or 'club' or joining an online programme.\n\nLocal policies vary but generally, funded referrals to a lifestyle weight management programme (in tier 2 services) lasts for around 12\xa0weeks or 12\xa0sessions.\n\nThere has been uncertainty about which weight management programmes are effective and constitute good value for money. Evidence published since 2006 (such as Loveman 2011) provides an opportunity to refine and clarify best practice (for both self-help and referral schemes) and provide guidance on the commissioning of such programmes.", 'Considerations': "This section describes the factors and issues the Programme Development Group (PDG) considered when developing the recommendations. Please note: this section does not contain the recommendations.\n\n# Protecting people's mental and physical wellbeing\n\nThe PDG considered that the overarching approach to lifestyle weight management should be to do no harm.\n\nGenerally, the more weight an adult loses as part of a lifestyle weight management programme, the more health benefits they are likely to gain. (For example, they could benefit from reducing their blood pressure or improving control of blood glucose levels.) A commonly stated 'realistic' goal is to lose around 5–10% of baseline weight. The evidence reviews for this guideline estimated that the mean percentage weight loss from participating in a lifestyle weight management programme was somewhat lower, with an average of around 3% of baseline weight. However, the PDG noted that even losing this relatively small amount of weight is likely to lead to health benefits (particularly if the weight loss is maintained for many years).\n\nObserved weight losses from multicomponent lifestyle weight management programmes (as identified in the evidence review) are unlikely to be associated with unintended or adverse effects. (For example, musculoskeletal injuries or increased anxiety.) But the PDG noted that any unintended or adverse effects were not actively investigated, or systematically reported, in the majority of trials reviewed.\n\nThe PDG heard that people who are obese may perceive or experience stigma on a daily basis, and that any failure to lose weight (or regaining weight following weight loss) may have a negative psychological effect. Although this should not be a reason to avoid managing weight, it does highlight the importance of adopting a respectful, non-judgemental approach. It also highlights the importance of providing long-term support. The PDG noted that it is vital people are enabled to make informed choices about if, when and how they manage their weight. Training and continuing professional development is, members believe, particularly important in both these contexts. The Group also noted that the type and level of training for weight management programmes varies substantially. In particular, healthcare professionals have reported concerns about their lack of training or confidence in raising the issue of weight management.\n\n# Evidence\n\nThe PDG considered a substantial body of evidence, including 29 randomised controlled trials of lifestyle weight management programmes lasting at least 12\xa0months. Seven of the 29 trials reported outcomes at 3\xa0years or longer. But no studies were identified with outcomes beyond 5\xa0years. Maintaining weight loss is known to be difficult and, as a result, extrapolating longer term outcomes from short term studies may be misleading. Modelling showed that even a small amount of weight loss is cost effective, but only if it is maintained long term on a lower weight trajectory.\n\nThe PDG concluded that multicomponent lifestyle weight management programmes that address dietary habits, physical activity and behaviour change techniques can help adults lose weight and maintain that weight loss for at least 12 to 18\xa0months. However, it was difficult to draw conclusions about why some programmes were more effective than others, or about the effect of specific components. (Examples of the latter include: the setting, face-to-face versus remote contact and the effect of the length or intensity of a programme.) Few studies reported outcomes for specific groups and it was unclear what any reported 'tailoring' meant in practice.\n\nThe PDG noted that obese adults may attempt to lose weight many times throughout their lives. The point at which they may be successful (and the number of times this translates into a referral to services) was unclear. In addition, the effect (both positive and negative) on their psychological or physical health remains unclear. The PDG agreed that people who are obese need as many opportunities as possible to lose weight. Members also agreed that this should be an ongoing area for research.\n\nThe PDG was unable to consider the relative effectiveness of alternative approaches to weight management – such as focusing on a healthy lifestyle and the prevention of weight gain rather than weight loss – because of a lack of trials that met the review inclusion criteria.\n\nThe PDG noted the lack of longer term follow-up of a range of approaches to weight management and the lack of standard evaluation of trials. This includes standard reporting of weight outcomes and strategies for dealing with missing data for different groups to judge the effect on inequalities in health. It has made a research recommendation on this to improve the evidence base.\n\n# Wider context\n\nThe guideline focused on multicomponent lifestyle weight management services and excluded other routes for managing obesity, such as drugs or surgery. Evidence that focused only on populations with linked conditions (such as type 2 diabetes) was excluded, as was evidence on people with more complex needs (such as those who are obese and also have alcohol or mental health problems). The relative effectiveness of, for example, specific dietary approaches or the effect of wider behaviours that have been linked to weight gain (such as shift working or sleep) was not considered. Therefore it is important to read this guideline in the context of broader NICE guidance on obesity.\n\nThe PDG noted that local services or activities that address the wider determinants of health may also help people to change their dietary habits or physical activity levels and manage their weight.\n\n# Commissioning\n\nThe PDG was concerned that people who have attended weight management services may not have enough sources of support to prevent them regaining the weight they have lost. Members recognised the importance of commissioned services addressing the prevention of weight regain. The evidence reviewed suggests that commercial multicomponent lifestyle weight management programmes available in the UK are likely to be effective, at least up to 12 to 18\xa0months. However, this finding is based on a relatively small number of trials and no head-to-head comparisons of the relative effectiveness of programmes were available. The evidence reviewed also suggests that primary care-led services may be less effective than commercial programmes, but it is unclear why. The PDG noted that local authority services may be established to support people living in particular geographic areas, or from lower income groups. This is particularly the case if their needs are not being met by commercial programmes.\n\nThe PDG discussed the importance of ensuring commissioners have access to robust, regularly updated information on effective lifestyle weight management programmes. Members noted how time consuming and potentially difficult it would be otherwise for each local area to decide which programmes may be most effective and cost effective. It was noted that programme range, content and evidence of effectiveness may be subject to change. They agreed that a national source of information on programmes shown to be effective – based on robust and consistent data – would be helpful. The PDG's conclusions were informed by the randomised controlled trials of programmes included in the evidence reviews. Members noted that it was unclear what impact any subsequent changes made to the format or content of programmes would have on effectiveness.\n\nThe PDG noted that the ability to review, improve or decommission programmes at a local level is dependent on monitoring processes being built into the programme from the outset. Members also agreed that establishing systems for information sharing between referrers and providers (such as weight outcomes at programme end or at 12\xa0months) was key.\n\nThe PDG was concerned that people from lower income groups may struggle to attend programmes once their referral period is over. This is a particular concern if participants wishing to continue the programme beyond the referral period have to pay for it.\n\nThe PDG noted the importance of an integrated approach to weight management to ensure referrals can easily be made within and across different tiers of weight management services. In addition, because some people who are obese may have other health issues, it noted the importance of local links between a variety of services. (This includes, for example, weight management, smoking cessation, mental health services, substance misuse and alcohol counselling services.)\n\nThe PDG noted that the recommendations in this guideline apply equally to all types of lifestyle weight management programme.\n\n# Cost effectiveness\n\nThe economic model estimated that a 12-week programme costing £100 or less will be cost-effective for adults who are overweight or obese under 2 conditions. First, the weight loss, compared with what it would have been without the intervention, must be maintained for life. Second, at least 1\xa0kg of weight is lost and this weight difference is maintained for life (that is, the person's lifetime weight trajectory is lowered by at least 1\xa0kg). A 24-week programme costing £200 or less was estimated to be cost effective under the same conditions. However, there were not enough data to populate the model for adults with an initial body mass index (BMI) of more than 40\xa0kg/m2. So it was unclear whether or not it would be cost effective for this group. For programmes costing £500 per head to be cost effective, it is estimated that an average 2\xa0kg weight differential must be maintained for life. A 3\xa0kg loss must be maintained for life for programmes costing £1000 or more per head. The model estimated that programmes costing £100 or more per head are not cost effective if, on average, participants regain the weight lost within 2\xa0to 3 years or less. This is regardless of the average initial weight loss. The key variable is thus the speed with which weight is regained. However, the PDG noted that evidence based on long term follow up of participants was limited.\n\nThe length of time that someone's weight trajectory must be below the 'without-intervention' trajectory and still remain cost effective is reduced by the following 4 factors:\n\na higher initial weight loss\n\nthe person being older (for a given BMI group)\n\nthe person having a higher BMI (for a given age group)\n\na lower cost per head of the intervention.\n\nIn relation to age, the model implies that the recommendations will generate better value for money for people older than 50 – even if they only maintain a lower weight trajectory for 3 to 10\xa0years. This is because older people will gain the health benefits sooner (not because older people lose more weight than younger people). Trials suggest average weight loss is similar for all ages and BMI groups. For people aged 20–39, weight loss may need to be maintained for up to 40\xa0years before the intervention is worth undertaking.\n\nIn relation to weight, the model implies that implementation of the recommendations will generate better value for money when used with adults who are obese (rather than overweight) (see adults who are overweight or obese). As a result, the PDG felt that people with a BMI between 30 and 40\xa0kg/m2 should be made a priority for funded referrals to lifestyle weight management programmes. But members also agreed that people who are overweight (BMI 25 to 30\xa0kg/m2) should not be excluded from funded referrals if there is enough capacity. There were insufficient data to make a judgement on this for people whose BMI is above 40\xa0kg/m2.\n\nThe modelling data relate to population cohorts of a given age, sex and BMI category – not to every individual in each cohort, because weight loss and gain vary greatly between people in each cohort. Effective interventions for a particular cohort will usually be cost effective for people who have lost at least the average amount of weight, or who have regained weight at an average or slower than average rate.", 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.\n\nAll the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity.\n\nFindings should be published in peer reviewed journals.\n\nHow effective are lifestyle weight management programmes available in the UK, when directly compared using high-quality trials? In particular, what effect do specific components of a multicomponent lifestyle weight management programme have on adherence, effectiveness and cost effectiveness? This includes:\n\ncomponents, or combinations of components, that support weight loss or the prevention of weight regain\n\nthe effect of programme length, intensity, setting and means of delivery (examples of the latter include group, individual and remote support)\n\nspecific behaviour change techniques (using a recognised taxonomy)\n\nthe effect of new technologies\n\nthe effect of additional support services, such as self-help groups and networks\n\napproaches to commissioning\n\nprocesses for collecting long-term follow-up data.\n\nHow effective and cost effective are lifestyle weight management programmes available in the UK over at least at least 3 to 5\xa0years, and ideally beyond 10\xa0years. Specifically:\n\nDo short-term (12-week) interventions provide adults with the self-management skills they need to maintain weight loss in the long term?\n\nAre alternative approaches to weight management (such as approaches that focus on a healthy lifestyle, behaviour change and the prevention of weight gain rather than weight loss) effective and cost effective in the long term?\n\nHow effective and cost effective are programmes for people of different ages, gender, sexuality or from different ethnic or socioeconomic groups?\n\nHow effective and cost effective are programmes for specific population groups, such as adults with depression or with disabilities?\n\nWhat is the effect of lifestyle weight management programmes available in the UK on:\n\nChanges to dietary habits and choices, physical activity level and sedentary behaviour?\n\nWider lifestyle factors, such as sleeping patterns or stress management?\n\nPsychological issues, such as body confidence or attitude, depression, anxiety or self-esteem?\n\nHealth conditions, such as changes to blood pressure or lipids?\n\nUnintended outcomes such as musculoskeletal injuries, symptoms of an eating disorder; increased anxiety or depression?\n\nUser adherence and satisfaction?\n\nQuality of life?\n\nHow can referrals to other services after involvement in a lifestyle weight management service be as effective and cost effective as possible? This includes: re-referrals to a lifestyle weight management service, referrals to other tiers of weight management services or referrals to other specialist services (such as alcohol or substance misuse). In particular:\n\nHow long should people wait before being re-referred to a programme?\n\nDoes re-referral to the same (or a similar programme) influence adherence, effectiveness or cost effectiveness?\n\nIn what circumstances should participants not be re-referred to the same (or a similar programme)?\n\nWho is best placed to provide ongoing support after the programme, and does this differ according to whether someone completed the programme or met their weight loss goal?\n\nAre there any unintended or adverse effects from repeated attempts to lose weight?\n\nWhat effect does lifestyle weight management training for health professionals and lifestyle weight management staff have on:\n\nThe referral process, including patient satisfaction?\n\nProgramme outcomes (weight loss and prevention of weight regain), adherence to the programme and participants' satisfaction with it?\n\nStaff confidence in discussing weight issues and any concerns about their own weight?\n\nStaff ability to deliver the programme?\n\nGeneral approach of staff (that is, whether they adopt a 'respectful and non-judgemental' approach as a result)?\n\nMore detail identified during development of this guideline is provided in Gaps in the evidence.", 'Glossary': "# Adults who are overweight or obese\n\nAdults are assessed to see if they are overweight or obese using their body mass index (BMI). The following are the cut-off points for a healthy weight or being overweight or obese:\n\nHealthy weight, BMI (kg/m2) 18.5–24.9\n\nOverweight, BMI 25–29.9\n\nObesity I, BMI 30–34.9\n\nObesity II, BMI 35–39.9\n\nObesity III, BMI 40 or more.\n\nBMI is a less accurate indicator of adiposity in adults who are highly muscular, so it should be interpreted with caution in this group.\n\nWaist circumference can also be used to assess whether someone is at risk of health problems because they are overweight or obese (up to a BMI of 35, see recommendation 1.2.2.9 in NICE's guideline on obesity prevention). For men, a waist circumference of less than 94\xa0cm is low risk, 94–102\xa0cm is high and more than 102\xa0cm is very high risk. For women, a waist circumference of less than 80\xa0cm is low risk, 80–88\xa0cm is high and more than 88\xa0cm is very high risk.\n\nThe use of lower BMI thresholds to trigger action to reduce the risk of conditions such as type 2 diabetes has been recommended for black African, African–Caribbean and Asian groups. The lower thresholds are 23\xa0kg/m2 to indicate increased risk and 27.5\xa0kg/m2 to indicate high risk. (See recommendations on BMI and waist circumference for Black, Asian and minority ethnic groups in NICE's guideline on obesity identification, assessment and management.)\n\n# Behaviour change techniques\n\nA collection of techniques that aim to help people change their behaviour to improve their health. The techniques are based on an established theory or rationale (see NICE guidance on behaviour change).\n\n# Body mass index\n\nBody mass index (BMI) is commonly used to measure whether or not adults are a healthy weight or underweight, overweight or obese. It is defined as weight in kilograms divided by the square of height in metres (kg/m2).\n\n# Complex needs\n\n'Complex needs' refers to issues that affect a person's health and wellbeing. They might include:\n\na behavioural issue such as substance misuse\n\nspecific conditions such as those limiting mobility or learning, mental health conditions, substantive or life-threatening comorbidities or dietary needs\n\npersonal social circumstances, such as homelessness.\n\n# Dietary habits\n\nThis includes a range of factors including the food and drink (including alcoholic drinks) consumed, energy and nutrient intake, portion size and the pattern and timing of eating. Population advice on food and nutrition is available on the NHS Choices website.\n\n# Lifestyle weight management programmes\n\nLifestyle weight management programmes for overweight or obese adults are multi-component programmes that aim to reduce a person's energy intake and help them to be more physically active by changing their behaviour. They may include weight management programmes, courses or clubs that:\n\naccept adults through self-referral or referral from a health or social care practitioner\n\nare provided by the public, private or voluntary sector\n\nare based in the community, workplaces, primary care or online.\n\nAlthough local definitions vary, these are usually called tier 2 services and are just one part of a comprehensive approach to preventing and treating obesity.\n\n# Physical activity\n\nThe full range of human movement, from competitive sport and exercise to active hobbies, walking, cycling and the other physical activities involved in daily living.\n\n# Physical activity instructor\n\nA qualified physical activity instructor meets the fitness industry's agreed qualification standards and undertakes continued professional development. Instructors working with people referred from a GP or another health professional should hold level\xa03 membership of the Register of Exercise Professionals (or equivalent).\n\n# Stigma\n\nStigma in relation to someone's weight may take the form of bullying, teasing, harsh comments, discrimination or prejudice based on a person's body size.\n\n# Tiers of weight management services\n\nDifferent tiers of weight management services cover different activities. Definitions vary locally but usually tier\xa01 covers universal services (such as health promotion or primary care); tier\xa02 covers lifestyle interventions; tier\xa03 covers specialist weight management services; and tier\xa04 covers bariatric surgery.\n\n# Weight loss\n\nIn this guideline, weight loss refers to the amount of weight lost through a lifestyle weight management programme.\n\n# Weight maintenance\n\nThe maintenance of a specific weight (whether or not weight has been lost).\n\n# Weight regain\n\nIn this guideline, weight regain means regaining some or all of the weight that was lost during a lifestyle weight management programme. The prevention of weight regain refers to keeping to a lower weight than the person would have been if they had not lost weight in the first place. This is also referred to as being on a lower weight trajectory.\n\n# Weight trajectory\n\nA weight trajectory refers to a general pattern of weight gain or weight loss over many years. Many adults gradually put on weight as they get older. This gradual increase in weight will be lower for someone who has lost weight during a lifestyle weight management programme, if they have not regained any of that lost weight.", 'References': 'Golubic R, Ekelund U, Wijndaele K et al. (2013). Rate of weight gain predicts change in physical activity levels: a longitudinal analysis of the EPIC-Norfolk cohort. International Journal of Obesity 37: 404–9\n\nLoveman E, Frampton GK, Shepherd J et al. (2011) The clinical effectiveness and cost-effectiveness of long-term weight management schemes for adults: a systematic review. Health Technology Assessment 15 (2)\n\nPuhl RM, Heuer CA (2009). The stigma of obesity: a review and update. Obesity 17: 941–64', 'Summary of the methods used to develop this guideline': "# Introduction\n\nThe reviews, commissioned report and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching question was: how effective and cost effective are multi-component lifestyle weight management programmes for adults?\n\nThe subsidiary questions were:\n\n. How does effectiveness and cost effectiveness vary for different population groups (for example, men, black and minority ethnic or low-income groups)?\n\n. What are the best practice principles for multi-component lifestyle weight management programmes for adults?\n\n. What are the most effective and cost effective behavioural or psychological components of a lifestyle weight management programme for adults – and who might best deliver them?\n\n. What are the views, perceptions and beliefs of adults in relation to lifestyle weight management programmes (whether or not they use such programmes)? How can overweight and obese adults from a diverse range of backgrounds be encouraged to join, and adhere to, these programmes?\n\n. How can lifestyle changes and weight loss be sustained once the weight management programme has ended?\n\n. What barriers and facilitators affect the delivery of effective weight-management programmes for adults and how do they vary for different population groups?\n\n. What are the best practice principles for primary care when referring people to commercial, voluntary or community sector or self-help lifestyle weight management programmes?\n\n. What are the best practice principles for commissioners of lifestyle weight management services for adults?\n\n. What training is needed for professionals involved directly or indirectly with lifestyle weight management programmes for adults?\n\n. How should lifestyle weight management programmes be monitored and evaluated locally?\n\nThese questions were made more specific for each review (see reviews for further details).\n\n# Reviewing the evidence\n\n## Effectiveness reviews\n\nOne review of effectiveness was conducted, split into 3 sections:\n\nReview 1a 'The clinical effectiveness of long-term weight management schemes for adults'.\n\nReview 1b 'How components of behavioural weight management programmes affect weight change'.\n\nReview 1c 'Weight regain after behavioural weight management programmes'.\n\nIdentifying the evidence\n\nThe review updated and expanded on an existing review (Loveman 2011) and uses similar methods.\n\nTen electronic databases were systematically searched in October\xa02012 for randomised controlled trials of multi-component behavioural weight management programmes. See review 1 for details of the databases searched.\n\nReference lists were also screened and references submitted to NICE in a call for evidence.\n\nSelection criteria\n\nStudies were included in the effectiveness review if they:\n\nwere multi-component interventions addressing physical activity, dietary intake and behaviour change\n\nwere randomised controlled trials.\n\nincluded at least 12\xa0months follow-up\n\nincluded a measure for weight loss (for example, weight or body mass index [BMI])\n\nincluded adults aged 18 and older who were overweight or obese\n\nwere undertaken in OECD (Organisation for Economic Co-operation and Development) countries\n\nwere published in English.\n\nStudies were excluded if they:\n\nincluded children and pregnant women\n\nincluded people with eating disorders\n\nonly included people with specific pre-existing medical condition such as diabetes, heart failure, uncontrolled hypertension or angina\n\nfocused on pharmacological or surgical interventions.\n\nSee review 1 for details of the inclusion and exclusion criteria.\n\n## Other reviews\n\nOne review of barriers and facilitators, referral, commissioning and training issues in relation to lifestyle weight management was conducted:\n\nReview 2: Managing overweight and obese adults.\n\nIdentifying the evidence\n\nSeveral databases and websites were searched in April 2013 for qualitative evidence, grey literature and best practice guidelines. See above for details.\n\n## Selection criteria\n\nStudies were included in the review if they:\n\naddressed questions included in the scope (except questions of effectiveness).\n\nfocused on adults aged\xa018 and older who were overweight or obese\n\nwere undertaken in the UK.\n\nStudies were excluded if they:\n\nincluded children and pregnant women\n\nincluded people with eating disorders\n\nfocused on pharmacological or surgical interventions\n\nonly included people with a specific pre-existing medical condition such as diabetes, heart failure, uncontrolled hypertension or angina\n\nfocused on pharmacological or surgical interventions.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in Methods for the development of NICE public health guidance. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution. Included studies were not evaluated on the basis of blinding.\n\nStudy quality: internal validity\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled, or not adequately described, are unlikely to alter the conclusions.\n\n− Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nThis was based on:\n\nrandomisation and allocation procedures\n\nevidence of selective reporting\n\nattrition (at 12\xa0months or at the closest point reported after 12\xa0months, as appropriate).\n\nStudy quality: external validity\n\nAs above, external validity was rated '++', '+' or '−' based on whether:\n\nparticipants were representative of the general population\n\nthe intervention needed any extraordinary efforts to implement in the UK (for example, the implementation of a particular infrastructure).\n\n## Summarising the evidence and making evidence statements\n\nThe review data were summarised in evidence tables (see the reviews in Supporting evidence).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see 'Supporting evidence'). The statements reflect their judgment of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Commissioned report\n\nA questionnaire covering practical and process issues was sent to known weight management providers operating in England. Responses to the survey were compiled by an independent researcher:\n\nPractical and process issues in the provision of lifestyle weight management services for adults.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and an economic modelling exercise. See Managing overweight and obesity among adults: report on economic modelling and cost consequence analysis.\n\n## Review of economic evaluations\n\nThe review of economic evaluations was an extension of the effectiveness review (review 1). Studies were considered if they had been undertaken in an OECD country and included a cost effectiveness analysis. For a description of the search strategy and the inclusion, exclusion and quality criteria used, see review 1.\n\n## Economic modelling\n\nAn economic model was constructed to incorporate data from review 1. The results are reported in: Managing overweight and obesity among adults: report on economic modelling and cost consequence analysis.\n\n# How the PDG formulated the recommendations\n\nAt its meetings in 2013, the Programme Development Group (PDG) considered the evidence, expert testimony, commissioned report and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgment\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guideline.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential effect on the target population's health.\n\nEffect on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgments.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nThe PDG noted that effectiveness can vary according to whether interventions are delivered to a group or on a one-to-one basis.\n\nWhere possible, recommendations were linked to an evidence statement(s) (see The evidence for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).", 'The evidence': 'The evidence statements from 2 reviews are provided by external contractors.\n\nThis section lists how the evidence statements and expert papers link to the recommendations and sets out a brief summary of findings from the economic analysis.\n\n# How the evidence and expert papers link to the recommendations\n\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from.\n\nEvidence statement number 1.2 indicates that the linked statement is numbered 1.2 in review 1. Evidence statement number 2.2 indicates that the statement is numbered 2.2 in review 2. EP1 indicates that expert paper 1 is linked to a recommendation. CR indicates that the commissioned report is linked to a recommendation. EM indicates that the economic modelling report is linked to a recommendation.\n\nWhere a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: EP2, EP4; IDE\n\nRecommendation 2: evidence statement 1.9; EP1, EP2, EP3; IDE\n\nRecommendation 3: evidence statements 2.8, 2.9, 2.10; EP2, EP4; CR; IDE\n\nRecommendation 4: evidence statements 2.8, 2.9, 2.10; EP2, EP4; CR; IDE\n\nRecommendation 5: evidence statement 2.1; EP2, EP4; CR; IDE\n\nRecommendation 6: evidence statements 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.10, 1.12, 2.1, 2.2, 2.3, 2.4, 2.5, 2.7, 2.8, 2.9, 2.11; EP1; EP2; CR, EM\n\nRecommendation 7: evidence statements 1.1, 1.3, 1.23, 2.1, 2.7, 2.8, 2.9; EP1, EP2, EP3, EP4; EM\n\nRecommendation 8: evidence statements 2.1, 2.2, 2.4, 2.5, 2.7, 2.8, 2.11; EP2, CR.\n\nRecommendation 9: evidence statements 1.2, 1.8, 1.9, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.22, 2.5, 2.6, 2.14; EP1, EP2, EP3; CR; EM\n\nRecommendation 10: evidence statements 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 2.5; EP2, EP3; EM\n\nRecommendation 11: evidence statements 1.2, 1.8, 1.9, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 2.5, 2.6, 2.14; EP1, EP2, EP3; CR; EM\n\nRecommendation 12: evidence statements 1.3, 2.13\n\nRecommendation 13: evidence statements 1.3, 1.4, 1.5, 1.6, 1.7, 1.10, 1.20, 1.23, 2.12, 2.13; EP2, EP4; CR\n\nRecommendation 14: evidence statements 2.9, 2.10, 2.11, 2.14; EP1, EP2, EP3\n\nRecommendation 15: evidence statements 2.9, 2.10, 2.11, 2.14; EP1, EP2, EP3\n\nRecommendation 16: evidence statement 2.8; EP4; CR\n\nRecommendation 17: evidence statements 2.8, 2.9, 2.11, 2.12, 2.13\n\nRecommendation 18: evidence statements 2.9, 2.10, 2.14; EP4\n\n## Expert papers and commissioned report\n\nExpert papers 1–4\n\nCommissioned report\n\n# Economic modelling\n\nOverall, the modelling showed that lifestyle weight management interventions that help people lose weight and then maintain the weight loss in the long term would be cost effective, if they can be identified.\n\nThe economic model considered cohorts of (virtual) adults of different ages and with a body mass index (BMI) of 25, 30, 35 and 40\xa0kg/m2. The model tested the effect of a 12-week lifestyle weight management programme. All cohorts were followed for the whole of their lives and they contract diseases and conditions at different rates, depending on their BMI.\n\nFrom a public sector perspective, the modelling showed that if the original weight loss achieved by attending a lifestyle weight management programme were to be maintained for life, most of these interventions would be cost effective. That is, provided they cost less than £500 per person and on average, participants lost more than 1\xa0kg in weight. This is true for all age groups and both sexes.\n\nHowever, if they were to regain the lost weight within 2 to 3 years, the modelling indicates that few, if any, of these interventions would be cost effective. To be cost effective, they would need to cost less than £100 per person and the average weight lost would need to be in excess of 5\xa0kg.\n\nMore detail (including any observed differences by age and gender) is given in the modelling report: Managing overweight and obesity among adults: report on economic modelling and cost consequence analysis.', 'Gaps in the evidence': "The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence. These gaps are set out below.\n\n. There is a lack of long-term (that is, 3\xa0years or longer) trials of lifestyle weight management programmes to determine cost effectiveness.\n\n(Source: evidence reviews 1a and 1c; economic modelling)\n\n. There is a lack of trials directly comparing lifestyle weight management programmes in the UK.\n\n(Source: evidence reviews 1a, 1b and 1c)\n\n. There is a lack of evidence on whether there are any adverse or unintended effects associated with long-term weight management programmes. There is also a lack of evidence on 'weight cycling' (repeated attempts to lose weight) in relation to these programmes.\n\n(Source: evidence reviews 1a, 1b and 1c; expert paper 1)\n\n. There is a general lack of evidence on which specific components of a lifestyle weight management programme ensure effectiveness. In particular, it is unclear what effect programme length and intensity has on effectiveness.\n\n(Source: evidence reviews 1a and 1b)\n\n. There is a lack of evidence on the effect of sexual orientation, disability, religion, place of residence, occupation, education, socioeconomic position or social capital on the effectiveness of lifestyle weight management programmes. There is also a lack of analysis of participants by age and gender.\n\n(Source: evidence review 1a)\n\n. The existing evidence base is limited by studies characterised by: short-term follow up, small sample sizes, the collection of data at only a limited number of time points (usually 2), demographic samples that limit the ability to generalise and non-reporting of reasons for people dropping out.\n\n(Source: evidence reviews 1a and 1b)\n\n. There is a lack of evidence on whether any particular approach to commissioning leads to better outcomes for participants in lifestyle weight management programmes.\n\n(Source: evidence review 2)\n\n. There is a lack of evidence as to whether any particular type of training for practitioners leads to more effective programmes.\n\n(Source: evidence review 2)\n\nThe Committee made 5 recommendations for research into areas that it believes will be a priority for developing future guidance.", 'About this guideline': "# What evidence is the guideline based on?\n\nThe evidence that the PDG considered included:\n\nEvidence reviews:\n\n\n\nReview 1 was divided into 3 sections and was carried out by the University of Oxford. The principal authors were: Paul Aveyard, Jamie Hartmann-Boyce and David Johns.\n\n\n\nReview 1a, 'The clinical effectiveness of long-term weight management schemes for adults'.\n\nReview 1b, 'How components of behavioural weight management programmes affect weight change'.\n\nReview 1c, 'Weight regain after behavioural weight management programmes'.\n\n\n\nReview 2: 'Managing overweight and obese adults' was carried out by the University of Oxford. The principal authors were: Paul Aveyard, Jamie Hartmann-Boyce and David Johns.\n\n\n\nEconomic modelling: 'Economic modelling and cost consequence analysis' was carried out by the UK Health Forum and the University of East Anglia. The authors were: Martin Brown, Tim Marsh, Lise Retat, Ric Fordham, Marc Suhrcke, David Turner, Richard Little and Oyebanji Filani.\n\nCommissioned report: 'Practical and process issues in the provision of lifestyle weight management services for adults' was carried out by GK research. The principal author was Graham Kelly.\n\nExpert papers:\n\n\n\nExpert paper 1 'Weight bias and stigma and the effectiveness of weight management programmes' by Jane Ogden, Professor in Health Psychology, University of Surrey.\n\nExpert paper 2 'Experience from practice – psychological issues' by Rachel Holt, Consultant Clinical Psychologist/Service Lead at Derbyshire Tier 3 Weight Reduction Service.\n\nExpert paper 3 'Weight bias and the impact of weight stigma on emotional and physical health' by Dr Rebecca Puhl, Director of Research and Weight Stigma Initiatives at the Rudd Center for Food Policy and Obesity, Yale University.\n\nExpert paper 4 'Commissioning and working with health and wellbeing boards' by Stephen Watkins, Director of Public Health, Stockport.\n\n\n\nNote: the views expressed in the expert papers above are the views of the authors and not those of NICE.\n\nIn some cases the evidence was insufficient and the PDG has made recommendations for future research, see Gaps in the evidence."}	https://www.nice.org.uk/guidance/ph53	This guideline covers multi-component lifestyle weight management services including programmes, courses, clubs or groups provided by the public, private and voluntary sector. The aim is to help people lose weight and become more physically active to reduce the risk of diseases associated with obesity. This includes coronary heart disease, stroke, type 2 diabetes and various cancers.
15ffbf1e73077cbfb780697a5319ca80e3d8d411	nice	Gastroelectrical stimulation for gastroparesis	Gastroelectrical stimulation for gastroparesis # Recommendations This document replaces previous guidance on gastroelectrical stimulation (interventional procedure guidance 103). Current evidence on the efficacy and safety of gastric electrical stimulation for gastroparesis is adequate to support the use of this procedure with normal arrangements for clinical governance, consent and audit. During the consent process, clinicians should inform patients considering gastric electrical stimulation for gastroparesis that some patients do not get any benefit from it. They should also give patients detailed written information about the risk of complications, which can be serious, including the need to remove the device. Patient selection and follow-up should be done in specialist gastroenterology units with expertise in gastrointestinal motility disorders, and the procedure should only be performed by surgeons working in these units. Further publications providing data about the effects of the procedure on symptoms in the long term and on device durability would be useful.# Indications and current treatments Gastroparesis is a chronic disorder in which the stomach empties more slowly than normal (delayed gastric emptying) in the absence of any type of mechanical obstruction. The most common symptoms are nausea and protracted vomiting. Other symptoms include abdominal bloating, and, in severe cases, malnutrition. Gastroparesis most commonly occurs in people with type 1 diabetes. It can also occur in other situations such as after abdominal surgery or in association with anorexia nervosa and abdominal migraine. Some cases are idiopathic. Conservative treatment options include modification of dietary intake and medical therapy with antiemetics or prokinetics. Treatment options for chronic intractable (drug-refractory) symptoms include jejunostomy tube insertion for feeding, gastrostomy tube insertion for stomach decompression, and pyloroplasty. Gastroelectrical stimulation is an option for treating chronic, intractable nausea and vomiting secondary to gastroparesis.# The procedure Electrical stimulation is delivered via an implanted system that consists of a neurostimulator and 2 leads. Implantation is done with the patient under general anaesthesia by an open or laparoscopic approach. The stimulating electrode of each intramuscular lead is fixed to the muscle of the distal part of the stomach. The connector end of each lead is then attached to the neurostimulator, which is placed in a pocket in the abdominal wall. When the neurostimulator is turned on, electrical impulses are delivered. The rate and amplitude of stimulation can be adjusted wirelessly with a hand-held external programmer. Patients may need to return to hospital for adjustment or reprogramming of the device, to optimise the effect on gastric emptying.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A meta-analysis of 4 studies including 169 patients with diabetic gastroparesis treated by gastroelectrical stimulation (part of a systematic review of 601 patients) reported improvement in total symptom severity score (weighted mean difference 8.96 ; p<0.00001; I2=68.6%). A meta-analysis of 3 studies including 58 patients with idiopathic gastroparesis treated by gastroelectrical stimulation reported improvement in total symptom severity score (weighted mean difference 7.5 ; p<0.00001; I2=52.9%). A meta-analysis of 2 studies including 33 patients with post-surgical gastroparesis treated by gastroelectrical stimulation reported improvement in total symptom severity score (weighted mean difference 8.3 ; p<0.00001; I2=0%). Length of follow-up was unclear in all the analyses. A meta-analysis of 7 studies including 378 patients with diabetic, idiopathic or post-surgical gastroparesis treated by gastroelectrical stimulation (part of a systematic review of 601 patients) reported a statistically significant improvement in gastric emptying at 4 hours (assessed using standardised radionucleotide scans of a solid meal: weighted mean difference 13.0 ; p<0.00001; I2=87.4%). Subgroup analysis showed that the improvement was statistically significant in patients with diabetic or idiopathic gastroparesis but not in patients with post-surgical gastroparesis. Length of follow-up was unclear in all the analyses. In a systematic review of 364 patients, a meta-analysis of 4 studies including 75 patients with gastroparesis treated by gastroelectrical stimulation reported no statistically significant change in weight (weighted mean difference 3.7 ; I2=0%). Length of follow-up was not reported but 12-month outcomes were preferred. In the systematic review of 364 patients, a meta-analysis of 8 studies including 184 patients with gastroparesis treated by gastroelectrical stimulation reported a reduction in need for nutritional support from 44% (96/216) of patients at baseline to 11% (21/184) at follow-up (odds ratio 5.5 ; p<0.00001; I2=27%). Length of follow-up was not reported but 12-month outcomes were preferred. A randomised controlled trial (RCT) of 32 patients with gastroparesis of idiopathic origin reported that there was a significant reduction in weekly vomiting frequency from 61 to 87% (p<0.001) and improvements in gastroparesis symptoms, gastric emptying and days of hospitalisation (all p<0.05) at 1-year follow-up. The systematic review of 364 patients reported a significant improvement in Short Form-36 physical component score (weighted mean difference 8.1 ) and the mental component score (weighted mean difference 8.16 ), based on meta-analyses of 4 studies with 78 patients. The difference was statistically significant (p<0.00001) for both outcomes with no heterogeneity. Length of follow-up was not reported but 12-month outcomes were preferred. The specialist advisers listed key efficacy outcomes as reduced symptoms, reduced need for nutritional support, improved nutritional status and reduced frequency of hospital admissions.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Death (within 30 days) was reported in 3% (2/72) of patients treated by gastroelectrical stimulation, due to small bowel infarction and heart failure, and 3% (1/31) of patients treated by gastrectomy, due to myocardial infarction, in a comparative case series of 103 patients. Gastric perforation related to an episode of vomiting (2 months after the procedure) was reported in 1 patient in a case series of 17 patients. The device was removed and the perforation was repaired. Device removal was reported in 11% (24/221) of patients in a case series of 221 patients (timing ranged from 1–43 months after the procedure). Reasons were infection at the pulse generator or electrode sites (13 patients), lack of symptom improvement (6 patients), lead dislodgements (2 patients), small bowel obstruction caused by wires (1 patient), penetration of electrode into the lumen of the stomach (1 patient) and 'associated with peptic ulcer disease' (1 patient). No further details were reported. Erosion through the skin (6 patients), device migration (1 patient) and pain at implantation site (4 patients) resulting in device removal or replacement (timing unclear) were reported in the systematic review of 364 patients. Battery failure resulting in device replacement was reported in 2% (4/221) of patients in the case series of 221 patients (timing unclear). Lead erosion (leading to a revision procedure) was reported in less than 1% (2/233) of patients in a case series of 266 patients. Treatment failure was reported in 26% (19/72) of patients treated by gastroelectrical stimulation in a case series of 103 patients. Reasons included 'failure to respond' (14 patients), device malfunction (1 patient) and damage to the device (1 patient). The device was removed in 1 patient. Thirteen patients whose symptoms failed to respond were treated by gastrectomy. The specialist advisers listed anecdotal events as pain at the site of insertion of the subcutaneous stimulation device, and 'pins and needles' sensation from the stimulation device.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. It updates and replaces NICE interventional procedure guidance 103. We have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0531-7	{'Recommendations': 'This document replaces previous guidance on gastroelectrical stimulation (interventional procedure guidance 103).\n\nCurrent evidence on the efficacy and safety of gastric electrical stimulation for gastroparesis is adequate to support the use of this procedure with normal arrangements for clinical governance, consent and audit.\n\nDuring the consent process, clinicians should inform patients considering gastric electrical stimulation for gastroparesis that some patients do not get any benefit from it. They should also give patients detailed written information about the risk of complications, which can be serious, including the need to remove the device.\n\nPatient selection and follow-up should be done in specialist gastroenterology units with expertise in gastrointestinal motility disorders, and the procedure should only be performed by surgeons working in these units.\n\nFurther publications providing data about the effects of the procedure on symptoms in the long term and on device durability would be useful.', 'Indications and current treatments': 'Gastroparesis is a chronic disorder in which the stomach empties more slowly than normal (delayed gastric emptying) in the absence of any type of mechanical obstruction. The most common symptoms are nausea and protracted vomiting. Other symptoms include abdominal bloating, and, in severe cases, malnutrition.\n\nGastroparesis most commonly occurs in people with type\xa01 diabetes. It can also occur in other situations such as after abdominal surgery or in association with anorexia nervosa and abdominal migraine. Some cases are idiopathic. Conservative treatment options include modification of dietary intake and medical therapy with antiemetics or prokinetics. Treatment options for chronic intractable (drug-refractory) symptoms include jejunostomy tube insertion for feeding, gastrostomy tube insertion for stomach decompression, and pyloroplasty.\n\nGastroelectrical stimulation is an option for treating chronic, intractable nausea and vomiting secondary to gastroparesis.', 'The procedure': 'Electrical stimulation is delivered via an implanted system that consists of a neurostimulator and 2 leads. Implantation is done with the patient under general anaesthesia by an open or laparoscopic approach. The stimulating electrode of each intramuscular lead is fixed to the muscle of the distal part of the stomach. The connector end of each lead is then attached to the neurostimulator, which is placed in a pocket in the abdominal wall. When the neurostimulator is turned on, electrical impulses are delivered. The rate and amplitude of stimulation can be adjusted wirelessly with a hand-held external programmer. Patients may need to return to hospital for adjustment or reprogramming of the device, to optimise the effect on gastric emptying.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA meta-analysis of 4 studies including\xa0169 patients with diabetic gastroparesis treated by gastroelectrical stimulation (part of a systematic review of 601\xa0patients) reported improvement in total symptom severity score (weighted mean difference\xa08.96 [95% confidence interval {CI} 6.1 to 11.8]; p<0.00001; I2=68.6%). A meta-analysis of 3\xa0studies including 58\xa0patients with idiopathic gastroparesis treated by gastroelectrical stimulation reported improvement in total symptom severity score (weighted mean difference\xa07.5 [95%\xa0CI 5.4 to 9.7]; p<0.00001; I2=52.9%). A meta-analysis of 2\xa0studies including 33\xa0patients with post-surgical gastroparesis treated by gastroelectrical stimulation reported improvement in total symptom severity score (weighted mean difference\xa08.3 [95%\xa0CI 5.5 to 11.1]; p<0.00001; I2=0%). Length of follow-up was unclear in all the analyses.\n\nA meta-analysis of 7\xa0studies including 378\xa0patients with diabetic, idiopathic or post-surgical gastroparesis treated by gastroelectrical stimulation (part of a systematic review of 601\xa0patients) reported a statistically significant improvement in gastric emptying at 4\xa0hours (assessed using standardised radionucleotide scans of a solid meal: weighted mean difference\xa013.0 [95%\xa0CI 7.4 to 18.6]; p<0.00001; I2=87.4%). Subgroup analysis showed that the improvement was statistically significant in patients with diabetic or idiopathic gastroparesis but not in patients with post-surgical gastroparesis. Length of follow-up was unclear in all the analyses.\n\nIn a systematic review of 364\xa0patients, a meta-analysis of 4\xa0studies including 75\xa0patients with gastroparesis treated by gastroelectrical stimulation reported no statistically significant change in weight (weighted mean difference\xa03.7 [95% CI −0.2 to 7.6]; I2=0%). Length of follow-up was not reported but 12-month outcomes were preferred.\n\nIn the systematic review of 364\xa0patients, a meta-analysis of 8\xa0studies including 184\xa0patients with gastroparesis treated by gastroelectrical stimulation reported a reduction in need for nutritional support from 44% (96/216) of patients at baseline to 11% (21/184) at follow-up (odds ratio\xa05.5 [95%\xa0CI 2.8 to 11.1]; p<0.00001; I2=27%). Length of follow-up was not reported but 12-month outcomes were preferred.\n\nA randomised controlled trial (RCT) of 32\xa0patients with gastroparesis of idiopathic origin reported that there was a significant reduction in weekly vomiting frequency from 61\xa0to 87% (p<0.001) and improvements in gastroparesis symptoms, gastric emptying and days of hospitalisation (all p<0.05) at 1-year follow-up.\n\nThe systematic review of 364\xa0patients reported a significant improvement in Short Form-36 physical component score (weighted mean difference\xa08.1 [95%\xa0CI 5.0 to 11.1]) and the mental component score (weighted mean difference\xa08.16 [95%\xa0CI 4.9 to 11.5]), based on meta-analyses of 4 studies with 78\xa0patients. The difference was statistically significant (p<0.00001) for both outcomes with no heterogeneity. Length of follow-up was not reported but 12-month outcomes were preferred.\n\nThe specialist advisers listed key efficacy outcomes as reduced symptoms, reduced need for nutritional support, improved nutritional status and reduced frequency of hospital admissions.', 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nDeath (within 30\xa0days) was reported in 3% (2/72) of patients treated by gastroelectrical stimulation, due to small bowel infarction and heart failure, and 3% (1/31) of patients treated by gastrectomy, due to myocardial infarction, in a comparative case series of 103\xa0patients.\n\nGastric perforation related to an episode of vomiting (2\xa0months after the procedure) was reported in 1\xa0patient in a case series of 17\xa0patients. The device was removed and the perforation was repaired.\n\nDevice removal was reported in 11% (24/221) of patients in a case series of 221\xa0patients (timing ranged from 1–43\xa0months after the procedure). Reasons were infection at the pulse generator or electrode sites (13\xa0patients), lack of symptom improvement (6\xa0patients), lead dislodgements (2\xa0patients), small bowel obstruction caused by wires (1\xa0patient), penetration of electrode into the lumen of the stomach (1\xa0patient) and 'associated with peptic ulcer disease' (1\xa0patient). No further details were reported. Erosion through the skin (6\xa0patients), device migration (1\xa0patient) and pain at implantation site (4\xa0patients) resulting in device removal or replacement (timing unclear) were reported in the systematic review of 364\xa0patients.\n\nBattery failure resulting in device replacement was reported in 2% (4/221) of patients in the case series of 221\xa0patients (timing unclear).\n\nLead erosion (leading to a revision procedure) was reported in less than 1% (2/233) of patients in a case series of 266\xa0patients.\n\nTreatment failure was reported in 26% (19/72) of patients treated by gastroelectrical stimulation in a case series of 103\xa0patients. Reasons included 'failure to respond' (14\xa0patients), device malfunction (1\xa0patient) and damage to the device (1\xa0patient). The device was removed in 1\xa0patient. Thirteen patients whose symptoms failed to respond were treated by gastrectomy.\n\nThe specialist advisers listed anecdotal events as pain at the site of insertion of the subcutaneous stimulation device, and 'pins and needles' sensation from the stimulation device.", 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 103.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0531-7'}	https://www.nice.org.uk/guidance/ipg489
b0c4ee53a8cabab2e0f13ae87b55a83e7b5032fa	nice	Endoscopic thoracic sympathectomy for primary hyperhidrosis of the upper limb	Endoscopic thoracic sympathectomy for primary hyperhidrosis of the upper limb # Recommendations Current evidence on the efficacy and safety of endoscopic thoracic sympathectomy (ETS) for primary hyperhidrosis of the upper limb is adequate to support the use of this procedure with normal arrangements for clinical governance, consent and audit. Clinicians wishing to undertake ETS for primary hyperhidrosis of the upper limb should ensure that patients understand the risks of the procedure. In particular they must explain that: there is a risk of serious complications hyperhidrosis elsewhere on the body is usual after the procedure: this can be severe and distressing and some patients regret having had the procedure (especially because of subsequent and persistent hyperhidrosis elsewhere) the procedure sometimes does not reduce upper limb hyperhidrosis.Clinicians should also provide patients considering the procedure with clear written information. In view of the risk of side effects this procedure should only be considered in patients suffering from severe and debilitating primary hyperhidrosis that has been refractory to other treatments. This procedure should only be undertaken by clinicians trained and experienced in thoracic endoscopy, and there should be the capacity to deal with intraoperative complications. Further research into ETS for primary hyperhidrosis of the upper limb should include clear information on patient selection and should seek to identify which patient characteristics might predict severe side effects. All complications should be reported. Outcomes should include measurements of efficacy, including quality of life and social functioning both in the short and long term and in particular the frequency and severity of compensatory hyperhidrosis.# Indications and current treatments Primary hyperhidrosis of the upper limb is characterised by excessive sweating of the palms and/or axillae. It typically begins during childhood or adolescence, but can occur at any age and is usually life-long. In a few people, symptoms can spontaneously improve over time. Excessive sweating can have a profound effect on quality of life, interfering with daily activities and causing anxiety and embarrassment. First-line management of primary hyperhidrosis includes lifestyle measures such as avoiding known triggers and tight clothing, and using antiperspirants (including aluminium chloride hexahydrate). Other treatments include iontophoresis and botulinum-toxin A injection, and oral medications such as anticholinergics, antimuscarinics, beta-blockers, antihypertensives and anxiolytics. If these do not work, surgical options include local sweat-gland excision by subcutaneous curettage or tumescent liposuction, or sympathectomy. Sympathectomy can be done either by open or endoscopic approaches: endoscopic sympathectomy is now usually the preferred technique because it is associated with less pain, improved cosmesis and more rapid recovery than open sympathectomy.# The procedure The aim of endoscopic thoracic sympathectomy (ETS) for primary hyperhidrosis of the upper limb is to relieve primary hyperhidrosis from the palms and axillae permanently by dividing the sympathetic nerves that lie along the sympathetic chain beside the vertebral column. ETS is usually done with the patient under general anaesthesia. Small incisions are made in the axilla and an endoscope is inserted. The lung is partially collapsed. The sympathetic chain is visualised and the chosen part of the chain is divided by electrocautery or endoscopic scissors, or surgical clips may be applied. The extent of division varies but usually involves the part of the sympathetic chain over the second or third ribs, or both. Gas is removed from the pleural space, allowing the lung to re-expand, and the wounds are closed. The procedure is then usually repeated on the other side.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A non-randomised comparative study of 154 patients with palmar hyperhidrosis treated by endoscopic thoracic sympathectomy (ETS) or botulinum-toxin A injection reported statistically significant improvements in both groups at 6‑ and 12‑month follow-up, assessed objectively using an iodine starch test and pad glove test (p<0.05). The improvement was significantly higher in the ETS group than the botulinum-toxin A injection group (94% and 30% change on the iodine starch test respectively, p=0.01). A case series of 1700 patients (1052 patients with hyperhidrosis, 536 patients with facial blushing and 112 patients with combinations of blushing and hyperhidrosis) reported that 85% of patients had a 'satisfactory and lasting effect' from the procedure at a mean follow-up of 15 years (absolute number not reported). A case series of 406 patients with palmar and/or axillary hyperhidrosis reported that 91% (n=239) of patients treated by conventional ETS had dry limbs at a mean follow-up of 17 years. The non-randomised comparative study of 154 patients reported a statistically significant higher mean satisfaction score for ETS compared with botulinum-toxin A injection at 12‑month follow-up (4.52 and 3.12, respectively , p=0.001). The case series of 1700 patients reported satisfaction rates of 87% and 67% for palmar and axillary hyperhidrosis respectively (p<0.001). Overall, 75% of patients stated that the procedure had improved their quality of life (absolute numbers not reported). A case series of 2000 patients reported recurrence rates of 0% and 4% for palmar and axillary hyperhidrosis respectively at 1‑year follow-up and 1% and 17% respectively at 5‑year follow-up. A case series of 9988 patients with palmar hyperhidrosis reported that 'almost all' patients obtained satisfactory relief immediately after ETS; recurrence rates were about 1% at 1‑year follow-up and less than 3% at 3‑year follow-up (absolute numbers not reported). The case series of 453 patients with palmar, axillary or facial hyperhidrosis reported that 91% (412/453) had better quality of life 30 days after ETS and 90% (409/453) had better quality of life 5 years after ETS. All patients had poor or very poor quality of life before treatment. The specialist advisers stated that key efficacy outcomes were reduction in hyperhidrosis and patient satisfaction.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A non-systematic review article reported that 5 patients died because of major intrathoracic bleeding after endoscopic thoracic sympathectomy (ETS) but the total number of patients treated by the procedure was not documented: in 2 patients a trocar lacerated the subclavian artery; in 1 patient an intercostal vein was damaged; the causes in the other 2 patients were not described. Intrathoracic venous bleeding of more than 300 ml was reported in 1 patient in a case series of 453 patients. Bleeding needing chest tube drainage was reported in 'about 0.1%' of patients in the case series of 9988 patients. An additional 4 deaths after ETS were reported in the non-systematic review article: 3 were due to problems related to anaesthetic technique, and 1 patient had an unexplained cerebral event 'some hours' after ETS. The total number of patients treated by the procedure was not documented. Compensatory hyperhidrosis was reported in 92% (416/453), 86% (1720/2000) and 74% (1265/1700) of patients in 3 case series. In 2 of these studies 33% (557/1700 and 150/453) of patients reported compensatory hyperhidrosis that was either 'severe' or 'incapacitating'. Studies reported a wide range in the proportion of patients reporting dissatisfaction with the procedure. The case series of 453 patients reported that 2% (7/453) of patients were dissatisfied with the results at 5‑year follow-up. These patients had severe compensatory hyperhidrosis and said that they regretted having ETS. The case series of 406 patients reported that 7% (n=17) of patients treated by conventional ETS were dissatisfied and regretted the operation at a mean follow-up of 17 years. The case series of 1700 patients with hyperhidrosis or facial blushing reported that 20% (absolute numbers not reported) of patients were dissatisfied or regretted having the procedure at a mean follow-up of 15 years. Pneumothorax requiring drainage was reported in 0.5% (10/2000) of patients and 1% (8/734) of procedures in the 2 case series of 2000 and 406 patients respectively. Pneumothorax or haemothorax that needed to be drained was reported in 'about 0.3%' of patients in a case series of 9988 patients. Chylothorax was reported in 3 patients included in the non-systematic review article, 2 of whom were described in more detail: 1 patient needed postoperative tube drainage and parenteral nutrition for 6 days and in 1 patient the leak was recognised at surgery and the thoracic duct clipped. Intraoperative cardiac arrest was reported in 2 case reports. Both patients recovered after cardiopulmonary resuscitation. Horner's syndrome was reported in less than 0.1%, 0.2% (1/453) and 2% of patients in the 3 case series of 9988, 453 and 406 patients respectively. No cases of Horner's syndrome were reported in the case series of 2000 patients. Other adverse events reported in case reports and in the non-systematic review included surgical emphysema, pleural effusion, bronchospasm, segmental collapse and atelectasis, wound infection, severe postoperative pain, brachial plexus injury, extensor pollicis longus paralysis, distal upper limb ischaemia, paraparesis, rhinitis, persistent bradycardia, heatstroke, and gustatory sweating. In addition to the above, the specialist advisers described conversion to open surgery because of lung adhesions as an anecdotal adverse event. Additional reported adverse events were cerebral oedema, pulmonary oedema, and pulmonary embolus.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0438-9	{'Recommendations': 'Current evidence on the efficacy and safety of endoscopic thoracic sympathectomy (ETS) for primary hyperhidrosis of the upper limb is adequate to support the use of this procedure with normal arrangements for clinical governance, consent and audit.\n\nClinicians wishing to undertake ETS for primary hyperhidrosis of the upper limb should ensure that patients understand the risks of the procedure. In particular they must explain that:\n\nthere is a risk of serious complications\n\nhyperhidrosis elsewhere on the body is usual after the procedure: this can be severe and distressing and some patients regret having had the procedure (especially because of subsequent and persistent hyperhidrosis elsewhere)\n\nthe procedure sometimes does not reduce upper limb hyperhidrosis.Clinicians should also provide patients considering the procedure with clear written information.\n\nIn view of the risk of side effects this procedure should only be considered in patients suffering from severe and debilitating primary hyperhidrosis that has been refractory to other treatments.\n\nThis procedure should only be undertaken by clinicians trained and experienced in thoracic endoscopy, and there should be the capacity to deal with intraoperative complications.\n\nFurther research into ETS for primary hyperhidrosis of the upper limb should include clear information on patient selection and should seek to identify which patient characteristics might predict severe side effects. All complications should be reported. Outcomes should include measurements of efficacy, including quality of life and social functioning both in the short and long term and in particular the frequency and severity of compensatory hyperhidrosis.', 'Indications and current treatments': 'Primary hyperhidrosis of the upper limb is characterised by excessive sweating of the palms and/or axillae. It typically begins during childhood or adolescence, but can occur at any age and is usually life-long. In a few people, symptoms can spontaneously improve over time. Excessive sweating can have a profound effect on quality of life, interfering with daily activities and causing anxiety and embarrassment.\n\nFirst-line management of primary hyperhidrosis includes lifestyle measures such as avoiding known triggers and tight clothing, and using antiperspirants (including aluminium chloride hexahydrate). Other treatments include iontophoresis and botulinum-toxin\xa0A injection, and oral medications such as anticholinergics, antimuscarinics, beta-blockers, antihypertensives and anxiolytics. If these do not work, surgical options include local sweat-gland excision by subcutaneous curettage or tumescent liposuction, or sympathectomy. Sympathectomy can be done either by open or endoscopic approaches: endoscopic sympathectomy is now usually the preferred technique because it is associated with less pain, improved cosmesis and more rapid recovery than open sympathectomy.', 'The procedure': 'The aim of endoscopic thoracic sympathectomy (ETS) for primary hyperhidrosis of the upper limb is to relieve primary hyperhidrosis from the palms and axillae permanently by dividing the sympathetic nerves that lie along the sympathetic chain beside the vertebral column.\n\nETS is usually done with the patient under general anaesthesia. Small incisions are made in the axilla and an endoscope is inserted. The lung is partially collapsed. The sympathetic chain is visualised and the chosen part of the chain is divided by electrocautery or endoscopic scissors, or surgical clips may be applied. The extent of division varies but usually involves the part of the sympathetic chain over the second or third ribs, or both. Gas is removed from the pleural space, allowing the lung to re-expand, and the wounds are closed. The procedure is then usually repeated on the other side.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA non-randomised comparative study of 154 patients with palmar hyperhidrosis treated by endoscopic thoracic sympathectomy (ETS) or botulinum-toxin\xa0A injection reported statistically significant improvements in both groups at 6‑ and 12‑month follow-up, assessed objectively using an iodine starch test and pad glove test (p<0.05). The improvement was significantly higher in the ETS group than the botulinum-toxin A injection group (94% and 30% change on the iodine starch test respectively, p=0.01).\n\nA case series of 1700 patients (1052 [62%] patients with hyperhidrosis, 536 [32%] patients with facial blushing and 112 [7%] patients with combinations of blushing and hyperhidrosis) reported that 85% of patients had a 'satisfactory and lasting effect' from the procedure at a mean follow-up of 15\xa0years (absolute number not reported). A case series of 406 patients with palmar and/or axillary hyperhidrosis reported that 91% (n=239) of patients treated by conventional ETS had dry limbs at a mean follow-up of 17\xa0years.\n\nThe non-randomised comparative study of 154 patients reported a statistically significant higher mean satisfaction score for ETS compared with botulinum-toxin A injection at 12‑month follow-up (4.52 and 3.12, respectively [score range 1 to 5 with 1 being very poor and 5 being excellent], p=0.001). The case series of 1700\xa0patients reported satisfaction rates of 87% and 67% for palmar and axillary hyperhidrosis respectively (p<0.001). Overall, 75% of patients stated that the procedure had improved their quality of life (absolute numbers not reported).\n\nA case series of 2000\xa0patients reported recurrence rates of 0% and 4% for palmar and axillary hyperhidrosis respectively at 1‑year follow-up and 1% and 17% respectively at 5‑year follow-up. A case series of 9988 patients with palmar hyperhidrosis reported that 'almost all' patients obtained satisfactory relief immediately after ETS; recurrence rates were about 1% at 1‑year follow-up and less than 3% at 3‑year follow-up (absolute numbers not reported).\n\nThe case series of 453\xa0patients with palmar, axillary or facial hyperhidrosis reported that 91% (412/453) had better quality of life 30\xa0days after ETS and 90% (409/453) had better quality of life 5\xa0years after ETS. All patients had poor or very poor quality of life before treatment.\n\nThe specialist advisers stated that key efficacy outcomes were reduction in hyperhidrosis and patient satisfaction.", 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA non-systematic review article reported that 5 patients died because of major intrathoracic bleeding after endoscopic thoracic sympathectomy (ETS) but the total number of patients treated by the procedure was not documented: in 2 patients a trocar lacerated the subclavian artery; in 1 patient an intercostal vein was damaged; the causes in the other 2 patients were not described. Intrathoracic venous bleeding of more than 300\xa0ml was reported in 1 patient in a case series of 453 patients. Bleeding needing chest tube drainage was reported in 'about 0.1%' of patients in the case series of 9988 patients.\n\nAn additional 4 deaths after ETS were reported in the non-systematic review article: 3 were due to problems related to anaesthetic technique, and 1 patient had an unexplained cerebral event 'some hours' after ETS. The total number of patients treated by the procedure was not documented.\n\nCompensatory hyperhidrosis was reported in 92% (416/453), 86% (1720/2000) and 74% (1265/1700) of patients in 3 case series. In 2 of these studies 33% (557/1700 and 150/453) of patients reported compensatory hyperhidrosis that was either 'severe' or 'incapacitating'.\n\nStudies reported a wide range in the proportion of patients reporting dissatisfaction with the procedure. The case series of 453 patients reported that 2% (7/453) of patients were dissatisfied with the results at 5‑year follow-up. These patients had severe compensatory hyperhidrosis and said that they regretted having ETS. The case series of 406 patients reported that 7% (n=17) of patients treated by conventional ETS were dissatisfied and regretted the operation at a mean follow-up of 17\xa0years. The case series of 1700 patients with hyperhidrosis or facial blushing reported that 20% (absolute numbers not reported) of patients were dissatisfied or regretted having the procedure at a mean follow-up of 15\xa0years.\n\nPneumothorax requiring drainage was reported in 0.5% (10/2000) of patients and 1% (8/734) of procedures in the 2 case series of 2000 and 406 patients respectively. Pneumothorax or haemothorax that needed to be drained was reported in 'about 0.3%' of patients in a case series of 9988 patients. Chylothorax was reported in 3 patients included in the non-systematic review article, 2 of whom were described in more detail: 1 patient needed postoperative tube drainage and parenteral nutrition for 6\xa0days and in 1 patient the leak was recognised at surgery and the thoracic duct clipped.\n\nIntraoperative cardiac arrest was reported in 2 case reports. Both patients recovered after cardiopulmonary resuscitation.\n\nHorner's syndrome was reported in less than 0.1%, 0.2% (1/453) and 2% of patients in the 3 case series of 9988, 453 and 406\xa0patients respectively. No cases of Horner's syndrome were reported in the case series of 2000 patients.\n\nOther adverse events reported in case reports and in the non-systematic review included surgical emphysema, pleural effusion, bronchospasm, segmental collapse and atelectasis, wound infection, severe postoperative pain, brachial plexus injury, extensor pollicis longus paralysis, distal upper limb ischaemia, paraparesis, rhinitis, persistent bradycardia, heatstroke, and gustatory sweating.\n\nIn addition to the above, the specialist advisers described conversion to open surgery because of lung adhesions as an anecdotal adverse event. Additional reported adverse events were cerebral oedema, pulmonary oedema, and pulmonary embolus.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0438-9'}	https://www.nice.org.uk/guidance/ipg487
ece1e06f5b1b5426c8d0cfc87749242a9a70c62f	nice	Arthroscopic radiofrequency chondroplasty for discrete chondral defects of the knee	Arthroscopic radiofrequency chondroplasty for discrete chondral defects of the knee # Recommendations Evidence on the efficacy of arthroscopic radiofrequency chondroplasty for discrete chondral defects of the knee is limited but shows benefit in the short term, and there are no major safety concerns. Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit. The procedure should only be carried out by clinicians with specific training in the use of arthroscopic radiofrequency ablation and with particular attention to the avoidance of thermal injury. Further research into arthroscopic radiofrequency chondroplasty of the knee should clearly document patient selection and the types of chondral defects being treated. More evidence on long-term outcomes would be useful.# Indications and current treatments Discrete chondral defects in articular cartilage usually occur as a result of trauma. The rough, irregular edges of a defect may cause inflammation, swelling, pain and difficulty walking. Progressive degeneration of a chondral defect can expose the underlying bone and lead to arthritis. If pieces of cartilage break off from the edges of a chondral defect this may cause cartilage damage elsewhere in the knee and lead to further arthritic changes. Treatment options depend on the size and site of the chondral defect. The condition is usually chronic and different treatment strategies may be needed at different stages. Conservative treatment includes analgesics to relieve pain and inflammation. Physiotherapy and/or prescribed exercise may be used to improve knee function and mobility.# The procedure Radiofrequency chondroplasty aims to slow the progression of discrete chondral defects by removing the unstable edges of the defect, producing a smooth, stable articular cartilage surface. The procedure is usually done with the patient under general anaesthesia. An arthroscope is inserted into the knee and large chondral defects are trimmed from the weight-bearing surfaces of the femoral condyles, using instruments such as a blunt hook or an electric shaver. Under arthroscopic guidance, a radiofrequency probe is then used to smooth the edge of the chondral defect using irrigation to stabilise temperature and flush any debris. The aim is to improve mechanical stability and prevent further cartilage damage.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A randomised controlled trial of 60 patients treated by bipolar radiofrequency energy (n=30) or by mechanical shaver debridement (n=30) reported that patients in the bipolar radiofrequency energy group returned to work sooner than patients in the mechanical shaver debridement group (16.4±6.5 days compared with 21.7±6.1 days, p=0.002). In the randomised controlled trial of 60 patients treated by bipolar radiofrequency energy or mechanical shaver debridement, non‑steroidal anti‑inflammatory drugs were taken by 2% of patients in the bipolar radiofrequency energy group and 23% of patients in the mechanical shaver debridement group at 1‑year follow-up (p=0.026). In the randomised controlled trial of 60 patients treated by bipolar radiofrequency energy or mechanical shaver debridement, mean Knee injury and Osteoarthritis Outcome Score (KOOS) for pain, symptoms, activities of daily living, sports and quality of life (higher scores indicating better outcomes) were 81.2, 80.8, 81.5, 81.7 and 80.2 respectively in the bipolar radiofrequency energy group and 57.9, 58.3, 58.8, 57.3 and 56.2 respectively in the mechanical shaver debridement group at 1‑year follow-up (p<0.001 for all inter‑group comparisons). At 4‑year follow-up, patients in the radiofrequency group continued to report significantly higher scores than patients in the mechanical shaver debridement group. Mean KOOS scores for pain, symptoms, activities of daily living, sports and quality of life were 75.1, 72.7, 69.9, 75.0 and 67.0 respectively in the radiofrequency group (n=25) and 55.7, 53.1, 50.9, 56.7 and 52.9 respectively in the mechanical shaver debridement group (n=15) (p<0.001 for all inter-group comparisons). In a prospective case series of 15 patients (25 knees) treated by bipolar radiofrequency energy, the mean size of chondral defects decreased from 170.2 mm2 (range 9–625 mm2) at initial arthroscopy to 107.7 mm2 (range 0–300 mm2) at follow-up arthroscopy after a mean of 10.4 months: 32% (8/25) of defects showed no progression of degeneration; 32% (8/25) showed partial healing; and 24% (6/25) had healed completely. Twelve per cent (3/25) of defects showed unstable borders with progressive damage to the surrounding cartilage. A randomised controlled trial of 60 patients treated by monopolar radiofrequency energy plus mechanical shaver debridement (n=30) or by mechanical shaver debridement only (n=30) reported that mean International Knee Documentation Committee (IKDC) scores improved from 36 to 69 (p<0.05) and from 35 to 68 (p<0.05) respectively at a mean follow-up of 19 months (higher scores indicating better outcomes). No statistically significant differences in postoperative scores were observed between groups. The specialist advisers stated that key efficacy outcomes include MRI findings and functional scores such as the Tegner, IKDC and Lysholm scores.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A second-degree burn after radiofrequency chondroplasty was reported in the US Food and Drug Administration's (FDA) manufacturer and user facility device experience (MAUDE) database. This was attributed to improper use of the radiofrequency equipment: a suction line, which should have been attached to the probe during the procedure, had not been attached. Osteonecrosis of the medial femoral condyle was observed in 4% (2/50) of patients at a follow-up assessment that occurred at least 6 months after treatment, in a prospective case series of 50 patients. No clinical consequences were reported as a result of this. The confirmed or presumed detachment of a mechanical component of the radiofrequency probe within a patient's knee was reported on 7 occasions between 2002 and 2012 in the MAUDE database. The specialist advisers stated that theoretical adverse events include excessive debridement of articular cartilage, avascular necrosis of the underlying bone, chondrocyte death and damage to surrounding cartilage and other structures.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0615-4	{'Recommendations': 'Evidence on the efficacy of arthroscopic radiofrequency chondroplasty for discrete chondral defects of the knee is limited but shows benefit in the short term, and there are no major safety concerns. Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit.\n\nThe procedure should only be carried out by clinicians with specific training in the use of arthroscopic radiofrequency ablation and with particular attention to the avoidance of thermal injury.\n\nFurther research into arthroscopic radiofrequency chondroplasty of the knee should clearly document patient selection and the types of chondral defects being treated. More evidence on long-term outcomes would be useful.', 'Indications and current treatments': 'Discrete chondral defects in articular cartilage usually occur as a result of trauma. The rough, irregular edges of a defect may cause inflammation, swelling, pain and difficulty walking. Progressive degeneration of a chondral defect can expose the underlying bone and lead to arthritis. If pieces of cartilage break off from the edges of a chondral defect this may cause cartilage damage elsewhere in the knee and lead to further arthritic changes.\n\nTreatment options depend on the size and site of the chondral defect. The condition is usually chronic and different treatment strategies may be needed at different stages. Conservative treatment includes analgesics to relieve pain and inflammation. Physiotherapy and/or prescribed exercise may be used to improve knee function and mobility.', 'The procedure': 'Radiofrequency chondroplasty aims to slow the progression of discrete chondral defects by removing the unstable edges of the defect, producing a smooth, stable articular cartilage surface.\n\nThe procedure is usually done with the patient under general anaesthesia. An arthroscope is inserted into the knee and large chondral defects are trimmed from the weight-bearing surfaces of the femoral condyles, using instruments such as a blunt hook or an electric shaver. Under arthroscopic guidance, a radiofrequency probe is then used to smooth the edge of the chondral defect using irrigation to stabilise temperature and flush any debris. The aim is to improve mechanical stability and prevent further cartilage damage.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA randomised controlled trial of 60\xa0patients treated by bipolar radiofrequency energy (n=30) or by mechanical shaver debridement (n=30) reported that patients in the bipolar radiofrequency energy group returned to work sooner than patients in the mechanical shaver debridement group (16.4±6.5\xa0days compared with 21.7±6.1\xa0days, p=0.002).\n\nIn the randomised controlled trial of 60\xa0patients treated by bipolar radiofrequency energy or mechanical shaver debridement, non‑steroidal anti‑inflammatory drugs were taken by 2% of patients in the bipolar radiofrequency energy group and 23% of patients in the mechanical shaver debridement group at 1‑year follow-up (p=0.026).\n\nIn the randomised controlled trial of 60\xa0patients treated by bipolar radiofrequency energy or mechanical shaver debridement, mean Knee injury and Osteoarthritis Outcome Score (KOOS) for pain, symptoms, activities of daily living, sports and quality of life (higher scores indicating better outcomes) were 81.2, 80.8, 81.5, 81.7 and 80.2 respectively in the bipolar radiofrequency energy group and 57.9, 58.3, 58.8, 57.3 and 56.2 respectively in the mechanical shaver debridement group at 1‑year follow-up (p<0.001 for all inter‑group comparisons). At 4‑year follow-up, patients in the radiofrequency group continued to report significantly higher scores than patients in the mechanical shaver debridement group. Mean KOOS scores for pain, symptoms, activities of daily living, sports and quality of life were 75.1, 72.7, 69.9, 75.0 and 67.0 respectively in the radiofrequency group (n=25) and 55.7, 53.1, 50.9, 56.7 and 52.9 respectively in the mechanical shaver debridement group (n=15) (p<0.001 for all inter-group comparisons).\n\nIn a prospective case series of 15\xa0patients (25\xa0knees) treated by bipolar radiofrequency energy, the mean size of chondral defects decreased from 170.2\xa0mm2 (range 9–625\xa0mm2) at initial arthroscopy to 107.7\xa0mm2 (range 0–300\xa0mm2) at follow-up arthroscopy after a mean of 10.4\xa0months: 32% (8/25) of defects showed no progression of degeneration; 32% (8/25) showed partial healing; and 24% (6/25) had healed completely. Twelve per cent (3/25) of defects showed unstable borders with progressive damage to the surrounding cartilage.\n\nA randomised controlled trial of 60\xa0patients treated by monopolar radiofrequency energy plus mechanical shaver debridement (n=30) or by mechanical shaver debridement only (n=30) reported that mean International Knee Documentation Committee (IKDC) scores improved from 36 to 69 (p<0.05) and from 35 to 68 (p<0.05) respectively at a mean follow-up of 19\xa0months (higher scores indicating better outcomes). No statistically significant differences in postoperative scores were observed between groups.\n\nThe specialist advisers stated that key efficacy outcomes include MRI findings and functional scores such as the Tegner, IKDC and Lysholm scores.', 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA second-degree burn after radiofrequency chondroplasty was reported in the US Food and Drug Administration's (FDA) manufacturer and user facility device experience (MAUDE) database. This was attributed to improper use of the radiofrequency equipment: a suction line, which should have been attached to the probe during the procedure, had not been attached.\n\nOsteonecrosis of the medial femoral condyle was observed in 4% (2/50) of patients at a follow-up assessment that occurred at least 6\xa0months after treatment, in a prospective case series of 50\xa0patients. No clinical consequences were reported as a result of this.\n\nThe confirmed or presumed detachment of a mechanical component of the radiofrequency probe within a patient's knee was reported on 7 occasions between 2002 and 2012 in the MAUDE database.\n\nThe specialist advisers stated that theoretical adverse events include excessive debridement of articular cartilage, avascular necrosis of the underlying bone, chondrocyte death and damage to surrounding cartilage and other structures.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0615-4'}	https://www.nice.org.uk/guidance/ipg493
4e666e83e43d12cb0c262848b4842593a3da7944	nice	Afatinib for treating epidermal growth factor receptor mutation-positive locally advanced or metastatic non-small-cell lung cancer	Afatinib for treating epidermal growth factor receptor mutation-positive locally advanced or metastatic non-small-cell lung cancer Evidence-based recommendations on afatinib (Giotrif) for treating EGFR-positive locally advanced or metastatic non-small-cell lung cancer in adults. # Guidance Afatinib is recommended as an option, within its marketing authorisation, for treating adults with locally advanced or metastatic non-small-cell lung cancer only if: the tumour tests positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and the person has not previously had an EGFR-TK inhibitor and the manufacturer provides afatinib with the discount agreed in the patient access scheme.# The technology Afatinib (Giotrif, Boehringer Ingelheim) is an irreversible tyrosine kinase inhibitor (TKI) that blocks the epidermal growth factor receptor (EGFR) ErbB1 and other members of the ErbB family. The ErbB family is involved in the growth, migration and metabolism of tumour cells. Afatinib has a marketing authorisation as a monotherapy 'for the treatment of EGFR TKI-naive adult patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with activating EGFR mutation(s)'. The summary of product characteristics lists the following very common adverse reactions for afatinib: diarrhoea, rash/acne, blistering and dry skin conditions, pruritus, decreased appetite, nose bleed, stomatitis (inflammation in the mouth) and paronychia (nail infection). For full details of adverse reactions and contraindications, see the summary of product characteristics. Afatinib is given orally at a recommended dosage of 40 mg once daily. The dosage may be increased to a maximum of 50 mg/day in the first 3 weeks in patients who are able to tolerate 40 mg/day without adverse reactions of greater than grade 1 severity. For patients who have more severe adverse reactions, the dose may be reduced (usually by 10 mg decrements) or treatment interrupted or discontinued. For full details see the summary of product characteristics. The NHS list price, provided by the manufacturer, is £2023.28 per pack of 28 tablets (20 mg, 30 mg, 40 mg or 50 mg). The manufacturer stated that the NHS list price per course of treatment is expected to be around £22,000 per patient, based on a progression-free survival of 11 months. The manufacturer of afatinib has agreed a patient access scheme with the Department of Health in which a confidential discount is applied at the point of purchase or invoice. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission The Appraisal Committee (section 7) considered evidence submitted by the manufacturer of afatinib and a review of this submission by the Evidence Review Group (ERG, section 8). The clinical effectiveness data presented by the manufacturer were predominantly from 2 phase III open-label randomised controlled clinical trials. LUX-Lung 3 compared afatinib with cisplatin plus pemetrexed and LUX-Lung 6 compared afatinib with cisplatin plus gemcitabine. There was also a mixed treatment comparison that compared afatinib with erlotinib and gefitinib. LUX-Lung 3 was an international trial (ethnicity: 26% white, 72% Eastern Asian, 2.0% other) that compared afatinib (40 mg daily, n=230) with cisplatin plus pemetrexed (n=115) for patients with EGFR mutation-positive NSCLC. LUX-Lung 6 was conducted in China, Thailand and South Korea and compared afatinib (40 mg daily, n=242) with cisplatin plus gemcitabine (n=122) for patients with EGFR mutation-positive NSCLC. In both trials patients were included who had received no prior treatment with chemotherapy or EGFR-targeting drugs and adenocarcinoma was the predominant histology. The primary outcome of the clinical trials was progression-free survival, as assessed by central independent review by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). Secondary outcomes included objective response rate and overall survival. In LUX-Lung 3, there was a statistically significant increase in median progression-free survival for afatinib compared with cisplatin plus pemetrexed combination chemotherapy (11.14 months compared with 6.90 months; a gain of 4.24 months) with a hazard ratio of 0.58 (95% confidence interval 0.43 to 0.78) when assessed by independent review. When the outcome was assessed by the trial investigator, there was a statistically significant increase in median progression-free survival for afatinib compared with combination chemotherapy (11.07 months compared with 6.70 months; a gain of 4.37 months) with a hazard ratio of 0.49 (95% CI 0.37 to 0.65). In LUX-Lung 6, there was a statistically significant increase in median progression-free survival for afatinib compared with cisplatin plus gemcitabine combination chemotherapy (11.01 months compared with 5.59 months; a gain of 5.42 months) with a hazard ratio of 0.28 (95% CI 0.20 to 0.39) when assessed by independent review. When the outcome was assessed by the trial investigator, there was a statistically significant increase in median progression-free survival for afatinib compared with combination chemotherapy (13.73 months compared with 5.55 months; a gain of 8.18 months) with a hazard ratio of 0.26 (95% CI 0.19 to 0.36). In LUX-Lung 3, overall survival data were not mature by the cut-off date (February 2012) for the primary analysis because 67 patients (29.1%) in the afatinib arm and 31 patients (27.0%) in the chemotherapy arm had died. The manufacturer presented the results of the updated analysis (using additional data after the February 2012 cut-off) and the results of an updated analysis submitted to the European Medicines Agency using data up to January 2013). The manufacturer stated that final analysis of overall survival will be performed when 209 patients have died. No statistically significant difference in overall survival was seen in LUX-Lung 3 or LUX-Lung 6 between afatinib and chemotherapy with hazard ratios of 1.12 (95% CI 0.73 to 1.72) and 0.95 (95% CI 0.68 to 1.33) respectively. Treatment crossover occurred in both LUX-Lung 3 (72%) and LUX-Lung 6 (80%) with most patients receiving at least 1 line of subsequent anticancer therapy after stopping the study drugs. Crossover was not accounted for when estimating overall survival. The manufacturer conducted subgroup analyses of LUX-Lung 3 and LUX-Lung 6 for pre-specified baseline characteristics such as gender, age, family origin and common EGFR mutations, which was consistent with the analysis in the intention-to-treat populations. Health-related quality of life data from LUX-Lung 3 and LUX-Lung 6 were reported for the pre-specified NSCLC-related symptoms of cough, dyspnoea and pain, measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and QLQ-LC13 questionnaires. More than 87% of patients completed the questionnaires. Afatinib was associated with a statistically significant improvement in breathing, non-specific pain and chest pain, fatigue and the time to deterioration in cough, dyspnoea and pain compared with chemotherapy (cisplatin plus either pemetrexed or gemcitabine). EQ-5D (UK and Belgium) and EQ-VAS data collected during the LUX-Lung 3 clinical trial reported no statistically significant difference in values between afatinib and chemotherapy with an absolute improvement in utility of 0.008 (UK) and 0.007 (Belgium). Because there was no head-to-head randomised controlled trial comparing the effectiveness of afatinib with erlotinib or gefitinib for progression-free survival or overall survival, the manufacturer presented a mixed treatment comparison. This was based on a previous mixed treatment comparison conducted for NICE's technology appraisal guidance on gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NICE technology appraisal guidance 192), which was adapted to include data on the effectiveness of afatinib based on the LUX-Lung 3 and 6 studies and erlotinib.The studies used to populate the mixed treatment comparison were identified through systematic review. The manufacturer identified 20 randomised controlled trials, 4 of which included gefitinib (first SIGNAL trial, IPASS trial, Mitsudomi 2010, Maemondo 2010) and 1 that included erlotinib (EURTAC trial). The population of the studies included in the mixed treatment comparison was people with locally advanced or metastatic non-small cell lung cancer. However, only 7 of the trials were carried out exclusively in people with EGFR-positive disease. The manufacturer specified that the EURTAC trial was of average quality and the first SIGNAL trial only included 42 patients with EGFR-positive disease. All the trials included in the mixed treatment comparison permitted crossover after disease progression. A fixed-effects model was used to assess progression-free survival and a random-effects model was used to assess overall survival. There was no testing of the proportional hazards assumption. The results of the manufacturer's mixed treatment comparison showed that there was no statistically significant difference in progression-free survival or overall survival between afatinib and gefitinib or erlotinib. Afatinib had the highest probability (62.6%) of being the most effective treatment in terms of progression-free survival gain compared with all the comparator treatments including erlotinib (30.8%) and gefitinib (6.5%). Afatinib also had the highest probability (43%) of being the most effective treatment in terms of overall survival gain compared with all the comparator treatments including erlotinib (3%) and gefitinib (13%). The resulting hazard ratios from the mixed treatment comparison for the difference in median progression-free survival for afatinib were: (95% CI 0.25 to 0.52) compared with gemcitabine plus cisplatin (95% CI 0.32 to 0.66) compared with pemetrexed plus cisplatin (95% CI 0.47 to 1.20) compared with gefitinib (95% CI 0.53 to 1.50) compared with erlotinib. The resulting hazard ratios from the mixed treatment comparison for the difference in median overall survival for afatinib were (95% CI 0.67 to 1.10) compared with gemcitabine plus cisplatin (95% CI 0.78 to 1.27) compared with pemetrexed plus cisplatin (95% CI 0.55 to 1.30) compared with gefitinib (95% CI 0.56 to 1.14) compared with erlotinib. The manufacturer submitted evidence from the non-placebo controlled LUX-Lung 2 trial, a phase II multicentre trial conducted in the USA and Taiwan, which evaluated the safety and efficacy of afatinib in patients with locally advanced or metastatic EGFR-positive NSCLC. The patients in the study were predominantly Asian. This trial evaluated the effectiveness of afatinib in patients who had not previously received chemotherapy (n=61) and patients whose disease had progressed after 1 previous chemotherapy treatment (n=68). There were 2 study arms, afatinib 40 mg and afatinib 50 mg. The primary outcome of LUX-Lung 2 was progression-free survival, as assessed by central independent review by RECIST version 1.1. Secondary outcomes included objective response rate and median overall survival. In LUX-Lung 2, progression-free survival was shorter in patients who had received prior chemotherapy. The median progression-free survival was 11.9 months for patients who had not had chemotherapy before and 4.5 months for patients receiving the 40 mg dose of afatinib as a second-line treatment. LUX-Lung 2 reported shorter overall survival in patients who had prior chemotherapy compared with those who had not. The median overall survival was 23.1 months for patients who had not had chemotherapy and 14.6 months for patients receiving afatinib as a second-line treatment. LUX-Lung 3 reported higher rates of diarrhoea, rash/acne, stomatitis/mucositis and paronychia compared with chemotherapy but less nausea, fatigue, vomiting, anaemia, leukopenia and neutropenia. The manufacturer compared the adverse reactions from the pivotal clinical trials for afatinib (LUX-Lung 3), gefitinib (IPASS) and erlotinib (EURTAC), which showed that afatinib is associated with more diarrhoea (95%) than gefitinib (47%) and erlotinib (57%), more rash/acne (89%) than gefitinib (66%) and erlotinib (80%), more stomatitis/mucositis (72%) than gefitinib (17%), but less reduced appetite (21%) than erlotinib (53%) and less fatigue (18%) than erlotinib (47%). Dose reductions were higher with afatinib (57%, LUX-Lung 3) compared with gefitinib (16.1%, IPASS) or erlotinib (21%, EURTAC). The manufacturer presented a de novo disease-state cohort model consisting of 2 health states (progression-free and progressive disease) and death. The progression-free health state represented the period during which the patient's cancer did not worsen while receiving active treatment. The progressive disease health state represented the period that the cancer spread. The model allowed movement from the progression-free health state to the progressive-disease health state, or death state; or from the progressive-disease health state to the death state. The model had a lifetime horizon of 10 years and a cycle length of 1 month, with an NHS and personal social services perspective and 3.5% discounting for costs and health effects. The manufacturer's model used the partitioned survival method to determine the proportion of patients in each health state, for each model cycle. Data from LUX-Lung 3 and LUX-Lung 6 were used to estimate progression-free survival and overall survival for afatinib in the model, but parametric survival models based on hazard ratios produced from the mixed treatment comparison were used to project progression-free survival and overall survival over the 10-year model time horizon. The Weibull method was used to extrapolate the trial data in the base-case model to estimate progression-free survival and overall survival. Sensitivity analyses were conducted that used 2 further types of parametric survival modelling of the clinical trial Kaplan-Meier data: exponential and Gompertz. The progression-free survival and overall survival estimates for people treated with erlotinib and gefitinib were estimated by applying the mixed treatment comparison hazard ratios to the survival estimates for people treated with afatinib. Progression-free survival and overall survival were incorporated into the cost-effectiveness model by using full parametric approximation or by using Kaplan-Meier data from the clinical trials extrapolated using parametric survival models. Adverse reactions (diarrhoea, rash/acne, fatigue, anaemia and neutropenia) were applied in the model for the first year only, in both the progression-free and progressive disease health states. The type and frequency of adverse reactions was estimated from LUX-Lung 1 and LUX-Lung 3 for afatinib, and from the mixed treatment comparison for gefitinib and erlotinib. In the base-case model the utility value used in the progression-free health state was 0.78 (from LUX-Lung 3) and utility values from the literature were used for the progressive disease health state (0.73 and 0.46 for second- and third-line treatment respectively). Alternative utility values derived from the literature for the progression-free health state were used in a sensitivity analysis. Utility values did not change over time. To estimate the costs in the model, the manufacturer either used resource costs from the LUX-Lung 3 and 6 trials, or values from the literature. The resource costs associated with disease management (progression-free or progressed disease health states) and adverse reactions estimated from the LUX-Lung 3 and 6 trials included: -utpatient visits (GP, specialist, nurses, occupational therapist, physiotherapist) -utpatient interventions (CT scan, MRI scan, surgical procedure, ultrasound, X-ray, radiotherapy) unscheduled hospitalisations (unscheduled hospital stay, intensive care unit visit, emergency room visit) EGFR testing.All other values were taken from the literature. The model assumed that treatment with afatinib, erlotinib or gefitinib continues until disease progression. Disease progression is typically assessed every 3 months by CT scan, and this cost was incorporated into the model. Afatinib, gefitinib, and erlotinib each have patient access schemes agreed with the Department of Health, which were accounted for in the analyses. The deterministic pairwise results of the base-case analysis showed that afatinib was associated with an ICER of £10,076 per QALY gained (incremental costs £1723, incremental QALYs 0.171) compared with erlotinib and an ICER of £17,933 per QALY gained (incremental costs £3113, incremental QALYs 0.173) compared with gefitinib. The manufacturer stated that there was a 100% probability of afatinib being cost effective compared with erlotinib at £20,000 and £30,000 per QALY gained. Compared with gefitinib, there was a 72% and 81% probability of afatinib being cost effective at £20,000 and £30,000 per QALY gained respectively. The manufacturer conducted one-way sensitivity analyses of the pairwise comparisons with gefitinib and erlotinib. The main drivers of cost effectiveness were: the mixed treatment comparison-based hazard ratios for progression-free and overall survival, the cost per month for the progression-free health state and the cost per month for the best supportive care period of the progressive disease health state. Overall, the ICERs estimated for the one-way sensitivity analyses ranged from £7135 to £54,800 per QALY gained for afatinib compared with gefitinib, and from −£10,302 to £34,970 per QALY gained for afatinib compared with erlotinib. The manufacturer conducted some scenario analyses that varied the choice of second-line treatment (using pemetrexed rather than docetaxel as the second-line treatment), the duration of second-line treatment, the utility values in the progression-free health state and the studies used in the mixed treatment comparison. Using pemetrexed as second-line treatment had a minimal impact on the ICER. Applying a proportional duration of second-line treatment increased the ICER for afatinib compared with gefitinib to a maximum of £19,952 per QALY gained and £15,718 per QALY gained compared with erlotinib. Applying utility values derived from the literature for the progression-free health state also increased the ICER, most notably when afatinib was compared with gefitinib, which resulted in an ICER of £20,256 per QALY gained. For the comparison of afatinib with erlotinib, changing the utility values had a minimal impact on the ICER. Using only LUX-Lung 3 data in the mixed treatment comparison for afatinib (that is, excluding LUX-Lung 6, which was based in Asia) had the most impact on the ICER. It increased the ICER for afatinib compared with gefitinib to £24,339 per QALY gained, but had the opposite effect on the comparison with erlotinib in which afatinib dominated erlotinib (that is, was cheaper and more effective). When only LUX-Lung 3 data and data from the OPTIMAL trial of erlotinib comparing carboplatin plus gemcitabine were included, afatinib had an ICER of £15,257 per QALY gained when compared with gefitinib, and £13,013 per QALY gained when compared with erlotinib. # ERG's critique and exploratory analyses The ERG stated that the lack of a significant overall survival benefit with afatinib in the LUX-Lung 3 and 6 trials may have been masked by the high rates of crossover. The ERG considered Asian and non-Asian populations to be relevant subgroups. In response to the ERG request for clarification the manufacturer provided a subgroup analysis using updated data from LUX-Lung 3, which showed that Asian patients treated with chemotherapy may have a different progression-free survival and overall survival compared with non-Asian patients. The ERG undertook exploratory analyses using the manufacturer's data and noted that the mean expected post-progression survival was different for patients treated with afatinib in the Asian subgroup than in the non-Asian subgroup. The estimated mean progression-free survival in Asian patients was 19.5 months for afatinib and 8.7 months for pemetrexed plus cisplatin and in non-Asian patients was 14.8 months for afatinib and 4.7 months for pemetrexed plus cisplatin. The estimated mean overall survival in Asian patients was 37.3 months for both afatinib and pemetrexed plus cisplatin and in non-Asian patients was 31.4 months for afatinib and 25.3 months for pemetrexed plus cisplatin. The ERG considered the population of the trials included in the mixed treatment comparison in light of evidence from the subgroup analysis of LUX-Lung 3. The subgroup analysis showed that the clinical effectiveness of afatinib differed according to family origin (Asian or non-Asian). This would also have an impact on the results of the mixed treatment comparison (which included the intention-to-treat population) which the ERG considered were not useful for decision-making. The ERG stated that the UK population is likely to be much closer in terms of characteristics and prognosis to the non-Asian subgroup than to the overall LUX-Lung 3 population who were predominantly of Asian origin. The ERG questioned whether it was appropriate to include trials of EGFR mutation-positive populations with trials of unknown or mixed EGFR status populations in a single mixed treatment comparison. The ERG noted that there were differences in patient characteristics between studies of patients of EGFR mutation-positive NSCLC and those of unknown or mixed EGFR status in relation to the proportions of men, patients who had never smoked and patients with adenocarcinoma. The ERG also noted that the original mixed treatment comparison included patients with different histological types of NSCLC. The ERG concluded that the patient populations in the included trials were not sufficiently similar and therefore the results generated by the manufacturer's original mixed treatment comparison are not generalisable to a UK population. During clarification the ERG requested additional sensitivity analyses on the mixed treatment comparison to assess the impact of local investigator assessments, updated overall survival data (if available), using only data from the population of patients with EGFR activating mutations for both progression-free survival and overall survival and excluding EURTAC trial data (because it included only European patients). The resulting hazard ratios (random-effects model) for the difference in median progression-free survival for afatinib compared with gefitinib were 0.50 (95% CI 0.02 to 10.72) when assessed by independent review and 0.48 (95% CI 0.03 to 9.57) when assessed by the trial investigator. The hazard ratio for the difference in median overall survival was 0.91 (95% CI 0.07 to 12.03) for afatinib compared with gefitinib. The ERG considered that the model should be populated with data from non-Asian patients to appraise the cost effectiveness of treatments for use in England; it is only appropriate to use data that have been generated from a non-Asian population of EGFR mutation-positive patients, whether in terms of primary clinical trials or supporting evidence for use in a simple indirect comparison or mixed treatment comparison. The ERG further highlighted an ongoing study (LUX-Lung 7) which directly compares afatinib and gefitinib in people with EGFR mutation-positive advanced NSCLC and is due to report in 2015. The ERG disagreed with the approach taken by the manufacturer when fitting theoretical survival models to the LUX-Lung 3 data. The ERG did not consider that the Weibull models generated by the manufacturer for patients receiving afatinib or pemetrexed plus cisplatin accurately reflected the experience of LUX-Lung 3 patients, especially for progression-free survival which has an impact on the application of hazard ratios in the manufacturer's model. The ERG therefore considered that the progression-free survival results obtained from the Weibull model lacked credibility. In view of the issues with the manufacturer's model, the ERG did not consider it appropriate to carry out an exploratory analysis using the manufacturer's model. The ERG specified that it was not possible to incorporate alternative survival projections into the model because it had been structured around the use of hazard ratios to generate survival estimates rather than using directly obtained estimates. Because of the technical issues with the mixed treatment comparison, the ERG carried out an exploratory analysis to obtain an approximate estimate of the ICER for afatinib compared with combination chemotherapy. The results for the intention-to-treat population from LUX-Lung 3 showed that afatinib was associated with an ICER of £39,300 per QALY gained compared with pemetrexed plus cisplatin. The results for the non-Asian population showed that afatinib was associated with an ICER of £23,700 per QALY gained compared with pemetrexed plus cisplatin. The ERG concluded that the combination of patient access scheme pricing and use of data from the non-Asian subgroup of LUX-Lung 3 is likely to indicate that afatinib is cost effective compared with pemetrexed plus cisplatin in a predominantly white population of EGFR-positive patients. The ERG also carried out a cost analysis of afatinib, erlotinib and gefitinib incorporating the patient access schemes which have been agreed by the Department of Health. Two separate analyses were undertaken, which differed with regards to the assumption of effectiveness. The first analysis assumed that patients experience the same overall survival hazard profile as experienced in the LUX-Lung 3 trial, but experience the individual progression-free survival hazard profile from the key clinical trial for each treatment (that is, IPASS for gefitinib, EURTAC for erlotinib and LUX-Lung 3 for afatinib). The second analysis assumed that patients experience both the same overall survival and progression-free survival hazard profiles as experienced in the LUX-Lung 3 trial, irrespective of treatment. Given the discounts of the patient access schemes for both afatinib and erlotinib are commercial in confidence, the results of the cost comparison cannot be presented here. The estimated cost per patient of gefitinib was £11,886 using the progression-free survival estimate from the IPASS trial and the same overall survival as afatinib, and £12,069 assuming the same overall survival and progression-free survival as afatinib. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of afatinib, having considered evidence on the nature of epidermal growth factor receptor (EGFR) mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC) and the value placed on the benefits of afatinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Committee discussed current clinical practice for treating EGFR mutation-positive locally advanced or metastatic NSCLC. The clinical specialists highlighted that the standard first choice of treatment for NSCLC with EGFR-positive tyrosine kinase mutations was a tyrosine kinase inhibitor, which is in line with NICE's technology appraisal guidance on erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer (NICE technology appraisal guidance 258) and gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NICE technology appraisal guidance 192). The Committee was also aware of evidence presented in the manufacturer's submission which stated that 99% of eligible patients receive either erlotinib or gefitinib as a first-line treatment. The Committee concluded that treatment with erlotinib and gefitinib is standard practice for most people presenting with EGFR mutation-positive locally advanced or metastatic NSCLC. The Committee discussed the place of afatinib in the treatment pathway in relation to current clinical practice in the NHS. The Committee noted that the manufacturer's submission only presented evidence on the use of afatinib in people who have not been previously treated with a tyrosine kinase inhibitor and this was in line with afatinib's marketing authorisation. The Committee heard from the clinical specialists that if recommended, afatinib would be likely to be considered alongside erlotinib and gefitinib for locally advanced or metastatic NSCLC that had not been treated with a tyrosine kinase inhibitor. The Committee also heard from the clinical specialists that afatinib has a different adverse reaction profile from the other tyrosine kinase inhibitors, and that patients differ in their ability to tolerate different adverse reactions. They highlighted that if afatinib was recommended, it would enable clinicians to choose the tyrosine kinase inhibitor with the adverse reaction profile best suited to the individual patient. The Committee heard from clinical specialists that the irreversible binding of afatinib to the ErbB family of receptors (compared with the reversible binding of gefitinib and erlotinib) is believed to help reduce the possibility of resistance and delay its development. Therefore, the Committee concluded that erlotinib and gefitinib were appropriate comparators and that further first-line treatment options for EGFR mutation-positive locally advanced or metastatic NSCLC would be of value to clinicians and patients. The Committee discussed the clinical effectiveness evidence, focussing on the results of the LUX-Lung 3 and 6 trials which compared afatinib with pemetrexed plus cisplatin (LUX-Lung 3) and gemcitabine plus cisplatin (LUX-Lung 6). The Committee heard from the clinical specialists that the chemotherapy doublets used in these trials were regarded as best clinical practice at the time. It noted that both trials reported a statistically significant increase in median progression-free survival with afatinib compared with chemotherapy. However, no statistically significant difference in overall survival was seen in LUX-Lung 3 or LUX-Lung 6 because the data were immature and could have been confounded by treatment crossover between the treatment and control arms in both trials. Therefore, the Committee agreed that there was sufficient evidence to conclude that afatinib was clinically effective in prolonging progression-free survival but because of the immaturity of the overall survival data available, there was uncertainty about whether treatment with afatinib resulted in an overall survival benefit compared with chemotherapy. The Committee considered the pre-specified subgroup analyses of the LUX–Lung 3 progression-free survival data for baseline characteristics such as gender, age, family origin and common EGFR mutations, presented by the manufacturer in response to a request from the ERG for clarification. These analyses suggested there was no statistically significant difference in progression-free survival for any subgroup with the exception of common EGFR mutations compared with other EGFR mutations. The manufacturer's exploratory data (see section 3.21) suggested that people of Asian family origin may have a better progression-free survival than non-Asian patients. The Committee also noted that approximately one third of patients in LUX-Lung 3 were non-Asian, which represented a small number of patients and that the trial was underpowered to detect differences in progression-free survival based on ethnicity. The Committee noted that the results of a statistical test presented by the manufacturer for interaction between family origin and treatment effect were not statistically significant. However, the Committee also noted that the ERG analysis of cumulative mortality hazard in LUX-Lung 3 showed large differences in progression-free survival between the Asian and non-Asian populations both in the control and treatment arms of the trials, indicating that ethnicity may impact on the effectiveness of treatment. The Committee considered whether there was any biologically plausible reason why the effectiveness of afatinib would differ according to a person's family origin. The clinical specialists stated that based on their limited use of afatinib in small numbers of patients in England, there were no physiological differences between Asian and non-Asian patients that would explain the apparent differences in the effectiveness of afatinib. They emphasised that differences in the effectiveness of afatinib in NSCLC are more likely to be determined by EGFR mutation status rather than ethnicity; patients who are EGFR mutation-positive have similar response rates regardless of ethnic background. The Committee heard from the clinical specialists that the differences in the outcomes between the Asian and non-Asian population may be explained by the different standard of care and drug regimens used at trial centres in Asian compared with non-Asian countries, some of which may be more clinically effective than other regimens. Therefore, the Committee concluded that although there was uncertainty about the underlying reason, on balance the ERG analysis showed that ethnicity had an impact on the effectiveness of afatinib, and that the effectiveness of afatinib in clinical practice in England would be best represented by clinical effectiveness data in a non-Asian group. The Committee considered the evidence presented on the relative clinical effectiveness of afatinib compared with erlotinib and gefitinib. The Committee noted comments from the clinical specialists that the comparator chemotherapy regimen used in the LUX-Lung 3 trial, namely pemetrexed plus cisplatin, was considered to be more effective than the comparator chemotherapy regimens used in the erlotinib and gefitinib trials. The Committee noted that because there were no head-to-head trials comparing the clinical effectiveness of afatinib with erlotinib and gefitinib, the manufacturer presented a network meta-analysis (see sections 3.6 to 3.9). The Committee considered the methodology of the manufacturer's network mixed treatment comparison and the critique by the ERG. The Committee considered the ERG comments that in all 7 studies that included EGFR mutation-positive patients, the overall survival curves of the treatment arms cross. This indicated that the proportional hazards assumption had not been met, that is, the relative treatment effects captured by the hazard ratios were not constant across all time points. The Committee acknowledged that if the proportional hazards assumption was violated then using hazard ratios to form a network meta-analysis is not appropriate. It also heard from the ERG that although the manufacturer's original extrapolation of progression-free survival included in the economic model matched the trial data, ERG analysis of the Weibull models generated by the manufacturer to represent survival for patients receiving afatinib or pemetrexed plus cisplatin based on non-informative censoring (when each patient has a censoring time that is statistically independent of their treatment failure time) did not accurately reflect the experience of patients in LUX-Lung 3, especially for progression-free survival. The Committee acknowledged the ERG's view that based on a visual analysis, a 2-phase exponential model was a better fit to the trial data and therefore more accurately represented survival for patients treated with afatinib compared with pemetrexed plus cisplatin over the long term. The Committee therefore concluded that the underlying methodology of the mixed treatment comparison was not sufficiently robust. The Committee also noted that the manufacturer's original mixed treatment model included trials of patients with mixed or unknown EGFR mutation status as well as patients with EGFR mutation-positive disease. It acknowledged that this had been necessary to enable the manufacturer to join the network in the mixed treatment comparison to ensure all the tyrosine kinase inhibitors could be compared. However, the Committee noted the ERG comment that differences in patient characteristics between studies of patients of EGFR mutation-positive NSCLC and those of unknown or mixed EGFR mutation status (for example, in relation to the proportion of men, those who have never smoked and patients with adenocarcinoma) meant that the populations of the included trials were not sufficiently similar to be included in a mixed treatment comparison. The Committee considered the manufacturer's mixed treatment comparison that was limited to EGFR mutation-positive patients to be the most appropriate because it is in line with the marketing authorisation for afatinib and because of the widely accepted improved prognosis of EGFR mutation-positive patients. It noted that this analysis gave a slightly improved hazard ratio for afatinib compared with erlotinib and gefitinib. The Committee noted the statements from the manufacturer that the similarity of the results of the original and EGFR mutation-positive subgroup analysis demonstrated the robustness of the mixed treatment comparison. However, it noted that there were fewer than 50 patients included from the gefitinib trial in the EGFR mutation-positive subgroup analysis. The Committee also noted that the mixed treatment comparison of the EGFR mutation-positive subgroup included studies of predominantly Asian populations. It considered that a mixed treatment comparison for EGFR mutation-positive patients of non-Asian ethnicity would be more clinically relevant to people with NSCLC in England, but that this had not been done. The Committee noted that the European public assessment report considered the benefits of afatinib to be 'in line with the other tyrosine kinase inhibitors' and heard from the clinical specialists that based on their limited experience with small numbers of patients, afatinib has a similar efficacy to the tyrosine kinase inhibitors erlotinib and gefitinib. The Committee concluded that evidence from the mixed treatment comparison was not sufficiently robust because of the underlying methodology (violation of the proportional hazards assumption) and because it was based on a predominantly Asian population, who were not considered generalisable to the UK. The Committee concluded that on balance afatinib is likely to have similar clinical efficacy to erlotinib and gefitinib. The Committee was also aware of the LUX-Lung 7 study (due to report in 2015) which would provide more evidence on the relative clinical effectiveness of afatinib compared with gefitinib. The Committee considered the adverse reactions experienced by patients receiving treatment for locally advanced or metastatic EGFR mutation-positive NSCLC in the pivotal clinical trials with afatinib (LUX-Lung 3) compared with erlotinib (EURTAC) and gefitinib (IPASS). It noted that the incidence of diarrhoea and rash was considerably higher with afatinib compared with erlotinib and gefitinib. The patient expert stated that patients found adverse reactions with afatinib to be more easily tolerated than the adverse effects associated with many of the chemotherapy regimens. The Committee also heard from clinical specialists that diarrhoea is easily managed by dose reduction and drugs, which is demonstrated by the low rate of discontinuation because of diarrhoea (1.3%). The Committee further noted the conclusions of the European public assessment report that afatinib had similar toxicity to erlotinib and gefitinib. The Committee agreed that although afatinib has a higher rate of diarrhoea and rash, these were well managed in clinical practice. The Committee concluded that although afatinib has a different adverse reaction profile from erlotinib and gefitinib, overall the toxicity of the tyrosine kinase inhibitors was similar. # Cost effectiveness The Committee considered the manufacturer's base-case cost-effectiveness analysis incorporating the patient access schemes for afatinib, erlotinib and gefitinib, and the ERG critique. The Committee considered the population included in the base-case model. It noted that the population in the model (that is, people with mixed EGFR status and a combination of Asian and non-Asian patients) was not relevant to clinical practice in England (that is, EGFR mutation-positive and predominantly non-Asian). It also noted that methodological issues with the mixed treatment comparison (related to the violation of the assumption of proportional hazards and the extrapolation of progression-free survival and overall survival with afatinib) have an impact on the credibility of the economic model. The Committee considered whether it was possible to model the cost effectiveness of afatinib compared with erlotinib and gefitinib based on assumptions of the same clinical efficacy (in a similar way to that in NICE technology appraisal guidance 258). The Committee heard from the ERG that this was not possible because the structure of the model relies on using a single survival model formulation through a network of hazard ratios (assuming that the proportional hazard assumption applies throughout). Any attempt at modifying it would involve creating a new model. The Committee concluded that methodological issues related to the assumption of proportional hazards, the extrapolation of progression-free survival and the population of the base-case model prevented the Committee from assessing the cost effectiveness of afatinib compared with erlotinib and gefitinib based on the manufacturer's model. Therefore a most plausible ICER could not be estimated. The Committee considered the exploratory cost analysis presented by the ERG in which the average daily acquisition costs of afatinib, erlotinib and gefitinib were compared and which included the patient access schemes agreed by the Department of Health for each treatment. The Committee considered the 2 scenarios presented, firstly in which progression-free survival and overall survival were the same for all tyrosine kinase inhibitors, and secondly in which overall survival was the same but progression-free survival depended on the results of the pivotal trials. The Committee noted that the total costs, which incorporate the patient access schemes for afatinib and erlotinib have been designated as commercial in confidence and cannot be reported here. It also noted that the complexities of the patient access scheme make it difficult to assess the daily cost of gefitinib, which varies depending on the proportion of patients who stop taking gefitinib before the third pack is received. The Committee heard from the ERG that for consistency with the assumptions in the erlotinib appraisal, their analysis assumed that 5% of patients stopped taking gefitinib before the third pack and therefore did not incur any cost for gefitinib treatment. Without robust evidence on differences in the effectiveness of afatinib compared with erlotinib and gefitinib, the Committee considered the scenario based on equal progression-free survival and overall survival to be the most appropriate. It also accepted that in clinical practice the tyrosine kinase inhibitors were likely to have similar efficacy (see section 4.8). The Committee concluded that assuming progression-free survival for afatinib is equivalent to the other tyrosine kinase inhibitors, afatinib is a cost-effective use of NHS resources because it has comparable costs to erlotinib. Although the gefitinib patient access scheme makes it difficult to assess the daily acquisition cost of gefitinib, the Committee concluded that on balance afatinib was likely to have similar cost effectiveness to gefitinib. The Committee therefore concluded that afatinib could be considered an appropriate treatment alternative to erlotinib and gefitinib. The Committee considered the exploratory analyses conducted by the ERG, which estimated the cost effectiveness of afatinib compared with cisplatin in combination with pemetrexed, based on the trial data, noting that these analyses did not account for crossover in the trial, and could therefore be considered conservative. Although the comparator used in this analysis was not included in the scope, the Committee considered that it provided reassurance that afatinib was likely to be a cost-effective use of NHS resources compared with the chemotherapy that was the gold standard at the time the trials for afatinib were designed (before the tyrosine kinase inhibitors became established practice). The Committee concluded that on balance, based on all the evidence considered, afatinib is considered to be a reasonable alternative treatment option compared with erlotinib and gefitinib, in people with locally advanced or metastatic EGFR mutation-positive NSCLC that has not been previously treated with an EGFR tyrosine kinase inhibitor or chemotherapy. The Committee noted that most patients with locally advanced or metastatic EGFR mutation-positive NSCLC receive a tyrosine kinase inhibitor as first-line treatment. However, the clinical specialists advised that there is regional variation in the speed of EGFR testing and that it generally takes between 1 and 3 weeks to get the results. The clinical specialists also stated that a minority of patients with aggressive disease will therefore need treatment before EGFR mutation status is confirmed and will start treatment with chemotherapy (a third generation agent plus platinum) and receive a tyrosine kinase inhibitor as second-line treatment. The Committee noted that there is only limited evidence in small numbers of patients for the effectiveness of afatinib after prior chemotherapy. However, it acknowledged that the phase II LUX-Lung 2 trial suggested that afatinib is also effective when used as second-line treatment after chemotherapy. The Committee concluded that afatinib is likely to be clinically and cost effective as a second-line treatment for the minority of patients who have received chemotherapy as first-line treatment. The Committee therefore recommended afatinib as a treatment option in line with its marketing authorisation; that is, if the person has not previously had an EGFR tyrosine kinase inhibitor. The Committee considered whether afatinib should be considered as an innovative technology, given that it is another tyrosine kinase inhibitor for the treatment of EGFR mutation-positive NSCLC. The Committee noted that afatinib irreversibly binds to the ErbB family of receptors making it different, in vitro, from the tyrosine kinase inhibitors erlotinib and gefitinib (see section 2.1). The Committee heard from the clinical specialists that there is the possibility that, because of its mechanism of action, afatinib may be less likely to be associated with the development of resistance to tyrosine kinase inhibitors. However, the Committee concluded that the clinical evidence did not suggest that the mode of action for afatinib led to any significant benefit in clinical effectiveness compared with erlotinib and gefitinib. The Committee concluded that afatinib could not be considered to show significant innovation over the other tyrosine kinase inhibitors. The Committee again acknowledged the importance of the ongoing LUX-Lung 7 trial to provide further evidence on the clinical effectiveness of afatinib compared with gefitinib. # Summary of Appraisal Committee's key conclusions ## Key conclusion Afatinib is recommended as an option, within its marketing authorisation, for treating adults with locally advanced or metastatic non-small-cell lung cancer only if: the tumour tests positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and the person has not previously had an EGFR-TK inhibitor and the manufacturer provides afatinib with the discount agreed in the patient access scheme. The Committee concluded that on balance afatinib is likely to have similar clinical efficacy to erlotinib and gefitinib. The Committee concluded that methodological issues related to the assumption of proportional hazards, the extrapolation of progression-free survival and the population of the base-case model prevented the Committee from assessing the cost effectiveness of afatinib compared with erlotinib and gefitinib based on the manufacturer's model. Therefore a most plausible ICER could not be estimated. The Committee concluded that on balance, based on all the evidence considered, afatinib is considered to be a reasonable alternative treatment option compared with erlotinib and gefitinib, in people with locally advanced or metastatic EGFR mutation-positive NSCLC that has not been previously treated with an EGFR tyrosine kinase inhibitor or chemotherapy. The Committee concluded that afatinib is likely to be clinically and cost effective as a second-line treatment for the minority of patients who have received chemotherapy as first-line treatment. The Committee therefore recommended afatinib as a treatment option in line with its marketing authorisation. See sections 1.1, 4.8, 4.10, 4.12 and 4.13. ## Current practice The clinical specialists highlighted that the standard first choice of treatment for NSCLC with EGFR-positive tyrosine kinase mutations was a tyrosine kinase inhibitor, which is in line with NICE technology appraisal guidance 258 and 192. The Committee concluded that treatment with erlotinib or gefitinib is standard practice for most people presenting with EGFR mutation-positive locally advanced or metastatic NSCLC. The Committee also concluded that erlotinib and gefitinib were appropriate comparators and that further first-line treatment options for EGFR mutation-positive locally advanced or metastatic NSCLC would be of value to clinicians and patients. See sections 4.1 and 4.2. ## The technology The Committee heard from clinical specialists that the irreversible binding of afatinib to the ErbB family of receptors (compared with the reversible binding of gefitinib and erlotinib) is believed to help reduce the possibility of resistance and delay its development. See section 4.2. The Committee concluded that the clinical evidence did not suggest that the mode of action for afatinib led to any significant benefit in clinical effectiveness compared with erlotinib and gefitinib. The Committee concluded that afatinib could not be considered to show significant innovation over the other tyrosine kinase inhibitors. See section 4.14. The Committee heard from the clinical specialists that if recommended, afatinib would be likely to be considered alongside erlotinib and gefitinib for locally advanced or metastatic NSCLC that had not been treated with a tyrosine kinase inhibitor. See section 4.2. The Committee concluded that although afatinib has a different adverse reaction profile from erlotinib and gefitinib, overall the toxicity of the tyrosine kinase inhibitors was similar. See section 4.9. ## Evidence for clinical effectiveness The Committee heard from the clinical specialists that the chemotherapy doublets used in LUX-lung 3 and LUX-lung 6 were regarded as best clinical practice at the time. The Committee noted that because there were no head-to-head trials comparing the clinical effectiveness of afatinib with erlotinib and gefitinib, the manufacturer presented a network meta-analysis. The Committee concluded that evidence from the mixed treatment comparison was not sufficiently robust because of the underlying methodology (violation of the proportional hazards assumption) and because it was based on a predominantly Asian population, who were not considered generalisable to the UK. See sections 4.3, 4.6 and 4.8. The Committee concluded that a mixed treatment comparison for EGFR mutation-positive patients of non-Asian ethnicity would be more clinically relevant to people with NSCLC in England, but that this had not been done. See section 4.8. The LUX-Lung trials provided sufficient evidence to conclude that afatinib was clinically effective in prolonging progression-free survival but because of the immaturity of the overall survival data available, there was uncertainty about whether treatment with afatinib resulted in an overall survival benefit compared with chemotherapy. The Committee concluded that evidence from the mixed treatment comparison was not sufficiently robust because of the underlying methodology (violation of the proportional hazards assumption) and because it was based on a predominantly Asian population, who were not considered generalisable to the UK. See sections 4.3 and 4.8. The Committee concluded that although there was uncertainty about the underlying reason, on balance the ERG analysis showed that ethnicity had an impact on the effectiveness of afatinib in clinical practice, and that the effectiveness of afatinib in clinical practice in England would be best represented by clinical effectiveness data in a non-Asian group. See section 4.5. The Committee concluded that on balance afatinib is likely to have similar clinical efficacy to erlotinib and gefitinib. See section 4.6. ## Evidence for cost effectiveness The manufacturer of afatinib submitted cost-effectiveness evidence as part of its submission, based on a mixed treatment comparison. The ERG submitted an exploratory cost analysis and an exploratory economic analysis of afatinib compared with cisplatin in combination with pemetrexed, based on the trial data. See sections 4.10 to 4.12. The Committee concluded that methodological issues related to the assumption of proportional hazards, the extrapolation of progression-free survival and the population of the base-case model prevented the Committee from assessing the cost effectiveness of afatinib compared with erlotinib and gefitinib based on the manufacturer's model. Therefore a most plausible ICER could not be estimated. See section 4.10. The Committee did not draw any specific conclusions about the health-related quality-of-life benefits and utility values. None were identified. The main drivers of cost effectiveness were: the mixed treatment comparison-based hazard ratios for progression-free and overall survival, the cost per month for the progression-free health state and the cost per month for the best supportive care period of the progressive disease health state. See section 3.19. A most plausible ICER could not be estimated. The Committee concluded that on balance, based on all the evidence considered, afatinib is considered to be a reasonable alternative treatment option compared with erlotinib and gefitinib, in people with locally advanced or metastatic EGFR mutation-positive NSCLC that has not been previously treated with an EGFR tyrosine kinase inhibitor or chemotherapy. See sections 4.10 and 4.12. ## Additional factors taken into account The manufacturer of afatinib has agreed a patient access scheme with the Department of Health in which a confidential discount is applied at the point of purchase or invoice. See section 2.3. The manufacturer did not make a case for afatinib to be considered under the end of life criteria. No equality and diversity issues relating to population groups protected by equality legislation were highlighted when the scope for this appraisal was developed, or during the appraisal.# Recommendations for further research The Committee recognised the importance of further clinical trials comparing the effectiveness of the tyrosine kinase inhibitors (afatinib, erlotinib and gefitinib) in EGFR mutation-positive locally advanced or metastatic NSCLC. It acknowledged the relevance of the ongoing study (LUX-Lung 7) which directly compares afatinib and gefitinib in people with EGFR mutation-positive advanced NSCLC and is due to report in 2015.# Changes after publication June 2014: Minor maintenance ISBN: 978-1-4731-0555-3	{'Guidance': 'Afatinib is recommended as an option, within its marketing authorisation, for treating adults with locally advanced or metastatic non-small-cell lung cancer only if:\n\nthe tumour tests positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and\n\nthe person has not previously had an EGFR-TK inhibitor and\n\nthe manufacturer provides afatinib with the discount agreed in the patient access scheme.', 'The technology': "Afatinib (Giotrif, Boehringer Ingelheim) is an irreversible tyrosine kinase inhibitor (TKI) that blocks the epidermal growth factor receptor (EGFR) ErbB1 and other members of the ErbB family. The ErbB family is involved in the growth, migration and metabolism of tumour cells. Afatinib has a marketing authorisation as a monotherapy 'for the treatment of EGFR TKI-naive adult patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with activating EGFR mutation(s)'.\n\nThe summary of product characteristics lists the following very common adverse reactions for afatinib: diarrhoea, rash/acne, blistering and dry skin conditions, pruritus, decreased appetite, nose bleed, stomatitis (inflammation in the mouth) and paronychia (nail infection). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nAfatinib is given orally at a recommended dosage of 40\xa0mg once daily. The dosage may be increased to a maximum of 50\xa0mg/day in the first 3 weeks in patients who are able to tolerate 40\xa0mg/day without adverse reactions of greater than grade 1 severity. For patients who have more severe adverse reactions, the dose may be reduced (usually by 10\xa0mg decrements) or treatment interrupted or discontinued. For full details see the summary of product characteristics. The NHS list price, provided by the manufacturer, is £2023.28 per pack of 28\xa0tablets (20\xa0mg, 30\xa0mg, 40\xa0mg or 50\xa0mg). The manufacturer stated that the NHS list price per course of treatment is expected to be around £22,000 per patient, based on a progression-free survival of 11\xa0months. The manufacturer of afatinib has agreed a patient access scheme with the Department of Health in which a confidential discount is applied at the point of purchase or invoice. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (section 7) considered evidence submitted by the manufacturer of afatinib and a review of this submission by the Evidence Review Group (ERG, section 8).\n\nThe clinical effectiveness data presented by the manufacturer were predominantly from 2 phase III open-label randomised controlled clinical trials. LUX-Lung 3 compared afatinib with cisplatin plus pemetrexed and LUX-Lung 6 compared afatinib with cisplatin plus gemcitabine. There was also a mixed treatment comparison that compared afatinib with erlotinib and gefitinib. LUX-Lung 3 was an international trial (ethnicity: 26% white, 72% Eastern Asian, 2.0% other) that compared afatinib (40\xa0mg daily, n=230) with cisplatin plus pemetrexed (n=115) for patients with EGFR mutation-positive NSCLC. LUX-Lung 6 was conducted in China, Thailand and South Korea and compared afatinib (40\xa0mg daily, n=242) with cisplatin plus gemcitabine (n=122) for patients with EGFR mutation-positive NSCLC. In both trials patients were included who had received no prior treatment with chemotherapy or EGFR-targeting drugs and adenocarcinoma was the predominant histology. The primary outcome of the clinical trials was progression-free survival, as assessed by central independent review by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). Secondary outcomes included objective response rate and overall survival.\n\nIn LUX-Lung 3, there was a statistically significant increase in median progression-free survival for afatinib compared with cisplatin plus pemetrexed combination chemotherapy (11.14\xa0months compared with 6.90\xa0months; a gain of 4.24\xa0months) with a hazard ratio of 0.58 (95% confidence interval [CI] 0.43 to 0.78) when assessed by independent review. When the outcome was assessed by the trial investigator, there was a statistically significant increase in median progression-free survival for afatinib compared with combination chemotherapy (11.07\xa0months compared with 6.70\xa0months; a gain of 4.37\xa0months) with a hazard ratio of 0.49 (95% CI 0.37 to 0.65).\n\nIn LUX-Lung 6, there was a statistically significant increase in median progression-free survival for afatinib compared with cisplatin plus gemcitabine combination chemotherapy (11.01\xa0months compared with 5.59\xa0months; a gain of 5.42\xa0months) with a hazard ratio of 0.28 (95% CI 0.20 to 0.39) when assessed by independent review. When the outcome was assessed by the trial investigator, there was a statistically significant increase in median progression-free survival for afatinib compared with combination chemotherapy (13.73\xa0months compared with 5.55\xa0months; a gain of 8.18\xa0months) with a hazard ratio of 0.26 (95% CI 0.19 to 0.36).\n\nIn LUX-Lung 3, overall survival data were not mature by the cut-off date (February 2012) for the primary analysis because 67\xa0patients (29.1%) in the afatinib arm and 31\xa0patients (27.0%) in the chemotherapy arm had died. The manufacturer presented the results of the updated analysis (using additional data after the February 2012 cut-off) and the results of an updated analysis submitted to the European Medicines Agency using data up to January 2013). The manufacturer stated that final analysis of overall survival will be performed when 209\xa0patients have died. No statistically significant difference in overall survival was seen in LUX-Lung 3 or LUX-Lung 6 between afatinib and chemotherapy with hazard ratios of 1.12 (95% CI 0.73 to 1.72) and 0.95 (95% CI 0.68 to 1.33) respectively. Treatment crossover occurred in both LUX-Lung 3 (72%) and LUX-Lung 6 (80%) with most patients receiving at least 1\xa0line of subsequent anticancer therapy after stopping the study drugs. Crossover was not accounted for when estimating overall survival. The manufacturer conducted subgroup analyses of LUX-Lung 3 and LUX-Lung 6 for pre-specified baseline characteristics such as gender, age, family origin and common EGFR mutations, which was consistent with the analysis in the intention-to-treat populations.\n\nHealth-related quality of life data from LUX-Lung 3 and LUX-Lung 6 were reported for the pre-specified NSCLC-related symptoms of cough, dyspnoea and pain, measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and QLQ-LC13 questionnaires. More than 87% of patients completed the questionnaires. Afatinib was associated with a statistically significant improvement in breathing, non-specific pain and chest pain, fatigue and the time to deterioration in cough, dyspnoea and pain compared with chemotherapy (cisplatin plus either pemetrexed or gemcitabine). EQ-5D (UK and Belgium) and EQ-VAS data collected during the LUX-Lung 3 clinical trial reported no statistically significant difference in values between afatinib and chemotherapy with an absolute improvement in utility of 0.008 (UK) and 0.007 (Belgium).\n\nBecause there was no head-to-head randomised controlled trial comparing the effectiveness of afatinib with erlotinib or gefitinib for progression-free survival or overall survival, the manufacturer presented a mixed treatment comparison. This was based on a previous mixed treatment comparison conducted for NICE's technology appraisal guidance on gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NICE technology appraisal guidance 192), which was adapted to include data on the effectiveness of afatinib based on the LUX-Lung 3 and 6 studies and erlotinib.The studies used to populate the mixed treatment comparison were identified through systematic review. The manufacturer identified 20\xa0randomised controlled trials, 4 of which included gefitinib (first SIGNAL trial, IPASS trial, Mitsudomi 2010, Maemondo 2010) and 1 that included erlotinib (EURTAC trial). The population of the studies included in the mixed treatment comparison was people with locally advanced or metastatic non-small cell lung cancer. However, only 7 of the trials were carried out exclusively in people with EGFR-positive disease. The manufacturer specified that the EURTAC trial was of average quality and the first SIGNAL trial only included 42\xa0patients with EGFR-positive disease. All the trials included in the mixed treatment comparison permitted crossover after disease progression. A fixed-effects model was used to assess progression-free survival and a random-effects model was used to assess overall survival. There was no testing of the proportional hazards assumption.\n\nThe results of the manufacturer's mixed treatment comparison showed that there was no statistically significant difference in progression-free survival or overall survival between afatinib and gefitinib or erlotinib. Afatinib had the highest probability (62.6%) of being the most effective treatment in terms of progression-free survival gain compared with all the comparator treatments including erlotinib (30.8%) and gefitinib (6.5%). Afatinib also had the highest probability (43%) of being the most effective treatment in terms of overall survival gain compared with all the comparator treatments including erlotinib (3%) and gefitinib (13%).\n\nThe resulting hazard ratios from the mixed treatment comparison for the difference in median progression-free survival for afatinib were:\n\n(95% CI 0.25 to 0.52) compared with gemcitabine plus cisplatin\n\n(95% CI 0.32 to 0.66) compared with pemetrexed plus cisplatin\n\n(95% CI 0.47 to 1.20) compared with gefitinib\n\n(95% CI 0.53 to 1.50) compared with erlotinib.\n\nThe resulting hazard ratios from the mixed treatment comparison for the difference in median overall survival for afatinib were\n\n(95% CI 0.67 to 1.10) compared with gemcitabine plus cisplatin\n\n(95% CI 0.78 to 1.27) compared with pemetrexed plus cisplatin\n\n(95% CI 0.55 to 1.30) compared with gefitinib\n\n(95% CI 0.56 to 1.14) compared with erlotinib.\n\nThe manufacturer submitted evidence from the non-placebo controlled LUX-Lung 2 trial, a phase II multicentre trial conducted in the USA and Taiwan, which evaluated the safety and efficacy of afatinib in patients with locally advanced or metastatic EGFR-positive NSCLC. The patients in the study were predominantly Asian. This trial evaluated the effectiveness of afatinib in patients who had not previously received chemotherapy (n=61) and patients whose disease had progressed after 1\xa0previous chemotherapy treatment (n=68). There were 2\xa0study arms, afatinib 40\xa0mg and afatinib 50\xa0mg. The primary outcome of LUX-Lung 2 was progression-free survival, as assessed by central independent review by RECIST version 1.1. Secondary outcomes included objective response rate and median overall survival.\n\nIn LUX-Lung 2, progression-free survival was shorter in patients who had received prior chemotherapy. The median progression-free survival was 11.9\xa0months for patients who had not had chemotherapy before and 4.5\xa0months for patients receiving the 40\xa0mg dose of afatinib as a second-line treatment. LUX-Lung 2 reported shorter overall survival in patients who had prior chemotherapy compared with those who had not. The median overall survival was 23.1\xa0months for patients who had not had chemotherapy and 14.6\xa0months for patients receiving afatinib as a second-line treatment.\n\nLUX-Lung 3 reported higher rates of diarrhoea, rash/acne, stomatitis/mucositis and paronychia compared with chemotherapy but less nausea, fatigue, vomiting, anaemia, leukopenia and neutropenia. The manufacturer compared the adverse reactions from the pivotal clinical trials for afatinib (LUX-Lung 3), gefitinib (IPASS) and erlotinib (EURTAC), which showed that afatinib is associated with more diarrhoea (95%) than gefitinib (47%) and erlotinib (57%), more rash/acne (89%) than gefitinib (66%) and erlotinib (80%), more stomatitis/mucositis (72%) than gefitinib (17%), but less reduced appetite (21%) than erlotinib (53%) and less fatigue (18%) than erlotinib (47%). Dose reductions were higher with afatinib (57%, LUX-Lung 3) compared with gefitinib (16.1%, IPASS) or erlotinib (21%, EURTAC).\n\nThe manufacturer presented a de novo disease-state cohort model consisting of 2 health states (progression-free and progressive disease) and death. The progression-free health state represented the period during which the patient's cancer did not worsen while receiving active treatment. The progressive disease health state represented the period that the cancer spread. The model allowed movement from the progression-free health state to the progressive-disease health state, or death state; or from the progressive-disease health state to the death state. The model had a lifetime horizon of 10\xa0years and a cycle length of 1\xa0month, with an NHS and personal social services perspective and 3.5% discounting for costs and health effects.\n\nThe manufacturer's model used the partitioned survival method to determine the proportion of patients in each health state, for each model cycle. Data from LUX-Lung 3 and LUX-Lung 6 were used to estimate progression-free survival and overall survival for afatinib in the model, but parametric survival models based on hazard ratios produced from the mixed treatment comparison were used to project progression-free survival and overall survival over the 10-year model time horizon. The Weibull method was used to extrapolate the trial data in the base-case model to estimate progression-free survival and overall survival. Sensitivity analyses were conducted that used 2 further types of parametric survival modelling of the clinical trial Kaplan-Meier data: exponential and Gompertz. The progression-free survival and overall survival estimates for people treated with erlotinib and gefitinib were estimated by applying the mixed treatment comparison hazard ratios to the survival estimates for people treated with afatinib. Progression-free survival and overall survival were incorporated into the cost-effectiveness model by using full parametric approximation or by using Kaplan-Meier data from the clinical trials extrapolated using parametric survival models.\n\nAdverse reactions (diarrhoea, rash/acne, fatigue, anaemia and neutropenia) were applied in the model for the first year only, in both the progression-free and progressive disease health states. The type and frequency of adverse reactions was estimated from LUX-Lung 1 and LUX-Lung 3 for afatinib, and from the mixed treatment comparison for gefitinib and erlotinib.\n\nIn the base-case model the utility value used in the progression-free health state was 0.78 (from LUX-Lung 3) and utility values from the literature were used for the progressive disease health state (0.73 and 0.46 for second- and third-line treatment respectively). Alternative utility values derived from the literature for the progression-free health state were used in a sensitivity analysis. Utility values did not change over time.\n\nTo estimate the costs in the model, the manufacturer either used resource costs from the LUX-Lung 3 and 6 trials, or values from the literature. The resource costs associated with disease management (progression-free or progressed disease health states) and adverse reactions estimated from the LUX-Lung 3 and 6 trials included:\n\noutpatient visits (GP, specialist, nurses, occupational therapist, physiotherapist)\n\noutpatient interventions (CT scan, MRI scan, surgical procedure, ultrasound, X-ray, radiotherapy)\n\nunscheduled hospitalisations (unscheduled hospital stay, intensive care unit visit, emergency room visit)\n\nEGFR testing.All other values were taken from the literature. The model assumed that treatment with afatinib, erlotinib or gefitinib continues until disease progression. Disease progression is typically assessed every 3\xa0months by CT scan, and this cost was incorporated into the model. Afatinib, gefitinib, and erlotinib each have patient access schemes agreed with the Department of Health, which were accounted for in the analyses.\n\nThe deterministic pairwise results of the base-case analysis showed that afatinib was associated with an ICER of £10,076 per QALY gained (incremental costs £1723, incremental QALYs 0.171) compared with erlotinib and an ICER of £17,933 per QALY gained (incremental costs £3113, incremental QALYs 0.173) compared with gefitinib. The manufacturer stated that there was a 100% probability of afatinib being cost effective compared with erlotinib at £20,000 and £30,000 per QALY gained. Compared with gefitinib, there was a 72% and 81% probability of afatinib being cost effective at £20,000 and £30,000 per QALY gained respectively.\n\nThe manufacturer conducted one-way sensitivity analyses of the pairwise comparisons with gefitinib and erlotinib. The main drivers of cost effectiveness were: the mixed treatment comparison-based hazard ratios for progression-free and overall survival, the cost per month for the progression-free health state and the cost per month for the best supportive care period of the progressive disease health state. Overall, the ICERs estimated for the one-way sensitivity analyses ranged from £7135 to £54,800 per QALY gained for afatinib compared with gefitinib, and from −£10,302 to £34,970 per QALY gained for afatinib compared with erlotinib.\n\nThe manufacturer conducted some scenario analyses that varied the choice of second-line treatment (using pemetrexed rather than docetaxel as the second-line treatment), the duration of second-line treatment, the utility values in the progression-free health state and the studies used in the mixed treatment comparison. Using pemetrexed as second-line treatment had a minimal impact on the ICER. Applying a proportional duration of second-line treatment increased the ICER for afatinib compared with gefitinib to a maximum of £19,952 per QALY gained and £15,718 per QALY gained compared with erlotinib. Applying utility values derived from the literature for the progression-free health state also increased the ICER, most notably when afatinib was compared with gefitinib, which resulted in an ICER of £20,256 per QALY gained. For the comparison of afatinib with erlotinib, changing the utility values had a minimal impact on the ICER. Using only LUX-Lung 3 data in the mixed treatment comparison for afatinib (that is, excluding LUX-Lung 6, which was based in Asia) had the most impact on the ICER. It increased the ICER for afatinib compared with gefitinib to £24,339 per QALY gained, but had the opposite effect on the comparison with erlotinib in which afatinib dominated erlotinib (that is, was cheaper and more effective). When only LUX-Lung 3 data and data from the OPTIMAL trial of erlotinib comparing carboplatin plus gemcitabine were included, afatinib had an ICER of £15,257 per QALY gained when compared with gefitinib, and £13,013 per QALY gained when compared with erlotinib.\n\n# ERG's critique and exploratory analyses\n\nThe ERG stated that the lack of a significant overall survival benefit with afatinib in the LUX-Lung 3 and 6 trials may have been masked by the high rates of crossover. The ERG considered Asian and non-Asian populations to be relevant subgroups. In response to the ERG request for clarification the manufacturer provided a subgroup analysis using updated data from LUX-Lung 3, which showed that Asian patients treated with chemotherapy may have a different progression-free survival and overall survival compared with non-Asian patients. The ERG undertook exploratory analyses using the manufacturer's data and noted that the mean expected post-progression survival was different for patients treated with afatinib in the Asian subgroup than in the non-Asian subgroup. The estimated mean progression-free survival in Asian patients was 19.5\xa0months for afatinib and 8.7\xa0months for pemetrexed plus cisplatin and in non-Asian patients was 14.8\xa0months for afatinib and 4.7\xa0months for pemetrexed plus cisplatin. The estimated mean overall survival in Asian patients was 37.3\xa0months for both afatinib and pemetrexed plus cisplatin and in non-Asian patients was 31.4\xa0months for afatinib and 25.3\xa0months for pemetrexed plus cisplatin.\n\nThe ERG considered the population of the trials included in the mixed treatment comparison in light of evidence from the subgroup analysis of LUX-Lung 3. The subgroup analysis showed that the clinical effectiveness of afatinib differed according to family origin (Asian or non-Asian). This would also have an impact on the results of the mixed treatment comparison (which included the intention-to-treat population) which the ERG considered were not useful for decision-making. The ERG stated that the UK population is likely to be much closer in terms of characteristics and prognosis to the non-Asian subgroup than to the overall LUX-Lung 3 population who were predominantly of Asian origin.\n\nThe ERG questioned whether it was appropriate to include trials of EGFR mutation-positive populations with trials of unknown or mixed EGFR status populations in a single mixed treatment comparison. The ERG noted that there were differences in patient characteristics between studies of patients of EGFR mutation-positive NSCLC and those of unknown or mixed EGFR status in relation to the proportions of men, patients who had never smoked and patients with adenocarcinoma. The ERG also noted that the original mixed treatment comparison included patients with different histological types of NSCLC. The ERG concluded that the patient populations in the included trials were not sufficiently similar and therefore the results generated by the manufacturer's original mixed treatment comparison are not generalisable to a UK population.\n\nDuring clarification the ERG requested additional sensitivity analyses on the mixed treatment comparison to assess the impact of local investigator assessments, updated overall survival data (if available), using only data from the population of patients with EGFR activating mutations for both progression-free survival and overall survival and excluding EURTAC trial data (because it included only European patients). The resulting hazard ratios (random-effects model) for the difference in median progression-free survival for afatinib compared with gefitinib were 0.50 (95% CI 0.02 to 10.72) when assessed by independent review and 0.48 (95% CI 0.03 to 9.57) when assessed by the trial investigator. The hazard ratio for the difference in median overall survival was 0.91 (95% CI 0.07 to 12.03) for afatinib compared with gefitinib. The ERG considered that the model should be populated with data from non-Asian patients to appraise the cost effectiveness of treatments for use in England; it is only appropriate to use data that have been generated from a non-Asian population of EGFR mutation-positive patients, whether in terms of primary clinical trials or supporting evidence for use in a simple indirect comparison or mixed treatment comparison. The ERG further highlighted an ongoing study (LUX-Lung 7) which directly compares afatinib and gefitinib in people with EGFR mutation-positive advanced NSCLC and is due to report in 2015.\n\nThe ERG disagreed with the approach taken by the manufacturer when fitting theoretical survival models to the LUX-Lung 3 data. The ERG did not consider that the Weibull models generated by the manufacturer for patients receiving afatinib or pemetrexed plus cisplatin accurately reflected the experience of LUX-Lung 3 patients, especially for progression-free survival which has an impact on the application of hazard ratios in the manufacturer's model. The ERG therefore considered that the progression-free survival results obtained from the Weibull model lacked credibility.\n\nIn view of the issues with the manufacturer's model, the ERG did not consider it appropriate to carry out an exploratory analysis using the manufacturer's model. The ERG specified that it was not possible to incorporate alternative survival projections into the model because it had been structured around the use of hazard ratios to generate survival estimates rather than using directly obtained estimates.\n\nBecause of the technical issues with the mixed treatment comparison, the ERG carried out an exploratory analysis to obtain an approximate estimate of the ICER for afatinib compared with combination chemotherapy. The results for the intention-to-treat population from LUX-Lung 3 showed that afatinib was associated with an ICER of £39,300 per QALY gained compared with pemetrexed plus cisplatin. The results for the non-Asian population showed that afatinib was associated with an ICER of £23,700 per QALY gained compared with pemetrexed plus cisplatin. The ERG concluded that the combination of patient access scheme pricing and use of data from the non-Asian subgroup of LUX-Lung 3 is likely to indicate that afatinib is cost effective compared with pemetrexed plus cisplatin in a predominantly white population of EGFR-positive patients.\n\nThe ERG also carried out a cost analysis of afatinib, erlotinib and gefitinib incorporating the patient access schemes which have been agreed by the Department of Health. Two separate analyses were undertaken, which differed with regards to the assumption of effectiveness. The first analysis assumed that patients experience the same overall survival hazard profile as experienced in the LUX-Lung 3 trial, but experience the individual progression-free survival hazard profile from the key clinical trial for each treatment (that is, IPASS for gefitinib, EURTAC for erlotinib and LUX-Lung 3 for afatinib). The second analysis assumed that patients experience both the same overall survival and progression-free survival hazard profiles as experienced in the LUX-Lung 3 trial, irrespective of treatment. Given the discounts of the patient access schemes for both afatinib and erlotinib are commercial in confidence, the results of the cost comparison cannot be presented here. The estimated cost per patient of gefitinib was £11,886 using the progression-free survival estimate from the IPASS trial and the same overall survival as afatinib, and £12,069 assuming the same overall survival and progression-free survival as afatinib.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of afatinib, having considered evidence on the nature of epidermal growth factor receptor (EGFR) mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC) and the value placed on the benefits of afatinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee discussed current clinical practice for treating EGFR mutation-positive locally advanced or metastatic NSCLC. The clinical specialists highlighted that the standard first choice of treatment for NSCLC with EGFR-positive tyrosine kinase mutations was a tyrosine kinase inhibitor, which is in line with NICE's technology appraisal guidance on erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer (NICE technology appraisal guidance 258) and gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NICE technology appraisal guidance 192). The Committee was also aware of evidence presented in the manufacturer's submission which stated that 99% of eligible patients receive either erlotinib or gefitinib as a first-line treatment. The Committee concluded that treatment with erlotinib and gefitinib is standard practice for most people presenting with EGFR mutation-positive locally advanced or metastatic NSCLC.\n\nThe Committee discussed the place of afatinib in the treatment pathway in relation to current clinical practice in the NHS. The Committee noted that the manufacturer's submission only presented evidence on the use of afatinib in people who have not been previously treated with a tyrosine kinase inhibitor and this was in line with afatinib's marketing authorisation. The Committee heard from the clinical specialists that if recommended, afatinib would be likely to be considered alongside erlotinib and gefitinib for locally advanced or metastatic NSCLC that had not been treated with a tyrosine kinase inhibitor. The Committee also heard from the clinical specialists that afatinib has a different adverse reaction profile from the other tyrosine kinase inhibitors, and that patients differ in their ability to tolerate different adverse reactions. They highlighted that if afatinib was recommended, it would enable clinicians to choose the tyrosine kinase inhibitor with the adverse reaction profile best suited to the individual patient. The Committee heard from clinical specialists that the irreversible binding of afatinib to the ErbB family of receptors (compared with the reversible binding of gefitinib and erlotinib) is believed to help reduce the possibility of resistance and delay its development. Therefore, the Committee concluded that erlotinib and gefitinib were appropriate comparators and that further first-line treatment options for EGFR mutation-positive locally advanced or metastatic NSCLC would be of value to clinicians and patients.\n\nThe Committee discussed the clinical effectiveness evidence, focussing on the results of the LUX-Lung 3 and 6 trials which compared afatinib with pemetrexed plus cisplatin (LUX-Lung 3) and gemcitabine plus cisplatin (LUX-Lung 6). The Committee heard from the clinical specialists that the chemotherapy doublets used in these trials were regarded as best clinical practice at the time. It noted that both trials reported a statistically significant increase in median progression-free survival with afatinib compared with chemotherapy. However, no statistically significant difference in overall survival was seen in LUX-Lung 3 or LUX-Lung 6 because the data were immature and could have been confounded by treatment crossover between the treatment and control arms in both trials. Therefore, the Committee agreed that there was sufficient evidence to conclude that afatinib was clinically effective in prolonging progression-free survival but because of the immaturity of the overall survival data available, there was uncertainty about whether treatment with afatinib resulted in an overall survival benefit compared with chemotherapy.\n\nThe Committee considered the pre-specified subgroup analyses of the LUX–Lung 3 progression-free survival data for baseline characteristics such as gender, age, family origin and common EGFR mutations, presented by the manufacturer in response to a request from the ERG for clarification. These analyses suggested there was no statistically significant difference in progression-free survival for any subgroup with the exception of common EGFR mutations compared with other EGFR mutations. The manufacturer's exploratory data (see section 3.21) suggested that people of Asian family origin may have a better progression-free survival than non-Asian patients. The Committee also noted that approximately one third of patients in LUX-Lung 3 were non-Asian, which represented a small number of patients and that the trial was underpowered to detect differences in progression-free survival based on ethnicity. The Committee noted that the results of a statistical test presented by the manufacturer for interaction between family origin and treatment effect were not statistically significant. However, the Committee also noted that the ERG analysis of cumulative mortality hazard in LUX-Lung 3 showed large differences in progression-free survival between the Asian and non-Asian populations both in the control and treatment arms of the trials, indicating that ethnicity may impact on the effectiveness of treatment.\n\nThe Committee considered whether there was any biologically plausible reason why the effectiveness of afatinib would differ according to a person's family origin. The clinical specialists stated that based on their limited use of afatinib in small numbers of patients in England, there were no physiological differences between Asian and non-Asian patients that would explain the apparent differences in the effectiveness of afatinib. They emphasised that differences in the effectiveness of afatinib in NSCLC are more likely to be determined by EGFR mutation status rather than ethnicity; patients who are EGFR mutation-positive have similar response rates regardless of ethnic background. The Committee heard from the clinical specialists that the differences in the outcomes between the Asian and non-Asian population may be explained by the different standard of care and drug regimens used at trial centres in Asian compared with non-Asian countries, some of which may be more clinically effective than other regimens. Therefore, the Committee concluded that although there was uncertainty about the underlying reason, on balance the ERG analysis showed that ethnicity had an impact on the effectiveness of afatinib, and that the effectiveness of afatinib in clinical practice in England would be best represented by clinical effectiveness data in a non-Asian group.\n\nThe Committee considered the evidence presented on the relative clinical effectiveness of afatinib compared with erlotinib and gefitinib. The Committee noted comments from the clinical specialists that the comparator chemotherapy regimen used in the LUX-Lung 3 trial, namely pemetrexed plus cisplatin, was considered to be more effective than the comparator chemotherapy regimens used in the erlotinib and gefitinib trials. The Committee noted that because there were no head-to-head trials comparing the clinical effectiveness of afatinib with erlotinib and gefitinib, the manufacturer presented a network meta-analysis (see sections 3.6 to 3.9). The Committee considered the methodology of the manufacturer's network mixed treatment comparison and the critique by the ERG. The Committee considered the ERG comments that in all 7 studies that included EGFR mutation-positive patients, the overall survival curves of the treatment arms cross. This indicated that the proportional hazards assumption had not been met, that is, the relative treatment effects captured by the hazard ratios were not constant across all time points. The Committee acknowledged that if the proportional hazards assumption was violated then using hazard ratios to form a network meta-analysis is not appropriate. It also heard from the ERG that although the manufacturer's original extrapolation of progression-free survival included in the economic model matched the trial data, ERG analysis of the Weibull models generated by the manufacturer to represent survival for patients receiving afatinib or pemetrexed plus cisplatin based on non-informative censoring (when each patient has a censoring time that is statistically independent of their treatment failure time) did not accurately reflect the experience of patients in LUX-Lung 3, especially for progression-free survival. The Committee acknowledged the ERG's view that based on a visual analysis, a 2-phase exponential model was a better fit to the trial data and therefore more accurately represented survival for patients treated with afatinib compared with pemetrexed plus cisplatin over the long term. The Committee therefore concluded that the underlying methodology of the mixed treatment comparison was not sufficiently robust.\n\nThe Committee also noted that the manufacturer's original mixed treatment model included trials of patients with mixed or unknown EGFR mutation status as well as patients with EGFR mutation-positive disease. It acknowledged that this had been necessary to enable the manufacturer to join the network in the mixed treatment comparison to ensure all the tyrosine kinase inhibitors could be compared. However, the Committee noted the ERG comment that differences in patient characteristics between studies of patients of EGFR mutation-positive NSCLC and those of unknown or mixed EGFR mutation status (for example, in relation to the proportion of men, those who have never smoked and patients with adenocarcinoma) meant that the populations of the included trials were not sufficiently similar to be included in a mixed treatment comparison. The Committee considered the manufacturer's mixed treatment comparison that was limited to EGFR mutation-positive patients to be the most appropriate because it is in line with the marketing authorisation for afatinib and because of the widely accepted improved prognosis of EGFR mutation-positive patients. It noted that this analysis gave a slightly improved hazard ratio for afatinib compared with erlotinib and gefitinib. The Committee noted the statements from the manufacturer that the similarity of the results of the original and EGFR mutation-positive subgroup analysis demonstrated the robustness of the mixed treatment comparison. However, it noted that there were fewer than 50\xa0patients included from the gefitinib trial in the EGFR mutation-positive subgroup analysis.\n\nThe Committee also noted that the mixed treatment comparison of the EGFR mutation-positive subgroup included studies of predominantly Asian populations. It considered that a mixed treatment comparison for EGFR mutation-positive patients of non-Asian ethnicity would be more clinically relevant to people with NSCLC in England, but that this had not been done. The Committee noted that the European public assessment report considered the benefits of afatinib to be 'in line with the other tyrosine kinase inhibitors' and heard from the clinical specialists that based on their limited experience with small numbers of patients, afatinib has a similar efficacy to the tyrosine kinase inhibitors erlotinib and gefitinib. The Committee concluded that evidence from the mixed treatment comparison was not sufficiently robust because of the underlying methodology (violation of the proportional hazards assumption) and because it was based on a predominantly Asian population, who were not considered generalisable to the UK. The Committee concluded that on balance afatinib is likely to have similar clinical efficacy to erlotinib and gefitinib. The Committee was also aware of the LUX-Lung 7 study (due to report in 2015) which would provide more evidence on the relative clinical effectiveness of afatinib compared with gefitinib.\n\nThe Committee considered the adverse reactions experienced by patients receiving treatment for locally advanced or metastatic EGFR mutation-positive NSCLC in the pivotal clinical trials with afatinib (LUX-Lung 3) compared with erlotinib (EURTAC) and gefitinib (IPASS). It noted that the incidence of diarrhoea and rash was considerably higher with afatinib compared with erlotinib and gefitinib. The patient expert stated that patients found adverse reactions with afatinib to be more easily tolerated than the adverse effects associated with many of the chemotherapy regimens. The Committee also heard from clinical specialists that diarrhoea is easily managed by dose reduction and drugs, which is demonstrated by the low rate of discontinuation because of diarrhoea (1.3%). The Committee further noted the conclusions of the European public assessment report that afatinib had similar toxicity to erlotinib and gefitinib. The Committee agreed that although afatinib has a higher rate of diarrhoea and rash, these were well managed in clinical practice. The Committee concluded that although afatinib has a different adverse reaction profile from erlotinib and gefitinib, overall the toxicity of the tyrosine kinase inhibitors was similar.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's base-case cost-effectiveness analysis incorporating the patient access schemes for afatinib, erlotinib and gefitinib, and the ERG critique. The Committee considered the population included in the base-case model. It noted that the population in the model (that is, people with mixed EGFR status and a combination of Asian and non-Asian patients) was not relevant to clinical practice in England (that is, EGFR mutation-positive and predominantly non-Asian). It also noted that methodological issues with the mixed treatment comparison (related to the violation of the assumption of proportional hazards and the extrapolation of progression-free survival and overall survival with afatinib) have an impact on the credibility of the economic model. The Committee considered whether it was possible to model the cost effectiveness of afatinib compared with erlotinib and gefitinib based on assumptions of the same clinical efficacy (in a similar way to that in NICE technology appraisal guidance 258). The Committee heard from the ERG that this was not possible because the structure of the model relies on using a single survival model formulation through a network of hazard ratios (assuming that the proportional hazard assumption applies throughout). Any attempt at modifying it would involve creating a new model. The Committee concluded that methodological issues related to the assumption of proportional hazards, the extrapolation of progression-free survival and the population of the base-case model prevented the Committee from assessing the cost effectiveness of afatinib compared with erlotinib and gefitinib based on the manufacturer's model. Therefore a most plausible ICER could not be estimated.\n\nThe Committee considered the exploratory cost analysis presented by the ERG in which the average daily acquisition costs of afatinib, erlotinib and gefitinib were compared and which included the patient access schemes agreed by the Department of Health for each treatment. The Committee considered the 2 scenarios presented, firstly in which progression-free survival and overall survival were the same for all tyrosine kinase inhibitors, and secondly in which overall survival was the same but progression-free survival depended on the results of the pivotal trials. The Committee noted that the total costs, which incorporate the patient access schemes for afatinib and erlotinib have been designated as commercial in confidence and cannot be reported here. It also noted that the complexities of the patient access scheme make it difficult to assess the daily cost of gefitinib, which varies depending on the proportion of patients who stop taking gefitinib before the third pack is received. The Committee heard from the ERG that for consistency with the assumptions in the erlotinib appraisal, their analysis assumed that 5% of patients stopped taking gefitinib before the third pack and therefore did not incur any cost for gefitinib treatment. Without robust evidence on differences in the effectiveness of afatinib compared with erlotinib and gefitinib, the Committee considered the scenario based on equal progression-free survival and overall survival to be the most appropriate. It also accepted that in clinical practice the tyrosine kinase inhibitors were likely to have similar efficacy (see section 4.8). The Committee concluded that assuming progression-free survival for afatinib is equivalent to the other tyrosine kinase inhibitors, afatinib is a cost-effective use of NHS resources because it has comparable costs to erlotinib. Although the gefitinib patient access scheme makes it difficult to assess the daily acquisition cost of gefitinib, the Committee concluded that on balance afatinib was likely to have similar cost effectiveness to gefitinib. The Committee therefore concluded that afatinib could be considered an appropriate treatment alternative to erlotinib and gefitinib.\n\nThe Committee considered the exploratory analyses conducted by the ERG, which estimated the cost effectiveness of afatinib compared with cisplatin in combination with pemetrexed, based on the trial data, noting that these analyses did not account for crossover in the trial, and could therefore be considered conservative. Although the comparator used in this analysis was not included in the scope, the Committee considered that it provided reassurance that afatinib was likely to be a cost-effective use of NHS resources compared with the chemotherapy that was the gold standard at the time the trials for afatinib were designed (before the tyrosine kinase inhibitors became established practice). The Committee concluded that on balance, based on all the evidence considered, afatinib is considered to be a reasonable alternative treatment option compared with erlotinib and gefitinib, in people with locally advanced or metastatic EGFR mutation-positive NSCLC that has not been previously treated with an EGFR tyrosine kinase inhibitor or chemotherapy.\n\nThe Committee noted that most patients with locally advanced or metastatic EGFR mutation-positive NSCLC receive a tyrosine kinase inhibitor as first-line treatment. However, the clinical specialists advised that there is regional variation in the speed of EGFR testing and that it generally takes between 1 and 3 weeks to get the results. The clinical specialists also stated that a minority of patients with aggressive disease will therefore need treatment before EGFR mutation status is confirmed and will start treatment with chemotherapy (a third generation agent plus platinum) and receive a tyrosine kinase inhibitor as second-line treatment. The Committee noted that there is only limited evidence in small numbers of patients for the effectiveness of afatinib after prior chemotherapy. However, it acknowledged that the phase II LUX-Lung 2 trial suggested that afatinib is also effective when used as second-line treatment after chemotherapy. The Committee concluded that afatinib is likely to be clinically and cost effective as a second-line treatment for the minority of patients who have received chemotherapy as first-line treatment. The Committee therefore recommended afatinib as a treatment option in line with its marketing authorisation; that is, if the person has not previously had an EGFR tyrosine kinase inhibitor.\n\nThe Committee considered whether afatinib should be considered as an innovative technology, given that it is another tyrosine kinase inhibitor for the treatment of EGFR mutation-positive NSCLC. The Committee noted that afatinib irreversibly binds to the ErbB family of receptors making it different, in vitro, from the tyrosine kinase inhibitors erlotinib and gefitinib (see section 2.1). The Committee heard from the clinical specialists that there is the possibility that, because of its mechanism of action, afatinib may be less likely to be associated with the development of resistance to tyrosine kinase inhibitors. However, the Committee concluded that the clinical evidence did not suggest that the mode of action for afatinib led to any significant benefit in clinical effectiveness compared with erlotinib and gefitinib. The Committee concluded that afatinib could not be considered to show significant innovation over the other tyrosine kinase inhibitors. The Committee again acknowledged the importance of the ongoing LUX-Lung 7 trial to provide further evidence on the clinical effectiveness of afatinib compared with gefitinib.\n\n# Summary of Appraisal Committee's key conclusions\n\n## Key conclusion\n\nAfatinib is recommended as an option, within its marketing authorisation, for treating adults with locally advanced or metastatic non-small-cell lung cancer only if:\n\nthe tumour tests positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and\n\nthe person has not previously had an EGFR-TK inhibitor and\n\nthe manufacturer provides afatinib with the discount agreed in the patient access scheme.\n\nThe Committee concluded that on balance afatinib is likely to have similar clinical efficacy to erlotinib and gefitinib.\n\nThe Committee concluded that methodological issues related to the assumption of proportional hazards, the extrapolation of progression-free survival and the population of the base-case model prevented the Committee from assessing the cost effectiveness of afatinib compared with erlotinib and gefitinib based on the manufacturer's model. Therefore a most plausible ICER could not be estimated.\n\nThe Committee concluded that on balance, based on all the evidence considered, afatinib is considered to be a reasonable alternative treatment option compared with erlotinib and gefitinib, in people with locally advanced or metastatic EGFR mutation-positive NSCLC that has not been previously treated with an EGFR tyrosine kinase inhibitor or chemotherapy.\n\nThe Committee concluded that afatinib is likely to be clinically and cost effective as a second-line treatment for the minority of patients who have received chemotherapy as first-line treatment. The Committee therefore recommended afatinib as a treatment option in line with its marketing authorisation.\n\nSee sections 1.1, 4.8, 4.10, 4.12 and 4.13.\n\n## Current practice\n\nThe clinical specialists highlighted that the standard first choice of treatment for NSCLC with EGFR-positive tyrosine kinase mutations was a tyrosine kinase inhibitor, which is in line with NICE technology appraisal guidance 258 and 192.\n\nThe Committee concluded that treatment with erlotinib or gefitinib is standard practice for most people presenting with EGFR mutation-positive locally advanced or metastatic NSCLC.\n\nThe Committee also concluded that erlotinib and gefitinib were appropriate comparators and that further first-line treatment options for EGFR mutation-positive locally advanced or metastatic NSCLC would be of value to clinicians and patients.\n\nSee sections 4.1 and 4.2.\n\n## The technology\n\nThe Committee heard from clinical specialists that the irreversible binding of afatinib to the ErbB family of receptors (compared with the reversible binding of gefitinib and erlotinib) is believed to help reduce the possibility of resistance and delay its development.\n\nSee section 4.2.\n\nThe Committee concluded that the clinical evidence did not suggest that the mode of action for afatinib led to any significant benefit in clinical effectiveness compared with erlotinib and gefitinib. The Committee concluded that afatinib could not be considered to show significant innovation over the other tyrosine kinase inhibitors.\n\nSee section 4.14.\n\nThe Committee heard from the clinical specialists that if recommended, afatinib would be likely to be considered alongside erlotinib and gefitinib for locally advanced or metastatic NSCLC that had not been treated with a tyrosine kinase inhibitor.\n\nSee section 4.2.\n\nThe Committee concluded that although afatinib has a different adverse reaction profile from erlotinib and gefitinib, overall the toxicity of the tyrosine kinase inhibitors was similar.\n\nSee section 4.9.\n\n## Evidence for clinical effectiveness\n\nThe Committee heard from the clinical specialists that the chemotherapy doublets used in LUX-lung 3 and LUX-lung 6 were regarded as best clinical practice at the time.\n\nThe Committee noted that because there were no head-to-head trials comparing the clinical effectiveness of afatinib with erlotinib and gefitinib, the manufacturer presented a network meta-analysis.\n\nThe Committee concluded that evidence from the mixed treatment comparison was not sufficiently robust because of the underlying methodology (violation of the proportional hazards assumption) and because it was based on a predominantly Asian population, who were not considered generalisable to the UK.\n\nSee sections 4.3, 4.6 and 4.8.\n\nThe Committee concluded that a mixed treatment comparison for EGFR mutation-positive patients of non-Asian ethnicity would be more clinically relevant to people with NSCLC in England, but that this had not been done.\n\nSee section 4.8.\n\nThe LUX-Lung trials provided sufficient evidence to conclude that afatinib was clinically effective in prolonging progression-free survival but because of the immaturity of the overall survival data available, there was uncertainty about whether treatment with afatinib resulted in an overall survival benefit compared with chemotherapy.\n\nThe Committee concluded that evidence from the mixed treatment comparison was not sufficiently robust because of the underlying methodology (violation of the proportional hazards assumption) and because it was based on a predominantly Asian population, who were not considered generalisable to the UK.\n\nSee sections 4.3 and 4.8.\n\nThe Committee concluded that although there was uncertainty about the underlying reason, on balance the ERG analysis showed that ethnicity had an impact on the effectiveness of afatinib in clinical practice, and that the effectiveness of afatinib in clinical practice in England would be best represented by clinical effectiveness data in a non-Asian group.\n\nSee section 4.5.\n\nThe Committee concluded that on balance afatinib is likely to have similar clinical efficacy to erlotinib and gefitinib.\n\nSee section 4.6.\n\n## Evidence for cost effectiveness\n\nThe manufacturer of afatinib submitted cost-effectiveness evidence as part of its submission, based on a mixed treatment comparison.\n\nThe ERG submitted an exploratory cost analysis and an exploratory economic analysis of afatinib compared with cisplatin in combination with pemetrexed, based on the trial data.\n\nSee sections 4.10 to 4.12.\n\nThe Committee concluded that methodological issues related to the assumption of proportional hazards, the extrapolation of progression-free survival and the population of the base-case model prevented the Committee from assessing the cost effectiveness of afatinib compared with erlotinib and gefitinib based on the manufacturer's model. Therefore a most plausible ICER could not be estimated.\n\nSee section 4.10.\n\nThe Committee did not draw any specific conclusions about the health-related quality-of-life benefits and utility values.\n\nNone were identified.\n\nThe main drivers of cost effectiveness were: the mixed treatment comparison-based hazard ratios for progression-free and overall survival, the cost per month for the progression-free health state and the cost per month for the best supportive care period of the progressive disease health state.\n\nSee section 3.19.\n\nA most plausible ICER could not be estimated.\n\nThe Committee concluded that on balance, based on all the evidence considered, afatinib is considered to be a reasonable alternative treatment option compared with erlotinib and gefitinib, in people with locally advanced or metastatic EGFR mutation-positive NSCLC that has not been previously treated with an EGFR tyrosine kinase inhibitor or chemotherapy.\n\nSee sections 4.10 and 4.12.\n\n## Additional factors taken into account\n\nThe manufacturer of afatinib has agreed a patient access scheme with the Department of Health in which a confidential discount is applied at the point of purchase or invoice.\n\nSee section 2.3.\n\nThe manufacturer did not make a case for afatinib to be considered under the end of life criteria.\n\nNo equality and diversity issues relating to population groups protected by equality legislation were highlighted when the scope for this appraisal was developed, or during the appraisal.", 'Recommendations for further research': 'The Committee recognised the importance of further clinical trials comparing the effectiveness of the tyrosine kinase inhibitors (afatinib, erlotinib and gefitinib) in EGFR mutation-positive locally advanced or metastatic NSCLC. It acknowledged the relevance of the ongoing study (LUX-Lung 7) which directly compares afatinib and gefitinib in people with EGFR mutation-positive advanced NSCLC and is due to report in 2015.', 'Changes after publication': 'June 2014: Minor maintenance\n\nISBN: 978-1-4731-0555-3'}	https://www.nice.org.uk/guidance/ta310	Evidence-based recommendations on afatinib (Giotrif) for treating EGFR-positive locally advanced or metastatic non-small-cell lung cancer in adults.
dd5eebb1be3e3330d7c353a1cfa69a889055a0e7	nice	Bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem cell transplantation	Bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem cell transplantation Evidence-based recommendations on bortezomib (Velcade) for treating multiple myeloma before chemotherapy and stem cell transplant in adults. # Guidance Bortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.# The technology Bortezomib (Velcade, Janssen‑Cilag) is an anticancer drug that works by reversible proteasome inhibition. By inhibiting proteasomes (multi-enzyme complexes present in all cells), bortezomib interferes with the cell cycle leading to cell death. It is administered by intravenous infusion or subcutaneous injection. Bortezomib has a UK marketing authorisation for use 'in combination with dexamethasone, or with dexamethasone and thalidomide for the induction treatment of adult patients with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation'. The summary of product characteristics lists the following as the most commonly reported adverse reactions for bortezomib: nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia. For full details of adverse reactions and contraindications, see the summary of product characteristics. The cost of bortezomib is £762 per 3.5‑mg vial (excluding VAT; British National Formulary edition 66). According to the marketing authorisation bortezomib should be given in combination with dexamethasone (4 cycles of 21 days each) or with dexamethasone and thalidomide (4 cycles of 28 days each; 2 additional cycles of 28 days each for patients with at least partial response after the fourth cycle). Four intravenous infusions or subcutaneous injections of bortezomib are administered per cycle, on days 1, 4, 8 and 11 of each cycle. The average cost of a course of treatment with bortezomib given with dexamethasone is estimated to be £12,261 and the average cost of a course of treatment with bortezomib given with dexamethasone and thalidomide is estimated to be £24,840. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (section 7) considered evidence submitted by the manufacturer of bortezomib and a review of this submission by the Evidence Review Group (ERG; section 8). # Clinical effectiveness The main clinical evidence submitted by the manufacturer for the bortezomib, thalidomide and dexamethasone regimen came from the PETHEMA trial in which in people with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation received up to 6 cycles of bortezomib, thalidomide and dexamethasone, or thalidomide and dexamethasone. The evidence for the bortezomib and dexamethasone regimen came from the IFM trial, which compared 4 cycles of bortezomib and dexamethasone with 4 cycles of vincristine, doxorubicin and dexamethasone. The manufacturer also submitted data from the GIMEMA trial which compared the efficacy and safety of 3 cycles of bortezomib, thalidomide and dexamethasone with 3 cycles of thalidomide and dexamethasone as induction treatment before autologous stem cell transplantation followed by consolidation treatment with 2 cycles of either bortezomib, thalidomide and dexamethasone or thalidomide and dexamethasone. However, the manufacturer highlighted that the PETHEMA trial study design better reflected how the bortezomib, thalidomide and dexamethasone regimen is expected to be used in the UK and therefore was the focus of the manufacturer's submission. Data from the HOVON trial were provided by the manufacturer, but the bortezomib-containing regimen included in this study, bortezomib, doxorubicin and dexamethasone, was not approved by the European Medicines Agency and is therefore not a licensed regimen. The PETHEMA trial was a randomised, open-label phase III study that compared the efficacy and safety of bortezomib in combination with thalidomide and dexamethasone against thalidomide and dexamethasone in people with newly diagnosed symptomatic multiple myeloma and measurable disease (serum and/or urine M protein), who were eligible for autologous stem cell transplantation. Patients were randomised to either bortezomib, thalidomide and dexamethasone (n=130) or thalidomide and dexamethasone (n=127), both of which consisted of 6 cycles of 28 days, with each cycle including 4 infusions of bortezomib, oral dexamethasone (40 mg on days 1–4 and 8–11 of each cycle) and oral thalidomide (50 mg daily). After transplantation, patients who continued in the trial were re-randomised to receive 1 of 3 maintenance treatments (interferon alfa‑2b, thalidomide, or bortezomib plus thalidomide). Maintenance therapy was continued for up to 3 years, or until disease progression. Although the PETHEMA trial did not incorporate the discontinuation rule as per the summary of product characteristics, because patients in the GIMEMA trial received only 3 cycles, the manufacturer stated that the PETHEMA trial design better reflected how the bortezomib, thalidomide and dexamethasone regimen is expected to be used in the UK. The GIMEMA trial was a randomised, open-label, phase III study in 480 patients with newly diagnosed, previously untreated symptomatic multiple myeloma with measurable disease. The study was designed to compare the efficacy and safety of 3 cycles of bortezomib, thalidomide and dexamethasone with 3 cycles of thalidomide and dexamethasone as induction treatment before autologous stem cell transplantation. It also evaluated subsequent consolidation treatment consisting of 2 cycles of either bortezomib, thalidomide and dexamethasone, or thalidomide and dexamethasone. Maintenance treatment with dexamethasone was continued until disease progression or relapse. Each cycle of induction therapy consisted of 1.3 mg/m2 of bortezomib on days 1, 4, 8 and 11, with 100 mg of thalidomide daily for the first 14 days and 200 mg thereafter. Dexamethasone 40 mg was administered on days 1, 2, 4, 5, 8, 9, 11 and 12. Instead of the dosage recommended in the summary of product characteristics, patients randomised to the bortezomib, thalidomide and dexamethasone induction group received only 3 cycles of bortezomib-based treatment. The IFM trial was a randomised, open-label study designed to compare the efficacy and safety of bortezomib and dexamethasone (with or without consolidation treatment with dexamethasone, cyclophosphamide, etoposide and cis-platinum) against vincristine, doxorubicin and dexamethasone (with or without intensification). Treatment with bortezomib and dexamethasone consisted of 4 21‑day cycles of 1.3 mg/m2 of bortezomib and 40 mg of dexamethasone. However, the manufacturer stated that only the results without the intensification step were relevant to the decision problem. Moreover, as discussed previously, the manufacturer stated that this comparison was not in line with the decision problem because the vincristine, doxorubicin and dexamethasone regimen is not a thalidomide-containing regimen and therefore not an appropriate comparator. The manufacturer also stated that the vincristine, doxorubicin and dexamethasone regimen is not routinely used in UK clinical practice and excluded this from its base-case analysis. The primary outcome measures in the PETHEMA, GIMEMA and IFM trials were response rates reported after induction and after transplant. The manufacturer's submission reported 'response' in terms of: complete response near-complete response very good partial response (not used in the PETHEMA trial) partial response progressive disease -verall response rate.Overall response rate was calculated as the total proportion of patients who had a partial response or better. All response rates were evaluated using the European Group of Blood and Bone Marrow Transplant (EBMT) criteria and the International Myeloma Working Group uniform criteria. Patients who received bortezomib (bortezomib, thalidomide and dexamethasone) had a statistically significant difference in overall response rate after induction compared with the thalidomide regimen (thalidomide and dexamethasone) in both the PETHEMA (84.6% compared with 61.4%, p<0.001) and GIMEMA (93.2% compared with 78.6%, p<0.0001) trials. This difference in treatment effect on overall response rate was maintained after transplant (77.7% compared with 56.7%, p<0.001 in the PETHEMA trial and 93.2% compared with 84.5%, p<0.0025 in the GIMEMA trial). Patients receiving bortezomib in PETHEMA and GIMEMA also showed statistically higher post-induction and post-transplant complete response rates than those on the thalidomide-containing regimen. In the PETHEMA trial, 35.4% in the bortezomib, thalidomide and dexamethasone treatment group had a post-induction complete response compared with 13.4% in the thalidomide and dexamethasone group (p<0.001). In the GIMEMA trial, 18.6% had a post-induction complete response in the bortezomib, thalidomide and dexamethasone treatment group compared with 4.6% in the thalidomide and dexamethasone group (p<0.0001). In the post-transplant period, statistically significant differences were maintained for the bortezomib, thalidomide and dexamethasone treatment groups in both the PETHEMA and GIMEMA trials (p<0.001 and p=0.0004 respectively). Both the PETHEMA and GIMEMA trials reported a statistically significant lower proportion of patients experiencing disease progression when treated with bortezomib, thalidomide and dexamethasone compared with patients treated with thalidomide and dexamethasone induction therapy in the post-induction period (6.2% and 23.6%, p=0.0004 in the PETHEMA trial; and 0% and 5.0%, p<0.0005 in the GIMEMA trial). In the IFM trial, people who received bortezomib in combination with dexamethasone showed a statistically significant difference in overall response rate after induction compared with vincristine, doxorubicin and dexamethasone (77.1% compared with 60.7%, p<0.001) but this difference was not maintained after stem cell transplantation (79.6% compared with 74.4%, p=0.179). Secondary outcomes reported in the PETHEMA, GIMEMA, IFM and MRC Myeloma IX (described in section 3.12) trials included: progression-free survival time to progression -verall survival proportion of patients who had stem cell transplantation adverse events.Progression-free survival was measured from the date of randomisation to the date of disease progression or death from any cause, whichever occurred first. Time to progression was calculated from the date of randomisation to the date of disease progression or death due to disease progression. Overall survival was calculated from the date of randomisation to the date of death from any cause for the intention-to-treat populations. The manufacturer reported the unadjusted hazard ratios for progression-free survival for the PETHEMA, GIMEMA and IFM trials. Median follow-up in the trials was 35.9 months (PETHEMA), 36 months (GIMEMA) and 33 months (IFM). Progression-free survival was longer in the bortezomib, thalidomide and dexamethasone arms of both the PETHEMA and GIMEMA trials than the thalidomide and dexamethasone arms, and the difference was statistically significant (PETHEMA hazard ratio 0.65, 95% confidence interval 0.45 to 0.92, p=0.015; GIMEMA HR 0.63, 95% CI 0.45 to 0.88, p=0.0061). Progression-free survival was longer in the bortezomib and dexamethasone arm of the IFM trial compared with the vincristine, doxorubicin and dexamethasone arm, but the difference was not statistically significant (IFM HR 0.88, 95% CI 0.70 to 1.11, p value not reported). The manufacturer's submission reported the median time to progression and time to progression hazard ratios from the PETHEMA and IFM trials. In the PETHEMA study there was a statistically significant lower hazard of progression in patients treated with bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone (HR 0.64, 95% CI 0.44 to 0.93, p=0.017). No statistically significant difference in median time to progression was reported. In the IFM study there was a numerically lower hazard of progression in patients treated with bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone but this was not statistically significant (HR 0.82, 95% CI 0.63 to 1.06, p value no reported). The manufacturer's submission reported unadjusted overall survival hazard ratios for the PETHEMA and IFM trials. Median overall survival was not reached in either the PETHEMA trial (bortezomib, thalidomide and dexamethasone compared against thalidomide and dexamethasone, hazard ratio 0.80, 95% CI 0.48 to 1.34, p=0.393) or IFM trial (bortezomib and dexamethasone compared against vincristine, doxorubicin and dexamethasone, HR 0.8, 95% CI 0.54 to 1.19; p value not reported) and there was no statistically significant difference in overall survival between the treatment arms in each study. The manufacturer's submission highlighted clinical specialist opinion that the durations of the trials were too short to allow differences in overall survival and progression-free survival between treatment groups to be sufficiently captured, given the relatively long survival in this patient population after an autologous stem cell transplant. The bortezomib-containing arms of the PETHEMA and GIMEMA trials (bortezomib, thalidomide and dexamethasone) reported higher proportions of patients having stem cell transplantation compared with the thalidomide and dexamethasone arms (80.8% compared with 61.4% in PETHEMA, and 88.0% compared with 82% in GIMEMA). In addition, the bortezomib and dexamethasone arm of the IFM trial reported higher proportions of patients having stem cell transplantation compared with the vincristine, doxorubicin and dexamethasone arm (89.1% compared with 81.8%). However, no statistical tests were reported. In the absence of head-to-head trials comparing bortezomib-based regimens against cyclophosphamide in combination with thalidomide and dexamethasone, the manufacturer originally presented an indirect comparison based on the PETHEMA, GIMEMA, HOVON, IFM and MRC Myeloma IX randomised controlled trials. The MRC Myeloma IX trial is the only trial that has compared the efficacy of cyclophosphamide, vincristine, doxorubicin and dexamethasone against cyclophosphamide, thalidomide and dexamethasone in 1111 patients with newly diagnosed symptomatic myeloma. In this trial, patients were randomised to receive induction chemotherapy following either an intensive or non-intensive (attenuated treatment) pathway. The manufacturer considered that the MRC Myeloma IX trial provided the only potential evidence that allowed any form of comparison to be made between bortezomib-based regimens and cyclophosphamide, thalidomide and dexamethasone. The bortezomib plus doxorubicin and dexamethasone regimen (used in the HOVON trial) was included as part of the evidence submission but the manufacturer considered its inclusion in the indirect comparison to be inappropriate because this regimen was not included in the marketing authorisation. The manufacturer stated that a network could not be formed between the available trials, and an indirect comparison with cyclophosphamide, thalidomide and dexamethasone was not possible. In addition, bortezomib and dexamethasone could not be linked to a thalidomide-containing regimen. The manufacturer highlighted that assumptions to overcome the network limitations would generate considerable uncertainties and unreliable results. The manufacturer stated that an incremental analysis of the 2 licensed bortezomib regimens was therefore also not possible and stated that the base case should focus on the comparison of bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone. The manufacturer presented a summary of results for adverse events for the PETHEMA, GIMEMA, IFM and MRC Myeloma IX trials. Only adverse events for the post-induction phase were reported because the manufacturer considered the adverse events for the post-transplant phase not to be relevant. Across all trials a similar proportion of patients reported any adverse event, grade 3/4 adverse events, and serious adverse events in both the bortezomib and comparator treatment arms. However, in the PETHEMA trial a statistically significantly greater number of total treatment-related adverse events was reported during induction with bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone (relative risk =1.42; 95% CI 1.17 to 1.73). In the GIMEMA trial a statistically significantly greater proportion of patients receiving bortezomib, thalidomide and dexamethasone experienced any grade 3/4 adverse event than those receiving thalidomide and dexamethasone (RR=1.69; 95% CI 1.36 to 2.08). The 2 most common treatment-related adverse events in the PETHEMA trial (pneumonia and peripheral neuropathy) occurred more frequently in the bortezomib, thalidomide and dexamethasone arm than in the thalidomide and dexamethasone arm. The manufacturer's submission highlights that in the 4 bortezomib-based studies, bortezomib was given intravenously. In terms of tolerability, total withdrawals and withdrawals due to disease progression were statistically significantly less in the bortezomib, thalidomide and dexamethasone arm than the thalidomide and dexamethasone arm in the PETHEMA trial (HR 0.51 and HR 0.45 respectively). No health-related quality of life data were collected in the trials of bortezomib-containing regimens. To inform the cost-effectiveness evidence, the manufacturer conducted a systematic literature search to identify publications relevant to the decision problem in relation to health-related quality of life. ## Evidence Review Group comments The ERG stated that the manufacturer's search strategy was clear and comprehensive. The ERG noted that 5 trials were included in the manufacturer's original submission, but highlighted that only 2 trials (PETHEMA and GIMEMA) met the NICE scope and focused its critique on these trials. This was in line with the manufacturer's addendum. The ERG stated that both trials were unblinded and therefore at risk of detection bias. The ERG agreed with the manufacturer that the baseline characteristics were generally similar across the trials. However, the ERG also highlighted that the PETHEMA and GIMEMA trials excluded patients older than 65 years, which does not reflect UK clinical practice. The ERG commented that overall, the manufacturer's approach to the trial statistics was appropriate and reasonably well reported. However, the ERG commented that long-term outcomes such as progression-free survival and overall survival may be confounded by post-induction consolidation and maintenance treatments that do not reflect current UK clinical practice. The ERG also noted that there is uncertainty in the robustness of the progression-free survival and overall survival results because of the high censoring of data in the bortezomib, thalidomide and dexamethasone, and thalidomide and dexamethasone arms of the PETHEMA trial (57.7% and 44.9% respectively in the progression-free survival analysis, and 80.0% and 74.8% respectively in the overall survival analysis). The ERG noted that the manufacturer had highlighted that the results from the indirect comparison were subject to substantial uncertainty and were therefore not included in the economic modelling. The ERG agreed with this approach. # Cost effectiveness The manufacturer conducted a systematic search of the literature and identified 3 cost-effectiveness studies relevant to the decision problem. The manufacturer conducted a quality assessment of these studies but did not discuss them further in the submission. The manufacturer developed an Excel-based economic model to assess the cost effectiveness of bortezomib-based induction regimens compared with thalidomide-based induction regimens. As discussed previously, the manufacturer's base-case analysis focused on the cost-effectiveness analysis of bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The manufacturer presented cost-effectiveness analyses of bortezomib, thalidomide and dexamethasone (including the discontinuation rule stipulated in the marketing authorisation submitted as an addendum submission) compared with thalidomide and dexamethasone, and of bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone. The manufacturer acknowledged that the comparison with vincristine, doxorubicin and dexamethasone did not reflect current best clinical practice in the UK. The manufacturer stated that no comparisons of the bortezomib and dexamethasone regimen with relevant thalidomide-containing regimens (such as cyclophosphamide, thalidomide and dexamethasone) were possible using indirect mixed treatment comparisons. The manufacturer chose a state-transition Markov model, with a cycle length of 1 month, to reflect the length of a course of treatment with bortezomib, thalidomide and dexamethasone (28 days) and because clinical outcomes are reported in months. The model did not include a half-cycle correction because the cycle length was short relative to the time horizon used in the model. Costs and quality-adjusted life years (QALYs) were discounted over a lifetime (30 years) time horizon at 3.5% per annum. The manufacturer stated that the model captured the 2 most important outcomes: post-induction response rate and overall survival. However, the manufacturer clarified that because the pivotal trials were not powered to detect a statistically significant difference in overall survival, the model was based on response rate, and the relationship between response rate and overall survival was quantified using long-term survival data from older trials in the same patient population. The model assumed that patients entered at the start of their induction therapy. After induction, patients in the model entered one of 3 health states: complete response, partial response, or non-responders (defined as minimal response, stable disease and progressive disease respectively). Depending on their post-induction response rate, patients subsequently proceeded to high-dose chemotherapy and stem cell transplantation or to the post-induction progression-free survival health state (non-stem cell transplant group). After induction, all patients were assumed to incur the same survival benefit, which was dependent only on their response rate after the induction phase and was independent of the actual induction regimen that they received. On disease progression, patients would then receive a second treatment, followed by third-line and subsequent lines of treatment after further progression. Post-induction response rates were used as the main measure of efficacy in the model. Stem cell transplant rates for each response category in each treatment arm were used in the model evaluating bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The economic model for bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone used total stem cell transplant rates rather than transplant rates for each response category. The model also included mortality during the induction and transplant periods. In order to model long-term survival based on the post-induction response rates, the manufacturer extracted overall survival data from the MRC Myeloma VII trial because overall survival data from the PETHEMA trial were considered immature. The MRC Myeloma VII trial randomised a total of 407 previously untreated multiple myeloma patients to conventional chemotherapy (n=200) or high-dose chemotherapy followed by autologous stem cell transplant (n=201). The 5-year survival in the high-dose chemotherapy followed by autologous stem cell transplant group was 88.6 months (95% CI 61.4, upper CI not reported) for patients who had a complete response, 39.8 months (95% CI 33.8 to 61.4) for patients who had a partial response, and 25.6 months (95% CI 7.0 to 31.3) for patients who had no response. For a scenario analysis, the manufacturer also used long-term survival data from the IFM90 trial from 1996. The manufacturer used post-transplant time to progression from the PETHEMA trial to determine the probabilities of transition from the post-transplant progression-free health state to the start of second-line therapies. The manufacturer assumed that time to progression is affected by the interventions because it was modelled using separate parametric curves by treatment and response category. In the base case, time-to-progression transition probabilities were derived from exponential curves fitted to the PETHEMA data. Constant transition probabilities were used for transition from the second-line to the third-line health state across the 2 interventions, the estimates for which were derived from the subgroups of patients who had 1 or 2 lines of treatment respectively in the APEX trial (which compared bortezomib monotherapy with high-dose dexamethasone in patients with relapsed multiple myeloma). Probabilities of transition from third to further lines of treatment were derived by applying an exponential distribution to the time-to-progression data from the APEX trial. The overall survival data from the MRC Myeloma VII trial were used to determine the length of time that patients remained in the further lines of treatment health state before moving to the death state. The manufacturer conducted a systematic search of the literature to identify publications that identified health-related quality of life data relevant to the decision problem. Five relevant studies were identified, of which 3 reflected the current UK patient population and clinical practice. The manufacturer selected the van Agthoven study as the base-case source of utility values because the utility values were obtained using EQ‑5D. The study by van Agthoven et al. compared chemotherapy (n=129) with intensive chemotherapy followed by myeloablative chemotherapy with stem cell transplantation (n=132) and total body irradiation treatment regimens. Patients were from the Netherlands and Belgium, under the age of 65 years, and had newly diagnosed and untreated multiple myeloma. They received 3 or 4 cycles of vincristine, doxorubicin and dexamethasone and 2 cycles of intermediate-dose melphalan, after which they were randomised to have either stem cell transplantation and interferon maintenance, or interferon maintenance only. The manufacturer applied a disutility of 0.02 to each patient experiencing an adverse event associated with induction therapy. The costs applied in the model were taken from the BNF edition 64 (2012) and the 2012–13 Chemotherapy Regimens List. Administration of chemotherapy drugs, outpatient visits and tests as part of disease and treatment monitoring and the costs relating to stem cell transplantation were taken from the 2011–12 National Schedule Reference costs. The costs associated with treating adverse events were based on inpatient, outpatient or day-case visit National Schedule Reference costs. The manufacturer presented unit costs associated with each of the first-line induction therapies as well as drugs for prophylaxis, administration and monitoring. The total cost, including prophylaxis, administration and monitoring, of the bortezomib, thalidomide and dexamethasone regimen was £28,034, which compared with a total cost of £8,865 for thalidomide and dexamethasone. The total cost of the bortezomib and dexamethasone regimen was £14,104, whereas the total cost of vincristine, doxorubicin and dexamethasone was £2732. The manufacturer's economic model estimated a difference in total costs between the bortezomib, thalidomide and dexamethasone and the thalidomide and dexamethasone regimens of £20,682. The bortezomib, thalidomide and dexamethasone regimen was associated with a 1.01 QALY gain compared with thalidomide and dexamethasone. The manufacturer's estimated base-case incremental cost-effectiveness ratio (ICER) for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone was £20,468 per QALY gained. The incremental cost difference between the bortezomib and dexamethasone and the vincristine, doxorubicin and dexamethasone regimens was £12,710, and bortezomib and dexamethasone was associated with an incremental QALY gain of 0.88 resulting in an estimated ICER of £14,446 per QALY gained for the bortezomib and dexamethasone regimen compared with vincristine, doxorubicin and dexamethasone. The manufacturer's deterministic sensitivity analyses highlighted that the results for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone were most sensitive to the mortality for patients who had a complete response after induction therapy, and to drug costs. If the complete response mortality rate was varied within its 95% confidence interval, other things being equal, the ICER ranged from £17,018 to £28,867 per QALY gained. For the bortezomib, thalidomide and dexamethasone drug costs, sensitivity analyses were conducted using 4, 5 and 6 cycles of induction therapies. This was based on clinical opinion that the number of cycles will vary from one patient to another. The ICER range for the sensitivity analysis varying bortezomib, thalidomide and dexamethasone drug costs was £15,761 to £25,662 per QALY gained. For all other parameters varied in the sensitivity analyses, the ICER remained between £16,000 and £25,000 per QALY gained. Deterministic sensitivity analyses were also presented by the manufacturer for the comparison between the bortezomib and dexamethasone, and the vincristine, doxorubicin and dexamethasone regimens. Here, the results were most sensitive to the mortality for patients with complete response after induction therapy, with ICERs ranging from £10,961 to £18,354 per QALY gained. The results of the manufacturer's probabilistic sensitivity analysis showed that, at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained, there was a 35.4% and 71.3% probability respectively of the bortezomib, thalidomide and dexamethasone regimen being cost effective when compared with thalidomide and dexamethasone. The manufacturer estimated that at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained, there was a 68.9% and 83.2% probability respectively of the bortezomib and dexamethasone regimen being cost effective compared with vincristine, doxorubicin and dexamethasone. The ERG stated that the structure of the model was consistent with the clinical pathway of care for multiple myeloma and was clearly presented. However, the ERG highlighted that the manufacturer's analysis of bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone was outside the scope. It also highlighted that, given that the comparator in routine use in UK clinical practice is the cyclophosphamide, thalidomide and dexamethasone regimen, the comparison of bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone was not entirely relevant to clinical practice. The ERG also expressed some concerns that the model extrapolated level of response after induction therapy to long-term survival and time to progression based on data from the MRC Myeloma VII trial. The ERG cautioned that the MRC Myeloma VII trial was old and its outcomes may not reflect the more advanced treatments available today. Moreover, the ERG stated that data from the MRC Myeloma VII trial related to maximal response to treatment rather than post-induction response rate, and the resulting survival curves might be confounded to some extent with post-stem cell transplant response. The ERG clinical expert agreed that response rate at induction predicts progression-free survival and overall survival. However, the ERG stated that other surrogate outcomes, such as post-stem cell transplant response rate, may offer a better prediction of progression-free survival and overall survival. The ERG observed that although the model had separate states for those who received a stem cell transplant and those who did not, the model attached no explicit survival benefit to a stem cell transplant other than that achieved by delaying the transition to the post-induction/post-transplant progression-free survival state for the duration of the stem cell transplant period. The ERG clinical expert stated that stem cell transplantation offers a survival benefit of 12–18 months compared with no transplant, and the ERG stated that it would have been more transparent to distinguish the separate effects on survival of post-induction response and stem cell transplantation. Alternatively, post-stem cell transplant response rate could have been considered because it has been shown to be statistically significantly associated with improved overall survival. Overall, the ERG stated that external validity would have been strengthened if the model had been based on overall survival and time to progression Kaplan–Meier curves or post-stem cell transplant response, rather than post-induction response. The ERG was concerned that in the absence of this the results were systematically biased in favour of bortezomib, thalidomide and dexamethasone. The ERG stated that, in contrast to the manufacturer's description in the submission, the model implicitly assumed a continuing effect of induction treatment after induction is complete, because separate time to progression curves were used for each induction treatment arm and stem cell transplant mortality was also applied separately by treatment arm. The ERG also highlighted that, contrary to statements in the manufacturer's submission, the probability of receiving a stem cell transplant was not dependent on post-induction response, but only on treatment received. The ERG noted the manufacturer's approach to calculating transition probabilities (section 3.23), and stated that the exponential distribution fitted to the PETHEMA complete response time to progression data for bortezomib, thalidomide and dexamethasone resulted in a shorter median survival time (approximately 61 months) than the exponential distribution fitted to complete response time to progression data for patients receiving thalidomide and dexamethasone (median survival approximately 98 months). The ERG stated that this contrasted with overall findings for progression-free survival in the trial publication in which median progression-free survival was statistically significantly higher with bortezomib, thalidomide and dexamethasone than with thalidomide and dexamethasone. The ERG noted that the manufacturer derived transition probabilities for third and further treatment lines using data from the APEX trial, which compared bortezomib monotherapy with high-dose dexamethasone in patients with relapsed multiple myeloma. The ERG commented that because the APEX trial used bortezomib as a monotherapy treatment, it may have had different survival outcomes to those seen with bortezomib combination therapy. The ERG considered that the costs included in the model were reasonable. However, the ERG identified that a number of changes to the manufacturer's addendum economic model, submitted to take account of the discontinuation rule stipulated for bortezomib, thalidomide and dexamethasone (see section 3.19), were not documented by the manufacturer. Although the manufacturer's addendum referred to the original submission for discussion of resource identification, measurement and valuation, the ERG noted that many of the costs in the revised model were different from those in the original model. These included costs for drugs, induction, stem cell transplant, second-line treatment, third-line treatment, and some monitoring costs. The ERG noted that although these changes were generally minor, some were substantial. For example, the administration costs for high-dose dexamethasone increased from £168 to £1242 in second-line therapy, and from £168 to £1288 in third-line therapy. The ERG stated that when considering only model changes and assumptions that were documented in the manufacturer's addendum, the ICER was £23,958 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, compared with the £20,468 per QALY gained reported in the manufacturer's addendum. The ERG conducted a series of additional exploratory analyses. It considered that the MRC Myeloma VII trial was old and its outcomes may not reflect the more advanced treatments available today (see section 3.30) and noted that the manufacturer's sensitivity analysis used an even older study (the IFM90). Therefore, the ERG obtained data from a study by Alvares and from the NMSG 5/94 study to conduct scenario analyses. The NMSG 5/94 study was a prospective study with 247 patients recruited between 1994 and 1997, and Alvares was a retrospective study with 383 patients in England diagnosed with multiple myeloma between 1985 and 2004. The ERG considered that the Alvares data provided the better fit to the PETHEMA overall survival data. The ERG commented that because median overall survival for partial and non-responders in the Alvares study was much better than in the MRC Myeloma VII trial, this resulted in an increase in the base-case ICER from £20,468 per QALY gained to £30,368 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The ERG also provided the ICER using the data from the NMSG 5/94 study, but this did not include the discontinuation rule for the bortezomib, thalidomide and dexamethasone regimen and is therefore not presented. However, it resulted in a higher ICER than using the Alvares study data. The ERG also highlighted that data from the MRC Myeloma VII trial related to maximal response to treatment rather than post-induction response rate and that this was arguably more similar to post-stem cell transplant response. The ERG commented that post-stem cell transplant response rates provided a more consistent fit to the MRC Myeloma VII data and would better predict overall survival. Applying post-stem cell transplant response rates alone increased the manufacturer's base-case ICER from £20,468 to £26,292 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The ERG combined its preferred scenario analyses, that is, using data from Alvares to inform long-term survival and using post-stem cell transplant response rates. This resulted in an ICER of £38,985 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The ERG conducted further exploratory analyses using the relevant economic model outputs from the manufacturer's base-case cost-effectiveness results to calculate ICERs for all treatments compared with thalidomide and dexamethasone and with cyclophosphamide, thalidomide and dexamethasone, the latter of which is a more relevant comparator regimen in a UK population. The ERG commented that all results should be treated with extreme caution as they compare individual arms of separate trials, without adjusting for trial populations. Furthermore there were differences in the trial designs. For these reasons, the results should not be directly compared. Using the manufacturer's base-case model to compare bortezomib, thalidomide and dexamethasone against cyclophosphamide, thalidomide and dexamethasone resulted in an exploratory ICER of £228,159 per QALY gained. The ERG then applied its preferred assumptions, that is, using data from Alvares to inform long-term survival and using post-stem cell transplant response rates. This resulted in an exploratory ICER for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone of £81,983 per QALY gained. The ERG conducted the same exploratory analyses in order to calculate ICERs for the bortezomib and dexamethasone regimen compared with thalidomide and dexamethasone and with cyclophosphamide, thalidomide and dexamethasone. The ERG applied data from Alvares and used post-stem cell transplant response rates, and this resulted in an ICER of £26,701 per QALY gained for bortezomib and dexamethasone compared with thalidomide and dexamethasone. However, bortezomib and dexamethasone was dominated by (that is, was less effective and more expensive than) cyclophosphamide, thalidomide and dexamethasone. # Manufacturer's response to the appraisal consultation document Additional analyses were provided by the manufacturer in response to NICE's request for further work on the comparison between the regimen containing bortezomib and dexamethasone compared with the most relevant comparator (cyclophosphamide, thalidomide and dexamethasone) or an alternative comparator in circumstances when cyclophosphamide, thalidomide and dexamethasone is not suitable. Although the Committee did not request further analyses relating to the bortezomib, thalidomide and dexamethasone regimen, the manufacturer provided an amended model containing some revised assumptions to reflect some of the concerns raised by the ERG and the Committee's considerations in the appraisal consultation document. The manufacturer acknowledged that the cyclophosphamide, thalidomide and dexamethasone regimen was the most relevant comparator in UK clinical practice. However, it did not provide a comparison for the bortezomib, thalidomide and dexamethasone regimen with the cyclophosphamide, thalidomide and dexamethasone regimen. It highlighted that for the comparison of the bortezomib, thalidomide and dexamethasone regimen with the thalidomide and dexamethasone regimen presented in the manufacturer's base-case analysis, it was important to evaluate how much additional benefit would be gained in terms of response rates if cyclophosphamide was to be added to thalidomide and dexamethasone. The manufacturer stated that threshold analyses performed in its original submission indicated that the complete response rate for cyclophosphamide, thalidomide and dexamethasone would have to be nearly double that observed in the PETHEMA trial for thalidomide and dexamethasone for the ICER for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone to reach £30,000 per QALY gained. Therefore the manufacturer stated that the incremental clinical efficacy of cyclophosphamide, thalidomide and dexamethasone would not be substantially greater than thalidomide and dexamethasone. The manufacturer updated all the economic models so that: a survival benefit of 11.8 months for people who received a stem cell transplant was explicitly captured post-induction rates were applied on an intention-to-treat basis to all patients in the model probabilities of receiving a stem cell transplant were applied only to those who received a transplant transition probabilities to second-line therapy were included by treatment arm (rather than by treatment arm and response rate) drug administration costs were updated assuming that bortezomib is subcutaneously administered. For the model comparing the bortezomib, thalidomide and dexamethasone regimen against thalidomide and dexamethasone, the manufacturer provided a revised base-case ICER of £17,841 per QALY gained. Sensitivity analyses using data from alternative sources to inform overall survival were presented; using long-term overall survival data from the Alvares and NMSG 5/94 studies resulted in ICERs of £22,696 and £39,618 per QALY gained respectively. The probabilistic ICER for the manufacturer's revised base-case was £22,289 per QALY gained. The probabilistic ICERs for the sensitivity analyses using Alvares and NSMG5/94 were £22,952 and £39,881 per QALY gained respectively. The manufacturer also carried out sensitivity analyses by fitting parametric curves (exponential, Weibull and log-logistics) to the PETHEMA Kaplan-Meier curves. It selected the parametric functions it thought were most appropriate, providing justification for their suitability based on face validity with the trial data, resulting in a deterministic ICER of £19,359 per QALY gained and a probabilistic ICER of £19,668 per QALY gained. The manufacturer maintained that the most appropriate source to inform overall survival in model was from the MRC Myeloma VII trial. For the indirect comparison of bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone, the manufacturer used a 'matching-adjusted indirect comparison' method to account for differences in patients' baseline characteristics between the available trials. This created a new set of post-induction response rates, stem cell transplant rates and the post-transplant response rates for the bortezomib and dexamethasone arm. Using the MRC Myeloma VII trial as the source for long-term survival, the manufacturer's base-case deterministic ICER for the comparison of bortezomib and dexamethasone against cyclophosphamide, thalidomide and dexamethasone was £20,588 per QALY gained. The probabilistic ICER was £22,305 per QALY gained. Using long-term survival data from Alvares and NMSG 5/94 resulted in deterministic ICERs of £24,267 and £33,435 per QALY gained respectively, and the corresponding probabilistic ICERs were £23,816 and £33,107 per QALY gained. The manufacturer presented sensitivity by fitting parametric curves (exponential, Weibull and log-logistics) to the PETHEMA Kaplan-Meier curves (see section 3.39) which resulted in a deterministic ICER of £18,864 per QALY gained and a probabilistic ICER of £19,057 per QALY gained. In response to the Committee's request for a comparison of bortezomib and dexamethasone with a relevant comparator when cyclophosphamide, thalidomide and dexamethasone is not suitable, the manufacturer highlighted that the only relevant comparator for which there was direct available evidence was vincristine, doxorubicin and dexamethasone, which might be assumed to be approximately equivalent to cyclophosphamide and dexamethasone or other options lacking thalidomide. Therefore, the manufacturer presented a deterministic base-case ICER for bortezomib and dexamethasone compared with vincristine, thalidomide and dexamethasone (including the model amendments highlighted in section 3.38) of £18,914 per QALY gained, and a probabilistic ICER of £20,096 per QALY gained. Sensitivity analyses were presented for the alternative sources of overall survival using data from the Alvares and NMSG 5/94 studies and fitting parametric curves to the PETHEMA data, which resulted in deterministic ICERs of £25,575, £42,811 and £18,489 per QALY gained respectively. The corresponding probabilistic ICERs were £25,494, £42,528 and £18,761 per QALY gained. The ERG noted that the model structure had changed substantially from the original models and that the new approach appeared to be more intuitive. However, it highlighted that the manufacturer had not checked the external validity by validating overall survival against the PETHEMA trial. The ERG noted that the manufacturer's analysis of bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, using the MRC Myeloma VII as the source of overall survival, provided a poor fit for overall survival compared with the observed data in the PETHEMA trial. It stated that the model consistently underestimated overall survival and was systematically biased in favour of the bortezomib, thalidomide and dexamethasone regimen. The ERG noted that the bias appeared even more pronounced in the new analyses. The ERG maintained that the sensitivity analyses using data from the Alvares or NMSG 5/94 trials was a better fit for overall survival than the base-case analysis (using long-term overall survival data from the MRC Myeloma VII trial). For the comparison of the bortezomib and dexamethasone regimen with the cyclophosphamide, thalidomide and dexamethasone regimen, the ERG noted that stem cell transplant rates used in the manufacturer's model were 89.1% for the bortezomib arm (taken from the IFM trial) and 66.7% for the cyclophosphamide arm (taken from the MRC Myeloma IX trial). The ERG commented that the stem cell transplant rate for the cyclophosphamide-containing arm was inconsistent with the response data and may have substantially biased the bortezomib and dexamethasone cohort. The ERG explored the impact of assuming that the stem cell transplant rates for the cyclophosphamide-containing arm were similar to the IFM comparator arm (that is, 81.8% for vincristine, doxorubicin and dexamethasone) to better reflect the smaller differences observed between treatment arms in the other bortezomib trials (GIMEMA, HOVON and IFM). This increased the manufacturer's base-case ICER from £20,588 to £36,712 per QALY gained. The ERG stated that the manufacturer's analysis of bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone provided a poor fit for overall survival compared with the observed data in the IFM trial. The ERG noted that the manufacturer provided sensitivity analyses using alternative data sources and parametric curves to model overall survival and that it considered that these sensitivity analyses, using the Alvares or NMSG 5/94 trials, were a better fit for overall survival than the base-case analysis (using long term overall survival data from the MRC Myeloma VII trial). Full details of all the evidence are in the manufacturer's submission and the ERG report. Further evidence is available in the manufacturer's response to the appraisal consultation document and the ERG critique.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bortezomib, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of bortezomib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee noted statements from the clinical specialists and patient experts that multiple myeloma is a complex and incurable disease associated with a range of comorbidities and complications. It was aware that survival rates were historically poor until the introduction of drugs such as bortezomib, thalidomide and lenalidomide, which improved survival and quality of life. The patient experts highlighted the relapsing and remitting nature of multiple myeloma, emphasising the importance of the availability of a range of treatment options and the flexibility to choose the most appropriate treatment for individual patients because the best induction regimen is chosen based on both disease- and patient-related factors. The clinical specialists commented that bortezomib-based induction therapy would enable a higher proportion of patients to have a stem cell transplant and consequently experience longer progression-free survival and greater depth of response. The Committee also heard that bortezomib-based regimens were particularly valuable for people with clinically aggressive disease, but was aware that this group could not be clearly defined. The clinical specialists stated that induction treatment with bortezomib provides an important treatment option for patients with newly diagnosed multiple myeloma facing a high burden of disease, and when thalidomide is not a feasible treatment option because of contraindications. The Committee acknowledged the debilitating nature of the disease and the importance of having a range of treatment options available. The Committee discussed the current management of multiple myeloma for people who are newly diagnosed and eligible for high-dose chemotherapy and stem cell transplantation. It heard from the clinical specialists that stem cell transplantation is considered the gold standard treatment for multiple myeloma because it is associated with improved progression-free survival, greater depth of response and therefore improved survival. It heard from the clinical specialists that in the UK clinicians use biological age, fitness and comorbidities rather than numerical age to decide eligibility for stem cell transplantation. The Committee noted that around 20–25% of all people with multiple myeloma would be fit enough for high-dose chemotherapy followed by a stem cell transplant. The clinical specialists stated that the aim of induction therapy was to enable more people to have stem cell transplantation successfully. The clinical specialists stated that current standard induction therapy in the UK was the combination of cyclophosphamide, thalidomide and dexamethasone, and that although vincristine, doxorubicin and dexamethasone had been used in the past, this regimen is no longer used; in line with the guideline from the British Committee for Standards in Haematology on the diagnosis and management of multiple myeloma. The Committee was aware that the manufacturer's submission included a comparison of bortezomib and dexamethasone against vincristine, doxorubicin and dexamethasone. It noted that this was not a relevant comparison because it was not in line with UK clinical practice and was outside the NICE scope of the appraisal, which specified thalidomide-containing regimens as comparators. The Committee was also aware that the manufacturer did not present a comparison of bortezomib, thalidomide and dexamethasone against cyclophosphamide, thalidomide and dexamethasone, but instead presented a comparison of bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone, assuming clinical equivalence between thalidomide and dexamethasone, and cyclophosphamide, thalidomide and dexamethasone. The clinical specialists stated the 2 regimens could be considered broadly similar. However, they stated that the advantage of using a triple therapy such as cyclophosphamide, thalidomide and dexamethasone was that there was more flexibility to reduce doses in the case of toxicity. The Committee queried whether thalidomide and dexamethasone is used in UK clinical practice and heard that the cyclophosphamide, thalidomide and dexamethasone regimen is the standard induction treatment in the UK. The Committee considered that the cyclophosphamide, thalidomide and dexamethasone regimen was the most appropriate comparator. It was persuaded that the manufacturer's threshold analyses demonstrated that the addition of cyclophosphamide would have to add a clinically implausible level of additional benefit (almost double) before the ICER for bortezomib, thalidomide and dexamethasone increased above £30,000 per QALY gained compared with cyclophosphamide, thalidomide and dexamethasone (see section 3.37). Therefore the Committee concluded that bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone was a reasonable basis for appraising the clinical and cost effectiveness of bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone. # Clinical effectiveness The Committee noted that the manufacturer presented evidence on the clinical effectiveness of bortezomib from the PETHEMA, GIMEMA, HOVON and IFM trials. The Committee was aware that the HOVON trial included the bortezomib, doxorubicin and dexamethasone regimen, which was not included in the bortezomib marketing authorisation. It therefore excluded it from its clinical and cost-effectiveness discussions. It noted that the trials included different regimens of bortezomib and had different study designs. The Committee noted that in the GIMEMA trial patients only received 3 cycles of bortezomib, thalidomide and dexamethasone whereas in the PETHEMA trial patients received 6 cycles, which was more in line with the marketing authorisation. Moreover, the Committee noted that the PETHEMA and GIMEMA trials differed in the number of stem cell transplants given and the type of consolidation (intensification therapy to sustain remission before lower-dose maintenance therapy) and maintenance treatments used after transplant, and that consolidation and maintenance treatment was not standard clinical practice in the NHS. The Committee was aware that none of the trials included a comparison with cyclophosphamide, thalidomide and dexamethasone, which is standard clinical practice in England. The Committee discussed the results from the PETHEMA and IFM trials. It noted that in the PETHEMA trial, bortezomib, thalidomide and dexamethasone was associated with a statistically significant gain in overall response rate after induction compared with thalidomide and dexamethasone (84.6% compared with 61.4%, p<0.001) and that this was maintained after stem cell transplant (77.7% compared with 56.7%, p<0.001). The Committee also noted that, in the IFM trial, bortezomib and dexamethasone was associated with a similar gain in overall response rate compared with vincristine, doxorubicin and dexamethasone (77.1% compared with 60.7%, p<0.001) but a statistically significant difference was not shown after stem cell transplantation (79.6% compared with 74.4%, p=0.179). It noted that progression-free survival was longer in the bortezomib, thalidomide and dexamethasone arm of the PETHEMA trial than in the thalidomide and dexamethasone arm, and that the difference was statistically significant (hazard ratio 0.65, 95% confidence interval 0.45 to 0.92, p=0.015). It further noted that progression-free survival was longer in the bortezomib and dexamethasone arm of the IFM trial than in the vincristine, doxorubicin and dexamethasone arm, but the difference was not statistically significant (HR 0.88, 95% CI 0.70 to 1.11, p value not reported). The Committee agreed that induction treatment with bortezomib and dexamethasone was associated with statistically significant improvements in post-induction overall response rates compared with vincristine, doxorubicin and dexamethasone, and that induction treatment with bortezomib, thalidomide and dexamethasone resulted in statistically significant improvements in overall response rates (post-induction and post-stem cell transplant) and progression-free survival compared with thalidomide and dexamethasone. However, it concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone against cyclophosphamide, thalidomide and dexamethasone, the comparator regimen considered to be current standard care in the UK and therefore the most relevant comparator for the Committee's decision-making. The Committee considered the unadjusted overall survival reported in the manufacturer's submission for the PETHEMA and IFM trials. It noted that median overall survival was not reached in either the PETHEMA trial (bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, hazard ratio 0.80, 95% CI 0.48 to 1.34, p=0.393) or the IFM trial (bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone, HR 0.8, 95% CI 0.54 to 1.19, p value not reported) and there was no statistically significant difference in overall survival between the treatment arms in each study. The Committee heard from the manufacturer and from the clinical specialists that the duration of the trials was too short to allow differences in overall survival to be seen between treatment groups. The clinical specialists also stated that given the differences in trial design relating to the numbers of stem cell transplants and types of maintenance treatment received it was not possible to draw firm conclusions. The Committee concluded that although there was uncertainty in the magnitude of overall survival associated with bortezomib, it was plausible that bortezomib's impact on induction response could be associated with improved overall survival. The Committee considered the manufacturer's indirect comparison. It acknowledged the manufacturer's rationale that a network could not be formed to conduct an indirect comparison between the available trials and assumptions to overcome the network limitations would generate considerable uncertainties and unreliable results. At the appraisal consultation stage, the Committee requested further analysis comparing single arms of the available trials, adjusting for the differences between the trial designs and baseline characteristics of the patients included in each study. The Committee concluded that although there would be limitations to this approach, further analysis from the manufacturer would provide useful comparative data to draw conclusions on the relative effectiveness of bortezomib, thalidomide and dexamethasone, and bortezomib and dexamethasone, compared with the most relevant comparator cyclophosphamide, thalidomide and dexamethasone, or an alternative comparator in situations in which the cyclophosphamide, thalidomide and dexamethasone regimen is considered inappropriate. The Committee considered the adverse events associated with using a bortezomib-containing regimen. It heard from the clinical specialists that intravenously administered bortezomib had been associated with peripheral neuropathy, but that rapid dose reductions could effectively manage it. In addition, the clinical specialists highlighted that although the evidence presented was for intravenously administered bortezomib, the introduction of a subcutaneous formulation has substantially reduced the side effects related to peripheral neuropathy and also reduced the need for thromboprophylaxis. The Committee concluded that the adverse event profile of bortezomib was manageable (for full details of adverse reactions and contraindications, see the summary of product characteristics). # Cost effectiveness The Committee considered the structure, assumptions and results of the manufacturer's economic model, which was based on data from the PETHEMA and IFM trials for the bortezomib, thalidomide and dexamethasone and the bortezomib and dexamethasone regimens respectively. The Committee was aware that the model only provided comparisons for bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone and for bortezomib and dexamethasone against vincristine, doxorubicin and dexamethasone, which was not in line with current clinical practice in the UK, and that the vincristine, doxorubicin and dexamethasone regimen was outside of the scope of this appraisal. The Committee acknowledged that there was no direct evidence available to compare the bortezomib, thalidomide and dexamethasone and the bortezomib and dexamethasone regimens with cyclophosphamide, thalidomide and dexamethasone, and it asked the manufacturer to further explore this by conducting a further indirect comparison using single arms from the relevant clinical trials. The Committee considered the manufacturer's approach to using post-induction rates from the PETHEMA and IFM trials in the economic model for the bortezomib, thalidomide and dexamethasone and the bortezomib and dexamethasone regimens respectively. It noted the ERG's comments that data from the MRC Myeloma VII trial used by the manufacturer to estimate long-term survival related to maximal response to treatment rather than post-induction response rate and therefore using post-stem cell transplant response rates from the PETHEMA and IFM trials might better predict progression-free survival and overall survival. The clinical specialists stated that post-stem cell transplant response rates would be more appropriate as long as they were based on an intention-to-treat analysis that included all people who were randomised in the trials regardless of whether they received treatment or not; however, if they were based only on patients who received a transplant, post-induction response rates would be more meaningful. The ERG confirmed that post-stem cell transplant rates in both the PETHEMA and GIMEMA trials were based on an intention-to-treat analysis. The Committee concluded that using post-stem cell transplant response rates rather than post-induction response rates was more appropriate. The Committee considered the way in which long-term survival had been extrapolated in the manufacturer's model. The Committee was aware that that the model extrapolated level of response after induction therapy to long-term survival and time to progression based on data from the MRC Myeloma VII trial. It noted the ERG's comments that the MRC Myeloma VII trial was not very recent because it had recruited patients between 1993 and 2003, and that its rates for overall survival and progression-free survival were likely to be lower than would be seen in current clinical practice. The Committee was also aware that although long-term survival end points had not been reached in the PETHEMA and IFM trials, the data available in these trials suggested that the manufacturer's model, using data from MRC Myeloma VIl, underestimated overall survival. It noted that other data were available (for example, from a study by Alvares and the NMSG 5/94 study) that fit better with the data observed in the PETHEMA and IFM trials. The Committee concluded that the ERG's exploratory analysis using data from the Alvares and NMSG 5/94 studies was appropriate (see section 3.34) for estimating long-term survival and should be considered together with the analysis based on the MRC Myeloma VII study. The Committee considered the costs used in the manufacturer's economic model. It was aware that the clinical trials were all conducted using intravenously administered bortezomib, and it heard from the manufacturer that this was also assumed in the economic model and was therefore associated with a day-patient cost. The Committee was, however, aware that bortezomib is available as a subcutaneous formulation which is widely used and would therefore only be associated with an outpatient cost. The Committee also noted the comments from the clinical specialists that the subcutaneous formulation could reduce the risk of peripheral neuropathy and also reduce the need for thromboprophylaxis. The Committee considered that these issues combined might reduce the total cost of bortezomib in the model. The manufacturer updated the model to reflect this during consultation to reduce costs from £203 to £197 for first attendance and from £284 to £211 for subsequent visits. The Committee noted that the manufacturer's comparison of bortezomib and dexamethasone with vincristine, doxorubicin and dexamethasone was outside the NICE scope because the comparator did not contain thalidomide, and in addition, the clinical specialists commented that the vincristine, doxorubicin and dexamethasone regimen is no longer used as an induction therapy for multiple myeloma in the UK. The Committee decided, therefore, that it was not appropriate to consider the results from this comparison. However, the Committee also noted that the bortezomib and dexamethasone regimen had a lower acquisition cost than the bortezomib, thalidomide and dexamethasone regimen as it did not include thalidomide, and heard from clinical specialists that it would provide a valuable treatment option, especially for patients who cannot tolerate thalidomide. The Committee was aware that the ERG's exploratory analyses also included comparisons of bortezomib and dexamethasone against thalidomide and dexamethasone, and comparisons of bortezomib and dexamethasone against cyclophosphamide, thalidomide and dexamethasone. Based on the analyses incorporating the Alvares survival data and post-stem cell transplant response rates that were preferred by the Committee for the bortezomib, thalidomide and dexamethasone analysis, the Committee noted that the ERG's exploratory ICER for bortezomib and dexamethasone compared with thalidomide and dexamethasone was £26,700 per QALY gained. It also noted that in the comparison of bortezomib and dexamethasone with cyclophosphamide, thalidomide and the dexamethasone, the bortezomib and dexamethasone regimen was dominated by (that is, it was more costly and less effective than) cyclophosphamide, thalidomide and dexamethasone. The Committee acknowledged the lack of an appropriate comparison in the manufacturer's submission and the caveats surrounding the ERG's exploratory analysis, and asked the manufacturer to further explore the cost effectiveness of the bortezomib and dexamethasone (see section 4.15). The Committee noted the manufacturer's original comparison of bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone, which resulted in a deterministic incremental cost-effectiveness ratio (ICER) of £20,500 per QALY gained, and that the manufacturer had not presented probabilistic ICERs. The Committee then discussed the results of the ERG's exploratory analyses. The Committee noted that using post-stem cell transplant response rates instead of post-induction response rates (see section 4.10) resulted in an ICER of £26,300 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The Committee also noted that using data from the Alvares study instead of the MRC Myeloma VII study to model long-term survival resulted in an ICER of £30,400 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The clinical specialists raised concerns that the Alvares study was retrospective in design and also quite old and therefore a more recent study would be more appropriate. The ERG confirmed that it had also conducted an exploratory analysis based on data from the NMSG 5/94 study and that this resulted in an ICER higher than £30,400 per QALY gained, that but this did not include the discontinuation rule and was therefore not presented (see section 3.34). The Committee noted that given the disparity between the overall survival results from the trials and those in the model, using an alternative data source such as the Alvares study, which was a better fit to the trial data, was appropriate. The Committee noted that incorporating post-stem cell transplant rates and using the Alvares study to inform overall survival together resulted in an ICER of £39,000 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The Committee concluded that based on the analyses that were available before the appraisal consultation document was released, the ERG's exploratory analyses were appropriate and that £39,000 per QALY gained was an appropriate starting point for discussion on the most plausible ICER for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The Committee was aware of the ERGs further exploratory analyses on bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone. The Committee understood that there were limitations with this approach because the data were drawn from a range of heterogeneous studies containing different comparators and different study designs and therefore could not be directly compared. Moreover, differences in trial design and baseline characteristics had not been taken into account. The Committee noted that this approach resulted in an ICER of £228,200 per QALY gained for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone when using the manufacturer's base-case assumptions. Applying post-stem cell transplant response rates and survival data from the Alvares study resulted in an ICER of £82,000 per QALY gained for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone. The Committee agreed that although there was considerable uncertainty associated with such an approach, the ICER based on the analyses that were available before the appraisal consultation document was released for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone was likely to be higher than the ICER of £39,000 per QALY gained compared with thalidomide and dexamethasone. The Committee considered that further analyses were needed to explore the cost effectiveness of the bortezomib and dexamethasone regimen and asked the manufacturer to present: An indirect comparison of bortezomib in combination with dexamethasone, compared with cyclophosphamide in combination with thalidomide and dexamethasone, and compared with an alternative comparator in circumstances in which cyclophosphamide in combination with thalidomide and dexamethasone is not suitable. In the absence of a network to facilitate a robust comparison, the Committee requested that this should be a careful comparison using single arms from relevant clinical trials, taking into account differences in trial design and baseline characteristics. It should include sensitivity analyses using assumptions suggested by the Evidence Review Group: using data from wider sources than the MRC Melanoma VII trial, including the Alvares and NMSG 5/94 studies, and extrapolation from the trials of bortezomib-containing regimens to inform overall survival in the economic model using post-stem cell transplant response rates from the IFM trial rather than post-induction response rates using transplant rates by response category rather than total stem cell transplant rates updated costs to reflect the use of a subcutaneous formulation of bortezomib. Probabilistic incremental cost-effectiveness ratios for the revised comparisons. The Committee considered the manufacturer's response to the appraisal consultation document that included changes to the economic models for all the bortezomib regimens (see section 3.38). The Committee considered the manufacturer's revised modelling assumption that incorporated an 11.8 month survival benefit for people who received a stem cell transplant. The Committee noted that the model included survival curves for complete responders in addition to the assumption of survival benefit from receiving a stem cell transplant and discussed whether this amounted to double counting. It heard from the clinical specialists that incorporating the additional survival benefit was not double counting because the purpose of a stem cell transplant is to increase the depth of response, which could provide additive effect resulting in a survival benefit of up to a year. The Committee heard from the manufacturer that the additional survival benefit assumption was not a key driver of cost effectiveness because removing this benefit had minimal effect on the ICERs. The Committee concluded that the manufacturer's approach to modelling stem cell transplant benefit was acceptable for its decision making. The Committee was aware that the manufacturer used the stem cell transplant rates from the PETHEMA trial to inform the comparison of bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone (80.8% and 61.4% respectively) but that other bortezomib trials (GIMEMA, HOVON and IFM) indicated rates were above 80% regardless of the treatment arm. The Committee was also aware that transplant rates for the comparison of bortezomib and dexamethasone (without thalidomide) against cyclophosphamide, thalidomide and dexamethasone, were incorporated from the IFM trial for the bortezomib and dexamethasone arm (89.1%) and from the MRC Myeloma IX trial for the cyclophosphamide, thalidomide and dexamethasone arm (66.7%). The Committee noted the ERG's concerns that this was inconsistent with transplant rates taken from the control arm of the IFM trial (81.8%, which was directly comparable and would be expected to be no better than a cyclophosphamide, thalidomide and dexamethasone control arm). The Committee noted that the ERG had explored the impact of incorporating a stem cell transplant rate of 81.8%, which resulted in the manufacturer's revised base-case ICER increasing from £20,588 to £36,700 per QALY gained. The Committee discussed whether the differences in the transplant rates were too wide for both comparisons. It heard from the clinical specialists that in clinical practice cyclophosphamide, thalidomide and dexamethasone was associated with a stem cell transplant rate of approximately 50% and this was corroborated by 2 large population-based studies. The clinical specialists stated that bortezomib regimens were likely to be associated with stem transplant rates of 60–65%. The clinical specialists also suggested that stem cell transplant rates should better reflect complete response rates than the control arms of the other trials suggest. The Committee agreed that although a bortezomib regimen might be expected to improve the rate of stem cell transplant, it would be to a lesser extent than was modelled by the manufacturer, and more closely linked to response in clinical practice. However, the Committee also agreed that the differences in transplant rates between treatment arms in the models were plausible. The Committee concluded that although the impact of stem cell transplant rates included in the model on cost-effectiveness results was uncertain, it was unlikely to undermine the manufacturer's base-case cost-effectiveness results. The Committee discussed the overall survival modelling informing the manufacturer's revised ICERs for the comparison of bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone. It noted that the manufacturer preferred the MRC Myeloma VII data as the source for long-term survival, which resulted in an ICER of £17,800 per QALY gained. The Committee heard from the ERG that the MRC Myeloma VII data did not fit the observed PETHEMA data. The Committee was aware that incorporating data from the ERG's preferred Alvares and NMSG 5/94 studies resulted in ICERs of £22,700 and £39,600 per QALY gained respectively. The manufacturer stated that caution should be taken in interpreting the fit with PETHEMA trial data beyond 30 months because of the level of censoring. The Committee questioned why data from the PETHEMA trial had not been used directly. The manufacturer argued that the data were immature. The Committee also heard from the clinical specialists that because patients in the PETHEMA trial could receive bortezomib as maintenance treatment (which is not standard practice in the UK) there would be substantial convergence between the treatment arms when more long-term survival data become available. The Committee recognised that even though there was little face validity in the modelling of survival, it appreciated that the Kaplan−Meier curve from the PETHEMA trial was confounded by post-induction treatment. The Committee noted that incorporating only the NMSG 5/94 data resulted in ICERs that would not normally be considered to be cost effective (above £30,000 per QALY gained). The Committee considered concerns raised by the manufacturer and consultees that the NMSG study did not provide fully relevant data because it did not report median overall survival for partial and non-responders. The Committee concluded that using data from the NMSG 5/94 study would represent a pessimistic scenario and that the ICERs based on survival data from the MRC Myeloma VII (£17,800 per QALY gained) and Alvares (£22,700 per QALY gained) studies were appropriate for its decision making. The Committee considered the manufacturer's ICERs for bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone, as requested in the appraisal consultation document. It noted that using the MRC Myeloma VII, Alvares and NMSG 5/94 data sources to inform overall survival in the model resulted in ICERS of £20,600, £24,300 and £33,400 per QALY gained respectively. It noted that only using the NMSG 5/94 study data resulted in ICERs above £30,000 per QALY gained. Having discussed the concerns around the NMSG 5/94 data (see section 4.18), the Committee considered that results based on these data were likely to represent a pessimistic scenario. The Committee also considered the analyses presented by manufacturer when cyclophosphamide, thalidomide and dexamethasone may not be suitable, noting that vincristine, doxorubicin and dexamethasone was included as the most appropriate comparator in this situation. The Committee noted that the ICERs ranged from £18,900 per QALY gained using MRC Myeloma VII survival data to £25,600 using survival data from the Alvares study. The Committee concluded that most plausible ICERs based on survival data from the MRC Myeloma VII and Alvares studies were appropriate for its decision making. The Committee remained concerned that the modelling was subject to uncertainties, and that the manufacturer had also not provided sufficient external and internal validity. However, the Committee acknowledged that bortezomib regimens had a clear advantage with respect to induction response and that a link between improved response and survival was plausible. In particular, the Committee considered that there were people with clinically aggressive disease, with organ function at risk, or at risk of irreversible renal damage, who would benefit from a fast response associated with treatment with bortezomib, but heard that this group could not be categorically defined. Taking into account its consideration that the uncertainty around stem cell transplant rates was not likely to have a substantial impact on the ICER (section 4.16) and taking into consideration ICERs based on survival data from the MRC Myeloma VII and Alvares studies, the Committee concluded that, on balance, the ICERs for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, and for bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone and compared with vincristine, doxorubicin and dexamethasone, were likely to be below £30,000 per QALY gained. Therefore both bortezomib regimens could be considered a cost-effective use of NHS resources. # Summary of Appraisal Committee's key conclusions TA311 Appraisal title: Bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem cell transplantation Section Key conclusion Bortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation. The Committee was concerned that the modelling was subject to uncertainties, however it acknowledged that bortezomib regimens had a clear advantage with respect to induction response and that a link between improved response and survival was plausible. For the cost-effectiveness analysis, and in response to consultation, the manufacturer presented additional evidence that included changes to the economic models and comparisons with cyclophosphamide, thalidomide, and dexamethasone, the comparator regimen considered to be current standard care in the UK. Based on a threshold analysis presented by the manufacturer, the Committee concluded that bortezomib, thalidomide, and dexamethasone compared with thalidomide and dexamethasone was a reasonable basis for appraising the clinical and cost effectiveness of bortezomib, thalidomide, and dexamethasone compared with cyclophosphamide, thalidomide, and dexamethasone. The Committee considered and explored a range of ICERs using several studies included in the submissions, and concluded that, on balance, the ICERs for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, and for bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone and compared with vincristine, doxorubicin and dexamethasone, were likely to be below £30,000 per QALY gained. Current practice Clinical need of patients, including the availability of alternative treatments The Committee heard from clinical specialists that stem cell transplantation is considered the gold standard treatment for multiple myeloma because it is associated with improved progression-free survival, greater depth of response and therefore improved survival. The clinical specialists stated that the aim of induction therapy was to enable more people to proceed to stem cell transplantation successfully. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The clinical specialists commented that bortezomib-based induction therapy would enable a higher proportion of patients to have a stem cell transplant and consequently experience longer progression-free survival and greater depth of response. The Committee also heard that bortezomib-based regimens were particularly valuable for people with clinically aggressive disease, but was aware that this group could not be clearly defined. The Committee agreed that induction treatment with bortezomib and dexamethasone was associated with statistically significant improvements in post-induction overall response rates compared with vincristine, doxorubicin and dexamethasone, and that induction treatment with bortezomib, thalidomide and dexamethasone resulted in statistically significant improvements in overall response rates (post-induction and post-stem cell transplantation) and progression-free survival compared with thalidomide and dexamethasone. However, it concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone with cyclophosphamide, thalidomide and dexamethasone, the comparator regimen considered to be current standard care in the UK and therefore the most relevant comparator for the Committee's decision-making. What is the position of the treatment in the pathway of care for the condition? The clinical specialists stated that induction treatment with bortezomib provides an important treatment option for patients with newly diagnosed multiple myeloma, and when thalidomide is not a feasible treatment option because of contraindications. Adverse reactions Clinical specialists highlighted that although the evidence presented was for intravenously administered bortezomib, the introduction of a subcutaneous formulation has substantially reduced the side effects related to peripheral neuropathy and also reduced the need for thromboprophylaxis. The Committee concluded that the adverse event profile of bortezomib was manageable (for full details of adverse reactions and contraindications, see the summary of product characteristics). Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee noted that the manufacturer presented evidence on the clinical effectiveness of bortezomib from the PETHEMA, GIMEMA, HOVON and IFM trials. The Committee was aware that the HOVON trial included the bortezomib, doxorubicin and dexamethasone regimen, which was not included in the bortezomib marketing authorisation. It therefore excluded it from its clinical and cost-effectiveness discussions. The Committee noted that the trials included different regimens of bortezomib and had different study designs. It noted that in the GIMEMA trial patients only received 3 cycles of bortezomib, thalidomide and dexamethasone whereas in the PETHEMA trial patients received 6 cycles, which was more in line with the marketing authorisation. Moreover, the Committee noted that the PETHEMA and GIMEMA trials differed in the number of stem cell transplants given and the type of consolidation (intensification therapy to sustain remission before lower dose maintenance therapy) and maintenance treatments used after transplant, and that consolidation and maintenance treatment was not standard clinical practice in the NHS. The Committee was aware that none of the trials included a comparison with cyclophosphamide, thalidomide and dexamethasone, which is standard clinical practice in England. Relevance to general clinical practice in the NHS The Committee noted that the PETHEMA and GIMEMA trials differed in the number of stem cell transplants and the type of consolidation and maintenance treatments used after transplant and that consolidation and maintenance treatment was not standard clinical practice in the NHS. The Committee was aware that none of the trials included a comparison with cyclophosphamide, thalidomide and dexamethasone which is standard clinical practice in England. Moreover, the IFM trial included a comparison of bortezomib and dexamethasone with vincristine, doxorubicin and dexamethasone, which is no longer used. Uncertainties generated by the evidence The Committee concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone against cyclophosphamide, thalidomide and dexamethasone, the comparator regimen considered to be current standard care in the UK and therefore the most relevant comparator for the Committee's decision-making. The Committee heard from the manufacturer and from the clinical specialists that the duration of the trials was too short to allow differences in overall survival to be seen between treatment groups. It concluded that although there was uncertainty in the magnitude of overall survival gain associated with bortezomib, it was plausible that bortezomib's impact on induction response could be associated with improved overall survival. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? None Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that in the PETHEMA trial, bortezomib, thalidomide and dexamethasone was associated with statistically significant gain in overall response rate post-induction compared with thalidomide and dexamethasone (84.6% compared with 61.4%, p<0.001) and that this was maintained after stem cell transplant (77.7% compared with 56.7%, p<0.001). The Committee also noted that, in the IFM trial, bortezomib and dexamethasone was associated with a similar gain in overall response rate compared with vincristine, doxorubicin and dexamethasone (77.1% compared with 60.7%, p<0.001) but a statistical difference was not shown after stem cell transplant (79.6% compared with 74.4%, p=0.179). The Committee noted that median overall survival was not reached in either the PETHEMA trial (bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, hazard ratio 0.80, 95% 0.48 to 1.34, p=0.393) or IFM trial (bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone, HR 0.8, 95% CI 0.54 to 1.19, p value not reported) and there was no statistically significant difference in overall survival between the treatment arms in each study. It concluded that although there was uncertainty in the magnitude of overall survival gain associated with bortezomib, it was plausible that bortezomib's impact on induction response could be associated with improved overall survival. Evidence for cost effectiveness Availability and nature of evidence The Committee was aware that the model only provided comparisons for bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone and for bortezomib and dexamethasone against vincristine, doxorubicin and dexamethasone, which was not in line with current clinical practice in the UK, and that the vincristine, doxorubicin and dexamethasone regimen was outside of the scope of this appraisal. The Committee acknowledged that there was no direct evidence available to compare the bortezomib, thalidomide and dexamethasone and the bortezomib and dexamethasone regimens with cyclophosphamide, thalidomide and dexamethasone, and it asked the manufacturer to further explore this by conducting a further indirect comparison using single arms from the relevant clinical trials. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee noted the ERG's comments that the MRC Myeloma VII trial was not very recent because it recruited patients between 1993 and 2003, and its rates for overall survival and progression-free survival were likely to be lower than would be seen in current clinical practice. The Committee was also aware that although long-term survival end points had not been reached in the PETHEMA and IFM trials, the data available in these trials suggested that the manufacturer's model, using data from MRC Myeloma VIl, underestimated overall survival. The Committee concluded that although the impact of stem cell transplant rates included in the model on cost-effectiveness results was uncertain, it was unlikely to undermine the manufacturer's base-case cost-effectiveness results. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The manufacturer selected the van Agthoven study as the base-case source of utility values because the utility values were obtained using EQ‑5D. With regard to adverse events the manufacturer applied a disutility of 0.02 to each patient experiencing an adverse event associated with induction therapy. The Committee noted the comments from the clinical specialists that the subcutaneous formulation could reduce the risk of peripheral neuropathy and also reduce the need for thromboprophylaxis. The Committee considered that these issues combined might reduce the total cost of bortezomib in the model. Are there specific groups of people for whom the technology is particularly cost effective? No. What are the key drivers of cost effectiveness? The manufacturer's deterministic sensitivity analyses highlighted that the results were most sensitive to the mortality for patients who had a complete response after the induction therapy, and to drug costs. Most likely cost-effectiveness estimate (given as an ICER) The Committee noted that for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, the manufacturer's base-case using the MRC Myeloma VII data as the source for long-term survival ICER resulted in an ICER of £17,800 per QALY gained. The Committee was aware that incorporating data from the ERG's preferred Alvares and NMSG 5/94 studies resulted in ICERs of £22,700 and £39,600 per QALY gained respectively. For bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone, using the MRC Myeloma VII, Alvares and NMSG 5/94 data sources to inform overall survival in the model, the ICERs were £20,600, £24,300 and £33,400 per QALY gained respectively. The Committee concluded that the ICERs based on survival data from the MRC Myeloma VII and Alvares study were appropriate for its decision making. Additional factors taken into account Patient access schemes (PPRS) None submitted. End-of-life considerations Not applicable. Equalities considerations and social value judgements No equality issues relevant to the Committee's recommendations were raised. # Review of guidance The guidance on this technology will be considered for review in February 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew Dillon Chief ExecutiveApril 2014# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS. This guidance was developed using the NICE single technology appraisal process. It has been incorporated into the NICE pathway on blood and bone marrow cancers along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0557-7	{'Guidance': 'Bortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.', 'The technology ': "Bortezomib (Velcade, Janssen‑Cilag) is an anticancer drug that works by reversible proteasome inhibition. By inhibiting proteasomes (multi-enzyme complexes present in all cells), bortezomib interferes with the cell cycle leading to cell death. It is administered by intravenous infusion or subcutaneous injection. Bortezomib has a UK marketing authorisation for use 'in combination with dexamethasone, or with dexamethasone and thalidomide for the induction treatment of adult patients with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation'.\n\nThe summary of product characteristics lists the following as the most commonly reported adverse reactions for bortezomib: nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe cost of bortezomib is £762 per 3.5‑mg vial (excluding VAT; British National Formulary [BNF] edition 66). According to the marketing authorisation bortezomib should be given in combination with dexamethasone (4 cycles of 21\xa0days each) or with dexamethasone and thalidomide (4 cycles of 28\xa0days each; 2 additional cycles of 28\xa0days each for patients with at least partial response after the fourth cycle). Four intravenous infusions or subcutaneous injections of bortezomib are administered per cycle, on days 1, 4, 8 and 11 of each cycle. The average cost of a course of treatment with bortezomib given with dexamethasone is estimated to be £12,261 and the average cost of a course of treatment with bortezomib given with dexamethasone and thalidomide is estimated to be £24,840. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (section\xa07) considered evidence submitted by the manufacturer of bortezomib and a review of this submission by the Evidence Review Group (ERG; section\xa08).\n\n# Clinical effectiveness\n\nThe main clinical evidence submitted by the manufacturer for the bortezomib, thalidomide and dexamethasone regimen came from the PETHEMA trial in which in people with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation received up to 6 cycles of bortezomib, thalidomide and dexamethasone, or thalidomide and dexamethasone. The evidence for the bortezomib and dexamethasone regimen came from the IFM trial, which compared 4 cycles of bortezomib and dexamethasone with 4 cycles of vincristine, doxorubicin and dexamethasone. The manufacturer also submitted data from the GIMEMA trial which compared the efficacy and safety of 3 cycles of bortezomib, thalidomide and dexamethasone with 3 cycles of thalidomide and dexamethasone as induction treatment before autologous stem cell transplantation followed by consolidation treatment with 2 cycles of either bortezomib, thalidomide and dexamethasone or thalidomide and dexamethasone. However, the manufacturer highlighted that the PETHEMA trial study design better reflected how the bortezomib, thalidomide and dexamethasone regimen is expected to be used in the UK and therefore was the focus of the manufacturer's submission. Data from the HOVON trial were provided by the manufacturer, but the bortezomib-containing regimen included in this study, bortezomib, doxorubicin and dexamethasone, was not approved by the European Medicines Agency and is therefore not a licensed regimen.\n\nThe PETHEMA trial was a randomised, open-label phase III study that compared the efficacy and safety of bortezomib in combination with thalidomide and dexamethasone against thalidomide and dexamethasone in people with newly diagnosed symptomatic multiple myeloma and measurable disease (serum and/or urine M protein), who were eligible for autologous stem cell transplantation. Patients were randomised to either bortezomib, thalidomide and dexamethasone (n=130) or thalidomide and dexamethasone (n=127), both of which consisted of 6 cycles of 28\xa0days, with each cycle including 4 infusions of bortezomib, oral dexamethasone (40\xa0mg on days 1–4 and 8–11 of each cycle) and oral thalidomide (50\xa0mg daily). After transplantation, patients who continued in the trial were re-randomised to receive 1 of 3 maintenance treatments (interferon alfa‑2b, thalidomide, or bortezomib plus thalidomide). Maintenance therapy was continued for up to 3\xa0years, or until disease progression. Although the PETHEMA trial did not incorporate the discontinuation rule as per the summary of product characteristics, because patients in the GIMEMA trial received only 3 cycles, the manufacturer stated that the PETHEMA trial design better reflected how the bortezomib, thalidomide and dexamethasone regimen is expected to be used in the UK.\n\nThe GIMEMA trial was a randomised, open-label, phase III study in 480 patients with newly diagnosed, previously untreated symptomatic multiple myeloma with measurable disease. The study was designed to compare the efficacy and safety of 3 cycles of bortezomib, thalidomide and dexamethasone with 3 cycles of thalidomide and dexamethasone as induction treatment before autologous stem cell transplantation. It also evaluated subsequent consolidation treatment consisting of 2 cycles of either bortezomib, thalidomide and dexamethasone, or thalidomide and dexamethasone. Maintenance treatment with dexamethasone was continued until disease progression or relapse. Each cycle of induction therapy consisted of 1.3\xa0mg/m2 of bortezomib on days 1, 4, 8 and 11, with 100\xa0mg of thalidomide daily for the first 14\xa0days and 200\xa0mg thereafter. Dexamethasone 40\xa0mg was administered on days 1, 2, 4, 5, 8, 9, 11 and 12. Instead of the dosage recommended in the summary of product characteristics, patients randomised to the bortezomib, thalidomide and dexamethasone induction group received only 3 cycles of bortezomib-based treatment.\n\nThe IFM trial was a randomised, open-label study designed to compare the efficacy and safety of bortezomib and dexamethasone (with or without consolidation treatment with dexamethasone, cyclophosphamide, etoposide and cis-platinum) against vincristine, doxorubicin and dexamethasone (with or without intensification). Treatment with bortezomib and dexamethasone consisted of 4 21‑day cycles of 1.3\xa0mg/m2 of bortezomib and 40\xa0mg of dexamethasone. However, the manufacturer stated that only the results without the intensification step were relevant to the decision problem. Moreover, as discussed previously, the manufacturer stated that this comparison was not in line with the decision problem because the vincristine, doxorubicin and dexamethasone regimen is not a thalidomide-containing regimen and therefore not an appropriate comparator. The manufacturer also stated that the vincristine, doxorubicin and dexamethasone regimen is not routinely used in UK clinical practice and excluded this from its base-case analysis.\n\nThe primary outcome measures in the PETHEMA, GIMEMA and IFM trials were response rates reported after induction and after transplant. The manufacturer's submission reported 'response' in terms of:\n\ncomplete response\n\nnear-complete response\n\nvery good partial response (not used in the PETHEMA trial)\n\npartial response\n\nprogressive disease\n\noverall response rate.Overall response rate was calculated as the total proportion of patients who had a partial response or better. All response rates were evaluated using the European Group of Blood and Bone Marrow Transplant (EBMT) criteria and the International Myeloma Working Group uniform criteria.\n\nPatients who received bortezomib (bortezomib, thalidomide and dexamethasone) had a statistically significant difference in overall response rate after induction compared with the thalidomide regimen (thalidomide and dexamethasone) in both the PETHEMA (84.6% compared with 61.4%, p<0.001) and GIMEMA (93.2% compared with 78.6%, p<0.0001) trials. This difference in treatment effect on overall response rate was maintained after transplant (77.7% compared with 56.7%, p<0.001 in the PETHEMA trial and 93.2% compared with 84.5%, p<0.0025 in the GIMEMA trial). Patients receiving bortezomib in PETHEMA and GIMEMA also showed statistically higher post-induction and post-transplant complete response rates than those on the thalidomide-containing regimen. In the PETHEMA trial, 35.4% in the bortezomib, thalidomide and dexamethasone treatment group had a post-induction complete response compared with 13.4% in the thalidomide and dexamethasone group (p<0.001). In the GIMEMA trial, 18.6% had a post-induction complete response in the bortezomib, thalidomide and dexamethasone treatment group compared with 4.6% in the thalidomide and dexamethasone group (p<0.0001). In the post-transplant period, statistically significant differences were maintained for the bortezomib, thalidomide and dexamethasone treatment groups in both the PETHEMA and GIMEMA trials (p<0.001 and p=0.0004 respectively). Both the PETHEMA and GIMEMA trials reported a statistically significant lower proportion of patients experiencing disease progression when treated with bortezomib, thalidomide and dexamethasone compared with patients treated with thalidomide and dexamethasone induction therapy in the post-induction period (6.2% and 23.6%, p=0.0004 in the PETHEMA trial; and 0% and 5.0%, p<0.0005 in the GIMEMA trial).\n\nIn the IFM trial, people who received bortezomib in combination with dexamethasone showed a statistically significant difference in overall response rate after induction compared with vincristine, doxorubicin and dexamethasone (77.1% compared with 60.7%, p<0.001) but this difference was not maintained after stem cell transplantation (79.6% compared with 74.4%, p=0.179).\n\nSecondary outcomes reported in the PETHEMA, GIMEMA, IFM and MRC Myeloma IX (described in section 3.12) trials included:\n\nprogression-free survival\n\ntime to progression\n\noverall survival\n\nproportion of patients who had stem cell transplantation\n\nadverse events.Progression-free survival was measured from the date of randomisation to the date of disease progression or death from any cause, whichever occurred first. Time to progression was calculated from the date of randomisation to the date of disease progression or death due to disease progression. Overall survival was calculated from the date of randomisation to the date of death from any cause for the intention-to-treat populations. The manufacturer reported the unadjusted hazard ratios for progression-free survival for the PETHEMA, GIMEMA and IFM trials. Median follow-up in the trials was 35.9\xa0months (PETHEMA), 36\xa0months (GIMEMA) and 33\xa0months (IFM). Progression-free survival was longer in the bortezomib, thalidomide and dexamethasone arms of both the PETHEMA and GIMEMA trials than the thalidomide and dexamethasone arms, and the difference was statistically significant (PETHEMA hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.45 to 0.92, p=0.015; GIMEMA HR 0.63, 95% CI 0.45 to 0.88, p=0.0061). Progression-free survival was longer in the bortezomib and dexamethasone arm of the IFM trial compared with the vincristine, doxorubicin and dexamethasone arm, but the difference was not statistically significant (IFM HR 0.88, 95% CI 0.70 to 1.11, p value not reported).\n\nThe manufacturer's submission reported the median time to progression and time to progression hazard ratios from the PETHEMA and IFM trials. In the PETHEMA study there was a statistically significant lower hazard of progression in patients treated with bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone (HR 0.64, 95% CI 0.44 to 0.93, p=0.017). No statistically significant difference in median time to progression was reported. In the IFM study there was a numerically lower hazard of progression in patients treated with bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone but this was not statistically significant (HR 0.82, 95% CI 0.63 to 1.06, p value no reported).\n\nThe manufacturer's submission reported unadjusted overall survival hazard ratios for the PETHEMA and IFM trials. Median overall survival was not reached in either the PETHEMA trial (bortezomib, thalidomide and dexamethasone compared against thalidomide and dexamethasone, hazard ratio 0.80, 95% CI 0.48 to 1.34, p=0.393) or IFM trial (bortezomib and dexamethasone compared against vincristine, doxorubicin and dexamethasone, HR 0.8, 95% CI 0.54 to 1.19; p value not reported) and there was no statistically significant difference in overall survival between the treatment arms in each study. The manufacturer's submission highlighted clinical specialist opinion that the durations of the trials were too short to allow differences in overall survival and progression-free survival between treatment groups to be sufficiently captured, given the relatively long survival in this patient population after an autologous stem cell transplant.\n\nThe bortezomib-containing arms of the PETHEMA and GIMEMA trials (bortezomib, thalidomide and dexamethasone) reported higher proportions of patients having stem cell transplantation compared with the thalidomide and dexamethasone arms (80.8% compared with 61.4% in PETHEMA, and 88.0% compared with 82% in GIMEMA). In addition, the bortezomib and dexamethasone arm of the IFM trial reported higher proportions of patients having stem cell transplantation compared with the vincristine, doxorubicin and dexamethasone arm (89.1% compared with 81.8%). However, no statistical tests were reported.\n\nIn the absence of head-to-head trials comparing bortezomib-based regimens against cyclophosphamide in combination with thalidomide and dexamethasone, the manufacturer originally presented an indirect comparison based on the PETHEMA, GIMEMA, HOVON, IFM and MRC Myeloma IX randomised controlled trials. The MRC Myeloma IX trial is the only trial that has compared the efficacy of cyclophosphamide, vincristine, doxorubicin and dexamethasone against cyclophosphamide, thalidomide and dexamethasone in 1111 patients with newly diagnosed symptomatic myeloma. In this trial, patients were randomised to receive induction chemotherapy following either an intensive or non-intensive (attenuated treatment) pathway. The manufacturer considered that the MRC Myeloma IX trial provided the only potential evidence that allowed any form of comparison to be made between bortezomib-based regimens and cyclophosphamide, thalidomide and dexamethasone. The bortezomib plus doxorubicin and dexamethasone regimen (used in the HOVON trial) was included as part of the evidence submission but the manufacturer considered its inclusion in the indirect comparison to be inappropriate because this regimen was not included in the marketing authorisation. The manufacturer stated that a network could not be formed between the available trials, and an indirect comparison with cyclophosphamide, thalidomide and dexamethasone was not possible. In addition, bortezomib and dexamethasone could not be linked to a thalidomide-containing regimen. The manufacturer highlighted that assumptions to overcome the network limitations would generate considerable uncertainties and unreliable results. The manufacturer stated that an incremental analysis of the 2 licensed bortezomib regimens was therefore also not possible and stated that the base case should focus on the comparison of bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone.\n\nThe manufacturer presented a summary of results for adverse events for the PETHEMA, GIMEMA, IFM and MRC Myeloma IX trials. Only adverse events for the post-induction phase were reported because the manufacturer considered the adverse events for the post-transplant phase not to be relevant. Across all trials a similar proportion of patients reported any adverse event, grade 3/4 adverse events, and serious adverse events in both the bortezomib and comparator treatment arms. However, in the PETHEMA trial a statistically significantly greater number of total treatment-related adverse events was reported during induction with bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone (relative risk [RR]=1.42; 95% CI 1.17 to 1.73). In the GIMEMA trial a statistically significantly greater proportion of patients receiving bortezomib, thalidomide and dexamethasone experienced any grade 3/4 adverse event than those receiving thalidomide and dexamethasone (RR=1.69; 95% CI 1.36 to 2.08). The 2 most common treatment-related adverse events in the PETHEMA trial (pneumonia and peripheral neuropathy) occurred more frequently in the bortezomib, thalidomide and dexamethasone arm than in the thalidomide and dexamethasone arm. The manufacturer's submission highlights that in the 4 bortezomib-based studies, bortezomib was given intravenously. In terms of tolerability, total withdrawals and withdrawals due to disease progression were statistically significantly less in the bortezomib, thalidomide and dexamethasone arm than the thalidomide and dexamethasone arm in the PETHEMA trial (HR 0.51 [95% CI 0.34 to 0.77] and HR 0.45 [95% CI 0.25 to 0.84] respectively).\n\nNo health-related quality of life data were collected in the trials of bortezomib-containing regimens. To inform the cost-effectiveness evidence, the manufacturer conducted a systematic literature search to identify publications relevant to the decision problem in relation to health-related quality of life.\n\n## Evidence Review Group comments\n\nThe ERG stated that the manufacturer's search strategy was clear and comprehensive. The ERG noted that 5 trials were included in the manufacturer's original submission, but highlighted that only 2 trials (PETHEMA and GIMEMA) met the NICE scope and focused its critique on these trials. This was in line with the manufacturer's addendum. The ERG stated that both trials were unblinded and therefore at risk of detection bias. The ERG agreed with the manufacturer that the baseline characteristics were generally similar across the trials. However, the ERG also highlighted that the PETHEMA and GIMEMA trials excluded patients older than 65\xa0years, which does not reflect UK clinical practice.\n\nThe ERG commented that overall, the manufacturer's approach to the trial statistics was appropriate and reasonably well reported. However, the ERG commented that long-term outcomes such as progression-free survival and overall survival may be confounded by post-induction consolidation and maintenance treatments that do not reflect current UK clinical practice. The ERG also noted that there is uncertainty in the robustness of the progression-free survival and overall survival results because of the high censoring of data in the bortezomib, thalidomide and dexamethasone, and thalidomide and dexamethasone arms of the PETHEMA trial (57.7% and 44.9% respectively in the progression-free survival analysis, and 80.0% and 74.8% respectively in the overall survival analysis).\n\nThe ERG noted that the manufacturer had highlighted that the results from the indirect comparison were subject to substantial uncertainty and were therefore not included in the economic modelling. The ERG agreed with this approach.\n\n# Cost effectiveness\n\nThe manufacturer conducted a systematic search of the literature and identified 3 cost-effectiveness studies relevant to the decision problem. The manufacturer conducted a quality assessment of these studies but did not discuss them further in the submission.\n\nThe manufacturer developed an Excel-based economic model to assess the cost effectiveness of bortezomib-based induction regimens compared with thalidomide-based induction regimens. As discussed previously, the manufacturer's base-case analysis focused on the cost-effectiveness analysis of bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The manufacturer presented cost-effectiveness analyses of bortezomib, thalidomide and dexamethasone (including the discontinuation rule stipulated in the marketing authorisation submitted as an addendum submission) compared with thalidomide and dexamethasone, and of bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone. The manufacturer acknowledged that the comparison with vincristine, doxorubicin and dexamethasone did not reflect current best clinical practice in the UK. The manufacturer stated that no comparisons of the bortezomib and dexamethasone regimen with relevant thalidomide-containing regimens (such as cyclophosphamide, thalidomide and dexamethasone) were possible using indirect mixed treatment comparisons.\n\nThe manufacturer chose a state-transition Markov model, with a cycle length of 1\xa0month, to reflect the length of a course of treatment with bortezomib, thalidomide and dexamethasone (28\xa0days) and because clinical outcomes are reported in months. The model did not include a half-cycle correction because the cycle length was short relative to the time horizon used in the model. Costs and quality-adjusted life years (QALYs) were discounted over a lifetime (30\xa0years) time horizon at 3.5% per annum. The manufacturer stated that the model captured the 2 most important outcomes: post-induction response rate and overall survival. However, the manufacturer clarified that because the pivotal trials were not powered to detect a statistically significant difference in overall survival, the model was based on response rate, and the relationship between response rate and overall survival was quantified using long-term survival data from older trials in the same patient population. The model assumed that patients entered at the start of their induction therapy. After induction, patients in the model entered one of 3 health states: complete response, partial response, or non-responders (defined as minimal response, stable disease and progressive disease respectively). Depending on their post-induction response rate, patients subsequently proceeded to high-dose chemotherapy and stem cell transplantation or to the post-induction progression-free survival health state (non-stem cell transplant group). After induction, all patients were assumed to incur the same survival benefit, which was dependent only on their response rate after the induction phase and was independent of the actual induction regimen that they received. On disease progression, patients would then receive a second treatment, followed by third-line and subsequent lines of treatment after further progression.\n\nPost-induction response rates were used as the main measure of efficacy in the model. Stem cell transplant rates for each response category in each treatment arm were used in the model evaluating bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The economic model for bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone used total stem cell transplant rates rather than transplant rates for each response category. The model also included mortality during the induction and transplant periods.\n\nIn order to model long-term survival based on the post-induction response rates, the manufacturer extracted overall survival data from the MRC Myeloma VII trial because overall survival data from the PETHEMA trial were considered immature. The MRC Myeloma VII trial randomised a total of 407 previously untreated multiple myeloma patients to conventional chemotherapy (n=200) or high-dose chemotherapy followed by autologous stem cell transplant (n=201). The 5-year survival in the high-dose chemotherapy followed by autologous stem cell transplant group was 88.6\xa0months (95% CI 61.4, upper CI not reported) for patients who had a complete response, 39.8\xa0months (95% CI 33.8 to 61.4) for patients who had a partial response, and 25.6\xa0months (95% CI 7.0 to 31.3) for patients who had no response. For a scenario analysis, the manufacturer also used long-term survival data from the IFM90 trial from 1996.\n\nThe manufacturer used post-transplant time to progression from the PETHEMA trial to determine the probabilities of transition from the post-transplant progression-free health state to the start of second-line therapies. The manufacturer assumed that time to progression is affected by the interventions because it was modelled using separate parametric curves by treatment and response category. In the base case, time-to-progression transition probabilities were derived from exponential curves fitted to the PETHEMA data. Constant transition probabilities were used for transition from the second-line to the third-line health state across the 2 interventions, the estimates for which were derived from the subgroups of patients who had 1 or 2 lines of treatment respectively in the APEX trial (which compared bortezomib monotherapy with high-dose dexamethasone in patients with relapsed multiple myeloma). Probabilities of transition from third to further lines of treatment were derived by applying an exponential distribution to the time-to-progression data from the APEX trial. The overall survival data from the MRC Myeloma VII trial were used to determine the length of time that patients remained in the further lines of treatment health state before moving to the death state.\n\nThe manufacturer conducted a systematic search of the literature to identify publications that identified health-related quality of life data relevant to the decision problem. Five relevant studies were identified, of which 3 reflected the current UK patient population and clinical practice. The manufacturer selected the van Agthoven study as the base-case source of utility values because the utility values were obtained using EQ‑5D. The study by van Agthoven et\xa0al. compared chemotherapy (n=129) with intensive chemotherapy followed by myeloablative chemotherapy with stem cell transplantation (n=132) and total body irradiation treatment regimens. Patients were from the Netherlands and Belgium, under the age of 65 years, and had newly diagnosed and untreated multiple myeloma. They received 3 or 4 cycles of vincristine, doxorubicin and dexamethasone and 2 cycles of intermediate-dose melphalan, after which they were randomised to have either stem cell transplantation and interferon maintenance, or interferon maintenance only. The manufacturer applied a disutility of 0.02 to each patient experiencing an adverse event associated with induction therapy.\n\nThe costs applied in the model were taken from the BNF edition 64 (2012) and the 2012–13 Chemotherapy Regimens List. Administration of chemotherapy drugs, outpatient visits and tests as part of disease and treatment monitoring and the costs relating to stem cell transplantation were taken from the 2011–12 National Schedule Reference costs. The costs associated with treating adverse events were based on inpatient, outpatient or day-case visit National Schedule Reference costs. The manufacturer presented unit costs associated with each of the first-line induction therapies as well as drugs for prophylaxis, administration and monitoring. The total cost, including prophylaxis, administration and monitoring, of the bortezomib, thalidomide and dexamethasone regimen was £28,034, which compared with a total cost of £8,865 for thalidomide and dexamethasone. The total cost of the bortezomib and dexamethasone regimen was £14,104, whereas the total cost of vincristine, doxorubicin and dexamethasone was £2732.\n\nThe manufacturer's economic model estimated a difference in total costs between the bortezomib, thalidomide and dexamethasone and the thalidomide and dexamethasone regimens of £20,682. The bortezomib, thalidomide and dexamethasone regimen was associated with a 1.01 QALY gain compared with thalidomide and dexamethasone. The manufacturer's estimated base-case incremental cost-effectiveness ratio (ICER) for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone was £20,468 per QALY gained. The incremental cost difference between the bortezomib and dexamethasone and the vincristine, doxorubicin and dexamethasone regimens was £12,710, and bortezomib and dexamethasone was associated with an incremental QALY gain of 0.88 resulting in an estimated ICER of £14,446 per QALY gained for the bortezomib and dexamethasone regimen compared with vincristine, doxorubicin and dexamethasone.\n\nThe manufacturer's deterministic sensitivity analyses highlighted that the results for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone were most sensitive to the mortality for patients who had a complete response after induction therapy, and to drug costs. If the complete response mortality rate was varied within its 95% confidence interval, other things being equal, the ICER ranged from £17,018 to £28,867 per QALY gained. For the bortezomib, thalidomide and dexamethasone drug costs, sensitivity analyses were conducted using 4, 5 and 6 cycles of induction therapies. This was based on clinical opinion that the number of cycles will vary from one patient to another. The ICER range for the sensitivity analysis varying bortezomib, thalidomide and dexamethasone drug costs was £15,761 to £25,662 per QALY gained. For all other parameters varied in the sensitivity analyses, the ICER remained between £16,000 and £25,000 per QALY gained. Deterministic sensitivity analyses were also presented by the manufacturer for the comparison between the bortezomib and dexamethasone, and the vincristine, doxorubicin and dexamethasone regimens. Here, the results were most sensitive to the mortality for patients with complete response after induction therapy, with ICERs ranging from £10,961 to £18,354 per QALY gained.\n\nThe results of the manufacturer's probabilistic sensitivity analysis showed that, at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained, there was a 35.4% and 71.3% probability respectively of the bortezomib, thalidomide and dexamethasone regimen being cost effective when compared with thalidomide and dexamethasone. The manufacturer estimated that at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained, there was a 68.9% and 83.2% probability respectively of the bortezomib and dexamethasone regimen being cost effective compared with vincristine, doxorubicin and dexamethasone.\n\nThe ERG stated that the structure of the model was consistent with the clinical pathway of care for multiple myeloma and was clearly presented. However, the ERG highlighted that the manufacturer's analysis of bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone was outside the scope. It also highlighted that, given that the comparator in routine use in UK clinical practice is the cyclophosphamide, thalidomide and dexamethasone regimen, the comparison of bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone was not entirely relevant to clinical practice.\n\nThe ERG also expressed some concerns that the model extrapolated level of response after induction therapy to long-term survival and time to progression based on data from the MRC Myeloma VII trial. The ERG cautioned that the MRC Myeloma VII trial was old and its outcomes may not reflect the more advanced treatments available today. Moreover, the ERG stated that data from the MRC Myeloma VII trial related to maximal response to treatment rather than post-induction response rate, and the resulting survival curves might be confounded to some extent with post-stem cell transplant response. The ERG clinical expert agreed that response rate at induction predicts progression-free survival and overall survival. However, the ERG stated that other surrogate outcomes, such as post-stem cell transplant response rate, may offer a better prediction of progression-free survival and overall survival. The ERG observed that although the model had separate states for those who received a stem cell transplant and those who did not, the model attached no explicit survival benefit to a stem cell transplant other than that achieved by delaying the transition to the post-induction/post-transplant progression-free survival state for the duration of the stem cell transplant period. The ERG clinical expert stated that stem cell transplantation offers a survival benefit of 12–18 months compared with no transplant, and the ERG stated that it would have been more transparent to distinguish the separate effects on survival of post-induction response and stem cell transplantation. Alternatively, post-stem cell transplant response rate could have been considered because it has been shown to be statistically significantly associated with improved overall survival. Overall, the ERG stated that external validity would have been strengthened if the model had been based on overall survival and time to progression Kaplan–Meier curves or post-stem cell transplant response, rather than post-induction response. The ERG was concerned that in the absence of this the results were systematically biased in favour of bortezomib, thalidomide and dexamethasone.\n\nThe ERG stated that, in contrast to the manufacturer's description in the submission, the model implicitly assumed a continuing effect of induction treatment after induction is complete, because separate time to progression curves were used for each induction treatment arm and stem cell transplant mortality was also applied separately by treatment arm. The ERG also highlighted that, contrary to statements in the manufacturer's submission, the probability of receiving a stem cell transplant was not dependent on post-induction response, but only on treatment received.\n\nThe ERG noted the manufacturer's approach to calculating transition probabilities (section 3.23), and stated that the exponential distribution fitted to the PETHEMA complete response time to progression data for bortezomib, thalidomide and dexamethasone resulted in a shorter median survival time (approximately 61\xa0months) than the exponential distribution fitted to complete response time to progression data for patients receiving thalidomide and dexamethasone (median survival approximately 98 months). The ERG stated that this contrasted with overall findings for progression-free survival in the trial publication in which median progression-free survival was statistically significantly higher with bortezomib, thalidomide and dexamethasone than with thalidomide and dexamethasone. The ERG noted that the manufacturer derived transition probabilities for third and further treatment lines using data from the APEX trial, which compared bortezomib monotherapy with high-dose dexamethasone in patients with relapsed multiple myeloma. The ERG commented that because the APEX trial used bortezomib as a monotherapy treatment, it may have had different survival outcomes to those seen with bortezomib combination therapy.\n\nThe ERG considered that the costs included in the model were reasonable. However, the ERG identified that a number of changes to the manufacturer's addendum economic model, submitted to take account of the discontinuation rule stipulated for bortezomib, thalidomide and dexamethasone (see section 3.19), were not documented by the manufacturer. Although the manufacturer's addendum referred to the original submission for discussion of resource identification, measurement and valuation, the ERG noted that many of the costs in the revised model were different from those in the original model. These included costs for drugs, induction, stem cell transplant, second-line treatment, third-line treatment, and some monitoring costs. The ERG noted that although these changes were generally minor, some were substantial. For example, the administration costs for high-dose dexamethasone increased from £168 to £1242 in second-line therapy, and from £168 to £1288 in third-line therapy. The ERG stated that when considering only model changes and assumptions that were documented in the manufacturer's addendum, the ICER was £23,958 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, compared with the £20,468 per QALY gained reported in the manufacturer's addendum.\n\nThe ERG conducted a series of additional exploratory analyses. It considered that the MRC Myeloma VII trial was old and its outcomes may not reflect the more advanced treatments available today (see section 3.30) and noted that the manufacturer's sensitivity analysis used an even older study (the IFM90). Therefore, the ERG obtained data from a study by Alvares and from the NMSG 5/94 study to conduct scenario analyses. The NMSG 5/94 study was a prospective study with 247\xa0patients recruited between 1994 and 1997, and Alvares was a retrospective study with 383\xa0patients in England diagnosed with multiple myeloma between 1985 and 2004. The ERG considered that the Alvares data provided the better fit to the PETHEMA overall survival data. The ERG commented that because median overall survival for partial and non-responders in the Alvares study was much better than in the MRC Myeloma VII trial, this resulted in an increase in the base-case ICER from £20,468 per QALY gained to £30,368 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The ERG also provided the ICER using the data from the NMSG 5/94 study, but this did not include the discontinuation rule for the bortezomib, thalidomide and dexamethasone regimen and is therefore not presented. However, it resulted in a higher ICER than using the Alvares study data. The ERG also highlighted that data from the MRC Myeloma VII trial related to maximal response to treatment rather than post-induction response rate and that this was arguably more similar to post-stem cell transplant response. The ERG commented that post-stem cell transplant response rates provided a more consistent fit to the MRC Myeloma VII data and would better predict overall survival. Applying post-stem cell transplant response rates alone increased the manufacturer's base-case ICER from £20,468 to £26,292 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The ERG combined its preferred scenario analyses, that is, using data from Alvares to inform long-term survival and using post-stem cell transplant response rates. This resulted in an ICER of £38,985 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone.\n\nThe ERG conducted further exploratory analyses using the relevant economic model outputs from the manufacturer's base-case cost-effectiveness results to calculate ICERs for all treatments compared with thalidomide and dexamethasone and with cyclophosphamide, thalidomide and dexamethasone, the latter of which is a more relevant comparator regimen in a UK population. The ERG commented that all results should be treated with extreme caution as they compare individual arms of separate trials, without adjusting for trial populations. Furthermore there were differences in the trial designs. For these reasons, the results should not be directly compared. Using the manufacturer's base-case model to compare bortezomib, thalidomide and dexamethasone against cyclophosphamide, thalidomide and dexamethasone resulted in an exploratory ICER of £228,159 per QALY gained. The ERG then applied its preferred assumptions, that is, using data from Alvares to inform long-term survival and using post-stem cell transplant response rates. This resulted in an exploratory ICER for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone of £81,983 per QALY gained. The ERG conducted the same exploratory analyses in order to calculate ICERs for the bortezomib and dexamethasone regimen compared with thalidomide and dexamethasone and with cyclophosphamide, thalidomide and dexamethasone. The ERG applied data from Alvares and used post-stem cell transplant response rates, and this resulted in an ICER of £26,701 per QALY gained for bortezomib and dexamethasone compared with thalidomide and dexamethasone. However, bortezomib and dexamethasone was dominated by (that is, was less effective and more expensive than) cyclophosphamide, thalidomide and dexamethasone.\n\n# Manufacturer's response to the appraisal consultation document\n\nAdditional analyses were provided by the manufacturer in response to NICE's request for further work on the comparison between the regimen containing bortezomib and dexamethasone compared with the most relevant comparator (cyclophosphamide, thalidomide and dexamethasone) or an alternative comparator in circumstances when cyclophosphamide, thalidomide and dexamethasone is not suitable. Although the Committee did not request further analyses relating to the bortezomib, thalidomide and dexamethasone regimen, the manufacturer provided an amended model containing some revised assumptions to reflect some of the concerns raised by the ERG and the Committee's considerations in the appraisal consultation document.\n\nThe manufacturer acknowledged that the cyclophosphamide, thalidomide and dexamethasone regimen was the most relevant comparator in UK clinical practice. However, it did not provide a comparison for the bortezomib, thalidomide and dexamethasone regimen with the cyclophosphamide, thalidomide and dexamethasone regimen. It highlighted that for the comparison of the bortezomib, thalidomide and dexamethasone regimen with the thalidomide and dexamethasone regimen presented in the manufacturer's base-case analysis, it was important to evaluate how much additional benefit would be gained in terms of response rates if cyclophosphamide was to be added to thalidomide and dexamethasone. The manufacturer stated that threshold analyses performed in its original submission indicated that the complete response rate for cyclophosphamide, thalidomide and dexamethasone would have to be nearly double that observed in the PETHEMA trial for thalidomide and dexamethasone for the ICER for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone to reach £30,000 per QALY gained. Therefore the manufacturer stated that the incremental clinical efficacy of cyclophosphamide, thalidomide and dexamethasone would not be substantially greater than thalidomide and dexamethasone.\n\nThe manufacturer updated all the economic models so that:\n\na survival benefit of 11.8\xa0 months for people who received a stem cell transplant was explicitly captured\n\npost-induction rates were applied on an intention-to-treat basis to all patients in the model\n\nprobabilities of receiving a stem cell transplant were applied only to those who received a transplant\n\ntransition probabilities to second-line therapy were included by treatment arm (rather than by treatment arm and response rate)\n\ndrug administration costs were updated assuming that bortezomib is subcutaneously administered.\n\nFor the model comparing the bortezomib, thalidomide and dexamethasone regimen against thalidomide and dexamethasone, the manufacturer provided a revised base-case ICER of £17,841 per QALY gained. Sensitivity analyses using data from alternative sources to inform overall survival were presented; using long-term overall survival data from the Alvares and NMSG 5/94 studies resulted in ICERs of £22,696 and £39,618 per QALY gained respectively. The probabilistic ICER for the manufacturer's revised base-case was £22,289 per QALY gained. The probabilistic ICERs for the sensitivity analyses using Alvares and NSMG5/94 were £22,952 and £39,881 per QALY gained respectively. The manufacturer also carried out sensitivity analyses by fitting parametric curves (exponential, Weibull and log-logistics) to the PETHEMA Kaplan-Meier curves. It selected the parametric functions it thought were most appropriate, providing justification for their suitability based on face validity with the trial data, resulting in a deterministic ICER of £19,359 per QALY gained and a probabilistic ICER of £19,668 per QALY gained. The manufacturer maintained that the most appropriate source to inform overall survival in model was from the MRC Myeloma VII trial.\n\nFor the indirect comparison of bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone, the manufacturer used a 'matching-adjusted indirect comparison' method to account for differences in patients' baseline characteristics between the available trials. This created a new set of post-induction response rates, stem cell transplant rates and the post-transplant response rates for the bortezomib and dexamethasone arm. Using the MRC Myeloma VII trial as the source for long-term survival, the manufacturer's base-case deterministic ICER for the comparison of bortezomib and dexamethasone against cyclophosphamide, thalidomide and dexamethasone was £20,588 per QALY gained. The probabilistic ICER was £22,305 per QALY gained. Using long-term survival data from Alvares and NMSG 5/94 resulted in deterministic ICERs of £24,267 and £33,435 per QALY gained respectively, and the corresponding probabilistic ICERs were £23,816 and £33,107 per QALY gained. The manufacturer presented sensitivity by fitting parametric curves (exponential, Weibull and log-logistics) to the PETHEMA Kaplan-Meier curves (see section 3.39) which resulted in a deterministic ICER of £18,864 per QALY gained and a probabilistic ICER of £19,057 per QALY gained.\n\nIn response to the Committee's request for a comparison of bortezomib and dexamethasone with a relevant comparator when cyclophosphamide, thalidomide and dexamethasone is not suitable, the manufacturer highlighted that the only relevant comparator for which there was direct available evidence was vincristine, doxorubicin and dexamethasone, which might be assumed to be approximately equivalent to cyclophosphamide and dexamethasone or other options lacking thalidomide. Therefore, the manufacturer presented a deterministic base-case ICER for bortezomib and dexamethasone compared with vincristine, thalidomide and dexamethasone (including the model amendments highlighted in section 3.38) of £18,914 per QALY gained, and a probabilistic ICER of £20,096 per QALY gained. Sensitivity analyses were presented for the alternative sources of overall survival using data from the Alvares and NMSG 5/94 studies and fitting parametric curves to the PETHEMA data, which resulted in deterministic ICERs of £25,575, £42,811 and £18,489 per QALY gained respectively. The corresponding probabilistic ICERs were £25,494, £42,528 and £18,761 per QALY gained.\n\nThe ERG noted that the model structure had changed substantially from the original models and that the new approach appeared to be more intuitive. However, it highlighted that the manufacturer had not checked the external validity by validating overall survival against the PETHEMA trial.\n\nThe ERG noted that the manufacturer's analysis of bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, using the MRC Myeloma VII as the source of overall survival, provided a poor fit for overall survival compared with the observed data in the PETHEMA trial. It stated that the model consistently underestimated overall survival and was systematically biased in favour of the bortezomib, thalidomide and dexamethasone regimen. The ERG noted that the bias appeared even more pronounced in the new analyses. The ERG maintained that the sensitivity analyses using data from the Alvares or NMSG 5/94 trials was a better fit for overall survival than the base-case analysis (using long-term overall survival data from the MRC Myeloma VII trial).\n\nFor the comparison of the bortezomib and dexamethasone regimen with the cyclophosphamide, thalidomide and dexamethasone regimen, the ERG noted that stem cell transplant rates used in the manufacturer's model were 89.1% for the bortezomib arm (taken from the IFM trial) and 66.7% for the cyclophosphamide arm (taken from the MRC Myeloma IX trial). The ERG commented that the stem cell transplant rate for the cyclophosphamide-containing arm was inconsistent with the response data and may have substantially biased the bortezomib and dexamethasone cohort. The ERG explored the impact of assuming that the stem cell transplant rates for the cyclophosphamide-containing arm were similar to the IFM comparator arm (that is, 81.8% for vincristine, doxorubicin and dexamethasone) to better reflect the smaller differences observed between treatment arms in the other bortezomib trials (GIMEMA, HOVON and IFM). This increased the manufacturer's base-case ICER from £20,588 to £36,712 per QALY gained.\n\nThe ERG stated that the manufacturer's analysis of bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone provided a poor fit for overall survival compared with the observed data in the IFM trial. The ERG noted that the manufacturer provided sensitivity analyses using alternative data sources and parametric curves to model overall survival and that it considered that these sensitivity analyses, using the Alvares or NMSG 5/94 trials, were a better fit for overall survival than the base-case analysis (using long term overall survival data from the MRC Myeloma VII trial).\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report. Further evidence is available in the manufacturer's response to the appraisal consultation document and the ERG critique.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bortezomib, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of bortezomib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee noted statements from the clinical specialists and patient experts that multiple myeloma is a complex and incurable disease associated with a range of comorbidities and complications. It was aware that survival rates were historically poor until the introduction of drugs such as bortezomib, thalidomide and lenalidomide, which improved survival and quality of life. The patient experts highlighted the relapsing and remitting nature of multiple myeloma, emphasising the importance of the availability of a range of treatment options and the flexibility to choose the most appropriate treatment for individual patients because the best induction regimen is chosen based on both disease- and patient-related factors. The clinical specialists commented that bortezomib-based induction therapy would enable a higher proportion of patients to have a stem cell transplant and consequently experience longer progression-free survival and greater depth of response. The Committee also heard that bortezomib-based regimens were particularly valuable for people with clinically aggressive disease, but was aware that this group could not be clearly defined. The clinical specialists stated that induction treatment with bortezomib provides an important treatment option for patients with newly diagnosed multiple myeloma facing a high burden of disease, and when thalidomide is not a feasible treatment option because of contraindications. The Committee acknowledged the debilitating nature of the disease and the importance of having a range of treatment options available.\n\nThe Committee discussed the current management of multiple myeloma for people who are newly diagnosed and eligible for high-dose chemotherapy and stem cell transplantation. It heard from the clinical specialists that stem cell transplantation is considered the gold standard treatment for multiple myeloma because it is associated with improved progression-free survival, greater depth of response and therefore improved survival. It heard from the clinical specialists that in the UK clinicians use biological age, fitness and comorbidities rather than numerical age to decide eligibility for stem cell transplantation. The Committee noted that around 20–25% of all people with multiple myeloma would be fit enough for high-dose chemotherapy followed by a stem cell transplant. The clinical specialists stated that the aim of induction therapy was to enable more people to have stem cell transplantation successfully. The clinical specialists stated that current standard induction therapy in the UK was the combination of cyclophosphamide, thalidomide and dexamethasone, and that although vincristine, doxorubicin and dexamethasone had been used in the past, this regimen is no longer used; in line with the guideline from the British Committee for Standards in Haematology on the diagnosis and management of multiple myeloma.\n\nThe Committee was aware that the manufacturer's submission included a comparison of bortezomib and dexamethasone against vincristine, doxorubicin and dexamethasone. It noted that this was not a relevant comparison because it was not in line with UK clinical practice and was outside the NICE scope of the appraisal, which specified thalidomide-containing regimens as comparators. The Committee was also aware that the manufacturer did not present a comparison of bortezomib, thalidomide and dexamethasone against cyclophosphamide, thalidomide and dexamethasone, but instead presented a comparison of bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone, assuming clinical equivalence between thalidomide and dexamethasone, and cyclophosphamide, thalidomide and dexamethasone. The clinical specialists stated the 2 regimens could be considered broadly similar. However, they stated that the advantage of using a triple therapy such as cyclophosphamide, thalidomide and dexamethasone was that there was more flexibility to reduce doses in the case of toxicity. The Committee queried whether thalidomide and dexamethasone is used in UK clinical practice and heard that the cyclophosphamide, thalidomide and dexamethasone regimen is the standard induction treatment in the UK. The Committee considered that the cyclophosphamide, thalidomide and dexamethasone regimen was the most appropriate comparator. It was persuaded that the manufacturer's threshold analyses demonstrated that the addition of cyclophosphamide would have to add a clinically implausible level of additional benefit (almost double) before the ICER for bortezomib, thalidomide and dexamethasone increased above £30,000 per QALY gained compared with cyclophosphamide, thalidomide and dexamethasone (see section 3.37). Therefore the Committee concluded that bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone was a reasonable basis for appraising the clinical and cost effectiveness of bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone.\n\n# Clinical effectiveness\n\nThe Committee noted that the manufacturer presented evidence on the clinical effectiveness of bortezomib from the PETHEMA, GIMEMA, HOVON and IFM trials. The Committee was aware that the HOVON trial included the bortezomib, doxorubicin and dexamethasone regimen, which was not included in the bortezomib marketing authorisation. It therefore excluded it from its clinical and cost-effectiveness discussions. It noted that the trials included different regimens of bortezomib and had different study designs. The Committee noted that in the GIMEMA trial patients only received 3 cycles of bortezomib, thalidomide and dexamethasone whereas in the PETHEMA trial patients received 6 cycles, which was more in line with the marketing authorisation. Moreover, the Committee noted that the PETHEMA and GIMEMA trials differed in the number of stem cell transplants given and the type of consolidation (intensification therapy to sustain remission before lower-dose maintenance therapy) and maintenance treatments used after transplant, and that consolidation and maintenance treatment was not standard clinical practice in the NHS. The Committee was aware that none of the trials included a comparison with cyclophosphamide, thalidomide and dexamethasone, which is standard clinical practice in England.\n\nThe Committee discussed the results from the PETHEMA and IFM trials. It noted that in the PETHEMA trial, bortezomib, thalidomide and dexamethasone was associated with a statistically significant gain in overall response rate after induction compared with thalidomide and dexamethasone (84.6% compared with 61.4%, p<0.001) and that this was maintained after stem cell transplant (77.7% compared with 56.7%, p<0.001). The Committee also noted that, in the IFM trial, bortezomib and dexamethasone was associated with a similar gain in overall response rate compared with vincristine, doxorubicin and dexamethasone (77.1% compared with 60.7%, p<0.001) but a statistically significant difference was not shown after stem cell transplantation (79.6% compared with 74.4%, p=0.179). It noted that progression-free survival was longer in the bortezomib, thalidomide and dexamethasone arm of the PETHEMA trial than in the thalidomide and dexamethasone arm, and that the difference was statistically significant (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.45 to 0.92, p=0.015). It further noted that progression-free survival was longer in the bortezomib and dexamethasone arm of the IFM trial than in the vincristine, doxorubicin and dexamethasone arm, but the difference was not statistically significant (HR 0.88, 95% CI 0.70 to 1.11, p value not reported). The Committee agreed that induction treatment with bortezomib and dexamethasone was associated with statistically significant improvements in post-induction overall response rates compared with vincristine, doxorubicin and dexamethasone, and that induction treatment with bortezomib, thalidomide and dexamethasone resulted in statistically significant improvements in overall response rates (post-induction and post-stem cell transplant) and progression-free survival compared with thalidomide and dexamethasone. However, it concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone against cyclophosphamide, thalidomide and dexamethasone, the comparator regimen considered to be current standard care in the UK and therefore the most relevant comparator for the Committee's decision-making.\n\nThe Committee considered the unadjusted overall survival reported in the manufacturer's submission for the PETHEMA and IFM trials. It noted that median overall survival was not reached in either the PETHEMA trial (bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, hazard ratio 0.80, 95% CI 0.48 to 1.34, p=0.393) or the IFM trial (bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone, HR 0.8, 95% CI 0.54 to 1.19, p\xa0value not reported) and there was no statistically significant difference in overall survival between the treatment arms in each study. The Committee heard from the manufacturer and from the clinical specialists that the duration of the trials was too short to allow differences in overall survival to be seen between treatment groups. The clinical specialists also stated that given the differences in trial design relating to the numbers of stem cell transplants and types of maintenance treatment received it was not possible to draw firm conclusions. The Committee concluded that although there was uncertainty in the magnitude of overall survival associated with bortezomib, it was plausible that bortezomib's impact on induction response could be associated with improved overall survival.\n\nThe Committee considered the manufacturer's indirect comparison. It acknowledged the manufacturer's rationale that a network could not be formed to conduct an indirect comparison between the available trials and assumptions to overcome the network limitations would generate considerable uncertainties and unreliable results. At the appraisal consultation stage, the Committee requested further analysis comparing single arms of the available trials, adjusting for the differences between the trial designs and baseline characteristics of the patients included in each study. The Committee concluded that although there would be limitations to this approach, further analysis from the manufacturer would provide useful comparative data to draw conclusions on the relative effectiveness of bortezomib, thalidomide and dexamethasone, and bortezomib and dexamethasone, compared with the most relevant comparator cyclophosphamide, thalidomide and dexamethasone, or an alternative comparator in situations in which the cyclophosphamide, thalidomide and dexamethasone regimen is considered inappropriate.\n\nThe Committee considered the adverse events associated with using a bortezomib-containing regimen. It heard from the clinical specialists that intravenously administered bortezomib had been associated with peripheral neuropathy, but that rapid dose reductions could effectively manage it. In addition, the clinical specialists highlighted that although the evidence presented was for intravenously administered bortezomib, the introduction of a subcutaneous formulation has substantially reduced the side effects related to peripheral neuropathy and also reduced the need for thromboprophylaxis. The Committee concluded that the adverse event profile of bortezomib was manageable (for full details of adverse reactions and contraindications, see the summary of product characteristics).\n\n# Cost effectiveness\n\nThe Committee considered the structure, assumptions and results of the manufacturer's economic model, which was based on data from the PETHEMA and IFM trials for the bortezomib, thalidomide and dexamethasone and the bortezomib and dexamethasone regimens respectively. The Committee was aware that the model only provided comparisons for bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone and for bortezomib and dexamethasone against vincristine, doxorubicin and dexamethasone, which was not in line with current clinical practice in the UK, and that the vincristine, doxorubicin and dexamethasone regimen was outside of the scope of this appraisal. The Committee acknowledged that there was no direct evidence available to compare the bortezomib, thalidomide and dexamethasone and the bortezomib and dexamethasone regimens with cyclophosphamide, thalidomide and dexamethasone, and it asked the manufacturer to further explore this by conducting a further indirect comparison using single arms from the relevant clinical trials.\n\nThe Committee considered the manufacturer's approach to using post-induction rates from the PETHEMA and IFM trials in the economic model for the bortezomib, thalidomide and dexamethasone and the bortezomib and dexamethasone regimens respectively. It noted the ERG's comments that data from the MRC Myeloma VII trial used by the manufacturer to estimate long-term survival related to maximal response to treatment rather than post-induction response rate and therefore using post-stem cell transplant response rates from the PETHEMA and IFM trials might better predict progression-free survival and overall survival. The clinical specialists stated that post-stem cell transplant response rates would be more appropriate as long as they were based on an intention-to-treat analysis that included all people who were randomised in the trials regardless of whether they received treatment or not; however, if they were based only on patients who received a transplant, post-induction response rates would be more meaningful. The ERG confirmed that post-stem cell transplant rates in both the PETHEMA and GIMEMA trials were based on an intention-to-treat analysis. The Committee concluded that using post-stem cell transplant response rates rather than post-induction response rates was more appropriate.\n\nThe Committee considered the way in which long-term survival had been extrapolated in the manufacturer's model. The Committee was aware that that the model extrapolated level of response after induction therapy to long-term survival and time to progression based on data from the MRC Myeloma VII trial. It noted the ERG's comments that the MRC Myeloma VII trial was not very recent because it had recruited patients between 1993 and 2003, and that its rates for overall survival and progression-free survival were likely to be lower than would be seen in current clinical practice. The Committee was also aware that although long-term survival end points had not been reached in the PETHEMA and IFM trials, the data available in these trials suggested that the manufacturer's model, using data from MRC Myeloma VIl, underestimated overall survival. It noted that other data were available (for example, from a study by Alvares and the NMSG 5/94 study) that fit better with the data observed in the PETHEMA and IFM trials. The Committee concluded that the ERG's exploratory analysis using data from the Alvares and NMSG 5/94 studies was appropriate (see section 3.34) for estimating long-term survival and should be considered together with the analysis based on the MRC Myeloma VII study.\n\nThe Committee considered the costs used in the manufacturer's economic model. It was aware that the clinical trials were all conducted using intravenously administered bortezomib, and it heard from the manufacturer that this was also assumed in the economic model and was therefore associated with a day-patient cost. The Committee was, however, aware that bortezomib is available as a subcutaneous formulation which is widely used and would therefore only be associated with an outpatient cost. The Committee also noted the comments from the clinical specialists that the subcutaneous formulation could reduce the risk of peripheral neuropathy and also reduce the need for thromboprophylaxis. The Committee considered that these issues combined might reduce the total cost of bortezomib in the model. The manufacturer updated the model to reflect this during consultation to reduce costs from £203 to £197 for first attendance and from £284 to £211 for subsequent visits.\n\nThe Committee noted that the manufacturer's comparison of bortezomib and dexamethasone with vincristine, doxorubicin and dexamethasone was outside the NICE scope because the comparator did not contain thalidomide, and in addition, the clinical specialists commented that the vincristine, doxorubicin and dexamethasone regimen is no longer used as an induction therapy for multiple myeloma in the UK. The Committee decided, therefore, that it was not appropriate to consider the results from this comparison. However, the Committee also noted that the bortezomib and dexamethasone regimen had a lower acquisition cost than the bortezomib, thalidomide and dexamethasone regimen as it did not include thalidomide, and heard from clinical specialists that it would provide a valuable treatment option, especially for patients who cannot tolerate thalidomide. The Committee was aware that the ERG's exploratory analyses also included comparisons of bortezomib and dexamethasone against thalidomide and dexamethasone, and comparisons of bortezomib and dexamethasone against cyclophosphamide, thalidomide and dexamethasone. Based on the analyses incorporating the Alvares survival data and post-stem cell transplant response rates that were preferred by the Committee for the bortezomib, thalidomide and dexamethasone analysis, the Committee noted that the ERG's exploratory ICER for bortezomib and dexamethasone compared with thalidomide and dexamethasone was £26,700 per QALY gained. It also noted that in the comparison of bortezomib and dexamethasone with cyclophosphamide, thalidomide and the dexamethasone, the bortezomib and dexamethasone regimen was dominated by (that is, it was more costly and less effective than) cyclophosphamide, thalidomide and dexamethasone. The Committee acknowledged the lack of an appropriate comparison in the manufacturer's submission and the caveats surrounding the ERG's exploratory analysis, and asked the manufacturer to further explore the cost effectiveness of the bortezomib and dexamethasone (see section 4.15).\n\nThe Committee noted the manufacturer's original comparison of bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone, which resulted in a deterministic incremental cost-effectiveness ratio (ICER) of £20,500 per QALY gained, and that the manufacturer had not presented probabilistic ICERs. The Committee then discussed the results of the ERG's exploratory analyses. The Committee noted that using post-stem cell transplant response rates instead of post-induction response rates (see section 4.10) resulted in an ICER of £26,300 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The Committee also noted that using data from the Alvares study instead of the MRC Myeloma VII study to model long-term survival resulted in an ICER of £30,400 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The clinical specialists raised concerns that the Alvares study was retrospective in design and also quite old and therefore a more recent study would be more appropriate. The ERG confirmed that it had also conducted an exploratory analysis based on data from the NMSG 5/94 study and that this resulted in an ICER higher than £30,400 per QALY gained, that but this did not include the discontinuation rule and was therefore not presented (see section 3.34). The Committee noted that given the disparity between the overall survival results from the trials and those in the model, using an alternative data source such as the Alvares study, which was a better fit to the trial data, was appropriate. The Committee noted that incorporating post-stem cell transplant rates and using the Alvares study to inform overall survival together resulted in an ICER of £39,000 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The Committee concluded that based on the analyses that were available before the appraisal consultation document was released, the ERG's exploratory analyses were appropriate and that £39,000 per QALY gained was an appropriate starting point for discussion on the most plausible ICER for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone.\n\nThe Committee was aware of the ERGs further exploratory analyses on bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone. The Committee understood that there were limitations with this approach because the data were drawn from a range of heterogeneous studies containing different comparators and different study designs and therefore could not be directly compared. Moreover, differences in trial design and baseline characteristics had not been taken into account. The Committee noted that this approach resulted in an ICER of £228,200 per QALY gained for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone when using the manufacturer's base-case assumptions. Applying post-stem cell transplant response rates and survival data from the Alvares study resulted in an ICER of £82,000 per QALY gained for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone. The Committee agreed that although there was considerable uncertainty associated with such an approach, the ICER based on the analyses that were available before the appraisal consultation document was released for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone was likely to be higher than the ICER of £39,000 per QALY gained compared with thalidomide and dexamethasone. The Committee considered that further analyses were needed to explore the cost effectiveness of the bortezomib and dexamethasone regimen and asked the manufacturer to present:\n\nAn indirect comparison of bortezomib in combination with dexamethasone, compared with cyclophosphamide in combination with thalidomide and dexamethasone, and compared with an alternative comparator in circumstances in which cyclophosphamide in combination with thalidomide and dexamethasone is not suitable. In the absence of a network to facilitate a robust comparison, the Committee requested that this should be a careful comparison using single arms from relevant clinical trials, taking into account differences in trial design and baseline characteristics. It should include sensitivity analyses using assumptions suggested by the Evidence Review Group:\n\n\n\nusing data from wider sources than the MRC\xa0Melanoma VII trial, including the Alvares and NMSG\xa05/94 studies, and extrapolation from the trials of bortezomib-containing regimens to inform overall survival in the economic model\n\nusing post-stem cell transplant response rates from the IFM trial rather than post-induction response rates\n\nusing transplant rates by response category rather than total stem cell transplant rates\n\nupdated costs to reflect the use of a subcutaneous formulation of bortezomib.\n\n\n\nProbabilistic incremental cost-effectiveness ratios for the revised comparisons.\n\nThe Committee considered the manufacturer's response to the appraisal consultation document that included changes to the economic models for all the bortezomib regimens (see section 3.38). The Committee considered the manufacturer's revised modelling assumption that incorporated an 11.8 month survival benefit for people who received a stem cell transplant. The Committee noted that the model included survival curves for complete responders in addition to the assumption of survival benefit from receiving a stem cell transplant and discussed whether this amounted to double counting. It heard from the clinical specialists that incorporating the additional survival benefit was not double counting because the purpose of a stem cell transplant is to increase the depth of response, which could provide additive effect resulting in a survival benefit of up to a year. The Committee heard from the manufacturer that the additional survival benefit assumption was not a key driver of cost effectiveness because removing this benefit had minimal effect on the ICERs. The Committee concluded that the manufacturer's approach to modelling stem cell transplant benefit was acceptable for its decision making.\n\nThe Committee was aware that the manufacturer used the stem cell transplant rates from the PETHEMA trial to inform the comparison of bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone (80.8% and 61.4% respectively) but that other bortezomib trials (GIMEMA, HOVON and IFM) indicated rates were above 80% regardless of the treatment arm. The Committee was also aware that transplant rates for the comparison of bortezomib and dexamethasone (without thalidomide) against cyclophosphamide, thalidomide and dexamethasone, were incorporated from the IFM trial for the bortezomib and dexamethasone arm (89.1%) and from the MRC Myeloma IX trial for the cyclophosphamide, thalidomide and dexamethasone arm (66.7%). The Committee noted the ERG's concerns that this was inconsistent with transplant rates taken from the control arm of the IFM trial (81.8%, which was directly comparable and would be expected to be no better than a cyclophosphamide, thalidomide and dexamethasone control arm). The Committee noted that the ERG had explored the impact of incorporating a stem cell transplant rate of 81.8%, which resulted in the manufacturer's revised base-case ICER increasing from £20,588 to £36,700 per QALY gained. The Committee discussed whether the differences in the transplant rates were too wide for both comparisons. It heard from the clinical specialists that in clinical practice cyclophosphamide, thalidomide and dexamethasone was associated with a stem cell transplant rate of approximately 50% and this was corroborated by 2 large population-based studies. The clinical specialists stated that bortezomib regimens were likely to be associated with stem transplant rates of 60–65%. The clinical specialists also suggested that stem cell transplant rates should better reflect complete response rates than the control arms of the other trials suggest. The Committee agreed that although a bortezomib regimen might be expected to improve the rate of stem cell transplant, it would be to a lesser extent than was modelled by the manufacturer, and more closely linked to response in clinical practice. However, the Committee also agreed that the differences in transplant rates between treatment arms in the models were plausible. The Committee concluded that although the impact of stem cell transplant rates included in the model on cost-effectiveness results was uncertain, it was unlikely to undermine the manufacturer's base-case cost-effectiveness results.\n\nThe Committee discussed the overall survival modelling informing the manufacturer's revised ICERs for the comparison of bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone. It noted that the manufacturer preferred the MRC Myeloma VII data as the source for long-term survival, which resulted in an ICER of £17,800 per QALY gained. The Committee heard from the ERG that the MRC Myeloma VII data did not fit the observed PETHEMA data. The Committee was aware that incorporating data from the ERG's preferred Alvares and NMSG 5/94 studies resulted in ICERs of £22,700 and £39,600 per QALY gained respectively. The manufacturer stated that caution should be taken in interpreting the fit with PETHEMA trial data beyond 30\xa0months because of the level of censoring. The Committee questioned why data from the PETHEMA trial had not been used directly. The manufacturer argued that the data were immature. The Committee also heard from the clinical specialists that because patients in the PETHEMA trial could receive bortezomib as maintenance treatment (which is not standard practice in the UK) there would be substantial convergence between the treatment arms when more long-term survival data become available. The Committee recognised that even though there was little face validity in the modelling of survival, it appreciated that the Kaplan−Meier curve from the PETHEMA trial was confounded by post-induction treatment. The Committee noted that incorporating only the NMSG 5/94 data resulted in ICERs that would not normally be considered to be cost effective (above £30,000 per QALY gained). The Committee considered concerns raised by the manufacturer and consultees that the NMSG study did not provide fully relevant data because it did not report median overall survival for partial and non-responders. The Committee concluded that using data from the NMSG 5/94 study would represent a pessimistic scenario and that the ICERs based on survival data from the MRC Myeloma VII (£17,800 per QALY gained) and Alvares (£22,700 per QALY gained) studies were appropriate for its decision making.\n\nThe Committee considered the manufacturer's ICERs for bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone, as requested in the appraisal consultation document. It noted that using the MRC Myeloma VII, Alvares and NMSG 5/94 data sources to inform overall survival in the model resulted in ICERS of £20,600, £24,300 and £33,400 per QALY gained respectively. It noted that only using the NMSG 5/94 study data resulted in ICERs above £30,000 per QALY gained. Having discussed the concerns around the NMSG 5/94 data (see section 4.18), the Committee considered that results based on these data were likely to represent a pessimistic scenario. The Committee also considered the analyses presented by manufacturer when cyclophosphamide, thalidomide and dexamethasone may not be suitable, noting that vincristine, doxorubicin and dexamethasone was included as the most appropriate comparator in this situation. The Committee noted that the ICERs ranged from £18,900 per QALY gained using MRC Myeloma VII survival data to £25,600 using survival data from the Alvares study. The Committee concluded that most plausible ICERs based on survival data from the MRC Myeloma VII and Alvares studies were appropriate for its decision making.\n\nThe Committee remained concerned that the modelling was subject to uncertainties, and that the manufacturer had also not provided sufficient external and internal validity. However, the Committee acknowledged that bortezomib regimens had a clear advantage with respect to induction response and that a link between improved response and survival was plausible. In particular, the Committee considered that there were people with clinically aggressive disease, with organ function at risk, or at risk of irreversible renal damage, who would benefit from a fast response associated with treatment with bortezomib, but heard that this group could not be categorically defined. Taking into account its consideration that the uncertainty around stem cell transplant rates was not likely to have a substantial impact on the ICER (section 4.16) and taking into consideration ICERs based on survival data from the MRC Myeloma VII and Alvares studies, the Committee concluded that, on balance, the ICERs for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, and for bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone and compared with vincristine, doxorubicin and dexamethasone, were likely to be below £30,000 per QALY gained. Therefore both bortezomib regimens could be considered a cost-effective use of NHS resources.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA311\n\nAppraisal title: Bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem cell transplantation\n\nSection\n\nKey conclusion\n\nBortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee was concerned that the modelling was subject to uncertainties, however it acknowledged that bortezomib regimens had a clear advantage with respect to induction response and that a link between improved response and survival was plausible.\n\nFor the cost-effectiveness analysis, and in response to consultation, the manufacturer presented additional evidence that included changes to the economic models and comparisons with cyclophosphamide, thalidomide, and dexamethasone, the comparator regimen considered to be current standard care in the UK. Based on a threshold analysis presented by the manufacturer, the Committee concluded that bortezomib, thalidomide, and dexamethasone compared with thalidomide and dexamethasone was a reasonable basis for appraising the clinical and cost effectiveness of bortezomib, thalidomide, and dexamethasone compared with cyclophosphamide, thalidomide, and dexamethasone.\n\nThe Committee considered and explored a range of ICERs using several studies included in the submissions, and concluded that, on balance, the ICERs for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, and for bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone and compared with vincristine, doxorubicin and dexamethasone, were likely to be below £30,000 per QALY gained.\n\n\n\n-4.20\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from clinical specialists that stem cell transplantation is considered the gold standard treatment for multiple myeloma because it is associated with improved progression-free survival, greater depth of response and therefore improved survival. The clinical specialists stated that the aim of induction therapy was to enable more people to proceed to stem cell transplantation successfully.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe clinical specialists commented that bortezomib-based induction therapy would enable a higher proportion of patients to have a stem cell transplant and consequently experience longer progression-free survival and greater depth of response. The Committee also heard that bortezomib-based regimens were particularly valuable for people with clinically aggressive disease, but was aware that this group could not be clearly defined.\n\nThe Committee agreed that induction treatment with bortezomib and dexamethasone was associated with statistically significant improvements in post-induction overall response rates compared with vincristine, doxorubicin and dexamethasone, and that induction treatment with bortezomib, thalidomide and dexamethasone resulted in statistically significant improvements in overall response rates (post-induction and post-stem cell transplantation) and progression-free survival compared with thalidomide and dexamethasone. However, it concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone with cyclophosphamide, thalidomide and dexamethasone, the comparator regimen considered to be current standard care in the UK and therefore the most relevant comparator for the Committee's decision-making.\n\n, 4.5\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe clinical specialists stated that induction treatment with bortezomib provides an important treatment option for patients with newly diagnosed multiple myeloma, and when thalidomide is not a feasible treatment option because of contraindications.\n\n\n\nAdverse reactions\n\nClinical specialists highlighted that although the evidence presented was for intravenously administered bortezomib, the introduction of a subcutaneous formulation has substantially reduced the side effects related to peripheral neuropathy and also reduced the need for thromboprophylaxis. The Committee concluded that the adverse event profile of bortezomib was manageable (for full details of adverse reactions and contraindications, see the summary of product characteristics).\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted that the manufacturer presented evidence on the clinical effectiveness of bortezomib from the PETHEMA, GIMEMA, HOVON and IFM trials. The Committee was aware that the HOVON trial included the bortezomib, doxorubicin and dexamethasone regimen, which was not included in the bortezomib marketing authorisation. It therefore excluded it from its clinical and cost-effectiveness discussions.\n\nThe Committee noted that the trials included different regimens of bortezomib and had different study designs. It noted that in the GIMEMA trial patients only received 3 cycles of bortezomib, thalidomide and dexamethasone whereas in the PETHEMA trial patients received 6 cycles, which was more in line with the marketing authorisation. Moreover, the Committee noted that the PETHEMA and GIMEMA trials differed in the number of stem cell transplants given and the type of consolidation (intensification therapy to sustain remission before lower dose maintenance therapy) and maintenance treatments used after transplant, and that consolidation and maintenance treatment was not standard clinical practice in the NHS.\n\nThe Committee was aware that none of the trials included a comparison with cyclophosphamide, thalidomide and dexamethasone, which is standard clinical practice in England.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee noted that the PETHEMA and GIMEMA trials differed in the number of stem cell transplants and the type of consolidation and maintenance treatments used after transplant and that consolidation and maintenance treatment was not standard clinical practice in the NHS. The Committee was aware that none of the trials included a comparison with cyclophosphamide, thalidomide and dexamethasone which is standard clinical practice in England.\n\nMoreover, the IFM trial included a comparison of bortezomib and dexamethasone with vincristine, doxorubicin and dexamethasone, which is no longer used.\n\n, 4.2\n\nUncertainties generated by the evidence\n\nThe Committee concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone against cyclophosphamide, thalidomide and dexamethasone, the comparator regimen considered to be current standard care in the UK and therefore the most relevant comparator for the Committee's decision-making.\n\nThe Committee heard from the manufacturer and from the clinical specialists that the duration of the trials was too short to allow differences in overall survival to be seen between treatment groups. It concluded that although there was uncertainty in the magnitude of overall survival gain associated with bortezomib, it was plausible that bortezomib's impact on induction response could be associated with improved overall survival.\n\n, 4.6\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that in the PETHEMA trial, bortezomib, thalidomide and dexamethasone was associated with statistically significant gain in overall response rate post-induction compared with thalidomide and dexamethasone (84.6% compared with 61.4%, p<0.001) and that this was maintained after stem cell transplant (77.7% compared with 56.7%, p<0.001). The Committee also noted that, in the IFM trial, bortezomib and dexamethasone was associated with a similar gain in overall response rate compared with vincristine, doxorubicin and dexamethasone (77.1% compared with 60.7%, p<0.001) but a statistical difference was not shown after stem cell transplant (79.6% compared with 74.4%, p=0.179).\n\nThe Committee noted that median overall survival was not reached in either the PETHEMA trial (bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, hazard ratio 0.80, 95% 0.48 to 1.34, p=0.393) or IFM trial (bortezomib and dexamethasone compared with vincristine, doxorubicin and dexamethasone, HR 0.8, 95% CI 0.54 to 1.19, p\xa0value not reported) and there was no statistically significant difference in overall survival between the treatment arms in each study.\n\nIt concluded that although there was uncertainty in the magnitude of overall survival gain associated with bortezomib, it was plausible that bortezomib's impact on induction response could be associated with improved overall survival.\n\n, 4.6\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee was aware that the model only provided comparisons for bortezomib, thalidomide and dexamethasone against thalidomide and dexamethasone and for bortezomib and dexamethasone against vincristine, doxorubicin and dexamethasone, which was not in line with current clinical practice in the UK, and that the vincristine, doxorubicin and dexamethasone regimen was outside of the scope of this appraisal. The Committee acknowledged that there was no direct evidence available to compare the bortezomib, thalidomide and dexamethasone and the bortezomib and dexamethasone regimens with cyclophosphamide, thalidomide and dexamethasone, and it asked the manufacturer to further explore this by conducting a further indirect comparison using single arms from the relevant clinical trials.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted the ERG's comments that the MRC Myeloma VII trial was not very recent because it recruited patients between 1993 and 2003, and its rates for overall survival and progression-free survival were likely to be lower than would be seen in current clinical practice. The Committee was also aware that although long-term survival end points had not been reached in the PETHEMA and IFM trials, the data available in these trials suggested that the manufacturer's model, using data from MRC Myeloma VIl, underestimated overall survival.\n\nThe Committee concluded that although the impact of stem cell transplant rates included in the model on cost-effectiveness results was uncertain, it was unlikely to undermine the manufacturer's base-case cost-effectiveness results.\n\n\n\n, 4.17\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe manufacturer selected the van Agthoven study as the base-case source of utility values because the utility values were obtained using EQ‑5D.\n\nWith regard to adverse events the manufacturer applied a disutility of 0.02 to each patient experiencing an adverse event associated with induction therapy.\n\n\n\n\n\n\n\nThe Committee noted the comments from the clinical specialists that the subcutaneous formulation could reduce the risk of peripheral neuropathy and also reduce the need for thromboprophylaxis. The Committee considered that these issues combined might reduce the total cost of bortezomib in the model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe manufacturer's deterministic sensitivity analyses highlighted that the results were most sensitive to the mortality for patients who had a complete response after the induction therapy, and to drug costs.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, the manufacturer's base-case using the MRC Myeloma VII data as the source for long-term survival ICER resulted in an ICER of £17,800 per QALY gained.\n\nThe Committee was aware that incorporating data from the ERG's preferred Alvares and NMSG 5/94 studies resulted in ICERs of £22,700 and £39,600 per QALY gained respectively.\n\n\n\n\n\n\n\nFor bortezomib and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone, using the MRC Myeloma VII, Alvares and NMSG 5/94 data sources to inform overall survival in the model, the ICERs were £20,600, £24,300 and £33,400 per QALY gained respectively.\n\nThe Committee concluded that the ICERs based on survival data from the MRC Myeloma VII and Alvares study were appropriate for its decision making.\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNone submitted.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues relevant to the Committee's recommendations were raised.\n\n", 'Review of guidance': 'The guidance on this technology will be considered for review in February 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon Chief ExecutiveApril 2014', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt has been incorporated into the NICE pathway on blood and bone marrow cancers along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0557-7'}	https://www.nice.org.uk/guidance/ta311	Evidence-based recommendations on bortezomib (Velcade) for treating multiple myeloma before chemotherapy and stem cell transplant in adults.
bb39473c79a836b4149bba23870191b3643dab94	nice	Pressure ulcers: prevention and management	Pressure ulcers: prevention and management This guideline covers risk assessment, prevention and treatment in children, young people and adults at risk of, or who have, a pressure ulcer (also known as a bedsore or pressure sore). It aims to reduce the number of pressure ulcers in people admitted to secondary or tertiary care or receiving NHS care in other settings, such as primary and community care and emergency departments. # Introduction This guideline updates and replaces 'Pressure ulcers' (NICE guideline CG29) and 'Pressure ulcer prevention' (NICE guideline CG7). See update information for details. Pressure ulcers are caused when an area of skin and the tissues below are damaged as a result of being placed under pressure sufficient to impair its blood supply. Typically they occur in a person confined to bed or a chair by an illness and as a result they are sometimes referred to as 'bedsores', or 'pressure sores'. All patients are potentially at risk of developing a pressure ulcer. However, they are more likely to occur in people who are seriously ill, have a neurological condition, impaired mobility, impaired nutrition, or poor posture or a deformity. Also, the use of equipment such as seating or beds which are not specifically designed to provide pressure relief, can cause pressure ulcers. As pressure ulcers can arise in a number of ways, interventions for prevention and treatment need to be applicable across a wide range of settings including community and secondary care. This may require organisational and individual change and a commitment to effective delivery. Pressure ulcers are often preventable and their prevention is included in domain 5 of the Department of Health's NHS outcomes framework 2014/15. The current guideline rationalises the approaches used for the prevention and management of pressure ulcers. Its implementation will ensure practice is based on the best available evidence. It covers prevention and treatment and applies to all people in NHS care and in care funded by the NHS. Recommendations for prevention include methods for identification and risk assessment and the preventive measures that should be applied. Treatment of pressure ulcers includes recommendations on wound care, adjunctive therapies and support surfaces. While there is much clinical expertise and good practice focused on preventing and treating pressure ulcers, it is hoped that this evidence-based guidance will contribute to reducing the number of pressure ulcers nationally through its implementation throughout the NHS. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients. See also the NHS Improvement revised definition and measurement framework for pressure ulcers. This will help deliver a consistent approach to defining and measuring pressure ulcers, and help to understand the level of pressure damage harm in England. Safeguarding children Remember that child maltreatment: is common can present anywhere, including primary and secondary care and community settings (such as the child's home) Consider or suspect abuse (particularly malnourishment) as a contributory factor to or cause of pressure ulcers in children. Abuse may also coexist with pressure ulcers. See the NICE guideline on child maltreatment for clinical features that may be associated with maltreatment. This section has been agreed with the Royal College of Paediatrics and Child Health. Safeguarding adults The Department of Health and Social Care has issued a protocol for safeguarding adults at risk of pressure ulcers. It aims to help practitioners and managers across health and care organisations to provide caring and quick responses to people at risk of developing pressure ulcers. It includes a process for deciding whether an adult safeguarding response is needed.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Terms used in this guideline ## Adults, neonates, infants, children and young people This guideline covers people of all ages at risk of, or who have, a pressure ulcer. These terms are defined as follows: adults: 18 years or older neonates: under 4 weeks infants: between 4 weeks and 1 year children: 1 year to under 13 years young people: 13 to 17 years. ## Risk assessment This guideline uses the terms 'at risk' and 'at high risk' to identify people who may develop a pressure ulcer. For the purposes of this guideline: Adults considered to be at risk of developing a pressure ulcer are those who, after assessment using clinical judgement and/or a validated risk assessment tool, are considered to be at risk of developing a pressure ulcer. Adults considered to be at high risk of developing a pressure ulcer will usually have multiple risk factors (for example, significantly limited mobility, nutritional deficiency, inability to reposition themselves, significant cognitive impairment) identified during risk assessment with or without a validated risk assessment tool. Adults with a history of pressure ulcers or a current pressure ulcer are also considered to be at high risk. Neonates, infants, children and young people considered to be at risk are those who, after assessment using clinical judgement and/or a validated risk assessment tool, are considered to be at risk of developing a pressure ulcer. Neonates, infants, children and young people considered to be at high risk of developing a pressure ulcer will usually have multiple risk factors (for example, significantly limited mobility, nutritional deficiency, inability to reposition themselves, significant cognitive impairment) identified during risk assessment with or without a validated risk assessment tool. Those with a history of pressure ulcers or a current pressure ulcer are also considered to be at high risk.Please note that the examples given are not exhaustive. # Prevention: adults ## Risk assessment Be aware that all patients are potentially at risk of developing a pressure ulcer. Carry out and document an assessment of pressure ulcer risk for adults: being admitted to secondary care or care homes in which NHS care is provided or receiving NHS care in other settings (such as primary and community care and emergency departments) if they have a risk factor, for example: significantly limited mobility (for example, people with a spinal cord injury) significant loss of sensation a previous or current pressure ulcer nutritional deficiency the inability to reposition themselves significant cognitive impairment. Consider using a validated scale to support clinical judgement (for example, the Braden scale, the Waterlow score or the Norton risk-assessment scale) when assessing pressure ulcer risk. Reassess pressure ulcer risk if there is a change in clinical status (for example, after surgery, on worsening of an underlying condition or with a change in mobility). ## Skin assessment Offer adults who have been assessed as being at high risk of developing a pressure ulcer a skin assessment by a trained healthcare professional (see recommendation 1.3.4). The assessment should take into account any pain or discomfort reported by the patient and the skin should be checked for: skin integrity in areas of pressure colour changes or discolorationHealthcare professionals should be aware that non-blanchable erythema may present as colour changes or discolouration, particularly in darker skin tones or types. variations in heat, firmness and moisture (for example, because of incontinence, oedema, dry or inflamed skin). Use finger palpation or diascopy to determine whether erythema or discolouration (identified by skin assessment) is blanchable. Start appropriate preventative action (see recommendations 1.1.1–1.1.17) in adults who have non-blanching erythema and consider repeating the skin assessment at least every 2 hours until resolved. ## Repositioning Encourage adults who have been assessed as being at risk of developing a pressure ulcer to change their position frequently and at least every 6 hours. If they are unable to reposition themselves, offer help to do so, using appropriate equipment if needed. Document the frequency of repositioning required. Encourage adults who have been assessed as being at high risk of developing a pressure ulcer to change their position frequently and at least every 4 hours. If they are unable to reposition themselves, offer help to do so, using appropriate equipment if needed. Document the frequency of repositioning required. ## Skin massage Do not offer skin massage or rubbing to adults to prevent a pressure ulcer. ## Nutritional supplements and hydration Do not offer nutritional supplements specifically to prevent a pressure ulcer in adults whose nutritional intake is adequate. Do not offer subcutaneous or intravenous fluids specifically to prevent a pressure ulcer in adults whose hydration status is adequate. ## Pressure redistributing devices Use a high-specification foam mattress for adults who are: admitted to secondary care assessed as being at high risk of developing a pressure ulcer in primary and community care settings. Consider a high-specification foam theatre mattress or an equivalent pressure redistributing surface for all adults who are undergoing surgery. Discuss with adults at high risk of developing a heel pressure ulcer and, where appropriate, their family or carers, a strategy to offload heel pressure, as part of their individualised care plan. Consider the seating needs of people at risk of developing a pressure ulcer who are sitting for prolonged periods. Consider a high-specification foam or equivalent pressure redistributing cushion for adults who use a wheelchair or who sit for prolonged periods. ## Barrier creams Consider using a barrier preparation to prevent skin damage in adults who are at high risk of developing a moisture lesion or incontinence-associated dermatitis, as identified by skin assessment (such as those with incontinence, oedema, dry or inflamed skin). # Prevention: neonates, infants, children and young people ## Risk assessment Carry out and document an assessment of pressure ulcer risk for neonates, infants, children and young people: being admitted to secondary or tertiary care or receiving NHS care in other settings (such as primary and community care and emergency departments) if they have a risk factor, for example: significantly limited mobility significant loss of sensation a previous or current pressure ulcer nutritional deficiency the inability to reposition themselves significant cognitive impairment. Use a scale validated for this population (for example, the Braden Q scale for children), to support clinical judgement. ## Skin assessment Offer neonates, infants, children and young people who are assessed as being at high risk of developing a pressure ulcer a skin assessment by a trained healthcare professional. Take into account: skin changes in the occipital area skin temperature the presence of blanching erythema or discoloured areas of skin. Be aware of specific sites (for example, the occipital area) where neonates, infants, children and young people are at risk of developing a pressure ulcer. ## Repositioning Ensure that neonates and infants who are at risk of developing a pressure ulcer are repositioned at least every 4 hours. Encourage children and young people who are at risk of developing a pressure ulcer to change their position at least every 4 hours. If they are unable to reposition themselves, offer help to do so, using appropriate equipment if needed. Consider more frequent repositioning than every 4 hours for neonates and infants who have been assessed as being at high risk of developing a pressure ulcer. Document the frequency of repositioning required. Encourage children and young people who have been assessed as being at high risk of developing a pressure ulcer to change their position more frequently than every 4 hours. If they are unable to reposition themselves, offer help to do so, using equipment if needed. Document the frequency of repositioning required. Ensure that repositioning equipment is available to aid the repositioning of children and young people, if needed. Ensure that healthcare professionals are trained in the use of repositioning equipment. Ensure that patients, parents and carers understand the reasons for repositioning. If children and young people decline repositioning, document and discuss their reasons for declining. Consider involving a play expert to encourage children who have difficulty with, or who have declined repositioning. Relieve pressure on the scalp and head when repositioning neonates, infants, children and young people at risk of developing a pressure ulcer. ## Skin massage Do not offer skin massage or rubbing to neonates, infants, children and young people to prevent a pressure ulcer. ## Nutritional supplements and hydration Do not offer nutritional supplements specifically to prevent a pressure ulcer in neonates, infants, children and young people with adequate nutritional status for their developmental stage and clinical condition. Do not offer subcutaneous or intravenous fluids specifically to prevent a pressure ulcer in neonates, infants, children and young people with adequate hydration status for their development stage and clinical condition. ## Pressure redistributing devices Use a high-specification foam cot mattress or overlay for all neonates and infants who have been assessed as being at high risk of developing a pressure ulcer as part of their individualised care plan. Use a high-specification foam mattress or overlay for all children and young people who have been assessed as being at high risk of developing a pressure ulcer as part of their individualised care plan. Discuss with children and young people at high risk of developing a heel pressure ulcer and their parents and carers, where appropriate, a strategy to offload heel pressure as part of their individualised care plan. Offer infants, children and young people who are long-term wheelchair users, regular wheelchair assessments and provide pressure relief or redistribution. Offer neonates, infants, children and young people at risk of developing an occipital pressure ulcer an appropriate pressure redistributing surface (for example, a suitable pillow or pressure redistributing pad). ## Barrier creams Use barrier preparations to help prevent skin damage, such as moisture lesions, for neonates, infants, children and young people who are incontinent. # Prevention: all ages ## Care planning Develop and document an individualised care plan for neonates, infants, children, young people and adults who have been assessed as being at high risk of developing a pressure ulcer, taking into account: the outcome of risk and skin assessment the need for additional pressure relief at specific at-risk sites their mobility and ability to reposition themselves -ther comorbidities patient preference. ## Patient and carer information Offer timely, tailored information to people who have been assessed as being at high risk of developing a pressure ulcer, and their family or carers. The information should be delivered by a trained or experienced healthcare professional and include: the causes of a pressure ulcer the early signs of a pressure ulcer ways to prevent a pressure ulcer the implications of having a pressure ulcer (for example, for general health, treatment options and the risk of developing pressure ulcers in the future).Demonstrate techniques and equipment used to prevent a pressure ulcer. Take into account individual needs when supplying information to people with: degenerative conditions impaired mobility neurological impairment cognitive impairment impaired tissue perfusion (for example, caused by peripheral arterial disease). ## Healthcare professional training and education Provide training to healthcare professionals on preventing a pressure ulcer, including: who is most likely to be at risk of developing a pressure ulcer how to identify pressure damage what steps to take to prevent new or further pressure damage who to contact for further information and for further action. Provide further training to healthcare professionals who have contact with anyone who has been assessed as being at high risk of developing a pressure ulcer. Training should include: how to carry out a risk and skin assessment how to reposition information on pressure redistributing devices discussion of pressure ulcer prevention with patients and their carers details of sources of advice and support. # Management: adults ## Ulcer measurement Document the surface area of all pressure ulcers in adults. If possible, use a validated measurement technique (for example, transparency tracing or a photograph). Document an estimate of the depth of all pressure ulcers and the presence of undermining, but do not routinely measure the volume of a pressure ulcer. ## Categorisation Categorise each pressure ulcer in adults using a validated classification tool (such as the International NPUAP‑EPUAP Pressure Ulcer Classification System). Use this to guide ongoing preventative strategies and management. Repeat and document each time the ulcer is assessed. ## Nutritional supplements and hydration See also the NICE guideline on nutrition support for details of nutrition support other than supplements, and advice on energy and protein intake levels. Offer adults with a pressure ulcer a nutritional assessment by a dietitian or other healthcare professional with the necessary skills and competencies. Offer nutritional supplements to adults with a pressure ulcer who have a nutritional deficiency. Provide information and advice to adults with a pressure ulcer and, where appropriate, their family or carers, on how to follow a balanced diet to maintain an adequate nutritional status, taking into account energy, protein and micronutrient requirements. Do not offer nutritional supplements to treat a pressure ulcer in adults whose nutritional intake is adequate. Do not offer subcutaneous or intravenous fluids to treat a pressure ulcer in adults whose hydration status is adequate. ## Pressure redistributing devices Use high-specification foam mattresses for adults with a pressure ulcer. If this is not sufficient to redistribute pressure, consider the use of a dynamic support surface. Do not use standard-specification foam mattresses for adults with a pressure ulcer. Consider the seating needs of adults who have a pressure ulcer who are sitting for prolonged periods. Consider a high-specification foam or equivalent pressure redistributing cushion for adults who use a wheelchair or sit for prolonged periods and who have a pressure ulcer. ## Negative pressure wound therapy Do not routinely offer adults negative pressure wound therapy to treat a pressure ulcer, unless it is necessary to reduce the number of dressing changes (for example, in a wound with a large amount of exudate). ## Hyperbaric oxygen therapy and electrotherapy Do not offer the following to adults to treat a pressure ulcer: electrotherapy hyperbaric oxygen therapy. ## Debridement Assess the need to debride a pressure ulcer in adults, taking into consideration: the amount of necrotic tissue the category, size and extent of the pressure ulcer patient tolerance any comorbidities. Offer debridement to adults if identified as needed in the assessment: use autolytic debridement, using an appropriate dressing to support it consider using sharp debridement if autolytic debridement is likely to take longer and prolong healing time. Do not routinely offer adults with a pressure ulcer: larval (maggot) therapy enzymatic debridement.Consider larval therapy if debridement is needed but sharp debridement is contraindicated or if there is associated vascular insufficiency. ## Systemic antibiotics and antiseptics See also the NICE guideline on antimicrobial stewardship. After a skin assessment, offer systemic antibiotics to adults with a pressure ulcer if there are any of the following: clinical evidence of systemic sepsis (see also the NICE guideline on sepsis) spreading cellulitis underlying osteomyelitis Discuss with a local hospital microbiology department which antibiotic to offer adults with infection to ensure that the chosen systemic antibiotic is effective against local strains of infection. Do not offer systemic antibiotics specifically to heal a pressure ulcer in adults. Do not offer systemic antibiotics to adults based only on positive wound cultures without clinical evidence of infection. ## Topical antimicrobials and antiseptics See also the NICE guideline on antimicrobial stewardship. Do not routinely use topical antiseptics or antimicrobials to treat a pressure ulcer in adults. ## Dressings Discuss with adults with a pressure ulcer and, if appropriate, their family or carers, what type of dressing should be used, taking into account: pain and tolerance position of the ulcer amount of exudate frequency of dressing change. Consider using a dressing for adults that promotes a warm, moist wound healing environment to treat category 2, 3 and 4 pressure ulcers. Do not offer gauze dressings to treat a pressure ulcer in adults. ## Heel pressure ulcers Discuss with adults with a heel pressure ulcer and, if appropriate, their family or carers, a strategy to offload heel pressure as part of their individualised care plan. (See also the NICE guideline on diabetic foot problems for advice on heel pressure offloading.) # Management: neonates, infants, children and young people ## Ulcer measurement Document the surface area of all pressure ulcers in neonates, infants, children and young people, preferably using a validated measurement technique (for example, transparency tracing or a photograph). Document an estimate of the depth of a pressure ulcer and the presence of undermining, but do not routinely measure the volume of a pressure ulcer in neonates, infants, children and young people. ## Categorisation Categorise each pressure ulcer in neonates, infants, children and young people at onset using a validated classification tool (such as the International NPUAP‑EPUAP) Pressure Ulcer Classification System) to guide ongoing preventative and management options. Repeat and document each time the ulcer is assessed. ## Nutritional supplements and hydration Offer an age-related nutritional assessment to neonates, infants, children and young people with a pressure ulcer. This should be performed by a paediatric dietitian or other healthcare professional with the necessary skills and competencies. Discuss with a paediatric dietitian (or other healthcare professional with the necessary skills and competencies) whether to offer nutritional supplements specifically to treat a pressure ulcer in neonates, infants, children and young people whose nutritional intake is adequate. Offer advice on a diet that provides adequate nutrition for growth and healing in neonates, infants, children and young people with a pressure ulcer. Discuss with a paediatric dietitian whether to offer nutritional supplements to correct nutritional deficiency in neonates, infants, children and young people with a pressure ulcer. Assess fluid balance in neonates, infants, children and young people with a pressure ulcer. Ensure there is adequate hydration for age, growth and healing in neonates, infants, children and young people. If there is any doubt, seek further medical advice. ## Pressure redistributing devices Consider using specialist support surfaces (including dynamic support surfaces where appropriate) for neonates, infants, children and young people with a pressure ulcer, taking into account their current pressure ulcer risk and mobility. Use a high-specification cot or bed mattress or overlay for all neonates, infants, children and young people with a pressure ulcer. If pressure on the affected area cannot be adequately relieved by other means (such as repositioning), consider a dynamic support surface, appropriate to the size and weight of the child or young person with a pressure ulcer, if this can be tolerated. Tailor the support surface to the location and cause of the pressure ulcer for neonates, infants, children and young people. ## Negative pressure wound therapy Do not routinely use negative pressure wound therapy to treat a pressure ulcer in neonates, infants, children and young people. ## Hyperbaric oxygen therapy and electrotherapy Do not use the following to treat a pressure ulcer in neonates, infants, children and young people: electrotherapy hyperbaric oxygen therapy. ## Debridement Consider autolytic debridement with appropriate dressings for dead tissue in neonates, infants, children and young people. Consider sharp and surgical debridement by trained staff if autolytic debridement is unsuccessful. ## Systemic antibiotics and antiseptics See also the NICE guideline on antimicrobial stewardship. Consider systemic antibiotics for neonates, infants, children and young people with a pressure ulcer with clinical evidence of local or systemic infection. Discuss with a local hospital microbiology department which antibiotic to offer neonates, infants, children and young people with infection to ensure that the chosen systemic antibiotic is effective against local strains of bacteria. ## Topical antimicrobials and antiseptics See also the NICE guideline on antimicrobial stewardship. Do not routinely use topical antiseptics or antimicrobials to treat a pressure ulcer in neonates, infants, children and young people. ## Dressings Consider using a dressing that promotes a warm, moist healing environment to treat category 2, 3 and 4 pressure ulcers in neonates, infants, children and young people. Consider using topical antimicrobial dressings to treat a pressure ulcer where clinically indicated in neonates, infants, children and young people, for example, where there is spreading cellulitis. Do not use iodine dressings to treat a pressure ulcer in neonates. Do not offer gauze dressings to treat a pressure ulcer in neonates, infants, children and young people. ## Heel pressure ulcers Discuss with the parents or carers of neonates and infants and with children and young people (and their parents or carers if appropriate), a strategy to offload heel pressure as part of their individualised care plan to manage their heel pressure ulcer, taking into account differences in size, mobility, pain and tolerance. (See also the NICE guideline on diabetic foot problems for advice on heel pressure offloading.)# Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. # Debridement What is the effect of enzymatic debridement of non-viable tissue compared with sharp debridement on the rate of healing of pressure ulcers in adults? Why this is important Debridement of dead tissue is vital as its presence can delay healing and encourage infection. Although autolytic debridement via natural processes (supported by use of an appropriate dressing) is considered to be adequate for the majority of pressure ulcers, other methods, including mechanical, enzymatic, sharp debridement and larval therapy are available. There is limited high quality evidence on whether removal of dead tissue via sharp (carried out at the bedside) or enzymatic debridement produces the best outcomes. Use of enzymatic debridement in the UK is limited and the availability of these agents is variable, however, it is used in other countries. Additionally, there is some evidence that it may be slower than sharp debridement and result in the removal of viable tissue. Identifying the best method of debridement may have significant benefits, including reducing the length of time people with pressure ulcers need to stay in hospital. # Negative pressure wound therapy Does negative pressure wound therapy (with appropriate dressing) improve the healing of pressure ulcers, compared with the use of dressing alone in adults with pressure ulcers? Why this is important Negative pressure wound therapy is used for a variety of wounds, including pressure ulcers. It aims to assist healing, reduce the surface area of a wound and remove wound exudate. Negative pressure wound therapy creates a suction force which helps drain the wound and promote wound healing. There is evidence to suggest some benefit in the use of negative pressure wound therapy in other wound areas (for example, surgical wounds) but there is limited evidence to support its use for pressure ulcers. Negative pressure wound therapy is used variably across the NHS and many trusts have purchased or hired negative pressure wound therapy pumps. There would be benefits to patients and the NHS in establishing whether negative pressure wound therapy improves the healing of pressure ulcers. # Risk assessment in neonates, infants, children and young people Which pressure ulcer tools are most effective for predicting pressure ulcer risk in children? Why this is important There are a few published pressure ulcer risk assessment tools for children, but most of these have no evidence of validity and over half have been developed from adult pressure ulcer risk assessment tools. Of the tools which have validation data, the evidence is mainly poor quality. When healthcare professionals are choosing a risk assessment tool to use in clinical practice, they should be looking for a tool that has evidence to demonstrate that it is good a predicting risk in the population of interest. # Pressure redistributing devices Dopressure redistributing devices reduce the development of pressure ulcers for those who are at risk of developing a pressure ulcer? Why this is important Pressure redistributing devices are widely accepted methods of trying to prevent the development of pressure areas for people assessed as being at risk. These devices include different types of mattresses, overlays, cushions and seating. They may work by reducing or redistributing pressure, friction or shearing forces. There is limited evidence on the effectiveness of these devices and much of the evidence has been funded by industry. The cost of pressure redistributing devices can vary significantly and there is limited evidence on whether more sophisticated devices (for example, alternating pressure devices) provide any additional benefit compared to more basic devices such as high-specification foam mattresses. There is also limited evidence on whether different at-risk sites benefit from using different pressure redistributing devices. For example, a pressure redistributing device used for pressure relief on one site could cause pressure on another site. Further research is needed to identify what devices are beneficial for specific at-risk sites for all age groups. # Repositioning When repositioning a person who is at risk of developing a pressure ulcer, what is the most effective position – and optimum frequency of repositioning – to prevent a pressure ulcer developing? Why this is important It is generally accepted that repositioning people who are at risk of developing a pressure ulcer can prevent one developing by removing pressure from the at-risk site. Identifying the most effective position – and the optimum frequency of repositioning – will minimise discomfort and maximise pressure ulcer prevention. There is limited evidence on the most efficient position and frequency of repositioning for all age groups. Many studies include people who are on pressure redistributing surfaces, so it is unclear whether prevention is because of the support surface or the repositioning. A randomised study of different frequencies and positions on a standard support surface (for example, a high-specification foam mattress) is needed.	{'Introduction': "This guideline updates and replaces 'Pressure ulcers' (NICE guideline CG29) and 'Pressure ulcer prevention' (NICE guideline CG7). See update information for details.\n\nPressure ulcers are caused when an area of skin and the tissues below are damaged as a result of being placed under pressure sufficient to impair its blood supply. Typically they occur in a person confined to bed or a chair by an illness and as a result they are sometimes referred to as 'bedsores', or 'pressure sores'.\n\nAll patients are potentially at risk of developing a pressure ulcer. However, they are more likely to occur in people who are seriously ill, have a neurological condition, impaired mobility, impaired nutrition, or poor posture or a deformity. Also, the use of equipment such as seating or beds which are not specifically designed to provide pressure relief, can cause pressure ulcers. As pressure ulcers can arise in a number of ways, interventions for prevention and treatment need to be applicable across a wide range of settings including community and secondary care. This may require organisational and individual change and a commitment to effective delivery.\n\nPressure ulcers are often preventable and their prevention is included in domain 5 of the Department of Health's NHS outcomes framework 2014/15. The current guideline rationalises the approaches used for the prevention and management of pressure ulcers. Its implementation will ensure practice is based on the best available evidence. It covers prevention and treatment and applies to all people in NHS care and in care funded by the NHS.\n\nRecommendations for prevention include methods for identification and risk assessment and the preventive measures that should be applied. Treatment of pressure ulcers includes recommendations on wound care, adjunctive therapies and support surfaces. While there is much clinical expertise and good practice focused on preventing and treating pressure ulcers, it is hoped that this evidence-based guidance will contribute to reducing the number of pressure ulcers nationally through its implementation throughout the NHS.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.\n\nSee also the NHS Improvement revised definition and measurement framework for pressure ulcers. This will help deliver a consistent approach to defining and measuring pressure ulcers, and help to understand the level of pressure damage harm in England.\n\nSafeguarding children\n\nRemember that child maltreatment:\n\nis common\n\ncan present anywhere, including primary and secondary care and community settings (such as the child's home)\n\nConsider or suspect abuse (particularly malnourishment) as a contributory factor to or cause of pressure ulcers in children. Abuse may also coexist with pressure ulcers. See the NICE guideline on child maltreatment for clinical features that may be associated with maltreatment.\n\nThis section has been agreed with the Royal College of Paediatrics and Child Health.\n\nSafeguarding adults\n\nThe Department of Health and Social Care has issued a protocol for safeguarding adults at risk of pressure ulcers. It aims to help practitioners and managers across health and care organisations to provide caring and quick responses to people at risk of developing pressure ulcers.\n\nIt includes a process for deciding whether an adult safeguarding response is needed.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Terms used in this guideline\n\n## Adults, neonates, infants, children and young people\n\nThis guideline covers people of all ages at risk of, or who have, a pressure ulcer. These terms are defined as follows:\n\nadults: 18 years or older\n\nneonates: under 4 weeks\n\ninfants: between 4 weeks and 1 year\n\nchildren: 1 year to under 13 years\n\nyoung people: 13 to 17 years.\n\n## Risk assessment\n\nThis guideline uses the terms 'at risk' and 'at high risk' to identify people who may develop a pressure ulcer. For the purposes of this guideline:\n\nAdults considered to be at risk of developing a pressure ulcer are those who, after assessment using clinical judgement and/or a validated risk assessment tool, are considered to be at risk of developing a pressure ulcer.\n\nAdults considered to be at high risk of developing a pressure ulcer will usually have multiple risk factors (for example, significantly limited mobility, nutritional deficiency, inability to reposition themselves, significant cognitive impairment) identified during risk assessment with or without a validated risk assessment tool. Adults with a history of pressure ulcers or a current pressure ulcer are also considered to be at high risk.\n\nNeonates, infants, children and young people considered to be at risk are those who, after assessment using clinical judgement and/or a validated risk assessment tool, are considered to be at risk of developing a pressure ulcer.\n\nNeonates, infants, children and young people considered to be at high risk of developing a pressure ulcer will usually have multiple risk factors (for example, significantly limited mobility, nutritional deficiency, inability to reposition themselves, significant cognitive impairment) identified during risk assessment with or without a validated risk assessment tool. Those with a history of pressure ulcers or a current pressure ulcer are also considered to be at high risk.Please note that the examples given are not exhaustive.\n\n# Prevention: adults\n\n## Risk assessment\n\nBe aware that all patients are potentially at risk of developing a pressure ulcer.\n\nCarry out and document an assessment of pressure ulcer risk for adults:\n\nbeing admitted to secondary care or care homes in which NHS care is provided or\n\nreceiving NHS care in other settings (such as primary and community care and emergency departments) if they have a risk factor, for example:\n\n\n\nsignificantly limited mobility (for example, people with a spinal cord injury)\n\nsignificant loss of sensation\n\na previous or current pressure ulcer\n\nnutritional deficiency\n\nthe inability to reposition themselves\n\nsignificant cognitive impairment.\n\n\n\nConsider using a validated scale to support clinical judgement (for example, the Braden scale, the Waterlow score or the Norton risk-assessment scale) when assessing pressure ulcer risk.\n\nReassess pressure ulcer risk if there is a change in clinical status (for example, after surgery, on worsening of an underlying condition or with a change in mobility).\n\n## Skin assessment\n\nOffer adults who have been assessed as being at high risk of developing a pressure ulcer a skin assessment by a trained healthcare professional (see recommendation 1.3.4). The assessment should take into account any pain or discomfort reported by the patient and the skin should be checked for:\n\nskin integrity in areas of pressure\n\ncolour changes or discolorationHealthcare professionals should be aware that non-blanchable erythema may present as colour changes or discolouration, particularly in darker skin tones or types.\n\nvariations in heat, firmness and moisture (for example, because of incontinence, oedema, dry or inflamed skin).\n\nUse finger palpation or diascopy to determine whether erythema or discolouration (identified by skin assessment) is blanchable.\n\nStart appropriate preventative action (see recommendations 1.1.1–1.1.17) in adults who have non-blanching erythema and consider repeating the skin assessment at least every 2 hours until resolved.\n\n## Repositioning\n\nEncourage adults who have been assessed as being at risk of developing a pressure ulcer to change their position frequently and at least every 6\xa0hours. If they are unable to reposition themselves, offer help to do so, using appropriate equipment if needed. Document the frequency of repositioning required.\n\nEncourage adults who have been assessed as being at high risk of developing a pressure ulcer to change their position frequently and at least every 4\xa0hours. If they are unable to reposition themselves, offer help to do so, using appropriate equipment if needed. Document the frequency of repositioning required.\n\n## Skin massage\n\nDo not offer skin massage or rubbing to adults to prevent a pressure ulcer.\n\n## Nutritional supplements and hydration\n\nDo not offer nutritional supplements specifically to prevent a pressure ulcer in adults whose nutritional intake is adequate.\n\nDo not offer subcutaneous or intravenous fluids specifically to prevent a pressure ulcer in adults whose hydration status is adequate.\n\n## Pressure redistributing devices\n\nUse a high-specification foam mattress for adults who are:\n\nadmitted to secondary care\n\nassessed as being at high risk of developing a pressure ulcer in primary and community care settings.\n\nConsider a high-specification foam theatre mattress or an equivalent pressure redistributing surface for all adults who are undergoing surgery.\n\nDiscuss with adults at high risk of developing a heel pressure ulcer and, where appropriate, their family or carers, a strategy to offload heel pressure, as part of their individualised care plan.\n\nConsider the seating needs of people at risk of developing a pressure ulcer who are sitting for prolonged periods.\n\nConsider a high-specification foam or equivalent pressure redistributing cushion for adults who use a wheelchair or who sit for prolonged periods.\n\n## Barrier creams\n\nConsider using a barrier preparation to prevent skin damage in adults who are at high risk of developing a moisture lesion or incontinence-associated dermatitis, as identified by skin assessment (such as those with incontinence, oedema, dry or inflamed skin).\n\n# Prevention: neonates, infants, children and young people\n\n## Risk assessment\n\nCarry out and document an assessment of pressure ulcer risk for neonates, infants, children and young people:\n\nbeing admitted to secondary or tertiary care or\n\nreceiving NHS care in other settings (such as primary and community care and emergency departments) if they have a risk factor, for example:\n\n\n\nsignificantly limited mobility\n\nsignificant loss of sensation\n\na previous or current pressure ulcer\n\nnutritional deficiency\n\nthe inability to reposition themselves\n\nsignificant cognitive impairment.\n\n\n\nUse a scale validated for this population (for example, the Braden\xa0Q scale for children), to support clinical judgement.\n\n## Skin assessment\n\nOffer neonates, infants, children and young people who are assessed as being at high risk of developing a pressure ulcer a skin assessment by a trained healthcare professional. Take into account:\n\nskin changes in the occipital area\n\nskin temperature\n\nthe presence of blanching erythema or discoloured areas of skin.\n\nBe aware of specific sites (for example, the occipital area) where neonates, infants, children and young people are at risk of developing a pressure ulcer.\n\n## Repositioning\n\nEnsure that neonates and infants who are at risk of developing a pressure ulcer are repositioned at least every 4\xa0hours.\n\nEncourage children and young people who are at risk of developing a pressure ulcer to change their position at least every 4\xa0hours. If they are unable to reposition themselves, offer help to do so, using appropriate equipment if needed.\n\nConsider more frequent repositioning than every 4\xa0hours for neonates and infants who have been assessed as being at high risk of developing a pressure ulcer. Document the frequency of repositioning required.\n\nEncourage children and young people who have been assessed as being at high risk of developing a pressure ulcer to change their position more frequently than every 4\xa0hours. If they are unable to reposition themselves, offer help to do so, using equipment if needed. Document the frequency of repositioning required.\n\nEnsure that repositioning equipment is available to aid the repositioning of children and young people, if needed.\n\nEnsure that healthcare professionals are trained in the use of repositioning equipment.\n\nEnsure that patients, parents and carers understand the reasons for repositioning. If children and young people decline repositioning, document and discuss their reasons for declining.\n\nConsider involving a play expert to encourage children who have difficulty with, or who have declined repositioning.\n\nRelieve pressure on the scalp and head when repositioning neonates, infants, children and young people at risk of developing a pressure ulcer.\n\n## Skin massage\n\nDo not offer skin massage or rubbing to neonates, infants, children and young people to prevent a pressure ulcer.\n\n## Nutritional supplements and hydration\n\nDo not offer nutritional supplements specifically to prevent a pressure ulcer in neonates, infants, children and young people with adequate nutritional status for their developmental stage and clinical condition.\n\nDo not offer subcutaneous or intravenous fluids specifically to prevent a pressure ulcer in neonates, infants, children and young people with adequate hydration status for their development stage and clinical condition.\n\n## Pressure redistributing devices\n\nUse a high-specification foam cot mattress or overlay for all neonates and infants who have been assessed as being at high risk of developing a pressure ulcer as part of their individualised care plan.\n\nUse a high-specification foam mattress or overlay for all children and young people who have been assessed as being at high risk of developing a pressure ulcer as part of their individualised care plan.\n\nDiscuss with children and young people at high risk of developing a heel pressure ulcer and their parents and carers, where appropriate, a strategy to offload heel pressure as part of their individualised care plan.\n\nOffer infants, children and young people who are long-term wheelchair users, regular wheelchair assessments and provide pressure relief or redistribution.\n\nOffer neonates, infants, children and young people at risk of developing an occipital pressure ulcer an appropriate pressure redistributing surface (for example, a suitable pillow or pressure redistributing pad).\n\n## Barrier creams\n\nUse barrier preparations to help prevent skin damage, such as moisture lesions, for neonates, infants, children and young people who are incontinent.\n\n# Prevention: all ages\n\n## Care planning\n\nDevelop and document an individualised care plan for neonates, infants, children, young people and adults who have been assessed as being at high risk of developing a pressure ulcer, taking into account:\n\nthe outcome of risk and skin assessment\n\nthe need for additional pressure relief at specific at-risk sites\n\ntheir mobility and ability to reposition themselves\n\nother comorbidities\n\npatient preference.\n\n## Patient and carer information\n\nOffer timely, tailored information to people who have been assessed as being at high risk of developing a pressure ulcer, and their family or carers. The information should be delivered by a trained or experienced healthcare professional and include:\n\nthe causes of a pressure ulcer\n\nthe early signs of a pressure ulcer\n\nways to prevent a pressure ulcer\n\nthe implications of having a pressure ulcer (for example, for general health, treatment options and the risk of developing pressure ulcers in the future).Demonstrate techniques and equipment used to prevent a pressure ulcer.\n\nTake into account individual needs when supplying information to people with:\n\ndegenerative conditions\n\nimpaired mobility\n\nneurological impairment\n\ncognitive impairment\n\nimpaired tissue perfusion (for example, caused by peripheral arterial disease).\n\n## Healthcare professional training and education\n\nProvide training to healthcare professionals on preventing a pressure ulcer, including:\n\nwho is most likely to be at risk of developing a pressure ulcer\n\nhow to identify pressure damage\n\nwhat steps to take to prevent new or further pressure damage\n\nwho to contact for further information and for further action.\n\nProvide further training to healthcare professionals who have contact with anyone who has been assessed as being at high risk of developing a pressure ulcer. Training should include:\n\nhow to carry out a risk and skin assessment\n\nhow to reposition\n\ninformation on pressure redistributing devices\n\ndiscussion of pressure ulcer prevention with patients and their carers\n\ndetails of sources of advice and support.\n\n# Management: adults\n\n## Ulcer measurement\n\nDocument the surface area of all pressure ulcers in adults. If possible, use a validated measurement technique (for example, transparency tracing or a photograph).\n\nDocument an estimate of the depth of all pressure ulcers and the presence of undermining, but do not routinely measure the volume of a pressure ulcer.\n\n## Categorisation\n\nCategorise each pressure ulcer in adults using a validated classification tool (such as the International NPUAP‑EPUAP Pressure Ulcer Classification System). Use this to guide ongoing preventative strategies and management. Repeat and document each time the ulcer is assessed.\n\n## Nutritional supplements and hydration\n\nSee also the NICE guideline on nutrition support for details of nutrition support other than supplements, and advice on energy and protein intake levels.\n\nOffer adults with a pressure ulcer a nutritional assessment by a dietitian or other healthcare professional with the necessary skills and competencies.\n\nOffer nutritional supplements to adults with a pressure ulcer who have a nutritional deficiency.\n\nProvide information and advice to adults with a pressure ulcer and, where appropriate, their family or carers, on how to follow a balanced diet to maintain an adequate nutritional status, taking into account energy, protein and micronutrient requirements.\n\nDo not offer nutritional supplements to treat a pressure ulcer in adults whose nutritional intake is adequate.\n\nDo not offer subcutaneous or intravenous fluids to treat a pressure ulcer in adults whose hydration status is adequate.\n\n## Pressure redistributing devices\n\nUse high-specification foam mattresses for adults with a pressure ulcer. If this is not sufficient to redistribute pressure, consider the use of a dynamic support surface.\n\nDo not use standard-specification foam mattresses for adults with a pressure ulcer.\n\nConsider the seating needs of adults who have a pressure ulcer who are sitting for prolonged periods.\n\nConsider a high-specification foam or equivalent pressure redistributing cushion for adults who use a wheelchair or sit for prolonged periods and who have a pressure ulcer.\n\n## Negative pressure wound therapy\n\nDo not routinely offer adults negative pressure wound therapy to treat a pressure ulcer, unless it is necessary to reduce the number of dressing changes (for example, in a wound with a large amount of exudate).\n\n## Hyperbaric oxygen therapy and electrotherapy\n\nDo not offer the following to adults to treat a pressure ulcer:\n\nelectrotherapy\n\nhyperbaric oxygen therapy.\n\n## Debridement\n\nAssess the need to debride a pressure ulcer in adults, taking into consideration:\n\nthe amount of necrotic tissue\n\nthe category, size and extent of the pressure ulcer\n\npatient tolerance\n\nany comorbidities.\n\nOffer debridement to adults if identified as needed in the assessment:\n\nuse autolytic debridement, using an appropriate dressing to support it\n\nconsider using sharp debridement if autolytic debridement is likely to take longer and prolong healing time.\n\nDo not routinely offer adults with a pressure ulcer:\n\nlarval (maggot) therapy\n\nenzymatic debridement.Consider larval therapy if debridement is needed but sharp debridement is contraindicated or if there is associated vascular insufficiency.\n\n## Systemic antibiotics and antiseptics\n\nSee also the NICE guideline on antimicrobial stewardship.\n\nAfter a skin assessment, offer systemic antibiotics to adults with a pressure ulcer if there are any of the following:\n\nclinical evidence of systemic sepsis (see also the NICE guideline on sepsis)\n\nspreading cellulitis\n\nunderlying osteomyelitis\n\nDiscuss with a local hospital microbiology department which antibiotic to offer adults with infection to ensure that the chosen systemic antibiotic is effective against local strains of infection.\n\nDo not offer systemic antibiotics specifically to heal a pressure ulcer in adults.\n\nDo not offer systemic antibiotics to adults based only on positive wound cultures without clinical evidence of infection.\n\n## Topical antimicrobials and antiseptics\n\nSee also the NICE guideline on antimicrobial stewardship.\n\nDo not routinely use topical antiseptics or antimicrobials to treat a pressure ulcer in adults.\n\n## Dressings\n\nDiscuss with adults with a pressure ulcer and, if appropriate, their family or carers, what type of dressing should be used, taking into account:\n\npain and tolerance\n\nposition of the ulcer\n\namount of exudate\n\nfrequency of dressing change.\n\nConsider using a dressing for adults that promotes a warm, moist wound healing environment to treat category 2, 3 and 4 pressure ulcers.\n\nDo not offer gauze dressings to treat a pressure ulcer in adults.\n\n## Heel pressure ulcers\n\nDiscuss with adults with a heel pressure ulcer and, if appropriate, their family or carers, a strategy to offload heel pressure as part of their individualised care plan. (See also the NICE guideline on diabetic foot problems for advice on heel pressure offloading.)\n\n# Management: neonates, infants, children and young people\n\n## Ulcer measurement\n\nDocument the surface area of all pressure ulcers in neonates, infants, children and young people, preferably using a validated measurement technique (for example, transparency tracing or a photograph).\n\nDocument an estimate of the depth of a pressure ulcer and the presence of undermining, but do not routinely measure the volume of a pressure ulcer in neonates, infants, children and young people.\n\n## Categorisation\n\nCategorise each pressure ulcer in neonates, infants, children and young people at onset using a validated classification tool (such as the International NPUAP‑EPUAP) Pressure Ulcer Classification System) to guide ongoing preventative and management options. Repeat and document each time the ulcer is assessed.\n\n## Nutritional supplements and hydration\n\nOffer an age-related nutritional assessment to neonates, infants, children and young people with a pressure ulcer. This should be performed by a paediatric dietitian or other healthcare professional with the necessary skills and competencies.\n\nDiscuss with a paediatric dietitian (or other healthcare professional with the necessary skills and competencies) whether to offer nutritional supplements specifically to treat a pressure ulcer in neonates, infants, children and young people whose nutritional intake is adequate.\n\nOffer advice on a diet that provides adequate nutrition for growth and healing in neonates, infants, children and young people with a pressure ulcer.\n\nDiscuss with a paediatric dietitian whether to offer nutritional supplements to correct nutritional deficiency in neonates, infants, children and young people with a pressure ulcer.\n\nAssess fluid balance in neonates, infants, children and young people with a pressure ulcer.\n\nEnsure there is adequate hydration for age, growth and healing in neonates, infants, children and young people. If there is any doubt, seek further medical advice.\n\n## Pressure redistributing devices\n\nConsider using specialist support surfaces (including dynamic support surfaces where appropriate) for neonates, infants, children and young people with a pressure ulcer, taking into account their current pressure ulcer risk and mobility.\n\nUse a high-specification cot or bed mattress or overlay for all neonates, infants, children and young people with a pressure ulcer.\n\nIf pressure on the affected area cannot be adequately relieved by other means (such as repositioning), consider a dynamic support surface, appropriate to the size and weight of the child or young person with a pressure ulcer, if this can be tolerated.\n\nTailor the support surface to the location and cause of the pressure ulcer for neonates, infants, children and young people.\n\n## Negative pressure wound therapy\n\nDo not routinely use negative pressure wound therapy to treat a pressure ulcer in neonates, infants, children and young people.\n\n## Hyperbaric oxygen therapy and electrotherapy\n\nDo not use the following to treat a pressure ulcer in neonates, infants, children and young people:\n\nelectrotherapy\n\nhyperbaric oxygen therapy.\n\n## Debridement\n\nConsider autolytic debridement with appropriate dressings for dead tissue in neonates, infants, children and young people. Consider sharp and surgical debridement by trained staff if autolytic debridement is unsuccessful.\n\n## Systemic antibiotics and antiseptics\n\nSee also the NICE guideline on antimicrobial stewardship.\n\nConsider systemic antibiotics for neonates, infants, children and young people with a pressure ulcer with clinical evidence of local or systemic infection.\n\nDiscuss with a local hospital microbiology department which antibiotic to offer neonates, infants, children and young people with infection to ensure that the chosen systemic antibiotic is effective against local strains of bacteria.\n\n## Topical antimicrobials and antiseptics\n\nSee also the NICE guideline on antimicrobial stewardship.\n\nDo not routinely use topical antiseptics or antimicrobials to treat a pressure ulcer in neonates, infants, children and young people.\n\n## Dressings\n\nConsider using a dressing that promotes a warm, moist healing environment to treat category 2, 3 and 4 pressure ulcers in neonates, infants, children and young people.\n\nConsider using topical antimicrobial dressings to treat a pressure ulcer where clinically indicated in neonates, infants, children and young people, for example, where there is spreading cellulitis.\n\nDo not use iodine dressings to treat a pressure ulcer in neonates.\n\nDo not offer gauze dressings to treat a pressure ulcer in neonates, infants, children and young people.\n\n## Heel pressure ulcers\n\nDiscuss with the parents or carers of neonates and infants and with children and young people (and their parents or carers if appropriate), a strategy to offload heel pressure as part of their individualised care plan to manage their heel pressure ulcer, taking into account differences in size, mobility, pain and tolerance. (See also the NICE guideline on diabetic foot problems for advice on heel pressure offloading.)", 'Research recommendations': 'The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Debridement\n\nWhat is the effect of enzymatic debridement of non-viable tissue compared with sharp debridement on the rate of healing of pressure ulcers in adults?\n\nWhy this is important\n\nDebridement of dead tissue is vital as its presence can delay healing and encourage infection. Although autolytic debridement via natural processes (supported by use of an appropriate dressing) is considered to be adequate for the majority of pressure ulcers, other methods, including mechanical, enzymatic, sharp debridement and larval therapy are available.\n\nThere is limited high quality evidence on whether removal of dead tissue via sharp (carried out at the bedside) or enzymatic debridement produces the best outcomes. Use of enzymatic debridement in the UK is limited and the availability of these agents is variable, however, it is used in other countries. Additionally, there is some evidence that it may be slower than sharp debridement and result in the removal of viable tissue.\n\nIdentifying the best method of debridement may have significant benefits, including reducing the length of time people with pressure ulcers need to stay in hospital.\n\n# Negative pressure wound therapy\n\nDoes negative pressure wound therapy (with appropriate dressing) improve the healing of pressure ulcers, compared with the use of dressing alone in adults with pressure ulcers?\n\nWhy this is important\n\nNegative pressure wound therapy is used for a variety of wounds, including pressure ulcers. It aims to assist healing, reduce the surface area of a wound and remove wound exudate. Negative pressure wound therapy creates a suction force which helps drain the wound and promote wound healing. There is evidence to suggest some benefit in the use of negative pressure wound therapy in other wound areas (for example, surgical wounds) but there is limited evidence to support its use for pressure ulcers.\n\nNegative pressure wound therapy is used variably across the NHS and many trusts have purchased or hired negative pressure wound therapy pumps. There would be benefits to patients and the NHS in establishing whether negative pressure wound therapy improves the healing of pressure ulcers.\n\n# Risk assessment in neonates, infants, children and young people\n\nWhich pressure ulcer tools are most effective for predicting pressure ulcer risk in children?\n\nWhy this is important\n\nThere are a few published pressure ulcer risk assessment tools for children, but most of these have no evidence of validity and over half have been developed from adult pressure ulcer risk assessment tools. Of the tools which have validation data, the evidence is mainly poor quality. When healthcare professionals are choosing a risk assessment tool to use in clinical practice, they should be looking for a tool that has evidence to demonstrate that it is good a predicting risk in the population of interest.\n\n# Pressure redistributing devices\n\nDopressure redistributing devices reduce the development of pressure ulcers for those who are at risk of developing a pressure ulcer?\n\nWhy this is important\n\nPressure redistributing devices are widely accepted methods of trying to prevent the development of pressure areas for people assessed as being at risk. These devices include different types of mattresses, overlays, cushions and seating. They may work by reducing or redistributing pressure, friction or shearing forces. There is limited evidence on the effectiveness of these devices and much of the evidence has been funded by industry. The cost of pressure redistributing devices can vary significantly and there is limited evidence on whether more sophisticated devices (for example, alternating pressure devices) provide any additional benefit compared to more basic devices such as high-specification foam mattresses.\n\nThere is also limited evidence on whether different at-risk sites benefit from using different pressure redistributing devices. For example, a pressure redistributing device used for pressure relief on one site could cause pressure on another site. Further research is needed to identify what devices are beneficial for specific at-risk sites for all age groups.\n\n# Repositioning\n\nWhen repositioning a person who is at risk of developing a pressure ulcer, what is the most effective position – and optimum frequency of repositioning – to prevent a pressure ulcer developing?\n\nWhy this is important\n\nIt is generally accepted that repositioning people who are at risk of developing a pressure ulcer can prevent one developing by removing pressure from the at-risk site. Identifying the most effective position – and the optimum frequency of repositioning – will minimise discomfort and maximise pressure ulcer prevention.\n\nThere is limited evidence on the most efficient position and frequency of repositioning for all age groups. Many studies include people who are on pressure redistributing surfaces, so it is unclear whether prevention is because of the support surface or the repositioning. A randomised study of different frequencies and positions on a standard support surface (for example, a high-specification foam mattress) is needed.'}	https://www.nice.org.uk/guidance/cg179	This guideline covers risk assessment, prevention and treatment in children, young people and adults at risk of, or who have, a pressure ulcer (also known as a bedsore or pressure sore). It aims to reduce the number of pressure ulcers in people admitted to secondary or tertiary care or receiving NHS care in other settings, such as primary and community care and emergency departments.
98f22485ee1bd2650066a9473dd2f4e5099ef791	nice	Measuring fractional exhaled nitric oxide concentration in asthma: NIOX MINO, NIOX VERO and NObreath	Measuring fractional exhaled nitric oxide concentration in asthma: NIOX MINO, NIOX VERO and NObreath Evidence-based recommendations on NIOX MINO, NIOX VERO and NObreath for measuring the amount of exhaled nitric oxide (FeNO) in the breath to help diagnose asthma. # Recommendations FeNO is recommended by NICE to help diagnose asthma; for further details please see NICE's guideline on asthma: diagnosis, monitoring and chronic asthma management. FeNO measurement is recommended as an option to support asthma management in people who are symptomatic despite using inhaled corticosteroids.# The technologies Three devices, NIOX MINO, NIOX VERO and NObreath, used for measuring fractional exhaled nitric oxide (FeNO) concentration in the diagnosis and management of asthma were evaluated. All 3 devices are CE marked. Additional details of the devices are provided in section 4. The devices and methods in this guidance were identified as being relevant to this assessment. NICE is aware that the devices and methods are evolving, so modifications and new devices are likely to be developed in the future.# Clinical need and practice # The problem addressed Nitric oxide, which is produced in the lungs and is present in exhaled breath, has been implicated in the pathophysiology of lung diseases, including asthma. It has been shown to act as a vasodilator, bronchodilator, neurotransmitter and inflammatory mediator in the lungs and airways. Over the years, fractional exhaled nitric oxide (FeNO) has been proposed as a non‑invasive marker of airway inflammation in asthma. FeNO levels are raised in people with asthma and can be lowered by effective treatment with corticosteroids. The purpose of this evaluation was to evaluate the clinical and cost effectiveness of measuring FeNO in the diagnosis and management of asthma. # The condition Asthma is a chronic disorder of the airways, caused primarily by inflammatory processes and constriction of the smooth muscle in airway walls (bronchoconstriction). It is generally characterised by reversible airflow obstruction and increased responsiveness of the airways to various stimuli. Symptoms include recurrent episodes of wheezing, breathlessness, chest tightness and coughing. Typical asthma symptoms tend to be variable, intermittent and worse at night. Asthma is commonly triggered by viral respiratory infections, exercise, or external factors such as smoke, a change in weather conditions and allergens (for example, pollen, mould and house dust mites). In people with asthma, cellular inflammation of the airways with eosinophils and neutrophils is considered to be a characteristic feature relevant to the pathogenesis of the disease. Eosinophilic asthma is a distinct phenotype of asthma associated with a rise in nitric oxide in exhaled breath. Eosinophilic asthma may respond to treatment with corticosteroids, while neutrophilic asthma generally does not. Asthma usually develops in childhood but may start at any age. There is no cure for asthma, although people may have long periods of remission. Poorly controlled asthma can have a significant impact on the quality of life of the affected person and their family. Because there may be variation in an individual's perception of asthma symptoms, clinical measures such as lung function do not always correlate with quality-of-life scores. However, if asthma is well controlled, near-maximal scores on quality-of-life instruments can be achieved. # The diagnostic and care pathways Asthma is diagnosed on the basis of symptoms and objective tests of lung function. Spirometry is used to assess lung function by measuring the volume of air that the patient is able to expel from the lungs after a maximal inspiration. Spirometry lung function measurements include peak expiratory flow rate (PEF), forced vital capacity (FVC; the total volume of air that a person can forcibly exhale in 1 breath), forced expiratory volume in the first second (FEV1) and percentage predicted FEV1 (calculated as a percentage of the predicted FEV1 for a person of the same height, sex and age without diagnosed asthma). Variability in PEF and FEV1, either spontaneously or in response to therapy, is a characteristic feature of asthma. The severity of asthma is judged according to symptoms and the amount of medication needed to control them, and is based on the British guideline on the management of asthma (2012) from the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN). Asthma is diagnosed clinically and there is no standardised definition of the condition. The presence of symptoms (wheezing, breathlessness, chest tightness and cough) and variable airflow obstruction is central to all definitions. More recently, descriptions of asthma have included airway hyper-responsiveness and airway inflammation. It is unclear how these features relate to each other, how they are best measured and how they contribute to the clinical manifestations of asthma. The diagnosis of asthma in children is based on recognising a characteristic pattern of episodic symptoms in the absence of an alternative explanation. If asthma is suspected, an initial clinical assessment should be carried out to estimate the probability of asthma. According to the British guideline on the management of asthma (2012), a child can be classed into 1 of 3 groups based on initial clinical assessment. These groups are: high probability – diagnosis of asthma likely low probability – diagnosis other than asthma likely intermediate probability – diagnosis uncertain. For children identified as having a low probability of asthma, a more detailed investigation and specialist referral should be considered. For children with a high probability of asthma, a trial of treatment should be started immediately. The response to treatment should be reassessed every 6 months. Those with a poor response to treatment should have more detailed investigations. In children with an intermediate probability of asthma who can perform spirometry and have no evidence of airway obstruction, tests for atopic status, assessment of bronchodilator reversibility and, if possible, tests for bronchial hyper-responsiveness using methacholine, exercise or mannitol should be considered. In such cases, specialist referral should always be considered. The diagnosis of asthma in adults is based on clinical history and includes the recognition of a characteristic pattern of symptoms and signs, and the absence of an alternative explanation for them. Spirometry is the preferred initial test to assess the presence and severity of airflow obstruction. Adults are also classified as having a high, low or intermediate probability of asthma. Chest X‑ray and specialist referral may be considered in any patient presenting atypically or with additional symptoms or signs. Asthma management aims to control symptoms (including nocturnal symptoms and exercise-induced asthma), prevent exacerbations and achieve the best possible lung function, with minimal side effects from treatment. The British guideline on the management of asthma (2012) recommends a stepwise approach to treatment in both adults and children. Treatment is started at the step most appropriate to the initial severity of the asthma, with the aim of achieving early control of symptoms and optimising respiratory function. Control is maintained by stepping up treatment as necessary and stepping down when control is achieved. Management options include interventions with or without the use of drugs. For most children and adults, asthma is monitored in primary care by routine clinical reviews on at least an annual basis. These reviews include (but are not limited to) assessment of the patient's symptom score (using a validated questionnaire), exacerbations, oral corticosteroid use, time off school or work, growth in children, inhaler technique and, in adults, lung function assessed by spirometry (PEF).# The diagnostic tests # The interventions ## NIOX MINO NIOX MINO (Aerocrine) is a diagnostic and monitoring device that analyses a breath sample using an electrochemical sensor to determine exhaled nitric oxide concentration. The technology is designed to help identify people whose airway inflammation is likely to respond to treatment with inhaled corticosteroids. It can also help to predict the onset of asthma symptoms or loss of asthma control, and to monitor compliance with corticosteroid therapy and the effectiveness of treatment. NIOX MINO determines exhaled nitric oxide concentration in a breath sample. The device is small, hand-held and portable, and can be used by adults and children. It needs a 10-second exhalation of breath at a pressure of 10–20 cm H2O to maintain a fixed flow rate of 50±5 ml/s. The last 3 seconds of the 10-second exhalation are analysed by a calibrated electrochemical sensor to give a definitive result in parts per billion. Clinical cut-off values can be applied to the exhaled nitric oxide values to categorise readings as low, intermediate or high according to the reference ranges for ages less than 12 years and 12 years or more. NIOX MINO is pre-calibrated and designed to be a service- and calibration-free system. The manufacturer states that the calibrated electrochemical sensors included in the test kit should be replaced every year or once all the tests in the kit have been used. It can be used alone or connected to a computer for monitoring with the NIOX MINO Data Management Program and Electronic Medical Record systems. The device is CE marked. ## NIOX VERO During the assessment phase, the manufacturer of NIOX MINO (Aerocrine) launched NIOX VERO, a new fractional exhaled nitric oxide (FeNO) device that is intended to replace NIOX MINO. The new device is battery powered and has a longer operational life and extended-test volume life compared with NIOX MINO. NIOX VERO is designed to be service and calibration free. The manufacturer states that the calibrated electrochemical sensors included in the test kit should be replaced every year or once all the tests in the kit have been used. The device is CE marked. ## NObreath NObreath (Bedfont Scientific) is a diagnostic monitoring device that measures exhaled nitric oxide produced by airway inflammation. The reading is presented in parts per billion and is claimed to be directly related to the severity of inflammatory disease (for example, asthma). NObreath needs 12 seconds of exhalation of breath in adults and 10 seconds in children. The device is CE marked. # The comparator Scoping workshop attendees indicated that following the British guideline on the management of asthma (2012) from the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) is an appropriate comparator for people with asthma.# Outcomes The Diagnostics Advisory Committee (section 9) considered evidence from several sources (section 10). # How outcomes were assessed The assessment was performed by an External Assessment Group and consisted of a systematic review and development of a decision analytical model. The systematic review was carried out to identify evidence on the equivalence of fractional exhaled nitric oxide (FeNO) devices (analytical validity), evidence of the diagnostic accuracy of FeNO testing for asthma diagnosis and evidence of the efficacy of FeNO‑guided asthma management. A decision analytical model and a Markov model were developed to assess the cost effectiveness of measuring FeNO in the diagnosis and management of asthma. # Review of equivalence of FeNO devices The External Assessment Group undertook this review to establish whether FeNO devices could be considered to be equivalent to one another in their measurements, and so whether studies that used other devices could helpfully inform this appraisal. Because there was insufficient evidence from primary research studies that used the mobile, hand-held FeNO electrochemical devices (NIOX MINO, NIOX VERO and NObreath), a review of equivalence to the precursory large, stationary FeNO chemiluminescent devices (including Niox, also made by Aerocrine) was conducted. The review identified 27 studies that compared NIOX MINO, NIOX VERO and NObreath with other devices. The External Assessment Group undertook 3 main comparisons for this purpose. The first included comparisons of means, which compare the reported mean FeNO values as measured by each device in the same cohort. The second compared correlation coefficients, which show whether measurements by 2 devices are correlated but not whether the actual values produced are the same. The third compared the result of Bland–Altman analyses, which produce statistics that assess agreement between devices rather than just correlation. ## NIOX MINO Eight studies compared NIOX MINO with Niox in adults. Of these studies, 5 were exclusively in adults and 3 were in adults and other age groups. There was variability in correlation between the devices among the studies. While 5 studies showed largely similar mean values between NIOX MINO and Niox, 3 studies showed higher FeNO readings with NIOX MINO (ranging from 0.5 to 9 parts per billion ). Small (non-significant) differences in the mean FeNO readings were observed between the devices when the cohort mean FeNO values were below 30 ppb (as measured by Niox). When the mean FeNO values were above 35 ppb, the differences in cohort means were larger and statistically significant. Correlation coefficients ranged from 0.73 to 0.998. The results of 1 study suggested that there may also be some variation between NIOX MINO devices themselves, although a second study showed good agreement. Across the 8 studies, Bland–Altman analyses were not reported in a consistent way. Limits of agreement were 10 ppb above and below the mean in some cases, and the studies with the largest mean differences did not report Bland–Altman statistics. Three studies comparing NIOX MINO with Niox included children. Of these, 2 studies reported statistically significantly higher mean FeNO values with NIOX MINO, while 1 study reported statistically significantly lower values. This study had low mean values (below 10 ppb). All studies reported good correlation between the devices, while Bland–Altman statistics reported in 2 studies showed that NIOX MINO gave higher readings (by 1.1 ppb and 3.9 ppb respectively). Twelve studies compared NIOX MINO with stationary chemiluminescent devices other than Niox in adults and children. Of these, 6 studies were in adults, 3 in an unspecified group and 3 in children. The chemiluminescence devices used in each of the 12 studies were different. In the adults and the unspecified age group, correlation coefficients ranged from 0.876 to 0.96, indicating good correlation between devices. However, the mean FeNO levels and Bland–Altman statistics did not suggest such good correlation. In 4 studies, NIOX MINO gave higher readings than the comparator device, while 2 studies reported lower readings and 2 studies showed the devices to be comparable. Bland–Altman statistics, reported in 4 studies, suggested that mean differences were small, but the limits of agreement were much greater. In children, correlation coefficients between NIOX MINO and other chemiluminescent devices ranged from 0.69 to 0.98, indicating variable correlation. The study with the poorer correlation reported higher mean FeNO levels, suggesting that poorer correlation is due to greater variability at higher FeNO values. However, the authors stated that correlation improved at higher values. One study noted that the direction of disagreement was different in children aged over and under 12 years. The back-transformed Bland–Altman statistics and range of ratios reported showed a wide range of agreement, suggesting that the devices are not interchangeable. The External Assessment Group stated that the comparability of NIOX MINO to chemiluminescent devices appears to be influenced by several factors. These include variability between NIOX MINO devices themselves, a lack of comparability between other chemiluminescent devices (which leads to heterogeneity in estimates of comparability between these devices and NIOX MINO) and poorer equivalence between the devices at higher FeNO levels. ## NIOX VERO The manufacturer of NIOX MINO and NIOX VERO provided details of a study (commercial in confidence) that compared the technical performance and accuracy of the 2 technologies. ## NObreath Four studies compared NObreath with 3 chemiluminescent devices other than Niox. Bland–Altman analysis done in 1 study in a healthy cohort with low FeNO values showed a mean difference of −3.95 ppb in comparison with the chemiluminescent device. Limits of agreement in this study were wide (−10.98 to 4.08). Another study reported an absolute mean difference in FeNO measurements of −3.81 ppb. Comparisons with the third type of chemiluminescent device showed small differences between mean FeNO values for the cohort, with NObreath giving lower values in some cohorts. Two studies that compared NObreath with NIOX MINO in adults found that NIOX MINO provided lower mean FeNO values than NObreath in most analyses. This contradicts the available evidence for comparisons of NIOX MINO with Niox and NObreath with Niox, which suggested that NIOX MINO should provide higher readings than NObreath. The 2 direct comparisons of NObreath and NIOX MINO included small numbers of patients, and only 1 included patients with asthma, but did not provide a Bland–Altman analysis to assess agreement. The External Assessment Group stated that, based on available evidence, any differences in absolute values between results from NObreath and other devices are relatively small, although derived cut-offs and maximum sensitivity and specificity may differ. # Diagnostic accuracy of FeNO devices No end-to-end studies were identified, and no cohort study compared use of FeNO testing within a sequence of tests with a suitable reference standard of the same sequence of tests without FeNO testing. The review identified 24 studies that met the inclusion criteria; 20 included adults of all ages and 4 included children. The studies were classified according to the position of the patients' asthma in the UK care pathway and the reference standards used. ## FeNo testing in adults with asthma symptoms compared with most of, or all, the UK care pathway The review identified 4 studies in this group. Cut-offs for the highest sum of sensitivity and specificity ranged from 20 ppb to 47 ppb in the 4 studies in this group. Sensitivities ranged from 32% to 88%, and specificities from 75% to 93%. Because of the heterogeneity in the results, study designs and the devices used, the External Assessment Group concluded that it is difficult to identify the optimal cut-off for sensitivity and specificity. Cut-offs yielding the highest sensitivity ranged from 9 ppb to 15 ppb, with sensitivities ranging from 85% to 96% and specificities from 13% to 48%. Cut-offs yielding the highest specificity ranged from 47 ppb to 76 ppb, with sensitivities ranging from 13% to 56% and specificity from 88% to 100%. Estimates of specificity consistently had a smaller range and higher values than estimates of sensitivity reported, suggesting that FeNO may be more reliable as a 'rule‑in' test than as a 'rule‑out' test. A rule‑in test implies that patients whose test is positive are assumed to have asthma and those testing negative go on to have further tests. However, the cost effectiveness of this balance will depend on the clinical and cost consequences of the correct or incorrect classification of patients. ## FeNO testing in patients with difficult-to-diagnose asthma compared with airway hyper-responsiveness Three studies used some form of airway hyper-responsiveness as the sole reference standard. Estimates of sensitivity and specificity appeared comparable to those in the studies of patients presenting in primary care with symptoms of asthma. One study included a set of patients whose methacholine challenge tests were negative and compared FeNO with an adenosine challenge test. This study produced 100% sensitivity (29% specificity) at a cut-off of 30 ppb, making it likely to operate well as a rule‑out test. The other 2 studies used methacholine challenge tests in people who had been found not to have asthma in previous tests. Cut-offs for the highest sum of sensitivity and specificity ranged from 34 ppb to 40 ppb when compared with a methacholine challenge test as a gold standard. Sensitivities ranged from 24% to 74%, and specificities from 73% to 99%, which is a similar range to the broader cohort. A range of cut-offs was not reported in these studies. ## FeNO testing in patients with difficult-to-diagnose asthma with chronic cough compared with response to a trial of inhaled corticosteroids Three studies included patients with chronic cough who had tested negative for other causes. All 3 studies used response to a trial of treatment with inhaled corticosteroids as a reference standard. Cut-offs for the highest sum of sensitivity and specificity were similar in all 3 studies. Accuracy was somewhat better in 2 studies at 90–95% sensitivity and 76–85% specificity. ## FeNO testing in children with asthma symptoms compared with various reference standards Four studies were identified that included children, and these had patients with a similar severity of asthma and similar reference standards as the adult cohorts, while the cut-offs derived were generally lower but with similar ranges of estimates of sensitivity and specificity. There was a high degree of agreement between studies in terms of the cut-off that produces the highest sum of sensitivity and specificity, despite the heterogeneity in devices and reference standards, with values between 19 ppb and 21 ppb. Estimates of sensitivity at these cut-off points were also wide-ranging and of a similar range to those in the studies in adults (49% to 86%). When selecting the cut-off with the highest sensitivity, results were similar to those for adult cohorts. Cut-offs ranged from 5 ppb to 20 ppb, sensitivities from 89% to 94% and specificities from 14% to 70%. When selecting the cut-off with the highest specificity, results were also similar to adult cohorts. Cut-offs were a little lower again, and ranged from 30 ppb to 50 ppb. Sensitivities ranged from 20% to 50% and specificities from 92% to 100%. The External Assessment Group did not conduct a meta-analysis in any group because of the high heterogeneity between studies. Estimates of cut-off points, sensitivity and specificity were not consistent within groups and ranged widely when used as a rule‑in or rule‑out test and when considering the highest sum of sensitivity and specificity. Because of this, the External Assessment Group found it difficult to estimate the relative diagnostic accuracy of FeNO testing in any situation and at any given cut-off point. However, there did not appear to be a difference in the relative diagnostic accuracy of FeNO testing in the 2 settings (primary and secondary care), either in comparison with the standard UK care pathway (entire or parts) or in comparison with airway hyper-responsiveness in patients whose asthma was difficult to diagnose. But the large variation in estimates within groups may obscure any true underlying differences in the accuracy of FeNO testing between groups and between different reference standards. ## FeNO testing in population subgroups included in the scope No cohort studies were found that provided evidence relating to the subgroups of pregnant women, older people, people who smoke or people exposed to environmental tobacco, and therefore lower levels of evidence were consulted. FeNO testing appeared to be able to distinguish people with asthma from people without asthma with similar accuracy in people who smoke and people who do not smoke or used to smoke. It seems likely that FeNO levels are generally lower in people who smoke, and it may be useful to consider a person's smoking status when interpreting results, or to select lower cut-off points for people who smoke. Limited data in children support the same conclusion as for adults. There is limited and conflicting evidence for the benefit of FeNO testing in older people and, therefore, uncertainty as to whether FeNO testing is useful for diagnosing asthma in the older population. A cross-sectional study suggested that pregnancy does not alter FeNO levels in women with or without asthma, and that FeNO testing can distinguish between healthy, pregnant women with asthma or without asthma. # Efficacy of FeNO-guided asthma management The External Assessment Group reviewed evidence relating to outcomes in adults, children and subgroups of people as defined in the scope for this assessment. The outcomes included exacerbations, inhaled corticosteroid use and health-related quality of life. ## FeNO-guided asthma management in adults Four studies (based in the UK, New Zealand, Sweden and the USA) were included in this review. The quality of the 4 studies was assessed according to the Cochrane Library and Centre for Reviews and Dissemination (CRD) handbook. The External Assessment Group indicated that the study with the highest risk of bias was the study by Syk et al. (2013); this was because of the lack of blinding, incomplete outcome data and selective reporting. All 4 studies were randomised controlled trials; 2 were single blind (Smith et al. 2005 and Shaw et al. 2007), 1 was open label (Syk et al. 2013) and 1 was described as 'multiply blinded' (Calhoun et al. 2013). There was a high degree of heterogeneity in all aspects of study design across the 4 studies. Three studies did not clearly report which device was used to measure FeNO levels. The inclusion criteria, trial protocols and treatment doses varied across the studies. Only 1 study reported using the British guideline on the management of asthma (2012), hereafter referred to as the 'British guideline', in the comparator arm. The number of patients in the trials ranged from 94 to 229, and they were recruited from primary care in 3 studies. For 1 study, it was unclear what setting people were recruited from. Exacerbations were reported in all 4 studies, although definitions varied and results were not always consistent across the studies. However, all 4 studies reported a fall in exacerbation rates per person year, although it appeared that this was mostly driven by mild and moderate exacerbations. For severe exacerbations, the Syk et al. (2013) study reported higher rates of oral corticosteroid use in the intervention arm (although the difference was not statistically significant), while the composite outcome of moderate or severe exacerbations favoured the intervention arm. In the other studies, the difference in direction of effect between the outcome for oral corticosteroid use and the composite outcomes that included less severe exacerbations was not evident. Oral corticosteroid use and the composite outcomes of severe and less severe exacerbations decreased in intervention arms, although there was still an apparently greater effect in the composite outcomes. Rate ratios calculated by the External Assessment Group for major/severe exacerbations ranged from 0.79 (95% confidence interval 0.44 to 1.41) to 1.29 (95% CI 0.51 to 3.30), while rate ratios calculated by the External Assessment Group for composite outcomes of all severity of exacerbation ranged from 0.52 (95% CI 0.30 to 0.91) to 0.63 (95% CI 0.40 to 0.98). Despite the high level of between-study heterogeneity, an exploratory meta-analysis of the rates of major and severe exacerbations using fixed effects methods was conducted. The result showed no heterogeneity, with an I2 statistic of 0%. The pooled estimate was 0.87 (95% CI 0.64 to 1.19, p=0.38). This indicates that there were fewer major exacerbations in the intervention arm, but the difference did not reach statistical significance. A sensitivity analysis was done using the results of studies that reported the number of exacerbations resulting in oral corticosteroid use. The pooled risk ratio was 0.90 (95% CI 0.56 to 1.45), indicating a statistically non-significant difference for asthma management with FeNO measurement. However, the External Assessment Group noted that there were only 2 studies in this analysis. Both studies reported non-significant differences, but with risk ratios on opposite sides of the line of no effect. This could suggest that differences in study design, step-up and step-down protocols, and patient characteristics may account for differences in direction of effect. When considering the composite outcome of all exacerbations and failure rates, 3 studies reported composite outcomes that the External Assessment Group considered to be broadly similar and to represent 'treatment failure'. In 2 studies, FeNO‑guided management groups showed numerically, but not statistically significant, lower rates of failure. In the Syk et al. (2013) study, the improvement was statistically significant, with a rate of 0.22 in the intervention arm compared with 0.41 in the control arm (p=0.024). The rate ratio calculated by the External Assessment Group was 0.52 (95% CI 0.30 to 0.91). A meta-analysis of these rates was conducted despite the high level of heterogeneity between study characteristics. The result showed a statistically significant effect, with a rate ratio of 0.58 (95% CI 0.43 to 0.77). This represents a statistically significant effect in favour of using FeNO‑guided management in people with asthma for the composite outcome of all exacerbations and treatment failure rates. An additional study (Honkoop et al. 2013) was identified by the External Assessment Group. The study was a randomised controlled trial with a 12‑month follow-up period and dose titration at baseline and every 3 months thereafter. The number of people in the study was larger than in the other 4 studies and they were recruited from primary care. Outcome data were limited because this study was only reported in a conference abstract; however, a non-significant trend towards a reduction in courses of oral prednisolone was reported for the FeNO measurement group compared with the comparator arms. The External Assessment Group performed an additional meta-analysis that included the Honkoop et al. study, calculating the rate ratio for exacerbation as 0.69. Errors could not be calculated for this meta-analysis because the exact numbers of people and events were not reported. Results of the meta-analysis ranged from significant to non-significant in favour of FeNO measurement, depending on the error rate imputed. All studies reported some data on inhaled corticosteroid use. Two studies reported inhaled corticosteroid use as a mean per day at the end of the study, with mean differences of −270 micrograms per day (95% CI −112 to −430, p=0.003) and −338 micrograms per day (95% CI −640 to −37 micrograms, p=0.028) respectively, in favour of FeNO‑guided management. The Syk et al. (2013) study showed a small (non-significant) increase in inhaled corticosteroid use in the intervention arm (586 micrograms, standard error 454; compared with 540 micrograms, SE 317, in the control arm). One study reported means per month, although it is unclear if this was an average over the whole course of the study, or the means for the final month of the study. The means were very similar at 1617 micrograms per month in the intervention arm and 1610 micrograms per month in the control arm. A meta-analysis used standardised mean difference analysis because outcomes were not reported in a standardised way. This showed an overall effect of −0.24 standard deviations in favour of FeNO‑guided management, although this narrowly missed significance (95% CI −0.56 to 0.07, p=0.13). Two studies used versions of the Asthma Quality of Life Questionnaire (AQLQ) to measure quality of life. Both showed no effect in the global score, but 1 investigated domains and found a statistically significant difference in the symptoms score. A meta-analysis of the overall scores showed no effect on quality of life, with a standardised mean of 0.00 (95% CI −0.20 to 0.20). All 4 original studies (excluding Honkoop et al. 2013) reported data for asthma control. In 3 studies, asthma control did not change but in the Syk et al. (2013) study there was a statistically significant increase in asthma control between the 2 trial arms. Two studies (Smith et al. 2005 and Calhoun et al. 2012) reported no significant difference between groups for bronchodilator use. Syk et al. did not report the significance of the difference between the 2 arms, reporting a median of 1.56 (interquartile range 0.06 to 5.18) uses per week in the intervention arm, and a median of 0.94 (IQR 0.03 to 2.81) in the control arm. No asthma-related adverse events or deaths were reported. ## FeNO-guided asthma management in children Five studies (based in Austria, the USA, Italy, the Netherlands and Australia) that included children (plus adolescents and young adults) and compared FeNO‑guided management with non-FeNO‑guided management were identified. The quality of the studies was assessed according to criteria proposed in the Cochrane Handbook and CRD Handbook. The study quality varied; no single study scored well in every item, and no item scored well in every study. There was a high degree of heterogeneity in all aspects of study design across 4 studies. No study reported using the British guideline in the comparator arm. Two studies included patients who appeared to be poorly controlled. One study included patients who had mild to moderate persistent asthma and 1 study included patients who had received a stable dose of inhaled corticosteroids for the previous 3 months, suggesting that their asthma was reasonably well controlled. All 5 studies reported some data on asthma exacerbations, although the definition of exacerbation was unclear in some cases. Two studies reported severe exacerbations in a way that allowed calculation of rates per person year. Both had lower rates in the intervention arm. In patients with uncontrolled asthma, the rate was 0.746 in the intervention arm and 0.950 in the control arm. In patients who had been on a stable dose of inhaled corticosteroids for 3 months, the rate was 0.21 in the intervention arm and 0.39 in the control arm. Both rates were calculated by the External Assessment Group and the statistical significance is unclear. For all definitions of exacerbations, 4 studies reported outcomes that were not defined as either major or minor and had different definitions to each another. All the studies showed a trend in favour of fewer exacerbations in the intervention arm. The only study to report a significant between-group difference was a conference abstract, which showed that exacerbations (not clearly defined) occurred in 6 of the 31 patients in the intervention group (19.4%) and 15 of 32 in the control group (46.9%, p=0.021). Overall, results showed that inhaled corticosteroid use increased in the intervention group compared with the comparator group, although there was variability between the studies. These differences could be attributed to the specifics of the step-up and step-down protocols or the characteristics of the patients selected. The 2 studies that included children whose asthma was hard-to-treat or uncontrolled (Szefler et al. 2009 and Fritsch et al. 2006) saw an increase in inhaled corticosteroid use, while the studies that did not include children with these characteristics saw no significant increase. Health-related quality of life was only reported in 1 study in abstract form and using an unknown tool. The External Assessment Group was not able to draw a definite conclusion from these data. Four studies provided some data on asthma control, none of which demonstrated any statistically significant effects favouring either intervention or control. With respect to additional medication use, 3 studies provided data, but there did not appear to be a clear direction of effect within the data. One study reported no difference in adverse events between groups and there were no deaths reported. The adverse events listed included gastrointestinal disorders, haematological disorders, infections, musculoskeletal symptoms and skin symptoms. # Cost effectiveness The economic analysis done by the External Assessment Group compared the cost effectiveness of measuring FeNO using NIOX MINO, NIOX VERO and NObreath with current standard tests for diagnosing and managing asthma in England and Wales. ## Review of existing economic analyses The External Assessment Group did a review to identify existing economic analyses of FeNO testing and measurement (using NIOX MINO, NIOX VERO or NObreath) for diagnosing and managing asthma respectively. The review also sought to identify existing models and potentially relevant evidence sources to inform parameter values within the de novo economic models developed by the External Assessment Group. Only 1 published UK cost-effectiveness model was identified for asthma diagnosis, and 1 for asthma management. Modified versions of these models were provided to NICE by the manufacturer of NIOX MINO and NIOX VERO. The wider review identified several economic analyses that the External Assessment Group described as including various methodological problems, questionable assumptions and weak evidence. ## De novo cost-effectiveness model The External Assessment Group developed 2 de novo models: 1 to assess the expected cost effectiveness of measuring FeNO in addition to, or in place of, standard tests for diagnosing asthma (the diagnostic model) and 1 to assess the expected cost effectiveness of FeNO plus the British guideline compared with the British guideline alone for managing people with diagnosed asthma (the management model). The 2 models, although distinct, shared several parameter values and assumptions. The diagnostic model was structured in the form of a decision tree. The decision tree model was used to estimate the probability that a person with asthma will be correctly diagnosed (true positive) or incorrectly diagnosed (false negative); and the probability that a person without asthma will be correctly diagnosed (true negative) or incorrectly diagnosed (false positive) and the expected health outcomes and costs arising from this. The management model was in the form of a simple Markov model with 2 states: alive with diagnosed asthma and dead. Estimates of test accuracy for measuring FeNO were drawn from several separate studies based on the results of the systematic review for clinical effectiveness, while estimates of test accuracy for comparator tests were drawn from best available evidence. The economic analyses included estimates of the sensitivity and specificity of individual tests as well as combinations of FeNO devices plus other standard tests. One study (Schneider et al. 2013) that used the NIOX MINO device was used to inform estimates of the sensitivity and specificity of FeNO alone. The true pre-test probability of asthma in undiagnosed patients was estimated as a weighted mean of several cases of asthma and non-asthma in the studies used, to inform the diagnostic test accuracy parameters. Across the included studies, 412 of 881 patients were diagnosed with asthma (p=0.47). Health-related quality of life values for people without asthma were estimated using a general population EQ‑5D regression model. The values were common to all diagnostic comparator groups and did not therefore have any effect on the estimates of incremental health gain for the diagnostic tests included in the economic analysis. The disutility associated with asthma, estimated to be −0.0463, was taken from the catalogue of EQ‑5D values reported by Sullivan et al. (2011). It was noted that this disutility was applied to all patients with asthma and to those who tested false positive (until their misdiagnosis was corrected). This disutility is unlikely to fully reflect health losses associated with the delayed diagnosis of more serious pathology, such as cancer or tuberculosis. The disutility associated with poor asthma control was derived from a study (McTaggart-Cowan et al. 2008) that reported EQ‑5D estimates for 4 health states: 'very well controlled', 'well controlled', 'adequately controlled' and 'not controlled'. EQ‑5D estimates ranged from 0.90 for 'very well controlled' to 0.80 for 'not controlled'. The External Assessment Group assumed that the health loss associated with poor control because of a false-negative diagnosis related to the difference between the 'well-controlled' state and the 'not-controlled' state (mean disutility of −0.04). This disutility was applied to all false-negatives until the misdiagnosis was corrected. Because of the lack of empirical evidence relating to the time needed to resolve incorrect diagnoses, the External Assessment Group attempted to elicit these values from clinical specialists. Based on the response received, the External Assessment Group assumed that the time to resolve a false-negative diagnosis has a mean of 8 months (95% CI 4 to 12 months) and the time to resolve a false-positive diagnosis has a mean of 18 months (95% CI 12 to 24 months). The External Assessment Group considered these estimates to be highly uncertain and tested them in sensitivity analyses. The following costs were used to inform the diagnostic and management models: Test costs: the marginal per-test costs for all 3 devices were calculated based on information provided by the manufacturers. The calculation was complicated by the fact that the devices each have different lifetimes, and that test kits and mouthpieces for each device are available at lower marginal costs if higher volumes of kits are purchased. These marginal per-test costs do not include any costs associated with education and training for NHS staff to use the devices. Maintenance costs: the External Assessment Group assumed that the manufacturer provides the maintenance of NObreath free of charge to the NHS. The External Assessment Group assumed zero maintenance costs for NIOX MINO and NIOX VERO. Primary care costs: the External Assessment Group assumed that spirometry, reversibility testing and measuring FeNO can be done in primary care and would need 2 GP visits and 1 nurse visit. The unit cost of a GP visit was based on published economic analyses that used an estimate of £43 (based on an appointment of 11.7 minutes, and including direct staff costs and qualifications). The cost of a GP practice nurse visit was assumed to be £13.69 (based on a visit of 15.5 minutes). For the management model, the External Assessment Group assumed that measuring FeNO would be done during routine GP visits and would need an additional nurse visit once every 3 months. The marginal cost of measuring FeNO was applied as the per-test cost plus the cost of a primary care nurse appointment. Secondary care costs: the External Assessment Group assumed that sputum induction and airway hyper-responsiveness (methacholine challenge test) would be done in secondary care and would need 2 secondary care visits, 1 laboratory visit and an initial GP visit for referral. Secondary care attendance costs were based on the Healthcare Resource Group for respiratory medicine attendances (£204.29). The cost of a laboratory visit was based on the Healthcare Resource Group for simple bronchodilator studies (£203.29). The External Assessment Group assumed the standard errors around these estimates were normally distributed, with a standard error equal to 15% of the mean. Costs of asthma management: estimates of the annual cost of combined inhalers were derived from 2 previous health technology assessment reports. For children, the least expensive annual cost for combined inhalers was estimated to be £201. For adults, the least expensive annual cost of the inhalers was estimated to be £231. Costs associated with resolving misdiagnoses: the assumption was made that 1 additional primary care attendance, 2 additional secondary care attendances and 1 laboratory visit would be needed to correctly diagnose false-positive and false-negative results. This same assumption was made in previously published models. Costs associated with loss of control for false-negatives: the External Assessment Group assumed that people who were falsely diagnosed as not having asthma would experience 1 exacerbation in each year they remain misdiagnosed. The model assumed that a proportion of these exacerbations would need hospitalisation. The following costs were used to inform the management model alone: Additional costs of FeNO measurement: The External Assessment Group assumed that FeNO measurement would be done during routine GP visits and would require 1 additional nurse visit every 3 months. Costs of managing exacerbations: the External Assessment Group assumed that a proportion of exacerbations would need hospitalisation while the remainder could be managed in primary care. It also assumed that severe exacerbations that do not need hospitalisation would need 1 GP attendance (£43.00) plus oral corticosteroids for 5 days (£1.73) based on an earlier health technology assessment report. The cost of asthma hospitalisation was derived from current NHS Reference Costs (£1266.72). ## Base-case results The base-case model was evaluated probabilistically using Monte Carlo sampling techniques. Deterministic one-way sensitivity analyses were also performed to account for different modelling assumptions. Central estimates of cost effectiveness were presented as incremental cost-effectiveness ratios (ICERs). Uncertainty surrounding the cost-effectiveness estimates was presented using cost-effectiveness planes and cost-effectiveness acceptability curves. The base-case results of the diagnostic model in children and adults suggested that, across the 17 diagnostic options included in the economic analysis, the expected difference in quality-adjusted life years (QALYs) is likely to be small (4.2686–4.2834). They also suggested that airway hyper-responsiveness (methacholine challenge test) is expected to produce the greatest QALY gain (4.2834), followed by FeNO testing (either NObreath, NIOX VERO or NIOX MINO) plus bronchodilator reversibility, with a QALY of 4.2829. The difference between the QALYs produced by the methacholine challenge test and FeNO testing plus a bronchodilator was very small (0.0005 QALYs). Other diagnostic test options, either with or without FeNO testing, resulted in increasingly lower QALYS, with spirometry (forced expiratory volume in the first second divided by the total volume of air that a person can forcibly exhale in 1 breath) producing the lowest QALY gain of 4.2686. The External Assessment Group presented an incremental cost-effectiveness analysis, in which the diagnostic options were ranked in decreasing order of QALY. The ICER for airway hyper-responsiveness (methacholine challenge test) compared with the next best option in terms of QALY (NObreath plus bronchodilator reversibility) was approximately £1.125 million per QALY gained. Following methacholine challenge, the option producing the next best QALY (FeNO testing plus bronchodilator reversibility) yielded 4.2829 QALYs, but the cost associated with the individual tests varied (£686.08 for NObreath, £687.61 for NIOX VERO and £688.33 for NIOX MINO). FeNO testing plus bronchodilator reversibility is therefore cost saving compared with methacholine challenge, but is estimated to produce marginally fewer QALYs (see section 5.62). All further options, with or without FeNO testing, were dominated because they were both more expensive and produced fewer QALYs. The External Assessment Group considered these results to be very uncertain. The base-case results for asthma management in children suggested that the British guideline plus FeNO measurement produces a small health benefit (0.05 QALYs) compared with the British guideline alone. The British guideline plus FeNO measurement was also more costly (£8148.59 for the British guideline plus NObreath, £8314.30 for the British guideline plus NIOX VERO and £8391.53 for the British guideline plus NIOX MINO) than the British guideline alone (£5860.06) because of projected inhaled corticosteroid use for the FeNO measurement groups. The resulting ICER for NObreath plus the British guideline compared with the British guideline alone was £45,213 per QALY gained. NIOX VERO and NIOX MINO were expected to be dominated by NObreath because of their higher marginal per-test costs. The base-case results for asthma management in adults showed that the British guideline plus FeNO measurement is expected to produce a small health benefit (0.04 QALYs) compared with the British guideline alone. The British guideline plus FeNO measurement was also more costly in adults (£7377.61 for the British guideline plus NObreath, £7535.43 for the British guideline plus NIOX VERO and £7608.99 for the British guideline plus NIOX MINO) than the British guideline alone (£7296.30) because of increased inhaled corticosteroid use in the FeNO measurement groups during the first 12 months of monitoring. Similarly to the children's model for asthma management, the model assumed that all 3 FeNO devices produce the same health benefits. NIOX MINO and NIOX VERO were dominated by NObreath because of their higher marginal per-test costs. The ICER of the British guideline plus NObreath compared with the British guideline alone was approximately £2146 per QALY gained. If dominance was ignored, the ICERs for the British guideline plus the NIOX devices, compared with the British guideline alone, were £6310 per QALY gained for NIOX VERO and £8250 per QALY gained for NIOX MINO. ## Sensitivity analysis results The External Assessment Group carried our several deterministic sensitivity analyses for the diagnostic and management models. For the diagnostic model, results of the deterministic sensitivity analyses indicated that the cost-effectiveness frontier presented in the base-case analysis was maintained across most scenarios. In most scenarios, most options were expected to be ruled out because of simple dominance. The results based on the point estimates of parameters were similar to the results of the probabilistic analysis, and discounting did not have a substantial effect on the cost effectiveness of the non-dominated diagnostic options. Other indications from the results of the sensitivity analysis showed that the costs of the various FeNO devices influenced which options were dominated, but had only a negligible impact on the cost-effectiveness results for non-dominated options. Longer misdiagnosis correction times substantially improved the cost effectiveness of airway hyper-responsiveness (methacholine challenge test) compared with FeNO testing plus bronchodilator reversibility, with the lowest ICER being £126,982 per QALY gained when time to correct diagnosis was extended 10-fold. In terms of diagnostic accuracy, the results of the sensitivity analyses showed that the use of other sources for the operating characteristics of FeNO testing and standard tests did not impact on the cost effectiveness of non-dominated options. Also, the use of a rule‑out decision approach may have improved the comparative effectiveness and cost effectiveness of FeNO testing alone. For the management model in children, the results of the sensitivity analyses indicated that NIOX MINO and NIOX VERO were expected to be consistently dominated by NObreath because of their higher marginal per-test cost. In addition, while the marginal per-test cost influenced which device would be preferred, it did not have a substantial impact on the overall cost effectiveness of the British guideline plus FeNO measurement compared with the British guideline alone. The results of the sensitivity analyses indicated that the length of time FeNO measurement was assumed to impact on exacerbations and inhaled corticosteroid use was a key source of uncertainty within the children's model. Shorter impact times improved the cost effectiveness of FeNO measurement. The British guideline plus FeNO measurement dominated the British guideline alone when it was assumed that the impact of FeNO‑guided management on exacerbations and inhaled corticosteroid use was reduced to 1–4 years, whereas assumptions for 5 years and 10 years produced ICERs of £7598 and £27,660 per QALY gained respectively. When alternative sources of exacerbation rates and inhaled corticosteroid use for children were explored, the ICERs for managing children changed considerably. The sensitivity analysis used values from the Pijnenburg et al. (2005) study, rather than the Szefler et al. (2008) study used in the base case, in which exacerbation rates were 0.18 for the British guideline plus FeNO measurement and 0.39 for the British guideline alone, and relative corticosteroid dose intensity beyond the first year was 1.23 for the British guideline plus FeNO measurement and 1.22 for the British guideline alone. The analysis based on Pijnenburg et al. suggested a considerably more favourable ICER for the British guideline plus FeNO measurement compared with the British guideline alone in children (£18,963 per QALY gained). The External Assessment Group noted that the Szefler et al. study included patients with uncontrolled asthma and the study protocol did not allow therapy to be stepped down on the basis of low FeNO levels alone. This may, in part, explain why inhaled corticosteroid use was higher for the British guideline plus FeNO measurement than for the British guideline alone. The results of the sensitivity analyses for managing children also indicated that the model was sensitive to the rate of exacerbations and the associated health loss. When exacerbation rates were doubled, the ICER for the British guideline plus FeNO measurement compared with the British guideline alone was £19,891 per QALY gained. When exacerbation rates were halved, the ICER was £95,632 per QALY gained. When the exacerbation disutility was doubled the ICER was £31,479 per QALY gained and £52,844 per QALY gained when halved. Results for the deterministic sensitivity analyses for the management model in adults showed that the model was highly sensitive to the exacerbation rates used. Exacerbation rates from Syk et al. (2013) increased the ICER to £184,000 per QALY gained for the British guideline plus FeNO measurement compared with the British guideline alone. When exacerbation rates from Syk et al. were used, the British guideline alone dominated the British guideline plus FeNO measurement. In addition, NIOX MINO and NIOX VERO were expected to be consistently dominated by NObreath because of their higher marginal per-test cost. However, while the marginal per-test cost influenced which device would be preferred, it did not have a substantial impact on the overall cost effectiveness of FeNO measurement compared with the British guideline. Another observation from the sensitivity analyses of the management in the adult model was that the length of time that FeNO measurement was assumed to impact on exacerbations and the use of inhaled corticosteroids was a key driver of cost effectiveness. In the adult model, the cost effectiveness improved when the duration of impact of FeNO measurement was extended (£885,451 per QALY gained when 1 years' duration was assumed, to £8898 per QALY gained when 40 years' duration was assumed). The opposite was true in the children's model in which cost effectiveness worsened when the duration of effect on exacerbations and inhaled corticosteroid use was increased (see section 5.71). The External Assessment Group stated that this was driven entirely by the observed differences in relative inhaled corticosteroid use at the last observed time point in the trials.# Considerations The Diagnostics Advisory Committee reviewed the evidence available on the clinical and cost effectiveness of measuring fractional exhaled nitric oxide (FeNO) to inform the diagnosis and management of asthma in children and adults. The Committee considered the report produced by the External Assessment Group and statements from patient experts on the Committee and from clinical specialists who acted as specialist Committee members on this assessment. The Committee considered whether NIOX MINO, NIOX VERO and NObreath could be considered equivalent for the purpose of this assessment. It noted the review by the External Assessment Group, which indicated that, although some differences were observed in test results, there was generally a good correlation with results from other chemiluminescence devices. The Committee noted that there appeared to be poorer equivalence between devices in some circumstances, such as at higher FeNO levels, and that the direction of disagreement varied between studies and devices. However, the Committee acknowledged that there is no commonly accepted definition of clinically acceptable differences in FeNO measurements. The Committee concluded that, based on the available evidence, the 3 devices could, on balance, be considered to be broadly equivalent. The Committee also thought that standardisation of FeNO devices should be encouraged. The Committee considered whether very young children would be able to perform the test. It heard from both manufacturers that the minimum recommended age for using FeNO monitoring devices is 5 years. The Committee also noted that the External Assessment Group's systematic review only included studies of children 5 years and older, in line with the review protocol. The Committee concluded that there was insufficient evidence to determine the suitability of FeNO testing for children younger than 5 years. The Committee discussed the lack of gold standard for asthma diagnosis. It heard from the clinical specialists that there is no single clinical definition of asthma and that the diagnosis is based on multiple factors, including the presence of symptoms and evidence of airway obstruction. It heard that high FeNO levels in people with symptoms suggestive of asthma, such as coughing and wheezing, may indicate that the patient has eosinophilic asthma, which may be treated with inhaled corticosteroids. However, FeNO levels are not raised in all patients with asthma and, conversely, not all people with raised FeNO levels have asthma. The Committee further heard from a clinical specialist that, although it is generally accepted that FeNO levels correlate with eosinophilic airway inflammation, this effect may be stronger in some groups of patients than others and that there are other causes of inflammation. The Committee also heard that clinical practice varies and so the use of standard clinical practice as a reference standard is problematic. The Committee therefore concluded that the lack of gold standard for diagnosis, the complexity of diagnosis and the variation in clinical practice introduced an increased uncertainty in the assessment of the clinical validity of FeNO devices. The Committee considered the diagnostic accuracy of FeNO testing. The Committee noted that the External Assessment Group had presented accuracy data for both children and adults against various reference standards and in different positions in the diagnostic pathway. It acknowledged that, because of the clinical heterogeneity of the data, a meta-analysis had not been performed and that estimates of specificity and sensitivity varied between studies. Overall, the Committee accepted the External Assessment Group's observation that the ranges of specificity were generally narrower than those for sensitivity, and that FeNO testing appeared to have a higher specificity than sensitivity. It heard from the clinical specialists that higher specificity would indicate that testing would be of greater use as a rule‑in test; that is, patients testing positive are assumed to have asthma and patients testing negative have further tests for asthma. The Committee considered that the absence of a meta-analysis of accuracy meant that there was a greater uncertainty about the accuracy of FeNO devices in this assessment. Nevertheless, it was satisfied that the specificity of the devices was acceptable if they are used in a rule‑in scenario. The Committee considered FeNO cut-off values for guiding diagnosis of asthma in adults and children. The Committee heard from the External Assessment Group that cut-offs were generally not interchangeable between the FeNO devices, and that there appeared to be a high degree of heterogeneity between the studies. The Committee also heard from a clinical specialist that, in their experience, the devices generally produce different readings when used by the same patient. However, the differences appeared to be consistent. The Committee noted that the highest sum of sensitivity and specificity was obtained when the cut-offs ranged from 19–21 parts per billion (ppb) in children and the highest sum of sensitivity and specificity was wider for adults (20–47 ppb). The Committee further noted that a higher cut-off was needed to optimise the specificity of the devices; a cut-off between 47 ppb and 76 ppb resulted in specificity of 88–100% in adults and a cut-off range of 30 ppb to 50 ppb resulted in specificity of 92–100% in children. The Committee was informed by clinical experts that cut-off values in the higher range would be preferred to reduce the rate of indeterminate results, and that the test could be used to rule in a diagnosis of asthma in people whose test is positive. The Committee concluded that cut-off values in the higher ranges should generally be used, and that cut-off values should be lower in children than adults. The Committee considered the generalisability of the clinical evidence to the whole population both for diagnosing and managing asthma. The Committee acknowledged that the clinical evidence was heterogeneous in terms of clinical characteristics and results, and that studies were identified based on their similarity to UK practice and similarity to the subgroups of interest as defined in the protocol (that is, in people in whom the condition is difficult to diagnose, or the wider population of people presenting with symptoms of asthma). As such, no single study can be generalised to the whole population. The Committee therefore concluded that both the variation in UK clinical practice and the heterogeneity of studies included in the assessment would increase the uncertainty around the clinical benefits of measuring FeNO. The Committee discussed the clinical evidence on the use of FeNO to guide asthma management in adults. The Committee noted that there was a statistically significant reduction in the meta-analysis for the composite outcome of any severity of exacerbations when FeNO measurement was used to guide management compared with treatment without FeNO measurement during the first 12 months of management. However, it acknowledged that the results from the individual studies were heterogeneous and that the meta-analysis did indicate a non-significant trend towards reduction in severe exacerbation rates. The Committee noted that the meta-analysis also showed a non-significant trend towards decreased inhaled corticosteroid use and considered that the effects of FeNO measurement on inhaled corticosteroid use were uncertain. It further noted that step-up and step-down protocols for inhaled corticosteroid use varied between studies and the effect of this on the outcomes was not known. The Committee concluded that FeNO‑guided management was likely to reduce exacerbation rates in adults, but the extent and duration of this effect was uncertain. The Committee discussed the additional meta-analysis, performed by the External Assessment Group, which incorporated the more recent Honkoop et al. study (2013). It recognised that the addition of this study provided some further support that severe exacerbations could be reduced when FeNO measurement was added to asthma management. However, because the External Assessment Group had been unable to calculate accurate error rates for outcomes, the Committee was still uncertain whether this effect was statistically significant. The Committee therefore concluded that the Honkoop et al. study appeared to lend weight to the assumption that FeNO‑guided management was effective, but was unable to establish whether this was statistically significant. The Committee then discussed the clinical results for FeNO‑guided management in children with asthma. As with the studies in adults, those in children appeared to have variations in design, including in the step-up and step-down protocols, medications and inclusion criteria. The Committee noted that all studies reported a decrease in exacerbations in the intervention arm, but only 1 reported a statistically significant reduction. It also noted that there was a greater uncertainty around whether inhaled corticosteroid use went up or down when FeNO measurement was added to asthma management. On balance, the Committee concluded that FeNO‑guided management in children is likely to result in reduced exacerbation rates, but that the extent and duration of this effect is still uncertain. The Committee further concluded that the effect of FeNO‑guided management on inhaled corticosteroid use is uncertain and recommended that further evidence is generated to establish its benefits. The Committee discussed the role of measuring FeNO in diagnosing and managing asthma in children and adults. It heard from the clinical specialists that diagnosis of asthma needs consideration of many different elements, including symptoms, response to treatment and physiological testing. Given the complexities of diagnosis, the Committee considered that FeNO testing would not be able to replace current practice for diagnosis. The Committee concluded that measuring FeNO had not been shown to be able to reliably replace other tests and clinical observations, and therefore should be used as an add‑on to current clinical diagnosis and management in people with asthma. The Committee discussed the additional benefits of measuring FeNO in the diagnosis and management of asthma. It heard from a patient expert that an accurate diagnosis of asthma can sometimes take many years, resulting in less than optimal treatment, which can have a direct impact on health. The Committee also heard from a patient expert that FeNO‑guided management could result in patients better understanding their own condition and disease progression, which could reduce hospitalisations and improve patient experience. The Committee also considered the effect that measuring FeNO could have on adherence to medication. The Committee was informed by a clinical specialist that approximately 30% of people do not take their medication as prescribed. The clinical specialist indicated that studies have shown that FeNO is a useful marker for medicine adherence and that FeNO devices could be a useful tool for doctors to improve concordance, by which the patient and clinicians make decisions together about the treatment. The Committee concluded that FeNO testing could potentially enable patients and doctors to improve treatment concordance in patients who are on medications for asthma. The Committee considered the areas of uncertainty in the economic models produced by the External Assessment Group for diagnosing and managing asthma. The Committee noted that the diagnostic models were sensitive to: assumptions about the length of time needed to resolve misdiagnoses; assumptions about health losses incurred by patients who have false-negative results; the costs of asthma management; and the use of rule‑in and rule‑out diagnostic decision rules. The Committee considered the assumptions made in the management model, in which it noted that the results in both the children and adult subgroups were particularly sensitive to: assumptions about changes in inhaled corticosteroid use over time; the annual number of nurse visits for FeNO measurement; and the length of time FeNO measurement was assumed to impact on exacerbation rates and inhaled corticosteroid use. The Committee concluded that both models for diagnosis and management were subject to considerable uncertainty, and therefore the results should be interpreted with caution. The Committee discussed the results from the base-case analysis for the use of FeNO testing in diagnosis. It noted that, although the methacholine challenge test produced the most quality-adjusted life years (QALYs), the incremental cost-effectiveness ratio (ICER) was very high at £1.25 million per QALY gained when compared with FeNO testing plus bronchodilator reversibility. The Committee also noted that the difference in the health benefit for methacholine challenge test compared with FeNO testing plus bronchodilator reversibility was estimated to be very small (0.0005 QALYs) and that costs were considerably lower for FeNO testing plus bronchodilator reversibility. Given that FeNO testing plus bronchodilator reversibility dominated the other tests, the Committee concluded that FeNO testing plus bronchodilator reversibility testing in adults and children delivered equal or greater QALYs at a lower ICER than other tests. Moreover, the Committee noted that the use of FeNO testing in conjunction with existing tests is more cost-effective than when the existing tests are used alone. The Committee therefore recommended FeNO testing as an option to help diagnose asthma in adults and children who, after initial clinical examination, are considered to have an intermediate probability of having asthma and where FeNO testing is intended to be done in combination with other diagnostic options according to the British guideline on the management of asthma (2012). The Committee then discussed the results from the base-case analysis for asthma management in children. It noted that, for base-case results, the External Assessment Group had used 2 studies, Szefler et al. (2008) and Pijnenburg et al. (2005), to inform the clinical effectiveness, and the ICER was £45,200 per QALY gained. The Committee then discussed the sensitivity analyses for management in children and noted that, when the analysis was based on Pijnenburg et al., a more favourable ICER of £19,000 per QALY gained was obtained. It also noted that, when it was assumed that FeNO measurement impacts for a shorter length of time on exacerbations and inhaled corticosteroid use, FeNO measurement plus management as recommended in the British guideline on the management of asthma (2012), hereafter referred to as the 'British guideline', dominated management by the British guideline use alone for up to 4 years. It also noted that the ICER was £7600 per QALY gained for 5 years and £27,700 per QALY gained for 10 years. The Committee assumed that shorter duration of up to 10 years, rather than lifetime duration, was a more reasonable assumption, given that children would not be expected to remain in the child-model for the rest of their lifetime. Moreover, the Committee heard from the External Assessment Group that the Szefler et al. study included patients with uncontrolled asthma, and the study protocol did not allow therapy to be stepped down on the basis of low FeNO levels. The Committee considered that, in clinical practice, it was unlikely that the assumption of higher inhaled corticosteroid use throughout the time horizon with FeNO measurement would be seen, and therefore preferred the sensitivity analysis based on the Pijnenburg et al. study over the base-case analysis. Considering the combined shorter duration of impact of FeNO measurement and analysis based on the Pijnenburg et al. study, the Committee concluded that the most plausible ICER for management in children was likely to be lower than £19,000 per QALY gained. The Committee discussed the results from the base-case analysis for asthma management in adults. It noted that the ICER for FeNO measurement plus the British guideline compared with the British guideline alone was £2100 per QALY gained. The Committee considered that, although there were uncertainties relating to this estimate, this ICER was low and therefore the use of FeNO measurement for asthma management in adults was likely to be cost effective. The Committee therefore accepted the base-case results for adults. The Committee then discussed its recommendation for the use of FeNO measurement in asthma management in children and adults. The Committee heard from clinical specialists that there was considerable uncertainty around the use of stepping-up and stepping-down protocols for inhaled corticosteroid use, and that the External Assessment Groups' review had not conclusively demonstrated that FeNO measurement would be effective and safe for guiding the stepping down of inhaled corticosteroids. The Committee expressed concerns about using FeNO measurement as a basis for stepping-down treatment and was not satisfied that the evidence was robust enough to show that the benefits out-weighed the potential harms of under treatment. The Committee therefore concluded that FeNO measurement should not be recommended to help with stepping down inhaled corticosteroid use in adults or children whose asthma is well managed. However, it considered FeNO measurement to be cost and clinically effective when used as an option to support symptomatic asthma management in people using inhaled corticosteroids. The Committee discussed the evidence in the subgroups defined in the scope for this assessment, (pregnant women, older people, people who smoke and those who have been exposed to tobacco smoke). The Committee heard from the External Assessment Group that there is little robust evidence for most of these groups (study designs were generally of lower quality), which could lead to biased results. It noted that randomised controlled trial evidence shows that measuring FeNO is at least as useful during pregnancy as it is for the general population, but it appears likely that FeNO is a less reliable indicator of airway inflammation in older people. The Committee therefore concluded that, in view of the limited evidence, it was unable to provide any specific recommendations for the subgroups defined in the scope.# Recommendations for further research The Committee discussed the potential for future research. The Committee accepted that there is a need to further establish the accuracy of current practice in diagnosing asthma and the incremental accuracy associated with the addition of FeNO testing. The Committee also considered the role of FeNO measurement in asthma management. It accepted that currently available evidence on the use of FeNO measurement in asthma management is unclear on whether benefits of treatment are maintained long-term. The Committee concluded that long-term studies following patients for several years could address this gap. The Committee also considered the role of FeNO in guiding inhaled corticosteroid dosing through stepping-up and stepping-down protocols. It accepted there is a need for more evidence on which protocols offer the safest and most optimal asthma management when used in UK clinical practice. Therefore, further studies are recommended, with consideration for the different protocols and cut-off points that may be necessary in different populations.	{'Recommendations': "FeNO is recommended by NICE to help diagnose asthma; for further details please see NICE's guideline on asthma: diagnosis, monitoring and chronic asthma management.\n\nFeNO measurement is recommended as an option to support asthma management in people who are symptomatic despite using inhaled corticosteroids.", 'The technologies': 'Three devices, NIOX MINO, NIOX VERO and NObreath, used for measuring fractional exhaled nitric oxide (FeNO) concentration in the diagnosis and management of asthma were evaluated. All 3 devices are CE marked. Additional details of the devices are provided in section\xa04.\n\nThe devices and methods in this guidance were identified as being relevant to this assessment. NICE is aware that the devices and methods are evolving, so modifications and new devices are likely to be developed in the future.', 'Clinical need and practice': "# The problem addressed\n\nNitric oxide, which is produced in the lungs and is present in exhaled breath, has been implicated in the pathophysiology of lung diseases, including asthma. It has been shown to act as a vasodilator, bronchodilator, neurotransmitter and inflammatory mediator in the lungs and airways. Over the years, fractional exhaled nitric oxide (FeNO) has been proposed as a non‑invasive marker of airway inflammation in asthma. FeNO levels are raised in people with asthma and can be lowered by effective treatment with corticosteroids.\n\nThe purpose of this evaluation was to evaluate the clinical and cost effectiveness of measuring FeNO in the diagnosis and management of asthma.\n\n# The condition\n\nAsthma is a chronic disorder of the airways, caused primarily by inflammatory processes and constriction of the smooth muscle in airway walls (bronchoconstriction). It is generally characterised by reversible airflow obstruction and increased responsiveness of the airways to various stimuli. Symptoms include recurrent episodes of wheezing, breathlessness, chest tightness and coughing. Typical asthma symptoms tend to be variable, intermittent and worse at night. Asthma is commonly triggered by viral respiratory infections, exercise, or external factors such as smoke, a change in weather conditions and allergens (for example, pollen, mould and house dust mites).\n\nIn people with asthma, cellular inflammation of the airways with eosinophils and neutrophils is considered to be a characteristic feature relevant to the pathogenesis of the disease. Eosinophilic asthma is a distinct phenotype of asthma associated with a rise in nitric oxide in exhaled breath. Eosinophilic asthma may respond to treatment with corticosteroids, while neutrophilic asthma generally does not.\n\nAsthma usually develops in childhood but may start at any age. There is no cure for asthma, although people may have long periods of remission. Poorly controlled asthma can have a significant impact on the quality of life of the affected person and their family. Because there may be variation in an individual's perception of asthma symptoms, clinical measures such as lung function do not always correlate with quality-of-life scores. However, if asthma is well controlled, near-maximal scores on quality-of-life instruments can be achieved.\n\n# The diagnostic and care pathways\n\nAsthma is diagnosed on the basis of symptoms and objective tests of lung function. Spirometry is used to assess lung function by measuring the volume of air that the patient is able to expel from the lungs after a maximal inspiration. Spirometry lung function measurements include peak expiratory flow rate (PEF), forced vital capacity (FVC; the total volume of air that a person can forcibly exhale in 1 breath), forced expiratory volume in the first second (FEV1) and percentage predicted FEV1 (calculated as a percentage of the predicted FEV1 for a person of the same height, sex and age without diagnosed asthma). Variability in PEF and FEV1, either spontaneously or in response to therapy, is a characteristic feature of asthma. The severity of asthma is judged according to symptoms and the amount of medication needed to control them, and is based on the British guideline on the management of asthma (2012) from the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN).\n\nAsthma is diagnosed clinically and there is no standardised definition of the condition. The presence of symptoms (wheezing, breathlessness, chest tightness and cough) and variable airflow obstruction is central to all definitions. More recently, descriptions of asthma have included airway hyper-responsiveness and airway inflammation. It is unclear how these features relate to each other, how they are best measured and how they contribute to the clinical manifestations of asthma.\n\nThe diagnosis of asthma in children is based on recognising a characteristic pattern of episodic symptoms in the absence of an alternative explanation. If asthma is suspected, an initial clinical assessment should be carried out to estimate the probability of asthma. According to the British guideline on the management of asthma (2012), a child can be classed into 1 of 3 groups based on initial clinical assessment. These groups are:\n\nhigh probability – diagnosis of asthma likely\n\nlow probability – diagnosis other than asthma likely\n\nintermediate probability – diagnosis uncertain.\n\nFor children identified as having a low probability of asthma, a more detailed investigation and specialist referral should be considered. For children with a high probability of asthma, a trial of treatment should be started immediately. The response to treatment should be reassessed every 6\xa0months. Those with a poor response to treatment should have more detailed investigations.\n\nIn children with an intermediate probability of asthma who can perform spirometry and have no evidence of airway obstruction, tests for atopic status, assessment of bronchodilator reversibility and, if possible, tests for bronchial hyper-responsiveness using methacholine, exercise or mannitol should be considered. In such cases, specialist referral should always be considered.\n\nThe diagnosis of asthma in adults is based on clinical history and includes the recognition of a characteristic pattern of symptoms and signs, and the absence of an alternative explanation for them. Spirometry is the preferred initial test to assess the presence and severity of airflow obstruction. Adults are also classified as having a high, low or intermediate probability of asthma. Chest X‑ray and specialist referral may be considered in any patient presenting atypically or with additional symptoms or signs.\n\nAsthma management aims to control symptoms (including nocturnal symptoms and exercise-induced asthma), prevent exacerbations and achieve the best possible lung function, with minimal side effects from treatment. The British guideline on the management of asthma (2012) recommends a stepwise approach to treatment in both adults and children. Treatment is started at the step most appropriate to the initial severity of the asthma, with the aim of achieving early control of symptoms and optimising respiratory function. Control is maintained by stepping up treatment as necessary and stepping down when control is achieved. Management options include interventions with or without the use of drugs.\n\nFor most children and adults, asthma is monitored in primary care by routine clinical reviews on at least an annual basis. These reviews include (but are not limited to) assessment of the patient's symptom score (using a validated questionnaire), exacerbations, oral corticosteroid use, time off school or work, growth in children, inhaler technique and, in adults, lung function assessed by spirometry (PEF).", 'The diagnostic tests': '# The interventions\n\n## NIOX MINO\n\nNIOX MINO (Aerocrine) is a diagnostic and monitoring device that analyses a breath sample using an electrochemical sensor to determine exhaled nitric oxide concentration. The technology is designed to help identify people whose airway inflammation is likely to respond to treatment with inhaled corticosteroids. It can also help to predict the onset of asthma symptoms or loss of asthma control, and to monitor compliance with corticosteroid therapy and the effectiveness of treatment.\n\nNIOX MINO determines exhaled nitric oxide concentration in a breath sample. The device is small, hand-held and portable, and can be used by adults and children. It needs a 10-second exhalation of breath at a pressure of 10–20\xa0cm H2O to maintain a fixed flow rate of 50±5\xa0ml/s. The last 3\xa0seconds of the 10-second exhalation are analysed by a calibrated electrochemical sensor to give a definitive result in parts per billion. Clinical cut-off values can be applied to the exhaled nitric oxide values to categorise readings as low, intermediate or high according to the reference ranges for ages less than 12\xa0years and 12\xa0years or more.\n\nNIOX MINO is pre-calibrated and designed to be a service- and calibration-free system. The manufacturer states that the calibrated electrochemical sensors included in the test kit should be replaced every year or once all the tests in the kit have been used. It can be used alone or connected to a computer for monitoring with the NIOX MINO Data Management Program and Electronic Medical Record systems. The device is CE marked.\n\n## NIOX VERO\n\nDuring the assessment phase, the manufacturer of NIOX MINO (Aerocrine) launched NIOX VERO, a new fractional exhaled nitric oxide (FeNO) device that is intended to replace NIOX MINO. The new device is battery powered and has a longer operational life and extended-test volume life compared with NIOX MINO. NIOX VERO is designed to be service and calibration free. The manufacturer states that the calibrated electrochemical sensors included in the test kit should be replaced every year or once all the tests in the kit have been used. The device is CE marked.\n\n## NObreath\n\nNObreath (Bedfont Scientific) is a diagnostic monitoring device that measures exhaled nitric oxide produced by airway inflammation. The reading is presented in parts per billion and is claimed to be directly related to the severity of inflammatory disease (for example, asthma). NObreath needs 12\xa0seconds of exhalation of breath in adults and 10\xa0seconds in children. The device is CE marked.\n\n# The comparator\n\nScoping workshop attendees indicated that following the British guideline on the management of asthma (2012) from the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) is an appropriate comparator for people with asthma.', 'Outcomes': "The Diagnostics Advisory Committee (section\xa09) considered evidence from several sources (section\xa010).\n\n# How outcomes were assessed\n\nThe assessment was performed by an External Assessment Group and consisted of a systematic review and development of a decision analytical model.\n\nThe systematic review was carried out to identify evidence on the equivalence of fractional exhaled nitric oxide (FeNO) devices (analytical validity), evidence of the diagnostic accuracy of FeNO testing for asthma diagnosis and evidence of the efficacy of FeNO‑guided asthma management.\n\nA decision analytical model and a Markov model were developed to assess the cost effectiveness of measuring FeNO in the diagnosis and management of asthma.\n\n# Review of equivalence of FeNO devices\n\nThe External Assessment Group undertook this review to establish whether FeNO devices could be considered to be equivalent to one another in their measurements, and so whether studies that used other devices could helpfully inform this appraisal. Because there was insufficient evidence from primary research studies that used the mobile, hand-held FeNO electrochemical devices (NIOX MINO, NIOX VERO and NObreath), a review of equivalence to the precursory large, stationary FeNO chemiluminescent devices (including Niox, also made by Aerocrine) was conducted.\n\nThe review identified 27 studies that compared NIOX MINO, NIOX VERO and NObreath with other devices. The External Assessment Group undertook 3 main comparisons for this purpose. The first included comparisons of means, which compare the reported mean FeNO values as measured by each device in the same cohort. The second compared correlation coefficients, which show whether measurements by 2 devices are correlated but not whether the actual values produced are the same. The third compared the result of Bland–Altman analyses, which produce statistics that assess agreement between devices rather than just correlation.\n\n## NIOX MINO\n\nEight studies compared NIOX MINO with Niox in adults. Of these studies, 5 were exclusively in adults and 3 were in adults and other age groups. There was variability in correlation between the devices among the studies. While 5 studies showed largely similar mean values between NIOX MINO and Niox, 3 studies showed higher FeNO readings with NIOX MINO (ranging from 0.5 to 9\xa0parts per billion [ppb]). Small (non-significant) differences in the mean FeNO readings were observed between the devices when the cohort mean FeNO values were below 30\xa0ppb (as measured by Niox). When the mean FeNO values were above 35\xa0ppb, the differences in cohort means were larger and statistically significant. Correlation coefficients ranged from 0.73 to 0.998. The results of 1 study suggested that there may also be some variation between NIOX MINO devices themselves, although a second study showed good agreement. Across the 8 studies, Bland–Altman analyses were not reported in a consistent way. Limits of agreement were 10\xa0ppb above and below the mean in some cases, and the studies with the largest mean differences did not report Bland–Altman statistics.\n\nThree studies comparing NIOX MINO with Niox included children. Of these, 2 studies reported statistically significantly higher mean FeNO values with NIOX MINO, while 1 study reported statistically significantly lower values. This study had low mean values (below 10\xa0ppb). All studies reported good correlation between the devices, while Bland–Altman statistics reported in 2 studies showed that NIOX MINO gave higher readings (by 1.1\xa0ppb [limits of agreement −4.4 to 6.7] and 3.9\xa0ppb [limits of agreement −1.1 to 8.9] respectively).\n\nTwelve studies compared NIOX MINO with stationary chemiluminescent devices other than Niox in adults and children. Of these, 6 studies were in adults, 3 in an unspecified group and 3 in children. The chemiluminescence devices used in each of the 12 studies were different. In the adults and the unspecified age group, correlation coefficients ranged from 0.876 to 0.96, indicating good correlation between devices. However, the mean FeNO levels and Bland–Altman statistics did not suggest such good correlation. In 4 studies, NIOX MINO gave higher readings than the comparator device, while 2 studies reported lower readings and 2 studies showed the devices to be comparable. Bland–Altman statistics, reported in 4 studies, suggested that mean differences were small, but the limits of agreement were much greater.\n\nIn children, correlation coefficients between NIOX MINO and other chemiluminescent devices ranged from 0.69 to 0.98, indicating variable correlation. The study with the poorer correlation reported higher mean FeNO levels, suggesting that poorer correlation is due to greater variability at higher FeNO values. However, the authors stated that correlation improved at higher values. One study noted that the direction of disagreement was different in children aged over and under 12\xa0years. The back-transformed Bland–Altman statistics and range of ratios reported showed a wide range of agreement, suggesting that the devices are not interchangeable.\n\nThe External Assessment Group stated that the comparability of NIOX MINO to chemiluminescent devices appears to be influenced by several factors. These include variability between NIOX MINO devices themselves, a lack of comparability between other chemiluminescent devices (which leads to heterogeneity in estimates of comparability between these devices and NIOX MINO) and poorer equivalence between the devices at higher FeNO levels.\n\n## NIOX VERO\n\nThe manufacturer of NIOX MINO and NIOX VERO provided details of a study (commercial in confidence) that compared the technical performance and accuracy of the 2 technologies.\n\n## NObreath\n\nFour studies compared NObreath with 3 chemiluminescent devices other than Niox. Bland–Altman analysis done in 1 study in a healthy cohort with low FeNO values showed a mean difference of −3.95\xa0ppb in comparison with the chemiluminescent device. Limits of agreement in this study were wide (−10.98 to 4.08). Another study reported an absolute mean difference in FeNO measurements of −3.81\xa0ppb. Comparisons with the third type of chemiluminescent device showed small differences between mean FeNO values for the cohort, with NObreath giving lower values in some cohorts.\n\nTwo studies that compared NObreath with NIOX MINO in adults found that NIOX MINO provided lower mean FeNO values than NObreath in most analyses. This contradicts the available evidence for comparisons of NIOX MINO with Niox and NObreath with Niox, which suggested that NIOX MINO should provide higher readings than NObreath. The 2 direct comparisons of NObreath and NIOX MINO included small numbers of patients, and only 1 included patients with asthma, but did not provide a Bland–Altman analysis to assess agreement.\n\nThe External Assessment Group stated that, based on available evidence, any differences in absolute values between results from NObreath and other devices are relatively small, although derived cut-offs and maximum sensitivity and specificity may differ.\n\n# Diagnostic accuracy of FeNO devices\n\nNo end-to-end studies were identified, and no cohort study compared use of FeNO testing within a sequence of tests with a suitable reference standard of the same sequence of tests without FeNO testing. The review identified 24 studies that met the inclusion criteria; 20 included adults of all ages and 4 included children. The studies were classified according to the position of the patients' asthma in the UK care pathway and the reference standards used.\n\n## FeNo testing in adults with asthma symptoms compared with most of, or all, the UK care pathway\n\nThe review identified 4 studies in this group. Cut-offs for the highest sum of sensitivity and specificity ranged from 20\xa0ppb to 47\xa0ppb in the 4 studies in this group. Sensitivities ranged from 32% to 88%, and specificities from 75% to 93%. Because of the heterogeneity in the results, study designs and the devices used, the External Assessment Group concluded that it is difficult to identify the optimal cut-off for sensitivity and specificity.\n\nCut-offs yielding the highest sensitivity ranged from 9\xa0ppb to 15\xa0ppb, with sensitivities ranging from 85% to 96% and specificities from 13% to 48%. Cut-offs yielding the highest specificity ranged from 47\xa0ppb to 76\xa0ppb, with sensitivities ranging from 13% to 56% and specificity from 88% to 100%.\n\nEstimates of specificity consistently had a smaller range and higher values than estimates of sensitivity reported, suggesting that FeNO may be more reliable as a 'rule‑in' test than as a 'rule‑out' test. A rule‑in test implies that patients whose test is positive are assumed to have asthma and those testing negative go on to have further tests. However, the cost effectiveness of this balance will depend on the clinical and cost consequences of the correct or incorrect classification of patients.\n\n## FeNO testing in patients with difficult-to-diagnose asthma compared with airway hyper-responsiveness\n\nThree studies used some form of airway hyper-responsiveness as the sole reference standard. Estimates of sensitivity and specificity appeared comparable to those in the studies of patients presenting in primary care with symptoms of asthma. One study included a set of patients whose methacholine challenge tests were negative and compared FeNO with an adenosine challenge test. This study produced 100% sensitivity (29% specificity) at a cut-off of 30\xa0ppb, making it likely to operate well as a rule‑out test.\n\nThe other 2 studies used methacholine challenge tests in people who had been found not to have asthma in previous tests. Cut-offs for the highest sum of sensitivity and specificity ranged from 34\xa0ppb to 40\xa0ppb when compared with a methacholine challenge test as a gold standard. Sensitivities ranged from 24% to 74%, and specificities from 73% to 99%, which is a similar range to the broader cohort. A range of cut-offs was not reported in these studies.\n\n## FeNO testing in patients with difficult-to-diagnose asthma with chronic cough compared with response to a trial of inhaled corticosteroids\n\nThree studies included patients with chronic cough who had tested negative for other causes. All 3 studies used response to a trial of treatment with inhaled corticosteroids as a reference standard. Cut-offs for the highest sum of sensitivity and specificity were similar in all 3 studies. Accuracy was somewhat better in 2 studies at 90–95% sensitivity and 76–85% specificity.\n\n## FeNO testing in children with asthma symptoms compared with various reference standards\n\nFour studies were identified that included children, and these had patients with a similar severity of asthma and similar reference standards as the adult cohorts, while the cut-offs derived were generally lower but with similar ranges of estimates of sensitivity and specificity. There was a high degree of agreement between studies in terms of the cut-off that produces the highest sum of sensitivity and specificity, despite the heterogeneity in devices and reference standards, with values between 19\xa0ppb and 21\xa0ppb. Estimates of sensitivity at these cut-off points were also wide-ranging and of a similar range to those in the studies in adults (49% to 86%).\n\nWhen selecting the cut-off with the highest sensitivity, results were similar to those for adult cohorts. Cut-offs ranged from 5\xa0ppb to 20\xa0ppb, sensitivities from 89% to 94% and specificities from 14% to 70%. When selecting the cut-off with the highest specificity, results were also similar to adult cohorts. Cut-offs were a little lower again, and ranged from 30\xa0ppb to 50\xa0ppb. Sensitivities ranged from 20% to 50% and specificities from 92% to 100%.\n\nThe External Assessment Group did not conduct a meta-analysis in any group because of the high heterogeneity between studies. Estimates of cut-off points, sensitivity and specificity were not consistent within groups and ranged widely when used as a rule‑in or rule‑out test and when considering the highest sum of sensitivity and specificity. Because of this, the External Assessment Group found it difficult to estimate the relative diagnostic accuracy of FeNO testing in any situation and at any given cut-off point. However, there did not appear to be a difference in the relative diagnostic accuracy of FeNO testing in the 2 settings (primary and secondary care), either in comparison with the standard UK care pathway (entire or parts) or in comparison with airway hyper-responsiveness in patients whose asthma was difficult to diagnose. But the large variation in estimates within groups may obscure any true underlying differences in the accuracy of FeNO testing between groups and between different reference standards.\n\n## FeNO testing in population subgroups included in the scope\n\nNo cohort studies were found that provided evidence relating to the subgroups of pregnant women, older people, people who smoke or people exposed to environmental tobacco, and therefore lower levels of evidence were consulted.\n\nFeNO testing appeared to be able to distinguish people with asthma from people without asthma with similar accuracy in people who smoke and people who do not smoke or used to smoke. It seems likely that FeNO levels are generally lower in people who smoke, and it may be useful to consider a person's smoking status when interpreting results, or to select lower cut-off points for people who smoke. Limited data in children support the same conclusion as for adults.\n\nThere is limited and conflicting evidence for the benefit of FeNO testing in older people and, therefore, uncertainty as to whether FeNO testing is useful for diagnosing asthma in the older population.\n\nA cross-sectional study suggested that pregnancy does not alter FeNO levels in women with or without asthma, and that FeNO testing can distinguish between healthy, pregnant women with asthma or without asthma.\n\n# Efficacy of FeNO-guided asthma management\n\nThe External Assessment Group reviewed evidence relating to outcomes in adults, children and subgroups of people as defined in the scope for this assessment. The outcomes included exacerbations, inhaled corticosteroid use and health-related quality of life.\n\n## FeNO-guided asthma management in adults\n\nFour studies (based in the UK, New Zealand, Sweden and the USA) were included in this review. The quality of the 4 studies was assessed according to the Cochrane Library and Centre for Reviews and Dissemination (CRD) handbook. The External Assessment Group indicated that the study with the highest risk of bias was the study by Syk et al. (2013); this was because of the lack of blinding, incomplete outcome data and selective reporting.\n\nAll 4 studies were randomised controlled trials; 2 were single blind (Smith et al. 2005 and Shaw et al. 2007), 1 was open label (Syk et al. 2013) and 1 was described as 'multiply blinded' (Calhoun et al. 2013). There was a high degree of heterogeneity in all aspects of study design across the 4\xa0studies. Three studies did not clearly report which device was used to measure FeNO levels.\n\nThe inclusion criteria, trial protocols and treatment doses varied across the studies. Only 1 study reported using the British guideline on the management of asthma (2012), hereafter referred to as the 'British guideline', in the comparator arm. The number of patients in the trials ranged from 94 to 229, and they were recruited from primary care in 3 studies. For 1 study, it was unclear what setting people were recruited from.\n\nExacerbations were reported in all 4 studies, although definitions varied and results were not always consistent across the studies. However, all 4 studies reported a fall in exacerbation rates per person year, although it appeared that this was mostly driven by mild and moderate exacerbations.\n\nFor severe exacerbations, the Syk et al. (2013) study reported higher rates of oral corticosteroid use in the intervention arm (although the difference was not statistically significant), while the composite outcome of moderate or severe exacerbations favoured the intervention arm. In the other studies, the difference in direction of effect between the outcome for oral corticosteroid use and the composite outcomes that included less severe exacerbations was not evident. Oral corticosteroid use and the composite outcomes of severe and less severe exacerbations decreased in intervention arms, although there was still an apparently greater effect in the composite outcomes. Rate ratios calculated by the External Assessment Group for major/severe exacerbations ranged from 0.79 (95% confidence interval [CI] 0.44 to 1.41) to 1.29 (95% CI 0.51 to 3.30), while rate ratios calculated by the External Assessment Group for composite outcomes of all severity of exacerbation ranged from 0.52 (95% CI 0.30 to 0.91) to 0.63 (95% CI 0.40 to 0.98).\n\nDespite the high level of between-study heterogeneity, an exploratory meta-analysis of the rates of major and severe exacerbations using fixed effects methods was conducted. The result showed no heterogeneity, with an I2 statistic of 0%. The pooled estimate was 0.87 (95% CI 0.64 to 1.19, p=0.38). This indicates that there were fewer major exacerbations in the intervention arm, but the difference did not reach statistical significance.\n\nA sensitivity analysis was done using the results of studies that reported the number of exacerbations resulting in oral corticosteroid use. The pooled risk ratio was 0.90 (95% CI 0.56 to 1.45), indicating a statistically non-significant difference for asthma management with FeNO measurement. However, the External Assessment Group noted that there were only 2 studies in this analysis. Both studies reported non-significant differences, but with risk ratios on opposite sides of the line of no effect. This could suggest that differences in study design, step-up and step-down protocols, and patient characteristics may account for differences in direction of effect.\n\nWhen considering the composite outcome of all exacerbations and failure rates, 3 studies reported composite outcomes that the External Assessment Group considered to be broadly similar and to represent 'treatment failure'. In 2 studies, FeNO‑guided management groups showed numerically, but not statistically significant, lower rates of failure. In the Syk et al. (2013) study, the improvement was statistically significant, with a rate of 0.22 in the intervention arm compared with 0.41 in the control arm (p=0.024). The rate ratio calculated by the External Assessment Group was 0.52 (95% CI 0.30 to 0.91). A meta-analysis of these rates was conducted despite the high level of heterogeneity between study characteristics. The result showed a statistically significant effect, with a rate ratio of 0.58 (95% CI 0.43 to 0.77). This represents a statistically significant effect in favour of using FeNO‑guided management in people with asthma for the composite outcome of all exacerbations and treatment failure rates.\n\nAn additional study (Honkoop et al. 2013) was identified by the External Assessment Group. The study was a randomised controlled trial with a 12‑month follow-up period and dose titration at baseline and every 3\xa0months thereafter. The number of people in the study was larger than in the other 4 studies and they were recruited from primary care. Outcome data were limited because this study was only reported in a conference abstract; however, a non-significant trend towards a reduction in courses of oral prednisolone was reported for the FeNO measurement group compared with the comparator arms. The External Assessment Group performed an additional meta-analysis that included the Honkoop et al. study, calculating the rate ratio for exacerbation as 0.69. Errors could not be calculated for this meta-analysis because the exact numbers of people and events were not reported. Results of the meta-analysis ranged from significant to non-significant in favour of FeNO measurement, depending on the error rate imputed.\n\nAll studies reported some data on inhaled corticosteroid use. Two studies reported inhaled corticosteroid use as a mean per day at the end of the study, with mean differences of −270\xa0micrograms per day (95% CI −112 to −430, p=0.003) and −338\xa0micrograms per day (95% CI −640 to −37\xa0micrograms, p=0.028) respectively, in favour of FeNO‑guided management. The Syk et al. (2013) study showed a small (non-significant) increase in inhaled corticosteroid use in the intervention arm (586\xa0micrograms, standard error [SE] 454; compared with 540\xa0micrograms, SE 317, in the control arm). One study reported means per month, although it is unclear if this was an average over the whole course of the study, or the means for the final month of the study. The means were very similar at 1617\xa0micrograms per month in the intervention arm and 1610\xa0micrograms per month in the control arm.\n\nA meta-analysis used standardised mean difference analysis because outcomes were not reported in a standardised way. This showed an overall effect of −0.24 standard deviations in favour of FeNO‑guided management, although this narrowly missed significance (95% CI −0.56 to 0.07, p=0.13).\n\nTwo studies used versions of the Asthma Quality of Life Questionnaire (AQLQ) to measure quality of life. Both showed no effect in the global score, but 1 investigated domains and found a statistically significant difference in the symptoms score. A meta-analysis of the overall scores showed no effect on quality of life, with a standardised mean of 0.00 (95% CI −0.20 to 0.20).\n\nAll 4 original studies (excluding Honkoop et al. 2013) reported data for asthma control. In 3 studies, asthma control did not change but in the Syk et al. (2013) study there was a statistically significant increase in asthma control between the 2 trial arms. Two studies (Smith et al. 2005 and Calhoun et al. 2012) reported no significant difference between groups for bronchodilator use. Syk et al. did not report the significance of the difference between the 2 arms, reporting a median of 1.56 (interquartile range [IQR] 0.06 to 5.18) uses per week in the intervention arm, and a median of 0.94 (IQR 0.03 to 2.81) in the control arm. No asthma-related adverse events or deaths were reported.\n\n## FeNO-guided asthma management in children\n\nFive studies (based in Austria, the USA, Italy, the Netherlands and Australia) that included children (plus adolescents and young adults) and compared FeNO‑guided management with non-FeNO‑guided management were identified. The quality of the studies was assessed according to criteria proposed in the Cochrane Handbook and CRD Handbook. The study quality varied; no single study scored well in every item, and no item scored well in every study.\n\nThere was a high degree of heterogeneity in all aspects of study design across 4 studies. No study reported using the British guideline in the comparator arm. Two studies included patients who appeared to be poorly controlled. One study included patients who had mild to moderate persistent asthma and 1 study included patients who had received a stable dose of inhaled corticosteroids for the previous 3\xa0months, suggesting that their asthma was reasonably well controlled.\n\nAll 5 studies reported some data on asthma exacerbations, although the definition of exacerbation was unclear in some cases. Two studies reported severe exacerbations in a way that allowed calculation of rates per person year. Both had lower rates in the intervention arm. In patients with uncontrolled asthma, the rate was 0.746 in the intervention arm and 0.950 in the control arm. In patients who had been on a stable dose of inhaled corticosteroids for 3\xa0months, the rate was 0.21 in the intervention arm and 0.39 in the control arm. Both rates were calculated by the External Assessment Group and the statistical significance is unclear.\n\nFor all definitions of exacerbations, 4 studies reported outcomes that were not defined as either major or minor and had different definitions to each another. All the studies showed a trend in favour of fewer exacerbations in the intervention arm. The only study to report a significant between-group difference was a conference abstract, which showed that exacerbations (not clearly defined) occurred in 6 of the 31 patients in the intervention group (19.4%) and 15 of 32 in the control group (46.9%, p=0.021).\n\nOverall, results showed that inhaled corticosteroid use increased in the intervention group compared with the comparator group, although there was variability between the studies. These differences could be attributed to the specifics of the step-up and step-down protocols or the characteristics of the patients selected. The 2 studies that included children whose asthma was hard-to-treat or uncontrolled (Szefler et al. 2009 and Fritsch et al. 2006) saw an increase in inhaled corticosteroid use, while the studies that did not include children with these characteristics saw no significant increase.\n\nHealth-related quality of life was only reported in 1 study in abstract form and using an unknown tool. The External Assessment Group was not able to draw a definite conclusion from these data. Four studies provided some data on asthma control, none of which demonstrated any statistically significant effects favouring either intervention or control. With respect to additional medication use, 3 studies provided data, but there did not appear to be a clear direction of effect within the data.\n\nOne study reported no difference in adverse events between groups and there were no deaths reported. The adverse events listed included gastrointestinal disorders, haematological disorders, infections, musculoskeletal symptoms and skin symptoms.\n\n# Cost effectiveness\n\nThe economic analysis done by the External Assessment Group compared the cost effectiveness of measuring FeNO using NIOX MINO, NIOX VERO and NObreath with current standard tests for diagnosing and managing asthma in England and Wales.\n\n## Review of existing economic analyses\n\nThe External Assessment Group did a review to identify existing economic analyses of FeNO testing and measurement (using NIOX MINO, NIOX VERO or NObreath) for diagnosing and managing asthma respectively. The review also sought to identify existing models and potentially relevant evidence sources to inform parameter values within the de\xa0novo economic models developed by the External Assessment Group.\n\nOnly 1 published UK cost-effectiveness model was identified for asthma diagnosis, and 1 for asthma management. Modified versions of these models were provided to NICE by the manufacturer of NIOX MINO and NIOX VERO. The wider review identified several economic analyses that the External Assessment Group described as including various methodological problems, questionable assumptions and weak evidence.\n\n## De novo cost-effectiveness model\n\nThe External Assessment Group developed 2 de novo models: 1 to assess the expected cost effectiveness of measuring FeNO in addition to, or in place of, standard tests for diagnosing asthma (the diagnostic model) and 1 to assess the expected cost effectiveness of FeNO plus the British guideline compared with the British guideline alone for managing people with diagnosed asthma (the management model). The 2 models, although distinct, shared several parameter values and assumptions.\n\nThe diagnostic model was structured in the form of a decision tree. The decision tree model was used to estimate the probability that a person with asthma will be correctly diagnosed (true positive) or incorrectly diagnosed (false negative); and the probability that a person without asthma will be correctly diagnosed (true negative) or incorrectly diagnosed (false positive) and the expected health outcomes and costs arising from this. The management model was in the form of a simple Markov model with 2 states: alive with diagnosed asthma and dead.\n\nEstimates of test accuracy for measuring FeNO were drawn from several separate studies based on the results of the systematic review for clinical effectiveness, while estimates of test accuracy for comparator tests were drawn from best available evidence. The economic analyses included estimates of the sensitivity and specificity of individual tests as well as combinations of FeNO devices plus other standard tests. One study (Schneider et al. 2013) that used the NIOX MINO device was used to inform estimates of the sensitivity and specificity of FeNO alone. The true pre-test probability of asthma in undiagnosed patients was estimated as a weighted mean of several cases of asthma and non-asthma in the studies used, to inform the diagnostic test accuracy parameters. Across the included studies, 412 of 881 patients were diagnosed with asthma (p=0.47).\n\nHealth-related quality of life values for people without asthma were estimated using a general population EQ‑5D regression model. The values were common to all diagnostic comparator groups and did not therefore have any effect on the estimates of incremental health gain for the diagnostic tests included in the economic analysis. The disutility associated with asthma, estimated to be −0.0463, was taken from the catalogue of EQ‑5D values reported by Sullivan et al. (2011). It was noted that this disutility was applied to all patients with asthma and to those who tested false positive (until their misdiagnosis was corrected). This disutility is unlikely to fully reflect health losses associated with the delayed diagnosis of more serious pathology, such as cancer or tuberculosis. The disutility associated with poor asthma control was derived from a study (McTaggart-Cowan et al. 2008) that reported EQ‑5D estimates for 4 health states: 'very well controlled', 'well controlled', 'adequately controlled' and 'not controlled'. EQ‑5D estimates ranged from 0.90 for 'very well controlled' to 0.80 for 'not controlled'.\n\nThe External Assessment Group assumed that the health loss associated with poor control because of a false-negative diagnosis related to the difference between the 'well-controlled' state and the 'not-controlled' state (mean disutility of −0.04). This disutility was applied to all false-negatives until the misdiagnosis was corrected.\n\nBecause of the lack of empirical evidence relating to the time needed to resolve incorrect diagnoses, the External Assessment Group attempted to elicit these values from clinical specialists. Based on the response received, the External Assessment Group assumed that the time to resolve a false-negative diagnosis has a mean of 8\xa0months (95% CI 4 to 12\xa0months) and the time to resolve a false-positive diagnosis has a mean of 18\xa0months (95% CI 12 to 24\xa0months). The External Assessment Group considered these estimates to be highly uncertain and tested them in sensitivity analyses.\n\nThe following costs were used to inform the diagnostic and management models:\n\nTest costs: the marginal per-test costs for all 3 devices were calculated based on information provided by the manufacturers. The calculation was complicated by the fact that the devices each have different lifetimes, and that test kits and mouthpieces for each device are available at lower marginal costs if higher volumes of kits are purchased. These marginal per-test costs do not include any costs associated with education and training for NHS staff to use the devices.\n\nMaintenance costs: the External Assessment Group assumed that the manufacturer provides the maintenance of NObreath free of charge to the NHS. The External Assessment Group assumed zero maintenance costs for NIOX MINO and NIOX VERO.\n\nPrimary care costs: the External Assessment Group assumed that spirometry, reversibility testing and measuring FeNO can be done in primary care and would need 2 GP visits and 1 nurse visit. The unit cost of a GP visit was based on published economic analyses that used an estimate of £43 (based on an appointment of 11.7\xa0minutes, and including direct staff costs and qualifications). The cost of a GP practice nurse visit was assumed to be £13.69 (based on a visit of 15.5\xa0minutes). For the management model, the External Assessment Group assumed that measuring FeNO would be done during routine GP visits and would need an additional nurse visit once every 3\xa0months. The marginal cost of measuring FeNO was applied as the per-test cost plus the cost of a primary care nurse appointment.\n\nSecondary care costs: the External Assessment Group assumed that sputum induction and airway hyper-responsiveness (methacholine challenge test) would be done in secondary care and would need 2 secondary care visits, 1 laboratory visit and an initial GP visit for referral. Secondary care attendance costs were based on the Healthcare Resource Group for respiratory medicine attendances (£204.29). The cost of a laboratory visit was based on the Healthcare Resource Group for simple bronchodilator studies (£203.29). The External Assessment Group assumed the standard errors around these estimates were normally distributed, with a standard error equal to 15% of the mean.\n\nCosts of asthma management: estimates of the annual cost of combined inhalers were derived from 2 previous health technology assessment reports. For children, the least expensive annual cost for combined inhalers was estimated to be £201. For adults, the least expensive annual cost of the inhalers was estimated to be £231.\n\nCosts associated with resolving misdiagnoses: the assumption was made that 1 additional primary care attendance, 2 additional secondary care attendances and 1 laboratory visit would be needed to correctly diagnose false-positive and false-negative results. This same assumption was made in previously published models.\n\nCosts associated with loss of control for false-negatives: the External Assessment Group assumed that people who were falsely diagnosed as not having asthma would experience 1 exacerbation in each year they remain misdiagnosed. The model assumed that a proportion of these exacerbations would need hospitalisation.\n\nThe following costs were used to inform the management model alone:\n\nAdditional costs of FeNO measurement: The External Assessment Group assumed that FeNO measurement would be done during routine GP visits and would require 1 additional nurse visit every 3\xa0months.\n\nCosts of managing exacerbations: the External Assessment Group assumed that a proportion of exacerbations would need hospitalisation while the remainder could be managed in primary care. It also assumed that severe exacerbations that do not need hospitalisation would need 1 GP attendance (£43.00) plus oral corticosteroids for 5\xa0days (£1.73) based on an earlier health technology assessment report. The cost of asthma hospitalisation was derived from current NHS Reference Costs (£1266.72).\n\n## Base-case results\n\nThe base-case model was evaluated probabilistically using Monte Carlo sampling techniques. Deterministic one-way sensitivity analyses were also performed to account for different modelling assumptions. Central estimates of cost effectiveness were presented as incremental cost-effectiveness ratios (ICERs). Uncertainty surrounding the cost-effectiveness estimates was presented using cost-effectiveness planes and cost-effectiveness acceptability curves.\n\nThe base-case results of the diagnostic model in children and adults suggested that, across the 17 diagnostic options included in the economic analysis, the expected difference in quality-adjusted life years (QALYs) is likely to be small (4.2686–4.2834). They also suggested that airway hyper-responsiveness (methacholine challenge test) is expected to produce the greatest QALY gain (4.2834), followed by FeNO testing (either NObreath, NIOX VERO or NIOX MINO) plus bronchodilator reversibility, with a QALY of 4.2829. The difference between the QALYs produced by the methacholine challenge test and FeNO testing plus a bronchodilator was very small (0.0005 QALYs). Other diagnostic test options, either with or without FeNO testing, resulted in increasingly lower QALYS, with spirometry (forced expiratory volume in the first second divided by the total volume of air that a person can forcibly exhale in 1 breath) producing the lowest QALY gain of 4.2686.\n\nThe External Assessment Group presented an incremental cost-effectiveness analysis, in which the diagnostic options were ranked in decreasing order of QALY. The ICER for airway hyper-responsiveness (methacholine challenge test) compared with the next best option in terms of QALY (NObreath plus bronchodilator reversibility) was approximately £1.125 million per QALY gained. Following methacholine challenge, the option producing the next best QALY (FeNO testing plus bronchodilator reversibility) yielded 4.2829 QALYs, but the cost associated with the individual tests varied (£686.08 for NObreath, £687.61 for NIOX VERO and £688.33 for NIOX MINO). FeNO testing plus bronchodilator reversibility is therefore cost saving compared with methacholine challenge, but is estimated to produce marginally fewer QALYs (see section\xa05.62). All further options, with or without FeNO testing, were dominated because they were both more expensive and produced fewer QALYs. The External Assessment Group considered these results to be very uncertain.\n\nThe base-case results for asthma management in children suggested that the British guideline plus FeNO measurement produces a small health benefit (0.05 QALYs) compared with the British guideline alone. The British guideline plus FeNO measurement was also more costly (£8148.59 for the British guideline plus NObreath, £8314.30 for the British guideline plus NIOX VERO and £8391.53 for the British guideline plus NIOX MINO) than the British guideline alone (£5860.06) because of projected inhaled corticosteroid use for the FeNO measurement groups. The resulting ICER for NObreath plus the British guideline compared with the British guideline alone was £45,213 per QALY gained. NIOX VERO and NIOX MINO were expected to be dominated by NObreath because of their higher marginal per-test costs.\n\nThe base-case results for asthma management in adults showed that the British guideline plus FeNO measurement is expected to produce a small health benefit (0.04 QALYs) compared with the British guideline alone. The British guideline plus FeNO measurement was also more costly in adults (£7377.61 for the British guideline plus NObreath, £7535.43 for the British guideline plus NIOX VERO and £7608.99 for the British guideline plus NIOX MINO) than the British guideline alone (£7296.30) because of increased inhaled corticosteroid use in the FeNO measurement groups during the first 12\xa0months of monitoring. Similarly to the children's model for asthma management, the model assumed that all 3 FeNO devices produce the same health benefits. NIOX MINO and NIOX VERO were dominated by NObreath because of their higher marginal per-test costs. The ICER of the British guideline plus NObreath compared with the British guideline alone was approximately £2146 per QALY gained. If dominance was ignored, the ICERs for the British guideline plus the NIOX devices, compared with the British guideline alone, were £6310 per QALY gained for NIOX VERO and £8250 per QALY gained for NIOX MINO.\n\n## Sensitivity analysis results\n\nThe External Assessment Group carried our several deterministic sensitivity analyses for the diagnostic and management models.\n\nFor the diagnostic model, results of the deterministic sensitivity analyses indicated that the cost-effectiveness frontier presented in the base-case analysis was maintained across most scenarios. In most scenarios, most options were expected to be ruled out because of simple dominance. The results based on the point estimates of parameters were similar to the results of the probabilistic analysis, and discounting did not have a substantial effect on the cost effectiveness of the non-dominated diagnostic options.\n\nOther indications from the results of the sensitivity analysis showed that the costs of the various FeNO devices influenced which options were dominated, but had only a negligible impact on the cost-effectiveness results for non-dominated options. Longer misdiagnosis correction times substantially improved the cost effectiveness of airway hyper-responsiveness (methacholine challenge test) compared with FeNO testing plus bronchodilator reversibility, with the lowest ICER being £126,982 per QALY gained when time to correct diagnosis was extended 10-fold.\n\nIn terms of diagnostic accuracy, the results of the sensitivity analyses showed that the use of other sources for the operating characteristics of FeNO testing and standard tests did not impact on the cost effectiveness of non-dominated options. Also, the use of a rule‑out decision approach may have improved the comparative effectiveness and cost effectiveness of FeNO testing alone.\n\nFor the management model in children, the results of the sensitivity analyses indicated that NIOX MINO and NIOX VERO were expected to be consistently dominated by NObreath because of their higher marginal per-test cost. In addition, while the marginal per-test cost influenced which device would be preferred, it did not have a substantial impact on the overall cost effectiveness of the British guideline plus FeNO measurement compared with the British guideline alone.\n\nThe results of the sensitivity analyses indicated that the length of time FeNO measurement was assumed to impact on exacerbations and inhaled corticosteroid use was a key source of uncertainty within the children's model. Shorter impact times improved the cost effectiveness of FeNO measurement. The British guideline plus FeNO measurement dominated the British guideline alone when it was assumed that the impact of FeNO‑guided management on exacerbations and inhaled corticosteroid use was reduced to 1–4\xa0years, whereas assumptions for 5\xa0years and 10\xa0years produced ICERs of £7598 and £27,660 per QALY gained respectively.\n\nWhen alternative sources of exacerbation rates and inhaled corticosteroid use for children were explored, the ICERs for managing children changed considerably. The sensitivity analysis used values from the Pijnenburg et al. (2005) study, rather than the Szefler et al. (2008) study used in the base case, in which exacerbation rates were 0.18 for the British guideline plus FeNO measurement and 0.39 for the British guideline alone, and relative corticosteroid dose intensity beyond the first year was 1.23 for the British guideline plus FeNO measurement and 1.22 for the British guideline alone. The analysis based on Pijnenburg et al. suggested a considerably more favourable ICER for the British guideline plus FeNO measurement compared with the British guideline alone in children (£18,963 per QALY gained). The External Assessment Group noted that the Szefler et al. study included patients with uncontrolled asthma and the study protocol did not allow therapy to be stepped down on the basis of low FeNO levels alone. This may, in part, explain why inhaled corticosteroid use was higher for the British guideline plus FeNO measurement than for the British guideline alone.\n\nThe results of the sensitivity analyses for managing children also indicated that the model was sensitive to the rate of exacerbations and the associated health loss. When exacerbation rates were doubled, the ICER for the British guideline plus FeNO measurement compared with the British guideline alone was £19,891 per QALY gained. When exacerbation rates were halved, the ICER was £95,632 per QALY gained. When the exacerbation disutility was doubled the ICER was £31,479 per QALY gained and £52,844 per QALY gained when halved.\n\nResults for the deterministic sensitivity analyses for the management model in adults showed that the model was highly sensitive to the exacerbation rates used. Exacerbation rates from Syk et al. (2013) increased the ICER to £184,000 per QALY gained for the British guideline plus FeNO measurement compared with the British guideline alone. When exacerbation rates from Syk et al. were used, the British guideline alone dominated the British guideline plus FeNO measurement. In addition, NIOX MINO and NIOX VERO were expected to be consistently dominated by NObreath because of their higher marginal per-test cost. However, while the marginal per-test cost influenced which device would be preferred, it did not have a substantial impact on the overall cost effectiveness of FeNO measurement compared with the British guideline.\n\nAnother observation from the sensitivity analyses of the management in the adult model was that the length of time that FeNO measurement was assumed to impact on exacerbations and the use of inhaled corticosteroids was a key driver of cost effectiveness. In the adult model, the cost effectiveness improved when the duration of impact of FeNO measurement was extended (£885,451 per QALY gained when 1\xa0years' duration was assumed, to £8898 per QALY gained when 40\xa0years' duration was assumed). The opposite was true in the children's model in which cost effectiveness worsened when the duration of effect on exacerbations and inhaled corticosteroid use was increased (see section\xa05.71). The External Assessment Group stated that this was driven entirely by the observed differences in relative inhaled corticosteroid use at the last observed time point in the trials.", 'Considerations': "The Diagnostics Advisory Committee reviewed the evidence available on the clinical and cost effectiveness of measuring fractional exhaled nitric oxide (FeNO) to inform the diagnosis and management of asthma in children and adults. The Committee considered the report produced by the External Assessment Group and statements from patient experts on the Committee and from clinical specialists who acted as specialist Committee members on this assessment.\n\nThe Committee considered whether NIOX MINO, NIOX VERO and NObreath could be considered equivalent for the purpose of this assessment. It noted the review by the External Assessment Group, which indicated that, although some differences were observed in test results, there was generally a good correlation with results from other chemiluminescence devices. The Committee noted that there appeared to be poorer equivalence between devices in some circumstances, such as at higher FeNO levels, and that the direction of disagreement varied between studies and devices. However, the Committee acknowledged that there is no commonly accepted definition of clinically acceptable differences in FeNO measurements. The Committee concluded that, based on the available evidence, the 3 devices could, on balance, be considered to be broadly equivalent. The Committee also thought that standardisation of FeNO devices should be encouraged.\n\nThe Committee considered whether very young children would be able to perform the test. It heard from both manufacturers that the minimum recommended age for using FeNO monitoring devices is 5 years. The Committee also noted that the External Assessment Group's systematic review only included studies of children 5 years and older, in line with the review protocol. The Committee concluded that there was insufficient evidence to determine the suitability of FeNO testing for children younger than 5 years.\n\nThe Committee discussed the lack of gold standard for asthma diagnosis. It heard from the clinical specialists that there is no single clinical definition of asthma and that the diagnosis is based on multiple factors, including the presence of symptoms and evidence of airway obstruction. It heard that high FeNO levels in people with symptoms suggestive of asthma, such as coughing and wheezing, may indicate that the patient has eosinophilic asthma, which may be treated with inhaled corticosteroids. However, FeNO levels are not raised in all patients with asthma and, conversely, not all people with raised FeNO levels have asthma. The Committee further heard from a clinical specialist that, although it is generally accepted that FeNO levels correlate with eosinophilic airway inflammation, this effect may be stronger in some groups of patients than others and that there are other causes of inflammation. The Committee also heard that clinical practice varies and so the use of standard clinical practice as a reference standard is problematic. The Committee therefore concluded that the lack of gold standard for diagnosis, the complexity of diagnosis and the variation in clinical practice introduced an increased uncertainty in the assessment of the clinical validity of FeNO devices.\n\nThe Committee considered the diagnostic accuracy of FeNO testing. The Committee noted that the External Assessment Group had presented accuracy data for both children and adults against various reference standards and in different positions in the diagnostic pathway. It acknowledged that, because of the clinical heterogeneity of the data, a meta-analysis had not been performed and that estimates of specificity and sensitivity varied between studies. Overall, the Committee accepted the External Assessment Group's observation that the ranges of specificity were generally narrower than those for sensitivity, and that FeNO testing appeared to have a higher specificity than sensitivity. It heard from the clinical specialists that higher specificity would indicate that testing would be of greater use as a rule‑in test; that is, patients testing positive are assumed to have asthma and patients testing negative have further tests for asthma. The Committee considered that the absence of a meta-analysis of accuracy meant that there was a greater uncertainty about the accuracy of FeNO devices in this assessment. Nevertheless, it was satisfied that the specificity of the devices was acceptable if they are used in a rule‑in scenario.\n\nThe Committee considered FeNO cut-off values for guiding diagnosis of asthma in adults and children. The Committee heard from the External Assessment Group that cut-offs were generally not interchangeable between the FeNO devices, and that there appeared to be a high degree of heterogeneity between the studies. The Committee also heard from a clinical specialist that, in their experience, the devices generally produce different readings when used by the same patient. However, the differences appeared to be consistent. The Committee noted that the highest sum of sensitivity and specificity was obtained when the cut-offs ranged from 19–21 parts per billion (ppb) in children and the highest sum of sensitivity and specificity was wider for adults (20–47\xa0ppb). The Committee further noted that a higher cut-off was needed to optimise the specificity of the devices; a cut-off between 47\xa0ppb and 76\xa0ppb resulted in specificity of 88–100% in adults and a cut-off range of 30\xa0ppb to 50\xa0ppb resulted in specificity of 92–100% in children. The Committee was informed by clinical experts that cut-off values in the higher range would be preferred to reduce the rate of indeterminate results, and that the test could be used to rule in a diagnosis of asthma in people whose test is positive. The Committee concluded that cut-off values in the higher ranges should generally be used, and that cut-off values should be lower in children than adults.\n\nThe Committee considered the generalisability of the clinical evidence to the whole population both for diagnosing and managing asthma. The Committee acknowledged that the clinical evidence was heterogeneous in terms of clinical characteristics and results, and that studies were identified based on their similarity to UK practice and similarity to the subgroups of interest as defined in the protocol (that is, in people in whom the condition is difficult to diagnose, or the wider population of people presenting with symptoms of asthma). As such, no single study can be generalised to the whole population. The Committee therefore concluded that both the variation in UK clinical practice and the heterogeneity of studies included in the assessment would increase the uncertainty around the clinical benefits of measuring FeNO.\n\nThe Committee discussed the clinical evidence on the use of FeNO to guide asthma management in adults. The Committee noted that there was a statistically significant reduction in the meta-analysis for the composite outcome of any severity of exacerbations when FeNO measurement was used to guide management compared with treatment without FeNO measurement during the first 12\xa0months of management. However, it acknowledged that the results from the individual studies were heterogeneous and that the meta-analysis did indicate a non-significant trend towards reduction in severe exacerbation rates. The Committee noted that the meta-analysis also showed a non-significant trend towards decreased inhaled corticosteroid use and considered that the effects of FeNO measurement on inhaled corticosteroid use were uncertain. It further noted that step-up and step-down protocols for inhaled corticosteroid use varied between studies and the effect of this on the outcomes was not known. The Committee concluded that FeNO‑guided management was likely to reduce exacerbation rates in adults, but the extent and duration of this effect was uncertain.\n\nThe Committee discussed the additional meta-analysis, performed by the External Assessment Group, which incorporated the more recent Honkoop et al. study (2013). It recognised that the addition of this study provided some further support that severe exacerbations could be reduced when FeNO measurement was added to asthma management. However, because the External Assessment Group had been unable to calculate accurate error rates for outcomes, the Committee was still uncertain whether this effect was statistically significant. The Committee therefore concluded that the Honkoop et al. study appeared to lend weight to the assumption that FeNO‑guided management was effective, but was unable to establish whether this was statistically significant.\n\nThe Committee then discussed the clinical results for FeNO‑guided management in children with asthma. As with the studies in adults, those in children appeared to have variations in design, including in the step-up and step-down protocols, medications and inclusion criteria. The Committee noted that all studies reported a decrease in exacerbations in the intervention arm, but only 1 reported a statistically significant reduction. It also noted that there was a greater uncertainty around whether inhaled corticosteroid use went up or down when FeNO measurement was added to asthma management. On balance, the Committee concluded that FeNO‑guided management in children is likely to result in reduced exacerbation rates, but that the extent and duration of this effect is still uncertain. The Committee further concluded that the effect of FeNO‑guided management on inhaled corticosteroid use is uncertain and recommended that further evidence is generated to establish its benefits.\n\nThe Committee discussed the role of measuring FeNO in diagnosing and managing asthma in children and adults. It heard from the clinical specialists that diagnosis of asthma needs consideration of many different elements, including symptoms, response to treatment and physiological testing. Given the complexities of diagnosis, the Committee considered that FeNO testing would not be able to replace current practice for diagnosis. The Committee concluded that measuring FeNO had not been shown to be able to reliably replace other tests and clinical observations, and therefore should be used as an add‑on to current clinical diagnosis and management in people with asthma.\n\nThe Committee discussed the additional benefits of measuring FeNO in the diagnosis and management of asthma. It heard from a patient expert that an accurate diagnosis of asthma can sometimes take many years, resulting in less than optimal treatment, which can have a direct impact on health. The Committee also heard from a patient expert that FeNO‑guided management could result in patients better understanding their own condition and disease progression, which could reduce hospitalisations and improve patient experience. The Committee also considered the effect that measuring FeNO could have on adherence to medication. The Committee was informed by a clinical specialist that approximately 30% of people do not take their medication as prescribed. The clinical specialist indicated that studies have shown that FeNO is a useful marker for medicine adherence and that FeNO devices could be a useful tool for doctors to improve concordance, by which the patient and clinicians make decisions together about the treatment. The Committee concluded that FeNO testing could potentially enable patients and doctors to improve treatment concordance in patients who are on medications for asthma.\n\nThe Committee considered the areas of uncertainty in the economic models produced by the External Assessment Group for diagnosing and managing asthma. The Committee noted that the diagnostic models were sensitive to: assumptions about the length of time needed to resolve misdiagnoses; assumptions about health losses incurred by patients who have false-negative results; the costs of asthma management; and the use of rule‑in and rule‑out diagnostic decision rules. The Committee considered the assumptions made in the management model, in which it noted that the results in both the children and adult subgroups were particularly sensitive to: assumptions about changes in inhaled corticosteroid use over time; the annual number of nurse visits for FeNO measurement; and the length of time FeNO measurement was assumed to impact on exacerbation rates and inhaled corticosteroid use. The Committee concluded that both models for diagnosis and management were subject to considerable uncertainty, and therefore the results should be interpreted with caution.\n\nThe Committee discussed the results from the base-case analysis for the use of FeNO testing in diagnosis. It noted that, although the methacholine challenge test produced the most quality-adjusted life years (QALYs), the incremental cost-effectiveness ratio (ICER) was very high at £1.25 million per QALY gained when compared with FeNO testing plus bronchodilator reversibility. The Committee also noted that the difference in the health benefit for methacholine challenge test compared with FeNO testing plus bronchodilator reversibility was estimated to be very small (0.0005 QALYs) and that costs were considerably lower for FeNO testing plus bronchodilator reversibility. Given that FeNO testing plus bronchodilator reversibility dominated the other tests, the Committee concluded that FeNO testing plus bronchodilator reversibility testing in adults and children delivered equal or greater QALYs at a lower ICER than other tests. Moreover, the Committee noted that the use of FeNO testing in conjunction with existing tests is more cost-effective than when the existing tests are used alone. The Committee therefore recommended FeNO testing as an option to help diagnose asthma in adults and children who, after initial clinical examination, are considered to have an intermediate probability of having asthma and where FeNO testing is intended to be done in combination with other diagnostic options according to the British guideline on the management of asthma (2012).\n\nThe Committee then discussed the results from the base-case analysis for asthma management in children. It noted that, for base-case results, the External Assessment Group had used 2 studies, Szefler et al. (2008) and Pijnenburg et al. (2005), to inform the clinical effectiveness, and the ICER was £45,200 per QALY gained. The Committee then discussed the sensitivity analyses for management in children and noted that, when the analysis was based on Pijnenburg et al., a more favourable ICER of £19,000 per QALY gained was obtained. It also noted that, when it was assumed that FeNO measurement impacts for a shorter length of time on exacerbations and inhaled corticosteroid use, FeNO measurement plus management as recommended in the British guideline on the management of asthma (2012), hereafter referred to as the 'British guideline', dominated management by the British guideline use alone for up to 4\xa0years. It also noted that the ICER was £7600 per QALY gained for 5\xa0years and £27,700 per QALY gained for 10\xa0years. The Committee assumed that shorter duration of up to 10\xa0years, rather than lifetime duration, was a more reasonable assumption, given that children would not be expected to remain in the child-model for the rest of their lifetime. Moreover, the Committee heard from the External Assessment Group that the Szefler et al. study included patients with uncontrolled asthma, and the study protocol did not allow therapy to be stepped down on the basis of low FeNO levels. The Committee considered that, in clinical practice, it was unlikely that the assumption of higher inhaled corticosteroid use throughout the time horizon with FeNO measurement would be seen, and therefore preferred the sensitivity analysis based on the Pijnenburg et al. study over the base-case analysis. Considering the combined shorter duration of impact of FeNO measurement and analysis based on the Pijnenburg et al. study, the Committee concluded that the most plausible ICER for management in children was likely to be lower than £19,000 per QALY gained.\n\nThe Committee discussed the results from the base-case analysis for asthma management in adults. It noted that the ICER for FeNO measurement plus the British guideline compared with the British guideline alone was £2100 per QALY gained. The Committee considered that, although there were uncertainties relating to this estimate, this ICER was low and therefore the use of FeNO measurement for asthma management in adults was likely to be cost effective. The Committee therefore accepted the base-case results for adults.\n\nThe Committee then discussed its recommendation for the use of FeNO measurement in asthma management in children and adults. The Committee heard from clinical specialists that there was considerable uncertainty around the use of stepping-up and stepping-down protocols for inhaled corticosteroid use, and that the External Assessment Groups' review had not conclusively demonstrated that FeNO measurement would be effective and safe for guiding the stepping down of inhaled corticosteroids. The Committee expressed concerns about using FeNO measurement as a basis for stepping-down treatment and was not satisfied that the evidence was robust enough to show that the benefits out-weighed the potential harms of under treatment. The Committee therefore concluded that FeNO measurement should not be recommended to help with stepping down inhaled corticosteroid use in adults or children whose asthma is well managed. However, it considered FeNO measurement to be cost and clinically effective when used as an option to support symptomatic asthma management in people using inhaled corticosteroids.\n\nThe Committee discussed the evidence in the subgroups defined in the scope for this assessment, (pregnant women, older people, people who smoke and those who have been exposed to tobacco smoke). The Committee heard from the External Assessment Group that there is little robust evidence for most of these groups (study designs were generally of lower quality), which could lead to biased results. It noted that randomised controlled trial evidence shows that measuring FeNO is at least as useful during pregnancy as it is for the general population, but it appears likely that FeNO is a less reliable indicator of airway inflammation in older people. The Committee therefore concluded that, in view of the limited evidence, it was unable to provide any specific recommendations for the subgroups defined in the scope.", 'Recommendations for further research': 'The Committee discussed the potential for future research. The Committee accepted that there is a need to further establish the accuracy of current practice in diagnosing asthma and the incremental accuracy associated with the addition of FeNO testing.\n\nThe Committee also considered the role of FeNO measurement in asthma management. It accepted that currently available evidence on the use of FeNO measurement in asthma management is unclear on whether benefits of treatment are maintained long-term. The Committee concluded that long-term studies following patients for several years could address this gap.\n\nThe Committee also considered the role of FeNO in guiding inhaled corticosteroid dosing through stepping-up and stepping-down protocols. It accepted there is a need for more evidence on which protocols offer the safest and most optimal asthma management when used in UK clinical practice. Therefore, further studies are recommended, with consideration for the different protocols and cut-off points that may be necessary in different populations.'}	https://www.nice.org.uk/guidance/dg12	Evidence-based recommendations on NIOX MINO, NIOX VERO and NObreath for measuring the amount of exhaled nitric oxide (FeNO) in the breath to help diagnose asthma.
1d26c49e50977655e5df5d3aacda1738ba462316	nice	Transoral carbon dioxide laser surgery for primary treatment of oropharyngeal malignancy	Transoral carbon dioxide laser surgery for primary treatment of oropharyngeal malignancy # Recommendations Current evidence on the efficacy and safety of transoral carbon dioxide laser surgery for the primary treatment of oropharyngeal malignancy is adequate to support the use of this procedure with normal arrangements for clinical governance, consent and audit. This procedure should only be carried out by clinicians who have been trained in the use of transoral carbon dioxide laser surgery in the oropharynx. Patient selection for this procedure should be done by a multidisciplinary team in accordance with the NICE cancer service guidance on improving outcomes in head and neck cancers (CSGNH 2004). Clinicians should enter details of all patients undergoing transoral carbon dioxide laser surgery for the primary treatment of oropharyngeal malignancy onto the Data for Head and Neck Oncology (DAHNO) database.# Indications and current treatments Malignancies in the oropharynx (which includes the tonsils, the base of the tongue and the soft palate) are usually squamous cell carcinomas originating in the epithelial cell lining. The incidence of these malignancies has increased significantly in younger patients, probably because of the increased prevalence of human papillomavirus infection. Presenting features include a persistent sore throat, a lesion in the mouth or throat, white or red patches that may be swollen or bleeding, and pain in the ear. Patients tend to present with advanced or sometimes metastatic disease. Oropharyngeal malignancies can be treated by surgery (using open or minimally invasive approaches for tumour resection and reconstruction), radiotherapy, chemotherapy, or a combination of these methods. Surgical resection may include neck dissection to remove lymph nodes. When the malignancy is considered to be unresectable, palliative chemotherapy and radiotherapy can be used.# The procedure Transoral carbon dioxide laser surgery is a minimally invasive endoscopic approach for treating tumours in the oropharynx. It is usually performed under general anaesthesia, with the patient supine and tilted head-down. The tumours are visualised using a modified mouth gag and/or an endoscope. The carbon dioxide laser device is coupled to an operating microscope and the laser beam is used to excise the tumour completely, together with an adequate margin of tissue around it. Large tumours are removed in 2 or more pieces as a multiblock resection. Fibre-optic carbon dioxide lasers, flexible delivery systems and robots have been developed, all of which increase the range of angles of approach that can be used to achieve tumour resection. Laser resection of tumours is sometimes combined with either simultaneous or staged neck dissection if there is cervical lymphadenopathy or a suspicion of occult metastases. Adjuvant radiotherapy and/or chemotherapy is also offered to some patients, based on a number of factors such as T-stage, nodal status, extracapsular spread of tumour, margin status and histology.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A retrospective comparative case series of 223 patients with T1 oropharyngeal carcinoma treated by transoral carbon dioxide laser surgery (TLS) with or without neck dissection (±ND) (n=53) or by electrocautery (n=170) reported that there was no significant difference in 5-year disease‑specific survival (89% for TLS±ND and 87% for electrocautery; p>0.05). A prospective case series of 204 patients (of whom 203 were analysed) with stage III or IV oropharyngeal cancers treated by TLS±ND alone (53 patients) or by TLS±ND and combined adjuvant treatment (150 patients: 117 radiotherapy alone, 33 chemoradiotherapy) reported that rates of 5-year overall survival, disease-specific survival and disease-free survival were 78%, 84% and 74% respectively across all groups. TLS combined with postoperative adjuvant radiotherapy (in 117/204 patients) reduced the risk of death by over 50% (hazard ratio 0.33 to 0.48) compared against the risk of death in the group who received TLS±ND alone (53/204 patients). The retrospective comparative case series of 223 patients reported a 5-year local control rate of 95% for TLS±ND and 91% for electrocautery (p>0.05; not significant). The retrospective case series of 69 patients reported that 4% (3/69) of patients had disease recurrence at the primary site at a mean follow-up of 44 months. The 5-year local regional control rate in patients in whom adjuvant therapy was not indicated was 82%. The 5-year local regional control rate in patients who declined adjuvant therapy was 74%. The specialist advisers listed key efficacy outcomes as local control, survival, margin control and local recurrence.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Bleeding within the first 7 days after the procedure was reported in 10% (5/48) of patients in a retrospective case series of 48 patients with squamous cell carcinoma of the base of the tongue treated by transoral carbon dioxide laser surgery with or without neck dissection (TLS±ND) and adjuvant radiotherapy. The bleeding was from a vessel at the base of the tongue in 1 patient, at the lateral oropharyngeal wall in 1 patient, at the aryepiglottic fold in 1 patient, and from the wound cavity (no further details given) in 2 patients. All complications were managed by micropharyngoscopy with electrocoagulation. Public consultation also reported a single death due to severe haemorrhage. Severe dysphagia and recurrent aspiration were reported in 6% (3/48) of patients in the retrospective case series of 48 patients, as a result of extended tumour resection, including 'resection in adjacent sites and structures'. All 3 patients needed gastrostomy tubes. Airway loss (needing surgical cricothyroidotomy) was reported in 1 patient in the prospective case series of 204 patients; this occurred during reoperative resection of a tumour-positive margin. Tracheostomies (permanent or temporary) were needed in 11% (6/53) of patients in the TLS±ND group and 5% (9/170) of patients in the electrocautery group in the retrospective comparative case series of 223 patients (no significance test reported). Bilateral hypoglossal nerve paresis (due to 'stretch-related complications' of the endoscopic approach to the pharynx) was reported in 1 patient in the prospective case series of 204 patients. Postoperative 'velopharyngeal incompetence' (not severe enough to prevent oral intake or good speech) was also reported in 11 patients. Further details were not reported. The specialist advisers listed theoretical adverse events as subcutaneous emphysema, numbness of the tongue, damage to the oral cavity or teeth during access retraction, and inadequate surgical margins.# Further information For related NICE guidance see the NICE website # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0498-3	{'Recommendations': 'Current evidence on the efficacy and safety of transoral carbon dioxide laser surgery for the primary treatment of oropharyngeal malignancy is adequate to support the use of this procedure with normal arrangements for clinical governance, consent and audit.\n\nThis procedure should only be carried out by clinicians who have been trained in the use of transoral carbon dioxide laser surgery in the oropharynx.\n\nPatient selection for this procedure should be done by a multidisciplinary team in accordance with the NICE cancer service guidance on improving outcomes in head and neck cancers (CSGNH 2004).\n\nClinicians should enter details of all patients undergoing transoral carbon dioxide laser surgery for the primary treatment of oropharyngeal malignancy onto the Data for Head and Neck Oncology (DAHNO) database.', 'Indications and current treatments': 'Malignancies in the oropharynx (which includes the tonsils, the base of the tongue and the soft palate) are usually squamous cell carcinomas originating in the epithelial cell lining. The incidence of these malignancies has increased significantly in younger patients, probably because of the increased prevalence of human papillomavirus infection. Presenting features include a persistent sore throat, a lesion in the mouth or throat, white or red patches that may be swollen or bleeding, and pain in the ear. Patients tend to present with advanced or sometimes metastatic disease.\n\nOropharyngeal malignancies can be treated by surgery (using open or minimally invasive approaches for tumour resection and reconstruction), radiotherapy, chemotherapy, or a combination of these methods. Surgical resection may include neck dissection to remove lymph nodes. When the malignancy is considered to be unresectable, palliative chemotherapy and radiotherapy can be used.', 'The procedure': 'Transoral carbon dioxide laser surgery is a minimally invasive endoscopic approach for treating tumours in the oropharynx. It is usually performed under general anaesthesia, with the patient supine and tilted head-down. The tumours are visualised using a modified mouth gag and/or an endoscope. The carbon dioxide laser device is coupled to an operating microscope and the laser beam is used to excise the tumour completely, together with an adequate margin of tissue around it. Large tumours are removed in 2 or more pieces as a multiblock resection.\n\nFibre-optic carbon dioxide lasers, flexible delivery systems and robots have been developed, all of which increase the range of angles of approach that can be used to achieve tumour resection.\n\nLaser resection of tumours is sometimes combined with either simultaneous or staged neck dissection if there is cervical lymphadenopathy or a suspicion of occult metastases. Adjuvant radiotherapy and/or chemotherapy is also offered to some patients, based on a number of factors such as T-stage, nodal status, extracapsular spread of tumour, margin status and histology.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA retrospective comparative case series of 223\xa0patients with T1 oropharyngeal carcinoma treated by transoral carbon dioxide laser surgery (TLS) with or without neck dissection (±ND) (n=53) or by electrocautery (n=170) reported that there was no significant difference in 5-year disease‑specific survival (89% for TLS±ND and 87% for electrocautery; p>0.05).\n\nA prospective case series of 204\xa0patients (of whom 203 were analysed) with stage III or IV oropharyngeal cancers treated by TLS±ND alone (53 patients) or by TLS±ND and combined adjuvant treatment (150 patients: 117 radiotherapy alone, 33 chemoradiotherapy) reported that rates of 5-year overall survival, disease-specific survival and disease-free survival were 78%, 84% and 74% respectively across all groups. TLS combined with postoperative adjuvant radiotherapy (in 117/204\xa0patients) reduced the risk of death by over 50% (hazard ratio 0.33 to 0.48) compared against the risk of death in the group who received TLS±ND alone (53/204\xa0patients).\n\nThe retrospective comparative case series of 223\xa0patients reported a 5-year local control rate of 95% for TLS±ND and 91% for electrocautery (p>0.05; not significant).\n\nThe retrospective case series of 69\xa0patients reported that 4% (3/69) of patients had disease recurrence at the primary site at a mean follow-up of 44\xa0months. The 5-year local regional control rate in patients in whom adjuvant therapy was not indicated was 82%. The 5-year local regional control rate in patients who declined adjuvant therapy was 74%.\n\nThe specialist advisers listed key efficacy outcomes as local control, survival, margin control and local recurrence.', 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nBleeding within the first 7\xa0days after the procedure was reported in 10% (5/48) of patients in a retrospective case series of 48\xa0patients with squamous cell carcinoma of the base of the tongue treated by transoral carbon dioxide laser surgery with or without neck dissection (TLS±ND) and adjuvant radiotherapy. The bleeding was from a vessel at the base of the tongue in 1\xa0patient, at the lateral oropharyngeal wall in 1\xa0patient, at the aryepiglottic fold in 1\xa0patient, and from the wound cavity (no further details given) in 2\xa0patients. All complications were managed by micropharyngoscopy with electrocoagulation. Public consultation also reported a single death due to severe haemorrhage.\n\nSevere dysphagia and recurrent aspiration were reported in 6% (3/48) of patients in the retrospective case series of 48\xa0patients, as a result of extended tumour resection, including 'resection in adjacent sites and structures'. All 3\xa0patients needed gastrostomy tubes.\n\nAirway loss (needing surgical cricothyroidotomy) was reported in 1\xa0patient in the prospective case series of 204\xa0patients; this occurred during reoperative resection of a tumour-positive margin.\n\nTracheostomies (permanent or temporary) were needed in 11% (6/53) of patients in the TLS±ND group and 5% (9/170) of patients in the electrocautery group in the retrospective comparative case series of 223\xa0patients (no significance test reported).\n\nBilateral hypoglossal nerve paresis (due to 'stretch-related complications' of the endoscopic approach to the pharynx) was reported in 1\xa0patient in the prospective case series of 204\xa0patients. Postoperative 'velopharyngeal incompetence' (not severe enough to prevent oral intake or good speech) was also reported in 11\xa0patients. Further details were not reported.\n\nThe specialist advisers listed theoretical adverse events as subcutaneous emphysema, numbness of the tongue, damage to the oral cavity or teeth during access retraction, and inadequate surgical margins.", 'Further information': 'For related NICE guidance see the NICE website\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0498-3'}	https://www.nice.org.uk/guidance/ipg484
4f9e3047a9eb04ead2265b92345162e2a4bbc285	nice	Faecal microbiota transplant for recurrent Clostridium difficile infection	Faecal microbiota transplant for recurrent Clostridium difficile infection Evidence-based recommendations on faecal microbiota transplant for recurrent Clostridium difficile infection. This involves introducing enteric bacteria from the faeces of healthy donors to restore a healthy balance of bacteria in the gut. # Recommendations Current evidence on the efficacy and safety of faecal microbiota transplant for recurrent Clostridium difficile infection is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Only consider this procedure for a recurrent episode of C. difficile infection in adults who have had 2 or more previous episodes (as outlined in recommendation 1.1.10 in the NICE antimicrobial prescribing guideline on Clostridioides difficile). Clinicians should ensure that a confidential record is kept of the donor and recipient of each faecal microbiota transplant. NICE encourages further research into faecal microbiota transplant for C. difficile infection, specifically to investigate optimal dosage, mode of administration and choice of donor.# Indications and current treatments Clostridium difficile is a bacterium that lives harmlessly in the gut of approximately 5% of healthy people. The use of broad-spectrum antibiotics and immunosuppressive agents can alter the balance of bacterial species in the gut, resulting in an overgrowth of C. difficile. Symptoms of mild C. difficile infections include purulent watery diarrhoea, abdominal cramps, nausea and dehydration. In more severe cases the infection can cause bloody diarrhoea and fever. In a few people C. difficile infection can lead to pseudomembranous colitis, sepsis, toxic megacolon, colonic rupture, and death. The risk of death increases in patients with multiple comorbidities. First-line treatment involves rehydration and antibiotic therapy. Clinical responses are generally favourable but some people have recurrent or refractory C. difficile infections. For these people, further courses of antibiotics are used. An example of management algorithms can be found in Public Health England's Updated guidance on the management and treatment of C. difficile infection (June 2013).# The procedure Faecal microbiota transplants aim to restore a healthy balance of bacteria in the gut of people who have recurrent Clostridium difficile infections by introducing enteric bacteria from the faeces of healthy donors. Before the procedure, donors (who can be family members or unrelated) are screened for enteric bacterial pathogens, viruses and parasites. Donor faeces are taken and diluted with water, saline or another liquid such as milk or yogurt, and subsequently strained to remove large particles. The resulting suspension is introduced into the recipient's gut via a nasogastric tube, nasoduodenal tube, rectal enema or via the biopsy channel of a colonoscope. Recipients may receive a bowel lavage before transplantation, in order to reduce the C. difficile load in the intestines.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures guidance overview. A trial of 43 patients treated by faecal transplant versus vancomycin with a bowel lavage versus vancomycin only, reported a primary cure rate of 81% (13/16), 23% (3/13) and 31% (4/13) respectively at 10‑week follow-up. The faecal transplant group had statistically significantly higher cure rates compared against the vancomycin with bowel lavage and vancomycin-only groups (p<0.001). Patients for whom an initial faecal transplant failed (n=3) had another transplant; 66% (2/3) of these patients were cured, resulting in an overall cure rate of 94% (15/16). A systematic review of 25 studies, which included 289 patients with refractory Clostridium difficile infection treated by a faecal transplant, reported complete resolution of symptoms in 91% of patients at a mean follow-up of 12.6 months. A non-randomised comparative study of 43 patients treated by faecal transplants using fresh stool from a related donor, transplants using fresh stool from an unrelated donor or transplants using frozen stool from an unrelated donor, reported resolution of symptoms with negative stool samples in 70% (7/10), 92% (11/12) and 90% (19/21) of patients respectively at 12‑month follow-up. There were no statistically significant differences between the success rates of related and unrelated donor faeces or between the success rates of fresh and frozen faeces. The randomised controlled trial of 43 patients treated by a faecal transplant, vancomycin with bowel lavage, or vancomycin only, reported relapses within 5 weeks of the start of therapy in 6% (1/16), 54% (7/13) and 62% (8/13) of patients respectively. The systematic review of 25 studies reported that 2.4% (7/289) of patients had a relapse between 29 days and 4 years after faecal microbiota transplant. The specialist advisers listed key efficacy outcomes as cure of infection and no further relapses of C. difficile infection.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures guidance overview. Belching, abdominal cramps and abdominal pain, on the day of faecal transplant, were reported in 19% (3/16), 31% (5/16) and 13% (2/16) of patients respectively in the randomised controlled trial of 43 patients treated by faecal transplant, vancomycin with a bowel lavage or vancomycin only. In the same study, diarrhoea that was not considered to be due to Clostridium difficile infection was reported in 94% (15/16) of patients on the day of faecal transplant. Constipation (during the 10‑week follow-up period) was reported in 19% (3/16) of patients. Suspected peritonitis was reported in 1 patient (timing not reported), and 3 patients had symptoms of enteritis within 2 days of receiving a faecal transplant, in the systematic review of 25 studies. The specialist advisers stated that theoretical adverse events include the transmission of biological agents and infections, and the administration of microbiologically uncharacterised material.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. ISBN: 978-1-4731-0440-2	{'Recommendations': 'Current evidence on the efficacy and safety of faecal microbiota transplant for recurrent Clostridium difficile infection is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nOnly consider this procedure for a recurrent episode of C.\xa0difficile infection in adults who have had 2\xa0or more previous episodes (as outlined in recommendation 1.1.10 in the NICE antimicrobial prescribing guideline on Clostridioides difficile). [23 July 2021]\n\nClinicians should ensure that a confidential record is kept of the donor and recipient of each faecal microbiota transplant.\n\nNICE encourages further research into faecal microbiota transplant for C.\xa0difficile infection, specifically to investigate optimal dosage, mode of administration and choice of donor.', 'Indications and current treatments': "Clostridium difficile is a bacterium that lives harmlessly in the gut of approximately 5% of healthy people. The use of broad-spectrum antibiotics and immunosuppressive agents can alter the balance of bacterial species in the gut, resulting in an overgrowth of C.\xa0difficile. Symptoms of mild C.\xa0difficile infections include purulent watery diarrhoea, abdominal cramps, nausea and dehydration. In more severe cases the infection can cause bloody diarrhoea and fever. In a few people C.\xa0difficile infection can lead to pseudomembranous colitis, sepsis, toxic megacolon, colonic rupture, and death. The risk of death increases in patients with multiple comorbidities.\n\nFirst-line treatment involves rehydration and antibiotic therapy. Clinical responses are generally favourable but some people have recurrent or refractory C.\xa0difficile infections. For these people, further courses of antibiotics are used. An example of management algorithms can be found in Public Health England's Updated guidance on the management and treatment of C. difficile infection (June 2013).", 'The procedure': "Faecal microbiota transplants aim to restore a healthy balance of bacteria in the gut of people who have recurrent Clostridium difficile infections by introducing enteric bacteria from the faeces of healthy donors.\n\nBefore the procedure, donors (who can be family members or unrelated) are screened for enteric bacterial pathogens, viruses and parasites. Donor faeces are taken and diluted with water, saline or another liquid such as milk or yogurt, and subsequently strained to remove large particles. The resulting suspension is introduced into the recipient's gut via a nasogastric tube, nasoduodenal tube, rectal enema or via the biopsy channel of a colonoscope. Recipients may receive a bowel lavage before transplantation, in order to reduce the C.\xa0difficile load in the intestines.", 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures guidance overview.\n\nA trial of 43\xa0patients treated by faecal transplant versus vancomycin with a bowel lavage versus vancomycin only, reported a primary cure rate of 81% (13/16), 23% (3/13) and 31% (4/13) respectively at 10‑week follow-up. The faecal transplant group had statistically significantly higher cure rates compared against the vancomycin with bowel lavage and vancomycin-only groups (p<0.001). Patients for whom an initial faecal transplant failed (n=3) had another transplant; 66% (2/3) of these patients were cured, resulting in an overall cure rate of 94% (15/16).\n\nA systematic review of 25\xa0studies, which included 289\xa0patients with refractory Clostridium difficile infection treated by a faecal transplant, reported complete resolution of symptoms in 91% of patients at a mean follow-up of 12.6\xa0months.\n\nA non-randomised comparative study of 43\xa0patients treated by faecal transplants using fresh stool from a related donor, transplants using fresh stool from an unrelated donor or transplants using frozen stool from an unrelated donor, reported resolution of symptoms with negative stool samples in 70% (7/10), 92% (11/12) and 90% (19/21) of patients respectively at 12‑month follow-up. There were no statistically significant differences between the success rates of related and unrelated donor faeces or between the success rates of fresh and frozen faeces.\n\nThe randomised controlled trial of 43\xa0patients treated by a faecal transplant, vancomycin with bowel lavage, or vancomycin only, reported relapses within 5\xa0weeks of the start of therapy in 6% (1/16), 54% (7/13) and 62% (8/13) of patients respectively.\n\nThe systematic review of 25\xa0studies reported that 2.4% (7/289) of patients had a relapse between 29\xa0days and 4\xa0years after faecal microbiota transplant.\n\nThe specialist advisers listed key efficacy outcomes as cure of infection and no further relapses of C.\xa0difficile infection.', 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedures guidance overview.\n\nBelching, abdominal cramps and abdominal pain, on the day of faecal transplant, were reported in 19% (3/16), 31% (5/16) and 13% (2/16) of patients respectively in the randomised controlled trial of 43\xa0patients treated by faecal transplant, vancomycin with a bowel lavage or vancomycin only. In the same study, diarrhoea that was not considered to be due to Clostridium difficile infection was reported in 94% (15/16) of patients on the day of faecal transplant. Constipation (during the 10‑week follow-up period) was reported in 19% (3/16) of patients.\n\nSuspected peritonitis was reported in 1\xa0patient (timing not reported), and 3\xa0patients had symptoms of enteritis within 2\xa0days of receiving a faecal transplant, in the systematic review of 25\xa0studies.\n\nThe specialist advisers stated that theoretical adverse events include the transmission of biological agents and infections, and the administration of microbiologically uncharacterised material.', 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-0440-2'}	https://www.nice.org.uk/guidance/ipg485	Evidence-based recommendations on faecal microbiota transplant for recurrent Clostridium difficile infection. This involves introducing enteric bacteria from the faeces of healthy donors to restore a healthy balance of bacteria in the gut.
754536a486ee59abae8e2b233175b6c8dc78f822	nice	Extracorporeal membrane oxygenation (ECMO) for acute heart failure in adults	Extracorporeal membrane oxygenation (ECMO) for acute heart failure in adults # Recommendations The evidence on the efficacy of extracorporeal membrane oxygenation (ECMO) for acute heart failure in adults is adequate but there is uncertainty about which patients are likely to benefit from this procedure, and the evidence on safety shows a high incidence of serious complications. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake ECMO for acute heart failure in adults should take the following actions. Inform the clinical governance leads in their NHS trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Submit data on all adults undergoing ECMO for acute heart failure to the international Extracorporeal Life Support Organization register. ECMO for acute heart failure in adults should only be carried out by clinical teams with specific training and expertise in the procedure. NICE encourages further research into ECMO for acute heart failure. This should include clear documentation of patient selection and indications for the use of ECMO. Outcome measures should include survival, quality of life and neurological status.# Indications and current treatments Heart failure is a complex clinical syndrome of symptoms and signs that occurs when the efficiency of the heart as a pump is impaired. It can lead to reduced blood flow to the body tissues and increased filling pressure in the heart, which causes congestion and oedema in the lungs (causing breathlessness) and/or the body (causing swelling of the legs). Other symptoms include reduced exercise tolerance, fatigue and malaise. Treatment for acute heart failure (specifically, sudden significant deterioration in people with known cardiac dysfunction or new onset of symptoms in people without previous cardiac dysfunction) involves pharmacological therapies, including diuretics and inotropic agents. Invasive therapies include electrophysiological interventions such as pacemakers or implantable cardioverter-defibrillators, revascularisation procedures such as percutaneous coronary intervention, valve replacement or repair, and temporary use of intra-aortic balloon pumps or ventricular assist devices.# The procedure Extracorporeal membrane oxygenation (ECMO) for acute heart failure in adults can be used after heart surgery to assist in the transition from cardiopulmonary bypass to ventilation. It can also be used as a bridge to myocardial recovery, cardiac transplantation or implantation of a left ventricular assist device. There are 2 main types of ECMO – venovenous and venoarterial. For acute heart failure in adults, the venoarterial method is used. Blood is withdrawn via the venous system (usually the femoral vein or right atrium) and pumped through an oxygenator, where gas exchange of oxygen and carbon dioxide takes place. It is then returned to the arterial system (usually the femoral artery or ascending aorta). Patients are given a continuous infusion of an anticoagulant, usually heparin, to prevent blood clotting in the external system. For patients with renal insufficiency, a haemofiltration unit may be integrated into the circuit.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A register including 3065 adult cardiac failure and cardiopulmonary resuscitation (CPR) patients reported survival to discharge or transfer in 39% (891/2312) of cardiac failure patients and in 27% (207/753) of CPR patients. A non-randomised comparative study of 79 patients (61 treated by extracorporeal membrane oxygenation compared with 18 treated by miniaturised percutaneous ventricular assist device ) reported in-hospital survival in 49% (30/61) of ECMO patients and 50% (9/18, p>0.999) of mp-VAD patients.Three case series of 81 patients (with acute refractory cardiogenic shock), 295 patients (treated by ECMO-supported CPR), 219 patients (with refractory postcardiotomy cardiogenic shock) and 1 systematic review of case series of 1150 patients (with cardiogenic shock postcardiotomy) reported survival to discharge in 42% (34/81), 27% (79/295), 24% (52/219) and 34% (386/1150) of patients respectively. A case series of 47 patients with refractory postcardiotomy cardiogenic shock who were discharged from hospital after ECMO reported an overall survival rate of 59% at 10 years. A non-randomised comparative study of 79 patients (61 ECMO compared with 18 mp-VAD) reported 31% (19/61) of the ECMO group and 28% (5/18, p>0.999) of the mp-VAD group were successfully bridged to long-term support or transplant. A systematic review of case series of 800 patients reported that 4% (29/800) were bridged to transplant. Seventy-six per cent (22/29) of these patients survived to discharge. The case series of 219 patients reported that 4% (8/219) of patients were bridged to a long-term ventricular assist device. Five patients subsequently died, 2 had a successful transplant and 1 was successfully weaned from ECMO. The case series of 81 patients (28 patients available for quality of life evaluation) reported significantly better scores in physical component (p=0.0001), general health (p=0.01) and vitality (p=0.02) domains of SF-36 quality of life scores in 14 patients who were followed up for 325 days or more than 14 patients who were followed up for fewer than 325 days. The specialist advisers listed key efficacy outcomes as survival (to discharge from hospital, at 28 days, at 6 months, to definitive therapy, and long term), successful bridge to recovery, functional capacity and quality of life in the long term.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Death during extracorporeal mechanical oxygenation (ECMO) support was reported in 40% (52/131) of patients in a case series of 131 patients with cardiogenic shock; in 'most cases' this was because of multi-organ failure or sepsis. Death within 30 days was reported in 76% (167/219) of patients in the case series of 219 patients with refractory postcardiotomy cardiogenic shock; the main cause of death was low cardiac output syndrome secondary to refractory myocardial failure. Intracranial haemorrhage was reported in 2% of patients in the register reporting on 2312 cardiac failure patients (absolute numbers not reported; timing unclear). Major or significant bleeding was reported to have a pooled incidence estimate of 41% (95% confidence interval 14.8% to 63.6%) in a systematic review of case series of 260 patients (5 studies). Rethoracotomy for bleeding or tamponade was reported to have a pooled incidence estimate of 42% (95% CI 16.1% to 83.7%) in a systematic review of case series of 828 postcardiotomy patients (6 studies). Stroke was reported in 9% (7/81) of patients in the case series of 81 patients (timing unclear). A pooled incidence estimate of 6% (95% CI 4.2% to 8.3%) was reported for stroke in a systematic review of case series of 630 patients (3 studies). Femoral artery perforation (leading to uncontrollable bleeding and subsequent death) was reported in 2 patients in the case series of 131 patients. Inferior vena cava tear was reported in 2% (2/92) of patients in a systematic review of case series of 92 patients (2 studies). Lower extremity amputation was reported to have a pooled incidence estimate of 5% (95% CI 2.3% to 9.3%) in a systematic review of case series of 192 patients (5 studies). Fasciotomy or compartment syndrome was reported to have a pooled estimate of 10% (95% CI 7.35% to 14.5%) in a systematic review of case series of 335 patients (5 studies). Lower extremity ischaemia was reported to have a pooled estimate of 17% (95% CI 12.5% to 22.6%) in a systematic review of case series of 677 patients (13 studies). Lower limb ischaemia was reported in 13% (28/219) of patients in the case series of 219 patients; fasciotomy for severe leg ischaemia was needed in 6% (13/219) of patients (timing unclear). Venous thrombus in either the femoral vein or the inferior vena cava was reported in 8% (18/217) of patients (4 studies) and arterial thrombus in 7% (13/192) of patients (3 studies) in a systematic review of case series. Significant post-ECMO infection had a pooled incidence estimate of 30% (95% CI 13.7% to 64.5%) in a systematic review of case series of 992 patients (10 studies). Significant infection was defined as sepsis or suspected sepsis needing antibiotics, which occurred in 8 of the 10 studies. Ventilator-associated pneumonia (1 or more episode) was reported in 49% (40/81) of patients, surgical wound infections in 17% (14/81) of patients, bacteraemia in 14% (11/81) of patients, and catheter-related infections in 6% (5/81) of patients in the case series of 81 patients (timing unclear). Mechanical complications, including oxygenator failure (15%; 36% of these patients survived), cannula problems (4%; 27% survived), tubing rupture (less than 1%; none survived) and pump malfunction (less than 1%; 28% survived), were reported in cardiac failure patients (n=2312) included in the register of patients treated by ECMO (absolute numbers not reported). Clots in the ECMO circuit were reported in 19% (56/295) of patients and air embolus in 2% (5/295) of patients in the case series of 295 patients. Brachial plexus injury was reported in 2 case reports of patients treated with ECMO. One of these patients died 55 days later from multiple systemic complications. Symptoms improved at 4‑month follow-up in the other patient. The specialist advisers said that anoxic neurological complications were additional adverse events reported in the literature. They listed the following anecdotal adverse events: intrathoracic bleeding, left ventricular thrombus formation and acute pulmonary injury.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0494-5	{'Recommendations': "The evidence on the efficacy of extracorporeal membrane oxygenation (ECMO) for acute heart failure in adults is adequate but there is uncertainty about which patients are likely to benefit from this procedure, and the evidence on safety shows a high incidence of serious complications. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake ECMO for acute heart failure in adults should take the following actions.\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nSubmit data on all adults undergoing ECMO for acute heart failure to the international Extracorporeal Life Support Organization register.\n\nECMO for acute heart failure in adults should only be carried out by clinical teams with specific training and expertise in the procedure.\n\nNICE encourages further research into ECMO for acute heart failure. This should include clear documentation of patient selection and indications for the use of ECMO. Outcome measures should include survival, quality of life and neurological status.", 'Indications and current treatments': 'Heart failure is a complex clinical syndrome of symptoms and signs that occurs when the efficiency of the heart as a pump is impaired. It can lead to reduced blood flow to the body tissues and increased filling pressure in the heart, which causes congestion and oedema in the lungs (causing breathlessness) and/or the body (causing swelling of the legs). Other symptoms include reduced exercise tolerance, fatigue and malaise.\n\nTreatment for acute heart failure (specifically, sudden significant deterioration in people with known cardiac dysfunction or new onset of symptoms in people without previous cardiac dysfunction) involves pharmacological therapies, including diuretics and inotropic agents. Invasive therapies include electrophysiological interventions such as pacemakers or implantable cardioverter-defibrillators, revascularisation procedures such as percutaneous coronary intervention, valve replacement or repair, and temporary use of intra-aortic balloon pumps or ventricular assist devices.', 'The procedure': 'Extracorporeal membrane oxygenation (ECMO) for acute heart failure in adults can be used after heart surgery to assist in the transition from cardiopulmonary bypass to ventilation. It can also be used as a bridge to myocardial recovery, cardiac transplantation or implantation of a left ventricular assist device.\n\nThere are 2 main types of ECMO – venovenous and venoarterial. For acute heart failure in adults, the venoarterial method is used. Blood is withdrawn via the venous system (usually the femoral vein or right atrium) and pumped through an oxygenator, where gas exchange of oxygen and carbon dioxide takes place. It is then returned to the arterial system (usually the femoral artery or ascending aorta). Patients are given a continuous infusion of an anticoagulant, usually heparin, to prevent blood clotting in the external system. For patients with renal insufficiency, a haemofiltration unit may be integrated into the circuit.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA register including 3065 adult cardiac failure and cardiopulmonary resuscitation (CPR) patients reported survival to discharge or transfer in 39% (891/2312) of cardiac failure patients and in 27% (207/753) of CPR patients. A non-randomised comparative study of 79\xa0patients (61 treated by extracorporeal membrane oxygenation [ECMO] compared with 18 treated by miniaturised percutaneous ventricular assist device [mp-VAD]) reported in-hospital survival in 49% (30/61) of ECMO patients and 50% (9/18, p>0.999) of mp-VAD patients.Three case series of 81\xa0patients (with acute refractory cardiogenic shock), 295\xa0patients (treated by ECMO-supported CPR), 219\xa0patients (with refractory postcardiotomy cardiogenic shock) and 1 systematic review of case series of 1150\xa0patients (with cardiogenic shock postcardiotomy) reported survival to discharge in 42% (34/81), 27% (79/295), 24% (52/219) and 34% (386/1150) of patients respectively.\n\nA case series of 47\xa0patients with refractory postcardiotomy cardiogenic shock who were discharged from hospital after ECMO reported an overall survival rate of 59% at 10\xa0years.\n\nA non-randomised comparative study of 79\xa0patients (61 ECMO compared with 18 mp-VAD) reported 31% (19/61) of the ECMO group and 28% (5/18, p>0.999) of the mp-VAD group were successfully bridged to long-term support or transplant. A systematic review of case series of 800\xa0patients reported that 4% (29/800) were bridged to transplant. Seventy-six per cent (22/29) of these patients survived to discharge. The case series of 219\xa0patients reported that 4% (8/219) of patients were bridged to a long-term ventricular assist device. Five patients subsequently died, 2 had a successful transplant and 1 was successfully weaned from ECMO.\n\nThe case series of 81\xa0patients (28 patients available for quality of life evaluation) reported significantly better scores in physical component (p=0.0001), general health (p=0.01) and vitality (p=0.02) domains of SF-36 quality of life scores in 14\xa0patients who were followed up for 325\xa0days or more than 14\xa0patients who were followed up for fewer than 325\xa0days.\n\nThe specialist advisers listed key efficacy outcomes as survival (to discharge from hospital, at 28\xa0days, at 6\xa0months, to definitive therapy, and long term), successful bridge to recovery, functional capacity and quality of life in the long term.', 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nDeath during extracorporeal mechanical oxygenation (ECMO) support was reported in 40% (52/131) of patients in a case series of 131\xa0patients with cardiogenic shock; in 'most cases' this was because of multi-organ failure or sepsis.\n\nDeath within 30\xa0days was reported in 76% (167/219) of patients in the case series of 219\xa0patients with refractory postcardiotomy cardiogenic shock; the main cause of death was low cardiac output syndrome secondary to refractory myocardial failure.\n\nIntracranial haemorrhage was reported in 2% of patients in the register reporting on 2312 cardiac failure patients (absolute numbers not reported; timing unclear).\n\nMajor or significant bleeding was reported to have a pooled incidence estimate of 41% (95% confidence interval [CI] 14.8% to 63.6%) in a systematic review of case series of 260\xa0patients (5\xa0studies).\n\nRethoracotomy for bleeding or tamponade was reported to have a pooled incidence estimate of 42% (95% CI 16.1% to 83.7%) in a systematic review of case series of 828 postcardiotomy patients (6\xa0studies).\n\nStroke was reported in 9% (7/81) of patients in the case series of 81 patients (timing unclear). A pooled incidence estimate of 6% (95% CI 4.2% to 8.3%) was reported for stroke in a systematic review of case series of 630\xa0patients (3\xa0studies).\n\nFemoral artery perforation (leading to uncontrollable bleeding and subsequent death) was reported in 2\xa0patients in the case series of 131\xa0patients. Inferior vena cava tear was reported in 2% (2/92) of patients in a systematic review of case series of 92\xa0patients (2\xa0studies).\n\nLower extremity amputation was reported to have a pooled incidence estimate of 5% (95% CI 2.3% to 9.3%) in a systematic review of case series of 192\xa0patients (5\xa0studies).\n\nFasciotomy or compartment syndrome was reported to have a pooled estimate of 10% (95% CI 7.35% to 14.5%) in a systematic review of case series of 335\xa0patients (5\xa0studies).\n\nLower extremity ischaemia was reported to have a pooled estimate of 17% (95% CI 12.5% to 22.6%) in a systematic review of case series of 677\xa0patients (13\xa0studies). Lower limb ischaemia was reported in 13% (28/219) of patients in the case series of 219\xa0patients; fasciotomy for severe leg ischaemia was needed in 6% (13/219) of patients (timing unclear).\n\nVenous thrombus in either the femoral vein or the inferior vena cava was reported in 8% (18/217) of patients (4\xa0studies) and arterial thrombus in 7% (13/192) of patients (3\xa0studies) in a systematic review of case series.\n\nSignificant post-ECMO infection had a pooled incidence estimate of 30% (95% CI 13.7% to 64.5%) in a systematic review of case series of 992 patients (10\xa0studies). Significant infection was defined as sepsis or suspected sepsis needing antibiotics, which occurred in 8 of the 10\xa0studies. Ventilator-associated pneumonia (1 or more episode) was reported in 49% (40/81) of patients, surgical wound infections in 17% (14/81) of patients, bacteraemia in 14% (11/81) of patients, and catheter-related infections in 6% (5/81) of patients in the case series of 81\xa0patients (timing unclear).\n\nMechanical complications, including oxygenator failure (15%; 36% of these patients survived), cannula problems (4%; 27% survived), tubing rupture (less than 1%; none survived) and pump malfunction (less than 1%; 28% survived), were reported in cardiac failure patients (n=2312) included in the register of patients treated by ECMO (absolute numbers not reported). Clots in the ECMO circuit were reported in 19% (56/295) of patients and air embolus in 2% (5/295) of patients in the case series of 295\xa0patients.\n\nBrachial plexus injury was reported in 2 case reports of patients treated with ECMO. One of these patients died 55\xa0days later from multiple systemic complications. Symptoms improved at 4‑month follow-up in the other patient.\n\nThe specialist advisers said that anoxic neurological complications were additional adverse events reported in the literature. They listed the following anecdotal adverse events: intrathoracic bleeding, left ventricular thrombus formation and acute pulmonary injury.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0494-5'}	https://www.nice.org.uk/guidance/ipg482
c9a6616b44b40539c9c6fc2fb75477277fa7a0e0	nice	Insertion of a magnetic bead band for faecal incontinence	Insertion of a magnetic bead band for faecal incontinence # Recommendations Current evidence on the safety and efficacy of insertion of a magnetic bead band for faecal incontinence is limited in quantity and quality. The available evidence was considered in the context of the distress that faecal incontinence can cause and of the other treatment options, which may be limited. If further evidence supports the efficacy of this procedure, it has the potential to significantly improve quality of life for appropriately selected patients. Therefore insertion of a magnetic bead band for faecal incontinence may be used with special arrangements for clinical governance, consent and audit. NICE encourages the publication of outcomes on all patients, with specific consideration of entering all eligible patients into the HTA trial – 12/35/07 (see section 1.3). Clinicians wishing to undertake insertion of a magnetic bead band for faecal incontinence should take the following actions. Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's efficacy (especially in the long term) and the risk of complications that may need removal of the band. They should inform them fully about other treatment options and about the value of research studies (when appropriate), and provide them with clear written information. In addition, the use of NICE's Information for the public is recommended. Clinicians should offer all eligible patients entry into the HTA trial – 12/35/07. Data about all patients who do not enter the trial should be collected for local audit and review with a view to collaborative publication of outcomes. The procedure should only be performed in units specialising in the assessment and treatment of faecal incontinence. NICE will review the procedure when the results of the HTA trial are available. Research outcomes for any future studies should include disease-related quality of life.# Indications and current treatments Faecal incontinence is an inability to control bowel movements, resulting in the involuntary passage of stools. Causes include problems in the rectum, problems with the sphincter muscles (such as damage caused by childbirth), or nerve damage (such as multiple sclerosis, stroke or spina bifida). Faecal incontinence can also occur in conditions such as dementia or severe learning disability. Initial management of faecal incontinence includes interventions related to diet, bowel habit and toilet access, and medication (see Faecal incontinence: the management of faecal incontinence in adults, NICE clinical guideline 49). Specialised management options depend on the underlying cause and include pelvic floor muscle training, bowel retraining, specialist dietary assessment and management, biofeedback, electrical stimulation and rectal irrigation. The main surgical treatment is anal sphincter repair. Sacral nerve stimulation is sometimes used for people with faecal incontinence in whom sphincter surgery is deemed inappropriate. If a trial of sacral nerve stimulation is unsuccessful, a neosphincter may be considered (stimulated graciloplasty or an artificial anal sphincter).# The procedure Insertion of a magnetic bead band for faecal incontinence aims to reinforce and improve the competence of the anal sphincter to prevent episodes of incontinence without creating obstruction, and with less morbidity than artificial bowel sphincter surgery. The magnetic bead band does not need to be adjusted once it has been inserted. The procedure is done with the patient under general anaesthesia, using stringent asepsis. A tunnel is created around the anal canal via an anterior incision in the perineal body. A sizing tool is inserted to assess the circumference of the anal canal and the size of implant needed. The sizing tool is then removed and the implant is placed circumferentially around the upper anal canal. Fluoroscopy may be used to confirm the correct position. The ends of the implant are tied together. The wound is then closed. The implant consists of a ring of interlinked titanium beads, each with a weak magnetic force that holds the beads together. During defecation, the beads separate, allowing the passage of stool. Magnetic attraction then brings the beads together to re-establish continence.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. There was considerable patient overlap between the studies. For more detailed information on the evidence, see the interventional procedure overview. A non-randomised comparative study of 28 patients treated by insertion of a magnetic bead band or sacral nerve stimulation reported improved median continence scores in both groups from 16.5 and 15 at baseline to 6 and 11.5 (p=0.001 and 0.0001) respectively at follow-up (median follow-up 18 and 22 months respectively). A non-randomised comparative study of 20 patients treated by insertion of a magnetic bead band or artificial bowel sphincter reported improved median continence scores in both groups from 17 and 16.5 at baseline to 6 and 5 (p=0.0002 and 0.0001) respectively at follow-up (median follow-up 8 and 22.5 months respectively). The non-randomised comparative study of 28 patients reported statistically significant improvements from baseline in mean quality-of-life scores at follow-up for all 4 domains (lifestyle, coping/behaviour, depression and embarrassment) in both groups (median follow-up 18 and 22 months respectively). The non-randomised comparative study of 20 patients reported statistically significant improvements in median quality-of-life scores in both groups from 1.9 and 1.8 at baseline to 3.4 and 3.6 (p=0.005 and 0.009) respectively at follow-up (median follow-up 8 and 22.5 months respectively). A case series of 24 patients reported that 70% (16/23) of patients were satisfied with the procedure and 61% (14/23) would recommend it to another person. A case series of 14 patients reported that 1 patient chose to have the magnetic bead band removed after 69 days because it did not meet her expectations: she opted for a stoma for personal reasons. The specialist advisers stated that the key efficacy outcome is improved continence with accompanying improvement in disease-specific and generic quality of life.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Infection was reported in 14% (2/14) of patients in the case series of 14 patients. One patient developed infection 9 days after the procedure and was treated with systemic antibiotics without success. The implant was removed after 47 days and the patient had a stoma. The other patient had a superficial wound infection 7 days after the procedure that was successfully treated with systemic antibiotics. Perineal abscess was reported in 1 patient at 6 months postoperatively in the case series of 24 patients; the device was explanted. Swelling and erythema in both gluteal regions 2 weeks after the procedure was reported in 31% (5/16) of patients in a case series of 16 patients. This resolved after conservative treatment. Obstructed defecation was reported in 1 patient in the case series of 14 patients. This resolved within 2 days after treatment with enemas. Rectal bleeding that resolved spontaneously was reported in 1 patient in the case series of 14 patients. Vaginal bleeding that resolved spontaneously was reported in 1 patient in the case series of 16 patients. Pain that resolved after medication was reported in 14% (2/14) of patients in the case series of 14 patients. Pain (not further described) was reported in 31% (5/16) of patients in the case series of 16 patients. Device separation was reported in 1 patient in the case series of 14 patients; the patient reported hearing a 'crack' during defecation approximately 1 month after implantation. X-ray showed the device had separated and within a week the patient passed the device without evidence of ulceration on clinical examination. The specialist advisers listed erosion and discomfort as anecdotal adverse events. Theoretical adverse events were chronic pain, device migration, constipation and loss of magnetism.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0496-9	{'Recommendations': "Current evidence on the safety and efficacy of insertion of a magnetic bead band for faecal incontinence is limited in quantity and quality. The available evidence was considered in the context of the distress that faecal incontinence can cause and of the other treatment options, which may be limited. If further evidence supports the efficacy of this procedure, it has the potential to significantly improve quality of life for appropriately selected patients. Therefore insertion of a magnetic bead band for faecal incontinence may be used with special arrangements for clinical governance, consent and audit. NICE encourages the publication of outcomes on all patients, with specific consideration of entering all eligible patients into the HTA trial – 12/35/07 (see section 1.3).\n\nClinicians wishing to undertake insertion of a magnetic bead band for faecal incontinence should take the following actions.\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy (especially in the long term) and the risk of complications that may need removal of the band. They should inform them fully about other treatment options and about the value of research studies (when appropriate), and provide them with clear written information. In addition, the use of NICE's Information for the public is recommended.\n\nClinicians should offer all eligible patients entry into the HTA trial – 12/35/07. Data about all patients who do not enter the trial should be collected for local audit and review with a view to collaborative publication of outcomes.\n\nThe procedure should only be performed in units specialising in the assessment and treatment of faecal incontinence.\n\nNICE will review the procedure when the results of the HTA trial are available. Research outcomes for any future studies should include disease-related quality of life.", 'Indications and current treatments': 'Faecal incontinence is an inability to control bowel movements, resulting in the involuntary passage of stools. Causes include problems in the rectum, problems with the sphincter muscles (such as damage caused by childbirth), or nerve damage (such as multiple sclerosis, stroke or spina bifida). Faecal incontinence can also occur in conditions such as dementia or severe learning disability.\n\nInitial management of faecal incontinence includes interventions related to diet, bowel habit and toilet access, and medication (see Faecal incontinence: the management of faecal incontinence in adults, NICE clinical guideline 49). Specialised management options depend on the underlying cause and include pelvic floor muscle training, bowel retraining, specialist dietary assessment and management, biofeedback, electrical stimulation and rectal irrigation. The main surgical treatment is anal sphincter repair. Sacral nerve stimulation is sometimes used for people with faecal incontinence in whom sphincter surgery is deemed inappropriate. If a trial of sacral nerve stimulation is unsuccessful, a neosphincter may be considered (stimulated graciloplasty or an artificial anal sphincter).', 'The procedure': 'Insertion of a magnetic bead band for faecal incontinence aims to reinforce and improve the competence of the anal sphincter to prevent episodes of incontinence without creating obstruction, and with less morbidity than artificial bowel sphincter surgery. The magnetic bead band does not need to be adjusted once it has been inserted.\n\nThe procedure is done with the patient under general anaesthesia, using stringent asepsis. A tunnel is created around the anal canal via an anterior incision in the perineal body. A sizing tool is inserted to assess the circumference of the anal canal and the size of implant needed. The sizing tool is then removed and the implant is placed circumferentially around the upper anal canal. Fluoroscopy may be used to confirm the correct position. The ends of the implant are tied together. The wound is then closed.\n\nThe implant consists of a ring of interlinked titanium beads, each with a weak magnetic force that holds the beads together. During defecation, the beads separate, allowing the passage of stool. Magnetic attraction then brings the beads together to re-establish continence.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. There was considerable patient overlap between the studies. For more detailed information on the evidence, see the interventional procedure overview.\n\nA non-randomised comparative study of 28\xa0patients treated by insertion of a magnetic bead band or sacral nerve stimulation reported improved median continence scores in both groups from 16.5 and 15 at baseline to 6 and 11.5 (p=0.001 and 0.0001) respectively at follow-up (median follow-up 18 and 22\xa0months respectively). A non-randomised comparative study of 20\xa0patients treated by insertion of a magnetic bead band or artificial bowel sphincter reported improved median continence scores in both groups from 17 and 16.5 at baseline to 6 and 5 (p=0.0002 and 0.0001) respectively at follow-up (median follow-up 8 and 22.5\xa0months respectively).\n\nThe non-randomised comparative study of 28\xa0patients reported statistically significant improvements from baseline in mean quality-of-life scores at follow-up for all 4 domains (lifestyle, coping/behaviour, depression and embarrassment) in both groups (median follow-up 18 and 22\xa0months respectively). The non-randomised comparative study of 20\xa0patients reported statistically significant improvements in median quality-of-life scores in both groups from 1.9 and 1.8 at baseline to 3.4 and 3.6 (p=0.005 and 0.009) respectively at follow-up (median follow-up 8 and 22.5\xa0months respectively).\n\nA case series of 24\xa0patients reported that 70% (16/23) of patients were satisfied with the procedure and 61% (14/23) would recommend it to another person. A case series of 14\xa0patients reported that 1\xa0patient chose to have the magnetic bead band removed after 69\xa0days because it did not meet her expectations: she opted for a stoma for personal reasons.\n\nThe specialist advisers stated that the key efficacy outcome is improved continence with accompanying improvement in disease-specific and generic quality of life.', 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nInfection was reported in 14% (2/14) of patients in the case series of 14\xa0patients. One patient developed infection 9\xa0days after the procedure and was treated with systemic antibiotics without success. The implant was removed after 47\xa0days and the patient had a stoma. The other patient had a superficial wound infection 7\xa0days after the procedure that was successfully treated with systemic antibiotics. Perineal abscess was reported in 1\xa0patient at 6\xa0months postoperatively in the case series of 24\xa0patients; the device was explanted.\n\nSwelling and erythema in both gluteal regions 2\xa0weeks after the procedure was reported in 31% (5/16) of patients in a case series of 16\xa0patients. This resolved after conservative treatment.\n\nObstructed defecation was reported in 1 patient in the case series of 14 patients. This resolved within 2\xa0days after treatment with enemas.\n\nRectal bleeding that resolved spontaneously was reported in 1\xa0patient in the case series of 14\xa0patients. Vaginal bleeding that resolved spontaneously was reported in 1\xa0patient in the case series of 16 patients.\n\nPain that resolved after medication was reported in 14% (2/14) of patients in the case series of 14 patients. Pain (not further described) was reported in 31% (5/16) of patients in the case series of 16\xa0patients.\n\nDevice separation was reported in 1 patient in the case series of 14\xa0patients; the patient reported hearing a 'crack' during defecation approximately 1\xa0month after implantation. X-ray showed the device had separated and within a week the patient passed the device without evidence of ulceration on clinical examination.\n\nThe specialist advisers listed erosion and discomfort as anecdotal adverse events. Theoretical adverse events were chronic pain, device migration, constipation and loss of magnetism.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0496-9'}	https://www.nice.org.uk/guidance/ipg483
b51072f5c4d4ea97015042833ad3f5ea99e4e3a1	nice	Contraceptive services for under 25s	Contraceptive services for under 25s This guideline covers contraceptive services for under-25s. It aims to ensure all under-25s are given advice and information on all types of contraception. This includes additional tailored support to meet the particular needs and choices of those who are socially disadvantaged or who may find it difficult to use these services. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The guidance complements, but does not replace, NICE's guidelines on long-acting reversible contraception, looked after children and reducing sexually transmitted infections. The evidence statements underpinning the recommendations are listed in appendix C. The Programme Development Group (PDG) considers that the recommended measures are cost effective. Recommendations for research are available. See also the full evidence reviews, supporting evidence statements and economic modelling report. # Introduction The recommendations advocate providing information and advice on all types of contraception. The aim is to help young men and women choose the method that best suits their individual needs and lifestyle, so making it more likely that they will use contraception and use it effectively. The information should comprise verbal advice and printed material giving details about the: full range of contraceptive methods available, but with a focus on the most effective and appropriate choice for the individual concerned benefits and risks of each method and how to manage any side effects. # Definitions For the purposes of this guidance young men and women refers to everyone aged under 25 who is competent to consent to contraceptive treatment under the Department of Health's best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health. This guidance states: 'A doctor or health professional is able to provide contraception, sexual and reproductive health advice and treatment, without parental knowledge or consent, to a young person aged under 16, provided that: she/he understands the advice provided and its implications her/his physical or mental health would otherwise be likely to suffer and so provision of advice or treatment is in their best interest.' In addition, it is considered good practice for doctors and other health professionals to follow the criteria outlined by Lord Fraser in 1985, commonly known as the Fraser Guidelines: the young person understands the health professional's advice the health professional cannot persuade the young person to inform his or her parents or allow the doctor to inform the parents that he or she is seeking contraceptive advice the young person is very likely to begin or continue having intercourse with or without contraceptive treatment unless he or she receives contraceptive advice or treatment, the young person's physical or mental health or both are likely to suffer the young person's best interests require the health professional to give contraceptive advice, treatment or both without parental consent. Note: some of the recommendations, for example those on information provision, may also be relevant to young people who are not competent to consent to treatment. The recommendations are based on interventions and programmes proven to be effective with all young people aged under 25. They emphasise the need for services that are universal and inclusive. They also emphasise the need to offer additional tailored support to meet the particular needs and choices of those who are socially disadvantaged or who may find it difficult to use contraceptive services. (The latter might include those who are members of some faith and religious groups.) The guidance is based on the principle of progressive universalism (Fair society, healthy lives: strategic review of health inequalities in England post-2010). For the purposes of this guidance 'socially disadvantaged young people' may include those who are: living in a deprived area from a minority ethnic group (including gypsy and traveller communities) refugees, asylum seekers and people recently arrived in the UK teenage parents or the children of teenage parents looked after or leaving care excluded from school or do not attend regularly or have poor educational attainment unemployed or not in education or training homeless living with mental health problems living with physical or learning disabilities living with HIV or AIDS substance misusers (including alcohol misusers) criminal offenders. Contraceptive services refers to the whole range of contraceptive, sexual and reproductive health services. This includes services: in primary care -ffered by community, education and pharmacy outlets (commissioned by local authorities from the NHS, the private or voluntary sectors) commissioned by clinical commissioning groups (for example, termination of pregnancy services) commissioned by the NHS Commissioning Board (for example, contraceptive services provided within other specialist services, such as maternity services). # Recommendation 1 Assessing local need and capacity to target services ## Whose health will benefit? All young women and men aged up to 25. ## Who should take action? Health and wellbeing boards, local authority commissioners and other commissioners of young people's services. Directors of public health and directors of children's services. Those responsible for joint strategic needs assessment, data collection and analysis in local authorities, children's services and their partners. Managers of contraceptive services in primary and acute care, the voluntary and private sectors. Public health practitioners with a responsibility for contraception and sexual health. Those responsible for young people's advisory services. ## What action should they take? Directors of public health, public health practitioners and public health surveillance systems should collect and analyse anonymised regional and local demographic data and information on local contraception and sexual health inequalities. In conjunction with sexual health leads in the NHS and local authorities, they should disseminate the data to inform local strategic needs assessments, so that resources and services can be provided for those with the greatest need. Commissioners, with support from members of local public health networks, should use anonymised local health data and routinely collected surveillance data on, for example, conceptions, abortions, births and contraceptive prescribing, to identify local needs. These data could be geographical or in relation to specific population groups. Health and wellbeing boards, including directors of public health, local public health leads and local authorities, should carry out and publish the results of comprehensive joint strategic needs assessments for young people's contraceptive services. This should include details on socially disadvantaged young people. Map the current range of local services, service activity levels and capacity across all contraceptive service providers. (Take account of services further afield that may be used by local young people, for example, large pharmacies in nearby town centres.) The mapping should include, but should not be limited to: services provided by GPs, community contraceptive clinics, paediatricians, pharmacies, the voluntary sector and within schools and colleges 'out of hours' (evening and weekend) and outreach provision staffing levels and the range of professional skills available (including for GP practices) the size of premises, location, opening hours and accessibility. Use the data to develop an action plan setting out organisational responsibilities for local services for young people, including those who are socially disadvantaged. Ensure provision is at times and in locations that meet young people's needs. Regularly evaluate services in the context of this guidance and changing local needs. Use local accountability mechanisms (for example, health scrutiny reports) to examine specific issues. Ensure the mapping process involves young women and men, including those who are socially disadvantaged, in assessing the need for services (including the type of services needed, opening hours and location). Involve young men and women, including those who are socially disadvantaged, in planning, monitoring and evaluating services. # Recommendation 2 Commissioning coordinated and comprehensive services ## Whose health will benefit? All young women and men aged up to 25. ## Who should take action? Health and wellbeing boards and commissioners in local authorities and clinical commissioning groups with responsibility for hospital, community, education-based and primary care contraceptive services. Primary care, maternity and young people's services and pharmacies. Contraceptive services provided by NHS, voluntary and private sector organisations. ## What action should they take? Identify priorities and targets based on local need, using tools such as health equity audit and equality impact assessment. Use Commissioning for Quality and Innovation (CQUIN) indicators and other arrangements and processes to improve the uptake of effective methods of contraception, as appropriate. Establish collaborative, evidence-based commissioning arrangements between different localities to ensure comprehensive, open-access services are sited in convenient locations, such as city centres, or near to colleges and schools. Ensure no young person is denied contraceptive services because of where they live. Provide contraceptive services within genitourinary medicine and sexual health clinics, either as part of that clinic's services or by hosting contraceptive services provided by another organisation. Ensure all contraceptive services (including those provided in general practice) meet, as a minimum requirement, the Department of Health's you're welcome quality criteria. They should also meet the Faculty of Sexual and Reproductive Healthcare service standards for sexual and reproductive healthcare and follow their clinical guidance on contraceptive choices for young people. Develop joint commissioning of needs-led contraceptive services for young people. This should include coordinated and managed service networks. It should also include comprehensive referral pathways that include abortion, maternity, genitourinary medicine, pharmacy and all other relevant health, social care and children's services. Referral pathways should also cover youth and community services, education, and services offered by the voluntary and private sectors. Ensure pharmacies, walk-in centres and all organisations commissioned to provide contraceptive services (including those providing oral emergency contraception) maintain a consistent service. If this is not possible, staff should inform young people, without having to be asked, about appropriate alternative, timely and convenient services providing oral emergency contraception. # Recommendation 3 Providing contraceptive services for young people ## Whose health will benefit? All young women and men aged up to 25. ## Who should take action? Managers, doctors, midwives, nurses, pharmacists, receptionists and other staff working in contraceptive services, including those offered in education, GP services, pharmacies, maternity and postnatal care services, walk-in centres, acute and emergency care, and the voluntary and private sectors. ## What action should they take? Ensure young people have access, without delay, to confidential, dedicated young people's contraceptive services that, as a minimum requirement, meet the quality criteria set out in recommendation 2. Doctors, nurses and pharmacists should: -ffer culturally appropriate, confidential, non-judgmental, empathic advice and guidance according to the needs of each young person set aside adequate consultation time to encourage young people to make an informed decision, according to their needs and circumstances provide information about the full range of contraceptives available, including emergency contraception (both oral and intrauterine) and long-acting reversible contraception (LARC; also referred to as lasting and reliable contraception), and the benefits and side effects -ffer advice on the most effective methods and how to use them effectively and consistently if possible, provide the full range of contraceptive methods, including LARC, condoms to prevent transmission of sexually transmitted infections (STIs) and emergency contraception (both oral and intrauterine). If this is not possible, provide contraception to meet immediate needs and provide access to services that can offer advice and timely provision of the full range of methods provide free and confidential pregnancy testing with same-day results and, if appropriate, offer counselling or information about where to obtain free counselling assess the risk of an STI, advise testing if appropriate, and provide information about local STI services. Service managers, with the support of doctors, nurses and other staff, should offer services that: are flexible, for example, offer out-of-hours services at weekends and in the late afternoon and evening are available both without prior appointment (drop-in) and by appointment in any given area provide appointments within 2 working days strive to ensure that scheduled appointments run on time and that the waiting time for drop-in consultations is less than 60 minutes inform young people about the amount of time they can expect to wait provide accurate information about opening times and make it clear whether they operate on a drop-in or appointment basis, or a mix of both are open to young people aged under 16 who present for any service without a parent or carer. Service managers, doctors, nurses, receptionists, pharmacists and other staff should promote contraceptive services (including those that provide both oral and intrauterine emergency contraception) to young people. They should encourage both young men and women to use them by: providing clear information on all local services in a range of formats that appeal to young people, including leaflets, posters and other formats that are accessible for those with sensory impairments and learning disabilities, with low levels of literacy, or whose English may be poor advertising them through the local media, the Internet (for example, via social networking sites), local and community networks (for example, youth services and youth inclusion projects), schools, colleges and other education settings working with school and college governors, head teachers, college principals and personal, social, health and economic (PSHE) education lead teachers. # Recommendation 4 Tailoring services for socially disadvantaged young people ## Whose health will benefit? Socially disadvantaged young people aged up to 25. ## Who should take action? Service managers and staff working in contraceptive services. This includes doctors, nurses and pharmacists. ## What action should they take? Provide additional support for socially disadvantaged young people to help them gain immediate access to contraceptive services and to support them, as necessary, to use the services. This could include providing access to trained interpreters or offering one-to-one sessions. It could also include introducing special facilities for those with physical and sensory disabilities and assistance for those with learning disabilities. Encourage and help young mothers (including teenage mothers) to use contraceptive services, for example, by working with family nurse partnerships or children's centres. Offer support and referral to specialist services (including counselling) to those who may need it. For example, young people who misuse drugs or alcohol and those who may have been (or who may be at risk of being) sexually exploited or trafficked may need such support. The same is true of those who have been the victim of sexual violence. Provide outreach contraceptive services that offer information, advice, and the full range of options. This includes provision for those living in rural areas who cannot reach existing clinics and services. Offer culturally appropriate, confidential, non-judgmental, empathic advice and support tailored to the needs of the young person. Tailored support might involve, for example, providing relevant information in small manageable amounts, checking whether it has been understood, and reiterating and revising information if required. It could also include using more pictures and diagrams than text. # Recommendation 5 Seeking consent and ensuring confidentiality ## Whose health will benefit? All young women and men up to the age of 25. ## Who should take action? Managers and staff, including receptionists and administrators, working in services that provide contraception and contraceptive advice to young people. This includes education, maternity services, pharmacies and voluntary and private sector organisations. Managers and staff in children's services, social care organisations and young people's advisory and support services. This includes guardians, chaperones, interpreters and advocates. ## What action should they take? Ensure staff are trained to understand the duty of confidentiality and adhere to the recommendations and standards laid out in their organisation's confidentiality policy. Ensure staff are familiar with best practice guidance on how to give young people aged under 16 years contraceptive advice and support (Department of Health's best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health). Ensure they are also familiar with local and national guidance on working with vulnerable young people. Ensure those providing contraceptive services can assess the competence of young people aged under 16 to consent to receiving contraceptive advice and any treatment that may involve. They should also be able to assess the competence of other young people who may be vulnerable, for example, those with learning disabilities. Staff need to be able to gauge the young person's ability to understand the information provided, to weigh up the risks and benefits, and to voluntarily express their own wishes. Staff should also encourage young people to involve a parent or person with parental responsibility in the decision-making, where possible. Ensure young people understand that their personal information and the reason why they are using the service will be confidential. Even if it is decided that a young person is not mature enough to consent to contraceptive advice and treatment, the discussion should remain confidential. Reassure young people that they will not be discussed with others without their explicit consent. Explain that sharing information with another professional may be necessary if there are concerns, for example to protect a young person from possible harm or abuse. If this is the case, the young person should be told who needs to be informed and why. Ensure the organisation's confidentiality and complaints policy is prominently displayed in waiting and reception areas, and is in a format that is appropriate for all young people. Ensure young people are asked in private whether they wish anyone else to be present at their consultation Ensure staff are adequately supported and supervised. This includes establishing a formal debriefing process to help maintain client confidentiality and respect. # Recommendation 6 Providing contraceptive services after a pregnancy ## Whose health will benefit? Young women aged up to 25 who are pregnant, or who have recently been pregnant, and their partners. ## Who should take action? Midwives, obstetricians and all those working in maternity and postnatal care services. GPs, health visitors, pharmacists, school nurses and other health professionals working in contraceptive services, primary and community services, family nurse partnerships and acute and emergency care. ## What action should they take? Midwives should discuss with pregnant women what type of contraception they intend to use after their pregnancy. They should provide information on the full range of options and should advise them (and their partners, if appropriate) on an effective method that best meets their needs. They should also provide information on how and where to obtain it. After pregnancy, midwives should check that women have chosen a method of contraception. If not, they should offer contraceptive advice on a range of effective methods tailored to the woman's circumstances and sensitive to any concerns she may have. This includes advice on contraception for women who are breastfeeding, in accordance with guidance from the Faculty of Sexual and Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists (see Postnatal Sexual and Reproductive Health). They should discuss the benefits and risks of different methods so that those who are breastfeeding are able to continue. Midwives should provide women with the contraceptive they want before they are discharged from midwifery services. If this is not possible, they should offer a referral to contraceptive services. Health visitors, family nurse practitioners and health professionals working with new mothers should check that women have been given advice on contraception and do have contraceptives. If not, they should help them obtain information and advice so that they can choose and receive effective and appropriate contraceptives. Where necessary, they should consider using outreach or home services to provide this support. # Recommendation 7 Providing contraceptive services after an abortion ## Whose health will benefit? Young women aged up to 25 who have had an abortion and their partners. ## Who should take action? GPs and other primary care practitioners. Contraceptive services. Abortion services (including those providing early medical abortion). Counsellors working with abortion services. ## What action should they take? Before – and as soon as possible after – an abortion, discuss contraception and explain the full range of contraceptive methods available. Help young women and their partners identify and obtain the most effective method that best meets their needs. Dispel the myth that there is no need for contraception after an abortion and explain that women are fertile immediately following an abortion. Provide contraception to prevent another unintended pregnancy or refer them to contraceptive services for advice and contraception. If appropriate, offer counselling. If the young woman does not want to be referred on, offer to contact her after her abortion to give advice on the most effective and suitable method of contraception for her, using a communication method of her choice (for example, text messages). Also consider using outreach or home services to provide information and contraceptives. # Recommendation 8 Providing school and education-based contraceptive services ## Whose health will benefit? Young people up to age 25 who are of school age or in education. ## Who should take action? Nurses, doctors and counsellors working in contraceptive services within, or associated with, schools, sixth form and further education colleges, universities and other education‑based settings. This includes short-stay schools and young offender institutes. Governors, head teachers, teachers, student welfare officers and youth workers in schools, principals and tutors in sixth form and further education colleges and universities and staff in short-stay schools and young offender institutes. ## What action should they take? Involve young people in the design, implementation, promotion and review of on-site and outreach contraceptive services in and near schools, colleges and other education settings. School nurses, doctors and counsellors working with young people in schools, colleges and universities should conform to health service standards of confidentiality and to those set by their professional body. All young people should be made aware that one-to-one consultations with them will be confidential, except under the provisions made by law, for example, in relation to child protection. Ensure accurate and up-to-date contraceptive advice, information and support is readily available to all young women and men. Information on the location and hours of local services should be available outside designated clinic hours. Ensure contraceptive advice, free and confidential pregnancy testing and the full range of contraceptive methods, including both LARC and emergency contraception, is easily available. If the full range is not available, offer prompt and easy referral to appropriate local contraceptive services outside the school or college. Ensure continuity of service, for example by making it clear to young people when and where local services are available during school, college or university holidays. Ensure services not only provide contraceptives but are staffed by people trained to be respectful and non-judgmental. They should also be trained to help young men and women identify, choose and use contraception that is the most appropriate for them. # Recommendation 9 Providing emergency contraception ## Whose health will benefit? Young women up to the age of 25. ## Who should take action? Managers, doctors, nurses (including school nurses), pharmacists and reception staff working in: contraceptive services, schools, primary and community care, acute and emergency services, pharmacies, maternity services, walk-in centres and voluntary and private sector health services. ## What action should they take? Establish patient group directions (PGDs) and local arrangements to ensure all young women can easily obtain free oral emergency contraception. (Patient group directions enable suitably qualified nurses and pharmacists to dispense specific medicines in specific circumstances. See NICE's guideline on patient group directions.) Ensure young women (and young men) know where to obtain free emergency contraception. Inform young women that an intrauterine device is a more effective form of emergency contraception than the oral method and can also be used on an ongoing basis. Ensure young women have timely access to emergency contraception using an intrauterine device. Ensure young women who are given oral emergency contraception are: advised that this needs to be used as soon as possible after sex and that it is only effective if taken within a limited time advised that other methods are more effective and reliable as a primary method of contraception encouraged to consider and choose a suitable form of contraception for their future needs referred to, or given clear information about, local contraceptive services -ffered immediate referral for an intrauterine device, if they choose this method advised where they can obtain a free, confidential pregnancy test with same-day results. Ensure all health professionals providing oral emergency contraception are aware that they can provide this to young women aged under 16 without parental knowledge or consent, in accordance with best practice guidance (Department of Health's best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health). Also ensure they are aware that they have a duty of care and confidentiality to young people under the age of 16. Health professionals, including pharmacists, who are unwilling (or unable) to provide emergency contraception should give young women details of other local services where they can be seen urgently. Ensure arrangements are in place to provide a course of oral emergency contraception in advance, in specific circumstances where the regular contraceptive method being used, for example condoms or the pill, is subject to 'user failure'. (Methods where there can be 'user failure' are those that the user has to think about regularly or each time they have sex and which must be used according to instructions, such as condoms or the pill.) # Recommendation 10 Providing condoms in addition to other methods of contraception ## Whose health will benefit? All young men and women up to the age of 25. ## Who should take action? Managers and staff working in contraceptive services (including GP services, pharmacies, maternity services, walk-in centres, acute and emergency care), the voluntary and private sector. Practitioners with a responsibility for the health and wellbeing of young people in social care and children's services and the voluntary and private sector. This includes social care professionals, workers in drug and alcohol services, youth workers and counsellors, and people involved with condom distribution schemes. Public health specialists, PSHE education and sex and relationships education teachers, and all others who provide information about contraception and sexual and reproductive health. ## What action should they take? Advise all young people to use condoms consistently and correctly in addition to other contraception. Condoms should always be provided along with other contraception because they help prevent the transmission of STIs. Advise them to use a water-based lubricant with a condom if they want or need a lubricant. Ensure free condoms (including female condoms) are readily accessible (this could include, for example, at schools, colleges and youth clubs). Ensure information and advice on using condoms is available at all condom distribution points and, where possible, young people should be shown how to use them correctly. When providing condoms, offer information about emergency contraception and other contraceptive services, including when, where and how to access them locally. # Recommendation 11 Communicating with young people ## Whose health will benefit? Young people up to the age of 25 who use contraceptive services or who might need information on contraception. ## Who should take action? Commissioners and providers of contraceptive services. Information service providers including, for example, libraries, job centres, schools, colleges and youth services. ## What action should they take? Use a range of methods, including the latest communication technologies, to provide young people, especially socially disadvantaged young people, with advice on sexual health and contraception. This could include using: bespoke websites or dedicated pages on social networking sites which enable young people to discuss sensitive issues anonymously -nline NHS information such as the NHS your contraception guide websites provided by specialist service providers such as Brook or FPA that provide reliable, up-to-date, evidence-based health information and advice (schools and colleges should ensure their firewalls do not block these websites) telephone helplines offering up-to-date and accurate information and details about local services – for example, 'Ask Brook'. These should, where possible, use local numbers that qualify for free calls as part of many mobile phone contracts. Wherever possible, ensure schools, colleges, youth clubs and other places that young people visit have up-to-date and accessible information on contraceptive methods and local services. Ensure information is available in a range of formats. For example, it should be available in languages other than English, in large print, or text relay (for those who are deaf or hard of hearing). It should also be distributed via a range of media, for example, via mobile phones (text messaging or calls) or emails. (Practitioners should be mindful of confidentiality when using these media.) Involve young people in the design of any media and distribution strategies. # Recommendation 12 Training and continuing professional development ## Whose health will benefit? Young people up to the age of 25 who use contraceptive services or who might need information on contraception. ## Who is the target population? Doctors, midwives, nurses, pharmacists, and other health professionals who provide contraceptive services. Managers and staff working in, or involved with, young people's contraceptive services. ## Who should take action? Commissioners and managers of young people's contraceptive services. Primary and community care services, children's services, social services and young people's advisory and support services. Royal colleges and professional associations, further and higher education training boards, and organisations responsible for setting competencies and developing continuing professional development programmes for health professionals, healthcare assistants and support staff. ## What action should they take? Managers should ensure all doctors, midwives, nurses, pharmacists and other health professionals working in contraceptive services have received the post-registration training required by their professional body. They should also have evidence to show that they are maintaining their skills and competencies. Health professionals (including pharmacists) who advise young people about contraception should be competent to help them compare the risks and benefits of the different methods, according to their needs and circumstances. They should also be able to help them understand and manage any common side effects. (This is an edited extract from NICE's guideline on long-acting reversible contraception.) Colleges and training organisations should ensure doctors and nurses offering contraceptive services have easy, prompt access to pre- and post-registration theoretical and practical training in all methods of contraception. This includes intrauterine devices and systems and contraceptive implants. Ensure all support staff who may come into contact with young people, particularly socially disadvantaged young people, are experienced in working with them. This includes being able to communicate with those who have physical or learning disabilities. It also includes being aware of, and sensitive to, the needs of young people from different ethnic and faith communities in relation to contraception. Ensure all support staff who work in contraceptive services with young people receive both formal and on-the-job training in how to offer basic information and advice about contraception. They should be aware of the range of methods available, the advantages and disadvantages of each method, and the measures that can be taken to manage any side effects. Training should be regularly updated and tailored to individual needs to ensure staff have the skills and knowledge relevant for their role. Ensure all staff working for contraceptive services for young people, including administrative staff, know about the duty of confidentiality and child protection processes and legislation. They should be trained in the Department of Health's best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health. They should also be aware of local mechanisms for reporting concerns relating to safeguarding policy and procedures. Ensure all staff are aware of local contraceptive service referral pathways so that they know how to direct young people to the services they need – whether it is for advice on, or the provision of, contraceptives (including condoms and emergency contraception) or abortion services.# Public health need and practice # Background Young people's adolescent years, and the period up to their mid-twenties, are a time when they are exploring and establishing sexual relationships. According to the 2000/01 'National survey of sexual attitudes and lifestyles' (Johnson et al. 2005), the median age of first intercourse was 16 years for both men and women. It is estimated that between one-quarter and one-third of all young people have sex before they reach age 16. Among those leaving school at 16 with no qualifications, 60% of boys and 47% of girls had sex before they were 16 (Wellings et al. 2001). Among those aged 16–19, 7% of men and 10% of women reported using no form of contraception at first intercourse. Unprotected first sex was more likely for the youngest age groups (Johnson et al. 2001). A survey of young people aged 16–18 in London reported that 32% of black African men, 25% of Asian women, 25% of black African women and 23% of black Caribbean men did not use contraception at first intercourse (Testa and Coleman 2006). Access to contraceptive services is most problematic for people in disadvantaged communities. There is a 6-fold difference in teenage conception and birth rates between the poorest areas in England and the most affluent. There is a clear link between sexual ill-health, deprivation and social exclusion; unintended pregnancies can have a long-term impact on people's lives. Under‑18 conceptions can lead to socioeconomic deprivation, mental health difficulties and lower levels of educational attainment. In addition, resulting children are at greater risk of low educational attainment, emotional and behavioural problems, maltreatment or harm, and illness, accidents and injuries (Department for Children, Schools and Families 2008). England has one of the highest rates of teenage pregnancy in western Europe. Figures for England and Wales show that the 2010 under‑18 conception rate (35.5 conceptions per 1000) is the lowest estimated rate since 1969. The 7.3% decline in under‑18 conceptions from 2009 to 2010 represents the greatest single year decrease since 1975/76. Data for England and Wales show that conception numbers and rates fell among all age groups under‑18. Younger age groups (especially those under 15) continue to account for a very small proportion of teenage conceptions. In 2010, under‑15s accounted for 5% of under‑18 conceptions (Department for Education 2012). National progress masks significant variation in local area performance. In England, the north east region had the highest pregnancy rate of 44.3 per 1000 young women aged 15–17 years while the east of England had the lowest rate at 29.8 per 1000. In virtually every local authority there are hotspots in which annual conception rates are greater than 60 per 1000 young women aged 15–17. However, some of the most deprived boroughs in the country have achieved reductions of more than 25% since 1998 (Department for Children, Schools and Families 2010). Although 88% of women in a heterosexual relationship report using at least 1 method of contraception, abortion rates have increased since the Teenage Pregnancy Strategy was published (Office for National Statistics 2009). In 2009, the highest abortion rate was in women aged 19–21, at 33 per 1000 pregnancies (DH 2010). The abortion rate for those under 16 was 4 per 1000, and for those under 18 the rate was 17.6 per 1000 (DH 2010). Repeat abortions accounted for 25% of all abortions in women under 25 in 2009. The percentage of conceptions among women under 25 that end in abortion demonstrates that many of these pregnancies are unwanted. It suggests that contraceptive services are failing to meet the needs of young people, who are not getting access to effective methods of contraception and advice about using contraception effectively. Since the Teenage Pregnancy Strategy was published in 1999, the focus has been on reducing under‑18 conceptions. The contraceptive and sexual health needs of those aged between 19 and 24, a group that has high rates of unintended or unwanted pregnancy, may have been neglected. Campaigns and services aimed at teenagers may not be as relevant to this group (Independent Advisory Group on Sexual Health and HIV and Medical Foundation for AIDS and Sexual Health 2008). Teenage pregnancies have a high cost implication for public funds. It has been estimated that the cost to the NHS is £63 million a year (Department for Children, Schools and Families 2006). Teenage pregnancies place significant pressures on local authority social care, housing and education services. In 2006/07, local authorities spent £23 million on support services for teenage parents (Department for Children, Schools and Families 2008). National Statistics data on abortions during 2009, combined with reference cost data for the same year, indicate that abortions for women aged under 25 cost the NHS approximately £53.3 million in 2009. # Government action The Department of Health's framework for sexual health improvement in England aims to reduce unwanted pregnancies by ensuring people: have access to the full range of contraception can obtain their chosen method quickly and easily can plan the number of children they have and when. A review of the previous National Strategy for Sexual Health and HIV identified that contraceptive services needed further attention (Independent Advisory Group on Sexual Health and HIV and Medical Foundation for AIDS and Sexual Health 2008). Some local areas have suffered from disinvestment in community contraceptive services, although young people and those from vulnerable communities generally prefer these services to primary care services (Independent Advisory Group on Sexual Health and HIV 2009). The recommended standards for sexual health services suggest that people should have access to accurate information about, and free provision of, all contraceptive methods (Medical Foundation for AIDS and Sexual Health 2005). To reinforce these standards and the continuation of the Teenage Pregnancy Strategy, the Department of Health announced additional resources for primary care trusts and strategic health authorities between 2008 and 2011 to improve access to and uptake of effective contraception. The additional funding was focused on developing services in more schools and colleges and extending the range of services they provide, although the Teenage Pregnancy Independent Advisory Group was concerned that take up of the new money had been patchy and there was no national monitoring (Teenage Pregnancy Independent Advisory Group 2009). From April 2009, GPs have been provided with incentives, through the quality outcomes framework, to provide advice on contraception and particularly long-acting methods, and abortion services are required to provide advice on contraception to all their clients (Department for Children, Schools and Families 2010). From 1 April 2013, local authorities have a mandatory responsibility for commissioning and delivering all community and pharmacy contraceptive services (apart from services provided by general practitioners). Clinical Commissioning Groups are responsible for commissioning termination of pregnancy services (abortions) and a fully integrated range of contraception, STI testing and treatment services. They are also responsible for commissioning vasectomy and female sterilisation services.# Considerations The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations. Most of the evidence considered for the reviews of effectiveness is from the USA. The UK healthcare system differs from the US system in its organisation, use of resources and access. Furthermore, the ethnic composition of the UK population differs in a number of respects. There was little direct evidence about young people from socially disadvantaged groups. In addition, the PDG had to consider, on a case by case basis, whether it was reasonable to apply evidence derived from the USA (for example, on African Americans) to socially disadvantaged young people in the UK. The PDG was clear that service providers should not be discriminating and judgmental, and should respect young people's choices and way of life. Attitudes that could be perceived as critical might deter young people, particularly socially disadvantaged young people, from attending services again. Services must be fully accessible for young people with disabilities and should prioritise individual needs. The local pharmacy has a vital role in meeting the needs of diverse communities, particularly the needs of young people who may be anxious about approaching contraceptive services. Pharmacists, including those working for private retail chains, are part of a local primary care and wider health service network. The pharmacy section in a large supermarket may be the only service that is easily available and accessible within some rural areas. The PDG recognised that all health professionals and service providers have the right to refuse to provide or prescribe contraception, if doing so is contrary to their personal or religious beliefs. However, the PDG did not think it acceptable that provision of contraception, including emergency contraception, should depend on whoever happens to be on duty. If, for any reason, there is limited or variable provision in the local pharmacy, young people requiring urgent treatment, for example emergency contraception, may find it difficult to reach alternative services. This was a cause of concern. The evidence shows that advance provision of oral emergency contraception does not encourage risky sexual behaviour among young people. Evidence also shows that women who have emergency contraception in advance are more likely to use it, and to use it sooner after unprotected sex. Having emergency contraception on hand does not affect the use of other kinds of contraception (Polis 2007). The PDG felt that advance provision of free oral emergency contraception could fulfil an unmet need for some young people. It might also provide an early opportunity to discuss contraception and broader sexual health issues and needs. The focus of the guidance is on the provision of effective contraceptive services, but not all methods of contraception are designed to protect against STIs. Young people may not always realise that the most appropriate contraceptive method for them may offer no protection against STIs. Only the condom is effective against STIs, including HIV. The PDG recognised that sexual health is an important aspect of the physical and mental wellbeing of young people, and that contraceptive services should be delivered in the broader context of sexual, physical, emotional and mental health and wellbeing. Self-referral to contraceptive services through GP services, young people's services, community contraceptive services and 'one stop shops' is valuable. Assumptions about where young people prefer to get their services must be avoided, and a range of 'young-people friendly' contraceptive services will continue to be required. Young people's needs for information and demands for services may differ according to their age, way of life and cultural background. It is important that contraceptive services are available for all young people. A universal service does not imply that every young person has the same needs. Socially disadvantaged young people are likely to need more support than others. Some may need more personalised and tailored advice and support. The guidance applies to all young people but there is a greater focus on young people who could be considered to be socially disadvantaged, and those from areas with a higher concentration of socially disadvantaged young people. The PDG acknowledged that the term 'socially disadvantaged young people' covers a range of people who may not be easily identified, that those considered to be socially disadvantaged might vary in different local areas, and that people may move in and out of social disadvantage at different points in their lives. There are some socially disadvantaged groups who have very limited access to contraceptive services, for example asylum seekers or Gypsy and traveller communities. Some socially disadvantaged young people may have multiple health and sexual health needs. They may also need or be receiving support from social, voluntary or children's services, which is often fragmented or inconsistent. Information and advice about contraception and sexual health may be provided by different teams and different provider organisations. In the economic modelling undertaken for this topic, it was argued that the savings in government-funded benefits to young mothers having fewer teenage births was a real saving to the community. In most cases, transfers of money from taxpayers to recipients (known as 'transfer payments') are not counted as either costs or benefits from a societal perspective because they cancel out, and involve simply a redistribution of existing wealth. However, in the case of government-funded benefits to single mothers, the need for paying the benefits is removed if there is no baby. The funds that would have been used for this purpose can be used for something else. The PDG considered the argument that reductions in government-funded benefits were a saving of costs and concurred with it. The modelling considered cases in which increased use of contraception delays pregnancy until the woman reaches her 20s, and those in which it results in the absence of a pregnancy altogether. Good quality contraceptive services for young people depend on doctors and nurses who not only are sensitive to their needs but properly trained. The PDG believes that all doctors and nurses need access to high quality pre- and post-registration contraception and sexual health training modules and courses and clinical placements without delay. There are unseen barriers to contraceptive use for some socially disadvantaged young people. For example some hormonal methods may not be suitable for women on highly active antiretroviral therapy (HAART). In addition, some young women might be worried if their periods stop or become irregular as a result of some forms of contraception. There was no evidence on the effectiveness of national media campaigns. It would be beneficial for any future national media campaigns to be planned with involvement of local organisations. There is variation in practice across the country in terms of meeting the standards set out in 'You're welcome' (DH 2007). Some services will surpass the standards, whereas others will not yet have met them. The high rates of unwanted and unintended pregnancy among women aged 19–24 years is a cause for concern. There was little evidence about their attitude towards contraception and their use of contraceptive services. Service providers have focused on targets and priorities related to the Teenage Pregnancy Strategy, yet the needs of those who are slightly older, particularly those who are socially disadvantaged, are not well understood and are not being met. The PDG acknowledged that there are many myths surrounding contraception, for example, the idea that using 2 condoms is better than using 1, or that you cannot get pregnant the first time you have sex. Lack of knowledge and misinformation about pregnancy risk and contraception is likely to prevent young women from seeking advice and support when they most need it.# Recommendations for research The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects. . What are the most effective and cost effective ways to provide contraceptive services for socially disadvantaged young people to prevent unwanted pregnancies? In particular, what are the most effective and cost effective ways to provide contraceptive services for looked after children, those with learning difficulties, those who are not in education, employment or training or women who have had an abortion? . What are the most effective ways to get socially disadvantaged young women and men involved in designing contraceptive services that meet their needs and reduce the barriers to access? . How effective and cost effective are interventions that reduce unintended conception and abortion rates among young people aged under 25 years? . What is the differential impact of interventions that aim to reduce unintended conception and abortion rates among young people aged under 25 years on subgroups of socially disadvantaged young people? . What interventions and service models enable young people from diverse faith and cultural communities to access contraceptive services and meet their contraceptive needs? More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.# References Department for Children, Schools and Families (2006) Teenage pregnancy: accelerating the strategy to 2010. London: Department for Children, Schools and Families Department for Children, Schools and Families (2008) Teenage parents: who cares? A guide to commissioning and delivering maternity services for young parents. London: Department for Children, Schools and Families Department for Children, Schools and Families, Department of Health (2010) Teenage pregnancy strategy: beyond 2010. London: Department for Children, Schools and Families Department for Education (2012) Under-18 and under-16 conception statistics. London: Department for Education Department of Health (2004) Best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health. London: Department of Health Department of Health (2011) You're welcome quality criteria: making health services young people friendly. London: Department of Health Department of Health (2010) Abortion statistics, England and Wales: 2009. statistical bulletin 2010/01. London: Department of Health Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit (2004) Contraceptive choices for breastfeeding women. Journal of Family Planning and Reproductive Health Care 30: 181–9 Faculty of Sexual and Reproductive Healthcare (2012) Service standards for sexual and reproductive health services. London: Faculty of Sexual and Reproductive Healthcare Faculty of Sexual and Reproductive Healthcare (2010) Contraceptive choices for young people. Clinical guidance. London: Faculty of Sexual and Reproductive Healthcare Independent Advisory Group on Sexual Health and HIV and Medical Foundation for AIDS and Sexual Health (2008) Progress and priorities – working together for high quality sexual health: Review of the national strategy for sexual health and HIV London: Medical Foundation for AIDS and Sexual Health Independent Advisory Group on Sexual Health and HIV (2009) The time is now: achieving world class contraceptive and abortion services. London: Department of Health Johnson A, Fenton A, Copas et al. (2005) National survey of sexual attitudes and lifestyles (NATSAL II) 2000–2001. London: National Centre for Social Research Johnson AM, Mercer CH, Erens B et al. (2001) Sexual behaviour in Britain: partnerships, practices, and HIV risk behaviours. Lancet 358: 1835–42 Marmot M (2010) Fair society, healthy lives: strategic review of health inequalities in England post-2010. London: University College London Medical Foundation for AIDS and Sexual Health (2005) Recommended standards for sexual health services. London: Medical Foundation for AIDS and Sexual Health Office for National Statistics (2009) Opinions survey report no. 41 contraception and sexual heath, 2008/09 Office for National Statistics (2010)Conception statistics in England and Wales, 2008 Accessed 12 May 2010 Polis CB, Grimes DA, Schaffer K et al. (2007) Advance provision of emergency contraception for pregnancy prevention. Cochrane Database of Systematic Reviews Issue 2: CD005497 Population Action International (2007) A measure of survival: calculating women's sexual and reproductive risk. Washington DC: Population Action International Teenage Pregnancy Independent Advisory Group (2009) Annual report 2008/9. London: Department for Children, Schools and Families Testa A, Coleman L (2006) Sexual knowledge, attitudes and behaviours among black and minority ethnic youth in London. London: Trust for the Study of Adolescence and Naz Project Wellings K, Nanchahal K, Macdowall W et al. (2001) Sexual behaviour in Britain: early heterosexual experience. Lancet 358: 1843–50# Appendix B Summary of the methods used to develop this guidance # Introduction The reviews and economic analysis include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations. All supporting documents are listed in appendix E. # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were: What is the effectiveness and cost effectiveness of interventions to encourage young people, especially socially disadvantaged young people, to use contraceptives and contraceptive services (including access to, and information about, contraceptive services)? What are socially disadvantaged young people and their families' perceptions, views and beliefs about contraception and contraceptive services, and where do they get their information about contraception and contraceptive services? These questions were made more specific for each review (see reviews for further details). # Reviewing the evidence ## Effectiveness reviews Five reviews were conducted: a mapping review settings-based reviews of effectiveness a review of views and barriers. The following databases were searched in August 2008 for both quantitative and qualitative studies (1995 to 2008) for all of the reviews: Applied Social Science Index and Abstracts (ASSIA) British Nursing Index Cochrane Database of Systematic Reviews Cinahl Cochrane – Central Cochrane DARE Cochrane Health Technology Assessment Embase MEDLINE PsycINFO Science and Social Science Citation Indices Social Care Online Additionally, the following websites were searched for relevant publications: British Association for Sexual Health and HIV British Medical Association Brook Centre for Reviews and Dissemination Connexions Department for Children, Schools and Families Department of Health Every Child Matters Faculty of Public Health FPA Health Protection Agency Joseph Rowntree Foundation Margaret Pyke Centre Medical Foundation for AIDS and Sexual Health National Electronic Library for Health – Guidelines Finder National Electronic Library for Health – Public Health NICE (and HDA) Royal College of General Practitioners Royal College of Nursing Royal College of Obstetricians and Gynaecologists Royal College of Paediatrics and Child Health Royal Pharmaceutical Society of Great Britain Sex Education Forum Sex Education Forum at the National Children's Bureau SIGN (Scottish Intercollegiate Guidelines Network) Social Care Institute for Excellence South West Public Health Observatories Teenage Pregnancy Unit US National Guidelines Clearinghouse Welsh Assembly Government – Health Promotion Wales World Health Organisation Studies were included in the effectiveness reviews if: They included under 25s. Studies were excluded if: They focused solely on people aged 25 and older. Although a younger age cut off was not explicitly stated, consideration was also given to the Fraser guidelines for competence to consent. They covered sexual health services that do not provide contraceptive services. They covered sterilisation, including vasectomy. They covered abortion (services which do not also provide contraception). They covered use of contraceptive methods for non-contraceptive reasons, for example, for menorrhagia (heavy periods). ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. − Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. The evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable). ## Summarising the evidence and making evidence statements The review data was summarised in evidence tables (see full reviews). The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect their judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope. # Cost effectiveness There was a review of economic evaluations and an economic modelling exercise. ## Review of economic evaluations One economic evaluation was identified within the 3 reviews which considered the cost effectiveness of an intensive, school-based intervention for teen mothers to prevent repeat pregnancies. This economic evaluation was poorly reported and appeared to contain some errors within the calculations. No other economic evaluations that met the inclusion criteria were identified by the reviews. ## Economic modelling A number of assumptions were made that could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details). An economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in: Modelling the cost-effectiveness of interventions to encourage young people, especially socially disadvantaged young people, to use contraceptives and contraceptive services. # Fieldwork Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in contraceptive services, including those working in the NHS, private providers, education and the voluntary sector. The fieldwork comprised: Focus groups carried out nationally by GHK with practitioners and commissioners working in the NHS, education and the private and voluntary sectors. telephone interviews carried out by GHK. The 2 studies were commissioned to ensure there was ample geographical coverage. The main issues arising from these 2 studies are set out in appendix C under fieldwork findings. # How the PDG formulated the recommendations At its meetings in 2009 and 2010, the Programme Development Group (PDG) considered the evidence and cost effectiveness to determine: whether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guidance. The PDG developed draft recommendations through informal consensus, based on the following criteria: Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. Where evidence was lacking, the PDG also considered whether a recommendation should only be implemented as part of a research programme. Where possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence). The guidance was due to be published in November 2010. However it was put on hold pending a Government review of NICE's public health work and while the Department of Health finalised its sexual health framework. The recommendations have not changed, only factual amendments have been made, for example, where names of organisations have been changed.# Appendix C The evidence This appendix lists the evidence statements from 4 reviews (3 settings-based reviews and a views review) provided by the public health collaborating centre (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix E for details). It also lists 5 expert reports and their links to the recommendations and sets out a brief summary of findings from the economic analysis and the fieldwork. The 4 reviews of effectiveness are: A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in education settings. A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: views review. A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in healthcare settings. A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in community settings. Evidence statement E1a indicates that the linked statement is numbered 1a in the review 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in education settings'. Evidence statement V1a indicates that the linked statement is numbered 1a in the review 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: views review'. Evidence statement H1a indicates that the linked statement is numbered 1a in the review 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in healthcare settings'. Evidence statement C1a indicates that the linked statement is numbered 1a in the review 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in community settings'. ER-IHYP indicates evidence in the expert report 'Improving healthcare for young people'. ER-TPS indicates evidence in the expert report 'Teenage pregnancy strategy'. ER-AHC indicates evidence in the expert report 'Access to health care: how do we reach vulnerable groups?' ER-CSSDP indicates evidence in the expert report 'Contribution to NICE guidance on contraceptive services for socially disadvantaged young people'. ER-DH indicates evidence in the expert report 'DH evidence: NICE guidance on contraception for socially disadvantaged young people'. See also the full reviews, expert reports, economic analysis and fieldwork report. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: evidence statements V15, V25, V26, ER-IHYP, IDE Recommendation 2: evidence statements V2, V12, V15, V19, V22, V25, V26, ER-IHYP, IDE Recommendation 3: evidence statements C1a, C1c, H4, V1a, V1b, V2, V11, V12, V15, V16, V19, ER-IHYP, IDE Recommendation 4: evidence statements C2d, H1b, H4, E6a, V1a, V2, V12, V15, V19, ER-IHYP, IDE Recommendation 5: evidence statements V2, V12, V14, V17, V18, ER IHYP, IDE Recommendation 6: evidence statements C2a, H1b, E6a, V1a, IDE Recommendation 7: evidence statements C2a, H1b, E6a, V1a, IDE Recommendation 8: evidence statements E3a, V1a, V2, V11, V12, V15, V19, IDE Recommendation 9: evidence statements H2, V1a, V1b, V1c, V11, V20, IDE Recommendation 10: evidence statements H3, V1a, V1b, V7, IDE Recommendation 11: evidence statements C1a, C1c, E6b, V1a, V2, V11, V17, IDE Recommendation 12: evidence statements V1a, V1b, V2, V12, V14, V18, V19, V27, IDE # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style. ## Community review evidence statements There is mixed evidence from 5 studies to suggest that media based interventions may reduce teenage pregnancy, increase contraceptive use and improve the knowledge and attitudes of young people in relation to these outcomes: Moderate evidence from 1 randomised controlled trial (RCT) (++) showed that a computer based intervention could significantly reduce pregnancy and improve emergency hormonal contraception (EHC) use, as well as improving knowledge and attitudes based outcomes). Weak evidence from 2 before-and-after studies (2 −) suggest that social marketing campaigns may have a significant effect on the use of contraception or EHC as well as knowledge and attitude based outcomes. In the first study (−), compared with the controls, participants in the intervention group were significantly more likely to have heard of EHC, know the mechanism of action of EHC, have discussed EHC with a care provider, received an advanced prescription for EHC, and intend to use EHC in the future if needed. The second study (−) showed that increased exposure to the social marketing campaign was associated with a significant increase in condom use at last sexual experience. There is inconsistent evidence from 8 studies to suggest that community based interventions may be effective in preventing repeat pregnancy: Inconsistent evidence from 3 RCTs (2 ++, 1 +) suggests that home visitors may be effective in preventing repeat pregnancy; only 2 of the 3 studies measured repeat pregnancy rate as an outcome and only 1 of these provided evidence of clear benefit. The first RCT (++) showed a significant reduction in repeat birth for the intervention group. The second RCT (+) showed a significant improvement in parenting scores for the intervention group, but the effect on repeat pregnancy was not significant. The third RCT (++) showed a significant improvement in contraceptive use for the intervention group, but did not measure repeat pregnancy. Moderate evidence from 1 RCT (+) suggests that generic programmes for teen mothers (to prevent repeat pregnancy, increase school retention, reduce substance abuse, and improve wellbeing) could be effective in significantly reducing repeat pregnancy and consequent births. ## Healthcare review evidence statements Moderate evidence from 5 studies (2 +, 3 −) suggests that outreach programmes to encourage young people to attend mainstream sexual health services may be effective in increasing service use, but the effect on reducing teenage pregnancy rates is unclear. In the non-RCT study (+), compared with control, the outreach group was significantly more likely to likely to report consistent contraception use, and women were also less likely to report pregnancy. In the first cohort study (+) condom use increased and pregnancy decreased, but the impact of the intervention is unclear because of poor reporting. In the second cohort study (−), during the 5 years of the intervention, the number of attendees at family planning clinics aged under 20 and under 16 significantly increased. Pregnancy is reported to have 'remained low' but no data is given. In the third cohort study (−), those who attended an orientation session were significantly more likely to start using services, and attendance at the 3-month booster session was associated with significantly higher continued clinic contact at 1 year. In the interrupted time series study (−), the number of new users of family planning services aged under 26 years increased significantly in the first 18 months of the outreach programme. There is strong evidence from 4 RCTs (3 ++, 1 +) to support the advance provision of EHC to young people to increase EHC use. In most cases increased use was not at the expense of other contraceptive use, and did not promote risky sexual behaviour; the exception was 1 study (+) with adolescent mothers. In the first study (++), at 6-month follow up EHC use was significantly higher in the intervention (advanced provision) group than the control, and the mean time to use EHC was significantly shorter in the intervention group compared with the control group. There were no differences in hormonal contraception or condom use between the groups. In the second study (++) (with random allocation to receive EHC via pharmacy, clinical access or advance provision) EHC use at 6-month follow up was significantly greater in the advance provision group than the clinical access group. Pharmacy access did not affect EHC use when compared with clinic access. In the third study (++), the advance EHC group reported (non-significantly) higher emergency contraception use and significantly sooner use. In the fourth study (+), at 12-month follow up those in the advance provision group were significantly more likely than the controls to have used EHC, but also more likely to have had unprotected sex in the past 6 months. There is strong evidence from 5 studies (4 ++, 1 −) to support interventions that combine discussion and demonstration of condom use to increase adolescent condom use and engagement with clinical services. In the first study (++), at 6 month follow up intervention subjects reported statistically significant increase in condom use by their sexual partner for protection against STIs. In the second study (++), at 1 year clients were twice as likely to report having received condoms from the clinic. In the third study (++), of 2 methods of cognitive behavioural therapy (CBT) to reduce unprotected sex, those in the skills-based CBT group were significantly less likely to have unprotected sex at 12 months than those in the information-based CBT group or control group. In the fourth study (++), more of the intervention group than the comparator group returned for their scheduled clinic revisits (statistical significance not clear). In the fifth study (−) it is suggested that, compared with the rest of the country, attendance at the GUM clinic by young people is much higher, particularly at sites offering daily access and located geographically close to a school (no statistical data are given to validate this). Although the studies were mostly well designed, the data were not always well analysed and reported, which may have affected reliability. Applicability in the UK may also be limited because most of the studies were conducted in the USA/Canada (2 in populations that were majority black American and 1 population who were African American/Latino). Strong evidence from 2 RCTs (2 ++) and 1 non-RCT (+) suggests that interventions aimed to improve adolescent contraceptive use by additional service provision can be effective, but this depends on the intervention. The first study (++) was of a nurse led one-to-one intervention, the intervention group reported significantly greater oral contraception adherence than the controls. The second study (+) was of a computer based contraception decision aid intervention. At 1-year follow up the first intervention group had significantly higher contraception knowledge and (non-significantly) fewer pregnancies than the non-intervention group. This finding was not replicated in a second study population. The third study (++) was of an intervention to administer 'quick start' of contraception (immediately administered contraceptive injection), at 6-month follow up there were no differences in continuation rates or pregnancy rates between the groups. ## Education review evidence statements Strong evidence from 3 papers (2 +, 1 −) supports the direct provision of contraceptives dispensed on site from school based health centres as a way to increase contraceptive provision. However, the use of those contraceptives or any subsequent outcomes is unclear. In the first study (+), significantly more of the intervention cohort selected hormonal contraception at the first or second visit than the control cohort, and were also significantly less likely to select no contraception. In the second study (+), adolescents in the intervention group were significantly more likely to receive condom/HIV instruction, and significantly less likely to report lifetime or recent sexual intercourse. Sexually active adolescents in the intervention group were twice as likely to use condoms but less likely to use other contraceptives. In the third study (−), direct provision led to a statistically significant increase in the number of contraceptives prescribed to young people. The data analysis in this paper is poor, giving only percentage increases, but it does appear to indicate that on site dispensing increases contraceptive provision. Strong evidence from 3 studies (3 +) suggests curriculum interventions that include community outreach components can be effective in preventing teenage pregnancy and risky sexual behaviour. In the first study (+), rates of pregnancy, along with rate of school failure and academic suspension, were significantly lower in the Teen Outreach group than the control group. In the second study (+) Teen Outreach was again shown to be effective, especially for those who were already teen parents. In the third study (+) Reach for Health participants were significantly less likely than controls to report sexual initiation or recent sex. Moderate evidence from 1 study (+) suggests that a virtual world intervention was effective when associated with a curriculum based intervention about sexual risk behaviour. The intervention group had significantly better understanding than the control group of how reproduction works and the possible consequences of sex, and of the importance of behaving in ways that limit sexual experience. ## Views review evidence statements Three qualitative studies (1 ++, 1 +, 1 −) describe a lack of knowledge among young people about potential consequences of sexual activity. One paper covering interviews with 16–21 year olds as part of a mixed method study (−) describes a lack of knowledge before first sexual experience and lack of knowledge about the consequences of sexual activity. This was echoed in interviews with 16–23 year olds from black and ethnic minority groups, who reported a lack of knowledge about risky sexual activity (+). Also, interviews with young mothers aged 14–16 years reported gaps in their knowledge about becoming pregnant and abortion (++). Three qualitative studies (2 ++, 1 −) describe a lack of knowledge about correct use of contraception among young people. Gaps in knowledge about aspects of contraception were reported in young mothers aged 14–16 (++), in a mixed group of 16–25-year-old women (++) and in a mixed group of 15–18 year olds (−). One qualitative study (++) suggests that a lack of knowledge about contraception methods may be greater in young people from deprived areas and found that lack of knowledge regarding contraception methods was greater in socially disadvantaged young women aged 16–20. One qualitative interview study (++) highlights emergency hormonal contraception as an area of particular lack of knowledge among young women aged 16–25. Survey data suggest knowledge of emergency contraception in 78–90% of school aged girls. One survey linked less knowledge of emergency contraception with being a pupil at a school with lower academic achievement. One qualitative study (++) reports that discussion of sex and contraception is embarrassing. A study of mixed young city dwellers aged 16–25 reported that the younger participants reported that discussing sex or any type of contraception was embarrassing. The potential for feelings of embarrassment to inhibit young people from using contraceptive services is outlined in 7 papers (1 ++, 5 +, 1 −) reporting views from a variety of groups of young people. Clients of family planning clinics describe embarrassment or stigma associated with accessing contraceptive supplies (++). Young people from ethnic minorities also describe embarrassment if they are seen accessing a service (−). At a male drop-in service, 66% of clients reported that embarrassment would stop them using a service. Young people of school age (2 +) echo this embarrassment about accessing services. One survey reports 20–24% of 11–39 year old women had been embarrassed, scared or concerned about using a sexual health service. Another paper (+) describes women of 16–25 years old feeling embarrassed when using contraceptive services. Mixed groups of young people described embarrassment as a barrier to obtaining and using condoms (+). The importance of clinics overcoming young people's feelings of embarrassment was also recognised by staff (GPs and nurses) (2 +). Two papers (1 +, 1 ungraded survey) report embarrassment related specifically to particular services. One (+) reports that young people aged 14–25 perceive that at times teachers are clearly embarrassed when discussing sexual issues, leading to the young people also feeling embarrassed. The other states that 63% of young women and 46% of young men aged 15–16 years reported embarrassment about attending a consultation with a GP in regard to sexual health. One study (+) describes a particular aspect of accessing a service that is embarrassing. It reports that young people aged up to 24 feel embarrassed when giving their name and address at a reception desk. Three studies (1 ++, 1 +, 1 −) suggest that condoms can be perceived negatively, as uncomfortable or a barrier to intimacy, among some teenagers. Two (1 ++, 1 +) report these negative views among teenagers aged 14–15 and teenagers including those who were young mothers or pregnant, and another study (−) reports a mix of positive and negative perceptions of condom use among 12–13 year olds and 16–17 year olds. Four studies (1 ++, 1 +, 2 −) suggest some young people think that there are negative connotations for young women carrying condoms. Three studies (1 ++, 2 +) describe uncertainty among young people about where to go to access contraceptives, especially among young men and younger participants. Five papers (1 ++, 2 +, 2 −) describe the importance of young people perceiving that contraceptive services are trustworthy and legitimate, enabling them to feel confident, and being in control when using them. Five studies (1 ++, 4 +) report that some young people have concerns about attending a GP practice for contraceptive services because of a perceived potential loss of confidentiality. This seems to be a particular concern in rural communities. Eleven studies (5 ++, 5 +, 1 −) suggest the importance of accessibility of services for young people, with convenient location, extended opening hours, and choice in location as important elements. Studies report varying views about whether an appointment system or a drop-in service provides greater accessibility for young people. Four (2 ++, 1 +, 1 −) suggest an appointment-free system offers convenience. However, 1 (+) reports that staff perceive that waiting times in a clinic are not an obstacle to accessibility. One survey of young people reported that 62% would prefer a walk-in service. Another survey suggested that young people may appreciate the option of making appointments by telephone. Eight studies (1 ++, 6 +, 1 −) report that preserving anonymity when accessing services is a significant concern for young people. These concerns regarding anonymity are also perceived by staff (1 ++, 3 +, 1 −). Eleven papers (3 ++, 6 +, 2 −) report that confidentiality is a key concern for young people in accessing a sexual health service. Concerns regarding confidentiality feature particularly in regard to rural areas and GPs. A range of qualitative studies and survey data highlights that young people value staff who have a respectful and non-judgemental attitude towards them. Five papers (3 +, 1 −, 1 ungraded survey) report that staff also recognise the importance of being non-judgemental. However, they highlight that some staff may have ambivalent or varying attitudes towards young people and sexuality. Three studies (1 ++, 2 +) report that the cost of contraception is a concern for some young people. Four studies (1 ++, 2 +, 1 −) provide evidence from young people regarding the importance of a comfortable and welcoming atmosphere in sexual health service premises. This is echoed in a study of staff views. There is evidence from 5 studies (1 ++, 1 +, 3 −) that staff have concerns regarding limited availability of resources for sexual health services. There is evidence from 6 studies (3 ++, 1 +, 1 −, 1 ungraded survey) that staff perceive that well-organised services, and different agencies working together effectively, are important. There is evidence from 6 studies (2 +, 4 −) that staff perceive a need for greater training in providing contraceptive services for young people. ## Expert report/s Improving healthcare for young people Teenage pregnancy strategy: NICE meeting: 17 September Access to health care: how do we reach vulnerable groups? Learning from the teenage health demonstration sites Contribution to NICE guidance on contraceptive services focusing on socially disadvantaged young people Department of Health evidence: NICE guidance on contraception focusing on socially disadvantaged young people # Cost-effectiveness evidence The economic analysis indicates that, from a public sector perspective, providing contraceptives in schools and colleges is cost effective and results in net cost savings compared with no provision of contraceptives in these places. This result is robust to changes in the key model assumptions if the costs of government-funded benefits are included within the analysis. However, if government-funded benefits are excluded from the analysis, providing contraceptives within schools and colleges, while still being cost effective, has around a 50% probability of resulting in net cost savings. The analysis also suggests that providing hormonal contraception within schools and colleges is likely to be more effective than providing condoms in terms of preventing pregnancies. This may also lead to greater cost savings than dispensing condoms. However, this comparison is subject to considerable uncertainty. The economic analysis also suggests that, from a public sector perspective, intensive follow‑up and support after a teenage pregnancy results in a cost of £4000 for every repeat teenage pregnancy averted. This is in comparison with no follow-up after a teenage birth. Excluding government-funded benefits from the analysis leads to an estimated cost per repeat teenage pregnancy averted of £15,000. From a public sector perspective, advance provision of emergency hormonal contraception is estimated to be more effective and less costly than not providing it in advance. However, when government-funded benefits are excluded from the analysis (that is, an NHS and personal social services perspective is adopted), the intervention is estimated to cost £310 per pregnancy averted among those aged 15–19, compared with no advance provision. Finally, the analysis suggests that providing emergency hormonal contraception in advance is likely to be cost saving from a public sector perspective, when provided within schools and colleges alongside other contraceptives These results are informed by the following: The Teenage Pregnancy Strategy's target to halve the under‑18 conception rate by 2010. It has been assumed that before conception, the value of a future baby to society is neither positive nor negative. From this, it is clear that preventing conception cannot be measured in QALY terms, because future QALYs do not exist before conception. Thus the cost effectiveness of preventing a conception has been measured in terms of cost per pregnancy averted. However, once conceived and born, the baby is invested in a life expectancy, so that the loss of such a baby after birth can be measured as a loss of QALYs. A government-funded benefit given to young mothers can either be regarded as a transfer payment (from taxpayers to young mothers) or as a real resource cost. If it is seen as a transfer payment, the benefit to the mother is an equivalent cost to the taxpayer and these items cancel out. However, if the contraceptive intervention prevents a baby from being born, the money can be used by the government for other purposes without any opportunity cost. Following this logic, having fewer teenage births results in a much greater cost saving than if such benefits are considered as a transfer payment. # Fieldwork findings Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, see the fieldwork section in appendix B and the full fieldwork report. Fieldwork participants who work with socially deprived young people were very positive about the recommendations and their potential to help improve contraception service provision. Many participants stated that the recommendations represented best practice in the area, and although they did not offer an entirely new approach, they agreed that the measures had not been implemented universally. They believed wider and more systematic implementation would be achieved as a result of this guidance.# Appendix D Gaps in the evidence The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below. . There is little UK evidence about the effectiveness of interventions in this field. . There is little evidence about the effectiveness of services and interventions for socially deprived young people, or evidence that searches for a differential effect among different groups of young people. . There are few UK data about the cost effectiveness of contraceptive service provision. The Group made 5 recommendations for research.# Appendix E Supporting documents Supporting documents include: Evidence reviews: Review 1: 'Mapping review: contraceptive services for socially disadvantaged young people' Review 2: 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in education settings' Review 3: 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: views review' Review 4: 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in health care settings' Review 5: 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in community settings'. Economic modelling: 'Modelling the cost-effectiveness of interventions to encourage young people, especially socially disadvantaged young people, to use contraceptives and contraceptive services'. Fieldwork report: 'Fieldwork for draft guidance on contraceptive services focusing on socially disadvantaged young people'.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe guidance complements, but does not replace, NICE's guidelines on long-acting reversible contraception, looked after children and reducing sexually transmitted infections.\n\nThe evidence statements underpinning the recommendations are listed in appendix C.\n\nThe Programme Development Group (PDG) considers that the recommended measures are cost effective.\n\nRecommendations for research are available.\n\nSee also the full evidence reviews, supporting evidence statements and economic modelling report.\n\n# Introduction\n\nThe recommendations advocate providing information and advice on all types of contraception. The aim is to help young men and women choose the method that best suits their individual needs and lifestyle, so making it more likely that they will use contraception and use it effectively. The information should comprise verbal advice and printed material giving details about the:\n\nfull range of contraceptive methods available, but with a focus on the most effective and appropriate choice for the individual concerned\n\nbenefits and risks of each method and how to manage any side effects.\n\n# Definitions\n\nFor the purposes of this guidance young men and women refers to everyone aged under 25 who is competent to consent to contraceptive treatment under the Department of Health's best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health. This guidance states: 'A doctor or health professional is able to provide contraception, sexual and reproductive health advice and treatment, without parental knowledge or consent, to a young person aged under 16, provided that:\n\nshe/he understands the advice provided and its implications\n\nher/his physical or mental health would otherwise be likely to suffer and so provision of advice or treatment is in their best interest.'\n\nIn addition, it is considered good practice for doctors and other health professionals to follow the criteria outlined by Lord Fraser in 1985, commonly known as the Fraser Guidelines:\n\nthe young person understands the health professional's advice\n\nthe health professional cannot persuade the young person to inform his or her parents or allow the doctor to inform the parents that he or she is seeking contraceptive advice\n\nthe young person is very likely to begin or continue having intercourse with or without contraceptive treatment\n\nunless he or she receives contraceptive advice or treatment, the young person's physical or mental health or both are likely to suffer\n\nthe young person's best interests require the health professional to give contraceptive advice, treatment or both without parental consent.\n\nNote: some of the recommendations, for example those on information provision, may also be relevant to young people who are not competent to consent to treatment.\n\nThe recommendations are based on interventions and programmes proven to be effective with all young people aged under 25. They emphasise the need for services that are universal and inclusive. They also emphasise the need to offer additional tailored support to meet the particular needs and choices of those who are socially disadvantaged or who may find it difficult to use contraceptive services. (The latter might include those who are members of some faith and religious groups.) The guidance is based on the principle of progressive universalism (Fair society, healthy lives: strategic review of health inequalities in England post-2010).\n\nFor the purposes of this guidance 'socially disadvantaged young people' may include those who are:\n\nliving in a deprived area\n\nfrom a minority ethnic group (including gypsy and traveller communities)\n\nrefugees, asylum seekers and people recently arrived in the UK\n\nteenage parents or the children of teenage parents\n\nlooked after or leaving care\n\nexcluded from school or do not attend regularly or have poor educational attainment\n\nunemployed or not in education or training\n\nhomeless\n\nliving with mental health problems\n\nliving with physical or learning disabilities\n\nliving with HIV or AIDS\n\nsubstance misusers (including alcohol misusers)\n\ncriminal offenders.\n\nContraceptive services refers to the whole range of contraceptive, sexual and reproductive health services. This includes services:\n\nin primary care\n\noffered by community, education and pharmacy outlets (commissioned by local authorities from the NHS, the private or voluntary sectors)\n\ncommissioned by clinical commissioning groups (for example, termination of pregnancy [abortion] services)\n\ncommissioned by the NHS Commissioning Board (for example, contraceptive services provided within other specialist services, such as maternity services).\n\n# Recommendation 1 Assessing local need and capacity to target services\n\n## Whose health will benefit?\n\nAll young women and men aged up to 25.\n\n## Who should take action?\n\nHealth and wellbeing boards, local authority commissioners and other commissioners of young people's services.\n\nDirectors of public health and directors of children's services.\n\nThose responsible for joint strategic needs assessment, data collection and analysis in local authorities, children's services and their partners.\n\nManagers of contraceptive services in primary and acute care, the voluntary and private sectors.\n\nPublic health practitioners with a responsibility for contraception and sexual health.\n\nThose responsible for young people's advisory services.\n\n## What action should they take?\n\nDirectors of public health, public health practitioners and public health surveillance systems should collect and analyse anonymised regional and local demographic data and information on local contraception and sexual health inequalities. In conjunction with sexual health leads in the NHS and local authorities, they should disseminate the data to inform local strategic needs assessments, so that resources and services can be provided for those with the greatest need.\n\nCommissioners, with support from members of local public health networks, should use anonymised local health data and routinely collected surveillance data on, for example, conceptions, abortions, births and contraceptive prescribing, to identify local needs. These data could be geographical or in relation to specific population groups.\n\nHealth and wellbeing boards, including directors of public health, local public health leads and local authorities, should carry out and publish the results of comprehensive joint strategic needs assessments for young people's contraceptive services. This should include details on socially disadvantaged young people.\n\nMap the current range of local services, service activity levels and capacity across all contraceptive service providers. (Take account of services further afield that may be used by local young people, for example, large pharmacies in nearby town centres.) The mapping should include, but should not be limited to:\n\n\n\nservices provided by GPs, community contraceptive clinics, paediatricians, pharmacies, the voluntary sector and within schools and colleges\n\n'out of hours' (evening and weekend) and outreach provision\n\nstaffing levels and the range of professional skills available (including for GP practices)\n\nthe size of premises, location, opening hours and accessibility.\n\n\n\nUse the data to develop an action plan setting out organisational responsibilities for local services for young people, including those who are socially disadvantaged. Ensure provision is at times and in locations that meet young people's needs.\n\nRegularly evaluate services in the context of this guidance and changing local needs. Use local accountability mechanisms (for example, health scrutiny reports) to examine specific issues.\n\nEnsure the mapping process involves young women and men, including those who are socially disadvantaged, in assessing the need for services (including the type of services needed, opening hours and location).\n\nInvolve young men and women, including those who are socially disadvantaged, in planning, monitoring and evaluating services.\n\n# Recommendation 2 Commissioning coordinated and comprehensive services\n\n## Whose health will benefit?\n\nAll young women and men aged up to 25.\n\n## Who should take action?\n\nHealth and wellbeing boards and commissioners in local authorities and clinical commissioning groups with responsibility for hospital, community, education-based and primary care contraceptive services.\n\nPrimary care, maternity and young people's services and pharmacies.\n\nContraceptive services provided by NHS, voluntary and private sector organisations.\n\n## What action should they take?\n\nIdentify priorities and targets based on local need, using tools such as health equity audit and equality impact assessment.\n\nUse Commissioning for Quality and Innovation (CQUIN) indicators and other arrangements and processes to improve the uptake of effective methods of contraception, as appropriate.\n\nEstablish collaborative, evidence-based commissioning arrangements between different localities to ensure comprehensive, open-access services are sited in convenient locations, such as city centres, or near to colleges and schools. Ensure no young person is denied contraceptive services because of where they live.\n\nProvide contraceptive services within genitourinary medicine and sexual health clinics, either as part of that clinic's services or by hosting contraceptive services provided by another organisation.\n\nEnsure all contraceptive services (including those provided in general practice) meet, as a minimum requirement, the Department of Health's you're welcome quality criteria. They should also meet the Faculty of Sexual and Reproductive Healthcare service standards for sexual and reproductive healthcare and follow their clinical guidance on contraceptive choices for young people.\n\nDevelop joint commissioning of needs-led contraceptive services for young people. This should include coordinated and managed service networks. It should also include comprehensive referral pathways that include abortion, maternity, genitourinary medicine, pharmacy and all other relevant health, social care and children's services. Referral pathways should also cover youth and community services, education, and services offered by the voluntary and private sectors.\n\nEnsure pharmacies, walk-in centres and all organisations commissioned to provide contraceptive services (including those providing oral emergency contraception) maintain a consistent service. If this is not possible, staff should inform young people, without having to be asked, about appropriate alternative, timely and convenient services providing oral emergency contraception.\n\n# Recommendation 3 Providing contraceptive services for young people\n\n## Whose health will benefit?\n\nAll young women and men aged up to 25.\n\n## Who should take action?\n\nManagers, doctors, midwives, nurses, pharmacists, receptionists and other staff working in contraceptive services, including those offered in education, GP services, pharmacies, maternity and postnatal care services, walk-in centres, acute and emergency care, and the voluntary and private sectors.\n\n## What action should they take?\n\nEnsure young people have access, without delay, to confidential, dedicated young people's contraceptive services that, as a minimum requirement, meet the quality criteria set out in recommendation 2.\n\nDoctors, nurses and pharmacists should:\n\n\n\noffer culturally appropriate, confidential, non-judgmental, empathic advice and guidance according to the needs of each young person\n\nset aside adequate consultation time to encourage young people to make an informed decision, according to their needs and circumstances\n\nprovide information about the full range of contraceptives available, including emergency contraception (both oral and intrauterine) and long-acting reversible contraception (LARC; also referred to as lasting and reliable contraception), and the benefits and side effects\n\noffer advice on the most effective methods and how to use them effectively and consistently\n\nif possible, provide the full range of contraceptive methods, including LARC, condoms to prevent transmission of sexually transmitted infections (STIs) and emergency contraception (both oral and intrauterine). If this is not possible, provide contraception to meet immediate needs and provide access to services that can offer advice and timely provision of the full range of methods\n\nprovide free and confidential pregnancy testing with same-day results and, if appropriate, offer counselling or information about where to obtain free counselling\n\nassess the risk of an STI, advise testing if appropriate, and provide information about local STI services.\n\n\n\nService managers, with the support of doctors, nurses and other staff, should offer services that:\n\n\n\nare flexible, for example, offer out-of-hours services at weekends and in the late afternoon and evening\n\nare available both without prior appointment (drop-in) and by appointment in any given area\n\nprovide appointments within 2 working days\n\nstrive to ensure that scheduled appointments run on time and that the waiting time for drop-in consultations is less than 60\xa0minutes\n\ninform young people about the amount of time they can expect to wait\n\nprovide accurate information about opening times and make it clear whether they operate on a drop-in or appointment basis, or a mix of both\n\nare open to young people aged under 16 who present for any service without a parent or carer.\n\n\n\nService managers, doctors, nurses, receptionists, pharmacists and other staff should promote contraceptive services (including those that provide both oral and intrauterine emergency contraception) to young people. They should encourage both young men and women to use them by:\n\n\n\nproviding clear information on all local services in a range of formats that appeal to young people, including leaflets, posters and other formats that are accessible for those with sensory impairments and learning disabilities, with low levels of literacy, or whose English may be poor\n\nadvertising them through the local media, the Internet (for example, via social networking sites), local and community networks (for example, youth services and youth inclusion projects), schools, colleges and other education settings\n\nworking with school and college governors, head teachers, college principals and personal, social, health and economic (PSHE) education lead teachers.\n\n\n\n# Recommendation 4 Tailoring services for socially disadvantaged young people\n\n## Whose health will benefit?\n\nSocially disadvantaged young people aged up to 25.\n\n## Who should take action?\n\nService managers and staff working in contraceptive services. This includes doctors, nurses and pharmacists.\n\n## What action should they take?\n\nProvide additional support for socially disadvantaged young people to help them gain immediate access to contraceptive services and to support them, as necessary, to use the services. This could include providing access to trained interpreters or offering one-to-one sessions. It could also include introducing special facilities for those with physical and sensory disabilities and assistance for those with learning disabilities.\n\nEncourage and help young mothers (including teenage mothers) to use contraceptive services, for example, by working with family nurse partnerships or children's centres.\n\nOffer support and referral to specialist services (including counselling) to those who may need it. For example, young people who misuse drugs or alcohol and those who may have been (or who may be at risk of being) sexually exploited or trafficked may need such support. The same is true of those who have been the victim of sexual violence.\n\nProvide outreach contraceptive services that offer information, advice, and the full range of options. This includes provision for those living in rural areas who cannot reach existing clinics and services.\n\nOffer culturally appropriate, confidential, non-judgmental, empathic advice and support tailored to the needs of the young person. Tailored support might involve, for example, providing relevant information in small manageable amounts, checking whether it has been understood, and reiterating and revising information if required. It could also include using more pictures and diagrams than text.\n\n# Recommendation 5 Seeking consent and ensuring confidentiality\n\n## Whose health will benefit?\n\nAll young women and men up to the age of 25.\n\n## Who should take action?\n\nManagers and staff, including receptionists and administrators, working in services that provide contraception and contraceptive advice to young people. This includes education, maternity services, pharmacies and voluntary and private sector organisations.\n\nManagers and staff in children's services, social care organisations and young people's advisory and support services. This includes guardians, chaperones, interpreters and advocates.\n\n## What action should they take?\n\nEnsure staff are trained to understand the duty of confidentiality and adhere to the recommendations and standards laid out in their organisation's confidentiality policy.\n\nEnsure staff are familiar with best practice guidance on how to give young people aged under 16\xa0years contraceptive advice and support (Department of Health's best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health). Ensure they are also familiar with local and national guidance on working with vulnerable young people.\n\nEnsure those providing contraceptive services can assess the competence of young people aged under 16 to consent to receiving contraceptive advice and any treatment that may involve. They should also be able to assess the competence of other young people who may be vulnerable, for example, those with learning disabilities. Staff need to be able to gauge the young person's ability to understand the information provided, to weigh up the risks and benefits, and to voluntarily express their own wishes. Staff should also encourage young people to involve a parent or person with parental responsibility in the decision-making, where possible.\n\nEnsure young people understand that their personal information and the reason why they are using the service will be confidential. Even if it is decided that a young person is not mature enough to consent to contraceptive advice and treatment, the discussion should remain confidential.\n\nReassure young people that they will not be discussed with others without their explicit consent. Explain that sharing information with another professional may be necessary if there are concerns, for example to protect a young person from possible harm or abuse. If this is the case, the young person should be told who needs to be informed and why.\n\nEnsure the organisation's confidentiality and complaints policy is prominently displayed in waiting and reception areas, and is in a format that is appropriate for all young people.\n\nEnsure young people are asked in private whether they wish anyone else to be present at their consultation\n\nEnsure staff are adequately supported and supervised. This includes establishing a formal debriefing process to help maintain client confidentiality and respect.\n\n# Recommendation 6 Providing contraceptive services after a pregnancy\n\n## Whose health will benefit?\n\nYoung women aged up to 25 who are pregnant, or who have recently been pregnant, and their partners.\n\n## Who should take action?\n\nMidwives, obstetricians and all those working in maternity and postnatal care services.\n\nGPs, health visitors, pharmacists, school nurses and other health professionals working in contraceptive services, primary and community services, family nurse partnerships and acute and emergency care.\n\n## What action should they take?\n\nMidwives should discuss with pregnant women what type of contraception they intend to use after their pregnancy. They should provide information on the full range of options and should advise them (and their partners, if appropriate) on an effective method that best meets their needs. They should also provide information on how and where to obtain it.\n\nAfter pregnancy, midwives should check that women have chosen a method of contraception. If not, they should offer contraceptive advice on a range of effective methods tailored to the woman's circumstances and sensitive to any concerns she may have. This includes advice on contraception for women who are breastfeeding, in accordance with guidance from the Faculty of Sexual and Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists (see Postnatal Sexual and Reproductive Health). They should discuss the benefits and risks of different methods so that those who are breastfeeding are able to continue.\n\nMidwives should provide women with the contraceptive they want before they are discharged from midwifery services. If this is not possible, they should offer a referral to contraceptive services.\n\nHealth visitors, family nurse practitioners and health professionals working with new mothers should check that women have been given advice on contraception and do have contraceptives. If not, they should help them obtain information and advice so that they can choose and receive effective and appropriate contraceptives. Where necessary, they should consider using outreach or home services to provide this support.\n\n# Recommendation 7 Providing contraceptive services after an abortion\n\n## Whose health will benefit?\n\nYoung women aged up to 25 who have had an abortion and their partners.\n\n## Who should take action?\n\nGPs and other primary care practitioners.\n\nContraceptive services.\n\nAbortion services (including those providing early medical abortion).\n\nCounsellors working with abortion services.\n\n## What action should they take?\n\nBefore – and as soon as possible after – an abortion, discuss contraception and explain the full range of contraceptive methods available. Help young women and their partners identify and obtain the most effective method that best meets their needs. Dispel the myth that there is no need for contraception after an abortion and explain that women are fertile immediately following an abortion.\n\nProvide contraception to prevent another unintended pregnancy or refer them to contraceptive services for advice and contraception. If appropriate, offer counselling.\n\nIf the young woman does not want to be referred on, offer to contact her after her abortion to give advice on the most effective and suitable method of contraception for her, using a communication method of her choice (for example, text messages). Also consider using outreach or home services to provide information and contraceptives.\n\n# Recommendation 8 Providing school and education-based contraceptive services\n\n## Whose health will benefit?\n\nYoung people up to age 25 who are of school age or in education.\n\n## Who should take action?\n\nNurses, doctors and counsellors working in contraceptive services within, or associated with, schools, sixth form and further education colleges, universities and other education‑based settings. This includes short-stay schools and young offender institutes.\n\nGovernors, head teachers, teachers, student welfare officers and youth workers in schools, principals and tutors in sixth form and further education colleges and universities and staff in short-stay schools and young offender institutes.\n\n## What action should they take?\n\nInvolve young people in the design, implementation, promotion and review of on-site and outreach contraceptive services in and near schools, colleges and other education settings.\n\nSchool nurses, doctors and counsellors working with young people in schools, colleges and universities should conform to health service standards of confidentiality and to those set by their professional body. All young people should be made aware that one-to-one consultations with them will be confidential, except under the provisions made by law, for example, in relation to child protection.\n\nEnsure accurate and up-to-date contraceptive advice, information and support is readily available to all young women and men. Information on the location and hours of local services should be available outside designated clinic hours.\n\nEnsure contraceptive advice, free and confidential pregnancy testing and the full range of contraceptive methods, including both LARC and emergency contraception, is easily available. If the full range is not available, offer prompt and easy referral to appropriate local contraceptive services outside the school or college.\n\nEnsure continuity of service, for example by making it clear to young people when and where local services are available during school, college or university holidays.\n\nEnsure services not only provide contraceptives but are staffed by people trained to be respectful and non-judgmental. They should also be trained to help young men and women identify, choose and use contraception that is the most appropriate for them.\n\n# Recommendation 9 Providing emergency contraception\n\n## Whose health will benefit?\n\nYoung women up to the age of 25.\n\n## Who should take action?\n\nManagers, doctors, nurses (including school nurses), pharmacists and reception staff working in: contraceptive services, schools, primary and community care, acute and emergency services, pharmacies, maternity services, walk-in centres and voluntary and private sector health services.\n\n## What action should they take?\n\nEstablish patient group directions (PGDs) and local arrangements to ensure all young women can easily obtain free oral emergency contraception. (Patient group directions enable suitably qualified nurses and pharmacists to dispense specific medicines in specific circumstances. See NICE's guideline on patient group directions.)\n\nEnsure young women (and young men) know where to obtain free emergency contraception.\n\nInform young women that an intrauterine device is a more effective form of emergency contraception than the oral method and can also be used on an ongoing basis.\n\nEnsure young women have timely access to emergency contraception using an intrauterine device.\n\nEnsure young women who are given oral emergency contraception are:\n\n\n\nadvised that this needs to be used as soon as possible after sex and that it is only effective if taken within a limited time\n\nadvised that other methods are more effective and reliable as a primary method of contraception\n\nencouraged to consider and choose a suitable form of contraception for their future needs\n\nreferred to, or given clear information about, local contraceptive services\n\noffered immediate referral for an intrauterine device, if they choose this method\n\nadvised where they can obtain a free, confidential pregnancy test with same-day results.\n\n\n\nEnsure all health professionals providing oral emergency contraception are aware that they can provide this to young women aged under 16 without parental knowledge or consent, in accordance with best practice guidance (Department of Health's best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health). Also ensure they are aware that they have a duty of care and confidentiality to young people under the age of 16.\n\nHealth professionals, including pharmacists, who are unwilling (or unable) to provide emergency contraception should give young women details of other local services where they can be seen urgently.\n\nEnsure arrangements are in place to provide a course of oral emergency contraception in advance, in specific circumstances where the regular contraceptive method being used, for example condoms or the pill, is subject to 'user failure'. (Methods where there can be 'user failure' are those that the user has to think about regularly or each time they have sex and which must be used according to instructions, such as condoms or the pill.)\n\n# Recommendation 10 Providing condoms in addition to other methods of contraception\n\n## Whose health will benefit?\n\nAll young men and women up to the age of 25.\n\n## Who should take action?\n\nManagers and staff working in contraceptive services (including GP services, pharmacies, maternity services, walk-in centres, acute and emergency care), the voluntary and private sector.\n\nPractitioners with a responsibility for the health and wellbeing of young people in social care and children's services and the voluntary and private sector. This includes social care professionals, workers in drug and alcohol services, youth workers and counsellors, and people involved with condom distribution schemes.\n\nPublic health specialists, PSHE education and sex and relationships education teachers, and all others who provide information about contraception and sexual and reproductive health.\n\n## What action should they take?\n\nAdvise all young people to use condoms consistently and correctly in addition to other contraception. Condoms should always be provided along with other contraception because they help prevent the transmission of STIs.\n\nAdvise them to use a water-based lubricant with a condom if they want or need a lubricant.\n\nEnsure free condoms (including female condoms) are readily accessible (this could include, for example, at schools, colleges and youth clubs).\n\nEnsure information and advice on using condoms is available at all condom distribution points and, where possible, young people should be shown how to use them correctly.\n\nWhen providing condoms, offer information about emergency contraception and other contraceptive services, including when, where and how to access them locally.\n\n# Recommendation 11 Communicating with young people\n\n## Whose health will benefit?\n\nYoung people up to the age of 25 who use contraceptive services or who might need information on contraception.\n\n## Who should take action?\n\nCommissioners and providers of contraceptive services.\n\nInformation service providers including, for example, libraries, job centres, schools, colleges and youth services.\n\n## What action should they take?\n\nUse a range of methods, including the latest communication technologies, to provide young people, especially socially disadvantaged young people, with advice on sexual health and contraception. This could include using:\n\n\n\nbespoke websites or dedicated pages on social networking sites which enable young people to discuss sensitive issues anonymously\n\nonline NHS information such as the NHS your contraception guide\n\nwebsites provided by specialist service providers such as Brook or FPA that provide reliable, up-to-date, evidence-based health information and advice (schools and colleges should ensure their firewalls do not block these websites)\n\ntelephone helplines offering up-to-date and accurate information and details about local services – for example, 'Ask Brook'. These should, where possible, use local numbers that qualify for free calls as part of many mobile phone contracts.\n\n\n\nWherever possible, ensure schools, colleges, youth clubs and other places that young people visit have up-to-date and accessible information on contraceptive methods and local services.\n\nEnsure information is available in a range of formats. For example, it should be available in languages other than English, in large print, or text relay (for those who are deaf or hard of hearing). It should also be distributed via a range of media, for example, via mobile phones (text messaging or calls) or emails. (Practitioners should be mindful of confidentiality when using these media.)\n\nInvolve young people in the design of any media and distribution strategies.\n\n# Recommendation 12 Training and continuing professional development\n\n## Whose health will benefit?\n\nYoung people up to the age of 25 who use contraceptive services or who might need information on contraception.\n\n## Who is the target population?\n\nDoctors, midwives, nurses, pharmacists, and other health professionals who provide contraceptive services.\n\nManagers and staff working in, or involved with, young people's contraceptive services.\n\n## Who should take action?\n\nCommissioners and managers of young people's contraceptive services.\n\nPrimary and community care services, children's services, social services and young people's advisory and support services.\n\nRoyal colleges and professional associations, further and higher education training boards, and organisations responsible for setting competencies and developing continuing professional development programmes for health professionals, healthcare assistants and support staff.\n\n## What action should they take?\n\nManagers should ensure all doctors, midwives, nurses, pharmacists and other health professionals working in contraceptive services have received the post-registration training required by their professional body. They should also have evidence to show that they are maintaining their skills and competencies.\n\nHealth professionals (including pharmacists) who advise young people about contraception should be competent to help them compare the risks and benefits of the different methods, according to their needs and circumstances. They should also be able to help them understand and manage any common side effects. (This is an edited extract from NICE's guideline on long-acting reversible contraception.)\n\nColleges and training organisations should ensure doctors and nurses offering contraceptive services have easy, prompt access to pre- and post-registration theoretical and practical training in all methods of contraception. This includes intrauterine devices and systems and contraceptive implants.\n\nEnsure all support staff who may come into contact with young people, particularly socially disadvantaged young people, are experienced in working with them. This includes being able to communicate with those who have physical or learning disabilities. It also includes being aware of, and sensitive to, the needs of young people from different ethnic and faith communities in relation to contraception.\n\nEnsure all support staff who work in contraceptive services with young people receive both formal and on-the-job training in how to offer basic information and advice about contraception. They should be aware of the range of methods available, the advantages and disadvantages of each method, and the measures that can be taken to manage any side effects. Training should be regularly updated and tailored to individual needs to ensure staff have the skills and knowledge relevant for their role.\n\nEnsure all staff working for contraceptive services for young people, including administrative staff, know about the duty of confidentiality and child protection processes and legislation. They should be trained in the Department of Health's best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health. They should also be aware of local mechanisms for reporting concerns relating to safeguarding policy and procedures.\n\nEnsure all staff are aware of local contraceptive service referral pathways so that they know how to direct young people to the services they need – whether it is for advice on, or the provision of, contraceptives (including condoms and emergency contraception) or abortion services.", 'Public health need and practice': "# Background\n\nYoung people's adolescent years, and the period up to their mid-twenties, are a time when they are exploring and establishing sexual relationships. According to the 2000/01 'National survey of sexual attitudes and lifestyles' (Johnson et al. 2005), the median age of first intercourse was 16 years for both men and women.\n\nIt is estimated that between one-quarter and one-third of all young people have sex before they reach age 16. Among those leaving school at 16 with no qualifications, 60% of boys and 47% of girls had sex before they were 16 (Wellings et al. 2001). Among those aged 16–19, 7% of men and 10% of women reported using no form of contraception at first intercourse.\n\nUnprotected first sex was more likely for the youngest age groups (Johnson et al. 2001). A survey of young people aged 16–18 in London reported that 32% of black African men, 25% of Asian women, 25% of black African women and 23% of black Caribbean men did not use contraception at first intercourse (Testa and Coleman 2006).\n\nAccess to contraceptive services is most problematic for people in disadvantaged communities. There is a 6-fold difference in teenage conception and birth rates between the poorest areas in England and the most affluent. There is a clear link between sexual ill-health, deprivation and social exclusion; unintended pregnancies can have a long-term impact on people's lives.\n\nUnder‑18 conceptions can lead to socioeconomic deprivation, mental health difficulties and lower levels of educational attainment. In addition, resulting children are at greater risk of low educational attainment, emotional and behavioural problems, maltreatment or harm, and illness, accidents and injuries (Department for Children, Schools and Families 2008).\n\nEngland has one of the highest rates of teenage pregnancy in western Europe. Figures for England and Wales show that the 2010 under‑18 conception rate (35.5 conceptions per 1000) is the lowest estimated rate since 1969. The 7.3% decline in under‑18 conceptions from 2009 to 2010 represents the greatest single year decrease since 1975/76.\n\nData for England and Wales show that conception numbers and rates fell among all age groups under‑18. Younger age groups (especially those under 15) continue to account for a very small proportion of teenage conceptions. In 2010, under‑15s accounted for 5% of under‑18 conceptions (Department for Education 2012).\n\nNational progress masks significant variation in local area performance. In England, the north east region had the highest pregnancy rate of 44.3 per 1000 young women aged 15–17 years while the east of England had the lowest rate at 29.8 per 1000. In virtually every local authority there are hotspots in which annual conception rates are greater than 60 per 1000 young women aged 15–17. However, some of the most deprived boroughs in the country have achieved reductions of more than 25% since 1998 (Department for Children, Schools and Families 2010).\n\nAlthough 88% of women in a heterosexual relationship report using at least 1 method of contraception, abortion rates have increased since the Teenage Pregnancy Strategy was published (Office for National Statistics 2009).\n\nIn 2009, the highest abortion rate was in women aged 19–21, at 33 per 1000 pregnancies (DH 2010). The abortion rate for those under 16 was 4 per 1000, and for those under 18 the rate was 17.6 per 1000 (DH 2010). Repeat abortions accounted for 25% of all abortions in women under 25 in 2009.\n\nThe percentage of conceptions among women under 25 that end in abortion demonstrates that many of these pregnancies are unwanted. It suggests that contraceptive services are failing to meet the needs of young people, who are not getting access to effective methods of contraception and advice about using contraception effectively. Since the Teenage Pregnancy Strategy was published in 1999, the focus has been on reducing under‑18 conceptions.\n\nThe contraceptive and sexual health needs of those aged between 19 and 24, a group that has high rates of unintended or unwanted pregnancy, may have been neglected. Campaigns and services aimed at teenagers may not be as relevant to this group (Independent Advisory Group on Sexual Health and HIV and Medical Foundation for AIDS and Sexual Health 2008).\n\nTeenage pregnancies have a high cost implication for public funds. It has been estimated that the cost to the NHS is £63\xa0million a year (Department for Children, Schools and Families 2006). Teenage pregnancies place significant pressures on local authority social care, housing and education services.\n\nIn 2006/07, local authorities spent £23\xa0million on support services for teenage parents (Department for Children, Schools and Families 2008). National Statistics data on abortions during 2009, combined with reference cost data for the same year, indicate that abortions for women aged under 25 cost the NHS approximately £53.3\xa0million in 2009.\n\n# Government action\n\nThe Department of Health's framework for sexual health improvement in England aims to reduce unwanted pregnancies by ensuring people:\n\nhave access to the full range of contraception\n\ncan obtain their chosen method quickly and easily\n\ncan plan the number of children they have and when.\n\nA review of the previous National Strategy for Sexual Health and HIV identified that contraceptive services needed further attention (Independent Advisory Group on Sexual Health and HIV and Medical Foundation for AIDS and Sexual Health 2008). Some local areas have suffered from disinvestment in community contraceptive services, although young people and those from vulnerable communities generally prefer these services to primary care services (Independent Advisory Group on Sexual Health and HIV 2009).\n\nThe recommended standards for sexual health services suggest that people should have access to accurate information about, and free provision of, all contraceptive methods (Medical Foundation for AIDS and Sexual Health 2005).\n\nTo reinforce these standards and the continuation of the Teenage Pregnancy Strategy, the Department of Health announced additional resources for primary care trusts and strategic health authorities between 2008 and 2011 to improve access to and uptake of effective contraception. The additional funding was focused on developing services in more schools and colleges and extending the range of services they provide, although the Teenage Pregnancy Independent Advisory Group was concerned that take up of the new money had been patchy and there was no national monitoring (Teenage Pregnancy Independent Advisory Group 2009).\n\nFrom April 2009, GPs have been provided with incentives, through the quality outcomes framework, to provide advice on contraception and particularly long-acting methods, and abortion services are required to provide advice on contraception to all their clients (Department for Children, Schools and Families 2010).\n\nFrom 1 April 2013, local authorities have a mandatory responsibility for commissioning and delivering all community and pharmacy contraceptive services (apart from services provided by general practitioners). Clinical Commissioning Groups are responsible for commissioning termination of pregnancy services (abortions) and a fully integrated range of contraception, STI testing and treatment services. They are also responsible for commissioning vasectomy and female sterilisation services.", 'Considerations': "The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.\n\nMost of the evidence considered for the reviews of effectiveness is from the USA. The UK healthcare system differs from the US system in its organisation, use of resources and access. Furthermore, the ethnic composition of the UK population differs in a number of respects. There was little direct evidence about young people from socially disadvantaged groups. In addition, the PDG had to consider, on a case by case basis, whether it was reasonable to apply evidence derived from the USA (for example, on African Americans) to socially disadvantaged young people in the UK.\n\nThe PDG was clear that service providers should not be discriminating and judgmental, and should respect young people's choices and way of life. Attitudes that could be perceived as critical might deter young people, particularly socially disadvantaged young people, from attending services again. Services must be fully accessible for young people with disabilities and should prioritise individual needs.\n\nThe local pharmacy has a vital role in meeting the needs of diverse communities, particularly the needs of young people who may be anxious about approaching contraceptive services. Pharmacists, including those working for private retail chains, are part of a local primary care and wider health service network. The pharmacy section in a large supermarket may be the only service that is easily available and accessible within some rural areas. The PDG recognised that all health professionals and service providers have the right to refuse to provide or prescribe contraception, if doing so is contrary to their personal or religious beliefs. However, the PDG did not think it acceptable that provision of contraception, including emergency contraception, should depend on whoever happens to be on duty. If, for any reason, there is limited or variable provision in the local pharmacy, young people requiring urgent treatment, for example emergency contraception, may find it difficult to reach alternative services. This was a cause of concern.\n\nThe evidence shows that advance provision of oral emergency contraception does not encourage risky sexual behaviour among young people. Evidence also shows that women who have emergency contraception in advance are more likely to use it, and to use it sooner after unprotected sex. Having emergency contraception on hand does not affect the use of other kinds of contraception (Polis 2007).\n\nThe PDG felt that advance provision of free oral emergency contraception could fulfil an unmet need for some young people. It might also provide an early opportunity to discuss contraception and broader sexual health issues and needs.\n\nThe focus of the guidance is on the provision of effective contraceptive services, but not all methods of contraception are designed to protect against STIs. Young people may not always realise that the most appropriate contraceptive method for them may offer no protection against STIs. Only the condom is effective against STIs, including HIV.\n\nThe PDG recognised that sexual health is an important aspect of the physical and mental wellbeing of young people, and that contraceptive services should be delivered in the broader context of sexual, physical, emotional and mental health and wellbeing.\n\nSelf-referral to contraceptive services through GP services, young people's services, community contraceptive services and 'one stop shops' is valuable. Assumptions about where young people prefer to get their services must be avoided, and a range of 'young-people friendly' contraceptive services will continue to be required. Young people's needs for information and demands for services may differ according to their age, way of life and cultural background.\n\nIt is important that contraceptive services are available for all young people. A universal service does not imply that every young person has the same needs. Socially disadvantaged young people are likely to need more support than others. Some may need more personalised and tailored advice and support. The guidance applies to all young people but there is a greater focus on young people who could be considered to be socially disadvantaged, and those from areas with a higher concentration of socially disadvantaged young people.\n\nThe PDG acknowledged that the term 'socially disadvantaged young people' covers a range of people who may not be easily identified, that those considered to be socially disadvantaged might vary in different local areas, and that people may move in and out of social disadvantage at different points in their lives.\n\nThere are some socially disadvantaged groups who have very limited access to contraceptive services, for example asylum seekers or Gypsy and traveller communities.\n\nSome socially disadvantaged young people may have multiple health and sexual health needs. They may also need or be receiving support from social, voluntary or children's services, which is often fragmented or inconsistent. Information and advice about contraception and sexual health may be provided by different teams and different provider organisations.\n\nIn the economic modelling undertaken for this topic, it was argued that the savings in government-funded benefits to young mothers having fewer teenage births was a real saving to the community. In most cases, transfers of money from taxpayers to recipients (known as 'transfer payments') are not counted as either costs or benefits from a societal perspective because they cancel out, and involve simply a redistribution of existing wealth. However, in the case of government-funded benefits to single mothers, the need for paying the benefits is removed if there is no baby. The funds that would have been used for this purpose can be used for something else. The PDG considered the argument that reductions in government-funded benefits were a saving of costs and concurred with it. The modelling considered cases in which increased use of contraception delays pregnancy until the woman reaches her 20s, and those in which it results in the absence of a pregnancy altogether.\n\nGood quality contraceptive services for young people depend on doctors and nurses who not only are sensitive to their needs but properly trained. The PDG believes that all doctors and nurses need access to high quality pre- and post-registration contraception and sexual health training modules and courses and clinical placements without delay.\n\nThere are unseen barriers to contraceptive use for some socially disadvantaged young people. For example some hormonal methods may not be suitable for women on highly active antiretroviral therapy (HAART). In addition, some young women might be worried if their periods stop or become irregular as a result of some forms of contraception.\n\nThere was no evidence on the effectiveness of national media campaigns. It would be beneficial for any future national media campaigns to be planned with involvement of local organisations.\n\nThere is variation in practice across the country in terms of meeting the standards set out in 'You're welcome' (DH 2007). Some services will surpass the standards, whereas others will not yet have met them.\n\nThe high rates of unwanted and unintended pregnancy among women aged 19–24\xa0years is a cause for concern. There was little evidence about their attitude towards contraception and their use of contraceptive services. Service providers have focused on targets and priorities related to the Teenage Pregnancy Strategy, yet the needs of those who are slightly older, particularly those who are socially disadvantaged, are not well understood and are not being met.\n\nThe PDG acknowledged that there are many myths surrounding contraception, for example, the idea that using 2 condoms is better than using 1, or that you cannot get pregnant the first time you have sex. Lack of knowledge and misinformation about pregnancy risk and contraception is likely to prevent young women from seeking advice and support when they most need it.", 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects.\n\n. What are the most effective and cost effective ways to provide contraceptive services for socially disadvantaged young people to prevent unwanted pregnancies? In particular, what are the most effective and cost effective ways to provide contraceptive services for looked after children, those with learning difficulties, those who are not in education, employment or training or women who have had an abortion?\n\n. What are the most effective ways to get socially disadvantaged young women and men involved in designing contraceptive services that meet their needs and reduce the barriers to access?\n\n. How effective and cost effective are interventions that reduce unintended conception and abortion rates among young people aged under 25\xa0years?\n\n. What is the differential impact of interventions that aim to reduce unintended conception and abortion rates among young people aged under 25\xa0years on subgroups of socially disadvantaged young people?\n\n. What interventions and service models enable young people from diverse faith and cultural communities to access contraceptive services and meet their contraceptive needs?\n\nMore detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.", 'References': "Department for Children, Schools and Families (2006) Teenage pregnancy: accelerating the strategy to 2010. London: Department for Children, Schools and Families\n\nDepartment for Children, Schools and Families (2008) Teenage parents: who cares? A guide to commissioning and delivering maternity services for young parents. London: Department for Children, Schools and Families\n\nDepartment for Children, Schools and Families, Department of Health (2010) Teenage pregnancy strategy: beyond 2010. London: Department for Children, Schools and Families\n\nDepartment for Education (2012) Under-18 and under-16 conception statistics. London: Department for Education\n\nDepartment of Health (2004) Best practice guidance for doctors and other health professionals on the provision of advice and treatment to young people under 16 on contraception, sexual and reproductive health. London: Department of Health\n\nDepartment of Health (2011) You're welcome quality criteria: making health services young people friendly. London: Department of Health\n\nDepartment of Health (2010) Abortion statistics, England and Wales: 2009. statistical bulletin 2010/01. London: Department of Health\n\nFaculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit (2004) Contraceptive choices for breastfeeding women. Journal of Family Planning and Reproductive Health Care 30: 181–9\n\nFaculty of Sexual and Reproductive Healthcare (2012) Service standards for sexual and reproductive health services. London: Faculty of Sexual and Reproductive Healthcare\n\nFaculty of Sexual and Reproductive Healthcare (2010) Contraceptive choices for young people. Clinical guidance. London: Faculty of Sexual and Reproductive Healthcare\n\nIndependent Advisory Group on Sexual Health and HIV and Medical Foundation for AIDS and Sexual Health (2008) Progress and priorities – working together for high quality sexual health: Review of the national strategy for sexual health and HIV London: Medical Foundation for AIDS and Sexual Health\n\nIndependent Advisory Group on Sexual Health and HIV (2009) The time is now: achieving world class contraceptive and abortion services. London: Department of Health\n\nJohnson A, Fenton A, Copas et al. (2005) National survey of sexual attitudes and lifestyles (NATSAL II) 2000–2001. London: National Centre for Social Research\n\nJohnson AM, Mercer CH, Erens B et al. (2001) Sexual behaviour in Britain: partnerships, practices, and HIV risk behaviours. Lancet 358: 1835–42\n\nMarmot M (2010) Fair society, healthy lives: strategic review of health inequalities in England post-2010. London: University College London\n\nMedical Foundation for AIDS and Sexual Health (2005) Recommended standards for sexual health services. London: Medical Foundation for AIDS and Sexual Health\n\nOffice for National Statistics (2009) Opinions survey report no. 41 contraception and sexual heath, 2008/09 [online]\n\nOffice for National Statistics (2010)Conception statistics in England and Wales, 2008 [online] Accessed 12 May 2010\n\nPolis CB, Grimes DA, Schaffer K et al. (2007) Advance provision of emergency contraception for pregnancy prevention. Cochrane Database of Systematic Reviews Issue 2: CD005497\n\nPopulation Action International (2007) A measure of survival: calculating women's sexual and reproductive risk. Washington DC: Population Action International\n\nTeenage Pregnancy Independent Advisory Group (2009) Annual report 2008/9. London: Department for Children, Schools and Families\n\nTesta A, Coleman L (2006) Sexual knowledge, attitudes and behaviours among black and minority ethnic youth in London. London: Trust for the Study of Adolescence and Naz Project\n\nWellings K, Nanchahal K, Macdowall W et al. (2001) Sexual behaviour in Britain: early heterosexual experience. Lancet 358: 1843–50", 'Appendix B Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews and economic analysis include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were:\n\nWhat is the effectiveness and cost effectiveness of interventions to encourage young people, especially socially disadvantaged young people, to use contraceptives and contraceptive services (including access to, and information about, contraceptive services)?\n\nWhat are socially disadvantaged young people and their families' perceptions, views and beliefs about contraception and contraceptive services, and where do they get their information about contraception and contraceptive services?\n\nThese questions were made more specific for each review (see reviews for further details).\n\n# Reviewing the evidence\n\n## Effectiveness reviews\n\nFive reviews were conducted:\n\na mapping review\n\nsettings-based reviews of effectiveness\n\na review of views and barriers.\n\nThe following databases were searched in August 2008 for both quantitative and qualitative studies (1995 to 2008) for all of the reviews:\n\nApplied Social Science Index and Abstracts (ASSIA)\n\nBritish Nursing Index\n\nCochrane Database of Systematic Reviews\n\nCinahl\n\nCochrane – Central\n\nCochrane DARE\n\nCochrane Health Technology Assessment\n\nEmbase\n\nMEDLINE\n\nPsycINFO\n\nScience and Social Science Citation Indices\n\nSocial Care Online\n\nAdditionally, the following websites were searched for relevant publications:\n\nBritish Association for Sexual Health and HIV\n\nBritish Medical Association\n\nBrook\n\nCentre for Reviews and Dissemination\n\nConnexions\n\nDepartment for Children, Schools and Families\n\nDepartment of Health\n\nEvery Child Matters\n\nFaculty of Public Health\n\nFPA\n\nHealth Protection Agency\n\nJoseph Rowntree Foundation\n\nMargaret Pyke Centre\n\nMedical Foundation for AIDS and Sexual Health\n\nNational Electronic Library for Health – Guidelines Finder\n\nNational Electronic Library for Health – Public Health\n\nNICE (and HDA)\n\nRoyal College of General Practitioners\n\nRoyal College of Nursing\n\nRoyal College of Obstetricians and Gynaecologists\n\nRoyal College of Paediatrics and Child Health\n\nRoyal Pharmaceutical Society of Great Britain\n\nSex Education Forum\n\nSex Education Forum at the National Children's Bureau\n\nSIGN (Scottish Intercollegiate Guidelines Network)\n\nSocial Care Institute for Excellence\n\nSouth West Public Health Observatories\n\nTeenage Pregnancy Unit\n\nUS National Guidelines Clearinghouse\n\nWelsh Assembly Government – Health Promotion Wales\n\nWorld Health Organisation\n\nStudies were included in the effectiveness reviews if:\n\nThey included under\xa025s.\n\nStudies were excluded if:\n\nThey focused solely on people aged 25 and older. Although a younger age cut off was not explicitly stated, consideration was also given to the Fraser guidelines for competence to consent.\n\nThey covered sexual health services that do not provide contraceptive services.\n\nThey covered sterilisation, including vasectomy.\n\nThey covered abortion (services which do not also provide contraception).\n\nThey covered use of contraceptive methods for non-contraceptive reasons, for example, for menorrhagia (heavy periods).\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix\xa0E). Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n− Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nThe evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable).\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect their judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and an economic modelling exercise.\n\n## Review of economic evaluations\n\nOne economic evaluation was identified within the 3 reviews which considered the cost effectiveness of an intensive, school-based intervention for teen mothers to prevent repeat pregnancies. This economic evaluation was poorly reported and appeared to contain some errors within the calculations. No other economic evaluations that met the inclusion criteria were identified by the reviews.\n\n## Economic modelling\n\nA number of assumptions were made that could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details).\n\nAn economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in: Modelling the cost-effectiveness of interventions to encourage young people, especially socially disadvantaged young people, to use contraceptives and contraceptive services.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in contraceptive services, including those working in the NHS, private providers, education and the voluntary sector.\n\nThe fieldwork comprised:\n\nFocus groups carried out nationally by GHK with practitioners and commissioners working in the NHS, education and the private and voluntary sectors.\n\ntelephone interviews carried out by GHK.\n\nThe 2 studies were commissioned to ensure there was ample geographical coverage. The main issues arising from these 2 studies are set out in appendix C under fieldwork findings.\n\n# How the PDG formulated the recommendations\n\nAt its meetings in 2009 and 2010, the Programme Development Group (PDG) considered the evidence and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere evidence was lacking, the PDG also considered whether a recommendation should only be implemented as part of a research programme.\n\nWhere possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe guidance was due to be published in November 2010. However it was put on hold pending a Government review of NICE's public health work and while the Department of Health finalised its sexual health framework.\n\nThe recommendations have not changed, only factual amendments have been made, for example, where names of organisations have been changed.", 'Appendix C The evidence': "This appendix lists the evidence statements from 4 reviews (3 settings-based reviews and a views review) provided by the public health collaborating centre (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix E for details). It also lists 5 expert reports and their links to the recommendations and sets out a brief summary of findings from the economic analysis and the fieldwork.\n\nThe 4 reviews of effectiveness are:\n\nA review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in education settings.\n\nA review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: views review.\n\nA review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in healthcare settings.\n\nA review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in community settings.\n\nEvidence statement E1a indicates that the linked statement is numbered 1a in the review 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in education settings'.\n\nEvidence statement V1a indicates that the linked statement is numbered 1a in the review 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: views review'.\n\nEvidence statement H1a indicates that the linked statement is numbered 1a in the review 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in healthcare settings'.\n\nEvidence statement C1a indicates that the linked statement is numbered 1a in the review 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in community settings'.\n\nER-IHYP indicates evidence in the expert report 'Improving healthcare for young people'.\n\nER-TPS indicates evidence in the expert report 'Teenage pregnancy strategy'.\n\nER-AHC indicates evidence in the expert report 'Access to health care: how do we reach vulnerable groups?'\n\nER-CSSDP indicates evidence in the expert report 'Contribution to NICE guidance on contraceptive services for socially disadvantaged young people'.\n\nER-DH indicates evidence in the expert report 'DH evidence: NICE guidance on contraception for socially disadvantaged young people'.\n\nSee also the full reviews, expert reports, economic analysis and fieldwork report. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: evidence statements V15, V25, V26, ER-IHYP, IDE\n\nRecommendation 2: evidence statements V2, V12, V15, V19, V22, V25, V26, ER-IHYP, IDE\n\nRecommendation 3: evidence statements C1a, C1c, H4, V1a, V1b, V2, V11, V12, V15, V16, V19, ER-IHYP, IDE\n\nRecommendation 4: evidence statements C2d, H1b, H4, E6a, V1a, V2, V12, V15, V19, ER-IHYP, IDE\n\nRecommendation 5: evidence statements V2, V12, V14, V17, V18, ER IHYP, IDE\n\nRecommendation 6: evidence statements C2a, H1b, E6a, V1a, IDE\n\nRecommendation 7: evidence statements C2a, H1b, E6a, V1a, IDE\n\nRecommendation 8: evidence statements E3a, V1a, V2, V11, V12, V15, V19, IDE\n\nRecommendation 9: evidence statements H2, V1a, V1b, V1c, V11, V20, IDE\n\nRecommendation 10: evidence statements H3, V1a, V1b, V7, IDE\n\nRecommendation 11: evidence statements C1a, C1c, E6b, V1a, V2, V11, V17, IDE\n\nRecommendation 12: evidence statements V1a, V1b, V2, V12, V14, V18, V19, V27, IDE\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style.\n\n## Community review evidence statements\n\nThere is mixed evidence from 5 studies to suggest that media based interventions may reduce teenage pregnancy, increase contraceptive use and improve the knowledge and attitudes of young people in relation to these outcomes:\n\nModerate evidence from 1 randomised controlled trial (RCT) (++) showed that a computer based intervention could significantly reduce pregnancy and improve emergency hormonal contraception (EHC) use, as well as improving knowledge and attitudes based outcomes).\n\nWeak evidence from 2 before-and-after studies (2 −) suggest that social marketing campaigns may have a significant effect on the use of contraception or EHC as well as knowledge and attitude based outcomes. In the first study (−), compared with the controls, participants in the intervention group were significantly more likely to have heard of EHC, know the mechanism of action of EHC, have discussed EHC with a care provider, received an advanced prescription for EHC, and intend to use EHC in the future if needed. The second study (−) showed that increased exposure to the social marketing campaign was associated with a significant increase in condom use at last sexual experience.\n\nThere is inconsistent evidence from 8 studies to suggest that community based interventions may be effective in preventing repeat pregnancy:\n\nInconsistent evidence from 3 RCTs (2 ++, 1 +) suggests that home visitors may be effective in preventing repeat pregnancy; only 2 of the 3 studies measured repeat pregnancy rate as an outcome and only 1 of these provided evidence of clear benefit. The first RCT (++) showed a significant reduction in repeat birth for the intervention group. The second RCT (+) showed a significant improvement in parenting scores for the intervention group, but the effect on repeat pregnancy was not significant. The third RCT (++) showed a significant improvement in contraceptive use for the intervention group, but did not measure repeat pregnancy.\n\nModerate evidence from 1 RCT (+) suggests that generic programmes for teen mothers (to prevent repeat pregnancy, increase school retention, reduce substance abuse, and improve wellbeing) could be effective in significantly reducing repeat pregnancy and consequent births.\n\n## Healthcare review evidence statements\n\nModerate evidence from 5 studies (2 +, 3 −) suggests that outreach programmes to encourage young people to attend mainstream sexual health services may be effective in increasing service use, but the effect on reducing teenage pregnancy rates is unclear. In the non-RCT study (+), compared with control, the outreach group was significantly more likely to likely to report consistent contraception use, and women were also less likely to report pregnancy. In the first cohort study (+) condom use increased and pregnancy decreased, but the impact of the intervention is unclear because of poor reporting. In the second cohort study (−), during the 5 years of the intervention, the number of attendees at family planning clinics aged under 20 and under 16 significantly increased. Pregnancy is reported to have 'remained low' but no data is given. In the third cohort study (−), those who attended an orientation session were significantly more likely to start using services, and attendance at the 3-month booster session was associated with significantly higher continued clinic contact at 1 year. In the interrupted time series study\n\n(−), the number of new users of family planning services aged under 26 years increased significantly in the first 18 months of the outreach programme.\n\nThere is strong evidence from 4 RCTs (3 ++, 1 +) to support the advance provision of EHC to young people to increase EHC use. In most cases increased use was not at the expense of other contraceptive use, and did not promote risky sexual behaviour; the exception was 1 study (+) with adolescent mothers. In the first study (++), at 6-month follow up EHC use was significantly higher in the intervention (advanced provision) group than the control, and the mean time to use EHC was significantly shorter in the intervention group compared with the control group. There were no differences in hormonal contraception or condom use between the groups. In the second study (++) (with random allocation to receive EHC via pharmacy, clinical access or advance provision) EHC use at 6-month follow up was significantly greater in the advance provision group than the clinical access group. Pharmacy access did not affect EHC use when compared with clinic access. In the third study (++), the advance EHC group reported (non-significantly) higher emergency contraception use and significantly sooner use. In the fourth study (+), at 12-month follow up those in the advance provision group were significantly more likely than the controls to have used EHC, but also more likely to have had unprotected sex in the past 6 months.\n\nThere is strong evidence from 5 studies (4 ++, 1 −) to support interventions that combine discussion and demonstration of condom use to increase adolescent condom use and engagement with clinical services. In the first study (++), at 6 month follow up intervention subjects reported statistically significant increase in condom use by their sexual partner for protection against STIs. In the second study (++), at 1 year clients were twice as likely to report having received condoms from the clinic. In the third study (++), of 2 methods of cognitive behavioural therapy (CBT) to reduce unprotected sex, those in the skills-based CBT group were significantly less likely to have unprotected sex at 12 months than those in the information-based CBT group or control group. In the fourth study (++), more of the intervention group than the comparator group returned for their scheduled clinic revisits (statistical significance not clear). In the fifth study (−) it is suggested that, compared with the rest of the country, attendance at the GUM clinic by young people is much higher, particularly at sites offering daily access and located geographically close to a school (no statistical data are given to validate this).\n\nAlthough the studies were mostly well designed, the data were not always well analysed and reported, which may have affected reliability. Applicability in the UK may also be limited because most of the studies were conducted in the USA/Canada (2 in populations that were majority black American and 1 population who were African American/Latino).\n\nStrong evidence from 2 RCTs (2 ++) and 1 non-RCT (+) suggests that interventions aimed to improve adolescent contraceptive use by additional service provision can be effective, but this depends on the intervention. The first study (++) was of a nurse led one-to-one intervention, the intervention group reported significantly greater oral contraception adherence than the controls. The second study (+) was of a computer based contraception decision aid intervention. At 1-year follow up the first intervention group had significantly higher contraception knowledge and (non-significantly) fewer pregnancies than the non-intervention group. This finding was not replicated in a second study population. The third study (++) was of an intervention to administer 'quick start' of contraception (immediately administered contraceptive injection), at 6-month follow up there were no differences in continuation rates or pregnancy rates between the groups.\n\n## Education review evidence statements\n\nStrong evidence from 3 papers (2 +, 1 −) supports the direct provision of contraceptives dispensed on site from school based health centres as a way to increase contraceptive provision. However, the use of those contraceptives or any subsequent outcomes is unclear. In the first study (+), significantly more of the intervention cohort selected hormonal contraception at the first or second visit than the control cohort, and were also significantly less likely to select no contraception. In the second study (+), adolescents in the intervention group were significantly more likely to receive condom/HIV instruction, and significantly less likely to report lifetime or recent sexual intercourse. Sexually active adolescents in the intervention group were twice as likely to use condoms but less likely to use other contraceptives. In the third study (−), direct provision led to a statistically significant increase in the number of contraceptives prescribed to young people. The data analysis in this paper is poor, giving only percentage increases, but it does appear to indicate that on site dispensing increases contraceptive provision.\n\nStrong evidence from 3 studies (3 +) suggests curriculum interventions that include community outreach components can be effective in preventing teenage pregnancy and risky sexual behaviour. In the first study (+), rates of pregnancy, along with rate of school failure and academic suspension, were significantly lower in the Teen Outreach group than the control group. In the second study (+) Teen Outreach was again shown to be effective, especially for those who were already teen parents. In the third study (+) Reach for Health participants were significantly less likely than controls to report sexual initiation or recent sex.\n\nModerate evidence from 1 study (+) suggests that a virtual world intervention was effective when associated with a curriculum based intervention about sexual risk behaviour. The intervention group had significantly better understanding than the control group of how reproduction works and the possible consequences of sex, and of the importance of behaving in ways that limit sexual experience.\n\n## Views review evidence statements\n\nThree qualitative studies (1 ++, 1 +, 1 −) describe a lack of knowledge among young people about potential consequences of sexual activity. One paper covering interviews with 16–21\xa0year olds as part of a mixed method study (−) describes a lack of knowledge before first sexual experience and lack of knowledge about the consequences of sexual activity. This was echoed in interviews with 16–23\xa0year olds from black and ethnic minority groups, who reported a lack of knowledge about risky sexual activity (+). Also, interviews with young mothers aged 14–16\xa0years reported gaps in their knowledge about becoming pregnant and abortion (++).\n\nThree qualitative studies (2 ++, 1 −) describe a lack of knowledge about correct use of contraception among young people. Gaps in knowledge about aspects of contraception were reported in young mothers aged 14–16 (++), in a mixed group of 16–25-year-old women (++) and in a mixed group of 15–18\xa0year olds (−). One qualitative study (++) suggests that a lack of knowledge about contraception methods may be greater in young people from deprived areas and found that lack of knowledge regarding contraception methods was greater in socially disadvantaged young women aged 16–20.\n\nOne qualitative interview study (++) highlights emergency hormonal contraception as an area of particular lack of knowledge among young women aged 16–25. Survey data suggest knowledge of emergency contraception in 78–90% of school aged girls. One survey linked less knowledge of emergency contraception with being a pupil at a school with lower academic achievement.\n\nOne qualitative study (++) reports that discussion of sex and contraception is embarrassing. A study of mixed young city dwellers aged 16–25 reported that the younger participants reported that discussing sex or any type of contraception was embarrassing.\n\nThe potential for feelings of embarrassment to inhibit young people from using contraceptive services is outlined in 7 papers (1 ++, 5 +, 1 −) reporting views from a variety of groups of young people. Clients of family planning clinics describe embarrassment or stigma associated with accessing contraceptive supplies (++). Young people from ethnic minorities also describe embarrassment if they are seen accessing a service (−). At a male drop-in service, 66% of clients reported that embarrassment would stop them using a service. Young people of school age (2 +) echo this embarrassment about accessing services. One survey reports 20–24% of 11–39 year old women had been embarrassed, scared or concerned about using a sexual health service. Another paper (+) describes women of 16–25 years old feeling embarrassed when using contraceptive services. Mixed groups of young people described embarrassment as a barrier to obtaining and using condoms (+). The importance of clinics overcoming young people's feelings of embarrassment was also recognised by staff (GPs and nurses) (2 +).\n\nTwo papers (1 +, 1 ungraded survey) report embarrassment related specifically to particular services. One (+) reports that young people aged 14–25 perceive that at times teachers are clearly embarrassed when discussing sexual issues, leading to the young people also feeling embarrassed. The other states that 63% of young women and 46% of young men aged 15–16 years reported embarrassment about attending a consultation with a GP in regard to sexual health.\n\nOne study (+) describes a particular aspect of accessing a service that is embarrassing. It reports that young people aged up to 24 feel embarrassed when giving their name and address at a reception desk.\n\nThree studies (1 ++, 1 +, 1 −) suggest that condoms can be perceived negatively, as uncomfortable or a barrier to intimacy, among some teenagers. Two (1 ++, 1 +) report these negative views among teenagers aged 14–15 and teenagers including those who were young mothers or pregnant, and another study (−) reports a mix of positive and negative perceptions of condom use among 12–13\xa0year olds and 16–17\xa0year olds. Four studies (1 ++, 1 +, 2 −) suggest some young people think that there are negative connotations for young women carrying condoms.\n\nThree studies (1 ++, 2 +) describe uncertainty among young people about where to go to access contraceptives, especially among young men and younger participants.\n\nFive papers (1 ++, 2 +, 2 −) describe the importance of young people perceiving that contraceptive services are trustworthy and legitimate, enabling them to feel confident, and being in control when using them.\n\nFive studies (1 ++, 4 +) report that some young people have concerns about attending a GP practice for contraceptive services because of a perceived potential loss of confidentiality. This seems to be a particular concern in rural communities.\n\nEleven studies (5 ++, 5 +, 1 −) suggest the importance of accessibility of services for young people, with convenient location, extended opening hours, and choice in location as important elements.\n\nStudies report varying views about whether an appointment system or a drop-in service provides greater accessibility for young people. Four (2 ++, 1 +, 1 −) suggest an appointment-free system offers convenience. However, 1 (+) reports that staff perceive that waiting times in a clinic are not an obstacle to accessibility. One survey of young people reported that 62% would prefer a walk-in service. Another survey suggested that young people may appreciate the option of making appointments by telephone.\n\nEight studies (1 ++, 6 +, 1 −) report that preserving anonymity when accessing services is a significant concern for young people. These concerns regarding anonymity are also perceived by staff (1 ++, 3 +, 1 −).\n\nEleven papers (3 ++, 6 +, 2 −) report that confidentiality is a key concern for young people in accessing a sexual health service. Concerns regarding confidentiality feature particularly in regard to rural areas and GPs.\n\nA range of qualitative studies and survey data highlights that young people value staff who have a respectful and non-judgemental attitude towards them.\n\nFive papers (3 +, 1 −, 1 ungraded survey) report that staff also recognise the importance of being non-judgemental. However, they highlight that some staff may have ambivalent or varying attitudes towards young people and sexuality.\n\nThree studies (1 ++, 2 +) report that the cost of contraception is a concern for some young people.\n\nFour studies (1 ++, 2 +, 1 −) provide evidence from young people regarding the importance of a comfortable and welcoming atmosphere in sexual health service premises. This is echoed in a study of staff views.\n\nThere is evidence from 5 studies (1 ++, 1 +, 3 −) that staff have concerns regarding limited availability of resources for sexual health services.\n\nThere is evidence from 6 studies (3 ++, 1 +, 1 −, 1 ungraded survey) that staff perceive that well-organised services, and different agencies working together effectively, are important.\n\nThere is evidence from 6 studies (2 +, 4 −) that staff perceive a need for greater training in providing contraceptive services for young people.\n\n## Expert report/s\n\nImproving healthcare for young people\n\nTeenage pregnancy strategy: NICE meeting: 17\xa0September\n\nAccess to health care: how do we reach vulnerable groups? Learning from the teenage health demonstration sites\n\nContribution to NICE guidance on contraceptive services focusing on socially disadvantaged young people\n\nDepartment of Health evidence: NICE guidance on contraception focusing on socially disadvantaged young people\n\n# Cost-effectiveness evidence\n\nThe economic analysis indicates that, from a public sector perspective, providing contraceptives in schools and colleges is cost effective and results in net cost savings compared with no provision of contraceptives in these places. This result is robust to changes in the key model assumptions if the costs of government-funded benefits are included within the analysis. However, if government-funded benefits are excluded from the analysis, providing contraceptives within schools and colleges, while still being cost effective, has around a 50% probability of resulting in net cost savings.\n\nThe analysis also suggests that providing hormonal contraception within schools and colleges is likely to be more effective than providing condoms in terms of preventing pregnancies. This may also lead to greater cost savings than dispensing condoms. However, this comparison is subject to considerable uncertainty.\n\nThe economic analysis also suggests that, from a public sector perspective, intensive follow‑up and support after a teenage pregnancy results in a cost of £4000 for every repeat teenage pregnancy averted. This is in comparison with no follow-up after a teenage birth. Excluding government-funded benefits from the analysis leads to an estimated cost per repeat teenage pregnancy averted of £15,000.\n\nFrom a public sector perspective, advance provision of emergency hormonal contraception is estimated to be more effective and less costly than not providing it in advance. However, when government-funded benefits are excluded from the analysis (that is, an NHS and personal social services perspective is adopted), the intervention is estimated to cost £310 per pregnancy averted among those aged 15–19, compared with no advance provision.\n\nFinally, the analysis suggests that providing emergency hormonal contraception in advance is likely to be cost saving from a public sector perspective, when provided within schools and colleges alongside other contraceptives These results are informed by the following:\n\nThe Teenage Pregnancy Strategy's target to halve the under‑18 conception rate by 2010.\n\nIt has been assumed that before conception, the value of a future baby to society is neither positive nor negative. From this, it is clear that preventing conception cannot be measured in QALY terms, because future QALYs do not exist before conception. Thus the cost effectiveness of preventing a conception has been measured in terms of cost per pregnancy averted. However, once conceived and born, the baby is invested in a life expectancy, so that the loss of such a baby after birth can be measured as a loss of QALYs. A government-funded benefit given to young mothers can either be regarded as a transfer payment (from taxpayers to young mothers) or as a real resource cost. If it is seen as a transfer payment, the benefit to the mother is an equivalent cost to the taxpayer and these items cancel out. However, if the contraceptive intervention prevents a baby from being born, the money can be used by the government for other purposes without any opportunity cost. Following this logic, having fewer teenage births results in a much greater cost saving than if such benefits are considered as a transfer payment.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, see the fieldwork section in appendix B and the full fieldwork report.\n\nFieldwork participants who work with socially deprived young people were very positive about the recommendations and their potential to help improve contraception service provision. Many participants stated that the recommendations represented best practice in the area, and although they did not offer an entirely new approach, they agreed that the measures had not been implemented universally. They believed wider and more systematic implementation would be achieved as a result of this guidance.", 'Appendix D Gaps in the evidence': 'The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below.\n\n. There is little UK evidence about the effectiveness of interventions in this field.\n\n. There is little evidence about the effectiveness of services and interventions for socially deprived young people, or evidence that searches for a differential effect among different groups of young people.\n\n. There are few UK data about the cost effectiveness of contraceptive service provision.\n\nThe Group made 5 recommendations for research.', 'Appendix E Supporting documents': "Supporting documents include:\n\nEvidence reviews:\n\n\n\nReview 1: 'Mapping review: contraceptive services for socially disadvantaged young people'\n\nReview 2: 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in education settings'\n\nReview 3: 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: views review'\n\nReview 4: 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in health care settings'\n\nReview 5: 'A review of the effectiveness and cost effectiveness of contraceptive services and interventions to encourage use of those services for socially disadvantaged young people: services and interventions in community settings'.\n\n\n\nEconomic modelling: 'Modelling the cost-effectiveness of interventions to encourage young people, especially socially disadvantaged young people, to use contraceptives and contraceptive services'.\n\nFieldwork report: 'Fieldwork for draft guidance on contraceptive services focusing on socially disadvantaged young people'."}	https://www.nice.org.uk/guidance/ph51	This guideline covers contraceptive services for under-25s. It aims to ensure all under-25s are given advice and information on all types of contraception. This includes additional tailored support to meet the particular needs and choices of those who are socially disadvantaged or who may find it difficult to use these services.
88501abde8864ae4ee1c3b8f0e15f67af922a4fd	nice	Needle and syringe programmes	Needle and syringe programmes This guideline covers needle and syringe programmes for people (including those under 16) who inject drugs. The main aim is to reduce the transmission of viruses and other infections caused by sharing injecting equipment, such as HIV, hepatitis B and C. In turn, this will reduce the prevalence of blood-borne viruses and bacterial infections, so benefiting wider society. # What is this guidance about? This guidance makes recommendations on needle and syringe programmes, including those provided by pharmacies and drugs services for adults and young people (including those under 16) who inject drugs, including image- and performance-enhancing drugs. The main aim of needle and syringe programmes is to reduce the transmission of blood-borne viruses and other infections caused by sharing injecting equipment, such as HIV, hepatitis B and C. In turn, this will reduce the prevalence of blood-borne viruses and bacterial infections, so benefiting wider society. Many needle and syringe programmes also aim to reduce the other harms caused by drug use and include: Advice on minimising the harms caused by drugs. Help to stop using drugs by providing access to drug treatment (for example, opioid substitution therapy). Access to other health and welfare services. The guidance is for directors of public health, commissioners, providers of needle and syringe programmes and related services, and those with a remit for infectious disease prevention. (For further details, see who should take action?) In addition, it may be of interest to members of the public. See also the Department of Health and Social Care's Drug misuse and dependence: UK guidelines on clinical management, also known as the 'Orange Book', which provides advice to healthcare professionals on the delivery and implementation of a broad range of interventions for drug misuse, including those interventions covered in the present guideline.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Recommendation 1 Consult with and involve users, practitioners and the local community Health and wellbeing boards, directors of public health, commissioners and public health practitioners (see who should take action?) should: Involve the following when assessing the need for, and when planning, expanding or improving, a needle and syringe programme: different groups of people who inject drugs (including both those who use a needle and syringe programme and those who don't) under-represented groups, for example, young people and people from Black and minority ethnic groups who inject drugs families and carers of people who inject drugs frontline workers in needle and syringe programmes, pharmacies and related services in the statutory, voluntary and private sectors. Consult local communities about how best to implement new or reconfigured needle and syringe programmes. Promote the benefits of the service. For example, explain how these programmes have helped prevent an HIV epidemic in the UK and that they provide a route into drug treatment. Also explain that they may help reduce drug-related litter, by providing safe disposal facilities such as drop boxes and sharps bins. For further recommendations on how to work with communities, see the NICE guideline on community engagement. # Recommendation 2 Collate and analyse data on injecting drug use Health and wellbeing boards, directors of public health, commissioners and public health practitioners (see who should take action?) should: Regularly collate and analyse data from a range of sources (including data from Public Health England) to build reliable local estimates of the: Prevalence and incidence of infections related to injecting drug use (for example, hepatitis C and bacterial infections) and other problems caused by injecting drug use (for example, number of people overdosing). Types of drugs used and the numbers, demographics and other characteristics of people who inject, for example: rates of poly-drug use young people aged under 18 who are injecting, or being injected people who inject image- and performance-enhancing drugs (this includes new cohorts of users, for example, of tanning agents and other image-enhancing drugs) new psychoactive substance injectors people who inject occasionally, for example, when they go to night clubs -ther groups, such as men who have sex with men, ex-prisoners, sex workers or homeless people. Number and percentage of injections covered by sterile needles and syringes in each of the groups identified above. (That is, the number and percentage of occasions when sterile equipment was available to use.) Number and percentage of people who had more sterile needles and syringes than they needed (more than 100% coverage). Number and percentage of people who inject drugs and who are in regular contact with a needle and syringe programme. (The definition of regular will vary depending on the needle and syringe programme user and the types of drugs they use.) Map other services that are commonly used by people who inject drugs, for example, opioid substitution therapy services, homeless services and custody centres. # Recommendation 3 Commission both generic and targeted services to meet local need Health and wellbeing boards, directors of public health and commissioners (see who should take action?) should: Ensure the results of consultation and data analysis (in recommendation 1 and recommendation 2) inform the local joint strategic needs assessment. Commission a range of generic and targeted needle and syringe programmes to meet local need, based on these results. For example, ensure services are offered at a range of times and in a number of different locations. Take the geography and demographics of the area into account (for example, whether it is an urban or rural area). Targeted services should focus on the specific groups identified. Ensure services aim to be accessible and: Increase the proportion of people who have more than 100% coverage (that is, the number who have more than 1 sterile needle and syringe available for every injection). Increase the proportion of people who have been tested for hepatitis B and C and other blood-borne viruses (including HIV) in the past 12 months (see NICE's guideline on hepatitis B and C). Increase the proportion of each group of people who inject drugs who are in contact with a needle and syringe programme. Ensure syringes and needles are available in a range of sizes and at a range of locations throughout the area. Encourage identification schemes (involving, for example, the use of coloured syringes). Offer, and encourage the use of, low dead-space injecting equipment. Provide advice and information on services that aim to: reduce the harm associated with injecting drug use; encourage people to stop using drugs or to switch to a safer approach if one is available (for example, opioid substitution therapy); and address their other health needs. Where possible, offer referrals to those services. If applicable, commission outreach or detached services for areas where there are high levels of drug use or populations that do not use existing needle and syringe programmes. Promote needle and syringe programmes to groups that may be under-represented among those who use them, for example, club-drug injectors and people who inject image- and performance-enhancing drugs. Develop plans for needle and syringe disposal, in line with the Department for Environment, Food and Rural Affairs tackling drug-related litter: Guidance and good practice. Include the provision and disposal of sharps boxes for the safe disposal of needles. Consider providing public sharps bins (drop boxes) in areas where drug-related litter is common. Work with members of the local community, people who inject drugs and the local police service to agree the location for drop boxes. Commission integrated care pathways for people who inject drugs so that they can move seamlessly between the full range of services, including treatment services. # Recommendation 4 Monitor services Commissioners and providers of needle and syringe programmes, with support from public health practitioners, should: Collect data on service usage as follows: All services should monitor the number and types of packs or equipment they distribute. Specialist services should, where possible, collect more detailed data on: the amount and type of equipment distributed, the demographic details of the person who is injecting, along with details of their injecting practices and the drugs they are injecting (see recommendation 2). Practitioners should only ask for these details if they are confident it will not discourage the person from using the service. Ensure a local mechanism is in place to aggregate and analyse the data collected on at least an annual basis. Aim to build up a picture of injecting practices in the local area and how this may be changing over time. This data should be used as part of the collecting and analysing data process (see recommendation 2). Ensure local service use data are available, in anonymised form, for relevant national bodies and research units (for example, Public Health England). # Recommendation 5 Develop a policy for young people who inject drugs Directors of public health, children's safeguarding boards, commissioners and providers (see who should take action?) should: Develop and implement a local, area-wide policy on providing needle and syringe programmes and related services to meet the needs of different groups of young people aged under 18 (including young people under 16) who inject drugs. Ensure the policy details how local services will achieve the right balance between the imperative to provide young people with sterile injecting equipment and the duty to protect (safeguard) them and provide advice on harm reduction and other services. It should take account of: the young person's capacity to consent (see the Judgement on Gillick competence) the risks they face the benefits of using services the likelihood that they would inject anyway, even if sterile needles and syringes were not provided. Make the governance responsibilities of drug services and safeguarding boards clear. The safeguarding board should approve the local policy. Ensure the policy emphasises the need to provide young people with sterile injecting equipment. This should be provided as part of a broader package of care to meet their other health and social care needs, where possible. This is especially important for under-16s. Ensure the policy is responsive to the needs of young people in the local area. The developers of the policy should take into account: Provision of specialist young people's substance misuse services, including specialist provision of needle and syringe programmes for those under 18 (including young people under 16). How to encourage young people to ask for advice and help from staff providing the services (as well as providing them with needles, syringes and injecting equipment). How to assess service users: their age the degree or seriousness of their drug misuse whether the harm or risk they face is continuing or increasing the general context in which they are using drugs. The skills, knowledge and awareness that staff need to provide services. This includes ensuring staff are trained to assess whether young people are competent to consent (Gillick competence). The potential for using pharmacies to provide young people with needles, syringes and injecting equipment, if they also encourage the young person to make contact with specialist services. That parental or carer involvement should generally be encouraged, with the consent of the young person. Where this is not possible (or appropriate), the policy should include strategies to address their needs. The role of needle and syringe programmes as part of a range of services for young people that includes seamless transition from youth to adult services. Ensure needle and syringe programmes aimed at young people who inject drugs implement all the recommendations in this guidance, not just those for young people. Regularly review the policy. # Recommendation 6 Provide a mix of services Health and wellbeing boards and commissioners (see who should take action?) should: Use pharmacies, specialist needle and syringe programmes and other settings and approaches to provide geographical and demographic coverage. Examples of other settings and approaches that could be used include: custody centres, sexual health services, outreach and detached services. Provide a mix of the following levels of service to meet local needs: Level 1: distribution of injecting equipment either loose or in packs, suitable for different types of injecting practice, with written information on harm reduction. (For example, telling people about specialist agencies, or giving them details about safer injecting practices, including how to prevent an overdose.) Level 2: distribution of 'pick and mix' (bespoke) injecting equipment and referral to specialist services plus health promotion advice. (This includes advice and information on how to reduce the harms caused by injecting drugs.) Some level 2 services might also offer additional services, such as blood-borne virus testing or vaccination. Level 3: level 2 plus provision of, or referral to, other specialist services (for example, specialist clinics, vaccinations, drug treatment and secondary care). See recommendation 9. Establish links and referral pathways between the different levels of service to promote integration and to share learning and expertise. Coordinate services to ensure testing for hepatitis B and C and other blood-borne viruses is readily available to everyone who uses a needle and syringe programme (see NICE's guideline on hepatitis B and C). Coordinate services to ensure injecting equipment is available at times, and in places, that meet the needs of people who inject drugs. For example, it may be appropriate to provide out-of-hours vending machines for groups that would not otherwise have access to services – or not at the time that they need them. (The location of these machines would need to be considered carefully and their use would need to be regularly monitored.) Another example would be to encourage pharmacies with longer opening hours to provide needles, syringes and other injecting equipment. Ensure services offering opioid substitution therapy also make needles and syringes available to their service users. # Recommendation 7 Provide people with the right type of equipment and advice Needle and syringe programme providers should: Provide people who inject drugs with needles, syringes and other injecting equipment. The quantity provided should not be subject to a limit but, rather, should meet their needs. Make needles available in a range of lengths and gauges, provide syringes in a range of sizes, and Offer low dead-space injecting equipment. Not discourage people from taking equipment for others (secondary distribution), but rather, ask them to encourage those people to use the service themselves. Ensure people who use the programmes are provided with sharps bins and advice on how to dispose of needles and syringes safely. In addition, provide a means for safe disposal of used bins and equipment. Provide advice relevant to the type of drug and injecting practices, especially higher risk practices such as injecting in the groin or neck. Encourage people who inject drugs to mark their syringes and other injecting equipment, or to use easily identifiable equipment, to reduce the risk of accidental sharing. Encourage people who inject drugs to use other services as well. This includes services that aim to: reduce the harm associated with this practice; encourage them to switch to safer methods, if these are available (for example, opioid substitution therapy), or to stop using drugs; and address their other health needs. Tell them where to find these services and refer them as needed. # Recommendation 8 Provide community pharmacy-based needle and syringe programmes Community pharmacies, coordinators and local pharmaceutical committees (see who should take action?) should: Ensure staff who distribute needles and syringes are competent to deliver the level of service they offer. As a minimum, this should include awareness of the need for discretion and the need to respect the privacy and confidentiality of people who inject drugs. It should also include an understanding of how to treat people in a non-judgmental way. Ensure staff providing level 2 or 3 services (see recommendation 6) are competent to provide advice about the full range of drugs that people may be using. In particular, they should be able to advise on how to reduce the harm caused by injecting and how to prevent and manage an overdose. Ensure staff have received health and safety training, for example, in relation to blood-borne viruses, needlestick injuries and the safe disposal of needles, syringes and other injecting equipment. Ensure hepatitis B vaccination is available for staff directly involved in the needle and syringe programme. Ensure staff are aware of, encourage and can refer people to, other healthcare services including drug treatment services. Ensure pharmacy staff offer wider health promotion advice, as relevant, to individuals. See also recommendation 7. # Recommendation 9 Provide specialist (level 3) needle and syringe programmes Specialist needle and syringe programmes (including community pharmacies offering a level 3 service) should: Ensure a selection of individual needles, syringes and other injecting equipment is available. Provide sharps bins and advice on how to dispose of needles and syringes safely. In addition, provide a service for safe disposal of used equipment. Ensure staff are competent to deliver the service on offer. As a minimum, this should include awareness training on the need for discretion and the need to respect the privacy and confidentiality of people who inject drugs. It should also include training on how to treat people in a non-judgmental way. Ensure staff are competent to provide advice about the full range of drugs that people may be using, how to reduce the harm caused by injecting and how to prevent and manage an overdose. Ensure hepatitis B vaccination is available for staff directly involved in the needle and syringe programme. Offer comprehensive harm-reduction services. This includes: advice on safer injecting practices, assessment of injection-site infections, advice on preventing overdoses and help to stop injecting drugs. Offer (or help people to access): -pioid substitution therapy and other drug treatments treatment for injection-site infections vaccinations and boosters (including those offering protection from hepatitis A, hepatitis B and tetanus) testing and treatment for hepatitis B and hepatitis C (see NICE's guideline on hepatitis B and C) and HIV services for image- and performance-enhancing drug users specialist substance misuse services and specialist youth services (for young people under 18 who inject) -ther specialist clinics and services psychosocial interventions primary care services (including condom provision and general sexual health services, dental care and general health promotion advice) secondary care services (for example, mental health services) welfare and advocacy services (for example, advice on housing and legal issues). # Recommendation 10 Provide equipment and advice to people who inject image- and performance-enhancing drugs Commissioners, providers and public health practitioners (see who should take action?) should: Ensure needle and syringe programmes: Are provided at times and in places that meet the needs of people who inject image- and performance-enhancing drugs. (For example, offer services outside normal working hours, or provide outreach or detached services in gyms.) Provide the equipment, information and advice needed to support these users. Are provided by trained staff (in line with recommendation 8 and recommendation 9). Ensure those level 2 and 3 programmes used by a high proportion of people who take image- and performance-enhancing drugs provide specialist services for this group. This is in addition to routine services set out in recommendations 6 to 9. It includes: specialist advice about image- and performance-enhancing drugs specialist advice about the side effects of these drugs advice on alternatives (for example, nutrition and physical training can be used as an alternative to anabolic steroids) information about, and referral to, sexual and mental health services information about, and referral to, specialist image- and performance-enhancing drugs clinics, if these exist locally. # Who should take action? # Introduction The guidance is for directors of public health, commissioners and providers of needle and syringe programmes and related services, and those with a remit for infectious diseases. They could be working in local authorities, the NHS and other organisations in the public, private, voluntary and community sectors. This includes those working in: drug services, community pharmacies, local authorities and the wider public, voluntary and community sectors. In addition, it will be of interest to people who inject drugs, their families and other members of the public. Who should take action? Recommendation Health and wellbeing boards Children's safeguarding boards Local pharmaceutical committees Directors of public health Commissioners Providers of needle and syringe programmes Public health practitioners Coordinators of community pharmacy-based programmes Community pharmacies , 8, 9 (if relevant) Specialist needle and syringe programmes # Who should take action in detail ## Recommendation 1 Health and wellbeing boards; commissioners of drug, infectious disease, pharmacy and primary care services; directors of public health and public health practitioners whose remit includes needle and syringe programmes and infectious diseases ## Recommendation 2 Health and wellbeing boards; commissioners of drug, infectious disease, pharmacy and primary care services; directors of public health and public health practitioners whose remit includes needle and syringe programmes and infectious diseases ## Recommendation 3 Health and wellbeing boards; commissioners of drug, infectious disease, pharmacy and primary care services; directors of public health ## Recommendation 4 Health and wellbeing boards; commissioners and providers of needle and syringe programmes; public health practitioners whose remit includes needle and syringe programmes and infectious diseases ## Recommendation 5 Directors of public health; commissioners and providers of needle and syringe programmes; commissioners and providers of young people's services; commissioners of young people's specialist substance misuse services; children's safeguarding boards ## Recommendation 6 Health and wellbeing boards; commissioners of drug, infectious disease prevention, pharmacy and primary care services ## Recommendation 7 Needle and syringe programme providers ## Recommendation 8 Community pharmacies that run a needle and syringe programme, regardless of the level of service they offer (see recommendation 6); coordinators of community pharmacy-based needle and syringe programmes; local pharmaceutical committees ## Recommendation 9 Specialist needle and syringe programmes (including community pharmacies offering a level 3 service) ## Recommendation 10 Commissioners of needle and syringe programmes; providers of needle and syringe programmes; public health practitioners with a remit for needle and syringe programmes and for the prevention of infectious diseases# Context # Background Although it is difficult to estimate, figures suggest that the prevalence of opiate and crack cocaine injecting is in decline. The most recent figures (for 2010/11) suggest that an estimated 93,400 people inject opiates and/or crack in England (Hay et al. 2011). Prevalence seems to vary across regions. In 2006, almost one-quarter (23%) of respondents to the 'Unlinked anonymous monitoring survey of people who inject drugs' (Public Health England 2013a) reported sharing needles and syringes in the previous 4 weeks. Almost half (45%) reported that they had shared filters, mixing containers and water within that time (Health Protection Agency et al. 2007). Between 2001 and 2012, the number of people who injected drugs, and were in contact with specialist services that reported sharing needles and syringes, declined from 33% to 14%. The number who reported that they had shared filters, mixing containers and water declined to 34% (Public Health England (2013b). The number of opiate-related (heroin or methadone) deaths has decreased over the years. However, over the past decade (2002 to 2010), they have accounted for around two-thirds of all drug-related deaths in the UK (Davies et al. 2012). Although not all opiate-related deaths occur in people who inject, it is thought that the vast majority do. Sharing needles and syringes is a key route for transmitting blood-borne viruses among users. Sharing injecting equipment such as filters, mixing containers and water is also an important route of infection, particularly in the case of the hepatitis C virus. Data suggests that needle and syringe programmes are being accessed by increasing numbers of people who inject drugs across the UK. However, 'there remains a need to increase the amount of equipment distributed, with better targeting of this provision and education on appropriate needle and syringe cleaning techniques', according to Public Health England's hepatitis C in the UK 2013 report. Hepatitis C is still the most widespread infectious disease affecting people who inject drugs, with 49% of people in England testing positive for antibodies in 2012 (Public Health England 2013b). In contrast, HIV prevalence has remained relatively low among injecting drug populations over the last decade (Health Protection Agency 2012). In addition, the prevalence of hepatitis B infection has declined (Health Protection Agency 2010). # Image- and performance-enhancing drugs Information is limited regarding the number of people using image- and performance- enhancing drugs. Anabolic steroid use is relatively widespread, with an estimated 59,000 people aged 16 to 59 years in England and Wales having used them in the past year (Drug misuse: findings from the 2012 to 2013 Crime Survey for England and Wales). UK data suggest that the majority of people who use anabolic steroids inject them (Advisory Council on the Misuse of Drugs 2010), putting them at risk of bacterial and fungal infections and the transmission of blood-borne viruses. The risk of blood-borne virus transmission among people who inject image- and performance- enhancing drugs may be lower than among groups who inject other drugs. However, a recent analysis estimated that the prevalence of HIV among men who inject these drugs is similar to that among people who inject psychoactive drugs. The study also showed that few of the men injecting performance- and image- enhancing drugs had ever had an HIV test. The authors urge targeted interventions for this group (Hope et al. 2013). Users of image- and performance- enhancing drugs may represent a significant proportion of the people who use some needle and syringe programmes (Lenehan et al. 1996). There is evidence that people who inject steroids visit these services fewer times a year – collecting larger numbers of syringes in a single visit – than other users (McVeigh et al. 2003). Interviews with steroid injectors indicate that they often distribute injecting equipment among themselves (secondary distribution; McVeigh et al. 2007). In addition to anabolic steroids, increasing numbers of new products are being injected. These include growth hormone and novel drugs (such as those that claim to stimulate secretion of growth hormone), IGF‑1 and analogues, and human chorionic gonadotrophin, which may enhance physical performance (Evans-Brown et al. 2012). They also include melanotans – products that claim to contain melanotan II (and to a lesser extent melanotan I). These are injected to look tanned and, in the case of melanotan II and bremelanotide, for their effect on sexual behaviour and function. Although it is not known how many people use these new products, researchers have been alerted to their use in the general population through needle and syringe programmes seeking information after clients reported injecting these types of drugs (Evans-Brown et al. 2009). It is not known how many people in the United Kingdom use drugs such as botulinum toxin or dermal fillers to reduce the appearance of wrinkles and lines but a number of factors suggest that there may considerable interest in these types of products among the general population (Evans-Brown et al. 2012). # Young people who inject drugs Prevalence of drug injecting is higher among the 25 to 34 age group (17.9 per 1000) than the 15 to 24 age group (6.9 per 1000; Davies et al. 2010). It is not known how many people under 18 in England and Wales are involved. Data from the National Treatment Agency suggest that in 2011/12, 156 young people aged 17 or under who were in drug treatment were currently injecting drugs, and 257 of this same group had experience of injecting. This is a decrease from 2010/11. Data from the 'Unlinked anonymous monitoring survey of people who inject drugs' (Public Health England 2013a) suggest that in 2011, out of 2838 participants, 0.6% were under 18 (n=16) and 23% reported first injecting before age 18 (n=509). These numbers will represent a minority of young people who inject drugs, because UK evidence suggests that only 25% of this group are in treatment at any one time (Hickman 2004). It also suggests the proportion in treatment may be smaller for those under 18. Evidence also suggests that among young people, vulnerable groups are more likely to inject drugs. This includes: young offenders and those who are homeless or involved in sex work (Cusick et al. 2003) those excluded from school (Melrose 2004) young people with parents with drug or alcohol problems (Advisory Council on Misuse of Drugs 2003) those who are, or have been, in care (Ward et al. 2003). # Government action The government's 2010 drug strategy aims to reduce illicit and other harmful drug use. It also encourages an integrated approach to supporting people who want to recover from drug use. Although the strategy places an emphasis on recovery, it specifically states that needle and syringe programmes, alongside treatment, can help: 'reduce the harms caused by dependence such as the spread of blood-borne viruses like HIV'. Prevention of drug-related deaths and blood-borne viruses is also cited in the strategy as one of the eight 'best practice outcomes' that are key to successful delivery in a recovery-oriented system.# Considerations The Public Health Interventions Advisory Committee (PHIAC) for the original NICE guidance on needle and syringe programmes (NICE public health guidance 18, 2009) took account of a number of factors and issues when developing the recommendations. Many of these are still relevant (see 4.1 to 4.7 below) and informed the discussions of the Public Health Advisory Committee (PHAC) responsible for updating the guidance. In addition, PHAC took account of a number of additional factors and issues (see 4.8 to 4.19 below). Please note: this section does not contain the recommendations. Needle and syringe programmes (NSPs) need to be considered as part of a comprehensive substance-misuse strategy that covers prevention, treatment and harm reduction. The remit of this guidance was to consider the optimal provision of NSPs, not whether or not these programmes should be provided. Evidence from systematic reviews shows that NSPs are an effective way to reduce many of the risks associated with injecting drugs. The ethical issues and social values related to NSPs were discussed in some depth. The Public Health Interventions Advisory Committee (PHIAC) noted that it is difficult to meet the health needs of people who inject drugs without appearing to condone or 'normalise' drug use, especially in young people. It also noted that NSPs cannot reduce all of the potential harms associated with injecting drug use. Furthermore, NSPs might have disadvantages. For example, they may deter people who inject drugs from using safer drug taking methods or from stopping taking drugs altogether. On the other hand, NSPs can provide a means of contact with people who inject drugs and, hence, opportunities for harm reduction as well as support to help them stop injecting. NSPs can also help reduce blood-borne infections among people who inject drugs, to the benefit of society at large. After considering these issues at some length PHIAC felt that, on balance, recommendations on the optimal provision of NSPs were justified. Most published research was conducted in the USA. However, PHIAC judged that some of the evidence was applicable to England and could be used to inform the recommendations. The coverage provided by NSPs has been defined in a number of ways. The World Health Organization (2007) uses 3 definitions of 'coverage': percentage of injections 'covered' by sterile needles and syringes number of needles and syringes supplied to each injecting drug user per year percentage of injecting drug users in regular contact with NSPs.PHIAC used the first definition above to describe 'coverage': that is, 'coverage' in this guidance means the percentage of injections for which sterile equipment was available to use. Local communities need information about the aims of an NSP and evidence of its effectiveness when proposals are put forward for siting one in their neighbourhood. PHIAC emphasised the important 'gateway' function that NSPs may perform in bringing people who inject drugs into contact with a range of services. In particular, NSPs may bring them into contact with services that may help by: emphasising the dangers of overdosing (about 1% of people who inject drugs die of an overdose each year) encouraging people to switch to less harmful forms of drug taking encouraging people to opt for opioid substitution therapy encouraging people to stop using drugs encouraging people to be tested and treated for hepatitis C and HIV encouraging people to address their other health needs. The Public Health Advisory Committee (PHAC) took account of a number of additional factors and issues when developing the updated recommendations, as follows. PHAC noted that only a small amount of evidence had been published since the previous guidance, especially in relation to young people's drug use and the use of image- and performance- enhancing drugs. Furthermore, most of this evidence came from outside the UK. In response, Committee members' used their own knowledge and experience to apply the evidence to England and add further detail to the recommendations. PHAC noted the need to balance the number of people who have a sterile needle and syringe for each injection (coverage), with the number of people in direct contact with the NSP. Overall, members felt it was more important to achieve high rates of coverage, because this is the biggest predictor of sterile needle and syringe use. On this basis, the Committee felt that it was acceptable to knowingly provide equipment for secondary distribution (whereby drug users pass on sterile needles and syringes to others). Some evidence suggests that 100% coverage among 60% of the population is enough to slow the spread of blood-borne viruses and bacterial infections among people who inject drugs. However, higher coverage rates will have more of an impact. On this basis, PHAC retained the target of more than 100% coverage, as set out in the recommendations made in NICE public health guidance 18. The Committee also noted the need to monitor coverage rates for different sub-populations – not just for the overall population. PHAC noted that needle and syringe vending machines seem to be used by a different type of injector to needle and syringe programmes, notably young people and others at very high risk from injecting drugs. The Committee considered that they were a good way of providing additional, out-of-hours services – but not as a cheaper alternative to staffed NSP services. PHAC discussed the distinction between people who regularly inject drugs and those who inject occasionally. The evidence was not clear enough to make a specific recommendation for the latter. However, the Committee agreed that it was important to provide occasional users with a service. PHAC discussed at length the potential conflict between safeguarding young people and vulnerable adults who inject drugs and the need to provide them with harm reduction services, including sterile needles and syringes. The Committee was clear that a balance needed to be struck. It noted the need for competent professionals with skills in delivering needle and syringe programmes and with expertise in assessing young people from a safeguarding perspective. Members felt that, with adequate support, this could fall within the remit of both specialist workers and many community pharmacists. PHAC discussed how parents and carers could be consulted and involved when their children are using needle and syringe programmes. However, the Committee did not have enough evidence to make a recommendation on how to do this. PHAC noted that a focus on recovery (that is, encouraging people to stop taking drugs completely) should not compromise the provision of needle and syringe programmes and any associated harm-reduction initiatives. PHAC discussed the lack of information available about the needs of specific populations of people who inject, for example club-drug users or men who have sex with men. It also discussed innovative ways of reaching them to reduce the harms associated with injecting (see research recommendation 5.2). PHAC discussed the need for a national monitoring system to systematically gather and aggregate data on people who use needle and syringe programmes. It heard that Public Health England's Needle Exchange Monitoring System (NEXMS) was not well used. PHAC did not consider any evidence to allow a judgment on this matter. PHAC was satisfied that the provision of low dead-space injecting equipment was justified if its price was the same as, or only marginally higher than, other equipment. PHAC was aware of plans to make Naloxone more available for treating opiate overdose. However, it was not possible to make a recommendation on this due to the current status of the drug and lack of evidence of the effectiveness of providing it through needle and syringe programmes. PHAC considered a summary of the findings from the health economic modelling undertaken for the original guidance. This showed that providing people who inject opioid drugs with sterile injecting equipment is estimated to be cost effective from an NHS or personal social services (PSS) perspective (that is, excluding the costs of crime). It is similarly cost effective from a societal perspective. If the indirect 'gateway' effects of needle and syringe programmes – of increasing the proportion of people who inject drugs who take up opioid substitution therapy, or take part in other drug treatment – are included, a fall in the number who inject drugs is likely. This would, in turn, lead to a reduction in crime. If that is the case, modelling shows that these programmes are likely to be cost effective in the longer term. However, the figures in relation to the size of the 'gateway effect' are subject to considerable uncertainty, as are figures relating to any effect that an increase in needle and syringe programmes will have on the number of people injecting drugs. PHAC noted that there are insufficient data relating to young people aged under 18 who inject drugs to populate the economic model. However, PHAC thought that the findings are unlikely to differ significantly from people over that age. In fact, the benefits of needle and syringe programmes are probably greater for this group because they are more likely to reuse or share equipment. The marginal costs of extending provision to young people aged under 18 would be lower than the average cost for existing users. PHAC noted that there are insufficient data to allow useful modelling for people who inject image- and performance-enhancing drugs. The incidence of hepatitis C virus is probably lower in this group than among groups using other types of drugs because the substances used do not cause such acute withdrawal effects. As the need to inject may be less urgent, users probably have more time to obtain a sterile needle (and can think more clearly about where to get one). Also, many of these drugs are not controlled under the Misuse of Drugs Act Regulations, or have lesser penalties for use than opiates and stimulants. As a result, users will not be deterred from associating with a supplier of sterile needles. The cost of recommending that all people from this group use existing programmes would be relatively small. However, there is insufficient evidence to determine whether it is cost effective to develop dedicated services for this group.# Recommendations for research The Public Health Advisory Committee (PHAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects. All the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity. How can needle and syringe programmes encourage specific groups of people who inject drugs to use the service effectively? Examples include: those who have recently started injecting; women; sex workers; ex-prisoners; people who are homeless; people who occasionally inject drugs; and people who inject novel psychoactive drugs. What are the most effective and cost-effective ways of delivering needle and syringe programmes to: young people aged under 18 users of image- and performance-enhancing drugs? What type of behaviour-change interventions delivered by needle and syringe programmes are effective in promoting safer drug use practices and reducing the incidence of overdose (apart from providing needles, syringes and other injecting equipment)? What types of injecting equipment (including low dead-space syringes), paraphernalia and non-injecting equipment (for example, crack pipes or foil) effectively and cost effectively reduce the harm associated with injecting drug use? Do needle and syringe programmes have any unintended consequences: Do they increase the uptake, frequency and length of injecting drug use? Does the provision of disposal facilities (for example, drop-boxes) affect the amount of drug-related litter in an area? Do they have a negative impact on the local community, for example, in terms of crime rates or the fear of crime? More detail identified during development of this guidance is provided in gaps in the evidence.# Glossary # Detached services Workers from needle and syringe programmes deliver services away from the main venue. # Drugs The term 'drugs' is used in this guidance to mean: opioids (for example, heroin); stimulants (for example, cocaine) either separately or in combination (speedballing); novel psychoactive substances ('legal highs', for example, mephedrone); image- and performance-enhancing drugs (see below); and other drugs (for example, ketamine). # Image- and performance-enhancing drugs The term 'image- and performance- enhancing drugs' is used in this guidance to mean any substance injected with the intention of enhancing image or performance (except under medical supervision). It includes: anabolic steroids, growth hormone and novel drugs (such as those that stimulate secretion of growth hormone, IGF-1 and analogues, and human chorionic gonadotrophin) melanotans, bremelanotide, botulinum toxin and dermal fillers. # Injecting equipment The equipment supplied by needle and syringe programmes is regulated by a 2003 amendment to The Misuse of Drugs Act (2001). A Home Office circular on the supply of drug injecting paraphernalia clarifies that, in addition to needles and syringes, needle and syringe programmes may also supply: (a) swabs (b) utensils for the preparation of a controlled drug (that would include articles such as spoons, bowls, cups, dishes) (c) acidifiers (d) filters (e) ampoules of water for injection. In July 2013, a Home Office written ministerial statement on the lawful provision of foil explained it had accepted the Advisory Council on the Misuse of Drugs' advice to allow for the lawful provision of foil by drug treatment providers. This is subject to the strict condition that it is part of structured efforts to get people into treatment and off drugs. # Low dead-space injecting equipment Low dead-space injecting equipment seeks to limit the amount of (potentially contaminated) blood that remains in the equipment after it has been used, by reducing the amount of 'dead space' it contains. It is believed that this may reduce the risk of transmission of infectious diseases among people who share injecting equipment. There are 2 types of low dead-space injecting equipment: one uses fixed needles and the other uses detachable needles. # Needle and syringe programmes Needle and syringe programmes (NSPs) supply needles and syringes for people who inject drugs. In addition, they often supply other equipment used to prepare and take drugs (for example, filters, mixing containers and sterile water). The majority of needle and syringe programmes are run by pharmacies and drug services. They may operate from fixed, mobile or outreach sites. The main aim of needle and syringe programmes is to reduce the transmission of blood-borne viruses and other infections caused by sharing injecting equipment. Many also aim to reduce the other harms caused by injecting drug use and provide: advice on safer injecting practices advice on minimising the harm done by drugs, including image- and performance- enhancing drugs advice on how to avoid and manage an overdose information on the safe handling and disposal of injecting equipment access to blood-borne virus testing, vaccination and treatment services help to stop injecting drugs, including access to drug treatment (for example, opioid substitution therapy) and encouragement to switch to safer drug taking practices, if these are available -ther health and welfare services (including condom provision). # Outreach services Workers from drug and needle and syringe programmes go out and encourage people to use the service. # Poly-drug use Using more than one drug at the same time (although not necessarily in the same syringe). This practice is common among people who inject drugs. For example, people who use image- and performance-enhancing drugs often use one drug to enhance or counter the effects of another. They refer to this practice as 'stacking'. # Secondary distribution Where someone collects needles, syringes and other injecting equipment from the needle and syringe programme on behalf of others.# References Advisory Council on the Misuse of Drugs (2013) ACMD further advice on foil. London: Advisory Council on the Misuse of Drugs Advisory Council on the Misuse of Drugs (2010) Consideration of the anabolic steroids. London: Advisory Council on the Misuse of Drugs. Advisory Council on the Misuse of Drugs (2003) Hidden harm – responding to the needs of children of problem drug users. London: Advisory Council on the Misuse of Drugs. Cusick L, Martin A, May T (2003) Vulnerability and involvement and in drug use and sex work. London: Home Office. Davies C, English L, Lodwick A et al. (2010) United Kingdom drug situation: annual report to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) 2010. London: UK Focal Point on Drugs, Department of Health. Davies C, English L, Stewart C et al. (2012) United Kingdom drug situation: annual report to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) 2012. Liverpool: UK Focal Point on Drugs, Liverpool John Moores University Evans-Brown M, Dawson RT, Chandler M et al. (2009) Use of melanotan I and II in the general population. British Medical Journal 338: b566. Evans-Brown M, McVeigh J, Perkins C et al. (2012) Human enhancement drugs: the emerging challenges to public health. Liverpool: North West Public Health Observatory, Centre for Public Health, Liverpool John Moores University. Hay G, Rael dos Santos A, Millar T (2011) National and regional estimates of the prevalence of opiate and/or crack cocaine use, 2010–11: a summary of key findings. London: National Treatment Agency for Substance Misuse. Health Protection Agency (2012) United Kingdom. New HIV diagnoses to end of December 2012. Health Protection Agency (2010) Shooting up: infections among injecting drug users in the United Kingdom 2009. London: Health Protection Agency. Health Protection Agency, Health Protection Scotland, National Public Health Service for Wales et al. (2007) Shooting up: infections among injecting drug users in the United Kingdom, 2006. London: Health Protection Agency Hickman M, Higgins V, Hope V et al. (2004) Injecting drug use in Brighton, Liverpool, and London: best estimates of prevalence and coverage of public health indicators. Journal of Epidemiology and Community Health 58: 766–71 HM Government (2003) The Misuse of Drugs Act: 2003 (amendment) (no.2) regulations 2003 Home Office (2012) Drug misuse declared: findings from the 2011/12 British Crime Survey for England and Wales. London: Home Office. Home Office (2003) Home Office circular 035/2003 Supply of drug injecting paraphernalia. London: Home Office Hope VD, McVeigh J, Marongiu A et al. (2013) Prevalence of, and risk factors for, HIV, hepatitis B and C infections among men who inject image and performance enhancing drugs: a cross-sectional study. British Medical Journal Open 3: e003207 Lenehan P, Bellis MA, McVeigh J (1996) A study of anabolic steroid use in the North West of England. Journal of Performance Enhancing Drugs 1: 57–70 McVeigh J, Beynon C, Bellis MA (2003) New challenges for agency based syringe exchange schemes: analysis of 11 years of data (1991–2001) in Merseyside and Cheshire, United Kingdom. International Journal of Drug Policy 14: 399–405 McVeigh J, Chandler M, Beynon C et al. (2007) The injectors that harm reduction forgot. Poster presented at the 18th International Conference on the Reduction of Drug Related Harm, 13–17 May 2007, Warsaw, Poland. Melrose M (2004) Fractured transitions: disadvantaged young people, drug taking and risk. Probation Journal 51: 327–41 Public Health England, Centre for Infectious Disease Surveillance and Control and Microbiology Services (2013a). Unlinked anonymous monitoring survey of people who inject drugs in contact with specialist services: data tables. London: Public Health England. Public Health England (2013b) Hepatitis C in the UK 2013 report. London: Public Health England. Ward J, Henderson Z, Pearson G (2003) One problem among many: drug use among care leavers in transition to independent living Home Office Research Study. London: Home Office World Health Organization (2007) Guide to starting and managing needle and syringe programmes. Geneva: World Health Organization# Summary of the methods used to develop this guidance # Introduction The reviews include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Public Health Advisory Committee (PHAC) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations. # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PHAC to help develop the recommendations. The overarching questions for the original guidance were: Question 1: What level of coverage should needle and syringe programmes provide to keep HIV prevalence low and to reduce the prevalence of hepatitis C among people who inject drugs? Question 2: What type of needle and syringe programmes are effective and cost effective in reducing the transmission of blood-borne viruses and preventing injecting- site bacterial infections among people who inject drugs? Question 3: Which additional harm-reduction services offered by needle and syringe programmes are effective and cost effective in reducing the transmission of blood-borne viruses and preventing the occurrence of injecting-site bacterial infections among people who inject drugs? Question 4: Are needle and syringe programmes more effective and cost effective if they are offered in parallel with, or alongside, services that provide opiate substitution therapy? These questions were used to update the original review of the evidence. Subsidiary questions for the guidance update included: . What types of needle and syringe programme are effective and cost-effective for reducing the prevalence of HIV, hepatitis C and other blood-borne viruses, and morbidity and mortality relating to injecting drug use in people who inject image- and performance-enhancing drugs? . Which additional harm-reduction services offered by needle and syringe programmes are effective and cost-effective for reducing the prevalence of HIV, hepatitis C and other blood-borne viruses, and morbidity and mortality relating to injecting drug use in people who inject image- and performance-enhancing drugs? . What do people who inject image- and performance-enhancing drugs identify as suitable types of needle and syringe programme, and what do they believe to be a suitable level of coverage of needles, syringes and other types of injecting equipment? . What are their views and perspectives on, and experiences of, different types of needle and syringe programme? . How do the key harms associated with injecting drug use among people under 18 differ from those for older populations who inject drugs? . What are the barriers to service use among young people who inject drugs? . What are the social factors shaping patterns of use, perceptions of risk, harm, benefit and pleasure, and help-seeking (especially the use of needle and syringe programmes) among young people who use drugs? # Reviewing the evidence ## Evidence reviews for the original guidance Two reviews of the evidence were conducted for the original guidance: Injecting equipment schemes for injecting drug users: qualitative evidence review A review of the effectiveness and cost-effectiveness of needle and syringe programmes for injecting drug users ## Economic modelling for the original guidance The results of economic modelling are reported in: Assessing the cost-effectiveness of interventions linked to needle and syringe programmes for injecting drug users: an economic modelling report ## Evidence reviews for the update Two reviews of the evidence were conducted: Update of NICE guidance PH18 on needle and syringe programmes: PIEDs review Update of NICE guidance PH18 on needle and syringe programmes: qualitative and quantitative review updates Several databases were searched between January and March 2013 for all types of study published from 1990 onwards. See Update of NICE guidance PH18 on needle and syringe programmes: PIEDs review and Injecting drug use among young people – risk, harm and factors affecting access to services: a systematic review of the evidence. They were also searched for all types of study published from 2008 onwards. See Update of NICE guidance PH18 on needle and syringe programmes: qualitative and quantitative review updates. In addition, a call for evidence via the NICE website was used to generate further studies Inclusion and exclusion criteria for each review varied and details can be found in the evidence. ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in methods for the development of NICE public health guidance. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. − Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. ## Summarising the evidence and making evidence statements The review data was summarised in evidence tables (see the evidence reviews). The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see the evidence reviews). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope. # Policy review and consensus exercise Several databases and key websites were searched in January 2013 for policy documents from 1990 onwards. In addition, key websites were searched. In addition, a consensus development exercise was conducted through a series of interviews, a 1-day meeting and a subsequent Delphi study. See Analysis of national and local policy and protocols on the delivery of needle and syringe programme services to young people under 18: policy review and consensus development exercise. # Cost effectiveness See the economic modelling report for details of the cost-effectiveness evidence used to support the original guidance. No additional analyses were undertaken for this update. # Fieldwork Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with: commissioners, criminal justice workers, needle and syringe programme providers and workers in specialist needle and syringe programmes for young people, pharmacies and public health staff. The fieldwork comprised a focus group and interview analysis carried out by AddAction Research and Development. The main issues arising are set out in section 10 under fieldwork findings. Or see Needle and syringe programme fieldwork. # How the PHAC formulated the recommendations At its meetings in June, July and December 2013, the Public Health Advisory Committee (PHAC) considered the evidence and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention, programme or activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guidance. PHAC developed recommendations through informal consensus, based on the following criteria: Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations or settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. Where possible, recommendations were linked to evidence statements. Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).# The evidence # What evidence is the guidance based on? ## Original guidance The evidence used to develop the original guidance included: Evidence reviews: Injecting equipment schemes for injecting drug users: qualitative evidence review A review of the effectiveness and cost-effectiveness of needle and syringe programmes for injecting drug users Economic modelling: Assessing the cost-effectiveness of interventions linked to needle and syringe programmes for injecting drug users: an economic modelling report ## Updated guidance The evidence that the Public Health Advisory Committee (PHAC) considered included: Evidence and policy reviews: Review 1: Update of NICE guidance PH18 on needle and syringe programmes: qualitative and quantitative review updates, was carried out by Liverpool John Moores University. The principal authors were: Lisa Jones, Geoff Bates and Jim McVeigh. Review 2: Update of NICE guidance PH18 on needle and syringe programmes: PIEDs review, was carried out by Liverpool John Moores University. The principal authors were: Geoff Bates, Lisa Jones and Jim McVeigh. Review 3: Injecting drug use among young people – risk, harm and factors affecting access to services: a systematic review of the evidence, was carried out by the London School of Hygiene and Tropical Medicine. The principal authors were: Lucy Platt, Bethan McDonald, Neil Hunt, Adam Fletcher and Tim Rhodes. Policy review and consensus development exercise: Analysis of national and local policy and protocols on the delivery of needle and syringe programme services to young people under 18: policy review and consensus development exercise, was carried out by the London School of Hygiene and Tropical Medicine. The principal authors were: Neil Hunt and Lucy Platt. The fieldwork report Needle and syringe programme fieldwork was carried out by AddAction and Tiny Spark project. In some cases, the evidence was insufficient and the PHAC has made recommendations for future research. For the research recommendations and gaps in research, see recommendations for research and gaps in the evidence. # Introduction The evidence statements from 2 reviews conducted for the original guidance and 2 reviews conducted for the updated guidance are provided by external contractors. In addition, they provided consensus statements from the policy review and consensus development exercise. This section lists how the evidence statements and the consensus statements link to the recommendations and sets out a brief summary of findings from the economic analysis and the fieldwork. This section also sets out a brief summary of findings from the economic analysis conducted for the original guidance. # How the evidence links to the recommendations The evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. Evidence statement E6.2b indicates that the linked statement is numbered 6.2b in the review, 'A review of the effectiveness and cost-effectiveness of needle and syringe programmes for injecting drug users' (conducted for the original guidance). Evidence statement Q3.3a indicates that the linked statement is numbered 3.3a in the review, 'Injecting equipment schemes for injecting drug users: qualitative evidence review' (conducted for the original guidance). Evidence statement U2b indicates that the linked statement is numbered 2b in the review, 'Update of NICE guidance PH18 on needle and syringe programmes: qualitative and quantitative review updates'. Evidence statement Y10 indicates that the linked statement is numbered 10 in the review, 'Injecting drug use among young people – risk, harm and factors affecting access to services: a systematic review of the evidence'. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: evidence statements Q3.2a, Q3.3b, Q3.3c, Q3.3d, Q3.4a, Q3.6a, Q3.6b; IDE Recommendation 2: evidence statements E7.1b, E7.1c, U1a, U1b, Y13, IDE Recommendation 3: evidence statements E5.1a, E5.1b, E5.1c, E6.3b, E6.3c, E7.1a, E7.1b, E7.1c, Q3.3a, Q3.3b, Q3.3d, Q3.4a, Q3.4c, Q3.6a, U2c, U3c, U8; IDE Recommendation 4: IDE Recommendation 5: Y5, Y6; Consensus statements from table 1 of the policy review and consensus development Recommendation 6: evidence statements E5.1a, E5.1b, E5.1c, E6.3b, E6.3c, E6.4b, E7.1a, E7.1b, Q3.3c, Q3.3d, Q3.4b, Q3.5a, U2b; IDE Recommendation 7: evidence statements E5.1a, E5.1b, E6.3b, E6.3c, E7.1a, E7.1b, Q3.3a, U2e, U3a, U3b, U6; IDE Recommendation 8: evidence statements E5.1c, E6.3b, E6.3c, E7.1a, E7.1b, Q3.3b, Q3.4b, Q3.6b, U5, U7, Y14; IDE Recommendation 9: evidence statements E6.3b, E6.3c, E7.1a, E7.1b, Q3.3b, Q3.3c, Q3.4b, Q3.6b, U7; IDE Recommendation 10: IDE from 'Update of NICE guidance PH18 on needle and syringe programmes: PIEDs review' # Economic modelling The analyses for the original guidance estimated that needle and syringe programmes used as a channel for treating injecting drug users for chronic hepatitis C were cost effective. They can reduce the costs for society of drugs misuse by: improving the health of people who inject drugs ensuring the disease cannot be passed on after treatment. The modelling showed that if only health costs and benefits are counted, then a needle and syringe programme that increased coverage by 25% in a city with a high incidence of hepatitis C virus was cost effective (estimated ICER £11,400). However, an increase in coverage by 12.5% was not cost effective (estimated ICER £31,600). For a low-incidence city, the estimated ICER for an increase in coverage of 25% was £11,800, whereas for an increase of 12.5% the ICER was estimated as £26,100. If the costs to the criminal justice system are included, the modelling showed that a 12.5% increase in coverage for a high-incidence city was not cost effective (estimated ICER £38,700). But if coverage increased to 25%, the estimated ICER fell to £19,900. For a low-incidence city, for a 12.5% increase in coverage the ICER was £29,300, and for a 25% increase in coverage the ICER was £12,300. Needle and syringe programmes can also help reduce the number of people who are injecting drug users by acting as a 'gateway' to opiate substitution therapy. So these programmes may help reduce the costs of drug-related crime. When these indirect ('gateway') effects were modelled, it showed that a 13.5% increase in the rate of referral to opiate substitution therapy resulted in ICERs of between dominant and £17,000, depending on prevalence. The modelling found that overall, it is cost effective to give users more than one free needle per successful injection, if the cost of reaching them is not excessive and if use of this service increases by more than about 25% as a result. Full details can be found in Assessing the cost-effectiveness of interventions linked to needle and syringe programmes for injecting drug users: an economic modelling report. There were no additional analyses undertaken for the updated guidance. # Fieldwork findings The fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PHAC considered the findings when developing the final recommendations.. Fieldwork participants who work with people who inject drugs were very positive about the recommendations and their potential to improve needle and syringe programmes. Many participants stated that the new recommendations about young people and about people who inject image- and performance-enhancing drugs were much needed and would be very useful.# Gaps in the evidence The Public Health Advisory Committee (PHAC) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence. These gaps are set out below. . There is a lack of evidence about how many people inject drugs within different subgroups. This includes a lack of evidence about the number of young people who inject drugs and the number of people who inject image- and performance-enhancing drugs. . There is a lack of evidence about the injecting behaviours of different subgroups of young people and users of image- and performance-enhancing drugs. There is also a lack of evidence on how these groups use needle and syringe programmes and the effectiveness and cost effectiveness of providing needle and syringe programmes to these groups. . There is a lack of UK-based research on how best to target and tailor needle and syringe programmes to meet the needs of particular groups (such as young people who inject drugs, people who inject image- and performance-enhancing drugs and people who have recently started injecting drugs). For example, there is a lack of data on the effectiveness of using any of the following approaches with these groups: needle and syringe vending machines, specialist clinics, outreach or detached schemes. . There is a lack of evidence on how people who inject drugs perceive needle and syringe programmes and what encourages or discourages them from using the services. This may be particularly true for occasional users and use of image- and performance-enhancing drugs. . There is a lack of evidence on how to prevent people who are at high risk of injecting drugs (for example, those who smoke drugs) from moving from non-injecting to injecting drug use. This includes a lack of information about their needs and views. . There is a lack of evidence about the effectiveness (or otherwise) of providing needle and syringe programmes to children and very young people who are injecting drugs. This includes a lack of evidence about their specific needs. . There is a lack of evidence about the likelihood of children living with people who inject drugs becoming regular injectors themselves. . There is a lack of UK-based research on how the carers and families of people (including young people) who inject drugs and people who inject image- and performance-enhancing drugs view needle and syringe programmes. This includes a lack of evidence on how to get them involved with the programmes. . There is a lack of evidence about related behaviours that may occur among people who inject image- and performance-enhancing drugs, for example, poly-drug use or increased sexual activity. . There is a lack of UK-based research on the effectiveness and cost-effectiveness of prison-based needle and syringe programmes. . There is a lack of UK-based research into the potential unintended consequences of needle and syringe programmes. For example, there is a lack of evidence on whether or not they encourage people to inject more frequently. . There is a lack of standardised outcome measures for needle and syringe programmes in relation to safe injecting practices and the incidence and prevalence of blood-borne viruses, overdoses and wound infections. In particular, there is a lack of information regarding young people who inject drugs and people who inject image- and performance-enhancing drugs. . There is a lack of evidence on whether drug users who are referred to opioid substitution therapy programmes from needle and syringe programmes continue to attend after the first meeting. . There is a lack of evidence on the effectiveness of peer interventions that aim to prevent risky injecting practices and encourage people to use needle and syringe programmes. . There is a lack of evidence to determine whether secondary distribution increases risky injecting behaviour, and whether it increases or decreases the likelihood of people who inject coming into contact with a needle and syringe programme. . There is a lack of evidence on whether needle and syringe programmes encourage people to switch to safer injecting practices. . There is a lack of evidence about the impact that training needle and syringe programme staff can have on its effectiveness. The Committee made 5 recommendations for research into areas that it believes will be a priority for developing future guidelines.# Finding more information To find NICE guidance on related topics, including guidance in development, see the NICE topic page on drug misuse. For full details of the evidence and the guideline committee's discussions, see the evidence review, evidence statement and fieldwork report. You can also find information about how the guideline was developed, including details of the committee. NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.	{'What is this guidance about?': "This guidance makes recommendations on needle and syringe programmes, including those provided by pharmacies and drugs services for adults and young people (including those under\xa016) who inject drugs, including image- and performance-enhancing drugs.\n\nThe main aim of needle and syringe programmes is to reduce the transmission of blood-borne viruses and other infections caused by sharing injecting equipment, such as HIV, hepatitis\xa0B and\xa0C. In turn, this will reduce the prevalence of blood-borne viruses and bacterial infections, so benefiting wider society. Many needle and syringe programmes also aim to reduce the other harms caused by drug use and include:\n\nAdvice on minimising the harms caused by drugs.\n\nHelp to stop using drugs by providing access to drug treatment (for example, opioid substitution therapy).\n\nAccess to other health and welfare services.\n\nThe guidance is for directors of public health, commissioners, providers of needle and syringe programmes and related services, and those with a remit for infectious disease prevention. (For further details, see who should take action?) In addition, it may be of interest to members of the public.\n\nSee also the Department of Health and Social Care's Drug misuse and dependence: UK guidelines on clinical management, also known as the 'Orange Book', which provides advice to healthcare professionals on the delivery and implementation of a broad range of interventions for drug misuse, including those interventions covered in the present guideline.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Recommendation 1 Consult with and involve users, practitioners and the local community\n\nHealth and wellbeing boards, directors of public health, commissioners and public health practitioners (see who should take action?) should:\n\nInvolve the following when assessing the need for, and when planning, expanding or improving, a needle and syringe programme:\n\n\n\ndifferent groups of people who inject drugs (including both those who use a needle and syringe programme and those who don't)\n\nunder-represented groups, for example, young people and people from Black and minority ethnic groups who inject drugs\n\nfamilies and carers of people who inject drugs\n\nfrontline workers in needle and syringe programmes, pharmacies and related services in the statutory, voluntary and private sectors.\n\n\n\nConsult local communities about how best to implement new or reconfigured needle and syringe programmes. Promote the benefits of the service. For example, explain how these programmes have helped prevent an HIV epidemic in the UK and that they provide a route into drug treatment. Also explain that they may help reduce drug-related litter, by providing safe disposal facilities such as drop boxes and sharps bins.\n\nFor further recommendations on how to work with communities, see the NICE guideline on community engagement.\n\n# Recommendation 2 Collate and analyse data on injecting drug use\n\nHealth and wellbeing boards, directors of public health, commissioners and public health practitioners (see who should take action?) should:\n\nRegularly collate and analyse data from a range of sources (including data from Public Health England) to build reliable local estimates of the:\n\n\n\nPrevalence and incidence of infections related to injecting drug use (for example, hepatitis\xa0C and bacterial infections) and other problems caused by injecting drug use (for example, number of people overdosing).\n\nTypes of drugs used and the numbers, demographics and other characteristics of people who inject, for example:\n\n\n\nrates of poly-drug use\n\nyoung people aged under\xa018 who are injecting, or being injected\n\npeople who inject image- and performance-enhancing drugs (this includes new cohorts of users, for example, of tanning agents and other image-enhancing drugs)\n\nnew psychoactive substance injectors\n\npeople who inject occasionally, for example, when they go to night clubs\n\nother groups, such as men who have sex with men, ex-prisoners, sex workers or homeless people.\n\n\n\nNumber and percentage of injections covered by sterile needles and syringes in each of the groups identified above. (That is, the number and percentage of occasions when sterile equipment was available to use.)\n\nNumber and percentage of people who had more sterile needles and syringes than they needed (more than 100% coverage).\n\nNumber and percentage of people who inject drugs and who are in regular contact with a needle and syringe programme. (The definition of regular will vary depending on the needle and syringe programme user and the types of drugs they use.)\n\n\n\nMap other services that are commonly used by people who inject drugs, for example, opioid substitution therapy services, homeless services and custody centres.\n\n# Recommendation 3 Commission both generic and targeted services to meet local need\n\nHealth and wellbeing boards, directors of public health and commissioners (see who should take action?) should:\n\nEnsure the results of consultation and data analysis (in recommendation\xa01 and recommendation\xa02) inform the local joint strategic needs assessment.\n\nCommission a range of generic and targeted needle and syringe programmes to meet local need, based on these results. For example, ensure services are offered at a range of times and in a number of different locations. Take the geography and demographics of the area into account (for example, whether it is an urban or rural area). Targeted services should focus on the specific groups identified.\n\nEnsure services aim to be accessible and:\n\n\n\nIncrease the proportion of people who have more than 100% coverage (that is, the number who have more than 1\xa0sterile needle and syringe available for every injection).\n\nIncrease the proportion of people who have been tested for hepatitis\xa0B and\xa0C and other blood-borne viruses (including HIV) in the past 12\xa0months (see NICE's guideline on hepatitis\xa0B and\xa0C).\n\nIncrease the proportion of each group of people who inject drugs who are in contact with a needle and syringe programme.\n\nEnsure syringes and needles are available in a range of sizes and at a range of locations throughout the area.\n\nEncourage identification schemes (involving, for example, the use of coloured syringes).\n\nOffer, and encourage the use of, low dead-space injecting equipment.\n\nProvide advice and information on services that aim to: reduce the harm associated with injecting drug use; encourage people to stop using drugs or to switch to a safer approach if one is available (for example, opioid substitution therapy); and address their other health needs. Where possible, offer referrals to those services.\n\n\n\nIf applicable, commission outreach or detached services for areas where there are high levels of drug use or populations that do not use existing needle and syringe programmes.\n\nPromote needle and syringe programmes to groups that may be under-represented among those who use them, for example, club-drug injectors and people who inject image- and performance-enhancing drugs.\n\nDevelop plans for needle and syringe disposal, in line with the Department for Environment, Food and Rural Affairs tackling drug-related litter: Guidance and good practice. Include the provision and disposal of sharps boxes for the safe disposal of needles. Consider providing public sharps bins (drop boxes) in areas where drug-related litter is common. Work with members of the local community, people who inject drugs and the local police service to agree the location for drop boxes.\n\nCommission integrated care pathways for people who inject drugs so that they can move seamlessly between the full range of services, including treatment services.\n\n# Recommendation 4 Monitor services\n\nCommissioners and providers of needle and syringe programmes, with support from public health practitioners, should:\n\nCollect data on service usage as follows:\n\n\n\nAll services should monitor the number and types of packs or equipment they distribute.\n\nSpecialist services should, where possible, collect more detailed data on: the amount and type of equipment distributed, the demographic details of the person who is injecting, along with details of their injecting practices and the drugs they are injecting (see recommendation\xa02). Practitioners should only ask for these details if they are confident it will not discourage the person from using the service.\n\n\n\nEnsure a local mechanism is in place to aggregate and analyse the data collected on at least an annual basis. Aim to build up a picture of injecting practices in the local area and how this may be changing over time. This data should be used as part of the collecting and analysing data process (see recommendation\xa02).\n\nEnsure local service use data are available, in anonymised form, for relevant national bodies and research units (for example, Public Health England).\n\n# Recommendation 5 Develop a policy for young people who inject drugs\n\nDirectors of public health, children's safeguarding boards, commissioners and providers (see who should take action?) should:\n\nDevelop and implement a local, area-wide policy on providing needle and syringe programmes and related services to meet the needs of different groups of young people aged under\xa018 (including young people under\xa016) who inject drugs.\n\nEnsure the policy details how local services will achieve the right balance between the imperative to provide young people with sterile injecting equipment and the duty to protect (safeguard) them and provide advice on harm reduction and other services. It should take account of:\n\n\n\nthe young person's capacity to consent (see the Judgement on Gillick competence)\n\nthe risks they face\n\nthe benefits of using services\n\nthe likelihood that they would inject anyway, even if sterile needles and syringes were not provided.\n\n\n\nMake the governance responsibilities of drug services and safeguarding boards clear. The safeguarding board should approve the local policy.\n\nEnsure the policy emphasises the need to provide young people with sterile injecting equipment. This should be provided as part of a broader package of care to meet their other health and social care needs, where possible. This is especially important for under-16s.\n\nEnsure the policy is responsive to the needs of young people in the local area. The developers of the policy should take into account:\n\n\n\nProvision of specialist young people's substance misuse services, including specialist provision of needle and syringe programmes for those under\xa018 (including young people under\xa016).\n\nHow to encourage young people to ask for advice and help from staff providing the services (as well as providing them with needles, syringes and injecting equipment).\n\nHow to assess service users:\n\n\n\ntheir age\n\nthe degree or seriousness of their drug misuse\n\nwhether the harm or risk they face is continuing or increasing\n\nthe general context in which they are using drugs.\n\n\n\nThe skills, knowledge and awareness that staff need to provide services. This includes ensuring staff are trained to assess whether young people are competent to consent (Gillick competence).\n\nThe potential for using pharmacies to provide young people with needles, syringes and injecting equipment, if they also encourage the young person to make contact with specialist services.\n\nThat parental or carer involvement should generally be encouraged, with the consent of the young person. Where this is not possible (or appropriate), the policy should include strategies to address their needs.\n\nThe role of needle and syringe programmes as part of a range of services for young people that includes seamless transition from youth to adult services.\n\n\n\nEnsure needle and syringe programmes aimed at young people who inject drugs implement all the recommendations in this guidance, not just those for young people.\n\nRegularly review the policy.\n\n# Recommendation 6 Provide a mix of services\n\nHealth and wellbeing boards and commissioners (see who should take action?) should:\n\nUse pharmacies, specialist needle and syringe programmes and other settings and approaches to provide geographical and demographic coverage. Examples of other settings and approaches that could be used include: custody centres, sexual health services, outreach and detached services. Provide a mix of the following levels of service to meet local needs:\n\n\n\nLevel 1: distribution of injecting equipment either loose or in packs, suitable for different types of injecting practice, with written information on harm reduction. (For example, telling people about specialist agencies, or giving them details about safer injecting practices, including how to prevent an overdose.)\n\nLevel 2: distribution of 'pick and mix' (bespoke) injecting equipment and referral to specialist services plus health promotion advice. (This includes advice and information on how to reduce the harms caused by injecting drugs.) Some level\xa02 services might also offer additional services, such as blood-borne virus testing or vaccination.\n\nLevel 3: level 2 plus provision of, or referral to, other specialist services (for example, specialist clinics, vaccinations, drug treatment and secondary care). See recommendation\xa09.\n\n\n\nEstablish links and referral pathways between the different levels of service to promote integration and to share learning and expertise.\n\nCoordinate services to ensure testing for hepatitis\xa0B and\xa0C and other blood-borne viruses is readily available to everyone who uses a needle and syringe programme (see NICE's guideline on hepatitis\xa0B and\xa0C).\n\nCoordinate services to ensure injecting equipment is available at times, and in places, that meet the needs of people who inject drugs. For example, it may be appropriate to provide out-of-hours vending machines for groups that would not otherwise have access to services – or not at the time that they need them. (The location of these machines would need to be considered carefully and their use would need to be regularly monitored.) Another example would be to encourage pharmacies with longer opening hours to provide needles, syringes and other injecting equipment.\n\nEnsure services offering opioid substitution therapy also make needles and syringes available to their service users.\n\n# Recommendation 7 Provide people with the right type of equipment and advice\n\nNeedle and syringe programme providers should:\n\nProvide people who inject drugs with needles, syringes and other injecting equipment. The quantity provided should not be subject to a limit but, rather, should meet their needs.\n\n\n\nMake needles available in a range of lengths and gauges, provide syringes in a range of sizes, and\n\nOffer low dead-space injecting equipment.\n\n\n\nNot discourage people from taking equipment for others (secondary distribution), but rather, ask them to encourage those people to use the service themselves.\n\nEnsure people who use the programmes are provided with sharps bins and advice on how to dispose of needles and syringes safely. In addition, provide a means for safe disposal of used bins and equipment.\n\nProvide advice relevant to the type of drug and injecting practices, especially higher risk practices such as injecting in the groin or neck.\n\nEncourage people who inject drugs to mark their syringes and other injecting equipment, or to use easily identifiable equipment, to reduce the risk of accidental sharing.\n\nEncourage people who inject drugs to use other services as well. This includes services that aim to: reduce the harm associated with this practice; encourage them to switch to safer methods, if these are available (for example, opioid substitution therapy), or to stop using drugs; and address their other health needs. Tell them where to find these services and refer them as needed.\n\n# Recommendation 8 Provide community pharmacy-based needle and syringe programmes\n\nCommunity pharmacies, coordinators and local pharmaceutical committees (see who should take action?) should:\n\nEnsure staff who distribute needles and syringes are competent to deliver the level of service they offer. As a minimum, this should include awareness of the need for discretion and the need to respect the privacy and confidentiality of people who inject drugs. It should also include an understanding of how to treat people in a non-judgmental way.\n\nEnsure staff providing level\xa02 or\xa03 services (see recommendation\xa06) are competent to provide advice about the full range of drugs that people may be using. In particular, they should be able to advise on how to reduce the harm caused by injecting and how to prevent and manage an overdose.\n\nEnsure staff have received health and safety training, for example, in relation to blood-borne viruses, needlestick injuries and the safe disposal of needles, syringes and other injecting equipment.\n\nEnsure hepatitis\xa0B vaccination is available for staff directly involved in the needle and syringe programme.\n\nEnsure staff are aware of, encourage and can refer people to, other healthcare services including drug treatment services.\n\nEnsure pharmacy staff offer wider health promotion advice, as relevant, to individuals.\n\nSee also recommendation\xa07.\n\n# Recommendation 9 Provide specialist (level\xa03) needle and syringe programmes\n\nSpecialist needle and syringe programmes (including community pharmacies offering a level\xa03 service) should:\n\nEnsure a selection of individual needles, syringes and other injecting equipment is available.\n\nProvide sharps bins and advice on how to dispose of needles and syringes safely. In addition, provide a service for safe disposal of used equipment.\n\nEnsure staff are competent to deliver the service on offer. As a minimum, this should include awareness training on the need for discretion and the need to respect the privacy and confidentiality of people who inject drugs. It should also include training on how to treat people in a non-judgmental way.\n\nEnsure staff are competent to provide advice about the full range of drugs that people may be using, how to reduce the harm caused by injecting and how to prevent and manage an overdose.\n\nEnsure hepatitis\xa0B vaccination is available for staff directly involved in the needle and syringe programme.\n\nOffer comprehensive harm-reduction services. This includes: advice on safer injecting practices, assessment of injection-site infections, advice on preventing overdoses and help to stop injecting drugs.\n\nOffer (or help people to access):\n\n\n\nopioid substitution therapy and other drug treatments\n\ntreatment for injection-site infections\n\nvaccinations and boosters (including those offering protection from hepatitis\xa0A, hepatitis\xa0B and tetanus)\n\ntesting and treatment for hepatitis\xa0B and hepatitis\xa0C (see NICE's guideline on hepatitis\xa0B and\xa0C) and HIV\n\nservices for image- and performance-enhancing drug users\n\nspecialist substance misuse services and specialist youth services (for young people under\xa018 who inject)\n\nother specialist clinics and services\n\npsychosocial interventions\n\nprimary care services (including condom provision and general sexual health services, dental care and general health promotion advice)\n\nsecondary care services (for example, mental health services)\n\nwelfare and advocacy services (for example, advice on housing and legal issues).\n\n\n\n# Recommendation 10 Provide equipment and advice to people who inject image- and performance-enhancing drugs\n\nCommissioners, providers and public health practitioners (see who should take action?) should:\n\nEnsure needle and syringe programmes:\n\n\n\nAre provided at times and in places that meet the needs of people who inject image- and performance-enhancing drugs. (For example, offer services outside normal working hours, or provide outreach or detached services in gyms.)\n\nProvide the equipment, information and advice needed to support these users.\n\nAre provided by trained staff (in line with recommendation\xa08 and recommendation\xa09).\n\n\n\nEnsure those level\xa02 and\xa03 programmes used by a high proportion of people who take image- and performance-enhancing drugs provide specialist services for this group. This is in addition to routine services set out in recommendations 6\xa0to\xa09. It includes:\n\n\n\nspecialist advice about image- and performance-enhancing drugs\n\nspecialist advice about the side effects of these drugs\n\nadvice on alternatives (for example, nutrition and physical training can be used as an alternative to anabolic steroids)\n\ninformation about, and referral to, sexual and mental health services\n\ninformation about, and referral to, specialist image- and performance-enhancing drugs clinics, if these exist locally.\n\n", 'Who should take action?': "# Introduction\n\nThe guidance is for directors of public health, commissioners and providers of needle and syringe programmes and related services, and those with a remit for infectious diseases. They could be working in local authorities, the NHS and other organisations in the public, private, voluntary and community sectors. This includes those working in: drug services, community pharmacies, local authorities and the wider public, voluntary and community sectors.\n\nIn addition, it will be of interest to people who inject drugs, their families and other members of the public.\n\n\n\nWho should take action?\n\nRecommendation\n\nHealth and wellbeing boards\n\n, 2, 3, 6\n\nChildren's safeguarding boards\n\n\n\nLocal pharmaceutical committees\n\n\n\nDirectors of public health\n\n, 2, 3, 5\n\nCommissioners\n\n, 2, 3, 4, 5, 6, 10\n\nProviders of needle and syringe programmes\n\n, 7, 10\n\nPublic health practitioners\n\n, 2, 4, 10\n\nCoordinators of community pharmacy-based programmes\n\n\n\nCommunity pharmacies\n\n, 8, 9 (if relevant)\n\nSpecialist needle and syringe programmes\n\n\n\n# Who should take action in detail\n\n## Recommendation 1\n\nHealth and wellbeing boards; commissioners of drug, infectious disease, pharmacy and primary care services; directors of public health and public health practitioners whose remit includes needle and syringe programmes and infectious diseases\n\n## Recommendation 2\n\nHealth and wellbeing boards; commissioners of drug, infectious disease, pharmacy and primary care services; directors of public health and public health practitioners whose remit includes needle and syringe programmes and infectious diseases\n\n## Recommendation 3\n\nHealth and wellbeing boards; commissioners of drug, infectious disease, pharmacy and primary care services; directors of public health\n\n## Recommendation 4\n\nHealth and wellbeing boards; commissioners and providers of needle and syringe programmes; public health practitioners whose remit includes needle and syringe programmes and infectious diseases\n\n## Recommendation 5\n\nDirectors of public health; commissioners and providers of needle and syringe programmes; commissioners and providers of young people's services; commissioners of young people's specialist substance misuse services; children's safeguarding boards\n\n## Recommendation 6\n\nHealth and wellbeing boards; commissioners of drug, infectious disease prevention, pharmacy and primary care services\n\n## Recommendation 7\n\nNeedle and syringe programme providers\n\n## Recommendation 8\n\nCommunity pharmacies that run a needle and syringe programme, regardless of the level of service they offer (see recommendation\xa06); coordinators of community pharmacy-based needle and syringe programmes; local pharmaceutical committees\n\n## Recommendation 9\n\nSpecialist needle and syringe programmes (including community pharmacies offering a level\xa03 service)\n\n## Recommendation 10\n\nCommissioners of needle and syringe programmes; providers of needle and syringe programmes; public health practitioners with a remit for needle and syringe programmes and for the prevention of infectious diseases", 'Context': "# Background\n\nAlthough it is difficult to estimate, figures suggest that the prevalence of opiate and crack cocaine injecting is in decline. The most recent figures (for 2010/11) suggest that an estimated 93,400 people inject opiates and/or crack in England (Hay et al. 2011). Prevalence seems to vary across regions.\n\nIn 2006, almost one-quarter (23%) of respondents to the 'Unlinked anonymous monitoring survey of people who inject drugs' (Public Health England 2013a) reported sharing needles and syringes in the previous 4\xa0weeks. Almost half (45%) reported that they had shared filters, mixing containers and water within that time (Health Protection Agency et al. 2007).\n\nBetween 2001 and 2012, the number of people who injected drugs, and were in contact with specialist services that reported sharing needles and syringes, declined from 33% to 14%. The number who reported that they had shared filters, mixing containers and water declined to 34% (Public Health England (2013b).\n\nThe number of opiate-related (heroin or methadone) deaths has decreased over the years. However, over the past decade (2002 to 2010), they have accounted for around two-thirds of all drug-related deaths in the UK (Davies et al. 2012). Although not all opiate-related deaths occur in people who inject, it is thought that the vast majority do.\n\nSharing needles and syringes is a key route for transmitting blood-borne viruses among users. Sharing injecting equipment such as filters, mixing containers and water is also an important route of infection, particularly in the case of the hepatitis\xa0C virus. Data suggests that needle and syringe programmes are being accessed by increasing numbers of people who inject drugs across the UK. However, 'there remains a need to increase the amount of equipment distributed, with better targeting of this provision and education on appropriate needle and syringe cleaning techniques', according to Public Health England's hepatitis\xa0C in the UK 2013 report.\n\nHepatitis\xa0C is still the most widespread infectious disease affecting people who inject drugs, with 49% of people in England testing positive for antibodies in 2012 (Public Health England 2013b). In contrast, HIV prevalence has remained relatively low among injecting drug populations over the last decade (Health Protection Agency 2012). In addition, the prevalence of hepatitis\xa0B infection has declined (Health Protection Agency 2010).\n\n# Image- and performance-enhancing drugs\n\nInformation is limited regarding the number of people using image- and performance- enhancing drugs. Anabolic steroid use is relatively widespread, with an estimated 59,000 people aged 16\xa0to 59\xa0years in England and Wales having used them in the past year (Drug misuse: findings from the 2012 to 2013 Crime Survey for England and Wales).\n\nUK data suggest that the majority of people who use anabolic steroids inject them (Advisory Council on the Misuse of Drugs 2010), putting them at risk of bacterial and fungal infections and the transmission of blood-borne viruses.\n\nThe risk of blood-borne virus transmission among people who inject image- and performance- enhancing drugs may be lower than among groups who inject other drugs. However, a recent analysis estimated that the prevalence of HIV among men who inject these drugs is similar to that among people who inject psychoactive drugs. The study also showed that few of the men injecting performance- and image- enhancing drugs had ever had an HIV test. The authors urge targeted interventions for this group (Hope et al. 2013).\n\nUsers of image- and performance- enhancing drugs may represent a significant proportion of the people who use some needle and syringe programmes (Lenehan et al. 1996). There is evidence that people who inject steroids visit these services fewer times a year – collecting larger numbers of syringes in a single visit – than other users (McVeigh et al. 2003). Interviews with steroid injectors indicate that they often distribute injecting equipment among themselves (secondary distribution; McVeigh et al. 2007).\n\nIn addition to anabolic steroids, increasing numbers of new products are being injected. These include growth hormone and novel drugs (such as those that claim to stimulate secretion of growth hormone), IGF‑1 and analogues, and human chorionic gonadotrophin, which may enhance physical performance (Evans-Brown et al. 2012). They also include melanotans – products that claim to contain melanotan II (and to a lesser extent melanotan I). These are injected to look tanned and, in the case of melanotan II and bremelanotide, for their effect on sexual behaviour and function.\n\nAlthough it is not known how many people use these new products, researchers have been alerted to their use in the general population through needle and syringe programmes seeking information after clients reported injecting these types of drugs (Evans-Brown et al. 2009).\n\nIt is not known how many people in the United Kingdom use drugs such as botulinum toxin or dermal fillers to reduce the appearance of wrinkles and lines but a number of factors suggest that there may considerable interest in these types of products among the general population (Evans-Brown et al. 2012).\n\n# Young people who inject drugs\n\nPrevalence of drug injecting is higher among the 25\xa0to\xa034 age group (17.9 per 1000) than the 15\xa0to\xa024 age group (6.9 per 1000; Davies et al. 2010). It is not known how many people under\xa018 in England and Wales are involved.\n\nData from the National Treatment Agency suggest that in 2011/12, 156 young people aged 17 or under who were in drug treatment were currently injecting drugs, and 257 of this same group had experience of injecting. This is a decrease from 2010/11.\n\nData from the 'Unlinked anonymous monitoring survey of people who inject drugs' (Public Health England 2013a) suggest that in 2011, out of 2838 participants, 0.6% were under\xa018 (n=16) and 23% reported first injecting before age\xa018 (n=509). These numbers will represent a minority of young people who inject drugs, because UK evidence suggests that only 25% of this group are in treatment at any one time (Hickman 2004). It also suggests the proportion in treatment may be smaller for those under\xa018.\n\nEvidence also suggests that among young people, vulnerable groups are more likely to inject drugs. This includes:\n\nyoung offenders and those who are homeless or involved in sex work (Cusick et al. 2003)\n\nthose excluded from school (Melrose 2004)\n\nyoung people with parents with drug or alcohol problems (Advisory Council on Misuse of Drugs 2003)\n\nthose who are, or have been, in care (Ward et al. 2003).\n\n# Government action\n\nThe government's 2010 drug strategy aims to reduce illicit and other harmful drug use. It also encourages an integrated approach to supporting people who want to recover from drug use.\n\nAlthough the strategy places an emphasis on recovery, it specifically states that needle and syringe programmes, alongside treatment, can help: 'reduce the harms caused by dependence such as the spread of blood-borne viruses like HIV'.\n\nPrevention of drug-related deaths and blood-borne viruses is also cited in the strategy as one of the eight 'best practice outcomes' that are key to successful delivery in a recovery-oriented system.", 'Considerations': "The Public Health Interventions Advisory Committee (PHIAC) for the original NICE guidance on needle and syringe programmes (NICE public health guidance 18, 2009) took account of a number of factors and issues when developing the recommendations. Many of these are still relevant (see 4.1 to 4.7 below) and informed the discussions of the Public Health Advisory Committee (PHAC) responsible for updating the guidance. In addition, PHAC took account of a number of additional factors and issues (see 4.8 to 4.19 below).\n\nPlease note: this section does not contain the recommendations.\n\nNeedle and syringe programmes (NSPs) need to be considered as part of a comprehensive substance-misuse strategy that covers prevention, treatment and harm reduction.\n\nThe remit of this guidance was to consider the optimal provision of NSPs, not whether or not these programmes should be provided. Evidence from systematic reviews shows that NSPs are an effective way to reduce many of the risks associated with injecting drugs.\n\nThe ethical issues and social values related to NSPs were discussed in some depth. The Public Health Interventions Advisory Committee (PHIAC) noted that it is difficult to meet the health needs of people who inject drugs without appearing to condone or 'normalise' drug use, especially in young people. It also noted that NSPs cannot reduce all of the potential harms associated with injecting drug use. Furthermore, NSPs might have disadvantages. For example, they may deter people who inject drugs from using safer drug taking methods or from stopping taking drugs altogether. On the other hand, NSPs can provide a means of contact with people who inject drugs and, hence, opportunities for harm reduction as well as support to help them stop injecting. NSPs can also help reduce blood-borne infections among people who inject drugs, to the benefit of society at large. After considering these issues at some length PHIAC felt that, on balance, recommendations on the optimal provision of NSPs were justified.\n\nMost published research was conducted in the USA. However, PHIAC judged that some of the evidence was applicable to England and could be used to inform the recommendations.\n\nThe coverage provided by NSPs has been defined in a number of ways. The World Health Organization (2007) uses 3 definitions of 'coverage':\n\npercentage of injections 'covered' by sterile needles and syringes\n\nnumber of needles and syringes supplied to each injecting drug user per year\n\npercentage of injecting drug users in regular contact with NSPs.PHIAC used the first definition above to describe 'coverage': that is, 'coverage' in this guidance means the percentage of injections for which sterile equipment was available to use.\n\nLocal communities need information about the aims of an NSP and evidence of its effectiveness when proposals are put forward for siting one in their neighbourhood.\n\nPHIAC emphasised the important 'gateway' function that NSPs may perform in bringing people who inject drugs into contact with a range of services. In particular, NSPs may bring them into contact with services that may help by:\n\nemphasising the dangers of overdosing (about 1% of people who inject drugs die of an overdose each year)\n\nencouraging people to switch to less harmful forms of drug taking\n\nencouraging people to opt for opioid substitution therapy\n\nencouraging people to stop using drugs\n\nencouraging people to be tested and treated for hepatitis\xa0C and HIV\n\nencouraging people to address their other health needs. The Public Health Advisory Committee (PHAC) took account of a number of additional factors and issues when developing the updated recommendations, as follows.\n\nPHAC noted that only a small amount of evidence had been published since the previous guidance, especially in relation to young people's drug use and the use of image- and performance- enhancing drugs. Furthermore, most of this evidence came from outside the UK. In response, Committee members' used their own knowledge and experience to apply the evidence to England and add further detail to the recommendations.\n\nPHAC noted the need to balance the number of people who have a sterile needle and syringe for each injection (coverage), with the number of people in direct contact with the NSP. Overall, members felt it was more important to achieve high rates of coverage, because this is the biggest predictor of sterile needle and syringe use. On this basis, the Committee felt that it was acceptable to knowingly provide equipment for secondary distribution (whereby drug users pass on sterile needles and syringes to others).\n\nSome evidence suggests that 100% coverage among 60% of the population is enough to slow the spread of blood-borne viruses and bacterial infections among people who inject drugs. However, higher coverage rates will have more of an impact. On this basis, PHAC retained the target of more than 100% coverage, as set out in the recommendations made in NICE public health guidance\xa018. The Committee also noted the need to monitor coverage rates for different sub-populations – not just for the overall population.\n\nPHAC noted that needle and syringe vending machines seem to be used by a different type of injector to needle and syringe programmes, notably young people and others at very high risk from injecting drugs. The Committee considered that they were a good way of providing additional, out-of-hours services – but not as a cheaper alternative to staffed NSP services.\n\nPHAC discussed the distinction between people who regularly inject drugs and those who inject occasionally. The evidence was not clear enough to make a specific recommendation for the latter. However, the Committee agreed that it was important to provide occasional users with a service.\n\nPHAC discussed at length the potential conflict between safeguarding young people and vulnerable adults who inject drugs and the need to provide them with harm reduction services, including sterile needles and syringes. The Committee was clear that a balance needed to be struck. It noted the need for competent professionals with skills in delivering needle and syringe programmes and with expertise in assessing young people from a safeguarding perspective. Members felt that, with adequate support, this could fall within the remit of both specialist workers and many community pharmacists.\n\nPHAC discussed how parents and carers could be consulted and involved when their children are using needle and syringe programmes. However, the Committee did not have enough evidence to make a recommendation on how to do this.\n\nPHAC noted that a focus on recovery (that is, encouraging people to stop taking drugs completely) should not compromise the provision of needle and syringe programmes and any associated harm-reduction initiatives.\n\nPHAC discussed the lack of information available about the needs of specific populations of people who inject, for example club-drug users or men who have sex with men. It also discussed innovative ways of reaching them to reduce the harms associated with injecting (see research recommendation\xa05.2).\n\nPHAC discussed the need for a national monitoring system to systematically gather and aggregate data on people who use needle and syringe programmes. It heard that Public Health England's Needle Exchange Monitoring System (NEXMS) was not well used. PHAC did not consider any evidence to allow a judgment on this matter.\n\nPHAC was satisfied that the provision of low dead-space injecting equipment was justified if its price was the same as, or only marginally higher than, other equipment.\n\nPHAC was aware of plans to make Naloxone more available for treating opiate overdose. However, it was not possible to make a recommendation on this due to the current status of the drug and lack of evidence of the effectiveness of providing it through needle and syringe programmes.\n\nPHAC considered a summary of the findings from the health economic modelling undertaken for the original guidance. This showed that providing people who inject opioid drugs with sterile injecting equipment is estimated to be cost effective from an NHS or personal social services (PSS) perspective (that is, excluding the costs of crime). It is similarly cost effective from a societal perspective. If the indirect 'gateway' effects of needle and syringe programmes – of increasing the proportion of people who inject drugs who take up opioid substitution therapy, or take part in other drug treatment – are included, a fall in the number who inject drugs is likely. This would, in turn, lead to a reduction in crime. If that is the case, modelling shows that these programmes are likely to be cost effective in the longer term. However, the figures in relation to the size of the 'gateway effect' are subject to considerable uncertainty, as are figures relating to any effect that an increase in needle and syringe programmes will have on the number of people injecting drugs.\n\nPHAC noted that there are insufficient data relating to young people aged under\xa018 who inject drugs to populate the economic model. However, PHAC thought that the findings are unlikely to differ significantly from people over that age. In fact, the benefits of needle and syringe programmes are probably greater for this group because they are more likely to reuse or share equipment. The marginal costs of extending provision to young people aged under\xa018 would be lower than the average cost for existing users.\n\nPHAC noted that there are insufficient data to allow useful modelling for people who inject image- and performance-enhancing drugs. The incidence of hepatitis\xa0C virus is probably lower in this group than among groups using other types of drugs because the substances used do not cause such acute withdrawal effects. As the need to inject may be less urgent, users probably have more time to obtain a sterile needle (and can think more clearly about where to get one). Also, many of these drugs are not controlled under the Misuse of Drugs Act Regulations, or have lesser penalties for use than opiates and stimulants. As a result, users will not be deterred from associating with a supplier of sterile needles. The cost of recommending that all people from this group use existing programmes would be relatively small. However, there is insufficient evidence to determine whether it is cost effective to develop dedicated services for this group.", 'Recommendations for research': "The Public Health Advisory Committee (PHAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.\n\nAll the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity.\n\nHow can needle and syringe programmes encourage specific groups of people who inject drugs to use the service effectively? Examples include: those who have recently started injecting; women; sex workers; ex-prisoners; people who are homeless; people who occasionally inject drugs; and people who inject novel psychoactive drugs.\n\nWhat are the most effective and cost-effective ways of delivering needle and syringe programmes to:\n\nyoung people aged under\xa018\n\nusers of image- and performance-enhancing drugs?\n\nWhat type of behaviour-change interventions delivered by needle and syringe programmes are effective in promoting safer drug use practices and reducing the incidence of overdose (apart from providing needles, syringes and other injecting equipment)?\n\nWhat types of injecting equipment (including low dead-space syringes), paraphernalia and non-injecting equipment (for example, crack pipes or foil) effectively and cost effectively reduce the harm associated with injecting drug use?\n\nDo needle and syringe programmes have any unintended consequences:\n\nDo they increase the uptake, frequency and length of injecting drug use?\n\nDoes the provision of disposal facilities (for example, drop-boxes) affect the amount of drug-related litter in an area?\n\nDo they have a negative impact on the local community, for example, in terms of crime rates or the fear of crime?\n\nMore detail identified during development of this guidance is provided in gaps in the evidence.", 'Glossary': "# Detached services\n\nWorkers from needle and syringe programmes deliver services away from the main venue.\n\n# Drugs\n\nThe term 'drugs' is used in this guidance to mean: opioids (for example, heroin); stimulants (for example, cocaine) either separately or in combination (speedballing); novel psychoactive substances ('legal highs', for example, mephedrone); image- and performance-enhancing drugs (see below); and other drugs (for example, ketamine).\n\n# Image- and performance-enhancing drugs\n\nThe term 'image- and performance- enhancing drugs' is used in this guidance to mean any substance injected with the intention of enhancing image or performance (except under medical supervision). It includes:\n\nanabolic steroids, growth hormone and novel drugs (such as those that stimulate secretion of growth hormone, IGF-1 and analogues, and human chorionic gonadotrophin)\n\nmelanotans, bremelanotide, botulinum toxin and dermal fillers.\n\n# Injecting equipment\n\nThe equipment supplied by needle and syringe programmes is regulated by a 2003 amendment to The Misuse of Drugs Act (2001). A Home Office circular on the supply of drug injecting paraphernalia clarifies that, in addition to needles and syringes, needle and syringe programmes may also supply:\n\n(a) swabs\n\n(b) utensils for the preparation of a controlled drug (that would include articles such as spoons, bowls, cups, dishes)\n\n(c) acidifiers\n\n(d) filters\n\n(e) ampoules of water for injection.\n\nIn July 2013, a Home Office written ministerial statement on the lawful provision of foil explained it had accepted the Advisory Council on the Misuse of Drugs' advice to allow for the lawful provision of foil by drug treatment providers. This is subject to the strict condition that it is part of structured efforts to get people into treatment and off drugs.\n\n# Low dead-space injecting equipment\n\nLow dead-space injecting equipment seeks to limit the amount of (potentially contaminated) blood that remains in the equipment after it has been used, by reducing the amount of 'dead space' it contains. It is believed that this may reduce the risk of transmission of infectious diseases among people who share injecting equipment. There are 2 types of low dead-space injecting equipment: one uses fixed needles and the other uses detachable needles.\n\n# Needle and syringe programmes\n\nNeedle and syringe programmes (NSPs) supply needles and syringes for people who inject drugs. In addition, they often supply other equipment used to prepare and take drugs (for example, filters, mixing containers and sterile water). The majority of needle and syringe programmes are run by pharmacies and drug services. They may operate from fixed, mobile or outreach sites.\n\nThe main aim of needle and syringe programmes is to reduce the transmission of blood-borne viruses and other infections caused by sharing injecting equipment. Many also aim to reduce the other harms caused by injecting drug use and provide:\n\nadvice on safer injecting practices\n\nadvice on minimising the harm done by drugs, including image- and performance- enhancing drugs\n\nadvice on how to avoid and manage an overdose\n\ninformation on the safe handling and disposal of injecting equipment\n\naccess to blood-borne virus testing, vaccination and treatment services\n\nhelp to stop injecting drugs, including access to drug treatment (for example, opioid substitution therapy) and encouragement to switch to safer drug taking practices, if these are available\n\nother health and welfare services (including condom provision).\n\n# Outreach services\n\nWorkers from drug and needle and syringe programmes go out and encourage people to use the service.\n\n# Poly-drug use\n\nUsing more than one drug at the same time (although not necessarily in the same syringe). This practice is common among people who inject drugs. For example, people who use image- and performance-enhancing drugs often use one drug to enhance or counter the effects of another. They refer to this practice as 'stacking'.\n\n# Secondary distribution\n\nWhere someone collects needles, syringes and other injecting equipment from the needle and syringe programme on behalf of others.", 'References': 'Advisory Council on the Misuse of Drugs (2013) ACMD further advice on foil. London: Advisory Council on the Misuse of Drugs\n\nAdvisory Council on the Misuse of Drugs (2010) Consideration of the anabolic steroids. London: Advisory Council on the Misuse of Drugs.\n\nAdvisory Council on the Misuse of Drugs (2003) Hidden harm – responding to the needs of children of problem drug users. London: Advisory Council on the Misuse of Drugs.\n\nCusick L, Martin A, May T (2003) Vulnerability and involvement and in drug use and sex work. London: Home Office.\n\nDavies C, English L, Lodwick A et al. (2010) United Kingdom drug situation: annual report to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) 2010. London: UK Focal Point on Drugs, Department of Health.\n\nDavies C, English L, Stewart C et al. (2012) United Kingdom drug situation: annual report to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) 2012. Liverpool: UK Focal Point on Drugs, Liverpool John Moores University\n\nEvans-Brown M, Dawson RT, Chandler M et al. (2009) Use of melanotan I and II in the general population. British Medical Journal 338: b566.\n\nEvans-Brown M, McVeigh J, Perkins C et al. (2012) Human enhancement drugs: the emerging challenges to public health. Liverpool: North West Public Health Observatory, Centre for Public Health, Liverpool John Moores University.\n\nHay G, Rael dos Santos A, Millar T (2011) National and regional estimates of the prevalence of opiate and/or crack cocaine use, 2010–11: a summary of key findings. London: National Treatment Agency for Substance Misuse.\n\nHealth Protection Agency (2012) United Kingdom. New HIV diagnoses to end of December 2012. [Accessed 10 July 2013]\n\nHealth Protection Agency (2010) Shooting up: infections among injecting drug users in the United Kingdom 2009. London: Health Protection Agency.\n\nHealth Protection Agency, Health Protection Scotland, National Public Health Service for Wales et al. (2007) Shooting up: infections among injecting drug users in the United Kingdom, 2006. London: Health Protection Agency\n\nHickman M, Higgins V, Hope V et al. (2004) Injecting drug use in Brighton, Liverpool, and London: best estimates of prevalence and coverage of public health indicators. Journal of Epidemiology and Community Health 58: 766–71\n\nHM Government (2003) The Misuse of Drugs Act: 2003 (amendment) (no.2) regulations 2003\n\nHome Office (2012) Drug misuse declared: findings from the 2011/12 British Crime Survey for England and Wales. London: Home Office.\n\nHome Office (2003) Home Office circular 035/2003 Supply of drug injecting paraphernalia. London: Home Office\n\nHope VD, McVeigh J, Marongiu A et al. (2013) Prevalence of, and risk factors for, HIV, hepatitis\xa0B and\xa0C infections among men who inject image and performance enhancing drugs: a cross-sectional study. British Medical Journal Open 3: e003207\n\nLenehan P, Bellis MA, McVeigh J (1996) A study of anabolic steroid use in the North West of England. Journal of Performance Enhancing Drugs 1: 57–70\n\nMcVeigh J, Beynon C, Bellis MA (2003) New challenges for agency based syringe exchange schemes: analysis of 11 years of data (1991–2001) in Merseyside and Cheshire, United Kingdom. International Journal of Drug Policy 14: 399–405\n\nMcVeigh J, Chandler M, Beynon C et al. (2007) The injectors that harm reduction forgot. Poster presented at the 18th International Conference on the Reduction of Drug Related Harm, 13–17 May 2007, Warsaw, Poland.\n\nMelrose M (2004) Fractured transitions: disadvantaged young people, drug taking and risk. Probation Journal 51: 327–41\n\nPublic Health England, Centre for Infectious Disease Surveillance and Control and Microbiology Services (2013a). Unlinked anonymous monitoring survey of people who inject drugs in contact with specialist services: data tables. London: Public Health England.\n\nPublic Health England (2013b) Hepatitis\xa0C in the UK 2013 report. London: Public Health England.\n\nWard J, Henderson Z, Pearson G (2003) One problem among many: drug use among care leavers in transition to independent living Home Office Research Study. London: Home Office\n\nWorld Health Organization (2007) Guide to starting and managing needle and syringe programmes. Geneva: World Health Organization', 'Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Public Health Advisory Committee (PHAC) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PHAC to help develop the recommendations. The overarching questions for the original guidance were:\n\nQuestion 1: What level of coverage should needle and syringe programmes provide to keep HIV prevalence low and to reduce the prevalence of hepatitis\xa0C among people who inject drugs?\n\nQuestion 2: What type of needle and syringe programmes are effective and cost effective in reducing the transmission of blood-borne viruses and preventing injecting- site bacterial infections among people who inject drugs?\n\nQuestion 3: Which additional harm-reduction services offered by needle and syringe programmes are effective and cost effective in reducing the transmission of blood-borne viruses and preventing the occurrence of injecting-site bacterial infections among people who inject drugs?\n\nQuestion 4: Are needle and syringe programmes more effective and cost effective if they are offered in parallel with, or alongside, services that provide opiate substitution therapy?\n\nThese questions were used to update the original review of the evidence.\n\nSubsidiary questions for the guidance update included:\n\n. What types of needle and syringe programme are effective and cost-effective for reducing the prevalence of HIV, hepatitis\xa0C and other blood-borne viruses, and morbidity and mortality relating to injecting drug use in people who inject image- and performance-enhancing drugs?\n\n. Which additional harm-reduction services offered by needle and syringe programmes are effective and cost-effective for reducing the prevalence of HIV, hepatitis\xa0C and other blood-borne viruses, and morbidity and mortality relating to injecting drug use in people who inject image- and performance-enhancing drugs?\n\n. What do people who inject image- and performance-enhancing drugs identify as suitable types of needle and syringe programme, and what do they believe to be a suitable level of coverage of needles, syringes and other types of injecting equipment?\n\n. What are their views and perspectives on, and experiences of, different types of needle and syringe programme?\n\n. How do the key harms associated with injecting drug use among people under\xa018 differ from those for older populations who inject drugs?\n\n. What are the barriers to service use among young people who inject drugs?\n\n. What are the social factors shaping patterns of use, perceptions of risk, harm, benefit and pleasure, and help-seeking (especially the use of needle and syringe programmes) among young people who use drugs?\n\n# Reviewing the evidence\n\n## Evidence reviews for the original guidance\n\nTwo reviews of the evidence were conducted for the original guidance:\n\nInjecting equipment schemes for injecting drug users: qualitative evidence review\n\nA review of the effectiveness and cost-effectiveness of needle and syringe programmes for injecting drug users\n\n## Economic modelling for the original guidance\n\nThe results of economic modelling are reported in:\n\nAssessing the cost-effectiveness of interventions linked to needle and syringe programmes for injecting drug users: an economic modelling report\n\n## Evidence reviews for the update\n\nTwo reviews of the evidence were conducted:\n\nUpdate of NICE guidance PH18 on needle and syringe programmes: PIEDs review\n\nUpdate of NICE guidance PH18 on needle and syringe programmes: qualitative and quantitative review updates\n\nSeveral databases were searched between January and March 2013 for all types of study published from 1990 onwards. See Update of NICE guidance PH18 on needle and syringe programmes: PIEDs review and Injecting drug use among young people – risk, harm and factors affecting access to services: a systematic review of the evidence. They were also searched for all types of study published from 2008 onwards. See Update of NICE guidance PH18 on needle and syringe programmes: qualitative and quantitative review updates.\n\nIn addition, a call for evidence via the NICE website was used to generate further studies\n\nInclusion and exclusion criteria for each review varied and details can be found in the evidence.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in methods for the development of NICE public health guidance. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n− Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see the evidence reviews).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see the evidence reviews). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Policy review and consensus exercise\n\nSeveral databases and key websites were searched in January 2013 for policy documents from 1990 onwards. In addition, key websites were searched. In addition, a consensus development exercise was conducted through a series of interviews, a 1-day meeting and a subsequent Delphi study. See Analysis of national and local policy and protocols on the delivery of needle and syringe programme services to young people under\xa018: policy review and consensus development exercise.\n\n# Cost effectiveness\n\nSee the economic modelling report for details of the cost-effectiveness evidence used to support the original guidance. No additional analyses were undertaken for this update.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with: commissioners, criminal justice workers, needle and syringe programme providers and workers in specialist needle and syringe programmes for young people, pharmacies and public health staff.\n\nThe fieldwork comprised a focus group and interview analysis carried out by AddAction Research and Development.\n\nThe main issues arising are set out in section\xa010 under fieldwork findings. Or see Needle and syringe programme fieldwork.\n\n# How the PHAC formulated the recommendations\n\nAt its meetings in June, July and December 2013, the Public Health Advisory Committee (PHAC) considered the evidence and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention, programme or activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nPHAC developed recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations or settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to evidence statements. Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).", 'The evidence': "# What evidence is the guidance based on?\n\n## Original guidance\n\nThe evidence used to develop the original guidance included:\n\nEvidence reviews:\n\n\n\nInjecting equipment schemes for injecting drug users: qualitative evidence review\n\nA review of the effectiveness and cost-effectiveness of needle and syringe programmes for injecting drug users\n\n\n\nEconomic modelling:\n\n\n\nAssessing the cost-effectiveness of interventions linked to needle and syringe programmes for injecting drug users: an economic modelling report\n\n\n\n## Updated guidance\n\nThe evidence that the Public Health Advisory Committee (PHAC) considered included:\n\nEvidence and policy reviews:\n\n\n\nReview 1: Update of NICE guidance PH18 on needle and syringe programmes: qualitative and quantitative review updates, was carried out by Liverpool John Moores University. The principal authors were: Lisa Jones, Geoff Bates and Jim McVeigh.\n\nReview 2: Update of NICE guidance PH18 on needle and syringe programmes: PIEDs review, was carried out by Liverpool John Moores University. The principal authors were: Geoff Bates, Lisa Jones and Jim McVeigh.\n\nReview 3: Injecting drug use among young people – risk, harm and factors affecting access to services: a systematic review of the evidence, was carried out by the London School of Hygiene and Tropical Medicine. The principal authors were: Lucy Platt, Bethan McDonald, Neil Hunt, Adam Fletcher and Tim Rhodes.\n\nPolicy review and consensus development exercise: Analysis of national and local policy and protocols on the delivery of needle and syringe programme services to young people under\xa018: policy review and consensus development exercise, was carried out by the London School of Hygiene and Tropical Medicine. The principal authors were: Neil Hunt and Lucy Platt.\n\n\n\nThe fieldwork report Needle and syringe programme fieldwork was carried out by AddAction and Tiny Spark project.\n\nIn some cases, the evidence was insufficient and the PHAC has made recommendations for future research. For the research recommendations and gaps in research, see recommendations for research and gaps in the evidence.\n\n# Introduction\n\nThe evidence statements from 2\xa0reviews conducted for the original guidance and 2 reviews conducted for the updated guidance are provided by external contractors. In addition, they provided consensus statements from the policy review and consensus development exercise.\n\nThis section lists how the evidence statements and the consensus statements link to the recommendations and sets out a brief summary of findings from the economic analysis and the fieldwork.\n\nThis section also sets out a brief summary of findings from the economic analysis conducted for the original guidance.\n\n# How the evidence links to the recommendations\n\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from.\n\nEvidence statement E6.2b indicates that the linked statement is numbered 6.2b in the review, 'A review of the effectiveness and cost-effectiveness of needle and syringe programmes for injecting drug users' (conducted for the original guidance). Evidence statement Q3.3a indicates that the linked statement is numbered 3.3a in the review, 'Injecting equipment schemes for injecting drug users: qualitative evidence review' (conducted for the original guidance). Evidence statement U2b indicates that the linked statement is numbered 2b in the review, 'Update of NICE guidance PH18 on needle and syringe programmes: qualitative and quantitative review updates'. Evidence statement Y10 indicates that the linked statement is numbered 10 in the review, 'Injecting drug use among young people – risk, harm and factors affecting access to services: a systematic review of the evidence'.\n\nWhere a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: evidence statements Q3.2a, Q3.3b, Q3.3c, Q3.3d, Q3.4a, Q3.6a, Q3.6b; IDE\n\nRecommendation 2: evidence statements E7.1b, E7.1c, U1a, U1b, Y13, IDE\n\nRecommendation 3: evidence statements E5.1a, E5.1b, E5.1c, E6.3b, E6.3c, E7.1a, E7.1b, E7.1c, Q3.3a, Q3.3b, Q3.3d, Q3.4a, Q3.4c, Q3.6a, U2c, U3c, U8; IDE\n\nRecommendation 4: IDE\n\nRecommendation 5: Y5, Y6; Consensus statements from table 1 of the policy review and consensus development\n\nRecommendation 6: evidence statements E5.1a, E5.1b, E5.1c, E6.3b, E6.3c, E6.4b, E7.1a, E7.1b, Q3.3c, Q3.3d, Q3.4b, Q3.5a, U2b; IDE\n\nRecommendation 7: evidence statements E5.1a, E5.1b, E6.3b, E6.3c, E7.1a, E7.1b, Q3.3a, U2e, U3a, U3b, U6; IDE\n\nRecommendation 8: evidence statements E5.1c, E6.3b, E6.3c, E7.1a, E7.1b, Q3.3b, Q3.4b, Q3.6b, U5, U7, Y14; IDE\n\nRecommendation 9: evidence statements E6.3b, E6.3c, E7.1a, E7.1b, Q3.3b, Q3.3c, Q3.4b, Q3.6b, U7; IDE\n\nRecommendation 10: IDE from 'Update of NICE guidance PH18 on needle and syringe programmes: PIEDs review'\n\n# Economic modelling\n\nThe analyses for the original guidance estimated that needle and syringe programmes used as a channel for treating injecting drug users for chronic hepatitis\xa0C were cost effective. They can reduce the costs for society of drugs misuse by:\n\nimproving the health of people who inject drugs\n\nensuring the disease cannot be passed on after treatment.\n\nThe modelling showed that if only health costs and benefits are counted, then a needle and syringe programme that increased coverage by 25% in a city with a high incidence of hepatitis\xa0C virus was cost effective (estimated ICER £11,400). However, an increase in coverage by 12.5% was not cost effective (estimated ICER £31,600). For a low-incidence city, the estimated ICER for an increase in coverage of 25% was £11,800, whereas for an increase of 12.5% the ICER was estimated as £26,100.\n\nIf the costs to the criminal justice system are included, the modelling showed that a 12.5% increase in coverage for a high-incidence city was not cost effective (estimated ICER £38,700). But if coverage increased to 25%, the estimated ICER fell to £19,900. For a low-incidence city, for a 12.5% increase in coverage the ICER was £29,300, and for a 25% increase in coverage the ICER was £12,300.\n\nNeedle and syringe programmes can also help reduce the number of people who are injecting drug users by acting as a 'gateway' to opiate substitution therapy. So these programmes may help reduce the costs of drug-related crime. When these indirect ('gateway') effects were modelled, it showed that a 13.5% increase in the rate of referral to opiate substitution therapy resulted in ICERs of between dominant and £17,000, depending on prevalence.\n\nThe modelling found that overall, it is cost effective to give users more than one free needle per successful injection, if the cost of reaching them is not excessive and if use of this service increases by more than about 25% as a result.\n\nFull details can be found in Assessing the cost-effectiveness of interventions linked to needle and syringe programmes for injecting drug users: an economic modelling report.\n\nThere were no additional analyses undertaken for the updated guidance.\n\n# Fieldwork findings\n\nThe fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PHAC considered the findings when developing the final recommendations..\n\nFieldwork participants who work with people who inject drugs were very positive about the recommendations and their potential to improve needle and syringe programmes. Many participants stated that the new recommendations about young people and about people who inject image- and performance-enhancing drugs were much needed and would be very useful.", 'Gaps in the evidence': 'The Public Health Advisory Committee (PHAC) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence. These gaps are set out below.\n\n. There is a lack of evidence about how many people inject drugs within different subgroups. This includes a lack of evidence about the number of young people who inject drugs and the number of people who inject image- and performance-enhancing drugs.\n\n. There is a lack of evidence about the injecting behaviours of different subgroups of young people and users of image- and performance-enhancing drugs. There is also a lack of evidence on how these groups use needle and syringe programmes and the effectiveness and cost effectiveness of providing needle and syringe programmes to these groups.\n\n. There is a lack of UK-based research on how best to target and tailor needle and syringe programmes to meet the needs of particular groups (such as young people who inject drugs, people who inject image- and performance-enhancing drugs and people who have recently started injecting drugs). For example, there is a lack of data on the effectiveness of using any of the following approaches with these groups: needle and syringe vending machines, specialist clinics, outreach or detached schemes.\n\n. There is a lack of evidence on how people who inject drugs perceive needle and syringe programmes and what encourages or discourages them from using the services. This may be particularly true for occasional users and use of image- and performance-enhancing drugs.\n\n. There is a lack of evidence on how to prevent people who are at high risk of injecting drugs (for example, those who smoke drugs) from moving from non-injecting to injecting drug use. This includes a lack of information about their needs and views.\n\n. There is a lack of evidence about the effectiveness (or otherwise) of providing needle and syringe programmes to children and very young people who are injecting drugs. This includes a lack of evidence about their specific needs.\n\n. There is a lack of evidence about the likelihood of children living with people who inject drugs becoming regular injectors themselves.\n\n. There is a lack of UK-based research on how the carers and families of people (including young people) who inject drugs and people who inject image- and performance-enhancing drugs view needle and syringe programmes. This includes a lack of evidence on how to get them involved with the programmes.\n\n. There is a lack of evidence about related behaviours that may occur among people who inject image- and performance-enhancing drugs, for example, poly-drug use or increased sexual activity.\n\n. There is a lack of UK-based research on the effectiveness and cost-effectiveness of prison-based needle and syringe programmes.\n\n. There is a lack of UK-based research into the potential unintended consequences of needle and syringe programmes. For example, there is a lack of evidence on whether or not they encourage people to inject more frequently.\n\n. There is a lack of standardised outcome measures for needle and syringe programmes in relation to safe injecting practices and the incidence and prevalence of blood-borne viruses, overdoses and wound infections. In particular, there is a lack of information regarding young people who inject drugs and people who inject image- and performance-enhancing drugs.\n\n. There is a lack of evidence on whether drug users who are referred to opioid substitution therapy programmes from needle and syringe programmes continue to attend after the first meeting.\n\n. There is a lack of evidence on the effectiveness of peer interventions that aim to prevent risky injecting practices and encourage people to use needle and syringe programmes.\n\n. There is a lack of evidence to determine whether secondary distribution increases risky injecting behaviour, and whether it increases or decreases the likelihood of people who inject coming into contact with a needle and syringe programme.\n\n. There is a lack of evidence on whether needle and syringe programmes encourage people to switch to safer injecting practices.\n\n. There is a lack of evidence about the impact that training needle and syringe programme staff can have on its effectiveness.\n\nThe Committee made 5 recommendations for research into areas that it believes will be a priority for developing future guidelines.', 'Finding more information': "To find NICE guidance on related topics, including guidance in development, see the NICE topic page on drug misuse.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence review, evidence statement and fieldwork report. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice."}	https://www.nice.org.uk/guidance/ph52	This guideline covers needle and syringe programmes for people (including those under 16) who inject drugs. The main aim is to reduce the transmission of viruses and other infections caused by sharing injecting equipment, such as HIV, hepatitis B and C. In turn, this will reduce the prevalence of blood-borne viruses and bacterial infections, so benefiting wider society.
b3ea327e395cc7baa504f65cca00eeba02e876fa	nice	Rituximab in combination with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis	Rituximab in combination with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis Evidence-based recommendations on rituximab (MabThera) with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis in adults. # Guidance Rituximab, in combination with glucocorticoids, is recommended as an option for inducing remission in adults with anti-neutrophil cytoplasmic antibody -associated vasculitis (severely active granulomatosis with polyangiitis and microscopic polyangiitis), only if: further cyclophosphamide treatment would exceed the maximum cumulative cyclophosphamide dose or cyclophosphamide is contraindicated or not tolerated or the person has not completed their family and treatment with cyclophosphamide may materially affect their fertility or the disease has remained active or progressed despite a course of cyclophosphamide lasting 3–6 months or the person has had uroepithelial malignancy. People currently receiving treatment initiated within the NHS with rituximab that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.# The technology Rituximab (MabThera, Roche Products) is a genetically engineered chimeric (mouse/human) monoclonal antibody that depletes B cells by targeting cells bearing the CD20 surface marker. Within its marketing authorisation, rituximab in combination with glucocorticoids is indicated for 'the induction of remission in adult patients with severely active granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA)'. The summary of product characteristics states that limited data preclude any conclusions about the efficacy of subsequent courses of rituximab in people with granulomatosis with polyangiitis and microscopic polyangiitis. The summary of product characteristics also states that continued immunosuppressive therapy may be considered to prevent relapse, and may be especially appropriate in people at risk of relapse (for example, in people who have had previous relapses), but that the efficacy and safety of rituximab in maintenance therapy has not been established. The summary of product characteristics lists the following adverse events occurring at an incidence of 10% or greater in patients receiving rituximab to treat granulomatosis with polyangiitis and microscopic polyangiitis: diarrhoea, peripheral oedema, muscle spasms, arthralgia, back pain, dizziness, tremor, insomnia, cough, dyspnoea, epistaxis and hypertension. For full details of adverse reactions and contraindications, see the summary of product characteristics. Rituximab is priced at £174.63 per 10 ml vial and £873.15 per 50 ml vial (excluding VAT; British national formulary edition 66). The recommended dosage for treating granulomatosis with polyangiitis and microscopic polyangiitis (2 types of anti-neutrophil cytoplasmic antibody -associated vasculitis) is 375 mg/m2 body surface area, administered intravenously once weekly for 4 weeks (4 infusions in total). The manufacturer's estimate of the average cost of a course of treatment is £4889.64 (based on 1.79 m2 body surface area and no vial sharing). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (section 7) considered evidence submitted by the manufacturer of rituximab and reviews of this evidence by the Evidence Review Group (ERG; section 8). # Clinical effectiveness ## Manufacturer's original submission The manufacturer's systematic review identified 2 relevant randomised controlled trials for inclusion in its submission: RAVE and RITUXVAS. Seven non-randomised controlled trials were identified but the manufacturer judged that they contained insufficient data to be useful to the decision problem. The manufacturer explained that its submission focused on efficacy data from RAVE, complemented by the RITUXVAS results. Both RAVE and RITUXVAS compared rituximab with cyclophosphamide in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis or microscopic polyangiitis). RAVE recruited both newly diagnosed and relapsed patients, whereas RITUXVAS recruited newly diagnosed patients with renal involvement. RAVE was a randomised, multicentre, double-blind, double-dummy, placebo-controlled trial conducted in the USA and the Netherlands, which compared rituximab with conventional therapy (cyclophosphamide and azathioprine) in patients with severe ANCA-associated vasculitis. The study tested the hypothesis that rituximab was not inferior to (that is, was no worse than) conventional therapy in its ability to induce disease remission in ANCA-associated vasculitis at 6 months. Eligible patients had either granulomatosis with polyangiitis or microscopic polyangiitis, had tested positive for ANCA at screening, and had evidence of severe disease and a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 3 or more. BVAS/WG scores range from 0 to 68, with higher scores indicating more active disease. A 6-month remission induction phase was followed by a 12-month remission maintenance phase. In both groups, patients who went into remission before 6 months of treatment were eligible to switch to maintenance treatment from month 4 onwards. At the start of the study, all patients received an intravenous glucocorticoid pulse (methylprednisolone 1 g, or an equivalent dose of an alternative drug) followed by an oral prednisone taper (dosage starting at 1 mg/kg/day and not exceeding 80 mg/day). Patients in the rituximab group (n=99) received remission induction treatment consisting of once-weekly infusions of rituximab 375 mg/m2 for 4 weeks plus daily oral placebo and daily oral prednisone for 3–6 months. For the remission maintenance treatment, patients then switched to oral placebo as maintenance treatment until 18 months. Patients in the cyclophosphamide group (n=98) received remission induction treatment consisting of daily oral prednisone, oral cyclophosphamide 2 mg/kg/day plus placebo infusions for 3–6 months to induce remission. Remission maintenance treatment consisted of oral azathioprine 2 mg/kg/day until 18 months. Patients who had a severe flare (BVAS/WG of 3 or more, or a major BVAS/WG item that needed cyclophosphamide after remission ) in the first 6 months could cross over to the other treatment group and receive the other induction regimen in full. Limited flares (new occurrence or worsening of 1 or more minor BVAS/WG items) were managed by restarting or increasing the glucocorticoid dose. Patients whose BVAS/WG had not decreased by at least 1 point at 1 month or who had a new manifestation of disease were considered as having early treatment failure. These patients discontinued their assigned treatments and were treated according to best medical judgement. RAVE's primary end point was the induction of complete remission at 6 months, defined as a BVAS/WG of 0 and successful completion of the prednisone taper (that is, prednisone dose was reduced to 0 mg). A secondary analysis of the primary end point assessed the superiority of rituximab to cyclophosphamide in patients who had complete remission at 6 months. Tertiary end points included the number of severe flares at 6 months, the number of limited flares at 6 months, and quality of life using Short Form (SF‑36) physical component and mental component summary scores. End points for the assessment of efficacy up to 18 months included duration of complete remission and time to limited and/or severe flare after complete remission. Efficacy data were analysed on an intention-to-treat basis. Baseline demographic and disease characteristics in RAVE were generally similar between the treatment groups except for creatinine clearance, which was lower in the rituximab group. At the time of screening, 96 (48.7%) patients were newly diagnosed. There were 82 (83%) of the 98 patients remaining in the rituximab group and 79 (81%) of the 95 patients remaining in the cyclophosphamide group who completed the 6-month remission induction phase without crossover or change to treatment by best medical judgement. A similar proportion of patients in the 2 groups completed 18 months on randomised treatment (62% in the rituximab group and 63% in the cyclophosphamide group). Sixty-three (64.3%) patients in the rituximab group were in complete remission at 6 months, compared with 52 (54.7%) patients in the cyclophosphamide group. The absolute difference in rate of remission between the 2 groups was 9.5% (95% confidence interval −4.30% to 23.40%). This showed that rituximab was not inferior to cyclophosphamide in inducing complete remission because the lower limit of the 95% CI (−4.30%) was higher than the predetermined non-inferiority margin (−20%). After estimating missing data by worst case imputation, 63.6% of the 99 patients in the rituximab group achieved complete remission at 6 months compared with 53.1% of the 98 patients in the cyclophosphamide group (absolute treatment difference 10.6% ). The complete remission rate at 6 months in the rituximab group was not statistically significantly superior to the cyclophosphamide group (95% CI for the between-group difference −4.30% to 23.40%; p=0.177). The outcome was similar using worst case imputation (95% CI for the between-group difference −3.2% to 24.3%; p=0.132). There was no statistically significant difference between the treatment groups in the number of severe or limited flares during the first 6 months. Quality-of-life scores improved in both groups; there was no significant difference between treatment groups in the change in quality-of-life scores or their rate of change from baseline to 6 months. The manufacturer explored the effects of various baseline characteristics in relation to the primary end point, including relapsed disease. In patients who had relapsed disease at baseline, a statistically significantly higher proportion in the rituximab group went into complete remission at 6 months than in the cyclophosphamide group (66.7% compared with 42.0%, p=0.013). Complete remission rates in patients with new disease were similar in the 2 treatment groups (60.4% compared with 64.6%, p=0.673). RITUXVAS was a phase II, open-label, randomised controlled trial conducted in Europe and Australia. It compared the efficacy and safety of rituximab plus cyclophosphamide as induction therapy with cyclophosphamide plus azathioprine in 44 patients with newly diagnosed, severe ANCA-associated vasculitis and renal involvement. Patients were randomised to rituximab plus cyclophosphamide (n=33) or cyclophosphamide (n=11) and both groups received intravenous methylprednisolone (1 g) and an oral glucocorticoid (1 mg/kg/day initially, reducing to 5 mg/day at the end of 6 months). Patients in the rituximab group received infusions of rituximab (375 mg/m2 weekly, for 4 weeks), and intravenous cyclophosphamide (15 mg/kg with the first and third rituximab infusions). A further dose of intravenous cyclophosphamide (15 mg/kg) was permitted for patients who had progressive disease within the first 6 months. Patients in the rituximab group received no maintenance treatment. Patients in the control group received intravenous cyclophosphamide (15 mg/kg for 3–6 months; 6‑10 doses in total), followed by azathioprine maintenance (2 mg/kg/day). Further treatment with rituximab or cyclophosphamide was permitted if patients in either group relapsed. The primary end points for RITUXVAS were sustained remission at 12 months (defined as BVAS of 0 maintained for at least 6 months) and severe adverse events. Secondary end points included quality of life, assessed by the SF‑36 questionnaire between 0 and 12 months. Analyses were performed on an intention-to-treat basis. There were no major imbalances in baseline characteristics between the 2 groups, except for a greater proportion of patients with renal-limited vasculitis in the cyclophosphamide group and a greater proportion of patients needing dialysis in the rituximab plus cyclophosphamide group. No patients were lost to follow-up. Sustained remission occurred in 76% of patients in the rituximab plus cyclophosphamide group and 82% of patients in the cyclophosphamide group. The absolute difference in sustained remission with rituximab plus cyclophosphamide compared with cyclophosphamide was −6% (95% CI −33 to 21). Among patients who were still in the study at 12 months, 93% of patients in the rituximab plus cyclophosphamide group and 90% of patients in the cyclophosphamide group were in sustained remission. There was no statistically significant difference between treatment groups in median change in the physical component SF‑36 score (p=0.36). Patients in the cyclophosphamide group had a statistically significantly better mental component SF‑36 score compared with the rituximab plus cyclophosphamide group (p=0.04), but excluding outlying data for 2 patients eliminated the statistical significance (p=0.32). The manufacturer did not do any indirect comparisons or meta-analyses and advised that the economic evaluation was based solely on the RAVE results. It stated that RAVE reflected the marketing authorisation and scope of the appraisal, whereas the way rituximab was given in RITUXVAS was fundamentally different. The manufacturer's submission described rituximab's safety profile using the Summary of Clinical Safety provided to the European Medicines Agency to support the marketing authorisation application for rituximab for treating severe ANCA-associated vasculitis. The Summary of Clinical Safety summarised exposure to rituximab in the rituximab group of RAVE (n=99) after 18 months' follow-up. In addition, the rituximab plus cyclophosphamide group in RITUXVAS (n=33) was followed for up to 24 months, and 162 patients in other investigator-initiated studies were followed for between 3 and 55 months. The manufacturer reported that overall safety at 6 and 18 months was comparable between the rituximab and cyclophosphamide groups in RAVE, including the incidences and rates per patient-year of any adverse event, selected adverse events, adverse events that were grade 3 or higher, serious adverse events, and serious infections. The manufacturer stated that although the data are limited, safety in the other published studies was consistent with RAVE. Overall death rates and causes of death in RAVE and RITUXVAS were similar in the rituximab and cyclophosphamide groups. The most commonly reported type of serious adverse event in all studies was infection, with similar incidences between rituximab and cyclophosphamide groups in the controlled studies. The incidences and rates of serious adverse events were comparable between the rituximab and cyclophosphamide groups in RAVE at 6 months (33.3% compared with 33.7%) and 18 months (46.5% compared with 41.8%), and in RITUXVAS at 12 months (42% compared with 36%). There was no statistically significant difference between treatment groups in RITUXVAS in incidence rates of severe adverse events (p=0.77). ## Manufacturer's response to consultation In response to consultation, the manufacturer clarified the definition of severe disease. In RAVE, severe ANCA-associated vasculitis was defined as disease activity that threatened the function of the affected organ and had the potential to cause permanent organ damage or to threaten the patient's life unless effective therapy was implemented quickly. Severe disease had previously been referred to as 'generalised', 'generalised organ-threatening' or 'organ-threatening' disease. The manufacturer stated that when RAVE began, the standard of care for inducing remission in people with severe disease was cyclophosphamide and glucocorticoids. The manufacturer summarised the 18-month follow-up results from RAVE. The proportion of patients who achieved complete remission (BVAS/WG of 0 on a prednisone dose of 0 mg) at 6 months and who maintained complete remission at 12 and 18 months was similar in the rituximab group and the cyclophosphamide group. The rates of severe and limited flares at 6, 12, and 18 months did not differ significantly between the rituximab group and the cyclophosphamide group. Slightly more flares occurred after 6 months in the rituximab group. The manufacturer provided remission rates after re-treatment with rituximab. In RAVE, 16 patients received a second course of rituximab, of whom 7 (44%) entered complete remission. The manufacturer provided information about the maximum cumulative dose of cyclophosphamide and its mode of administration in UK clinical practice. The manufacturer advised that the maximum cumulative dose of cyclophosphamide is 25 g and that intravenous therapy is preferred to oral administration. These statements are consistent with the 2013 draft guidelines from the British Society for Rheumatology on the management of ANCA-associated vasculitis. The manufacturer indicated that 2 courses of intravenous therapy would equate to approximately 23 g of cyclophosphamide, based on a body weight of 78.89 kg. The manufacturer defined a subgroup of people for whom it is desirable to avoid cyclophosphamide: Women who wish to preserve their fertility. People at a higher risk of severe infection, tuberculosis, or chronic infection such as bronchiectasis. People with uroepithelial malignancy or dysplasia. People with cytopenia or bone marrow insufficiency. People with cyclophosphamide allergy or intolerance. The manufacturer provided evidence about the long-term safety of rituximab when used as a treatment for rheumatoid arthritis. A global clinical trial programme studied 3595 patients for over 11 years. The patients received up to 20 courses of rituximab. The manufacturer reported there was no evidence of an increased safety risk, an increased risk of malignancy, or increased rates of adverse events after prolonged exposure to rituximab. The manufacturer provided evidence that rituximab does not prevent women from conceiving children. A retrospective audit in the USA identified 157 women who received rituximab for ANCA-associated vasculitis. The audit identified 7 women who wanted to have children, of whom 6 became pregnant. ## Evidence Review Group's comments on the manufacturer's original submission The ERG noted that restricting the systematic review of clinical-effectiveness studies to the population and intervention in the marketing authorisation meant that it did not fulfil the scope or decision problem specified by NICE. The ERG did not identify any further randomised controlled trials directly comparing rituximab with the comparators in the NICE scope and decision problem in patients with ANCA-associated vasculitis. However, it did identify 5 ongoing or published trials that could potentially have enabled an indirect comparison or mixed treatment comparison of rituximab with the comparators other than cyclophosphamide that were specified in the NICE scope and decision problem. The ERG broadly agreed with the treatment pathway described by the manufacturer but noted some uncertainties: A high cumulative dose of cyclophosphamide indicates increased risk of adverse events. The ERG noted that giving the drug intravenously rather than orally may offer the opportunity to reduce the cumulative dose, or allow more courses to be given. A complete course of oral cyclophosphamide (2 mg/kg/day for 6 months) would be 31 g for a patient weighing 85 kg (the mean weight in RAVE). Conversely, a complete course of intravenous cyclophosphamide (15 mg/kg × 10 over a 6-month period) for a patient weighing 85 kg would be 12.75 g. The ERG judged this method of reducing the cumulative dose of cyclophosphamide to have been inadequately explored by the manufacturer. The ERG believed that the manufacturer's submission did not adequately consider alternative treatments to cyclophosphamide that may be used to induce remission. The ERG observed that the European Vasculitis Study Group guidelines recommend maintenance treatment after remission, and received clinical specialist advice that not receiving any maintenance treatment after remission with rituximab was unrealistic. The ERG also noted that relapse is not inevitable with appropriate maintenance treatment. The ERG stated that a 2 × 1000 mg dosage of rituximab is used more often in UK clinical practice to treat ANCA-associated vasculitis than the 4 × 375/mg2 dosage recommended in the marketing authorisation. In the ERG's view, the evidence suggested that rituximab was superior to oral cyclophosphamide (p=0.01) in inducing remission in the subgroup of patients with relapsed severe ANCA-associated vasculitis (who had previously received at least 1 dose of cyclophosphamide, methotrexate or azathioprine) and non-inferior to oral cyclophosphamide in patients with newly diagnosed disease. The ERG also highlighted that longer-term efficacy and safety end points of rituximab in treating ANCA-associated vasculitis are unknown, and that there are some potential questions concerning effects on fertility and certain adverse events, especially rates of mortality and malignancies. ## Evidence Review Group's comments on the manufacturer's response to consultation The ERG acknowledged that the manufacturer's definition of severe disease was helpful. However, the ERG noted that the clinical evidence submitted by the manufacturer is not relevant for allpeople with severe ANCA-associated vasculitis. RAVE excluded patients who needed mechanical ventilation because of alveolar haemorrhage or had a serum creatinine level greater than 4.0 mg/100 ml attributed to ANCA-associated vasculitis. RITUXVAS did include patients with more severe disease, but the treatment was rituximab plus cyclophosphamide. The ERG reviewed the 18-month follow-up results from RAVE. The ERG advised that, for patients with relapsed disease at baseline, rituximab was superior to cyclophosphamide followed by azathioprine at 6- and 12-month follow-up, but at 18 months the difference in remission rates was not statistically significant. The ERG noted that the estimate of remission rates after re‑treatment with rituximab provided by the manufacturer was based on small numbers of patients and was at risk of selection bias. The ERG acknowledged the value of the 18-month safety data from RAVE, which was submitted by the manufacturer in response to consultation, but noted that these data did not indicate an advantage of rituximab compared with cyclophosphamide. The ERG accepted the relevance of long-term data in rheumatoid arthritis, which suggest that rituximab is well tolerated. The ERG also acknowledged data which indicate that rituximab allows people with ANCA-associated vasculitis to maintain fertility. The ERG advised that the duration of the RAVE study was limited and longer follow-up may be needed to evaluate the safety of rituximab plus glucocorticoids. # Cost effectiveness ## Manufacturer's original submission The manufacturer's systematic review did not identify any studies that reported on the cost effectiveness of treatment for ANCA-associated vasculitis. The manufacturer therefore submitted a de novo model, which it subsequently revised in its clarification response, evaluating the cost effectiveness of rituximab compared with cyclophosphamide in people with ANCA-associated vasculitis. In line with its marketing authorisation, the manufacturer restricted its analysis to inducing remission only and did not look at treating flares or maintenance therapy. The original base case included the population from RAVE, and subgroup analyses investigated people with newly diagnosed disease and with relapsed disease. A separate subgroup analysis estimated the cost effectiveness of rituximab in people for whom cyclophosphamide was not considered to be the standard of care (because this group was not represented in RAVE). The analysis was conducted from an NHS and personal and social services perspective. A lifetime time horizon was used and a 3.5% discount rate was adopted for health benefits and costs. The manufacturer developed a Markov model with a similar design to that used in another NICE technology appraisal (Tocilizumab for the treatment of rheumatoid arthritis ). It consisted of 4 different health states: non-remission, complete remission, uncontrolled disease and death. 'Complete remission' reflected treatment success as assessed in RAVE, 'non-remission' reflected non-attainment of remission and 'uncontrolled disease' reflected a state of worse health that patients enter after the simulated treatment options have been exhausted. Patients entered the model in the non-remission health state, received induction therapy and either moved to the complete remission health state (if they went into remission) or remained in the non-remission health state (if they did not go into remission). During each 6-month cycle, moving from 1 treatment to the next in each arm's sequence was triggered either by failing to attain complete remission or by the patient eventually relapsing. After receiving all possible treatment options, patients entered the uncontrolled disease health state. The original base-case analysis was designed to compare 2 sequences of treatments: In the 'standard of care' sequence, patients received cyclophosphamide as induction therapy. Patients who went into remission with cyclophosphamide switched to azathioprine during remission. Patients who did not go into remission, or who relapsed, received another course of cyclophosphamide. Clinical specialist advice to the manufacturer was that a maximum of 2 courses of cyclophosphamide would be used in standard clinical practice. The manufacturer assumed that 72% of patients received cyclophosphamide intravenously, with the remainder receiving it orally. In the 'intervention' sequence, patients received rituximab as a first-line induction treatment. Patients who went into remission did not receive any further treatment until relapse. Patients who did not go into complete remission received a further course of rituximab (this is based on expert opinion, because RAVE did not investigate the effects of re‑treatment). Patients whose disease responded to rituximab could not have re‑treatment on relapse because this is outside the scope of the marketing authorisation. After relapse following 1 or 2 cycles of rituximab, patients received 1 course of cyclophosphamide (it was assumed that 72% of patients received cyclophosphamide intravenously, with the remainder receiving it orally).If patients received all available induction treatments in the treatment sequence and relapsed, they entered the 'uncontrolled disease' health state and received best supportive care. The transition probabilities in the manufacturer's original base-case model were based on the primary endpoints from RAVE. A constant rate of relapse was applied in the model and it was assumed that the second course of treatment was associated with a lower probability of achieving remission than the first course. The manufacturer estimated the probability of achieving remission with the second course of treatment using RAVE results from the subgroup of patients with relapsed disease. The same probability of remission was used for re‑treatment with rituximab and with cyclophosphamide. Transition probabilities for adverse events were also based on RAVE data. Disease-specific mortality risks in the manufacturer's economic model were derived from a retrospective cohort study of UK patients with ANCA-associated vasculitis. The costs used in the manufacturer's original economic model comprised treatment-associated costs plus health-state costs. Cost data (excluding drug costs) were largely derived from National reference costs. Drug costs were derived from the British national formulary (BNF) edition 64. Average drug costs per cycle were £4689.78 for rituximab, £99.15 for oral cyclophosphamide, £110.84 for intravenous cyclophosphamide, £44.17 for azathioprine, £28.01 for methylprednisone, £1497.96 for prednisone and £21.38 for trimethoprim. Treatment administration costs per cycle were £721.16 for rituximab and £1802.89 for intravenous cyclophosphamide, and it was assumed that these included monitoring costs. Monitoring costs for oral cyclophosphamide and azathioprine were £108. The per-cycle cost of best supportive care for patients with uncontrolled disease was £4415.73. Health-state costs were £778.10 for the remission health state and £6309.01 for the non-remission and uncontrolled disease health states. The manufacturer's systematic review did not identify any relevant studies that reported usable utility values. Health-related quality of life data were collected in RAVE using the SF‑36 questionnaire, which was administered at baseline and at 6 months. The SF‑36 scores were converted from the non-remission and remission health states to the EQ‑5D in a post-hoc analysis using a published model (Ara and Brazier 2008) and adjusted for age. Disutility adjustments were applied for adverse events. The manufacturer's original base-case results, provided after the request for clarification, showed that treating ANCA-associated vasculitis with rituximab increased the cost of treatment but was associated with more quality-adjusted life years (QALYs) than cyclophosphamide. The manufacturer's incremental cost-effectiveness ratio (ICER) for the comparison of rituximab with cyclophosphamide in patients with ANCA-associated vasculitis was £8544 per QALY gained (incremental costs £1391; incremental QALYs 0.1628). In its response to clarification, the manufacturer provided the results of scenario analyses, one-way deterministic sensitivity analyses, and probabilistic sensitivity analyses. These original analyses have been superseded by the manufacturer's response to consultation (see sections 3.54 to 3.62). ## Evidence Review Group's comments on the manufacturer's original submission The ERG found that the manufacturer's economic model generally followed NICE's reference case, but noted that not all comparators had been included, and that it may have been more appropriate to consider intravenous cyclophosphamide as the primary comparator because of its lower adverse-event risk, and because its lower cumulative dose could potentially allow additional courses of treatment. The ERG described some uncertainties in the population in the manufacturer's base case. It considered the manufacturer's decision to focus on severe granulomatosis with polyangiitis and microscopic polyangiitis to be appropriate given that this is the population specified in the marketing authorisation and given the populations in RAVE and RITUXVAS. However, the ERG was aware that there is no clear definition of severe disease, and that the definition of severity used in RAVE was closer to that classified as generalised disease in treatment guidelines. The ERG also noted that RAVE excluded patients with severe renal disease and other life-threatening forms of the disease, so the clinical evidence submitted by the manufacturer did not cover the full population with severe disease. The ERG was also concerned that the manufacturer had used values for weight and body surface area that would be likely to underestimate those of the UK population with ANCA-associated vasculitis. The ERG noted that treatment sequences depend on the patient population under consideration (for example, previous treatment with cyclophosphamide will limit its further use). Consequently, different sequences are available for newly diagnosed patients, patients with relapsed disease, and patients who cannot receive or cannot tolerate cyclophosphamide. The ERG expressed concerns about the treatment sequences used in the manufacturer's economic model: The ERG questioned the assumption in the manufacturer's model that all patients in the standard care group would receive 2 courses of cyclophosphamide, given that 28% of cyclophosphamide treatment was given orally, which would result in a high cumulative dose. The ERG had concerns about the assumption that after receiving 2 courses of cyclophosphamide, patients would receive only best supportive care. The ERG was unsure why rituximab was only considered as the firstinduction treatment in the manufacturer's economic model. It believed it was relevant to consider the relative cost effectiveness of rituximab used before and after cyclophosphamide in the treatment pathway. It noted that the NHS Commissioning Board recommended rituximab as first-line treatment in newly diagnosed patients only when avoiding cyclophosphamide is desirable. Clinical specialist advice received by the ERG suggested that it would be unlikely that patients who did not respond to an initial course of rituximab would receive a second course (because of a lack of evidence) and they would instead receive an alternative treatment. Based on clinical specialist advice, the ERG believed that the results presented by the manufacturer should be approached with considerable caution because other more appropriate treatment sequences exist, and these have not been modelled by the manufacturer. Clinical specialist advice to the ERG suggested that it was very unlikely that patients who go into remission after treatment with rituximab would not receive subsequent maintenance therapy. The ERG noted that it would seem appropriate to assume that patients who go into remission after rituximab would then receive maintenance therapy with azathioprine or methotrexate. However, in its economic model the manufacturer did not include maintenance treatment for patients who go into remission after receiving rituximab. The ERG had concerns about how the relapse rates used in the manufacturer's model had been derived from RAVE, and believed they had been poorly estimated. It noted that exponential model distributions were fitted to data from patients who went into complete remission at 6 months in order to estimate the time-to-event for relapse, and was aware that the manufacturer had used summary statistics rather than individual patient-level data. It noted that the Kaplan–Meier time to relapse curves for the rituximab and cyclophosphamide groups crossed, indicating that the proportional hazards assumption did not hold and that applying a constant relapse rate to each treatment group was unlikely to be appropriate. It further noted that the relapse rate for the cyclophosphamide group had potentially been overestimated. The ERG concluded that it appeared highly likely that an alternative parametric model (for example, Weibull, Gompertz, log normal or log-logistic) would have provided a better fit to the relapse data, but that these would not be suitable for use with the standard Markov model structure, so the standard Markov model may not have been an appropriate choice. The ERG was unable to assess the relative fit of the exponential models for the subgroup relapse data, and noted the manufacturer's statement that these were less precise than the all-patient data. The ERG was aware that the manufacturer had not modelled different severities of relapse, despite the availability of data from RAVE for minor and severe flares. The ERG's clinical specialists advised that treatment options and the subsequent disease pathway depend critically upon severity of relapse. The ERG noted that the manufacturer had assumed that all relapses lead to immediate re‑treatment with cyclophosphamide or rituximab because it believed almost all minor relapses would lead to severe relapses needing re‑treatment. However, the ERG received clinical specialist advice that minor relapses may be controlled in other ways (for example, an increase in glucocorticoid dose) and that not all patients would progress to a severe relapse. The ERG anticipated that modelling severe relapse rates for the subgroups of patients with newly diagnosed or relapsed disease would be likely to be highly uncertain because of very low event numbers, and suggested it may be preferable to assume similar relapse rates in these 2 subgroups. The ERG believed it would be more appropriate to have included a health state for non-complete remission (that is, when glucocorticoids and other less immunosuppressive treatments are still used). It considered that the failure to model different levels of treatment response and unrealistically high relapse rates may have led to patients in both treatment sequences entering the uncontrolled disease state too quickly. The ERG noted that patients in the standard of care sequence spent 70.7% of their discounted mean life expectancy in this health state, compared with 63.2% of patients in the intervention sequence. However, clinical specialist advice to the ERG suggested that it is very rare for patients with severe ANCA-associated vasculitis to be in this health state because a treatment strategy can usually be identified that offers some disease control. The ERG stated that ideally the manufacturer's model would have included additional lines of treatment, such as mycophenolate mofetil, leflunomide, azathioprine and methotrexate, in line with clinical specialist advice received by the ERG. The ERG believed that patients in the uncontrolled disease health state would have some disease control, so the health state would have a higher utility score than that assumed by the manufacturer. The ERG indicated that costs for this health state would be lower than those assumed by the manufacturer because it was unlikely patients would have outpatient appointments to receive specialist palliative care every 1.5 weeks. The ERG described several concerns about the costs used in the manufacturer's economic model. It stated that health-state costs were the largest proportion of total costs generated by the manufacturer's economic model (93% for the cyclophosphamide group and 89% for the rituximab group in the manufacturer's base-case analysis) and noted the impact of these on the cost-effectiveness results. The ERG noted that certain costs (including some tests and the total number of outpatient appointments) were not realistic and believed that these costs were substantially overestimated by the manufacturer, creating a significant bias in favour of rituximab. The ERG also considered that the manufacturer's approach to estimating the drug costs may be biased in favour of the rituximab group (by overestimating the amount of oral cyclophosphamide used in a typical treatment course), and noted that wastage costs from part-used vials had not been included in the manufacturer's base-case analysis. ## Evidence Review Group's exploratory analyses using the manufacturer's original model The ERG corrected several apparent technical errors in the manufacturer's economic model, which included using costs of prednisolone instead of prednisone in line with UK clinical practice. Other cost changes were for cyclophosphamide, trimethoprim and blood tests. The ERG also adjusted the utility value for pneumonia, adjusted the numbers at risk of relapse, used normal distributions for cost parameters, included distributions for standardised mortality rates and outpatient appointments in the probabilistic sensitivity analyses, and adjusted the mortality risk for patients aged 91 years and older in the uncontrolled disease health state. Cumulatively, these changes decreased the ICER for the comparison of rituximab with cyclophosphamide for all patients with ANCA-associated vasculitis. The ERG's corrected ICER was £6006 per QALY gained (incremental costs £986; incremental QALYs 0.1642) compared with the manufacturer's base-case ICER of £8544 per QALY gained (incremental costs £1391; incremental QALYs 0.1628). Replacing the cost of prednisone with the cost of prednisolone had the greatest impact. In further exploratory analyses, the ERG altered several parameter values in the manufacturer's economic model: Body surface area and weight were increased to better reflect patients in RAVE. It was assumed that patients who went into remission after receiving rituximab would receive azathioprine maintenance treatment at the same dosage as patients who went into remission after receiving cyclophosphamide. Relapse rates were re‑estimated based on data from patients who had severe flares after receiving cyclophosphamide in RAVE, to reflect the assumption that only severe flares would lead to renewed induction treatment. Given the assumption that patients receiving rituximab induction treatment also received azathioprine maintenance, the same relapse rate was applied to patients in the rituximab group and patients in the cyclophosphamide group. Costs and utility values in the uncontrolled disease state were amended to reflect that patients in this state are likely to have some disease control. The number and costs of routine tests were amended to reflect recommendations in published guidelines. Methylprednisolone administration costs were increased. The costs of X-rays and CT scans were taken from NHS reference costs. Wastage costs were included. The number of outpatient appointments was reduced.When these changes in the manufacturer's economic model were added to those described in section 3.45, the ERG's cumulative ICER increased to £26,347 per QALY gained (incremental costs £5704; incremental QALYs 0.2165) for the comparison of rituximab with cyclophosphamide for the full population of patients with ANCA-associated vasculitis. The ERG noted that reducing the number of outpatient appointments (especially in the uncontrolled disease health state) substantially decreased the benefits associated with the rituximab treatment sequence. The ERG modelled several treatment sequences that it considered to be more appropriate than those in the manufacturer's submission for the different populations (described in sections 3.48–3.52): the full population in the manufacturer's economic model patients with newly diagnosed ANCA-associated vasculitis patients with relapsed ANCA-associated vasculitis who could have further treatment with cyclophosphamide patients with relapsed ANCA-associated vasculitis who could not have further cyclophosphamide treatment patients who are unable to tolerate cyclophosphamide. The ERG investigated how different treatment sequences could impact on the cost-effectiveness estimates for the full patient population with ANCA-associated vasculitis in the manufacturer's economic model: Adding rituximab to the treatment sequence after 2 courses of cyclophosphamide gave an ICER of £12,075 per QALY gained (incremental costs £3894; incremental QALYs 0.32). Using rituximab after 1 course of cyclophosphamide increased the ICER to £69,710 per QALY gained (incremental costs £355; incremental QALYs 0.0051) compared with using it after 2 courses. Using rituximab as first-line treatment further increased the ICER to £127,456 per QALY gained (incremental costs £579; incremental QALYs 0.0045) compared with using rituximab as second-line treatment. At £30,000 per QALY gained, the probability of rituximab being cost effective after 2 courses of cyclophosphamide was 58.3%. The probability that excluding rituximab from the treatment sequence was cost effective was 11.7%. The ERG did exploratory analyses for the population with newly diagnosed ANCA-associated vasculitis: Adding rituximab to the treatment sequence after 2 courses of cyclophosphamide gave an ICER of £12,851 per QALY gained (incremental costs £3783; incremental QALYs 0.29). Using rituximab after 1 course of cyclophosphamide increased the ICER to £81,604 per QALY gained (incremental costs £364; incremental QALYs 0.0045) compared with using rituximab after 2 courses of cyclophosphamide. The ICER for using rituximab as a first-line treatment further increased the ICER to £317,038 per QALY gained (incremental costs £843; incremental QALYs 0.0027) compared with using rituximab as second-line treatment.At £30,000 per QALY gained, the probability that using rituximab after 2 courses of cyclophosphamide was cost effective in patients with newly diagnosed disease was 59.7%. The probability that excluding rituximab from the treatment sequence was cost effective was 13.9%. The ERG did exploratory analyses on the population of patients with relapsed ANCA-associated vasculitis who could have further treatment with cyclophosphamide: Adding rituximab to the treatment sequence after 1 course of cyclophosphamide gave an ICER of £11,129 per QALY gained (incremental costs £4702; incremental QALYs 0.4225). The ICER for rituximab as first-line treatment was £51,842 per QALY gained (incremental costs £325; incremental QALYs 0.0063) compared with rituximab as second-line treatment.The probability of rituximab being cost effective after 1 course of cyclophosphamide was 51.3% at £30,000 per QALY gained. The probability that excluding rituximab from the treatment sequence was cost effective was 10.4%. The ERG did exploratory analyses on the population of patients with relapsed ANCA-associated vasculitis who could not have further cyclophosphamide treatment. Using rituximab instead of best supportive care gave an ICER of £10,699 per QALY gained (incremental costs £5385; incremental QALYs 0.5033). The ERG assumed that patients who could not tolerate further cyclophosphamide treatment and were receiving best supportive care moved directly to a low-grade disease health state (with partial disease control), and explained that this assumption limited the analysis because active comparators were excluded. At £30,000 per QALY gained, the probability of rituximab being cost effective was 90.4%. The probability that excluding rituximab from the treatment sequence was cost effective was 9.6%. The ERG did an exploratory subgroup analysis on patients who were unable to tolerate cyclophosphamide. This subgroup did not necessarily have relapsed disease, but could not take cyclophosphamide for a reason other than exceeding the maximum recommended lifetime cumulative dose. Model parameter inputs were based on the full patient population in RAVE. Using rituximab instead of best supportive care gave an ICER of £11,277 per QALY gained (incremental costs £5437; incremental QALYs 0.48). The ERG assumed that patients who could not tolerate further cyclophosphamide treatment and were receiving best supportive care moved directly to a low-grade disease health state (with partial disease control), and explained that this assumption limited the analysis because active comparators were excluded. At £30,000 per QALY gained, the probability of rituximab being cost effective in patients who cannot tolerate cyclophosphamide was 90.5%. The probability that excluding rituximab from the treatment sequence was cost effective was 9.5%. After receiving feedback from clinical specialists on its exploratory analyses, the ERG did other scenario analyses on the data from the full patient population to further explore uncertainty associated with some parameters used in the economic model. The parameters tested were: reduced administration costs for methylprednisone and cyclophosphamide (because of shorter infusion time); substituting co-trimoxazole for trimethoprim; fewer cyclophosphamide infusions (6 instead of 10); and increased weight and body surface (to reflect the UK population with ANCA-associated vasculitis). These amendments had little cumulative impact on the ICER associated with adding rituximab to the treatment sequence after 2 courses of cyclophosphamide treatment compared with best supportive care after 2 courses of cyclophosphamide treatment, which increased slightly from £12,075 per QALY gained (ERG's base-case ICER) to £12,670 per QALY gained. However, the cumulative ICERs for using rituximab earlier in the treatment sequence increased more markedly because of reduced costs for intravenous cyclophosphamide and increased costs for rituximab (owing to higher body surface area). The ICER for using rituximab after 1 course of cyclophosphamide was £117,545 per QALY gained compared with after 2 courses of cyclophosphamide, and the ICER for using rituximab as first-line treatment was £191,013 per QALY gained compared with using it as second-line treatment. The ERG anticipated that these findings using the full patient population would be mirrored in the subgroups of patients who were newly diagnosed or had relapsed disease. ## Manufacturer's response to consultation In response to consultation, the manufacturer provided 2 updated economic models; one for patients who can have cyclophosphamide and one for patients who cannot have cyclophosphamide. Both models incorporated the following changes: The minor technical changes proposed in section 3.45. The mean body surface area of patients was increased to 1.90 m2 and the mean weight of patients was increased to 78.89 kg, based on data from 30 patients with vasculitis treated at Manchester Royal Infirmary. The model assumed that only severe relapses would be treated with induction therapy. The utility value in the uncontrolled disease health state was increased from 0.671 to 0.710. The cost of administering methylprednisolone was included. The cost was assumed to be equivalent to the cost of delivering rituximab and cyclophosphamide. The cost of an X-ray was updated to £18.56 and the cost of a CT scan was increased to £100.00. It was assumed that 80% of scans received in the modelled population would be X-rays and 20% would be CT scans. The model included wastage costs associated with drug delivery. There were 4 outpatient visits every 6 months in the uncontrolled disease health state. The model included only intravenous administration of cyclophosphamide (whereas the original model assumed 28% of patients would receive oral cyclophosphamide). In the uncontrolled disease health state, patients were assumed to receive the recommended dosage of mycophenolate mofetil, methotrexate, or azathioprine. The average cost of the 3 therapies was used in the model. The model assumed no difference in efficacy between treatment arms once patients entered the uncontrolled disease heath state. The models did not include any maintenance therapy after induction treatment with rituximab. In the manufacturer's updated model for patients who can have cyclophosphamide, the base-case analysis was designed to compare 2 sequences of treatments: In the 'standard of care' sequence, patients received intravenous cyclophosphamide as induction therapy. Patients who went into remission with cyclophosphamide received azathioprine as maintenance therapy during remission. Patients who did not go into remission, or who relapsed, received a second course of intravenous cyclophosphamide. In the 'intervention' sequence, patients received 1 course of intravenous cyclophosphamide as induction therapy. Patients who went into remission with cyclophosphamide received azathioprine as maintenance therapy during remission. Patients who did not go into remission, or who relapsed, received 2 courses of rituximab. Patients who went into remission with rituximab did not receive any maintenance therapy. In the manufacturer's updated model, the base-case transition probabilities were based on data from RAVE. In both the 'standard of care' sequence and the 'intervention' sequence, the probability of achieving remission with the first course of cyclophosphamide was estimated using data from the subgroup of patients in RAVE who had newly-diagnosed disease and were treated with cyclophosphamide. In the 'standard of care' sequence, the probability of achieving remission with the second course of cyclophosphamide was estimated using data from the subgroup of patients in RAVE who had relapsed disease and were treated with cyclophosphamide. In the 'intervention' sequence, the probability of achieving remission with rituximab following a course of cyclophosphamide was estimated using data from the subgroup of patients in RAVE who had relapsed disease and were treated with rituximab. The probability of achieving remission with the subsequent course of rituximab was estimated using data from the subgroup of patients in RAVE who were re-treated with rituximab. In the manufacturer's updated base-case model, the estimate of relapse rates was based on data from patients who had severe flares after receiving cyclophosphamide in RAVE. The same relapse rate was applied to patients in the rituximab group and patients in the cyclophosphamide group. The relapse rate was assumed to be identical after subsequent lines of therapy. The manufacturer's updated model for people with ANCA-associated vasculitis who can have cyclophosphamide produced an ICER for the comparison of rituximab with cyclophosphamide of £18,556 per QALY gained (incremental costs £6117; incremental QALYs 0.330). The model for people with ANCA-associated vasculitis who cannot have cyclophosphamide was the same as the updated base-case model for patients who can have cyclophosphamide, except that it compared the following 2 sequences of treatments: In the 'standard of care' sequence, patients received a 6-month course of either mycophenolate mofetil or methotrexate. These treatments were assumed to have the same complete remission rates as cyclophosphamide. Patients who went into remission with mycophenolate mofetil or methotrexate received azathioprine as maintenance therapy during remission. The probability of relapse was assumed to be higher than that with cyclophosphamide or rituximab and was set at 0.103. In the 'intervention' sequence, patients received 2 courses of rituximab. Patients who went into remission with rituximab did not receive any maintenance therapy. The probability of relapse was 0.086, based on data from RAVE. The manufacturer's updated model for people with ANCA-associated vasculitis who cannot have cyclophosphamide produced an ICER for the comparison of rituximab with mycophenolate mofetil or methotrexate of £35,003 per QALY gained (incremental costs £10,186; incremental QALYs 0.291). The manufacturer conducted one-way sensitivity analyses to explore the effect of assumptions about key parameters on the results of the base-case model. The following changes, when implemented independently, gave ICERs that were higher than the base case: a higher relapse rate in the rituximab arm, treating both minor and severe relapses with induction therapy, reducing the number of outpatient appointments in the uncontrolled disease health state, and assuming that no patients received a second course of rituximab. When it was assumed that there was less wastage of rituximab, the ICERs were lower than the base case. The Committee had requested analyses that incorporated the costs and disutility of the cumulative long-term toxicity of cyclophosphamide. The Committee had also requested analyses that incorporated the inpatient costs associated with non-remission, and separate analyses of the benefit of rituximab for patients who wished to have children. The manufacturer stated that they did not provide these analyses because of time constraints and a lack of data. ## Evidence Review Group's comments on the manufacturer's response to consultation The ERG advised that the manufacturer's model submitted in response to consultation was incorrect because of several apparent errors: The cost of treatment in the uncontrolled disease health state was incorrectly multiplied by 4. There were coding errors in the sensitivity analyses that examined re-treatment with rituximab. The unit costs for mycophenolate mofetil and methotrexate were incorrect. The ERG consulted clinical specialists to assess the plausibility of the treatment sequences in the manufacturer's model for patients who can have cyclophosphamide. The model assumed that only 1 course of cyclophosphamide would be provided in the rituximab arm. The ERG advised that some patients may receive a second course of cyclophosphamide even if rituximab was available. The ERG observed that, in the manufacturer's model, all patients in the rituximab arm received 2 courses of rituximab regardless of the effect of the first course of rituximab. The ERG advised that, at the first Committee meeting, the Committee agreed this assumption was not plausible. The ERG noted that the manufacturer had not modelled all possible treatment sequences as requested by the Committee. The ERG acknowledged there is a lack of consensus about the use of maintenance therapy after remission induced by rituximab. The 2013 draft guidelines from the British Society for Rheumatology include 4 options for maintenance therapy. These are, to wait for relapse and then re-treat, to use an immunosuppressive agent (azathioprine or methotrexate), or to use rituximab as maintenance therapy (2 rituximab regimes are described). Only 1 of the options (wait for relapse and then re-treat) was modelled by the manufacturer. In the manufacturer's model for patients who cannot have cyclophosphamide, the 'standard of care' arm included only 1 course of mycophenolate mofetil or methotrexate. The ERG stated this may not be realistic. The ERG received clinical advice that cumulative glucocorticoid use is likely to be higher with mycophenolate mofetil or methotrexate than with rituximab, yet this was not reflected in the manufacturer's model. In the uncontrolled disease health state, the ERG considered 3 outpatient appointments every 6 months to be a reasonable assumption. The manufacturer's model assumed 4 appointments every 6 months. The ERG noted that in RAVE the rate of severe relapse was lower at 18 months than at 6 or 12 months in the cyclophosphamide group, but was increasing in the rituximab group. The ERG advised that it would be relevant to consider scenarios in which the relapse rate was higher in the rituximab group in the long term. The manufacturer's model did not allow relapse rates to alter over time. In response to consultation, the manufacturer stated that there were additional QALY gains associated with rituximab because of the preservation of fertility, but these gains were not included in the economic model. The ERG advised that, in the model that included the subgroup of patients who wished to maintain fertility, the comparators were mycophenolate mofetil and methotrexate. The ERG understood that mycophenolate mofetil and methotrexate do not impair long-term fertility. Thus, in the view of the ERG, the manufacturer's argument about QALY gains was not relevant because no fertility advantage had been demonstrated for rituximab compared with mycophenolate mofetil and methotrexate. The ERG noted that 2 additional changes, which were included as scenario analyses in the ERG's original report, had not been implemented by the manufacturer. First, cyclophosphamide can be infused more quickly than rituximab and therefore may have a lower administration cost. Second, some patients receive fewer than 10 infusions of intravenous cyclophosphamide. The ERG advised that the ICER associated with rituximab would increase if these 2 amendments were made to the manufacturer's economic model. ## Evidence Review Group's exploratory analyses after consultation The ERG made the following changes to the manufacturer's model: The apparent errors listed in section 3.63 were amended. The ERG incorporated uncertainty around the remission rate after re-treatment with rituximab. Only patients who entered remission with rituximab were given a second course of rituximab. The ERG ran probabilistic sensitivity analyses. The ERG also ran the following scenario analyses for the subgroups who can and cannot have cyclophosphamide: The rituximab arm included maintenance therapy with azathioprine. There was no re-treatment with rituximab. The ERG's exploratory analyses examined the cost effectiveness of rituximab for patients who can have cyclophosphamide. Assuming only patients who entered remission with rituximab would be given a second course of rituximab and no maintenance treatment after rituximab, the ICER for the comparison of rituximab with cyclophosphamide was £20,879 per QALY gained (incremental costs £5075; incremental QALYs 0.24). The probability of rituximab being cost effective compared with cyclophosphamide was 40.7% at £20,000 per QALY gained and 56.7% at £30,000 per QALY gained. Assuming only patients who entered remission with rituximab would be given a second course of rituximab and azathioprine as maintenance treatment after rituximab, the ICER for the comparison of rituximab with cyclophosphamide was £23,444 per QALY gained (incremental costs £5698; incremental QALYs 0.24). The probability of rituximab being cost effective compared with cyclophosphamide was 34.8% at £20,000 per QALY gained and 52.8% at £30,000 per QALY gained. Assuming no re-treatment with rituximab and no maintenance treatment after rituximab, the ICER for the comparison of rituximab with cyclophosphamide was £20,080 per QALY gained (incremental costs £2790; incremental QALYs 0.14). The probability of rituximab being cost effective compared with cyclophosphamide was 42.0% at £20,000 per QALY gained and 53.7% at £30,000 per QALY gained. The ERG's exploratory analyses also examined the cost effectiveness of rituximab for patients who cannot have cyclophosphamide. Assuming that only patients who entered remission with rituximab would be given a second course of rituximab and no maintenance treatment after rituximab, the ICER for the comparison of rituximab with mycophenolate mofetil or methotrexate was £60,569 per QALY gained (incremental costs £8345; incremental QALYs 0.14). The probability of rituximab being cost effective compared with mycophenolate mofetil or methotrexate was 13.8% at £20,000 per QALY gained and 25.3% at £30,000 per QALY gained. Assuming only patients who entered remission with rituximab would be given a second course of rituximab and azathioprine as maintenance treatment after rituximab, the ICER for the comparison of rituximab with mycophenolate mofetil or methotrexate was £65,700 per QALY gained (incremental costs £9052; incremental QALYs 0.14). The probability of rituximab being cost effective compared with mycophenolate mofetil or methotrexate was 10.9% at £20,000 per QALY gained and 22.4% at £30,000 per QALY gained. Assuming no re-treatment with rituximab and no maintenance treatment after rituximab, the ICER for the comparison of rituximab with mycophenolate mofetil or methotrexate was £118,154 per QALY gained (incremental costs £5463; incremental QALYs 0.05). The probability of rituximab being cost effective compared with mycophenolate mofetil or methotrexate was 14.7% at £20,000 per QALY gained and 23.1% at £30,000 per QALY gained. ## Manufacturer's response to second consultation In response to the second consultation, the manufacturer provided a weighted-average threshold analysis. The aim was to calculate an ICER for rituximab for treating the entire population of people with severely active granulomatosis with polyangiitis and microscopic polyangiitis (including both people who can and people who cannot have cyclophosphamide). For the subgroup of people who can have cyclophosphamide, the manufacturer used an ICER of £12,100 per QALY gained (see section 3.48). Based on the opinion of clinical specialists, the manufacturer assumed that 10% of patients cannot have cyclophosphamide. For the subgroup of people who cannot have cyclophosphamide, the manufacturer used a range of ICERs from £80,000 to £200,000 per QALY gained. The weighted-average ICERs for the entire population of people with severely active granulomatosis with polyangiitis and microscopic polyangiitis ranged from £18,890 to £30,890 per QALY gained. ## ERG's response to second consultation In response to the second consultation, the ERG provided illustrative analyses based on the manufacturer's updated model for people who cannot have cyclophosphamide; this model compared 2 courses of rituximab with 1 course of mycophenolate mofetil or methotrexate (see section 3.74). The following changes were made to the 'standard of care' sequence in the model: The utility in the remission health state was decreased from 0.84 to 0.79. The cost of glucocorticoids in the remission health state was increased from £293 to £439 per 6-month treatment cycle. The remission rate was decreased from 0.65 to 0.52. Mycophenolate mofetil was the only active treatment in the 'standard of care' sequence. The changes resulted in an ICER for rituximab compared with mycophenolate mofetil of £26,406 per QALY gained. Full details of all the evidence are in the manufacturer's original submission, the manufacturer's responses to consultation, the ERG's original report, the ERG's critique of the manufacturer's response to consultation, and the ERG's response to the second consultation.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab, having considered evidence on the nature of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and the value placed on the benefits of rituximab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee discussed the current clinical pathway of care for people with ANCA-associated vasculitis. It heard from the clinical specialists that induction treatment with cyclophosphamide is the standard of care for people with severe ANCA-associated vasculitis, and that this includes people with granulomatosis with polyangiitis and microscopic polyangiitis. The Committee recognised that induction treatment lasts for up to 6 months, and that cyclophosphamide is administered either orally or intravenously with glucocorticoids. The Committee was advised by the clinical specialists that alternatives to cyclophosphamide (such as mycophenolate mofetil, methotrexate and deoxyspergualin) were associated with higher relapse rates and would not normally be used to treat severe disease (unless cyclophosphamide was unsuitable). The Committee heard from the clinical specialists that, after going into remission with cyclophosphamide, the glucocorticoid dose is tapered and patients switch to maintenance treatment (such as azathioprine) for up to 2 years to reduce the likelihood of relapse. The Committee learned from clinical specialists that minor relapses would likely be managed with an increased dose of glucocorticoid first. The Committee concluded that cyclophosphamide is the standard of care for people with ANCA-associated vasculitis who can have cyclophosphamide. The Committee reviewed the safety of treatments currently used in UK clinical practice to induce remission in severe ANCA-associated vasculitis. It recognised that the risk of long-term toxicity (for example, uroepithelial malignancies) increases with the cumulative dose of cyclophosphamide, and understood from the clinical specialists that the cumulative dose should not exceed 25 g and that they aim to keep it below this level if possible. Draft guidelines from the British Society for Rheumatology also state that the cumulative dose of cyclophosphamide should not exceed 25 g. The Committee was advised by the clinical specialists that people would receive 6–10 cycles of intravenous cyclophosphamide to induce remission, that the cumulative dose administered would depend on body weight, and would generally be 10–15 g for 10 cycles. It further heard that intravenous cyclophosphamide was typically preferred to oral cyclophosphamide, because 1 course of oral cyclophosphamide would result in a cumulative dose of up to 30 g. The Committee concluded that alternative treatments for severe ANCA-associated vasculitis would be welcomed by clinicians and patients. The Committee heard from the patient experts about the demands of living with ANCA-associated vasculitis and its treatment. It learned how each relapse can cause further progressive damage to the body and that this may be permanent, and how considerable stress results from the fear of relapse. The Committee further heard about the effects of cyclophosphamide's long-term toxicity. The Committee understood that some people with ANCA-associated vasculitis cannot have cyclophosphamide or have disease that is refractory to cyclophosphamide. The Committee heard from the patient experts that currently the only suitable alternative treatment option for these people is rituximab. The Committee acknowledged that ANCA-associated vasculitis has a significant impact on patients' quality of life and that cyclophosphamide treatment can be associated with a range of adverse events that could also impair their quality of life. # Clinical effectiveness The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of rituximab. It noted that the evidence was primarily from the RAVE study and this was complemented by the RITUXVAS study. The Committee reviewed the suitability of the clinical trial evidence and noted that only RAVE used the regimen recommended in the marketing authorisation for ANCA-associated vasculitis. Overall, the Committee concluded that the studies provided adequate evidence for assessing rituximab for inducing remission of ANCA-associated vasculitis and were generalisable to UK clinical practice. The Committee discussed the clinical effectiveness of rituximab compared with cyclophosphamide as induction therapy in people with severe ANCA-associated vasculitis. The Committee accepted that the RAVE results showed rituximab was non-inferior to cyclophosphamide in inducing complete remission in the full study population at 6 months, but was uncertain if the treatment benefit persisted because of the short duration of RAVE. In response to consultation, the manufacturer provided 18-month follow-up data from RAVE. The Committee acknowledged that rituximab was non-inferior to cyclophosphamide in inducing complete remission at 6, 12, and 18 months. In response to consultation, the manufacturer stated that patients in RAVE had severe disease, meaning the disease threatened the function of the affected organ and had the potential to cause permanent organ damage or to threaten the patient's life unless effective therapy was implemented quickly. The Committee concluded that rituximab was not less effective than cyclophosphamide as an induction treatment for people with severe ANCA-associated vasculitis. The Committee discussed the need for maintenance treatment after rituximab induction therapy. The 2013 draft British Society for Rheumatology guidelines include 4 options for maintenance treatment (see section 3.65). The Committee was aware of a difference of opinion between clinical specialists about the use of maintenance treatment. Some specialists stated that maintenance treatments such as azathioprine would be given after rituximab induction therapy, whereas others stated that azathioprine would not normally be given and is not supported by clinical trial evidence. In response to consultation, several specialists stated that rituximab would be used as maintenance treatment. The Committee recalled that the marketing authorisation was specifically for inducing remission (with a recommended dosage of 375 mg/m2 administered as an intravenous infusion once weekly for 4 weeks) and did not include rituximab being used as maintenance treatment. It further noted that the summary of product characteristics for rituximab states that the efficacy and safety of rituximab as maintenance treatment have not been established. The Committee concluded that maintenance treatment with rituximab was outside the scope of the appraisal. The Committee reviewed the subgroups presented by the manufacturer to identify which people were likely to experience a greater treatment benefit. The Committee was aware that, at 6-month follow-up from RAVE, the complete remission rate for the subgroup with relapsed disease was statistically significantly higher in patients who received rituximab compared with patients who received cyclophosphamide. The Committee noted that the 18-month follow-up results for this subgroup, submitted in response to consultation, showed no significant difference in remission rates between the treatment groups. The Committee observed that, at 6-month follow-up for the subgroup with newly diagnosed disease, there was no significant difference in remission rates between the treatment groups. The Committee concluded that, over a period of 18 months, rituximab and cyclophosphamide have similar effectiveness in inducing remission in both newly diagnosed and relapsed patients. The Committee considered whether there were additional patient subgroups who might experience a greater treatment benefit. The Committee heard from the clinical specialists that there may be a small subgroup of people who would benefit from avoiding cyclophosphamide. In response to consultation, the manufacturer defined this subgroup (see section 3.21). The Committee noted that the manufacturer's definition is broadly in agreement with draft guidelines from the British Society for Rheumatology. Both the manufacturer and the British Society for Rheumatology stated that patients at risk of infection would benefit from avoiding cyclophosphamide. However, the Committee observed that the summary of product characteristics states that rituximab should not be used for patients with active, severe infection. In response to the second consultation, clinical specialists advised that there is evidence from case series to support the use of rituximab for people who cannot have cyclophosphamide. The Committee concluded that, for the purposes of this guidance, 'people who cannot have cyclophosphamide' refers to people: for whom cyclophosphamide is contraindicated (as defined in the summary of product characteristics) or not tolerated; or who have not completed their family and whose fertility may be materially affected by treatment with cyclophosphamide; or with disease that has remained active or progressed despite a course of cyclophosphamide lasting 3–6 months; or with a previous uroepithelial malignancy. The Committee discussed the safety of rituximab compared with cyclophosphamide. It was aware that intravenous administration of cyclophosphamide is associated with a more favourable adverse-event profile than oral administration. The Committee noted that the frequency and severity of short-term adverse events were broadly comparable for rituximab and cyclophosphamide in RAVE (in which cyclophosphamide was administered orally) and RITUXVAS (in which cyclophosphamide was administered intravenously). The Committee noted that there were long-term adverse events associated with cyclophosphamide (such as bladder cancer and loss of fertility), but that it was not possible to form any conclusions on the long-term safety profile of rituximab because the data in the manufacturer's submission only extended to a maximum of 18 months. In response to consultation, the manufacturer submitted evidence of the long-term safety of rituximab as a treatment for rheumatoid arthritis, and evidence that rituximab does not prevent women from conceiving children. The Committee concluded that the safety profiles of rituximab and cyclophosphamide seemed broadly similar in the short term, and there was uncertainty about any long-term safety benefits of rituximab because of a lack of data from patients with ANCA-associated vasculitis. The Committee discussed potential advantages associated with rituximab that were not related to its efficacy or safety. It heard from the clinical specialists and patient experts that induction treatment with rituximab was 4 weeks instead of up to 6 months with cyclophosphamide, which was more convenient for patients. The Committee concluded that this benefit was important to patients. # Cost effectiveness The Committee discussed the manufacturer's approach to developing its economic model. It noted that the ERG considered the manufacturer's approach to be generally in line with the NICE reference case, but that the manufacturer's decision problem did not match the final NICE scope in all areas (notably excluding some comparators and some end points). The Committee concluded that the outlined economic analysis was acceptable for assessing the cost effectiveness of rituximab in treating ANCA-associated vasculitis. The Committee considered the comparators included in the manufacturer's economic analysis. The clinical specialists, and responses to consultation, confirmed that cyclophosphamide is the standard of care for inducing remission in people who can have cyclophosphamide; typically administered intravenously. The Committee noted that there was a lack of consensus about the appropriate comparator for people who cannot have cyclophosphamide. The Committee recalled that the ERG's exploratory analyses for this subgroup, based on the manufacturer's original model, used a comparator of best supportive care. The Committee was uncertain whether best supportive care was a realistic comparator. The Committee was aware that the manufacturer's updated model for this subgroup used a comparator of either mycophenolate mofetil or methotrexate. Clinical specialists at the meeting advised that neither of these drugs is a treatment of choice for people with severe disease, and methotrexate is unsuitable for people with renal disease. Also, the British Society for Rheumatology draft guidelines recommend mycophenolate mofetil or methotrexate for patients with low disease activity who are not at risk of organ damage. The Committee heard from the manufacturer that the clinical specialists it consulted advised that mycophenolate mofetil or methotrexate would be used as an induction treatment for people who cannot have cyclophosphamide. The Committee concluded that it was appropriate to include intravenous cyclophosphamide as the comparator in the economic analysis for people who can have cyclophosphamide, and that there was uncertainty about the appropriate comparator for people who cannot have cyclophosphamide. The Committee evaluated the treatment sequences used in the manufacturer's original economic analysis. It considered the treatment sequences to be incomplete and unsuitable because they did not enable fully incremental analyses for all populations of interest. Also, the Committee learned from clinical specialists that the manufacturer's assumption that patients who had not responded to a first course of rituximab would then receive a second course did not reflect UK clinical practice. The Committee agreed that the treatment sequences used by the ERG in its exploratory analyses using the manufacturer's original model were more comprehensive and therefore more appropriate. However, the Committee agreed that it needed additional analyses for all possible treatment sequences for the different subgroup populations, with ICERs presented in a fully incremental analysis and as pairwise comparisons. The Committee then evaluated the treatment sequences used in the manufacturer's updated economic analysis, submitted in response to consultation. The Committee observed that the updated model did not consider all treatment sequences and assumed that all patients received a second course of rituximab. The results were not presented in a fully incremental analysis. The Committee concluded that these issues with the manufacturer's updated economic analysis added considerable uncertainty to the cost-effectiveness estimates. The Committee discussed the uncontrolled disease health state in the manufacturer's original economic model. It noted the ERG's concerns that patients in the model spent 60–70% of their average lifespan in the uncontrolled disease state and heard from the clinical specialists that this was not realistic. The Committee was aware that this health state was associated with a low utility value and understood from the clinical specialists that patients would be expected to have some disease control with treatments other than cyclophosphamide. It noted the ERG's opinion that the costs for this health state had been overestimated and was advised by the clinical specialists that the number of outpatient appointments was not plausible. The Committee agreed that the utility value had been underestimated and costs had been overestimated for the uncontrolled disease health state in the manufacturer's original model. The Committee noted that, in response to consultation, the manufacturer submitted an updated model with a higher utility value and lower costs in the uncontrolled disease health state. It heard from the manufacturer and the ERG that the revised utility value was based on extrapolation from the utility values in the remission and non-remission health states. The Committee noted that the utility value could have been estimated using data from patients in RAVE who had not entered remission during the trial, but this analysis had not been presented. The Committee concluded that the revised utility value in the uncontrolled disease health state was more plausible than the value in the original model, but was still a source of some uncertainty. The Committee discussed how adverse events and disease consequences had been incorporated into the manufacturer's original model. It noted that disutilities for cyclophosphamide's cumulative long-term toxicity had not been included in the analyses by the manufacturer, and that the costs of managing long-term toxicity could be substantial (for example, treating uroepithelial cancer or fertility problems). The Committee noted that the long-term toxicity of rituximab also had not been modelled and was not fully established. It was aware that the manufacturer's model did not include inpatient costs (such as treating infections) or the costs of disease consequences (for example, managing renal disease). The manufacturer's updated model, submitted in response to consultation, did not include disutilities for long-term toxicity, inpatient costs, or the costs of disease consequences. The Committee concluded that the manufacturer's original and updated models had not captured all relevant costs and disutilities, which added some uncertainty to the cost-effectiveness estimates. The Committee reviewed how the manufacturer had estimated relapse rates in its original economic model and noted that the model assumed that both minor and severe relapses would need induction treatment. The Committee noted from the manufacturer's submission that, when possible, minor relapses in RAVE were managed by increasing the glucocorticoid dose. It understood from the clinical specialists that this would generally be the first approach in UK clinical practice (unless, for example, it was considered that there was a high risk of progression to a severe relapse). The Committee was aware that the manufacturer had used summary statistics rather than individual patient-level data, and noted the poor fit of the exponential distributions to the Kaplan–Meier relapse curves. It agreed with the ERG's opinion that the relapse rates derived from RAVE had been poorly estimated. In response to consultation, the manufacturer submitted an updated model which assumed that only severe relapses would need induction treatment. The Committee continued to have concerns about the manufacturer's use of summary statistics and concluded that the relapse rates in the manufacturer's updated model were a source of uncertainty. The Committee then considered the manufacturer's updated models submitted in response to the first consultation (see sections 3.54–3.62). The Committee noted that the manufacturer had not provided all the analyses requested at consultation. The manufacturer's response did not include all treatment sequences, pairwise and incremental comparisons, incorporate the costs and disutility of the cumulative long-term toxicity of cyclophosphamide, or include inpatient costs associated with non-remission. The ERG identified several errors in the manufacturer's models (see section 3.63). The Committee then considered the manufacturer's weighted-average threshold analysis submitted in response to the second consultation (see section 3.75). It was aware that one of the reasons the manufacturer used this analysis was that another Committee had agreed to consider a whole-population weighted-ICER analysis in Omalizumab for treating severe persistent allergic asthma (NICE technology appraisal guidance 278). However, the Committee noted that the circumstances were different to the current appraisal. For example, the omalizumab appraisal considered subgroups created by an arbitrary cut-off between age groups whereas the current appraisal considered 2 clinically distinct subgroups (people who can and cannot have cyclophosphamide). The Committee recalled that NICE's Guide to the methods of technology appraisal states that estimates of clinical and cost effectiveness should be provided separately for each relevant subgroup of patients. The Committee concluded that the manufacturer's models submitted in response to the first consultation, and the manufacturer's weighted-average threshold analysis submitted in response to the second consultation, did not provide a suitable basis for decision-making. The Committee considered the ERG's exploratory analyses using the manufacturer's updated model for people who can have cyclophosphamide (see section 3.73). The Committee noted that the ERG had corrected the errors identified in the manufacturer's updated model. The Committee also noted the ERG's exploratory analysis allowed re-treatment of patients who responded to rituximab rather than re-treatment of all patients in the manufacturer's updated model. It also considered the treatment sequence, which was 1 course of cyclophosphamide followed by 2 courses of rituximab compared with 2 courses of cyclophosphamide in the comparator arm. The Committee noted that there was no incremental analysis of rituximab in different places in the treatment pathway. Therefore, the ICER of £20,900 per QALY gained from the ERG's exploratory analyses did not reflect the true cost effectiveness of rituximab given after 1 course of cyclophosphamide compared with cyclophosphamide. The Committee then discussed the ERG's exploratory analyses using the manufacturer's original model (see section 3.48), because these incremental analyses explored the use of rituximab in different places in the treatment pathway. The Committee was aware that a treatment sequence of 2 courses of cyclophosphamide followed by 1 course of rituximab compared with 2 courses of cyclophosphamide resulted in an ICER of £12,100 per QALY gained. It noted that using rituximab after 1 course of cyclophosphamide (compared with using it after 2 courses of cyclophosphamide) or as a first-line treatment (compared with using rituximab after 1 course of cyclophosphamide), resulted in ICERs of £69,700 and £127,500 per QALY gained respectively (see section 3.48). The Committee agreed that the ICERs for rituximab after 1 course of cyclophosphamide or as a first-line treatment were outside the range normally considered a cost-effective use of NHS resources. The Committee noted that these exploratory analyses included maintenance treatment with azathioprine after rituximab, which may not reflect UK clinical practice (see section 4.6). The Committee heard from the ERG that, based on previous exploratory analyses (see section 3.73), including maintenance treatment with azathioprine was likely to have a small impact on the ICER. The Committee concluded that the most plausible ICER on which to base its decision for people who can have cyclophosphamide was £12,100 per QALY gained, provided by the comparison of 2 courses of cyclophosphamide followed by 1 course of rituximab with 2 courses of cyclophosphamide. The Committee considered the cumulative dose provided by 2 courses of intravenous cyclophosphamide. Based on the manufacturer's response to consultation, the Committee was persuaded that 2 courses of intravenous cyclophosphamide provides a cumulative dose of approximately 23 g on average, which is within the limit of 25 g advised by draft guidelines from the British Society for Rheumatology. The Committee further noted that approximately 23 g cyclophosphamide represented 10 infusions (the maximum number that would be administered per course of treatment) and that, according to the clinical specialists, some patients would respond with fewer infusions per cycle. The Committee noted that when possible, giving 2 courses of cyclophosphamide before rituximab would represent a more cost-effective option than giving 1 course of cyclophosphamide before rituximab. The Committee concluded that rituximab could be recommended as a cost-effective use of NHS resources in people with severe ANCA-associated vasculitis who can have cyclophosphamide, only if further treatment with cyclophosphamide would exceed the maximum cumulative dose (25 g) of cyclophosphamide. The Committee discussed the ERG's exploratory analyses using the manufacturer's updated model for people who cannot have cyclophosphamide (see section 3.74). The treatment sequence included 2 courses of rituximab compared with 1 course of either mycophenolate mofetil or methotrexate and the ERG's exploratory analysis of the manufacturer's updated model gave an ICER of £60,600 per QALY gained. The Committee was aware of substantial uncertainty about the assumptions in the model, such as the utility of the remission health state, the cost and disutility associated with glucocorticoids, and the remission and relapse rates. Therefore, the Committee agreed that the ICER of £60,600 per QALY gained was not plausible. The Committee considered the ERG's illustrative analyses, submitted in response to the second consultation (see section 3.76). The ERG's illustrative analyses changed some assumptions in the model and gave an ICER of £26,400 per QALY gained for the comparison of 2 courses of rituximab with 1 course of mycophenolate mofetil. The Committee heard from the ERG that the analyses illustrate the uncertainty in the estimates of cost effectiveness for people who cannot have cyclophosphamide. The Committee was aware that the clinical specialists did not agree about the use of mycophenolate mofetil or methotrexate as an induction treatment in people who cannot have cyclophosphamide (see section 4.12). The Committee then discussed the ERG's exploratory analyses using the manufacturer's original model for people who cannot have cyclophosphamide (see section 3.52), because these analyses included an alternative comparator. The Committee noted that 1 course of rituximab compared with best supportive care gave an ICER of £11,300 per QALY gained. The Committee agreed that there was a lack of consensus about the appropriate comparator for people who cannot have cyclophosphamide. The Committee concluded there was substantial uncertainty about the cost effectiveness of rituximab for people who cannot have cyclophosphamide, but on balance the ICER was likely to be lower than £30,000 per QALY gained. The Committee discussed whether rituximab was innovative in its potential to make a significant and substantial impact on health-related benefits. The Committee was aware that, in response to the second consultation, clinical specialists and patient experts stated that rituximab was 'scene-changing' in the treatment of ANCA-associated vasculitis. Consultees also advised that rituximab was the first new effective treatment since the introduction of cyclophosphamide in the 1970s, and rituximab may be the first of a new generation of treatments. In addition, consultees advised that people who cannot have cyclophosphamide have the highest unmet need because no alternative treatments are as effective as rituximab. The manufacturer noted that cyclophosphamide reduces fertility in men and women, and stated that the benefit of maintaining fertility while treating the disease effectively cannot be captured in the QALY. The Committee was aware that the manufacturer had provided evidence that rituximab does not prevent women from conceiving children. The Committee concluded that rituximab was an innovative treatment. In summary, for people who cannot have cyclophosphamide, the Committee considered the manufacturer's original and updated analyses, the ERG's exploratory and illustrative analyses, and comments received during consultation. The Committee took into account the estimates of cost effectiveness and noted the uncertainty associated with them. The Committee also recognised that rituximab is an innovative treatment and the high unmet need for treatment options for people who cannot have cyclophosphamide. Having taken into account all of the evidence submitted and the comments received during consultation and noting the NICE Social Value Judgements, the Committee concluded that rituximab was a cost-effective use of NHS resources for treating people with severe ANCA-associated vasculitis who cannot have cyclophosphamide, as defined in section 4.8. The Committee considered whether its recommendations were associated with any issues related to the equality legislation and the requirement for fairness. The Committee noted that the manufacturer stated that cyclophosphamide reduces fertility in both men and women. The Committee was also aware that the manufacturer had provided evidence that rituximab does not prevent women from conceiving children and that no evidence was presented regarding the effect of rituximab on male fertility. Based on the available evidence, the Committee considered that it was appropriate to accept that rituximab was likely to have a less detrimental effect on male fertility than cyclophosphamide. The Committee considered that, in this context, guidance that only recommended rituximab for women who had not completed their family would potentially constitute unlawful sex discrimination. The Committee concluded that it was appropriate to recommend rituximab for men and women who have not completed their family and whose fertility may be materially affected by treatment with cyclophosphamide. The Committee further considered issues related to the equality legislation. Considering that the guidance in section 1.1 recommends rituximab for people who have not completed their family and whose fertility may be materially affected by treatment with cyclophosphamide, the Committee was aware that this recommendation would affect access for post-menopausal women whereas younger women and men of all ages could potentially receive rituximab. The Committee discussed whether this could be regarded as indirect discrimination. The Committee noted that any differential treatment of post-menopausal women arises from the different physiological features of fertility in men and women. The Committee noted that rituximab and cyclophosphamide have similar effectiveness as induction treatments for severe ANCA-associated vasculitis (see section 4.7), so an effective induction treatment will also be available for post-menopausal women. Therefore, the Committee agreed that its recommendations do not constitute detrimental treatment of post-menopausal women. The Committee noted that the safety profiles of rituximab and cyclophosphamide are broadly similar in the short term, and there was uncertainty about any long-term safety benefits of rituximab compared with cyclophosphamide (see section 4.9). The Committee concluded that the guidance would permit an effective induction treatment for all groups of people, and there was no evidence that some groups would experience more adverse effects of treatment than other groups, and therefore there was no unfairness. In considering the potential equalities issues, the Committee took into account the size and characteristics of the overall population of people with ANCA-associated vasculitis and the subgroup of people who would be affected by the recommendation relating to fertility. The Committee was aware that around 1200 people are diagnosed with ANCA-associated vasculitis each year in England and Wales and the peak age of onset is between 60 and 70 years. Therefore, the Committee concluded that the number of people with ANCA-associated vasculitis who have not completed their family is likely to be small. The Committee further discussed issues related to the equality legislation. Consultees suggested that children should be included in the population, but the marketing authorisation specifies 'adults' so this is not an equality issue that falls within the remit of a NICE technology appraisal. The Committee concluded that its decision on the use of rituximab would not have a disproportionate impact on any group with a protected characteristic that cannot be objectively justified, and that therefore there was no need to alter or add to its recommendations. # Summary of Appraisal Committee's key conclusions TA308 Appraisal title: Rituximab in combination with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis Section Key conclusion Rituximab, in combination with glucocorticoids, is recommended as an option for inducing remission in adults with anti-neutrophil cytoplasmic antibody -associated vasculitis (severely active granulomatosis with polyangiitis and microscopic polyangiitis), only if: further cyclophosphamide treatment would exceed the maximum cumulative cyclophosphamide dose or cyclophosphamide is contraindicated or not tolerated or the person has not completed their family and treatment with cyclophosphamide may materially affect their fertility or the disease has remained active or progressed despite a course of cyclophosphamide lasting 3–6 months or the person has had uroepithelial malignancy. The Committee concluded that a plausible treatment sequence for people who can have cyclophosphamide was 2 courses of cyclophosphamide followed by 1 course of rituximab. The Committee noted that 2 courses of cyclophosphamide would provide a cumulative dose of 23 g on average, which is within the limit of 25 g advised by draft guidelines from the British Society for Rheumatology. The Committee noted that using rituximab earlier in the treatment sequence, either as a first-line treatment or after 1 course of cyclophosphamide, was not cost effective. It concluded that, for patients for whom further cyclophosphamide treatment would exceed the maximum cumulative dose, rituximab is a cost-effective use of NHS resources and therefore should be recommended. The Committee concluded there was substantial uncertainty regarding the cost effectiveness of rituximab for people who cannot have cyclophosphamide, but on balance the ICER was likely to be lower than £30,000 per QALY gained. The Committee recognised that rituximab is an innovative treatment and the high unmet need of treatment options for people who cannot have cyclophosphamide. Therefore, the Committee concluded that rituximab was a cost-effective use of NHS resources for treating people with severe ANCA-associated vasculitis who cannot have cyclophosphamide, as defined in section 4.8. Current practice Clinical need of patients, including the availability of alternative treatments The Committee heard from the clinical specialists that induction treatment with cyclophosphamide is the standard of care for people with severe ANCA-associated vasculitis, and that alternative treatments such as mycophenolate mofetil, methotrexate and deoxyspergualin were associated with higher relapse rates and would not normally be used to treat severe disease (unless cyclophosphamide was unsuitable). The Committee recognised that the risk of long-term toxicity (for example, uroepithelial malignancies) increases with the cumulative dose of cyclophosphamide and understood that the cumulative dose should not exceed 25 g. The Committee concluded that alternative treatments for ANCA-associated vasculitis would be welcomed by clinicians and patients. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Rituximab (MabThera, Roche Products) is a genetically engineered chimeric (mouse/human) monoclonal antibody that depletes B cells by targeting cells bearing the CD20 surface marker. The Committee was aware that clinical specialists and patient experts stated that rituximab was 'scene-changing' in the treatment of ANCA-associated vasculitis. Consultees also advised that rituximab was the first new effective treatment since the introduction of cyclophosphamide in the 1970s, and rituximab may be the first of a new generation of treatments. The manufacturer noted that cyclophosphamide reduces fertility in men and women, stated that the benefit of maintaining fertility while treating the disease effectively cannot be captured in the QALY, and provided evidence that rituximab does not prevent women from conceiving children. The Committee agreed that rituximab was an innovative treatment and therefore the Committee would consider an ICER at the top end of the range that would normally be considered a cost-effective use of NHS resources (£20,000–30,000 per QALY gained). What is the position of the treatment in the pathway of care for the condition? The Committee assessed the clinical effectiveness of rituximab compared with cyclophosphamide as induction therapy in people with severe ANCA-associated vasculitis. Adverse reactions The Committee noted that the frequency and severity of short-term adverse events were broadly comparable for rituximab and cyclophosphamide in RAVE and RITUXVAS. The Committee noted that there were long-term adverse events associated with cyclophosphamide (such as bladder cancer and loss of fertility). It was aware of evidence of the long-term safety of rituximab as a treatment for rheumatoid arthritis, and evidence that rituximab does not prevent women from conceiving children. The Committee concluded that the safety profiles of rituximab and cyclophosphamide seemed broadly similar in the short term, and there was uncertainty about any long-term safety benefits of rituximab because of a lack of data from patients with ANCA-associated vasculitis. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee considered the evidence from RAVE and RITUXVAS presented by the manufacturer and noted that only RAVE used the regimen recommended in the marketing authorisation. The Committee concluded that the studies provided adequate evidence for assessing rituximab for inducing remission of ANCA-associated vasculitis and were generalisable to UK clinical practice. Relevance to general clinical practice in the NHS The Committee discussed the need for maintenance treatment after rituximab induction therapy. It was aware that British Society for Rheumatology draft guidelines include 4 options for maintenance treatment, but clinical specialists did not agree about which options would be used in routine practice. The Committee concluded that maintenance treatment with rituximab was outside the scope of the appraisal because it was not included in the marketing authorisation. Uncertainties generated by the evidence The Committee concluded there was uncertainty about any long-term safety benefits of rituximab compared with cyclophosphamide because of a lack of data from people with ANCA-associated vasculitis. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee noted that rituximab was superior to cyclophosphamide in inducing remission in patients with relapsed disease at 6-month follow-up, but the difference between treatments was not significantly different at 18-month follow-up. The Committee heard from the clinical specialists that there may be a small subgroup of people who would benefit from avoiding cyclophosphamide, and that there is evidence from case series to support the use of rituximab for this subgroup. The Committee concluded that, for the purposes of this guidance, 'people who cannot have cyclophosphamide' refers to people: for whom cyclophosphamide is contraindicated (as defined in the summary of product characteristics) or not tolerated; or who have not completed their family and whose fertility may be materially affected by treatment with cyclophosphamide; or with disease that has remained active or progressed despite a course of cyclophosphamide lasting 3–6 months; or with a previous uroepithelial malignancy. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee accepted that the RAVE results showed rituximab was non-inferior to cyclophosphamide in inducing complete remission in the full study population at 6, 12, and 18 months. The Committee concluded that the RAVE and RITUXVAS studies provided adequate evidence for assessing rituximab for inducing remission of ANCA-associated vasculitis and were generalisable to UK clinical practice. Evidence for cost effectiveness Availability and nature of evidence The Committee observed that the manufacturer's approach was generally in line with the NICE reference case, but that the manufacturer's decision problem did not match the final NICE scope in all areas (notably excluding some comparators and end points). The Committee concluded that the outlined economic analysis was acceptable for assessing the cost effectiveness of rituximab in treating ANCA-associated vasculitis. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee identified several reasons for uncertainty in the results of the manufacturer's updated economic models submitted in response to the first consultation. The reasons included: not all treatment sequences were modelled, no incremental analyses were reported, not all costs and consequences were included, there were concerns about the way relapse rates were calculated, there were errors in the model, and there was uncertainty about utility values. The Committee then considered the manufacturer's weighted-average threshold analysis submitted in response to the second consultation. It was aware that another Committee had agreed to consider a whole-population weighted-ICER analysis in Omalizumab for treating severe persistent allergic asthma (NICE technology appraisal guidance 278), but the circumstances were different to the current appraisal. The Committee recalled that NICE's Guide to the methods of technology appraisal states that estimates of clinical and cost effectiveness should be provided separately for each relevant subgroup of patients. The Committee concluded that the manufacturer's models submitted in response to the first consultation, and the manufacturer's weighted-average threshold analysis submitted in response to the second consultation, did not provide a suitable basis for decision-making. Some of the Committee's concerns had been resolved in the ERG's exploratory analyses. Accordingly, the Committee was able to identify the most plausible ICER for people who can have cyclophosphamide. For people who cannot have cyclophosphamide, the Committee considered the manufacturer's original and updated analyses, and the ERG's exploratory and illustrative analyses. The Committee agreed that, for people who cannot have cyclophosphamide, there was a lack of consensus about the appropriate comparator treatment. The Committee concluded there was substantial uncertainty about the cost effectiveness of rituximab for people who cannot have cyclophosphamide, but on balance the ICER was likely to be lower than £30,000 per QALY gained. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee noted that, in the manufacturer's updated models, the utility value in the uncontrolled disease health state was based on extrapolation from the utility values in the remission and non-remission health states. It concluded that that the revised utility value in the uncontrolled disease health state was more plausible than the value in the original model, but was still a source of some uncertainty. The Committee noted that the economic model did not include disutilities for cyclophosphamide's cumulative long-term toxicity or the costs of managing long-term toxicity. It agreed that these issues added some uncertainty to the cost-effectiveness estimates. Are there specific groups of people for whom the technology is particularly cost effective? The Committee agreed that rituximab was cost effective for adults with ANCA-associated vasculitis (severely active granulomatosis with polyangiitis and microscopic polyangiitis), only if: further cyclophosphamide treatment would exceed the maximum cumulative dose (25 g) of cyclophosphamide; or the person cannot have cyclophosphamide (as specified in section 4.8). What are the key drivers of cost effectiveness? The Committee was aware from the ERG's exploratory analyses based on the manufacturer's original model that the ICER substantially increased when the number of outpatient appointments was reduced. The Committee also noted that the ICERs presented by the manufacturer and the ERG were sensitive to changes in treatment sequence. Most likely cost-effectiveness estimate (given as an ICER) The Committee agreed that the most plausible ICER on which to base its decision for people who can have cyclophosphamide was £12,100 per QALY gained, provided by the comparison of 2 courses of cyclophosphamide followed by 1 course of rituximab with 2 courses of cyclophosphamide. The Committee concluded there was substantial uncertainty about the cost effectiveness of rituximab for people who cannot have cyclophosphamide, but on balance the ICER was likely to be lower than £30,000 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) Not applicable. End-of-life considerations Not applicable. Equalities considerations and social value judgements For people who cannot have cyclophosphamide, the Committee considered the evidence, the comments received during consultation, and the NICE Social Value Judgements. The Committee took into account the estimates of cost effectiveness and noted the uncertainty associated with them. The Committee also recognised that rituximab is an innovative treatment and the high unmet need for treatment options for people who cannot have cyclophosphamide. The Committee concluded that rituximab was a cost-effective use of NHS resources for treating people with severe ANCA-associated vasculitis who cannot have cyclophosphamide, as defined in section 4.8. The Committee considered whether its recommendations were associated with any issues related to the equality legislation. The Committee noted that the manufacturer stated that cyclophosphamide reduces fertility in both men and women. The Committee was aware of evidence that rituximab does not prevent women from conceiving children but no evidence had been presented regarding the effect of rituximab on male fertility. The Committee considered that it was appropriate to accept that rituximab was likely to have a less detrimental effect on male fertility than cyclophosphamide. The Committee concluded that it was appropriate to recommend rituximab for men and women who have not completed their family whose fertility may be materially affected by treatment with cyclophosphamide. The Committee was aware that the recommendation regarding fertility would affect access for post-menopausal women whereas younger women and men of all ages could potentially receive rituximab. The Committee discussed whether this could be regarded as indirect discrimination. The Committee noted that rituximab and cyclophosphamide have similar effectiveness as induction treatments for severe ANCA-associated vasculitis. The Committee also noted that the safety profiles of rituximab and cyclophosphamide are broadly similar in the short term, and there was uncertainty about any long-term safety benefits of rituximab compared with cyclophosphamide. The Committee concluded that the guidance would permit an effective induction treatment for all groups of people, and there was no evidence that some groups would experience more adverse effects of treatment than other groups, and therefore there was no unfairness. The Committee also concluded that the number of people with ANCA-associated vasculitis who have not completed their family is likely to be small. –4.25# Review of guidance The guidance on this technology will be considered for review in March 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew Dillon Chief ExecutiveMarch 2014# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. A tool to help you put the guidance into practice and information about the evidence it is based on are also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0500-3	{'Guidance': "Rituximab, in combination with glucocorticoids, is recommended as an option for inducing remission in adults with anti-neutrophil cytoplasmic antibody [ANCA]-associated vasculitis (severely active granulomatosis with polyangiitis [Wegener's] and microscopic polyangiitis), only if:\n\nfurther cyclophosphamide treatment would exceed the maximum cumulative cyclophosphamide dose or\n\ncyclophosphamide is contraindicated or not tolerated or\n\nthe person has not completed their family and treatment with cyclophosphamide may materially affect their fertility or\n\nthe disease has remained active or progressed despite a course of cyclophosphamide lasting 3–6\xa0months or\n\nthe person has had uroepithelial malignancy.\n\nPeople currently receiving treatment initiated within the NHS with rituximab that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.", 'The technology ': "Rituximab (MabThera, Roche Products) is a genetically engineered chimeric (mouse/human) monoclonal antibody that depletes B cells by targeting cells bearing the CD20 surface marker. Within its marketing authorisation, rituximab in combination with glucocorticoids is indicated for 'the induction of remission in adult patients with severely active granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA)'. The summary of product characteristics states that limited data preclude any conclusions about the efficacy of subsequent courses of rituximab in people with granulomatosis with polyangiitis and microscopic polyangiitis. The summary of product characteristics also states that continued immunosuppressive therapy may be considered to prevent relapse, and may be especially appropriate in people at risk of relapse (for example, in people who have had previous relapses), but that the efficacy and safety of rituximab in maintenance therapy has not been established.\n\nThe summary of product characteristics lists the following adverse events occurring at an incidence of 10% or greater in patients receiving rituximab to treat granulomatosis with polyangiitis and microscopic polyangiitis: diarrhoea, peripheral oedema, muscle spasms, arthralgia, back pain, dizziness, tremor, insomnia, cough, dyspnoea, epistaxis and hypertension. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRituximab is priced at £174.63 per 10\xa0ml vial and £873.15 per 50\xa0ml vial (excluding VAT; British national formulary [BNF] edition\xa066). The recommended dosage for treating granulomatosis with polyangiitis and microscopic polyangiitis (2\xa0types of anti-neutrophil cytoplasmic antibody [ANCA]-associated vasculitis) is 375\xa0mg/m2 body surface area, administered intravenously once weekly for 4\xa0weeks (4\xa0infusions in total). The manufacturer's estimate of the average cost of a course of treatment is £4889.64 (based on 1.79\xa0m2 body surface area and no vial sharing). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (section\xa07) considered evidence submitted by the manufacturer of rituximab and reviews of this evidence by the Evidence Review Group (ERG; section\xa08).\n\n# Clinical effectiveness\n\n## Manufacturer's original submission\n\nThe manufacturer's systematic review identified 2\xa0relevant randomised controlled trials for inclusion in its submission: RAVE and RITUXVAS. Seven non-randomised controlled trials were identified but the manufacturer judged that they contained insufficient data to be useful to the decision problem. The manufacturer explained that its submission focused on efficacy data from RAVE, complemented by the RITUXVAS results. Both RAVE and RITUXVAS compared rituximab with cyclophosphamide in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis or microscopic polyangiitis). RAVE recruited both newly diagnosed and relapsed patients, whereas RITUXVAS recruited newly diagnosed patients with renal involvement.\n\nRAVE was a randomised, multicentre, double-blind, double-dummy, placebo-controlled trial conducted in the USA and the Netherlands, which compared rituximab with conventional therapy (cyclophosphamide and azathioprine) in patients with severe ANCA-associated vasculitis. The study tested the hypothesis that rituximab was not inferior to (that is, was no worse than) conventional therapy in its ability to induce disease remission in ANCA-associated vasculitis at 6\xa0months. Eligible patients had either granulomatosis with polyangiitis or microscopic polyangiitis, had tested positive for ANCA at screening, and had evidence of severe disease and a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 3 or more. BVAS/WG scores range from 0 to 68, with higher scores indicating more active disease. A 6-month remission induction phase was followed by a 12-month remission maintenance phase. In both groups, patients who went into remission before 6\xa0months of treatment were eligible to switch to maintenance treatment from month\xa04 onwards.\n\nAt the start of the study, all patients received an intravenous glucocorticoid pulse (methylprednisolone 1\xa0g, or an equivalent dose of an alternative drug) followed by an oral prednisone taper (dosage starting at 1\xa0mg/kg/day and not exceeding 80\xa0mg/day). Patients in the rituximab group (n=99) received remission induction treatment consisting of once-weekly infusions of rituximab 375\xa0mg/m2 for 4\xa0weeks plus daily oral placebo and daily oral prednisone for 3–6\xa0months. For the remission maintenance treatment, patients then switched to oral placebo as maintenance treatment until 18\xa0months. Patients in the cyclophosphamide group (n=98) received remission induction treatment consisting of daily oral prednisone, oral cyclophosphamide 2\xa0mg/kg/day plus placebo infusions for 3–6\xa0months to induce remission. Remission maintenance treatment consisted of oral azathioprine 2\xa0mg/kg/day until 18\xa0months. Patients who had a severe flare (BVAS/WG of 3 or more, or a major BVAS/WG item that needed cyclophosphamide after remission [BVAS/WG of 0]) in the first 6\xa0months could cross over to the other treatment group and receive the other induction regimen in full. Limited flares (new occurrence or worsening of 1 or more minor BVAS/WG items) were managed by restarting or increasing the glucocorticoid dose. Patients whose BVAS/WG had not decreased by at least 1\xa0point at 1\xa0month or who had a new manifestation of disease were considered as having early treatment failure. These patients discontinued their assigned treatments and were treated according to best medical judgement.\n\nRAVE's primary end point was the induction of complete remission at 6\xa0months, defined as a BVAS/WG of 0 and successful completion of the prednisone taper (that is, prednisone dose was reduced to 0\xa0mg). A secondary analysis of the primary end point assessed the superiority of rituximab to cyclophosphamide in patients who had complete remission at 6\xa0months. Tertiary end points included the number of severe flares at 6\xa0months, the number of limited flares at 6\xa0months, and quality of life using Short Form (SF‑36) physical component and mental component summary scores. End points for the assessment of efficacy up to 18\xa0months included duration of complete remission and time to limited and/or severe flare after complete remission. Efficacy data were analysed on an intention-to-treat basis.\n\nBaseline demographic and disease characteristics in RAVE were generally similar between the treatment groups except for creatinine clearance, which was lower in the rituximab group. At the time of screening, 96\xa0(48.7%) patients were newly diagnosed. There were 82\xa0(83%) of the 98 patients remaining in the rituximab group and 79\xa0(81%) of the 95\xa0patients remaining in the cyclophosphamide group who completed the 6-month remission induction phase without crossover or change to treatment by best medical judgement. A similar proportion of patients in the 2\xa0groups completed 18\xa0months on randomised treatment (62% in the rituximab group and 63% in the cyclophosphamide group).\n\nSixty-three (64.3%) patients in the rituximab group were in complete remission at 6\xa0months, compared with 52\xa0(54.7%) patients in the cyclophosphamide group. The absolute difference in rate of remission between the 2\xa0groups was 9.5% (95% confidence interval [CI] −4.30% to 23.40%). This showed that rituximab was not inferior to cyclophosphamide in inducing complete remission because the lower limit of the 95% CI (−4.30%) was higher than the predetermined non-inferiority margin (−20%). After estimating missing data by worst case imputation, 63.6% of the 99\xa0patients in the rituximab group achieved complete remission at 6\xa0months compared with 53.1% of the 98\xa0patients in the cyclophosphamide group (absolute treatment difference 10.6% [95% CI −3.18% to 24.33%]).\n\nThe complete remission rate at 6\xa0months in the rituximab group was not statistically significantly superior to the cyclophosphamide group (95% CI for the between-group difference −4.30% to 23.40%; p=0.177). The outcome was similar using worst case imputation (95% CI for the between-group difference −3.2% to 24.3%; p=0.132).\n\nThere was no statistically significant difference between the treatment groups in the number of severe or limited flares during the first 6\xa0months. Quality-of-life scores improved in both groups; there was no significant difference between treatment groups in the change in quality-of-life scores or their rate of change from baseline to 6\xa0months.\n\nThe manufacturer explored the effects of various baseline characteristics in relation to the primary end point, including relapsed disease. In patients who had relapsed disease at baseline, a statistically significantly higher proportion in the rituximab group went into complete remission at 6\xa0months than in the cyclophosphamide group (66.7% compared with 42.0%, p=0.013). Complete remission rates in patients with new disease were similar in the 2\xa0treatment groups (60.4% compared with 64.6%, p=0.673).\n\nRITUXVAS was a phase\xa0II, open-label, randomised controlled trial conducted in Europe and Australia. It compared the efficacy and safety of rituximab plus cyclophosphamide as induction therapy with cyclophosphamide plus azathioprine in 44\xa0patients with newly diagnosed, severe ANCA-associated vasculitis and renal involvement. Patients were randomised to rituximab plus cyclophosphamide (n=33) or cyclophosphamide (n=11) and both groups received intravenous methylprednisolone (1\xa0g) and an oral glucocorticoid (1\xa0mg/kg/day initially, reducing to 5\xa0mg/day at the end of 6\xa0months). Patients in the rituximab group received infusions of rituximab (375\xa0mg/m2 weekly, for 4\xa0weeks), and intravenous cyclophosphamide (15\xa0mg/kg with the first and third rituximab infusions). A further dose of intravenous cyclophosphamide (15\xa0mg/kg) was permitted for patients who had progressive disease within the first 6\xa0months. Patients in the rituximab group received no maintenance treatment. Patients in the control group received intravenous cyclophosphamide (15\xa0mg/kg for 3–6\xa0months; 6‑10\xa0doses in total), followed by azathioprine maintenance (2\xa0mg/kg/day). Further treatment with rituximab or cyclophosphamide was permitted if patients in either group relapsed. The primary end points for RITUXVAS were sustained remission at 12\xa0months (defined as BVAS of 0 maintained for at least 6\xa0months) and severe adverse events. Secondary end points included quality of life, assessed by the SF‑36 questionnaire between 0 and 12\xa0months. Analyses were performed on an intention-to-treat basis.\n\nThere were no major imbalances in baseline characteristics between the 2\xa0groups, except for a greater proportion of patients with renal-limited vasculitis in the cyclophosphamide group and a greater proportion of patients needing dialysis in the rituximab plus cyclophosphamide group. No patients were lost to follow-up.\n\nSustained remission occurred in 76% of patients in the rituximab plus cyclophosphamide group and 82% of patients in the cyclophosphamide group. The absolute difference in sustained remission with rituximab plus cyclophosphamide compared with cyclophosphamide was −6% (95% CI −33 to 21). Among patients who were still in the study at 12\xa0months, 93% of patients in the rituximab plus cyclophosphamide group and 90% of patients in the cyclophosphamide group were in sustained remission.\n\nThere was no statistically significant difference between treatment groups in median change in the physical component SF‑36 score (p=0.36). Patients in the cyclophosphamide group had a statistically significantly better mental component SF‑36 score compared with the rituximab plus cyclophosphamide group (p=0.04), but excluding outlying data for 2\xa0patients eliminated the statistical significance (p=0.32).\n\nThe manufacturer did not do any indirect comparisons or meta-analyses and advised that the economic evaluation was based solely on the RAVE results. It stated that RAVE reflected the marketing authorisation and scope of the appraisal, whereas the way rituximab was given in RITUXVAS was fundamentally different.\n\nThe manufacturer's submission described rituximab's safety profile using the Summary of Clinical Safety provided to the European Medicines Agency to support the marketing authorisation application for rituximab for treating severe ANCA-associated vasculitis. The Summary of Clinical Safety summarised exposure to rituximab in the rituximab group of RAVE (n=99) after 18\xa0months' follow-up. In addition, the rituximab plus cyclophosphamide group in RITUXVAS (n=33) was followed for up to 24\xa0months, and 162\xa0patients in other investigator-initiated studies were followed for between 3 and 55\xa0months.\n\nThe manufacturer reported that overall safety at 6 and 18\xa0months was comparable between the rituximab and cyclophosphamide groups in RAVE, including the incidences and rates per patient-year of any adverse event, selected adverse events, adverse events that were grade\xa03 or higher, serious adverse events, and serious infections. The manufacturer stated that although the data are limited, safety in the other published studies was consistent with RAVE. Overall death rates and causes of death in RAVE and RITUXVAS were similar in the rituximab and cyclophosphamide groups. The most commonly reported type of serious adverse event in all studies was infection, with similar incidences between rituximab and cyclophosphamide groups in the controlled studies. The incidences and rates of serious adverse events were comparable between the rituximab and cyclophosphamide groups in RAVE at 6\xa0months (33.3% compared with 33.7%) and 18\xa0months (46.5% compared with 41.8%), and in RITUXVAS at 12\xa0months (42% compared with 36%). There was no statistically significant difference between treatment groups in RITUXVAS in incidence rates of severe adverse events (p=0.77).\n\n## Manufacturer's response to consultation\n\nIn response to consultation, the manufacturer clarified the definition of severe disease. In RAVE, severe ANCA-associated vasculitis was defined as disease activity that threatened the function of the affected organ and had the potential to cause permanent organ damage or to threaten the patient's life unless effective therapy was implemented quickly. Severe disease had previously been referred to as 'generalised', 'generalised organ-threatening' or 'organ-threatening' disease. The manufacturer stated that when RAVE began, the standard of care for inducing remission in people with severe disease was cyclophosphamide and glucocorticoids.\n\nThe manufacturer summarised the 18-month follow-up results from RAVE. The proportion of patients who achieved complete remission (BVAS/WG of 0 on a prednisone dose of 0\xa0mg) at 6\xa0months and who maintained complete remission at 12 and 18\xa0months was similar in the rituximab group and the cyclophosphamide group. The rates of severe and limited flares at 6, 12, and 18\xa0months did not differ significantly between the rituximab group and the cyclophosphamide group. Slightly more flares occurred after 6\xa0months in the rituximab group.\n\nThe manufacturer provided remission rates after re-treatment with rituximab. In RAVE, 16\xa0patients received a second course of rituximab, of whom 7\xa0(44%) entered complete remission.\n\nThe manufacturer provided information about the maximum cumulative dose of cyclophosphamide and its mode of administration in UK clinical practice. The manufacturer advised that the maximum cumulative dose of cyclophosphamide is 25\xa0g and that intravenous therapy is preferred to oral administration. These statements are consistent with the 2013 draft guidelines from the British Society for Rheumatology on the management of ANCA-associated vasculitis. The manufacturer indicated that 2\xa0courses of intravenous therapy would equate to approximately 23\xa0g of cyclophosphamide, based on a body weight of 78.89\xa0kg.\n\nThe manufacturer defined a subgroup of people for whom it is desirable to avoid cyclophosphamide:\n\nWomen who wish to preserve their fertility.\n\nPeople at a higher risk of severe infection, tuberculosis, or chronic infection such as bronchiectasis.\n\nPeople with uroepithelial malignancy or dysplasia.\n\nPeople with cytopenia or bone marrow insufficiency.\n\nPeople with cyclophosphamide allergy or intolerance.\n\nThe manufacturer provided evidence about the long-term safety of rituximab when used as a treatment for rheumatoid arthritis. A global clinical trial programme studied 3595\xa0patients for over 11\xa0years. The patients received up to 20\xa0courses of rituximab. The manufacturer reported there was no evidence of an increased safety risk, an increased risk of malignancy, or increased rates of adverse events after prolonged exposure to rituximab.\n\nThe manufacturer provided evidence that rituximab does not prevent women from conceiving children. A retrospective audit in the USA identified 157\xa0women who received rituximab for ANCA-associated vasculitis. The audit identified 7\xa0women who wanted to have children, of whom 6 became pregnant.\n\n## Evidence Review Group's comments on the manufacturer's original submission\n\nThe ERG noted that restricting the systematic review of clinical-effectiveness studies to the population and intervention in the marketing authorisation meant that it did not fulfil the scope or decision problem specified by NICE. The ERG did not identify any further randomised controlled trials directly comparing rituximab with the comparators in the NICE scope and decision problem in patients with ANCA-associated vasculitis. However, it did identify 5\xa0ongoing or published trials that could potentially have enabled an indirect comparison or mixed treatment comparison of rituximab with the comparators other than cyclophosphamide that were specified in the NICE scope and decision problem.\n\nThe ERG broadly agreed with the treatment pathway described by the manufacturer but noted some uncertainties:\n\nA high cumulative dose of cyclophosphamide indicates increased risk of adverse events. The ERG noted that giving the drug intravenously rather than orally may offer the opportunity to reduce the cumulative dose, or allow more courses to be given. A complete course of oral cyclophosphamide (2\xa0mg/kg/day for 6\xa0months) would be 31\xa0g for a patient weighing 85\xa0kg (the mean weight in RAVE). Conversely, a complete course of intravenous cyclophosphamide (15\xa0mg/kg\xa0×\xa010 over a 6-month period) for a patient weighing 85\xa0kg would be 12.75\xa0g. The ERG judged this method of reducing the cumulative dose of cyclophosphamide to have been inadequately explored by the manufacturer.\n\nThe ERG believed that the manufacturer's submission did not adequately consider alternative treatments to cyclophosphamide that may be used to induce remission.\n\nThe ERG observed that the European Vasculitis Study Group guidelines recommend maintenance treatment after remission, and received clinical specialist advice that not receiving any maintenance treatment after remission with rituximab was unrealistic. The ERG also noted that relapse is not inevitable with appropriate maintenance treatment.\n\nThe ERG stated that a 2\xa0×\xa01000\xa0mg dosage of rituximab is used more often in UK clinical practice to treat ANCA-associated vasculitis than the 4\xa0×\xa0375/mg2 dosage recommended in the marketing authorisation.\n\nIn the ERG's view, the evidence suggested that rituximab was superior to oral cyclophosphamide (p=0.01) in inducing remission in the subgroup of patients with relapsed severe ANCA-associated vasculitis (who had previously received at least 1\xa0dose of cyclophosphamide, methotrexate or azathioprine) and non-inferior to oral cyclophosphamide in patients with newly diagnosed disease. The ERG also highlighted that longer-term efficacy and safety end points of rituximab in treating ANCA-associated vasculitis are unknown, and that there are some potential questions concerning effects on fertility and certain adverse events, especially rates of mortality and malignancies.\n\n## Evidence Review Group's comments on the manufacturer's response to consultation\n\nThe ERG acknowledged that the manufacturer's definition of severe disease was helpful. However, the ERG noted that the clinical evidence submitted by the manufacturer is not relevant for allpeople with severe ANCA-associated vasculitis. RAVE excluded patients who needed mechanical ventilation because of alveolar haemorrhage or had a serum creatinine level greater than 4.0\xa0mg/100\xa0ml attributed to ANCA-associated vasculitis. RITUXVAS did include patients with more severe disease, but the treatment was rituximab plus cyclophosphamide.\n\nThe ERG reviewed the 18-month follow-up results from RAVE. The ERG advised that, for patients with relapsed disease at baseline, rituximab was superior to cyclophosphamide followed by azathioprine at 6- and 12-month follow-up, but at 18\xa0months the difference in remission rates was not statistically significant.\n\nThe ERG noted that the estimate of remission rates after re‑treatment with rituximab provided by the manufacturer was based on small numbers of patients and was at risk of selection bias.\n\nThe ERG acknowledged the value of the 18-month safety data from RAVE, which was submitted by the manufacturer in response to consultation, but noted that these data did not indicate an advantage of rituximab compared with cyclophosphamide. The ERG accepted the relevance of long-term data in rheumatoid arthritis, which suggest that rituximab is well tolerated. The ERG also acknowledged data which indicate that rituximab allows people with ANCA-associated vasculitis to maintain fertility. The ERG advised that the duration of the RAVE study was limited and longer follow-up may be needed to evaluate the safety of rituximab plus glucocorticoids.\n\n# Cost effectiveness\n\n## Manufacturer's original submission\n\nThe manufacturer's systematic review did not identify any studies that reported on the cost effectiveness of treatment for ANCA-associated vasculitis. The manufacturer therefore submitted a de novo model, which it subsequently revised in its clarification response, evaluating the cost effectiveness of rituximab compared with cyclophosphamide in people with ANCA-associated vasculitis. In line with its marketing authorisation, the manufacturer restricted its analysis to inducing remission only and did not look at treating flares or maintenance therapy. The original base case included the population from RAVE, and subgroup analyses investigated people with newly diagnosed disease and with relapsed disease. A separate subgroup analysis estimated the cost effectiveness of rituximab in people for whom cyclophosphamide was not considered to be the standard of care (because this group was not represented in RAVE). The analysis was conducted from an NHS and personal and social services perspective. A lifetime time horizon was used and a 3.5% discount rate was adopted for health benefits and costs.\n\nThe manufacturer developed a Markov model with a similar design to that used in another NICE technology appraisal (Tocilizumab for the treatment of rheumatoid arthritis [NICE technology appraisal guidance 247]). It consisted of 4\xa0different health states: non-remission, complete remission, uncontrolled disease and death. 'Complete remission' reflected treatment success as assessed in RAVE, 'non-remission' reflected non-attainment of remission and 'uncontrolled disease' reflected a state of worse health that patients enter after the simulated treatment options have been exhausted.\n\nPatients entered the model in the non-remission health state, received induction therapy and either moved to the complete remission health state (if they went into remission) or remained in the non-remission health state (if they did not go into remission). During each 6-month cycle, moving from 1\xa0treatment to the next in each arm's sequence was triggered either by failing to attain complete remission or by the patient eventually relapsing. After receiving all possible treatment options, patients entered the uncontrolled disease health state. The original base-case analysis was designed to compare 2\xa0sequences of treatments:\n\nIn the 'standard of care' sequence, patients received cyclophosphamide as induction therapy. Patients who went into remission with cyclophosphamide switched to azathioprine during remission. Patients who did not go into remission, or who relapsed, received another course of cyclophosphamide. Clinical specialist advice to the manufacturer was that a maximum of 2\xa0courses of cyclophosphamide would be used in standard clinical practice. The manufacturer assumed that 72% of patients received cyclophosphamide intravenously, with the remainder receiving it orally.\n\nIn the 'intervention' sequence, patients received rituximab as a first-line induction treatment. Patients who went into remission did not receive any further treatment until relapse. Patients who did not go into complete remission received a further course of rituximab (this is based on expert opinion, because RAVE did not investigate the effects of re‑treatment). Patients whose disease responded to rituximab could not have re‑treatment on relapse because this is outside the scope of the marketing authorisation. After relapse following 1 or 2\xa0cycles of rituximab, patients received 1\xa0course of cyclophosphamide (it was assumed that 72% of patients received cyclophosphamide intravenously, with the remainder receiving it orally).If patients received all available induction treatments in the treatment sequence and relapsed, they entered the 'uncontrolled disease' health state and received best supportive care.\n\nThe transition probabilities in the manufacturer's original base-case model were based on the primary endpoints from RAVE. A constant rate of relapse was applied in the model and it was assumed that the second course of treatment was associated with a lower probability of achieving remission than the first course. The manufacturer estimated the probability of achieving remission with the second course of treatment using RAVE results from the subgroup of patients with relapsed disease. The same probability of remission was used for re‑treatment with rituximab and with cyclophosphamide. Transition probabilities for adverse events were also based on RAVE data. Disease-specific mortality risks in the manufacturer's economic model were derived from a retrospective cohort study of UK patients with ANCA-associated vasculitis.\n\nThe costs used in the manufacturer's original economic model comprised treatment-associated costs plus health-state costs. Cost data (excluding drug costs) were largely derived from National reference costs. Drug costs were derived from the British national formulary (BNF) edition 64. Average drug costs per cycle were £4689.78 for rituximab, £99.15 for oral cyclophosphamide, £110.84 for intravenous cyclophosphamide, £44.17 for azathioprine, £28.01 for methylprednisone, £1497.96 for prednisone and £21.38 for trimethoprim. Treatment administration costs per cycle were £721.16 for rituximab and £1802.89 for intravenous cyclophosphamide, and it was assumed that these included monitoring costs. Monitoring costs for oral cyclophosphamide and azathioprine were £108. The per-cycle cost of best supportive care for patients with uncontrolled disease was £4415.73. Health-state costs were £778.10 for the remission health state and £6309.01 for the non-remission and uncontrolled disease health states.\n\nThe manufacturer's systematic review did not identify any relevant studies that reported usable utility values. Health-related quality of life data were collected in RAVE using the SF‑36 questionnaire, which was administered at baseline and at 6\xa0months. The SF‑36 scores were converted from the non-remission and remission health states to the EQ‑5D in a post-hoc analysis using a published model (Ara and Brazier 2008) and adjusted for age. Disutility adjustments were applied for adverse events.\n\nThe manufacturer's original base-case results, provided after the request for clarification, showed that treating ANCA-associated vasculitis with rituximab increased the cost of treatment but was associated with more quality-adjusted life years (QALYs) than cyclophosphamide. The manufacturer's incremental cost-effectiveness ratio (ICER) for the comparison of rituximab with cyclophosphamide in patients with ANCA-associated vasculitis was £8544 per QALY gained (incremental costs £1391; incremental QALYs 0.1628). In its response to clarification, the manufacturer provided the results of scenario analyses, one-way deterministic sensitivity analyses, and probabilistic sensitivity analyses. These original analyses have been superseded by the manufacturer's response to consultation (see sections 3.54 to 3.62).\n\n## Evidence Review Group's comments on the manufacturer's original submission\n\nThe ERG found that the manufacturer's economic model generally followed NICE's reference case, but noted that not all comparators had been included, and that it may have been more appropriate to consider intravenous cyclophosphamide as the primary comparator because of its lower adverse-event risk, and because its lower cumulative dose could potentially allow additional courses of treatment. The ERG described some uncertainties in the population in the manufacturer's base case. It considered the manufacturer's decision to focus on severe granulomatosis with polyangiitis and microscopic polyangiitis to be appropriate given that this is the population specified in the marketing authorisation and given the populations in RAVE and RITUXVAS. However, the ERG was aware that there is no clear definition of severe disease, and that the definition of severity used in RAVE was closer to that classified as generalised disease in treatment guidelines. The ERG also noted that RAVE excluded patients with severe renal disease and other life-threatening forms of the disease, so the clinical evidence submitted by the manufacturer did not cover the full population with severe disease. The ERG was also concerned that the manufacturer had used values for weight and body surface area that would be likely to underestimate those of the UK population with ANCA-associated vasculitis.\n\nThe ERG noted that treatment sequences depend on the patient population under consideration (for example, previous treatment with cyclophosphamide will limit its further use). Consequently, different sequences are available for newly diagnosed patients, patients with relapsed disease, and patients who cannot receive or cannot tolerate cyclophosphamide. The ERG expressed concerns about the treatment sequences used in the manufacturer's economic model:\n\nThe ERG questioned the assumption in the manufacturer's model that all patients in the standard care group would receive 2\xa0courses of cyclophosphamide, given that 28% of cyclophosphamide treatment was given orally, which would result in a high cumulative dose.\n\nThe ERG had concerns about the assumption that after receiving 2\xa0courses of cyclophosphamide, patients would receive only best supportive care.\n\nThe ERG was unsure why rituximab was only considered as the firstinduction treatment in the manufacturer's economic model. It believed it was relevant to consider the relative cost effectiveness of rituximab used before and after cyclophosphamide in the treatment pathway. It noted that the NHS Commissioning Board recommended rituximab as first-line treatment in newly diagnosed patients only when avoiding cyclophosphamide is desirable.\n\nClinical specialist advice received by the ERG suggested that it would be unlikely that patients who did not respond to an initial course of rituximab would receive a second course (because of a lack of evidence) and they would instead receive an alternative treatment. Based on clinical specialist advice, the ERG believed that the results presented by the manufacturer should be approached with considerable caution because other more appropriate treatment sequences exist, and these have not been modelled by the manufacturer.\n\nClinical specialist advice to the ERG suggested that it was very unlikely that patients who go into remission after treatment with rituximab would not receive subsequent maintenance therapy. The ERG noted that it would seem appropriate to assume that patients who go into remission after rituximab would then receive maintenance therapy with azathioprine or methotrexate. However, in its economic model the manufacturer did not include maintenance treatment for patients who go into remission after receiving rituximab.\n\nThe ERG had concerns about how the relapse rates used in the manufacturer's model had been derived from RAVE, and believed they had been poorly estimated. It noted that exponential model distributions were fitted to data from patients who went into complete remission at 6\xa0months in order to estimate the time-to-event for relapse, and was aware that the manufacturer had used summary statistics rather than individual patient-level data. It noted that the Kaplan–Meier time to relapse curves for the rituximab and cyclophosphamide groups crossed, indicating that the proportional hazards assumption did not hold and that applying a constant relapse rate to each treatment group was unlikely to be appropriate. It further noted that the relapse rate for the cyclophosphamide group had potentially been overestimated. The ERG concluded that it appeared highly likely that an alternative parametric model (for example, Weibull, Gompertz, log normal or log-logistic) would have provided a better fit to the relapse data, but that these would not be suitable for use with the standard Markov model structure, so the standard Markov model may not have been an appropriate choice. The ERG was unable to assess the relative fit of the exponential models for the subgroup relapse data, and noted the manufacturer's statement that these were less precise than the all-patient data.\n\nThe ERG was aware that the manufacturer had not modelled different severities of relapse, despite the availability of data from RAVE for minor and severe flares. The ERG's clinical specialists advised that treatment options and the subsequent disease pathway depend critically upon severity of relapse. The ERG noted that the manufacturer had assumed that all relapses lead to immediate re‑treatment with cyclophosphamide or rituximab because it believed almost all minor relapses would lead to severe relapses needing re‑treatment. However, the ERG received clinical specialist advice that minor relapses may be controlled in other ways (for example, an increase in glucocorticoid dose) and that not all patients would progress to a severe relapse. The ERG anticipated that modelling severe relapse rates for the subgroups of patients with newly diagnosed or relapsed disease would be likely to be highly uncertain because of very low event numbers, and suggested it may be preferable to assume similar relapse rates in these 2\xa0subgroups.\n\nThe ERG believed it would be more appropriate to have included a health state for non-complete remission (that is, when glucocorticoids and other less immunosuppressive treatments are still used). It considered that the failure to model different levels of treatment response and unrealistically high relapse rates may have led to patients in both treatment sequences entering the uncontrolled disease state too quickly. The ERG noted that patients in the standard of care sequence spent 70.7% of their discounted mean life expectancy in this health state, compared with 63.2% of patients in the intervention sequence. However, clinical specialist advice to the ERG suggested that it is very rare for patients with severe ANCA-associated vasculitis to be in this health state because a treatment strategy can usually be identified that offers some disease control. The ERG stated that ideally the manufacturer's model would have included additional lines of treatment, such as mycophenolate mofetil, leflunomide, azathioprine and methotrexate, in line with clinical specialist advice received by the ERG. The ERG believed that patients in the uncontrolled disease health state would have some disease control, so the health state would have a higher utility score than that assumed by the manufacturer. The ERG indicated that costs for this health state would be lower than those assumed by the manufacturer because it was unlikely patients would have outpatient appointments to receive specialist palliative care every 1.5\xa0weeks.\n\nThe ERG described several concerns about the costs used in the manufacturer's economic model. It stated that health-state costs were the largest proportion of total costs generated by the manufacturer's economic model (93% for the cyclophosphamide group and 89% for the rituximab group in the manufacturer's base-case analysis) and noted the impact of these on the cost-effectiveness results. The ERG noted that certain costs (including some tests and the total number of outpatient appointments) were not realistic and believed that these costs were substantially overestimated by the manufacturer, creating a significant bias in favour of rituximab. The ERG also considered that the manufacturer's approach to estimating the drug costs may be biased in favour of the rituximab group (by overestimating the amount of oral cyclophosphamide used in a typical treatment course), and noted that wastage costs from part-used vials had not been included in the manufacturer's base-case analysis.\n\n## Evidence Review Group's exploratory analyses using the manufacturer's original model\n\nThe ERG corrected several apparent technical errors in the manufacturer's economic model, which included using costs of prednisolone instead of prednisone in line with UK clinical practice. Other cost changes were for cyclophosphamide, trimethoprim and blood tests. The ERG also adjusted the utility value for pneumonia, adjusted the numbers at risk of relapse, used normal distributions for cost parameters, included distributions for standardised mortality rates and outpatient appointments in the probabilistic sensitivity analyses, and adjusted the mortality risk for patients aged 91\xa0years and older in the uncontrolled disease health state. Cumulatively, these changes decreased the ICER for the comparison of rituximab with cyclophosphamide for all patients with ANCA-associated vasculitis. The ERG's corrected ICER was £6006 per QALY gained (incremental costs £986; incremental QALYs 0.1642) compared with the manufacturer's base-case ICER of £8544 per QALY gained (incremental costs £1391; incremental QALYs 0.1628). Replacing the cost of prednisone with the cost of prednisolone had the greatest impact.\n\nIn further exploratory analyses, the ERG altered several parameter values in the manufacturer's economic model:\n\nBody surface area and weight were increased to better reflect patients in RAVE.\n\nIt was assumed that patients who went into remission after receiving rituximab would receive azathioprine maintenance treatment at the same dosage as patients who went into remission after receiving cyclophosphamide.\n\nRelapse rates were re‑estimated based on data from patients who had severe flares after receiving cyclophosphamide in RAVE, to reflect the assumption that only severe flares would lead to renewed induction treatment. Given the assumption that patients receiving rituximab induction treatment also received azathioprine maintenance, the same relapse rate was applied to patients in the rituximab group and patients in the cyclophosphamide group.\n\nCosts and utility values in the uncontrolled disease state were amended to reflect that patients in this state are likely to have some disease control.\n\nThe number and costs of routine tests were amended to reflect recommendations in published guidelines.\n\nMethylprednisolone administration costs were increased.\n\nThe costs of X-rays and CT scans were taken from NHS reference costs.\n\nWastage costs were included.\n\nThe number of outpatient appointments was reduced.When these changes in the manufacturer's economic model were added to those described in section\xa03.45, the ERG's cumulative ICER increased to £26,347 per QALY gained (incremental costs £5704; incremental QALYs 0.2165) for the comparison of rituximab with cyclophosphamide for the full population of patients with ANCA-associated vasculitis. The ERG noted that reducing the number of outpatient appointments (especially in the uncontrolled disease health state) substantially decreased the benefits associated with the rituximab treatment sequence.\n\nThe ERG modelled several treatment sequences that it considered to be more appropriate than those in the manufacturer's submission for the different populations (described in sections\xa03.48–3.52):\n\nthe full population in the manufacturer's economic model\n\npatients with newly diagnosed ANCA-associated vasculitis\n\npatients with relapsed ANCA-associated vasculitis who could have further treatment with cyclophosphamide\n\npatients with relapsed ANCA-associated vasculitis who could not have further cyclophosphamide treatment\n\npatients who are unable to tolerate cyclophosphamide.\n\nThe ERG investigated how different treatment sequences could impact on the cost-effectiveness estimates for the full patient population with ANCA-associated vasculitis in the manufacturer's economic model:\n\nAdding rituximab to the treatment sequence after 2\xa0courses of cyclophosphamide gave an ICER of £12,075 per QALY gained (incremental costs £3894; incremental QALYs 0.32).\n\nUsing rituximab after 1\xa0course of cyclophosphamide increased the ICER to £69,710 per QALY gained (incremental costs £355; incremental QALYs 0.0051) compared with using it after 2\xa0courses.\n\nUsing rituximab as first-line treatment further increased the ICER to £127,456 per QALY gained (incremental costs £579; incremental QALYs 0.0045) compared with using rituximab as second-line treatment.\n\nAt £30,000 per QALY gained, the probability of rituximab being cost effective after 2\xa0courses of cyclophosphamide was 58.3%. The probability that excluding rituximab from the treatment sequence was cost effective was 11.7%.\n\nThe ERG did exploratory analyses for the population with newly diagnosed ANCA-associated vasculitis:\n\nAdding rituximab to the treatment sequence after 2\xa0courses of cyclophosphamide gave an ICER of £12,851 per QALY gained (incremental costs £3783; incremental QALYs 0.29).\n\nUsing rituximab after 1\xa0course of cyclophosphamide increased the ICER to £81,604 per QALY gained (incremental costs £364; incremental QALYs 0.0045) compared with using rituximab after 2\xa0courses of cyclophosphamide.\n\nThe ICER for using rituximab as a first-line treatment further increased the ICER to £317,038 per QALY gained (incremental costs £843; incremental QALYs 0.0027) compared with using rituximab as second-line treatment.At £30,000 per QALY gained, the probability that using rituximab after 2\xa0courses of cyclophosphamide was cost effective in patients with newly diagnosed disease was 59.7%. The probability that excluding rituximab from the treatment sequence was cost effective was 13.9%.\n\nThe ERG did exploratory analyses on the population of patients with relapsed ANCA-associated vasculitis who could have further treatment with cyclophosphamide:\n\nAdding rituximab to the treatment sequence after 1\xa0course of cyclophosphamide gave an ICER of £11,129 per QALY gained (incremental costs £4702; incremental QALYs 0.4225).\n\nThe ICER for rituximab as first-line treatment was £51,842 per QALY gained (incremental costs £325; incremental QALYs 0.0063) compared with rituximab as second-line treatment.The probability of rituximab being cost effective after 1\xa0course of cyclophosphamide was 51.3% at £30,000 per QALY gained. The probability that excluding rituximab from the treatment sequence was cost effective was 10.4%.\n\nThe ERG did exploratory analyses on the population of patients with relapsed ANCA-associated vasculitis who could not have further cyclophosphamide treatment. Using rituximab instead of best supportive care gave an ICER of £10,699 per QALY gained (incremental costs £5385; incremental QALYs 0.5033). The ERG assumed that patients who could not tolerate further cyclophosphamide treatment and were receiving best supportive care moved directly to a low-grade disease health state (with partial disease control), and explained that this assumption limited the analysis because active comparators were excluded. At £30,000 per QALY gained, the probability of rituximab being cost effective was 90.4%. The probability that excluding rituximab from the treatment sequence was cost effective was 9.6%.\n\nThe ERG did an exploratory subgroup analysis on patients who were unable to tolerate cyclophosphamide. This subgroup did not necessarily have relapsed disease, but could not take cyclophosphamide for a reason other than exceeding the maximum recommended lifetime cumulative dose. Model parameter inputs were based on the full patient population in RAVE. Using rituximab instead of best supportive care gave an ICER of £11,277 per QALY gained (incremental costs £5437; incremental QALYs 0.48). The ERG assumed that patients who could not tolerate further cyclophosphamide treatment and were receiving best supportive care moved directly to a low-grade disease health state (with partial disease control), and explained that this assumption limited the analysis because active comparators were excluded. At £30,000 per QALY gained, the probability of rituximab being cost effective in patients who cannot tolerate cyclophosphamide was 90.5%. The probability that excluding rituximab from the treatment sequence was cost effective was 9.5%.\n\nAfter receiving feedback from clinical specialists on its exploratory analyses, the ERG did other scenario analyses on the data from the full patient population to further explore uncertainty associated with some parameters used in the economic model. The parameters tested were: reduced administration costs for methylprednisone and cyclophosphamide (because of shorter infusion time); substituting co-trimoxazole for trimethoprim; fewer cyclophosphamide infusions (6 instead of 10); and increased weight and body surface (to reflect the UK population with ANCA-associated vasculitis). These amendments had little cumulative impact on the ICER associated with adding rituximab to the treatment sequence after 2\xa0courses of cyclophosphamide treatment compared with best supportive care after 2\xa0courses of cyclophosphamide treatment, which increased slightly from £12,075 per QALY gained (ERG's base-case ICER) to £12,670 per QALY gained. However, the cumulative ICERs for using rituximab earlier in the treatment sequence increased more markedly because of reduced costs for intravenous cyclophosphamide and increased costs for rituximab (owing to higher body surface area). The ICER for using rituximab after 1\xa0course of cyclophosphamide was £117,545 per QALY gained compared with after 2\xa0courses of cyclophosphamide, and the ICER for using rituximab as first-line treatment was £191,013 per QALY gained compared with using it as second-line treatment. The ERG anticipated that these findings using the full patient population would be mirrored in the subgroups of patients who were newly diagnosed or had relapsed disease.\n\n## Manufacturer's response to consultation\n\nIn response to consultation, the manufacturer provided 2\xa0updated economic models; one for patients who can have cyclophosphamide and one for patients who cannot have cyclophosphamide. Both models incorporated the following changes:\n\nThe minor technical changes proposed in section 3.45.\n\nThe mean body surface area of patients was increased to 1.90\xa0m2 and the mean weight of patients was increased to 78.89\xa0kg, based on data from 30\xa0patients with vasculitis treated at Manchester Royal Infirmary.\n\nThe model assumed that only severe relapses would be treated with induction therapy.\n\nThe utility value in the uncontrolled disease health state was increased from 0.671 to 0.710.\n\nThe cost of administering methylprednisolone was included. The cost was assumed to be equivalent to the cost of delivering rituximab and cyclophosphamide.\n\nThe cost of an X-ray was updated to £18.56 and the cost of a CT scan was increased to £100.00. It was assumed that 80% of scans received in the modelled population would be X-rays and 20% would be CT scans.\n\nThe model included wastage costs associated with drug delivery.\n\nThere were 4\xa0outpatient visits every 6\xa0months in the uncontrolled disease health state.\n\nThe model included only intravenous administration of cyclophosphamide (whereas the original model assumed 28% of patients would receive oral cyclophosphamide).\n\nIn the uncontrolled disease health state, patients were assumed to receive the recommended dosage of mycophenolate mofetil, methotrexate, or azathioprine. The average cost of the 3\xa0therapies was used in the model. The model assumed no difference in efficacy between treatment arms once patients entered the uncontrolled disease heath state.\n\nThe models did not include any maintenance therapy after induction treatment with rituximab.\n\nIn the manufacturer's updated model for patients who can have cyclophosphamide, the base-case analysis was designed to compare 2\xa0sequences of treatments:\n\nIn the 'standard of care' sequence, patients received intravenous cyclophosphamide as induction therapy. Patients who went into remission with cyclophosphamide received azathioprine as maintenance therapy during remission. Patients who did not go into remission, or who relapsed, received a second course of intravenous cyclophosphamide.\n\nIn the 'intervention' sequence, patients received 1\xa0course of intravenous cyclophosphamide as induction therapy. Patients who went into remission with cyclophosphamide received azathioprine as maintenance therapy during remission. Patients who did not go into remission, or who relapsed, received 2\xa0courses of rituximab. Patients who went into remission with rituximab did not receive any maintenance therapy.\n\nIn the manufacturer's updated model, the base-case transition probabilities were based on data from RAVE. In both the 'standard of care' sequence and the 'intervention' sequence, the probability of achieving remission with the first course of cyclophosphamide was estimated using data from the subgroup of patients in RAVE who had newly-diagnosed disease and were treated with cyclophosphamide.\n\nIn the 'standard of care' sequence, the probability of achieving remission with the second course of cyclophosphamide was estimated using data from the subgroup of patients in RAVE who had relapsed disease and were treated with cyclophosphamide.\n\nIn the 'intervention' sequence, the probability of achieving remission with rituximab following a course of cyclophosphamide was estimated using data from the subgroup of patients in RAVE who had relapsed disease and were treated with rituximab. The probability of achieving remission with the subsequent course of rituximab was estimated using data from the subgroup of patients in RAVE who were re-treated with rituximab.\n\nIn the manufacturer's updated base-case model, the estimate of relapse rates was based on data from patients who had severe flares after receiving cyclophosphamide in RAVE. The same relapse rate was applied to patients in the rituximab group and patients in the cyclophosphamide group. The relapse rate was assumed to be identical after subsequent lines of therapy.\n\nThe manufacturer's updated model for people with ANCA-associated vasculitis who can have cyclophosphamide produced an ICER for the comparison of rituximab with cyclophosphamide of £18,556 per QALY gained (incremental costs £6117; incremental QALYs 0.330).\n\nThe model for people with ANCA-associated vasculitis who cannot have cyclophosphamide was the same as the updated base-case model for patients who can have cyclophosphamide, except that it compared the following 2\xa0sequences of treatments:\n\nIn the 'standard of care' sequence, patients received a 6-month course of either mycophenolate mofetil or methotrexate. These treatments were assumed to have the same complete remission rates as cyclophosphamide. Patients who went into remission with mycophenolate mofetil or methotrexate received azathioprine as maintenance therapy during remission. The probability of relapse was assumed to be higher than that with cyclophosphamide or rituximab and was set at 0.103.\n\nIn the 'intervention' sequence, patients received 2\xa0courses of rituximab. Patients who went into remission with rituximab did not receive any maintenance therapy. The probability of relapse was 0.086, based on data from RAVE.\n\nThe manufacturer's updated model for people with ANCA-associated vasculitis who cannot have cyclophosphamide produced an ICER for the comparison of rituximab with mycophenolate mofetil or methotrexate of £35,003 per QALY gained (incremental costs £10,186; incremental QALYs 0.291).\n\nThe manufacturer conducted one-way sensitivity analyses to explore the effect of assumptions about key parameters on the results of the base-case model. The following changes, when implemented independently, gave ICERs that were higher than the base case: a higher relapse rate in the rituximab arm, treating both minor and severe relapses with induction therapy, reducing the number of outpatient appointments in the uncontrolled disease health state, and assuming that no patients received a second course of rituximab. When it was assumed that there was less wastage of rituximab, the ICERs were lower than the base case.\n\nThe Committee had requested analyses that incorporated the costs and disutility of the cumulative long-term toxicity of cyclophosphamide. The Committee had also requested analyses that incorporated the inpatient costs associated with non-remission, and separate analyses of the benefit of rituximab for patients who wished to have children. The manufacturer stated that they did not provide these analyses because of time constraints and a lack of data.\n\n## Evidence Review Group's comments on the manufacturer's response to consultation\n\nThe ERG advised that the manufacturer's model submitted in response to consultation was incorrect because of several apparent errors:\n\nThe cost of treatment in the uncontrolled disease health state was incorrectly multiplied by 4.\n\nThere were coding errors in the sensitivity analyses that examined re-treatment with rituximab.\n\nThe unit costs for mycophenolate mofetil and methotrexate were incorrect.\n\nThe ERG consulted clinical specialists to assess the plausibility of the treatment sequences in the manufacturer's model for patients who can have cyclophosphamide. The model assumed that only 1\xa0course of cyclophosphamide would be provided in the rituximab arm. The ERG advised that some patients may receive a second course of cyclophosphamide even if rituximab was available. The ERG observed that, in the manufacturer's model, all patients in the rituximab arm received 2\xa0courses of rituximab regardless of the effect of the first course of rituximab. The ERG advised that, at the first Committee meeting, the Committee agreed this assumption was not plausible. The ERG noted that the manufacturer had not modelled all possible treatment sequences as requested by the Committee.\n\nThe ERG acknowledged there is a lack of consensus about the use of maintenance therapy after remission induced by rituximab. The 2013 draft guidelines from the British Society for Rheumatology include 4\xa0options for maintenance therapy. These are, to wait for relapse and then re-treat, to use an immunosuppressive agent (azathioprine or methotrexate), or to use rituximab as maintenance therapy (2\xa0rituximab regimes are described). Only 1\xa0of the options (wait for relapse and then re-treat) was modelled by the manufacturer.\n\nIn the manufacturer's model for patients who cannot have cyclophosphamide, the 'standard of care' arm included only 1\xa0course of mycophenolate mofetil or methotrexate. The ERG stated this may not be realistic. The ERG received clinical advice that cumulative glucocorticoid use is likely to be higher with mycophenolate mofetil or methotrexate than with rituximab, yet this was not reflected in the manufacturer's model.\n\nIn the uncontrolled disease health state, the ERG considered 3\xa0outpatient appointments every 6\xa0months to be a reasonable assumption. The manufacturer's model assumed 4\xa0appointments every 6\xa0months.\n\nThe ERG noted that in RAVE the rate of severe relapse was lower at 18\xa0months than at 6 or 12\xa0months in the cyclophosphamide group, but was increasing in the rituximab group. The ERG advised that it would be relevant to consider scenarios in which the relapse rate was higher in the rituximab group in the long term. The manufacturer's model did not allow relapse rates to alter over time.\n\nIn response to consultation, the manufacturer stated that there were additional QALY gains associated with rituximab because of the preservation of fertility, but these gains were not included in the economic model. The ERG advised that, in the model that included the subgroup of patients who wished to maintain fertility, the comparators were mycophenolate mofetil and methotrexate. The ERG understood that mycophenolate mofetil and methotrexate do not impair long-term fertility. Thus, in the view of the ERG, the manufacturer's argument about QALY gains was not relevant because no fertility advantage had been demonstrated for rituximab compared with mycophenolate mofetil and methotrexate.\n\nThe ERG noted that 2\xa0additional changes, which were included as scenario analyses in the ERG's original report, had not been implemented by the manufacturer. First, cyclophosphamide can be infused more quickly than rituximab and therefore may have a lower administration cost. Second, some patients receive fewer than 10\xa0infusions of intravenous cyclophosphamide. The ERG advised that the ICER associated with rituximab would increase if these 2\xa0amendments were made to the manufacturer's economic model.\n\n## Evidence Review Group's exploratory analyses after consultation\n\nThe ERG made the following changes to the manufacturer's model:\n\nThe apparent errors listed in section 3.63 were amended.\n\nThe ERG incorporated uncertainty around the remission rate after re-treatment with rituximab.\n\nOnly patients who entered remission with rituximab were given a second course of rituximab.\n\nThe ERG ran probabilistic sensitivity analyses. The ERG also ran the following scenario analyses for the subgroups who can and cannot have cyclophosphamide:\n\nThe rituximab arm included maintenance therapy with azathioprine.\n\nThere was no re-treatment with rituximab.\n\nThe ERG's exploratory analyses examined the cost effectiveness of rituximab for patients who can have cyclophosphamide.\n\nAssuming only patients who entered remission with rituximab would be given a second course of rituximab and no maintenance treatment after rituximab, the ICER for the comparison of rituximab with cyclophosphamide was £20,879 per QALY gained (incremental costs £5075; incremental QALYs 0.24). The probability of rituximab being cost effective compared with cyclophosphamide was 40.7% at £20,000 per QALY gained and 56.7% at £30,000 per QALY gained.\n\nAssuming only patients who entered remission with rituximab would be given a second course of rituximab and azathioprine as maintenance treatment after rituximab, the ICER for the comparison of rituximab with cyclophosphamide was £23,444 per QALY gained (incremental costs £5698; incremental QALYs 0.24). The probability of rituximab being cost effective compared with cyclophosphamide was 34.8% at £20,000 per QALY gained and 52.8% at £30,000 per QALY gained.\n\nAssuming no re-treatment with rituximab and no maintenance treatment after rituximab, the ICER for the comparison of rituximab with cyclophosphamide was £20,080 per QALY gained (incremental costs £2790; incremental QALYs 0.14). The probability of rituximab being cost effective compared with cyclophosphamide was 42.0% at £20,000 per QALY gained and 53.7% at £30,000 per QALY gained.\n\nThe ERG's exploratory analyses also examined the cost effectiveness of rituximab for patients who cannot have cyclophosphamide.\n\nAssuming that only patients who entered remission with rituximab would be given a second course of rituximab and no maintenance treatment after rituximab, the ICER for the comparison of rituximab with mycophenolate mofetil or methotrexate was £60,569 per QALY gained (incremental costs £8345; incremental QALYs 0.14). The probability of rituximab being cost effective compared with mycophenolate mofetil or methotrexate was 13.8% at £20,000 per QALY gained and 25.3% at £30,000 per QALY gained.\n\nAssuming only patients who entered remission with rituximab would be given a second course of rituximab and azathioprine as maintenance treatment after rituximab, the ICER for the comparison of rituximab with mycophenolate mofetil or methotrexate was £65,700 per QALY gained (incremental costs £9052; incremental QALYs 0.14). The probability of rituximab being cost effective compared with mycophenolate mofetil or methotrexate was 10.9% at £20,000 per QALY gained and 22.4% at £30,000 per QALY gained.\n\nAssuming no re-treatment with rituximab and no maintenance treatment after rituximab, the ICER for the comparison of rituximab with mycophenolate mofetil or methotrexate was £118,154 per QALY gained (incremental costs £5463; incremental QALYs 0.05). The probability of rituximab being cost effective compared with mycophenolate mofetil or methotrexate was 14.7% at £20,000 per QALY gained and 23.1% at £30,000 per QALY gained.\n\n## Manufacturer's response to second consultation\n\nIn response to the second consultation, the manufacturer provided a weighted-average threshold analysis. The aim was to calculate an ICER for rituximab for treating the entire population of people with severely active granulomatosis with polyangiitis and microscopic polyangiitis (including both people who can and people who cannot have cyclophosphamide). For the subgroup of people who can have cyclophosphamide, the manufacturer used an ICER of £12,100 per QALY gained (see section\xa03.48). Based on the opinion of clinical specialists, the manufacturer assumed that 10% of patients cannot have cyclophosphamide. For the subgroup of people who cannot have cyclophosphamide, the manufacturer used a range of ICERs from £80,000 to £200,000 per QALY gained. The weighted-average ICERs for the entire population of people with severely active granulomatosis with polyangiitis and microscopic polyangiitis ranged from £18,890 to £30,890 per QALY gained.\n\n## ERG's response to second consultation\n\nIn response to the second consultation, the ERG provided illustrative analyses based on the manufacturer's updated model for people who cannot have cyclophosphamide; this model compared 2\xa0courses of rituximab with 1\xa0course of mycophenolate mofetil or methotrexate (see section\xa03.74). The following changes were made to the 'standard of care' sequence in the model:\n\nThe utility in the remission health state was decreased from 0.84 to 0.79.\n\nThe cost of glucocorticoids in the remission health state was increased from £293 to £439 per 6-month treatment cycle.\n\nThe remission rate was decreased from 0.65 to 0.52.\n\nMycophenolate mofetil was the only active treatment in the 'standard of care' sequence. The changes resulted in an ICER for rituximab compared with mycophenolate mofetil of £26,406 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's original submission, the manufacturer's responses to consultation, the ERG's original report, the ERG's critique of the manufacturer's response to consultation, and the ERG's response to the second consultation.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab, having considered evidence on the nature of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and the value placed on the benefits of rituximab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the current clinical pathway of care for people with ANCA-associated vasculitis. It heard from the clinical specialists that induction treatment with cyclophosphamide is the standard of care for people with severe ANCA-associated vasculitis, and that this includes people with granulomatosis with polyangiitis and microscopic polyangiitis. The Committee recognised that induction treatment lasts for up to 6\xa0months, and that cyclophosphamide is administered either orally or intravenously with glucocorticoids. The Committee was advised by the clinical specialists that alternatives to cyclophosphamide (such as mycophenolate mofetil, methotrexate and deoxyspergualin) were associated with higher relapse rates and would not normally be used to treat severe disease (unless cyclophosphamide was unsuitable). The Committee heard from the clinical specialists that, after going into remission with cyclophosphamide, the glucocorticoid dose is tapered and patients switch to maintenance treatment (such as azathioprine) for up to 2\xa0years to reduce the likelihood of relapse. The Committee learned from clinical specialists that minor relapses would likely be managed with an increased dose of glucocorticoid first. The Committee concluded that cyclophosphamide is the standard of care for people with ANCA-associated vasculitis who can have cyclophosphamide.\n\nThe Committee reviewed the safety of treatments currently used in UK clinical practice to induce remission in severe ANCA-associated vasculitis. It recognised that the risk of long-term toxicity (for example, uroepithelial malignancies) increases with the cumulative dose of cyclophosphamide, and understood from the clinical specialists that the cumulative dose should not exceed 25\xa0g and that they aim to keep it below this level if possible. Draft guidelines from the British Society for Rheumatology also state that the cumulative dose of cyclophosphamide should not exceed 25\xa0g. The Committee was advised by the clinical specialists that people would receive 6–10\xa0cycles of intravenous cyclophosphamide to induce remission, that the cumulative dose administered would depend on body weight, and would generally be 10–15\xa0g for 10\xa0cycles. It further heard that intravenous cyclophosphamide was typically preferred to oral cyclophosphamide, because 1\xa0course of oral cyclophosphamide would result in a cumulative dose of up to 30\xa0g. The Committee concluded that alternative treatments for severe ANCA-associated vasculitis would be welcomed by clinicians and patients.\n\nThe Committee heard from the patient experts about the demands of living with ANCA-associated vasculitis and its treatment. It learned how each relapse can cause further progressive damage to the body and that this may be permanent, and how considerable stress results from the fear of relapse. The Committee further heard about the effects of cyclophosphamide's long-term toxicity. The Committee understood that some people with ANCA-associated vasculitis cannot have cyclophosphamide or have disease that is refractory to cyclophosphamide. The Committee heard from the patient experts that currently the only suitable alternative treatment option for these people is rituximab. The Committee acknowledged that ANCA-associated vasculitis has a significant impact on patients' quality of life and that cyclophosphamide treatment can be associated with a range of adverse events that could also impair their quality of life.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of rituximab. It noted that the evidence was primarily from the RAVE study and this was complemented by the RITUXVAS study. The Committee reviewed the suitability of the clinical trial evidence and noted that only RAVE used the regimen recommended in the marketing authorisation for ANCA-associated vasculitis. Overall, the Committee concluded that the studies provided adequate evidence for assessing rituximab for inducing remission of ANCA-associated vasculitis and were generalisable to UK clinical practice.\n\nThe Committee discussed the clinical effectiveness of rituximab compared with cyclophosphamide as induction therapy in people with severe ANCA-associated vasculitis. The Committee accepted that the RAVE results showed rituximab was non-inferior to cyclophosphamide in inducing complete remission in the full study population at 6\xa0months, but was uncertain if the treatment benefit persisted because of the short duration of RAVE. In response to consultation, the manufacturer provided 18-month follow-up data from RAVE. The Committee acknowledged that rituximab was non-inferior to cyclophosphamide in inducing complete remission at 6, 12, and 18\xa0months. In response to consultation, the manufacturer stated that patients in RAVE had severe disease, meaning the disease threatened the function of the affected organ and had the potential to cause permanent organ damage or to threaten the patient's life unless effective therapy was implemented quickly. The Committee concluded that rituximab was not less effective than cyclophosphamide as an induction treatment for people with severe ANCA-associated vasculitis.\n\nThe Committee discussed the need for maintenance treatment after rituximab induction therapy. The 2013 draft British Society for Rheumatology guidelines include 4\xa0options for maintenance treatment (see section 3.65). The Committee was aware of a difference of opinion between clinical specialists about the use of maintenance treatment. Some specialists stated that maintenance treatments such as azathioprine would be given after rituximab induction therapy, whereas others stated that azathioprine would not normally be given and is not supported by clinical trial evidence. In response to consultation, several specialists stated that rituximab would be used as maintenance treatment. The Committee recalled that the marketing authorisation was specifically for inducing remission (with a recommended dosage of 375\xa0mg/m2 administered as an intravenous infusion once weekly for 4\xa0weeks) and did not include rituximab being used as maintenance treatment. It further noted that the summary of product characteristics for rituximab states that the efficacy and safety of rituximab as maintenance treatment have not been established. The Committee concluded that maintenance treatment with rituximab was outside the scope of the appraisal.\n\nThe Committee reviewed the subgroups presented by the manufacturer to identify which people were likely to experience a greater treatment benefit. The Committee was aware that, at 6-month follow-up from RAVE, the complete remission rate for the subgroup with relapsed disease was statistically significantly higher in patients who received rituximab compared with patients who received cyclophosphamide. The Committee noted that the 18-month follow-up results for this subgroup, submitted in response to consultation, showed no significant difference in remission rates between the treatment groups. The Committee observed that, at 6-month follow-up for the subgroup with newly diagnosed disease, there was no significant difference in remission rates between the treatment groups. The Committee concluded that, over a period of 18\xa0months, rituximab and cyclophosphamide have similar effectiveness in inducing remission in both newly diagnosed and relapsed patients.\n\nThe Committee considered whether there were additional patient subgroups who might experience a greater treatment benefit. The Committee heard from the clinical specialists that there may be a small subgroup of people who would benefit from avoiding cyclophosphamide. In response to consultation, the manufacturer defined this subgroup (see section 3.21). The Committee noted that the manufacturer's definition is broadly in agreement with draft guidelines from the British Society for Rheumatology. Both the manufacturer and the British Society for Rheumatology stated that patients at risk of infection would benefit from avoiding cyclophosphamide. However, the Committee observed that the summary of product characteristics states that rituximab should not be used for patients with active, severe infection. In response to the second consultation, clinical specialists advised that there is evidence from case series to support the use of rituximab for people who cannot have cyclophosphamide. The Committee concluded that, for the purposes of this guidance, 'people who cannot have cyclophosphamide' refers to people:\n\nfor whom cyclophosphamide is contraindicated (as defined in the summary of product characteristics) or not tolerated; or\n\nwho have not completed their family and whose fertility may be materially affected by treatment with cyclophosphamide; or\n\nwith disease that has remained active or progressed despite a course of cyclophosphamide lasting 3–6 months; or\n\nwith a previous uroepithelial malignancy.\n\nThe Committee discussed the safety of rituximab compared with cyclophosphamide. It was aware that intravenous administration of cyclophosphamide is associated with a more favourable adverse-event profile than oral administration. The Committee noted that the frequency and severity of short-term adverse events were broadly comparable for rituximab and cyclophosphamide in RAVE (in which cyclophosphamide was administered orally) and RITUXVAS (in which cyclophosphamide was administered intravenously). The Committee noted that there were long-term adverse events associated with cyclophosphamide (such as bladder cancer and loss of fertility), but that it was not possible to form any conclusions on the long-term safety profile of rituximab because the data in the manufacturer's submission only extended to a maximum of 18\xa0months. In response to consultation, the manufacturer submitted evidence of the long-term safety of rituximab as a treatment for rheumatoid arthritis, and evidence that rituximab does not prevent women from conceiving children. The Committee concluded that the safety profiles of rituximab and cyclophosphamide seemed broadly similar in the short term, and there was uncertainty about any long-term safety benefits of rituximab because of a lack of data from patients with ANCA-associated vasculitis.\n\nThe Committee discussed potential advantages associated with rituximab that were not related to its efficacy or safety. It heard from the clinical specialists and patient experts that induction treatment with rituximab was 4\xa0weeks instead of up to 6\xa0months with cyclophosphamide, which was more convenient for patients. The Committee concluded that this benefit was important to patients.\n\n# Cost effectiveness\n\nThe Committee discussed the manufacturer's approach to developing its economic model. It noted that the ERG considered the manufacturer's approach to be generally in line with the NICE reference case, but that the manufacturer's decision problem did not match the final NICE scope in all areas (notably excluding some comparators and some end points). The Committee concluded that the outlined economic analysis was acceptable for assessing the cost effectiveness of rituximab in treating ANCA-associated vasculitis.\n\nThe Committee considered the comparators included in the manufacturer's economic analysis. The clinical specialists, and responses to consultation, confirmed that cyclophosphamide is the standard of care for inducing remission in people who can have cyclophosphamide; typically administered intravenously. The Committee noted that there was a lack of consensus about the appropriate comparator for people who cannot have cyclophosphamide. The Committee recalled that the ERG's exploratory analyses for this subgroup, based on the manufacturer's original model, used a comparator of best supportive care. The Committee was uncertain whether best supportive care was a realistic comparator. The Committee was aware that the manufacturer's updated model for this subgroup used a comparator of either mycophenolate mofetil or methotrexate. Clinical specialists at the meeting advised that neither of these drugs is a treatment of choice for people with severe disease, and methotrexate is unsuitable for people with renal disease. Also, the British Society for Rheumatology draft guidelines recommend mycophenolate mofetil or methotrexate for patients with low disease activity who are not at risk of organ damage. The Committee heard from the manufacturer that the clinical specialists it consulted advised that mycophenolate mofetil or methotrexate would be used as an induction treatment for people who cannot have cyclophosphamide. The Committee concluded that it was appropriate to include intravenous cyclophosphamide as the comparator in the economic analysis for people who can have cyclophosphamide, and that there was uncertainty about the appropriate comparator for people who cannot have cyclophosphamide.\n\nThe Committee evaluated the treatment sequences used in the manufacturer's original economic analysis. It considered the treatment sequences to be incomplete and unsuitable because they did not enable fully incremental analyses for all populations of interest. Also, the Committee learned from clinical specialists that the manufacturer's assumption that patients who had not responded to a first course of rituximab would then receive a second course did not reflect UK clinical practice. The Committee agreed that the treatment sequences used by the ERG in its exploratory analyses using the manufacturer's original model were more comprehensive and therefore more appropriate. However, the Committee agreed that it needed additional analyses for all possible treatment sequences for the different subgroup populations, with ICERs presented in a fully incremental analysis and as pairwise comparisons. The Committee then evaluated the treatment sequences used in the manufacturer's updated economic analysis, submitted in response to consultation. The Committee observed that the updated model did not consider all treatment sequences and assumed that all patients received a second course of rituximab. The results were not presented in a fully incremental analysis. The Committee concluded that these issues with the manufacturer's updated economic analysis added considerable uncertainty to the cost-effectiveness estimates.\n\nThe Committee discussed the uncontrolled disease health state in the manufacturer's original economic model. It noted the ERG's concerns that patients in the model spent 60–70% of their average lifespan in the uncontrolled disease state and heard from the clinical specialists that this was not realistic. The Committee was aware that this health state was associated with a low utility value and understood from the clinical specialists that patients would be expected to have some disease control with treatments other than cyclophosphamide. It noted the ERG's opinion that the costs for this health state had been overestimated and was advised by the clinical specialists that the number of outpatient appointments was not plausible. The Committee agreed that the utility value had been underestimated and costs had been overestimated for the uncontrolled disease health state in the manufacturer's original model. The Committee noted that, in response to consultation, the manufacturer submitted an updated model with a higher utility value and lower costs in the uncontrolled disease health state. It heard from the manufacturer and the ERG that the revised utility value was based on extrapolation from the utility values in the remission and non-remission health states. The Committee noted that the utility value could have been estimated using data from patients in RAVE who had not entered remission during the trial, but this analysis had not been presented. The Committee concluded that the revised utility value in the uncontrolled disease health state was more plausible than the value in the original model, but was still a source of some uncertainty.\n\nThe Committee discussed how adverse events and disease consequences had been incorporated into the manufacturer's original model. It noted that disutilities for cyclophosphamide's cumulative long-term toxicity had not been included in the analyses by the manufacturer, and that the costs of managing long-term toxicity could be substantial (for example, treating uroepithelial cancer or fertility problems). The Committee noted that the long-term toxicity of rituximab also had not been modelled and was not fully established. It was aware that the manufacturer's model did not include inpatient costs (such as treating infections) or the costs of disease consequences (for example, managing renal disease). The manufacturer's updated model, submitted in response to consultation, did not include disutilities for long-term toxicity, inpatient costs, or the costs of disease consequences. The Committee concluded that the manufacturer's original and updated models had not captured all relevant costs and disutilities, which added some uncertainty to the cost-effectiveness estimates.\n\nThe Committee reviewed how the manufacturer had estimated relapse rates in its original economic model and noted that the model assumed that both minor and severe relapses would need induction treatment. The Committee noted from the manufacturer's submission that, when possible, minor relapses in RAVE were managed by increasing the glucocorticoid dose. It understood from the clinical specialists that this would generally be the first approach in UK clinical practice (unless, for example, it was considered that there was a high risk of progression to a severe relapse). The Committee was aware that the manufacturer had used summary statistics rather than individual patient-level data, and noted the poor fit of the exponential distributions to the Kaplan–Meier relapse curves. It agreed with the ERG's opinion that the relapse rates derived from RAVE had been poorly estimated. In response to consultation, the manufacturer submitted an updated model which assumed that only severe relapses would need induction treatment. The Committee continued to have concerns about the manufacturer's use of summary statistics and concluded that the relapse rates in the manufacturer's updated model were a source of uncertainty.\n\nThe Committee then considered the manufacturer's updated models submitted in response to the first consultation (see sections 3.54–3.62). The Committee noted that the manufacturer had not provided all the analyses requested at consultation. The manufacturer's response did not include all treatment sequences, pairwise and incremental comparisons, incorporate the costs and disutility of the cumulative long-term toxicity of cyclophosphamide, or include inpatient costs associated with non-remission. The ERG identified several errors in the manufacturer's models (see section 3.63). The Committee then considered the manufacturer's weighted-average threshold analysis submitted in response to the second consultation (see section 3.75). It was aware that one of the reasons the manufacturer used this analysis was that another Committee had agreed to consider a whole-population weighted-ICER analysis in Omalizumab for treating severe persistent allergic asthma (NICE technology appraisal guidance\xa0278). However, the Committee noted that the circumstances were different to the current appraisal. For example, the omalizumab appraisal considered subgroups created by an arbitrary cut-off between age groups whereas the current appraisal considered 2 clinically distinct subgroups (people who can and cannot have cyclophosphamide). The Committee recalled that NICE's Guide to the methods of technology appraisal states that estimates of clinical and cost effectiveness should be provided separately for each relevant subgroup of patients. The Committee concluded that the manufacturer's models submitted in response to the first consultation, and the manufacturer's weighted-average threshold analysis submitted in response to the second consultation, did not provide a suitable basis for decision-making.\n\nThe Committee considered the ERG's exploratory analyses using the manufacturer's updated model for people who can have cyclophosphamide (see section 3.73). The Committee noted that the ERG had corrected the errors identified in the manufacturer's updated model. The Committee also noted the ERG's exploratory analysis allowed re-treatment of patients who responded to rituximab rather than re-treatment of all patients in the manufacturer's updated model. It also considered the treatment sequence, which was 1\xa0course of cyclophosphamide followed by 2\xa0courses of rituximab compared with 2\xa0courses of cyclophosphamide in the comparator arm. The Committee noted that there was no incremental analysis of rituximab in different places in the treatment pathway. Therefore, the ICER of £20,900 per QALY gained from the ERG's exploratory analyses did not reflect the true cost effectiveness of rituximab given after 1\xa0course of cyclophosphamide compared with cyclophosphamide. The Committee then discussed the ERG's exploratory analyses using the manufacturer's original model (see section\xa03.48), because these incremental analyses explored the use of rituximab in different places in the treatment pathway. The Committee was aware that a treatment sequence of 2\xa0courses of cyclophosphamide followed by 1\xa0course of rituximab compared with 2\xa0courses of cyclophosphamide resulted in an ICER of £12,100 per QALY gained. It noted that using rituximab after 1 course of cyclophosphamide (compared with using it after 2 courses of cyclophosphamide) or as a first-line treatment (compared with using rituximab after 1 course of cyclophosphamide), resulted in ICERs of £69,700 and £127,500 per QALY gained respectively (see section 3.48). The Committee agreed that the ICERs for rituximab after 1 course of cyclophosphamide or as a first-line treatment were outside the range normally considered a cost-effective use of NHS resources. The Committee noted that these exploratory analyses included maintenance treatment with azathioprine after rituximab, which may not reflect UK clinical practice (see section\xa04.6). The Committee heard from the ERG that, based on previous exploratory analyses (see section 3.73), including maintenance treatment with azathioprine was likely to have a small impact on the ICER. The Committee concluded that the most plausible ICER on which to base its decision for people who can have cyclophosphamide was £12,100 per QALY gained, provided by the comparison of 2\xa0courses of cyclophosphamide followed by 1\xa0course of rituximab with 2\xa0courses of cyclophosphamide.\n\nThe Committee considered the cumulative dose provided by 2\xa0courses of intravenous cyclophosphamide. Based on the manufacturer's response to consultation, the Committee was persuaded that 2\xa0courses of intravenous cyclophosphamide provides a cumulative dose of approximately 23\xa0g on average, which is within the limit of 25\xa0g advised by draft guidelines from the British Society for Rheumatology. The Committee further noted that approximately 23\xa0g cyclophosphamide represented 10\xa0infusions (the maximum number that would be administered per course of treatment) and that, according to the clinical specialists, some patients would respond with fewer infusions per cycle. The Committee noted that when possible, giving 2\xa0courses of cyclophosphamide before rituximab would represent a more cost-effective option than giving 1\xa0course of cyclophosphamide before rituximab. The Committee concluded that rituximab could be recommended as a cost-effective use of NHS resources in people with severe ANCA-associated vasculitis who can have cyclophosphamide, only if further treatment with cyclophosphamide would exceed the maximum cumulative dose (25\xa0g) of cyclophosphamide.\n\nThe Committee discussed the ERG's exploratory analyses using the manufacturer's updated model for people who cannot have cyclophosphamide (see section 3.74). The treatment sequence included 2\xa0courses of rituximab compared with 1\xa0course of either mycophenolate mofetil or methotrexate and the ERG's exploratory analysis of the manufacturer's updated model gave an ICER of £60,600 per QALY gained. The Committee was aware of substantial uncertainty about the assumptions in the model, such as the utility of the remission health state, the cost and disutility associated with glucocorticoids, and the remission and relapse rates. Therefore, the Committee agreed that the ICER of £60,600 per QALY gained was not plausible. The Committee considered the ERG's illustrative analyses, submitted in response to the second consultation (see section\xa03.76). The ERG's illustrative analyses changed some assumptions in the model and gave an ICER of £26,400 per QALY gained for the comparison of 2\xa0courses of rituximab with 1\xa0course of mycophenolate mofetil. The Committee heard from the ERG that the analyses illustrate the uncertainty in the estimates of cost effectiveness for people who cannot have cyclophosphamide. The Committee was aware that the clinical specialists did not agree about the use of mycophenolate mofetil or methotrexate as an induction treatment in people who cannot have cyclophosphamide (see section\xa04.12). The Committee then discussed the ERG's exploratory analyses using the manufacturer's original model for people who cannot have cyclophosphamide (see section\xa03.52), because these analyses included an alternative comparator. The Committee noted that 1\xa0course of rituximab compared with best supportive care gave an ICER of £11,300 per QALY gained. The Committee agreed that there was a lack of consensus about the appropriate comparator for people who cannot have cyclophosphamide. The Committee concluded there was substantial uncertainty about the cost effectiveness of rituximab for people who cannot have cyclophosphamide, but on balance the ICER was likely to be lower than £30,000 per QALY gained.\n\nThe Committee discussed whether rituximab was innovative in its potential to make a significant and substantial impact on health-related benefits. The Committee was aware that, in response to the second consultation, clinical specialists and patient experts stated that rituximab was 'scene-changing' in the treatment of ANCA-associated vasculitis. Consultees also advised that rituximab was the first new effective treatment since the introduction of cyclophosphamide in the 1970s, and rituximab may be the first of a new generation of treatments. In addition, consultees advised that people who cannot have cyclophosphamide have the highest unmet need because no alternative treatments are as effective as rituximab. The manufacturer noted that cyclophosphamide reduces fertility in men and women, and stated that the benefit of maintaining fertility while treating the disease effectively cannot be captured in the QALY. The Committee was aware that the manufacturer had provided evidence that rituximab does not prevent women from conceiving children. The Committee concluded that rituximab was an innovative treatment.\n\nIn summary, for people who cannot have cyclophosphamide, the Committee considered the manufacturer's original and updated analyses, the ERG's exploratory and illustrative analyses, and comments received during consultation. The Committee took into account the estimates of cost effectiveness and noted the uncertainty associated with them. The Committee also recognised that rituximab is an innovative treatment and the high unmet need for treatment options for people who cannot have cyclophosphamide. Having taken into account all of the evidence submitted and the comments received during consultation and noting the NICE Social Value Judgements, the Committee concluded that rituximab was a cost-effective use of NHS resources for treating people with severe ANCA-associated vasculitis who cannot have cyclophosphamide, as defined in section 4.8.\n\nThe Committee considered whether its recommendations were associated with any issues related to the equality legislation and the requirement for fairness. The Committee noted that the manufacturer stated that cyclophosphamide reduces fertility in both men and women. The Committee was also aware that the manufacturer had provided evidence that rituximab does not prevent women from conceiving children and that no evidence was presented regarding the effect of rituximab on male fertility. Based on the available evidence, the Committee considered that it was appropriate to accept that rituximab was likely to have a less detrimental effect on male fertility than cyclophosphamide. The Committee considered that, in this context, guidance that only recommended rituximab for women who had not completed their family would potentially constitute unlawful sex discrimination. The Committee concluded that it was appropriate to recommend rituximab for men and women who have not completed their family and whose fertility may be materially affected by treatment with cyclophosphamide.\n\nThe Committee further considered issues related to the equality legislation. Considering that the guidance in section 1.1 recommends rituximab for people who have not completed their family and whose fertility may be materially affected by treatment with cyclophosphamide, the Committee was aware that this recommendation would affect access for post-menopausal women whereas younger women and men of all ages could potentially receive rituximab. The Committee discussed whether this could be regarded as indirect discrimination. The Committee noted that any differential treatment of post-menopausal women arises from the different physiological features of fertility in men and women. The Committee noted that rituximab and cyclophosphamide have similar effectiveness as induction treatments for severe ANCA-associated vasculitis (see section 4.7), so an effective induction treatment will also be available for post-menopausal women. Therefore, the Committee agreed that its recommendations do not constitute detrimental treatment of post-menopausal women. The Committee noted that the safety profiles of rituximab and cyclophosphamide are broadly similar in the short term, and there was uncertainty about any long-term safety benefits of rituximab compared with cyclophosphamide (see section 4.9). The Committee concluded that the guidance would permit an effective induction treatment for all groups of people, and there was no evidence that some groups would experience more adverse effects of treatment than other groups, and therefore there was no unfairness.\n\nIn considering the potential equalities issues, the Committee took into account the size and characteristics of the overall population of people with ANCA-associated vasculitis and the subgroup of people who would be affected by the recommendation relating to fertility. The Committee was aware that around 1200 people are diagnosed with ANCA-associated vasculitis each year in England and Wales and the peak age of onset is between 60 and 70\xa0years. Therefore, the Committee concluded that the number of people with ANCA-associated vasculitis who have not completed their family is likely to be small.\n\nThe Committee further discussed issues related to the equality legislation. Consultees suggested that children should be included in the population, but the marketing authorisation specifies 'adults' so this is not an equality issue that falls within the remit of a NICE technology appraisal. The Committee concluded that its decision on the use of rituximab would not have a disproportionate impact on any group with a protected characteristic that cannot be objectively justified, and that therefore there was no need to alter or add to its recommendations.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA308\n\nAppraisal title: Rituximab in combination with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis\n\nSection\n\nKey conclusion\n\nRituximab, in combination with glucocorticoids, is recommended as an option for inducing remission in adults with anti-neutrophil cytoplasmic antibody [ANCA]-associated vasculitis (severely active granulomatosis with polyangiitis [Wegener's] and microscopic polyangiitis), only if:\n\nfurther cyclophosphamide treatment would exceed the maximum cumulative cyclophosphamide dose or\n\ncyclophosphamide is contraindicated or not tolerated or\n\nthe person has not completed their family and treatment with cyclophosphamide may materially affect their fertility or\n\nthe disease has remained active or progressed despite a course of cyclophosphamide lasting 3–6 months or\n\nthe person has had uroepithelial malignancy.\n\nThe Committee concluded that a plausible treatment sequence for people who can have cyclophosphamide was 2\xa0courses of cyclophosphamide followed by 1\xa0course of rituximab. The Committee noted that 2\xa0courses of cyclophosphamide would provide a cumulative dose of 23\xa0g on average, which is within the limit of 25\xa0g advised by draft guidelines from the British Society for Rheumatology. The Committee noted that using rituximab earlier in the treatment sequence, either as a first-line treatment or after 1 course of cyclophosphamide, was not cost effective. It concluded that, for patients for whom further cyclophosphamide treatment would exceed the maximum cumulative dose, rituximab is a cost-effective use of NHS resources and therefore should be recommended.\n\nThe Committee concluded there was substantial uncertainty regarding the cost effectiveness of rituximab for people who cannot have cyclophosphamide, but on balance the ICER was likely to be lower than £30,000 per QALY gained. The Committee recognised that rituximab is an innovative treatment and the high unmet need of treatment options for people who cannot have cyclophosphamide. Therefore, the Committee concluded that rituximab was a cost-effective use of NHS resources for treating people with severe ANCA-associated vasculitis who cannot have cyclophosphamide, as defined in section 4.8.\n\n, 4.8, 4.18, 4.19, 4.20–4.22\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from the clinical specialists that induction treatment with cyclophosphamide is the standard of care for people with severe ANCA-associated vasculitis, and that alternative treatments such as mycophenolate mofetil, methotrexate and deoxyspergualin were associated with higher relapse rates and would not normally be used to treat severe disease (unless cyclophosphamide was unsuitable). The Committee recognised that the risk of long-term toxicity (for example, uroepithelial malignancies) increases with the cumulative dose of cyclophosphamide and understood that the cumulative dose should not exceed 25\xa0g. The Committee concluded that alternative treatments for ANCA-associated vasculitis would be welcomed by clinicians and patients.\n\n–4.3\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nRituximab (MabThera, Roche Products) is a genetically engineered chimeric (mouse/human) monoclonal antibody that depletes B cells by targeting cells bearing the CD20 surface marker.\n\nThe Committee was aware that clinical specialists and patient experts stated that rituximab was 'scene-changing' in the treatment of ANCA-associated vasculitis. Consultees also advised that rituximab was the first new effective treatment since the introduction of cyclophosphamide in the 1970s, and rituximab may be the first of a new generation of treatments. The manufacturer noted that cyclophosphamide reduces fertility in men and women, stated that the benefit of maintaining fertility while treating the disease effectively cannot be captured in the QALY, and provided evidence that rituximab does not prevent women from conceiving children. The Committee agreed that rituximab was an innovative treatment and therefore the Committee would consider an ICER at the top end of the range that would normally be considered a cost-effective use of NHS resources (£20,000–30,000 per QALY gained).\n\n, 4.21\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee assessed the clinical effectiveness of rituximab compared with cyclophosphamide as induction therapy in people with severe ANCA-associated vasculitis.\n\n\n\nAdverse reactions\n\nThe Committee noted that the frequency and severity of short-term adverse events were broadly comparable for rituximab and cyclophosphamide in RAVE and RITUXVAS. The Committee noted that there were long-term adverse events associated with cyclophosphamide (such as bladder cancer and loss of fertility). It was aware of evidence of the long-term safety of rituximab as a treatment for rheumatoid arthritis, and evidence that rituximab does not prevent women from conceiving children. The Committee concluded that the safety profiles of rituximab and cyclophosphamide seemed broadly similar in the short term, and there was uncertainty about any long-term safety benefits of rituximab because of a lack of data from patients with ANCA-associated vasculitis.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee considered the evidence from RAVE and RITUXVAS presented by the manufacturer and noted that only RAVE used the regimen recommended in the marketing authorisation. The Committee concluded that the studies provided adequate evidence for assessing rituximab for inducing remission of ANCA-associated vasculitis and were generalisable to UK clinical practice.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee discussed the need for maintenance treatment after rituximab induction therapy. It was aware that British Society for Rheumatology draft guidelines include 4 options for maintenance treatment, but clinical specialists did not agree about which options would be used in routine practice. The Committee concluded that maintenance treatment with rituximab was outside the scope of the appraisal because it was not included in the marketing authorisation.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded there was uncertainty about any long-term safety benefits of rituximab compared with cyclophosphamide because of a lack of data from people with ANCA-associated vasculitis.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee noted that rituximab was superior to cyclophosphamide in inducing remission in patients with relapsed disease at 6-month follow-up, but the difference between treatments was not significantly different at 18-month follow-up.\n\nThe Committee heard from the clinical specialists that there may be a small subgroup of people who would benefit from avoiding cyclophosphamide, and that there is evidence from case series to support the use of rituximab for this subgroup. The Committee concluded that, for the purposes of this guidance, 'people who cannot have cyclophosphamide' refers to people:\n\nfor whom cyclophosphamide is contraindicated (as defined in the summary of product characteristics) or not tolerated; or\n\nwho have not completed their family and whose fertility may be materially affected by treatment with cyclophosphamide; or\n\nwith disease that has remained active or progressed despite a course of cyclophosphamide lasting 3–6\xa0months; or\n\nwith a previous uroepithelial malignancy.\n\n, 4.8\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee accepted that the RAVE results showed rituximab was non-inferior to cyclophosphamide in inducing complete remission in the full study population at 6, 12, and 18\xa0months. The Committee concluded that the RAVE and RITUXVAS studies provided adequate evidence for assessing rituximab for inducing remission of ANCA-associated vasculitis and were generalisable to UK clinical practice.\n\n, 4.5\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee observed that the manufacturer's approach was generally in line with the NICE reference case, but that the manufacturer's decision problem did not match the final NICE scope in all areas (notably excluding some comparators and end points). The Committee concluded that the outlined economic analysis was acceptable for assessing the cost effectiveness of rituximab in treating ANCA-associated vasculitis.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee identified several reasons for uncertainty in the results of the manufacturer's updated economic models submitted in response to the first consultation. The reasons included: not all treatment sequences were modelled, no incremental analyses were reported, not all costs and consequences were included, there were concerns about the way relapse rates were calculated, there were errors in the model, and there was uncertainty about utility values. The Committee then considered the manufacturer's weighted-average threshold analysis submitted in response to the second consultation. It was aware that another Committee had agreed to consider a whole-population weighted-ICER analysis in Omalizumab for treating severe persistent allergic asthma (NICE technology appraisal guidance 278), but the circumstances were different to the current appraisal. The Committee recalled that NICE's Guide to the methods of technology appraisal states that estimates of clinical and cost effectiveness should be provided separately for each relevant subgroup of patients. The Committee concluded that the manufacturer's models submitted in response to the first consultation, and the manufacturer's weighted-average threshold analysis submitted in response to the second consultation, did not provide a suitable basis for decision-making.\n\nSome of the Committee's concerns had been resolved in the ERG's exploratory analyses. Accordingly, the Committee was able to identify the most plausible ICER for people who can have cyclophosphamide.\n\nFor people who cannot have cyclophosphamide, the Committee considered the manufacturer's original and updated analyses, and the ERG's exploratory and illustrative analyses. The Committee agreed that, for people who cannot have cyclophosphamide, there was a lack of consensus about the appropriate comparator treatment. The Committee concluded there was substantial uncertainty about the cost effectiveness of rituximab for people who cannot have cyclophosphamide, but on balance the ICER was likely to be lower than £30,000 per QALY gained.\n\n–4.17, 4.18, 4.20\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that, in the manufacturer's updated models, the utility value in the uncontrolled disease health state was based on extrapolation from the utility values in the remission and non-remission health states. It concluded that that the revised utility value in the uncontrolled disease health state was more plausible than the value in the original model, but was still a source of some uncertainty.\n\nThe Committee noted that the economic model did not include disutilities for cyclophosphamide's cumulative long-term toxicity or the costs of managing long-term toxicity. It agreed that these issues added some uncertainty to the cost-effectiveness estimates.\n\n, 4.15\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee agreed that rituximab was cost effective for adults with ANCA-associated vasculitis (severely active granulomatosis with polyangiitis [Wegener's] and microscopic polyangiitis), only if:\n\nfurther cyclophosphamide treatment would exceed the maximum cumulative dose (25\xa0g) of cyclophosphamide; or\n\nthe person cannot have cyclophosphamide (as specified in section 4.8).\n\n, 4.18, 4.19\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee was aware from the ERG's exploratory analyses based on the manufacturer's original model that the ICER substantially increased when the number of outpatient appointments was reduced. The Committee also noted that the ICERs presented by the manufacturer and the ERG were sensitive to changes in treatment sequence.\n\n, 3.48\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee agreed that the most plausible ICER on which to base its decision for people who can have cyclophosphamide was £12,100 per QALY gained, provided by the comparison of 2\xa0courses of cyclophosphamide followed by 1\xa0course of rituximab with 2\xa0courses of cyclophosphamide.\n\nThe Committee concluded there was substantial uncertainty about the cost effectiveness of rituximab for people who cannot have cyclophosphamide, but on balance the ICER was likely to be lower than £30,000 per QALY gained.\n\n, 4.20\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nFor people who cannot have cyclophosphamide, the Committee considered the evidence, the comments received during consultation, and the NICE Social Value Judgements. The Committee took into account the estimates of cost effectiveness and noted the uncertainty associated with them. The Committee also recognised that rituximab is an innovative treatment and the high unmet need for treatment options for people who cannot have cyclophosphamide. The Committee concluded that rituximab was a cost-effective use of NHS resources for treating people with severe ANCA-associated vasculitis who cannot have cyclophosphamide, as defined in section 4.8.\n\nThe Committee considered whether its recommendations were associated with any issues related to the equality legislation. The Committee noted that the manufacturer stated that cyclophosphamide reduces fertility in both men and women. The Committee was aware of evidence that rituximab does not prevent women from conceiving children but no evidence had been presented regarding the effect of rituximab on male fertility. The Committee considered that it was appropriate to accept that rituximab was likely to have a less detrimental effect on male fertility than cyclophosphamide. The Committee concluded that it was appropriate to recommend rituximab for men and women who have not completed their family whose fertility may be materially affected by treatment with cyclophosphamide.\n\nThe Committee was aware that the recommendation regarding fertility would affect access for post-menopausal women whereas younger women and men of all ages could potentially receive rituximab. The Committee discussed whether this could be regarded as indirect discrimination. The Committee noted that rituximab and cyclophosphamide have similar effectiveness as induction treatments for severe ANCA-associated vasculitis. The Committee also noted that the safety profiles of rituximab and cyclophosphamide are broadly similar in the short term, and there was uncertainty about any long-term safety benefits of rituximab compared with cyclophosphamide. The Committee concluded that the guidance would permit an effective induction treatment for all groups of people, and there was no evidence that some groups would experience more adverse effects of treatment than other groups, and therefore there was no unfairness. The Committee also concluded that the number of people with ANCA-associated vasculitis who have not completed their family is likely to be small.\n\n–4.25", 'Review of guidance': 'The guidance on this technology will be considered for review in March 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon Chief ExecutiveMarch 2014', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. A tool to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0500-3'}	https://www.nice.org.uk/guidance/ta308	Evidence-based recommendations on rituximab (MabThera) with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis in adults.
02a531ff500f0a66c57f3cc6ebc30e167c2740c3	nice	Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy	Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy Evidence-based recommendations on aflibercept (Zaltrap) with irinotecan and fluorouracil-based therapy (FOLFIRI) for treating metastatic colorectal cancer after oxaliplatin-based chemotherapy in adults. # Guidance Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended within its marketing authorisation for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen. People currently receiving aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology Aflibercept (Zaltrap, Sanofi) is a recombinant human fusion protein that blocks the vascular endothelial growth factor (VEGF) pathway by preferentially binding to VEGF-A, VEGF-B and placental growth factor, which play an important role in the formation of new blood vessels in solid tumours (angiogenesis). By preventing these factors from activating their endogenous receptors, aflibercept interferes with the process by which blood vessels and capillaries expand into tumours (vascularisation), and so inhibits tumour growth. Aflibercept in combination with folinic acid/5-fluorouracil/irinotecan (FOLFIRI) (that is, in combination with irinotecan and fluorouracil-based therapy) has a UK marketing authorisation 'for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen'. The summary of product characteristics states that aflibercept should be administered as an intravenous infusion over 1 hour at a dose of 4 mg/kg of body weight, followed by the FOLFIRI regimen, every 2 weeks until the disease progresses or unacceptable toxicity occurs. The summary of product characteristics lists the following most common adverse reactions (according to the Common Terminology Criteria for Adverse Events v3.0) for aflibercept plus FOLFIRI in order of decreasing frequency: leukopenia, diarrhoea, neutropenia, proteinuria, increased plasma activity of aspartate aminotransferase, stomatitis, fatigue, thrombocytopenia, increased plasma activity of alanine aminotransferase, hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine and headache. For full details of adverse reactions and contraindications, see the summary of product characteristics. The manufacturer states that the net price of a vial of 100 mg aflibercept is £295.65, and the net price of a vial of 200 mg aflibercept is £591.30. The cost per patient will vary with dose adjustment and treatment duration. The manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (section 7) considered evidence submitted by the manufacturer of aflibercept and a review of this submission by the Evidence Review Group (ERG; section 8). # Clinical-effectiveness evidence The manufacturer did a systematic literature review of studies evaluating the efficacy and safety of second-line treatments for metastatic colorectal cancer. It identified 1 relevant randomised controlled trial (RCT), the VELOUR trial, from which it obtained the key clinical evidence. The VELOUR trial was a double-blind placebo-controlled phase III study that was conducted in 176 centres in 28 countries, including the UK. Eligible patients were adults who had inoperable metastatic colorectal cancer, and whose disease progressed on or after treatment with only 1 prior oxaliplatin-based chemotherapy regimen. Investigators randomised patients in a 1:1 ratio to either aflibercept plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) (n=612) or placebo plus FOLFIRI (n=614). They stratified randomisation by patients' wellbeing and ability to perform daily activities using the Eastern Cooperative Oncology Group Performance Status (ECOG PS), and whether or not the patient had received prior therapy with bevacizumab. Patients received either aflibercept at a dose of 4 mg/kg or placebo over 1 hour on day 1, every 2 weeks, both intravenously, immediately followed by FOLFIRI. During the trial, patients could stop 1 study treatment (aflibercept or placebo, or FOLFIRI) but still receive the other components of the regimen. Treatment continued until disease progressed, unacceptable toxicity occurred, or the patient declined further treatment. The primary end point in the VELOUR trial was overall survival, defined as time from randomisation to death from any cause. One of the secondary end points was progression-free survival as assessed by an independent review committee based on radiologic progression; it was determined as time from randomisation to first observation of disease progression (at least a 20% increase in the sum of the longest diameter of target tumours, the unequivocal increase in the size of non-target tumours or the appearance of 1 or more new tumours), or death from any cause. In addition, disease progression determined by local investigators was recorded during the trial. Other secondary end points were objective response (complete and partial responses) according to Response Evaluation Criteria In Solid Tumors criteria version 1, and adverse events and abnormal laboratory findings. The manufacturer stated that patient characteristics and disease history at baseline were well balanced between the aflibercept and placebo groups. Of the patients randomised in the study, the median age was 61 years, 58.6% were men, 97.8% had a baseline ECOG PS of 0 or 1, and 2.2% had a baseline ECOG PS of 2. The marketing authorisation for aflibercept stipulates prior treatment with an oxaliplatin-containing regimen. In the VELOUR trial, 90.2% of patients randomised to aflibercept plus FOLFIRI and 89.4% of those randomised to placebo plus FOLFIRI had received prior oxaliplatin-based chemotherapy for locally advanced or metastatic disease. Approximately 10% of patients had received prior oxaliplatin-based chemotherapy in the adjuvant setting (that is, as an additional treatment given after the primary treatment). Oxaliplatin-based regimens were given in combination with bevacizumab in 30.4% of patients. The manufacturer determined that it needed 863 death events to detect a statistically significant 20% risk reduction in the aflibercept group compared with the placebo group; this determined the study cut-off date. To estimate time-to-event parameters (overall survival and progression-free survival), the manufacturer used survival analysis. It calculated hazard ratios and confidence intervals for the primary and subgroup analyses using a Cox proportional hazards model. It also established heterogeneity of treatment effect among subgroups using a Cox proportional hazards model, and provided an interaction test for each subgroup analysis. If a patient neither died nor had disease progression during the trial, the manufacturer censored the patient at the date when the tumour was last assessed or at the study cut-off date. The median follow-up for the overall population at the time of the primary analysis was 22.28 months, with the longest follow-up being 36 months. At the study cut-off date, 403 patients (65.8%) randomised to aflibercept and 460 patients (74.9%) randomised to placebo had died. Median overall survival was estimated to be 1.44 months longer for aflibercept than placebo (aflibercept 13.50 months, placebo 12.06 months), and the corresponding hazard ratio was 0.817 (95.34% confidence interval 0.713 to 0.937, p=0.0032), suggesting a reduction in the risk of death of 18.3% with aflibercept compared with placebo. The probabilities of overall survival at 6, 12, 18, 24 and 30 months were consistently higher in the aflibercept group than in the placebo group; the probability of overall survival was 4% higher at 6 months, and 85% higher at 30 months. The manufacturer noted that the Kaplan–Meier curves for overall survival separated early and continued to separate over time, and suggested that there were patients who experienced a sustained benefit after treatment with aflibercept. Because of this, the manufacturer indicated that the difference in median overall survival of 1.44 months may underestimate the overall clinical benefit of adding aflibercept to FOLFIRI. In addition, the manufacturer calculated hazard ratios for overall survival by 6-month periods up to 18 months after randomisation, and it combined all time points thereafter into a single hazard ratio. This analysis showed that hazard ratios improved over time, implying that the difference in overall survival increased in favour of aflibercept the longer patients received treatment. In response to a clarification request by the ERG, the manufacturer provided hazard ratios and the number of patients at risk of dying 18 months after randomisation by 6-month periods. These hazard ratios continued to decrease over time (suggesting that the difference in overall survival continued to increase in favour of aflibercept), but had confidence intervals that crossed 1.00 (that is, the differences were not statistically significant). The manufacturer estimated the mean overall survival by fitting separate parametric functions to the trial data for each treatment group, and extrapolating to provide complete curves (given that calculating the mean required all patients to have died). It modelled each treatment group separately, rather than modelling treatment as a covariate, because the log-cumulative hazard plots (used to evaluate the assumption that a hazard ratio between 2 treatments remains constant over time) were not parallel and crossed. The manufacturer considered that the log-logistic function provided the best fit for overall survival for both treatment groups. The log-logistic function, however, gave a long tail (implying that some patients would live implausibly long), so the manufacturer truncated the curves at 15 years after randomisation (this assumed that all patients die by 15 years). Using this approach, the manufacturer estimated that aflibercept would extend mean overall survival by 4.7 months compared with placebo (aflibercept 22.8 months, placebo 18.1 months); without truncating the survival curves, the difference in mean overall survival was 6.6 months. In response to a clarification request by the ERG, the manufacturer provided estimates with the analysis truncated at 5 and 10 years. The manufacturer designated the results of this analysis as academic in confidence. The manufacturer also provided 'restricted' mean overall survivals for each treatment group based on actual data rather than an extrapolated model (that is, excluding patients who were alive at the end of the trial). This analysis estimated a difference in mean overall survival of 1.92 months in favour of aflibercept. The manufacturer found that aflibercept also prolonged progression-free survival compared with placebo; the difference in median progression-free survival was estimated to be 2.23 months when disease progression was assessed by an independent review committee (aflibercept 6.90 months, placebo 4.67 months, hazard ratio 0.758 ). The manufacturer also provided an estimate of 1.74 months for median progression-free survival when local investigators determined disease progression. For response rate (complete and partial responses), the results favoured aflibercept, with an estimated response rate of 19.8% (95% CI 16.4 to 23.2) in the aflibercept group and 11.1% (95% CI 8.5 to 13.8) in the placebo group. The manufacturer performed pre-specified subgroup analyses according to the following: Baseline characteristics: presence of liver metastasis, location of primary tumour, number of metastatic organs (metastases in 1 organ only, or metastases in more than 1 organ), prior history of hypertension. Stratification variables: ECOG PS, prior bevacizumab treatment. Demographic characteristics: age (less than 65 years old, or 65 years or older), sex, race, geographical region.The manufacturer focused on 2 subgroups in its submission: patients with liver metastases only (pre-specified), and a subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy (post hoc). The manufacturer stated that the subgroup of patients with liver metastases only was recognised as a relevant clinical subgroup for metastatic colorectal cancer in Cetuximab for the first-line treatment of metastatic colorectal cancer (NICE technology appraisal guidance 176). For the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy, the manufacturer performed a post hoc analysis after the results of the VELOUR trial had been compiled. The manufacturer stated that 10% of patients in the trial had cancer that had relapsed within 6 months of starting oxaliplatin-based adjuvant therapy, which the manufacturer interpreted as reflecting patients with aggressive disease who would be unlikely to benefit from anti-vascular endothelial growth factor (VEGF) therapy. For all the pre-specified subgroups, the manufacturer carried out an analysis of overall survival. It found no evidence of heterogeneity in treatment effect (non-significant interaction test), except in the subgroup of patients with liver metastases only (p value for interaction was 0.0899, statistically significant at the 10% level). The hazard ratio for this subgroup was 0.649 (95.34% CI 0.492 to 0.855) compared with a hazard ratio of 0.868 (95.34% CI 0.742 to 1.015) in patients who had no liver metastases or in whom the cancer spread to the liver and other organs (estimates of survival times are academic in confidence). In response to a clarification request by the ERG, the manufacturer provided the difference in mean overall survival for the subgroup using actual, rather than extrapolated, data; this estimate is academic in confidence. In the post hoc subgroup analysis, which excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy, the difference in median overall survival was estimated to be 1.9 months in favour of aflibercept. In this subgroup, the unadjusted hazard ratio was 0.78 (95% CI 0.68 to 0.90) compared with 1.09 (95% CI 0.70 to 1.69) in patients whose disease had relapsed 6 months or less after starting adjuvant therapy (p value for interaction 0.1265). For progression-free survival, the manufacturer did not find a statistically significant subgroup effect except in patients with liver metastases only (interaction test was statistically significant at the 10% level). These results, and those of the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy, are academic in confidence. The incidence of adverse events of any grade (according to the Common Terminology Criteria for Adverse Events v3.0) was similar in the aflibercept and placebo groups of the VELOUR trial (99.2% and 97.9% respectively), but the incidence of some adverse events was considerably higher in the aflibercept group (for example, 41.4% of patients receiving aflibercept had hypertension compared with 10.7% of those receiving placebo). Grade 3–4 adverse events were reported in 83.5% of patients in the aflibercept group and 62.5% of those in the placebo group. The grade 3–4 adverse events that occurred at least twice as frequently in the aflibercept group than in the placebo group, in order of decreasing relative incidence, were: hypertension (19.3% versus 1.5%), proteinuria (7.8% versus 1.2%), hand-foot syndrome (2.8% versus 0.5%), headache (1.6% versus 0.3%), arterial thromboembolic events (1.8% versus 0.5%), weight loss (2.6% versus 0.8%), stomatitis and ulceration (13.8% versus 5.0%), diarrhoea (19.3% versus 7.8%) and decreased platelet count (3.4% versus 1.6%). Typical anti-VEGF adverse reactions and adverse reactions associated with FOLFIRI were more common in the aflibercept group. The manufacturer indicated that most of the adverse events associated with aflibercept plus FOLFIRI were reversible and manageable using current clinical practice, although some (physical weakness, infections, diarrhoea and hypertension) led to permanent discontinuation of study treatment in 26.8% of patients receiving aflibercept compared with 12.1% of those receiving placebo. Furthermore, the European Public Assessment Report notes that more patients in the aflibercept than the placebo groups had their dose of FOLFIRI reduced or their treatment cycle delayed. To further characterise the adverse events of aflibercept, the manufacturer performed a meta-analysis by pooling safety data from 3 RCTs (VELOUR, VITAL and VANILLA). The VITAL trial evaluated aflibercept plus docetaxel compared with placebo plus docetaxel in patients with non-small cell lung cancer and, in the VANILLA trial, patients with metastatic pancreatic cancer were randomised to aflibercept plus gemcitabine or placebo plus gemcitabine. Overall, the meta-analysis included data from 2662 patients (1333 receiving aflibercept and 1329 receiving placebo). The analysis was framed so that risk ratios greater than 1 favoured placebo. The manufacturer found that, among patients treated with aflibercept, 0.4% and 0.5% had grade 4 hypertension and nephrotic syndrome respectively. It also found that adding aflibercept to concurrent chemotherapies did not increase the risk of venous thromboembolism, but it did increase the risk of grade 3–4 adverse reactions related to anti-VEGF therapy; the difference in this risk was statistically significant for hypertension (risk ratio 9.21, 95% CI 5.91 to 14.36), proteinuria (RR 8.37, 95% CI 4.37 to 16.06) and haemorrhage (RR 2.04, 95% CI 1.20 to 3.47). The incidence of adverse reactions typically associated with the background chemotherapy used in the 3 RCTs also increased with the addition of aflibercept, most notably for neutropenia (including neutropenic complications), various gastrointestinal toxicities and physical weakness. Data on health-related quality of life were not collected in the VELOUR trial. The manufacturer conducted the 'mCRC utilities study', an observational, cross-sectional study to estimate utility values in patients with metastatic colorectal cancer who would be eligible for treatment with aflibercept plus FOLFIRI as per the licensed indication, or who had progressed to subsequent phases of the disease. The study took place in the Netherlands and the UK, and collected EQ-5D data. The manufacturer used these data as its main source to estimate health-related quality of life for the cost-effectiveness analysis. ## ERG critique The ERG stated that the manufacturer presented a well-conducted systematic review of clinical evidence, and used a search strategy that was unlikely to have missed any relevant studies. It also stated that the manufacturer included sufficient detail about the VELOUR trial and used appropriate criteria to assess the quality of the trial. The ERG noted, however, that the manufacturer provided minimal details of its meta-analysis of aflibercept's adverse events, and of the quality of the VITAL and VANILLA trials. The ERG indicated that VELOUR was a good quality trial and directly related to the decision problem, and that the characteristics of patients at baseline and disease history were well balanced between the aflibercept and placebo groups. However, the ERG considered that patients in the trial were potentially fitter and younger than those seen in UK practice, and so patients in clinical practice may not achieve the level of benefit reported in the trial. The ERG highlighted the following dissimilarities between the VELOUR trial and clinical practice: In the UK, patients whose disease progresses after a break in treatment during intermittent first-line palliative chemotherapy are likely to be offered repeat treatment with the first-line chemotherapy regimen. If their disease progresses while receiving this treatment, or within 6 to 8 weeks of completing it, they would then move to second-line treatment. Although the manufacturer's submission does not state how many cycles of first-line oxaliplatin-based chemotherapy patients in the VELOUR trial received, the ERG indicated that the trial population may be healthier than patients in clinical practice who may have received several cycles of first-line treatment. Between 2007 and 2009, around 72% of patients diagnosed with colorectal cancer in the UK were aged 65 years or over. By contrast, in the VELOUR trial, only 33.5% of the aflibercept group and 38.9% of the placebo group were people aged 65 years or over. The proportion of patients with an ECOG PS of 2 in the VELOUR trial was 2.2%. According to the ERG's clinical adviser, this is lower than the proportion reported in other trials in the second-line setting, or in UK clinical practice. In the VELOUR trial, 42–44% of patients had metastasis in only 1 organ, which the ERG's clinical adviser considered higher than the proportion seen in clinical practice. The ERG noted that the hazard ratios for overall survival by 6-month periods had wide confidence intervals at the later time points of the VELOUR trial because by this time many patients were no longer alive, leaving few patients at risk of dying (around 5% at 30 months). The ERG stated that wide confidence intervals reflect imprecise estimates, and that interpreting hazard ratios towards the end of the trial is highly uncertain, particularly at 30 months and 36 months. To estimate mean overall survival using parametric analysis, the manufacturer assumed that the proportional hazards assumption does not hold (that is, it did not accept that the hazard ratio between the 2 treatment groups remained constant over time). The manufacturer stated that this was because the hazard ratios for overall survival decreased over time (treatment effect improved), and because the log-cumulative hazard plots were not parallel and crossed over one another. The ERG, conversely, considered that, while the hazard ratios decreased over time, they remained consistent with the proportional hazards assumption, although it acknowledged that using a proportional hazards approach is subject to judgement. In addition, the ERG noted that the log-cumulative hazard plots were very close to parallel. The ERG stated that rejecting the proportional hazards assumption and assuming a continued separation of the overall survival curves is highly uncertain given that no data were available beyond 36 months' follow-up, and particularly that the progression-free survival curves separate then converge at around 12 months. The ERG suggested that it would be reasonable to assume that the survival curves converge before 5 years (that is, there is no treatment effect after 5 years), in line with clinical experience in treating metastatic colorectal cancer. The ERG noted that the estimate of mean overall survival varied considerably depending on the parametric function the manufacturer used, indicating that the manufacturer's estimates of the difference in mean overall survival (4.7 months) were not robust to the choice of distribution. The ERG requested from the manufacturer the mean estimates of overall survival for each treatment group, restricted to patients who had died before the end of the trial (that is, results based on actual data rather than an extrapolated model), which gave a difference of 1.92 months in favour of aflibercept. The ERG indicated that this figure is likely to be an underestimate given that it does not take into account the patients with long survival times. The manufacturer used the log-logistic function to estimate mean overall survival, and it truncated the curves at 15 years. The ERG considered that 15 years is too long for the patient population under consideration because the treatment benefit is unlikely to extend beyond 5 years. The ERG requested that the manufacturer produce estimates with the analysis truncated at 5 years and 10 years. When the data were truncated at 5 years, the results from the different functions were more consistent with each other than when the data were truncated at 15 years. The ERG stated that it is unclear whether the mean based on extrapolating the curves and truncating the data at 5 years, or the restricted mean based on actual data, is more valid. Progression-free survival in the VELOUR trial was a secondary end point assessed by an independent review committee. The ERG advised that independent review committees may miss symptoms other than tumour growth caused by disease progression, which may have an impact on treatment duration and associated costs. The ERG noted that, when the manufacturer explored in a sensitivity analysis disease progression determined by investigator assessment taking into account symptomatic deterioration (as would happen in clinical practice), aflibercept was found to extend median progression-free survival by 1.74 months. The ERG stated that, while there was no evidence of a statistically significant interaction at the 5% level between treatment groups for most of the baseline patient characteristics, the results of the subgroup analyses suggested that patients with less advanced disease in the VELOUR trial (ECOG PS equal to 0, number of organs with metastasis less than or equal to 1, and patients with liver metastases only) may be more likely to benefit from treatment with aflibercept than those with more advanced cancer. # Cost-effectiveness evidence The manufacturer did not identify any published economic evaluations relevant to the decision problem. It submitted a de novo economic model to establish the cost effectiveness of aflibercept in patients with metastatic colorectal cancer who are eligible for second-line combination chemotherapy, and who were previously treated with an oxaliplatin-based regimen. The manufacturer performed subgroup analyses for patients with liver metastases only, and for a subgroup that excluded patients who had received oxaliplatin-based therapy in the adjuvant setting and whose disease relapsed within the following 6 months. The manufacturer conducted the analysis from the perspective of the NHS and personal social services and chose a time horizon of 15 years. It used a 2-week treatment cycle to reflect the treatment schedules of aflibercept and FOLFIRI, and applied a half-cycle correction. Costs and health effects were discounted at an annual rate of 3.5%. The manufacturer developed a state-transition Markov cohort model simulating 3 states: stable disease, progressed disease and death. The manufacturer further split the stable-disease health state into sub-states of 'on second-line treatment' and 'discontinued second-line treatment' to distinguish between patients who receive second-line treatment until their disease progresses, and those who stop second‑line treatment before their disease progresses. All simulated patients enter the model in the stable-disease health state and in the 'on second‑line treatment' sub-state. Patients can then continue treatment and remain in the 'on second-line treatment' sub-state, or move to the 'discontinued second‑line treatment' sub-state; they can instead move to the progressed-disease health state (and stop second-line treatment), or death. Patients cannot receive second-line treatment again once treatment is stopped, but they can receive further active therapy (systemic anticancer treatment, radiotherapy or surgery) or best supportive care. The manufacturer stated that the duration of second-line treatment in the model is based on the mean durations in the VELOUR trial to take into account dose delays or the discontinuation of aflibercept or FOLFIRI (for patients who were in the aflibercept group), or FOLFIRI (for patients who were in the placebo group), as observed in the trial. The manufacturer modelled adverse events as events (rather than health states) and it applied a utility decrement (disutility) for each adverse event. The manufacturer's model included parameters for overall survival, progression-free survival and time to discontinuing second-line treatment (before or after disease progression). To estimate the survival parameters, the manufacturer fitted alternative parametric functions (Weibull, log-normal, log-logistic and exponential) to observed Kaplan–Meier data from the VELOUR trial, and extrapolated the curves beyond the trial period for overall survival and time to discontinuing treatment, but not for progression-free survival, because the disease had progressed in all patients during the trial. In extrapolating those curves, the manufacturer assumed non-proportional hazards (that is, the hazard ratios between aflibercept plus FOLFIRI and FOLFIRI alone varied over time) so it modelled each treatment group separately. The manufacturer chose the base-case survival functions based on the results of statistical tests, visual inspection of the fit to the data and the clinical plausibility of the extrapolated portion of the curve. For overall survival, the manufacturer used the log-logistic function, and assumed that the survival benefit from treatment with aflibercept plus FOLFIRI increases relative to treatment with FOLFIRI alone until around 12 months after starting treatment, and then decreases over the 15-year time horizon, but does not cease at any point during the extrapolation period (that is, the overall survival curves start converging 12 months after starting treatment but never fully converge later in the extrapolation period). The manufacturer used the Weibull function for progression-free survival and time to treatment discontinuation. The difference in mean progression-free survival estimated by the manufacturer was 1.2 months in favour of aflibercept. Other parametric functions were explored in scenario analyses. The manufacturer stated that the model predicted a median overall survival and a median progression-free survival similar to those from the VELOUR trial. The largest difference was for progression-free survival in the FOLFIRI group, which the model overestimated compared with the survival time observed in the trial. Adverse events in the model included grade 3–4 adverse events that affected more than 5% of patients in the VELOUR trial, together with 6 rarer adverse events that the manufacturer's clinical advisory board considered important (gastrointestinal perforation, haemorrhage, febrile neutropenia, peripheral neuropathy, urinary tract infections and hand-foot syndrome). The subgroup analyses incorporated data specific to each subgroup. The manufacturer applied utility values in the model from its 'mCRC utilities study', in which investigators assigned patients to 1 of the following 3 groups: patients with stable disease who are receiving second-line treatment, and patients who had previously received second-line treatment but stopped it because of an adverse event, or because their disease progressed. Because the sample size of the group of patients who had an adverse event and stopped treatment was very small, the manufacturer did not use the utility estimates from this group, and instead assumed that all patients with stable disease have the same utility, equal to the utility of patients with stable disease who are receiving second-line treatment. The manufacturer got descriptions of health states from patients using the EQ-5D system, and derived the utility weights by applying UK valuation of health states estimated using the time trade-off method. The utility estimate used in the model for patients with progressed disease was 0.708. The manufacturer assumed that the utility in the progressed-disease health state is independent of time spent in the state. The manufacturer explained that, despite the age and health of patients, the utility values used in the model are relatively high because candidates for second-line chemotherapy must be fit enough to receive treatment. The manufacturer also identified relevant utility studies from a systematic review of the literature. It did not use the values in those studies to source the model, but used them to compare the estimates from its utility study, and noted that they were reasonably consistent. The utility estimates in the literature that the manufacturer considered relevant ranged from 0.73 to 0.81 for stable disease, and from 0.68 to 0.69 for the progressed disease. One other study, Best et al. (2010), reported utility values of 0.51 for stable metastatic disease and 0.21 for progressed metastatic disease, but the manufacturer did not consider this study relevant because the population included patients receiving adjuvant chemotherapy and patients in remission. The manufacturer got the disutilities associated with adverse events from the published literature, and supplemented these with clinical expert opinion. To calculate the average disutility per adverse event, the manufacturer assumed that an adverse event causes the same disutility regardless of the type of cancer. This gave an average disutility per adverse event of −0.0127 for patients receiving aflibercept plus FOLFIRI, and −0.0108 for those receiving FOLFIRI alone. The costs of aflibercept plus FOLFIRI and FOLFIRI alone did not depend on the duration of second-line treatment in the model; the manufacturer calculated them separately based on data from the VELOUR trial to reflect the dose delays (for example, because of an adverse event) and dose reductions observed in the trial. It assumed that any unused drug in a vial was discarded (wasted) for aflibercept and irinotecan (a component of FOLFIRI), but explored in scenario analyses other possibilities to model drug wastage. The cost of aflibercept in the model took into account the patient access scheme discount. To estimate costs of caring for people with metastatic colorectal cancer ('management costs' including supportive medications, clinician and nurse visits , imaging, laboratory tests, hospitalisations, palliative care, and personal and social care), the manufacturer conducted a retrospective observational study, and undertook a questionnaire-based survey of 6 UK clinical oncologists (both unpublished studies). In the observational study, the manufacturer collected resource-use data from patients who received oxaliplatin-based chemotherapy followed by FOLFIRI as second-line treatment, and used those data to estimate total management costs per 2-week cycle for different groups of patients (the manufacturer advised that every patient would eventually receive end-of-life care regardless of prior treatment, so it did not include resource use associated with end-of-life care in the model). The clinician survey aimed to gather data on community-based care, and on personal and social care. In this, the manufacturer elicited the average treatment practices of each oncologist to get data on managing patients with metastatic colorectal cancer. It also used the results of the survey, together with NHS reference costs, to estimate the costs associated with adverse events. The manufacturer used mean resource use for adverse events, but median resource use for community-based care, and personal and social care. The cost of subsequent therapies that patients could receive after stopping second-line treatment or experiencing disease progression was calculated based on the manufacturer's study of resource use, and was assumed to be independent of the type of second-line treatment. The manufacturer's deterministic base-case results estimated that the addition of aflibercept to FOLFIRI provides an additional 0.243 quality-adjusted life years (QALYs). This benefit is achieved with an additional cost of £8816, resulting in an incremental cost-effectiveness ratio (ICER) of £36,294 per QALY gained for aflibercept plus FOLFIRI compared with FOLFIRI alone. The manufacturer presented deterministic sensitivity analyses in which it varied the 20 parameters with the largest impact on the ICER, one at a time. The results showed that the ICER is most sensitive to the parametric function chosen for overall survival, the utility value chosen for the progressed-disease health state, and the number of administrations assumed for second-line treatment drugs. The manufacturer explained that improving overall survival and progression-free survival increased incremental QALYs in favour of aflibercept, but also increased drug costs and the costs incurred from prolonged overall survival after disease progression. The manufacturer carried out a probabilistic sensitivity analysis to summarise the uncertainty in the ICER. This showed that the probability of aflibercept plus FOLFIRI being cost effective when compared with FOLFIRI alone is less than 5% if the maximum acceptable ICER is £20,000 per QALY gained, and 22% at £30,000 per QALY gained. The manufacturer investigated the structural uncertainty in the model by fitting alternative parametric functions for overall survival and progression-free survival, and by directly applying patient-level data from the VELOUR trial to model progression-free survival (given that disease had progressed in all patients during the trial). It also performed scenario analyses to test the sensitivity of the ICER to alternative assumptions around drug wastage. In these, it explored the possibility of no drug wastage, and of reducing the dose to the nearest number of whole vials for patients who would otherwise use less than 5% of the vial contents. The highest ICER from these analyses was £49,805 per QALY gained (using the Weibull function to model overall survival). The manufacturer provided subgroup analyses to establish the cost effectiveness of aflibercept plus FOLFIRI compared with FOLFIRI alone in patients with liver metastases only, and in a subgroup that excluded those who had received oxaliplatin-based therapy in the adjuvant setting and whose disease had relapsed within the following 6 months. In comparison with the deterministic base-case ICER of £36,294 per QALY gained, the ICERs were £30,474 per QALY gained (incremental costs £10,974, incremental QALYs 0.360) and £32,480 per QALY gained (incremental costs £8573, incremental QALYs 0.264) respectively. At a maximum acceptable ICER of £30,000 per QALY gained, the probability of aflibercept plus FOLFIRI being cost effective compared with FOLFIRI alone in both subgroups is around 50% (numerical values not provided in the manufacturer's submission). ## ERG critique The ERG indicated that the manufacturer's economic evaluation is consistent with the NICE reference case. It noted that the modelled population is based on data from the VELOUR trial, which relate to patients who appear fitter and younger than those seen in clinical practice. In exploratory sensitivity analyses, the ERG investigated the effect of treating a population that better reflects patients with metastatic colorectal cancer in the UK than the VELOUR trial by modelling an older population with a lower health-related quality of life. The ERG considered that it is uncertain whether the hazard ratio for overall survival varies over time. The ERG reported that, when assuming in the manufacturer's model that the hazard ratio remains constant over time (that is, when applying the proportional hazards assumption), the ICER increased to £58,784 per QALY gained, with the difference being mainly driven by a reduction in incremental QALYs compared with the manufacturer's base case. The ERG considered that even this scenario may be relatively optimistic because the progression-free survival curves separate and then converge at around 12 months, suggesting that the hazard ratio could increase over time. In its cost-effectiveness analysis, the manufacturer assumed that the survival benefit from treatment with aflibercept plus FOLFIRI initially increases relative to treatment with FOLFIRI alone until around 12 months after starting treatment, and then decreases over the rest of the time horizon, but does not cease at any point during the extrapolation period. The ERG noted that the difference in overall survival between aflibercept plus FOLFIRI and FOLFIRI alone decreases at a relatively slow rate after the initial 12 months and, importantly, suggests a continuing treatment effect on overall survival during the entire 15-year horizon. The ERG explained that extrapolating overall survival data from the VELOUR trial, in which the median follow-up time was just under 2 years, over a 15-year time horizon meant that the assumptions underpinning the extrapolation are key to explaining the large differences between the observed median and the extrapolated mean estimates of overall survival. The ERG stressed that extrapolating the overall survival curves beyond the trial period is highly uncertain given that no data were available for more than 3 years' follow-up, and particularly that the progression-free survival curves separated and then converged at around 1 year. The ERG stated that the manufacturer did not explore this uncertainty sufficiently. Specifically, the manufacturer did not explore whether the risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups could become the same from the point at which the trial ends (that is, the treatment effect of aflibercept plus FOLFIRI does not continue over the extrapolation period). In addition, it did not explore whether the overall survival curves for aflibercept plus FOLFIRI and FOLFIRI alone could converge over the extrapolation period (that is, the treatment effect of aflibercept plus FOLFIRI gradually decreases from the point at which the trial ends), similar to the convergence observed with progression-free survival (in this scenario the risk of death may be higher in the aflibercept plus FOLFIRI group during the extrapolation period than in the FOLFIRI alone group). The ERG explored these 2 scenarios in its exploratory analyses. Regarding the utility estimates in the model, the ERG had concerns about the generalisability of the manufacturer's 'mCRC utilities study' because the study population appeared to be younger than UK patients, and the proportion of patients who had an ECOG PS of 2 was lower than that seen in UK clinical practice. Moreover, the ERG noted that the study was small, and produced counter-intuitive estimates in a subgroup analysis including UK patients only because the mean utility value for patients whose disease progressed was higher than for those who had stable disease and received second-line treatment. The ERG was concerned that the utility estimates used in the model from the manufacturer's utility study, as well as those reported in the literature, were high when compared with values used in previous appraisals of metastatic colorectal cancer, or with general UK population norms. The ERG was particularly concerned about the utility value in the model for patients whose disease had progressed. The ERG explained that, because the model predicts longer overall survival than progression-free survival, approximately three-quarters of absolute QALY increment is accrued after disease progression. Furthermore, the ERG stated that the manufacturer's assumption that utility in the progressed-disease health state is independent of time spent in the state is clinically implausible because patients' health-related quality of life decreases as disease progresses and patients get older. The ERG identified an error in the manufacturer's model in how disutilities associated with adverse events were applied, which reduced the disutilities in the model. Correcting this error increased the manufacturer's base-case ICER from £36,294 to £37,834 per QALY gained. The ERG applied this correction in its exploratory analyses. The costs of aflibercept plus FOLFIRI and FOLFIRI alone did not depend on the duration of second-line treatment in the model; the manufacturer calculated them separately based on data from the VELOUR trial to reflect the dose delays (for example, because of an adverse event) and dose reductions observed in the trial. The ERG stated that an alternative way to reflect dose delays and reductions would be to apply drug costs per administration (including administration costs) directly to the proportion of patients in each health state, in line with how utility values are applied. Adjusting this increased the manufacturer's base-case ICER from £36,294 to £37,539 per QALY gained. The ERG applied this change in its exploratory analyses. The manufacturer assumed that, because aflibercept is administered at the same time as FOLFIRI, no extra costs in terms of additional staff or inpatient admissions would be incurred. The ERG indicated that, even if given simultaneously, administering aflibercept involves preparing an additional infusion, which incurs an extra cost compared with FOLFIRI alone. The ERG highlighted that, in Cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy (NICE technology appraisal guidance 242), the pharmacy preparation of cetuximab and bevacizumab was estimated to be £15 per infusion. In addition, the ERG stated that, if aflibercept is given before or after FOLFIRI, instead of at the same time, administering aflibercept will include an additional hour of infusion time compared with administering FOLFIRI alone. The ERG noted that the model is sensitive to the assumptions underlying the administration costs of aflibercept plus FOLFIRI, and it explored these assumptions in sensitivity analyses. Regarding resource use for community, and personal and social care, the manufacturer modelled the median estimate from its survey of clinical oncologists, instead of the mean. The ERG indicated that mean values are more commonly used in cost-effectiveness analyses, and that the use of medians may underestimate expected costs. The ERG noted that, when the manufacturer used the mean value in a sensitivity analysis, the base-case ICER increased from £36,294 to £41,222 per QALY gained. The ERG stated that it is unclear in this case whether the median is a better estimate than the mean because there was a small number of survey responders (n=6) and the data were skewed. The ERG noted that the model is sensitive to this parameter and it further explored this in sensitivity analyses. The ERG advised that the results of the analysis of the liver metastases only subgroup should be interpreted cautiously. Because the parametric curves for overall survival and progression-free survival were fitted independently for each treatment group based on data for this subgroup from the VELOUR trial, and the subgroup corresponded to approximately 25% of the trial population, the ERG highlighted that the analysis may not have been powered to demonstrate a difference in treatment effect in this subgroup. For the analysis of the subgroup that excluded adjuvant chemotherapy, the ERG indicated that this analysis was performed post hoc, and so its results may be biased. The ERG's clinical advisers also stated that patients who receive adjuvant chemotherapy and whose disease relapses quickly afterwards would not be treated differently from other patients in UK clinical practice. ## ERG exploratory analyses The ERG investigated the uncertainty around how the manufacturer had chosen to extrapolate overall survival by considering other scenarios for the magnitude and duration of the overall survival benefit associated with second-line treatments. The ERG modelled the following scenarios by assuming that: The risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same 30 months after starting treatment. The risk of death in aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same 36 months after starting treatment.The ERG implemented the following scenarios to mimic the converging progression-free survival curves. The survival curves begin converging 30 months after starting treatment, and come together after a further 12 months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon. The survival curves begin converging 30 months after starting treatment, and come together after a further 18 months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon. The survival curves begin converging 36 months after starting treatment, and come together after a further 12 months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon. The survival curves begin converging 36 months after starting treatment, and come together after a further 18 months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon.In all of the above scenarios, the ERG assumed that the treatment effect of aflibercept plus FOLFIRI continues until either 30 months or 36 months. The ERG chose these time points because it identified them as particularly uncertain from the hazard ratios for overall survival by 6-month periods presented by the manufacturer. When the ERG assumed that the risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same beyond the trial period, the ICERs were £45,570 and £42,718 per QALY gained for a treatment effect of aflibercept plus FOLFIRI lasting until 30 months or 36 months respectively. In the scenario in which the ERG assumed that the survival curves begin converging 30 months or 36 months after starting treatment over a period of 12 months or 18 months, the ICERs ranged from £55,424 per QALY gained (when curves begin converging after 36 months over 18 months) to £66,377 per QALY gained (when curves begin converging after 30 months over 12 months). The ERG explained that, in this scenario, when the curves begin converging over 12 months, the magnitude of the additional survival benefit from treatment with aflibercept plus FOLFIRI is assumed to taper at a higher rate than when the curves begin converging over 18 months, and so convergence over 12 months results in higher ICERs. To address its concerns about some of the parameters used in the manufacturer's base-case model, the ERG performed the following sensitivity analyses, varying 1 parameter at a time: Applying 2 alternative utility values for patients whose disease progressed: 0.21 from Best et al. (2010) and 0.60 from Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer (NICE technology appraisal guidance 118). The ERG stated that the latter may better reflect the values reported in the literature. Including a cost for preparing an additional infusion of aflibercept, and a cost for an additional hour of infusion time for aflibercept plus FOLFIRI compared with administering FOLFIRI alone. For the preparation cost, the ERG applied a cost of £15, in line with NICE technology appraisal guidance 242 and, for the extra time for infusion, it applied £45, based on NHS reference costs. The ERG explored the impact of these 2 assumptions separately and jointly.When the ERG used the lower utility values of 0.21 and 0.6, the ICER increased from £36,294 per QALY gained (base-case ICER) to £71,143 and £40,608 per QALY gained respectively. Including a cost for preparing an additional infusion of aflibercept, and a cost for an additional hour of infusion time for aflibercept plus FOLFIRI, together increased the ICER to £39,258 per QALY gained. The ERG applied its preferred adjustments and model inputs to the manufacturer's base-case model (hereafter the 'ERG base case'). In this, the ERG corrected the error it identified in the manufacturer's model (section 3.43), and applied the acquisition and administration costs to all patients in the second-line treatment health state of the model (section 3.44). In addition, the ERG assumed that patients entered the model at the age of 70 years and accounted for the impact of age on health-related quality of life by applying a utility decrement for aging. The ICER resulting from the above 3 changes was £41,653 per QALY gained. The ERG then applied its preferred model inputs for the parameters it varied in one-way sensitivity analyses: an additional administration cost for aflibercept of £15 mean instead of median resource use estimates (section 3.46).The ERG applied the above with or without: a utility value of 0.60 for patients whose disease had progressed.When the ERG applied the 0.60 utility value, the analysis gave an ICER of £54,368 per QALY gained for aflibercept plus FOLFIRI compared with FOLFIRI alone. Without this modification (that is, using the same value in the manufacturer's base case), the ICER was £47,965 per QALY gained. The ERG presented deterministic results for the scenario analyses (section 3.48) within its base case, and using the utility value of 0.60 for patients whose disease had progressed. It presented results for the overall population, and separately for each subgroup the manufacturer had identified. When the ERG assumed that the risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same beyond the trial period, the ICERs were £66,506 and £62,894 per QALY gained for a treatment effect of aflibercept plus FOLFIRI lasting until 30 months or 36 months respectively. In the scenario in which the ERG assumed that the survival curves begin converging 30 months or 36 months after starting treatment over a period of 12 months or 18 months, the ICERs ranged from £78,226 per QALY gained (when the curves begin converging after 36 months over 18 months) to £92,089 per QALY gained (when the curves begin converging after 30 months over 12 months). The ERG found that, using median resource‑use estimates from the manufacturer's survey of UK oncologists (that is, as per the manufacturer's base case), instead of mean, consistently decreased the ICERs for the scenario analyses within the ERG base case by approximately £5000 per QALY gained. For the subgroup analyses combining the ERG's assumptions of overall survival and the ERG's alternative base case, the ICER for aflibercept plus FOLFIRI compared with FOLFIRI ranged from £46,576 to £58,257 per QALY gained for the liver metastases only subgroup, and from £57,224 to £80,187 per QALY gained for the subgroup that excluded patients who had received adjuvant oxaliplatin-based therapy and whose disease had relapsed within the following 6 months. # Manufacturer's response to consultation on the appraisal consultation document To address the Committee's considerations of the evidence described in the appraisal consultation document, the manufacturer submitted a response to the consultation, which included: a revised patient access scheme discount (the details of which are commercial in confidence), utility data for the stable-disease state from an interim analysis of a phase III study (ASQoP), and proposed changes to parameters in the model considered by the Committee. The ASQoP study was an international single-arm open-label phase III study. The primary objective of the study was to evaluate the safety of aflibercept in patients with metastatic colorectal cancer whose disease progressed following treatment with an oxaliplatin-based regimen. Its secondary objective was to establish health-related quality of life in this population. Because the study was not completed at the time of the second Committee meeting, the manufacturer provided interim results for mean EQ-5D utility values at baseline and after patients received 3 and 5 cycles of treatment. Data from this study were available for the stable-disease state only. The manufacturer derived a utility value of 0.78 for the stable-disease state by using a weighted average of the utility values for patients who received 3 and 5 cycles of treatment. In its response, the manufacturer made the following comments on some of the parameters in the model originally considered by the Committee: The manufacturer considered that it was more clinically plausible to assume that the hazard ratio tapers to 1.0 after the end of the trial over a short period of time than to assume that the hazard ratio immediately changes to 1.0 at the end of the trial (the Committee's preferred extrapolation scenario). The manufacturer did not agree that the utility value chosen by the ERG for the progressed-disease state in its base case (0.6) was appropriate because it was based on a comparison with population 'norm' data that reflects the general population, which includes people with significant morbidities. The manufacturer stated that the utility value for progressed disease used in its original base case came from a relevant 'real-world' study that met the requirements of the NICE reference case. However, the manufacturer acknowledged that, according to clinical opinion, health-related quality of life declines sharply towards the end of life for patients with metastatic colorectal cancer. The manufacturer considered that assuming a starting age of 70 years in the model (as in the ERG base case) was too high according to available evidence and feedback from experts, and that a starting age of 60 years was more appropriate. The manufacturer provided the average age of patients with metastatic colorectal cancer receiving second-line treatment in 4 UK observational studies. It stated that these data were closer to the average age of patients in the VELOUR trial (60 years) than the average age used by the ERG (70 years). The manufacturer argued that the median value, rather than the mean value, from its survey of clinical oncologists was more appropriate for estimating resource use. This was because the data on the parameter for the number of visits received by a patient from a palliative care team contained a clear outlier, which had a significant impact on the ICERs. The manufacturer further stated that the monthly cost of managing a patient whose disease had progressed used in NICE technology appraisal guidance 242 was closer to the median value than the mean. The manufacturer revised its original base case by: applying a revised discount to the patient access scheme assuming that, 36 months after starting treatment, the hazard ratio for overall survival tapers to 1.0 over a 12-month period assuming that patients enter the model at the age of 60 years, and accounting for the impact of age on health-related quality of life by applying a utility decrement for aging updating the utility value of 0.78 for the stable-disease state from the ASQoP study correcting the disutilities associated with adverse events (section 3.43) including a cost of £15 for preparing an additional infusion of aflibercept, and a cost of £45 for additional administration time (£60 in total).The manufacturer's deterministic results of the revised base case estimated that the addition of aflibercept to FOLFIRI would provide an additional 0.20 QALYs. This estimated benefit would cost an additional £8500, resulting in an estimated ICER of £42,242 per QALY gained for aflibercept plus FOLFIRI compared with FOLFIRI alone. The probabilistic ICER from this analysis was estimated to be £42,197 per QALY gained, and the probability of aflibercept plus FOLFIRI being cost effective when compared with FOLFIRI alone was around 10% if the maximum acceptable ICER was £30,000 per QALY gained, and 72% at £50,000 per QALY gained. The manufacturer performed the following scenario analyses, in which it varied one parameter at a time: assuming that, 30 months after starting treatment, the hazard ratio for overall survival tapers to 1.0 over a 12-month period assuming that, 24 months after starting treatment, the hazard ratio for overall survival tapers to 1.0 over a 12-month period assuming that, 36 months after starting treatment, the hazard ratio changes to 1.0 assuming that, 30 months after starting treatment, the hazard ratio changes to 1.0 assuming that patients enter the model at the age of 65 years (while also applying a utility decrement for aging) applying the utility value for the stable-disease health state from the 'mCRC utilities study' (the value used in the manufacturer's original base case) applying a utility value of 0.3 during the last 2 months of life applying the mean value from its survey of clinical oncologists after excluding the outlier in the data on the number of visits received by a patient from a palliative care team applying the cost of managing disease progression used in NICE technology appraisal guidance 242.The ICERs resulting from these scenario analyses ranged from £42,002 per QALY gained (when a utility value of 0.3 was applied during the last 2 months of life) to £47,246 per QALY gained (when the hazard ratio for overall survival begins tapering to 1.0 24 months after starting treatment over a 12-month period). ## ERG critique of the manufacturer's revised base case The ERG stated that the manufacturer's extrapolation of overall survival in its revised base case was not based on new data, and so the ERG did not consider it any more plausible than the other scenarios previously presented to the Committee. The ERG considered that the manufacturer's assumption of a 60-year age for starting treatment in the model was unrealistic, noting that 3 of the 4 observational studies provided by the manufacturer reported an average starting age of 63 years. However, the ERG also accepted that a starting age of 70 years may be high, and that an age of 65 years was a satisfactory compromise. The ERG considered it appropriate for the manufacturer to have sourced the stable-disease utility value from the ASQoP study. However, the ERG argued that, because the manufacturer applied this value in the model for patients both on and off treatment, it would have been more appropriate to use the utility value of 0.77 for patients before they started treatment than the value for patients receiving treatment. The ERG indicated that the manufacturer's approach may have biased the utility value if patients receiving treatment were healthier than those who were not on treatment. The ERG was concerned that, for the progressed-disease health state, the manufacturer continued to use the utility value from its 'mCRC utilities study', which the ERG considered high. Regarding the scenario analysis in which the manufacturer applied a utility value of 0.3 during the last 2 months of life, the ERG stated that this was not based on empirical evidence. The ERG agreed that the estimate from the manufacturer's survey of UK oncologists included an outlier. It considered that using the mean value after excluding this outlier (as in the manufacturer's scenario analysis) was more appropriate than using the median. To address remaining uncertainties, the ERG altered the manufacturer's revised base case by applying the utility value before treatment from the ASQoP study for the stable-disease state; the progressed-disease utility value of 0.6; and the mean resource use estimate from the manufacturer's survey of UK oncologists after excluding the potential outlier; and assuming patients start treatment at the age of 60 or 65 years. The ERG applied these changes together with each of the following extrapolation scenario: assuming a hazard ratio of 1.0 30 months after starting treatment assuming a hazard ratio of 1.0 36 months after starting treatment assuming that, 24 months after starting treatment, the hazard ratio tapers to 1.0 over 12 months assuming that, 30 months after starting treatment, the hazard ratio tapers to 1.0 over 12 months.When the ERG assumed that patients start treatment at the age of 60 years, the resulting ICERs with the above scenarios were £54,243, £50,991, £55,139 and £51,296 per QALY gained respectively. When it assumed that patients start treatment at the age of 65 years, the ICERs were £54,890, £51,634, £55,791 and £51,941 per QALY gained respectively. The ERG presented estimates of the difference in mean overall survival for different time horizons, while assuming a hazard ratio of 1.0 after 30 or 36 months. When the ERG set the time horizon to 5, 10 and 15 years, the differences in mean overall survival were 2.7–2.8, 3.2–3.5 and 3.4–3.7 months respectively. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aflibercept in combination with irinotecan and fluorouracil-based therapy, having considered evidence on the nature of metastatic colorectal cancer and the value placed on the benefits of aflibercept in combination with irinotecan and fluorouracil-based therapy by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee heard from the clinical specialists and patient experts about the nature of the condition. It heard that metastatic colorectal cancer can be debilitating, can affect a person's ability to work and lead a normal life, and can lead to premature death. The Committee noted that the illness also brings about a burden on relatives and friends. The Committee understood that the course of the disease varies, with some people's health deteriorating quickly and others' slowly. The Committee heard from patient experts that quality of life in people with the disease may be bad when it is first diagnosed because patients are usually very weak and may have many metastases, but that with treatment the quality of life may improve, as may the ability to work and socialise. The Committee understood that, in clinical practice, disease progression (in patients who already have metastatic disease) would be detected using radiological imaging, although symptoms would also be taken into account. It heard from patient experts that disease progression usually affects quality of life, but it may take a long time before it affects daily activities. The Committee heard further from patient experts that, although people would appreciate small extensions of life, they value quality of life more than length of life. The Committee noted that treatment is generally associated with unpleasant side effects, particularly high blood pressure and diarrhoea and that, while some people may be willing to tolerate the side effects, others may not. The Committee understood that clinicians are now more experienced in managing these side effects and 'optimising' treatment, although it heard from patient experts that the treatments for the side effects may themselves have side effects. The Committee discussed the management of metastatic colorectal cancer. It heard from clinical specialists that the current treatment options for this patient population are limited, and that treatment is determined individually. The Committee was aware that, in Colorectal cancer: the diagnosis and management of colorectal cancer (NICE clinical guideline 131), NICE recommends, as second-line treatment options, single-agent irinotecan or folinic acid/5-fluorouracil/irinotecan (FOLFIRI) after first‑line folinic acid/5-fluorouracil/oxaliplatin (FOLFOX), and single‑agent irinotecan after first-line capecitabine/oxaliplatin (XELOX). The Committee heard from the clinical specialists that resecting tumours surgically may be a treatment option in some patients with metastatic disease, noting that systemic therapy can make resection possible in some patients. The Committee understood that the proportion of patients with metastatic colorectal cancer who survive over 5 years has increased because of successful tumour resection. The Committee noted that patients consider biologic therapies such as aflibercept to improve quality of life compared with chemotherapy. # Clinical effectiveness The Committee considered the evidence on the clinical effectiveness of aflibercept, noting that it was derived from the VELOUR trial. The Committee agreed that the VELOUR trial was of good quality and directly relevant to the decision problem; however, it considered that the trial had limitations. The Committee, echoing comments from a patient expert, would have liked the manufacturer to have collected and presented trial data relating to health-related quality of life. The Committee would also have liked the manufacturer to have followed and presented event data for all patients after the end of the trial as defined. The Committee discussed the initial Evidence Review Group's (ERG) concern that patients in the VELOUR trial appeared to have been fitter and younger than those seen in UK clinical practice. The Committee also heard from clinical specialists that the disease and demographic characteristics seen in patients in the VELOUR trial differed from those for patients treated in UK clinical practice; however, evidence from the VELOUR trial showed that response to treatment does not vary across patient groups. The Committee was aware that the studies provided by the manufacturer in response to consultation suggested that patients receiving second-line treatment for metastatic colorectal cancer in the UK were somewhat older than those in the VELOUR trial. The Committee agreed that the patient population in the VELOUR trial was otherwise reasonably representative of patients seen in the UK and therefore concluded that the results of the VELOUR trial are generalisable to UK clinical practice. The Committee discussed the results for overall survival, the primary end point of the VELOUR trial. The Committee noted that, in its submission and in response to clarification requests by the ERG, the manufacturer produced a range of estimates for the difference in overall survival between the aflibercept and placebo groups of the trial. The Committee considered that the data observed directly from the trial were sufficiently mature at the study cut-off date to establish median overall survival, and agreed that the difference in median overall survival of 1.44 months reflects a statistically significant but clinically small benefit. The Committee noted that the restricted mean difference of 1.92 months (based on the unlikely and conservative assumption that all remaining patients die immediately at the end of the trial) was higher than the median. The Committee therefore concluded that the difference in median overall survival is likely to underestimate the mean survival benefit of aflibercept. The Committee discussed the estimated mean survival benefit of 4.7 months derived from extrapolation, in light of the trial data. The Committee noted that, to estimate this benefit, the manufacturer extrapolated the survival curves from a trial with a median follow-up of just under 2 years up to 15 years. The Committee noted the comments received in the ACD consultation, and agreed to explain its concerns over the survival extrapolation in more detail. The Committee noted the marked difference between the estimated mean survival benefit of 4.7 months and that of 1.44 months based on median values of overall survival. The Committee understood that the manufacturer considered the extrapolated mean value to represent the magnitude of the clinical benefit of aflibercept better than the median because there were a few patients who experienced a sustained survival benefit from treatment with aflibercept. Although the Committee agreed that a small proportion of patients, with as yet undefined characteristics, appeared to derive greater benefit from aflibercept than most patients in the trial, it agreed that extrapolating the survival curves over 15 years could result in highly uncertain estimates for overall survival. The Committee therefore discussed whether the manufacturer's estimates of mean overall survival were robust. It noted that, during the trial's maximum 3-year follow-up period, 66% of patients in the aflibercept group and 75% of those in the placebo group had died, and a proportion had been censored (data academic in confidence), reducing the number of patients at risk of dying to 47 patients (3.8%) at 30 months and 1 patient (0.1%) at 36 months. The Committee heard from the ERG that, because of this, the hazard ratios for overall survival for patients with follow-up nearing 36 months had wide confidence intervals, reflecting imprecise and uncertain estimates. The Committee noted that, at 36 months' follow-up, the Kaplan–Meier curves indicated that approximately 17% of patients randomised to aflibercept were alive but that this 17% represented only 1 patient remaining uncensored and at risk of dying, which considerably increased the uncertainty around the long-term effect on survival. The Committee noted that the cut-off date for the trial was 07 February 2011, and that the manufacturer was aware that some patients from the trial were still alive. The Committee met 18 months after this date, but no further data to support the manufacturer's extrapolation were available. The Committee appreciated that estimating mean overall survival often requires extrapolating beyond a trial period, but considered that the manufacturer's extrapolation of overall survival from a population with very few patients at risk of dying after 30 months' follow-up, over a further 12 years, was associated with great uncertainty (see section 4.24). The Committee discussed the mean survival benefit of 4.7 months in light of the different parametric functions used by the manufacturer to estimate overall survival. The Committee was aware that, to estimate this benefit, the manufacturer used the log-logistic function, which it considered to provide the best fit to the observed data, and extrapolated the survival curves over 15 years. The Committee noted that the estimates using other parametric functions ranged from 3.0 months (with the Weibull function) to 5.3 months (with the log-normal function). The Committee discussed which extrapolation period could be considered appropriate to estimate mean overall survival, in view of the life expectancy of patients with metastatic colorectal cancer in clinical practice. The Committee was aware that extrapolation periods should reflect the time in which all patients will have died, but that a longer than 5-year survival for patients with metastatic colorectal cancer is very unusual. It was also aware that, with surgical resection of liver metastases, survival can increase, but that a very small proportion of patients in the VELOUR trial had surgical resection of liver metastases (data designated as academic in confidence), and the Committee was not presented with information about their survival. The Committee also considered survival statistics from the US cancer registry Surveillance, Epidemiology, and End Results (SEER), which showed that 6.9% of patients with metastatic colorectal cancer survive for 5 years. However, because this registry included patients who had received multiple lines of therapy, including surgical resections of tumours and therapies that may not have been considered established NHS practice, the Committee did not consider the data from the SEER registry to be a reasonable proxy for the life expectancy of the population specified in the marketing authorisation of aflibercept. The Committee agreed that a shorter extrapolation period better reflected the natural history of the disease at this stage, and yet accounted for patients who derived greater benefit from aflibercept than most patients in the VELOUR trial. It considered the robustness of the mean overall survival benefit, obtained using the log-logistic function, of 3 months (5 years extrapolation time), 4.7 months (15 years extrapolation time) and 6.6 months (without truncating the survival curves). The Committee was concerned that the log-logistic function had a very 'heavy tail' (that is, a high probability of getting large values at the end of the time horizon) compared with other parametric functions, and that this is likely to have led to an overestimate of the survival benefit of aflibercept. The Committee was also concerned that the manufacturer did not characterise the uncertainty around any of the estimates. In summary, the Committee concluded that, because of the uncertainties around the survival extrapolation, the actual trial data and the life expectancy of patients at this stage of the disease, extrapolating overall survival with the log-logistic function over 15 years did not provide a plausible mean overall survival benefit. The Committee considered the relationship between progression-free survival and overall survival from the VELOUR trial. The Committee was aware that the manufacturer used disease progression assessed by an independent review committee in its base case. The difference in median progression-free survival between aflibercept and placebo using this methods was 2.23 months, which was a higher value than when disease progression was determined by investigator assessment (1.74 months) and higher than the mean progression-free survival (see section 3.25).The Committee considered the shapes of the Kaplan–Meier curves (reflecting the trial data) for overall survival and for progression-free survival. It noted that the curves continued to diverge during the trial period for overall survival, whereas, for progression-free survival, the curves initially diverged but then converged at around 12 months, reflecting almost the same rate of progression for patients randomised to aflibercept or placebo from that time onward. The Committee heard from the clinical specialists that, because the overall survival curves continued to separate for both patients who had or had not stopped treatment, the survival curves might reflect a disease-modifying effect in that aflibercept might have altered the natural course of the disease whereby, despite the disease progressing, patients lived longer even after treatment stopped (that is, survival post disease progression was increased more than progression-free survival). The Committee discussed how the disease-modifying effect could be explained clinically. It heard that aflibercept may have delayed death by shrinking tumours, and so extended the period before the tumour grew again. However, the Committee was not presented with evidence that tumours had shrunk, and was aware that the disease had progressed in all patients during the trial. The Committee agreed that there was no robust evidence to make firm conclusions about the likely cause of the different shapes of the overall survival and progression-free survival curves, and that the magnitude of progression-free survival depended on the method used to calculate it. The Committee considered that the subgroup analysis presented by the manufacturer for patients with liver metastases only compared with metastases not confined to the liver. The Committee noted that, in this subgroup, there was a statistically significant interaction test at the 10% level. The Committee was aware that the 10% significance level was less specific (that is, a higher chance of a positive finding) than the more conventional 5% level. The Committee agreed that there is no evidence to suggest that aflibercept would be more effective in patients with liver metastases only than in patients with metastases confined to other organs. The Committee was aware that patients with liver metastases only are more likely to be considered for surgical resection of the metastases and possibly live longer than those with widespread metastases. The Committee therefore discussed whether aflibercept can make liver metastases operable in patients with metastatic colorectal cancer. It noted that only a very small minority of patients in the VELOUR trial proceeded to have surgical resection of liver metastases after treatment with aflibercept. The Committee heard from the clinical specialist that, in approximately 20–30% of patients who have surgery to remove liver metastases, metastatic colorectal cancer can be cured. The Committee, however, was not presented with evidence about rates of resection and cure with aflibercept in the subgroup of patients with liver metastases only. The Committee also considered that resecting liver metastases to achieve a cure was more appropriate in the first-line setting than in the second-line setting. Furthermore, it heard from the manufacturer that the modelling of the subgroup did not include the costs of surgical resection. The Committee concluded that it would be appropriate to include this cost and that including it is likely to affect the incremental cost-effectiveness ratio (ICER). The Committee agreed that, given the lack of evidence, aflibercept cannot be considered an effective treatment option to make liver metastases resectable. The Committee therefore concluded that this subgroup should not be considered further. The Committee considered the subgroup that excluded patients who had received oxaliplatin-based therapy in the adjuvant setting and whose disease had relapsed within the following 6 months. The Committee heard from the clinical specialists that, in clinical practice, patients in this subgroup would not be treated differently from the overall trial population. In addition, the Committee noted that the manufacturer acknowledged that the analysis for this subgroup was planned after the trial results had been compiled (post hoc), and that the test for interaction did not show that the treatment effect in this subgroup differed from the effect in the rest of the trial population. The Committee therefore concluded that it did not need to consider further the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy. The Committee discussed the adverse events associated with aflibercept. The Committee noted that more patients in the aflibercept group (27%) stopped treatment because of adverse events than in the placebo group (12%). The Committee also noted that adding aflibercept to FOLFIRI increased the adverse events typically associated with FOLFIRI, most notably neutropenia, although it heard from clinical specialists that neutropenia would not routinely be treated in clinical practice. The Committee heard from the manufacturer that the dose of FOLFIRI used in the trial was higher than the dose that is routinely used in clinical practice and might have caused some of the adverse events. The Committee was also aware that aflibercept increased the risk of hypertension, as would other anti-vascular endothelial growth factor therapies. The Committee concluded that treatment with aflibercept plus FOLFIRI was associated with a considerable burden of adverse effects, but that, being a new treatment, less is known about its adverse effects profile than for other available treatments. # Cost effectiveness The Committee considered the structure of the model submitted by the manufacturer, and how it captured the main aspects of the condition. The Committee noted that the manufacturer chose to split the stable-disease health state into 2 sub-states to capture the costs and health benefits for patients with stable disease who either receive second-line treatment with aflibercept plus FOLFIRI or FOLFIRI alone, or who have stable disease but have stopped second-line treatment for reasons other than disease progression. The Committee heard from the ERG that the manufacturer applied the same utility value to the 2 sub-states of the stable-disease health state. It further heard that the acquisition and administration costs of second-line treatments in the model did not depend on the proportion of patients in each state, and that they were calculated outside the model. The Committee noted that the costs and quality-adjusted life years (QALYs) in the stable-disease health state were not specific to the 2 sub-states ('on second-line treatment' and 'post second-line treatment'). The Committee concluded that overall the model adhered to the NICE reference case for assessing cost effectiveness. The Committee discussed whether or not the 15-year time horizon used by the manufacturer in the model was appropriate. The Committee appreciated that that the choice of the time horizon is a sensitive parameter in the model given the uncertainty associated with extrapolating overall survival. The Committee was aware that the time horizon should be sufficiently long to capture all the costs and health benefits in the full population (that is, a lifetime horizon should be used). The Committee therefore concluded that a time horizon of 15 years was, in principle, appropriate because all patients are likely to have died by 15 years; however, the Committee agreed that, when the time horizon is much longer than the trial duration, and the life expectancy of most patients, it is particularly important to explore the assumptions underlying how overall survival is extrapolated. The Committee discussed the manufacturer's assumptions for extrapolating overall survival in the model, and the alternative assumptions considered by the ERG in its exploratory analyses. The Committee noted that the manufacturer assumed that the survival benefit from treatment with aflibercept plus FOLFIRI increases relative to treatment with FOLFIRI alone until around 12 months after starting treatment, and then decreases over the 15-year time horizon, but that the hazard ratio never reaches 1.0 (that is, a patient previously randomised to aflibercept will always have a lower risk of dying, even if not receiving aflibercept, relative to a patient previously randomised to placebo). The Committee noted that the ERG explored 2 alternative scenarios: the first assumed that the risk of death becomes the same in both treatment groups at the point at which the trial ends and continues to be the same for the remainder of the time horizon period (that is, the hazard ratio becomes 1.0 after 3 years) the second assumed that the overall survival curves for aflibercept plus FOLFIRI and FOLFIRI alone converge over the time horizon (that is, the hazard ratio gradually increases from the end of the trial until the survival curves come together, then the hazard ratio becomes 1.0 thereafter).The Committee understood that, in the ERG's second scenario, patients receiving aflibercept plus FOLFIRI need to have a higher risk of death than patients receiving FOLFIRI alone (that is, the hazard ratio may be greater than 1.0) for the curves to converge. The Committee considered that the manufacturer's assumption that the treatment benefit continues beyond the trial period and until 15 years is highly uncertain given that most patients had died during the 3-year follow-up period of the trial. The Committee considered that the ERG's analysis that allows the hazard ratio to become greater than 1.0 could be considered implausible. The Committee agreed that the ERG's first scenario, which assumes equal risk of death for all patients beyond the trial period (hazard ratio equals 1.0), represents an acceptable compromise between the 2 extremes of assuming continuing treatment effect (manufacturer's base case) and allowing for a reversed treatment effect (ERG's second scenario). The Committee noted that, in response to consultation, the manufacturer implemented a new scenario in its revised base case in which the hazard ratio begins to taper to 1.0 36 months after starting treatment, over a 12-month period. The Committee agreed that as a means to extrapolate overall survival both its preferred scenario (that is, the ERG's first scenario) and the manufacturer's new scenario were associated with some degree of uncertainty. In the absence of further evidence to validate the manufacturer's new approach, the Committee maintained its preference for the ERG's first scenario. The Committee considered the estimates of health-related quality of life used in the manufacturer's model, noting that it would have preferred these data to have been collected from the VELOUR trial. The Committee was aware that the manufacturer got the utility value for the stable-disease state from the 'mCRC utilities study' and revised it after consultation to a value derived from the ASQoP study because the data from this study were new, and not because the Committee questioned the validity of the original value. The Committee noted that the ERG preferred another value from the ASQoP study for the stable-disease state but, because the difference between the manufacturer's revised value (0.78) and the ERG's preferred value (0.77) was small and likely to have a negligible impact on the ICER, the Committee concluded that either value could be considered appropriate. The Committee discussed the appropriate utility value for the progressed-disease state in the model, noting that, because approximately three-quarters of the QALY gain in the model was accrued after disease progression, the model is highly sensitive to this parameter. The Committee, having noted the mean and median time to disease progression in the manufacturer's utility study, considered that the utility value chosen by the manufacturer for the progressed-disease state did not reflect the entire duration of progressed disease but only early progressed disease, and so was likely to be an overestimate (see section 3.28). The Committee was aware of the participation bias associated with studies of this nature. Furthermore, it heard from the ERG that the manufacturer's study was small, and produced counter-intuitive estimates in 1 subgroup analysis. The Committee was aware that, although the manufacturer stated that the data queries noted in its submission had been resolved, the manufacturer had yet to submit the study for peer-reviewed publication. The Committee was aware that, in its base case, the ERG used an alternative lower value of 0.60, which had been used in NICE technology appraisal guidance 118, and that the ERG considered this value to represent a reasonable balance of the utility values for progressed disease used in other NICE guidance, which ranged from 0.21 to 0.69. The Committee was aware that the utility value of 0.69 used in NICE technology appraisal guidance 242 for progressed disease was based on patients who had lived long enough to receive more courses of chemotherapy than patients in the VELOUR trial, and so likely reflected patients with a better health state. The Committee agreed that no utility values for progressed disease were universally accepted as valid, but that it would be important that the utility value reflected the entire progressed-disease state. The Committee was aware that the quality of life for patients with metastatic colorectal cancer deteriorates relatively slowly other than during the last few months, when it may deteriorate faster, and that exploring a utility value of 0.3 during the last 2 months of life was a reasonable attempt by the manufacturer to address this. The Committee also agreed that adjusting the utility values for age was appropriate to reflect the natural deterioration in health-related quality of life in patients with the disease. The Committee concluded that the most plausible utility value for the progressed-disease health state would lie between the manufacturer's and the ERG's estimate. The Committee discussed the costs of administering aflibercept plus FOLFIRI in the model, noting that the manufacturer assumed no extra cost for administering aflibercept in its original model. The Committee was aware that aflibercept would normally be prepared in a sterile compartment, and would therefore incur an extra cost; the Committee estimated that this cost is likely to be higher than the £15 used by the ERG. The Committee was also aware that the marketing authorisation for aflibercept stipulates that aflibercept should be administered over 1 hour before the infusion with FOLFIRI, but that the cost for an additional hour of infusion time (£45) was not included in the ERG base case. The Committee acknowledged that the manufacturer's revised base case accounted for the extra preparation cost and the cost for an additional infusion time for aflibercept. The Committee noted that, in response to consultation, the manufacturer had provided data showing that the average age of patients treated in the NHS with second-line chemotherapy for metastatic colorectal cancer was 60 years in 1 study and 63 years in 3 others. The Committee agreed that the 70-year age of starting treatment, as initially assumed by the ERG in its base case, was therefore too high. It concluded that an age between 60 and 65 years is more appropriate. The Committee discussed the costs in the model derived from the manufacturer's survey of clinical oncologists about community-based care, and personal and social care. The Committee noted that this study was small and therefore associated with uncertainty, and did not provide evidence that the oncologists in the survey were representative of practitioners in the UK. The Committee noted that the manufacturer's model incorporated median estimates from the survey because the responses from clinicians on 1 parameter (the number of visits received by a patient from a palliative care team) included an outlier, whereas the ERG argued that the mean was more appropriate. The Committee agreed that, if the sample of clinicians was appropriately homogenous and reflected similar practices, the distribution of the data collected from the survey would be largely uniform, and it would be more appropriate to use the mean rather than the median. The Committee noted that, although the manufacturer continued to use the median value in its revised base case, it presented a scenario analysis that incorporated the mean after excluding the outlier, an approach that the ERG considered appropriate. Although the Committee agreed that mean values should normally be used to estimate resource use and costs, it concluded that, in this instance, using the mean after excluding the outlier could be considered appropriate. The Committee discussed whether aflibercept should be considered an innovative treatment. The Committee acknowledged that aflibercept represented a novel recombinant fusion protein. However, the Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation. The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met. The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The Committee considered the criterion for short life expectancy and the evidence for life expectancy in this group of patients. The Committee noted the overall survival estimates presented by the manufacturer from the VELOUR trial with the observed median survival in the placebo group of VELOUR of 12.1 months and the estimated mean overall survival of 18.1 months. The Committee also noted the ERG's preferred estimate of 10.5 months from the literature. The Committee concluded that patients receiving current standard NHS treatment would have an expected survival of less than 24 months from the point at which they would be considered for second-line therapy and that therefore the criterion for short life expectancy was fulfilled in this appraisal. The Committee considered the criterion that the treatment is licensed or otherwise indicated for small patient populations. The Committee noted the manufacturer's suggestion that approximately 4000 patients in England and Wales would receive second-line treatment for metastatic colorectal cancer. The Committee was concerned that aflibercept holds a marketing authorisation for treatment of a much larger population with neovascular (wet) age-related macular degeneration, but that this was a different formulation of aflibercept marketed by another company. The Committee understood that when one technology is marketed by different companies (for different indications, using different brands), these should not be added for the purpose of establishing the cumulative population to be considered in the context of life-extending treatments at the end of life, and that therefore the criterion for a small population size was fulfilled in this appraisal. The Committee considered the criterion that treatment offers an extension to life of normally at least an additional 3 months. The Committee noted the comments received in consultation on the ACD, and agreed to explain its concerns over the magnitude of the mean survival benefit more fully. The Committee noted that, based on the number of patients who had died during the trial (70.4%), 50% of those who received aflibercept lived for up to 1.44 months longer than people who received placebo, and acknowledged the difficulty in finding robust mean overall survival data considering the issues with the extrapolation carried out (see section 4.7). The Committee noted that, in response to consultation, the manufacturer pointed out that the original base-case model, using the Committee's preferred assumption to extrapolate overall survival (section 4.14), predicted that aflibercept would extend life by 3.4–3.7 months. The Committee discussed whether the estimates for mean overall survival produced by the model were robust indicators of what overall survival benefit can be seen in clinical practice, noting that all of the extrapolation assumptions were associated with great uncertainty. The Committee was aware that the longer the time horizon, the greater the influence of the 'tails' of the extrapolation curves, which define the difference in mean overall survival between the treatment arms, and to which the model is highly sensitive. The Committee agreed that, although there is a rationale for a 15-year time horizon in order to capture the very small number of patients who might have very prolonged survival, this introduced considerable uncertainty, and produced implausible results given that the extrapolation was based on a population with a small number of patients still at risk of dying beyond 30 months. Although the use of a 15-year time horizon is, in principle, appropriate, when extrapolating the relative benefit is associated with uncertainty, the Committee considered it appropriate to consider shorter time horizons as a means to explore the uncertainty. The Committee noted that, when the model time horizon was shortened to 5 years, the difference in mean overall survival decreased to 2.7–2.8 months. The Committee was mindful that, when there is quantitative evidence that a treatment offers a 3-month life extension, it must also be persuaded that the estimates of life extension are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The Committee agreed that, given the considerable uncertainty around extrapolating overall survival and its implementation in the modelling, it is important to take into account what has actually been observed in the trial (see section 4.6 and 4.8) and in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled. The Committee therefore concluded that aflibercept did not meet the criteria for an end-of-life therapy as defined by NICE. The Committee noted that, in its response to consultation on the appraisal consultation document, the manufacturer pointed out that, in NICE technology appraisal guidance 242, the Committee had considered a modelled survival benefit of 2.7–3.2 months to show sufficient evidence for a 3-month survival benefit for panitumumab. The Committee was aware that, in judging whether panitumumab met the criterion for life extension, the Committee for NICE technology appraisal 242 had taken into consideration the difficulty in accommodating the cross‑over in the panitumumab trials and that the mean progression-free survival benefit for panitumumab was similar to that for cetuximab, and that the latter resulted in an overall survival benefit of 4.7 months. Therefore, it had considered that there was sufficient evidence to indicate that panitumumab offers an extension to life of approximately 3 months. The Committee discussed the ICERs for aflibercept in combination with irinotecan and fluorouracil-based therapy for metastatic colorectal cancer based on the revised analyses provided in response to consultation. The Committee agreed that the cost-effectiveness analysis should assume equal risk of death for all patients beyond the trial period, and that the starting age of the modelled cohort should be between 60 and 65 years. The Committee noted that the manufacturer's ICER closest to these assumptions was £44,000 per QALY gained (for age 60), but would increase for the higher age bracket, if the mean value was used from the manufacturer's survey of clinical oncologists after removing the outlier and if an extrapolation function with a less heavy tail had been used. Because the manufacturer's ICERs incorporated a utility value for progressed disease deemed by the Committee to be high, the Committee considered the ICER produced by the ERG using the Committee's preferred assumptions, but which used a utility value for progressed disease of 0.6. The Committee noted that this was approximately £51,000 per QALY gained and would be higher if an extrapolation function with a less heavy tail had been used. The Committee therefore concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained, and that aflibercept in combination with irinotecan and fluorouracil-based therapy could not be considered a cost-effective use of NHS resources for patients with metastatic colorectal cancer. The Committee noted the comments received during consultation on the appraisal consultation document that some patients appeared to gain particular benefit ('a bimodal distribution'), and which stressed the importance of offering only certain patients aflibercept. The Committee was aware that there is currently no established method in clinical practice to identify patients with metastatic colorectal cancer who could particularly benefit from treatment, and it was not presented with evidence on how these patients could be selected for treatment with aflibercept. The Committee was aware that, as a post-authorisation commitment to the European Medicines Agency, the manufacturer initiated a biomarker program encompassing 3 studies to help select patients who may be more likely to benefit. The Committee agreed that the results of these studies would be useful for a future review of this appraisal. # Summary of Appraisal Committee's key conclusions TA307 Appraisal title: Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy Section Key conclusion Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended within its marketing authorisation for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen. Given the considerable uncertainty around extrapolating overall survival and its implementation within the model, and in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled. The Committee concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained. Current practice Clinical need of patients, including the availability of alternative treatments The Committee noted that the current treatment options for patients with metastatic colorectal cancer are limited, and that treatment is determined individually. The Committee heard that resecting tumours surgically may be a treatment option in some patients with metastatic disease, noting that systemic therapy can make resection possible in some patients. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee noted that patients consider biologic therapies such as aflibercept to improve quality of life compared with chemotherapy. The Committee heard that, because the overall survival curves continued to separate for both patients who had or had not stopped treatment, the survival curves might reflect a disease modifying effect in that aflibercept might have altered the natural course of the disease whereby, despite the disease progressing, patients lived longer even after treatment stopped. The Committee agreed that there was no robust evidence to make firm conclusions about the likely cause of the different shapes of the overall survival and progression-free survival curves. The Committee acknowledged that aflibercept represented a novel recombinant fusion protein. However, the Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation. What is the position of the treatment in the pathway of care for the condition? Aflibercept in combination with FOLFIRI has a UK marketing authorisation 'for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen'. Adverse reactions The Committee concluded that treatment with aflibercept plus FOLFIRI was associated with a considerable burden of adverse effects, but that, being a new treatment, less is known about its adverse effects profile than for other available treatments. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee noted that the evidence on the clinical effectiveness of aflibercept was derived from the VELOUR trial. The Committee agreed that the VELOUR trial was of good quality and directly relevant to the decision problem. However, the Committee would have liked the manufacturer to have collected and presented trial data relating to health-related quality of life, and would have liked the manufacturer to have followed and presented event data for all patients after the end of the trial as defined. The Committee concluded that the results from the VELOUR trial are generalisable to UK clinical practice. Relevance to general clinical practice in the NHS No specific Committee considerations on the relevance to general clinical practice in the NHS. Uncertainties generated by the evidence The Committee noted that, to estimate aflibercept's mean survival benefit of 4.7 months, the manufacturer extrapolated the survival curves from a trial with a median follow-up of just under 2 years up to 15 years. Although the Committee agreed that a small proportion of patients, with as yet undefined characteristics, appeared to derive greater benefit from aflibercept than most patients in the trial, it considered that the manufacturer's extrapolation of overall survival based on a population with a very few patients at risk of dying after 30 months' follow-up over a further 12 years was associated with great uncertainty. The Committee was aware that the manufacturer estimated the mean survival benefit of 4.7 months by fitting the log-logistic function to the observed data, and extrapolating the survival curves over 15 years. The Committee noted that the estimates using other parametric functions ranged from 3.0–5.3 months. The Committee was aware that a longer than 5-year survival for patients with metastatic colorectal cancer is very unusual. Having considered the estimates obtained using different parametric functions and extrapolation periods, the Committee was concerned that the log-logistic function had a very 'heavy tail', and that this is likely to have overestimated the survival benefit of aflibercept. The Committee was also concerned that the manufacturer did not characterise the uncertainty around any of the estimates. The Committee concluded that extrapolating overall survival with the log-logistic function over 15 years did not provide a plausible mean overall survival benefit. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee agreed that there was no evidence to suggest that aflibercept would be more effective in patients with liver metastases only than in patients with metastases confined to other organs. The Committee was not presented with evidence about rates of resection and cure with aflibercept in the subgroup of patients with liver metastases only. The Committee therefore agreed that aflibercept cannot be considered an effective treatment option to make liver metastases resectable, concluding that this subgroup should not be considered further. The Committee heard from the clinical specialists that, in clinical practice, patients who had received oxaliplatin-based therapy in the adjuvant setting and relapsed within the following 6 months would not be treated differently to the overall trial population. In addition, the Committee noted that the analysis for this subgroup was planned after the trial results had been compiled (post hoc), and that the test for interaction did not show that the treatment effect in this subgroup differed from the effect in the rest of the trial population. The Committee therefore concluded that it did not need to consider further the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee agreed that the difference in median overall survival of 1.44 months reflects a statistically significant but clinically small benefit. The Committee considered that the manufacturer's extrapolation of overall survival from a population with very few patients at risk of dying after 30 months' follow-up, over a further 12 years, was associated with great uncertainty. Evidence for cost effectiveness Availability and nature of evidence The Committee concluded that overall the manufacturer's model adhered to the NICE reference case for assessing cost effectiveness. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee considered that the manufacturer's assumption that the treatment benefit continues beyond the trial period and until 15 years is highly uncertain given that most patients had died during the 3-year follow-up period of the trial. The Committee considered that the ERG's analysis that allows the hazard ratio to become greater than 1.0 could be considered implausible. The Committee agreed that the ERG's scenario, which assumes equal risk of death for all patients beyond the trial period (hazard ratio equals 1.0), represents an acceptable compromise between the 2 extremes of assuming continuing treatment effect (manufacturer's base case) and allowing for a reversed treatment effect (ERG's second scenario). The Committee noted that, in response to consultation, the manufacturer implemented a new scenario in its revised base case in which the hazard ratio begins to taper to 1.0 36 months after starting treatment, over a 12‑month period. The Committee agreed that as a means to extrapolate overall survival both its preferred scenario (that is, the ERG's first scenario) and the manufacturer's new scenario were associated with some degree of uncertainty. In the absence of further evidence to validate the manufacturer's new approach, the Committee maintained its preference for the ERG's first scenario. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee was aware that the manufacturer got the utility value for the stable-disease state from the 'mCRC utilities study' and revised it after consultation to a value derived from the ASQoP. The Committee noted that the ERG preferred another value from the ASQoP study for the stable-disease state. The Committee concluded that either value could be considered appropriate. The Committee considered that the utility value chosen by the manufacturer for the progressed-disease state did not reflect the entire duration of progressed disease but only early progressed disease, and so was likely to be an overestimate. The Committee was aware that, in its base case, the ERG used an alternative lower value of 0.60, which had been used in NICE technology appraisal guidance 118. The Committee agreed that no utility values for progressed disease were universally accepted as valid, but that it would be important that the utility value reflected the entire progressed-disease state. The Committee also agreed that adjusting the utility values for age was appropriate. The Committee concluded that the most plausible utility value for the progressed-disease health state would lie between the manufacturer's and the ERG's estimate. The Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation. Are there specific groups of people for whom the technology is particularly cost effective? Having considered the clinical evidence presented by the manufacturer for the 2 subgroups, the Committee concluded that it did not need to consider the cost effectiveness of the technology for any of the subgroups. What are the key drivers of cost effectiveness? The Committee considered the robustness of the mean overall survival benefit, obtained using the log-logistic function, of 3 months (5 years extrapolation time), 4.7 months (15 years extrapolation time) and 6.6 months (without truncating the survival curves. The Committee was aware that the longer the time horizon, the greater the influence of the 'tails' of the extrapolation curves, which define the difference in mean overall survival between the treatment arms, and to which the model is highly sensitive. The Committee noted that, because approximately three-quarters of the QALY gain in the model was accrued after disease progression, the model is highly sensitive to utility value for the progressed-disease state in the model. Most likely cost-effectiveness estimate (given as an ICER) The Committee noted that the manufacturer's ICER closest to its preferred assumptions was £44,000 per QALY gained (for age 60), but would increase for the higher age bracket, if the mean value was used from the manufacturer's survey of clinical oncologists after removing the outlier and if an extrapolation function with a less heavy tail had been used. Because the manufacturer's ICERs incorporated a utility value for progressed disease deemed by the Committee to be high, the Committee considered the ICER produced by the ERG using the Committee's preferred assumptions, but which used a utility value for progressed disease of 0.6. The Committee noted that this was approximately £51,000 per QALY gained and would be higher if an extrapolation function with a less heavy tail had been used. The Committee therefore concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) The manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence. End-of-life considerations The Committee agreed that, given the considerable uncertainty around extrapolating overall survival and its implementation within the model, it is important to take into account what has actually been observed in the trial (see section 4.6 and 4.8) and, in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled. The Committee therefore concluded that aflibercept did not meet the criteria for an end-of-life therapy as defined by NICE. Equalities considerations and social value judgements No equality issues relevant to the Committee's recommendations were raised. # Review of guidance The guidance on this technology will be considered for review in August 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveMarch 2014# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS. This guidance was developed using the NICE single technology appraisal process. It has been incorporated into the NICE pathway on colorectal cancer along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0519-5	{'Guidance': 'Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended within its marketing authorisation for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen.\n\nPeople currently receiving aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology': "Aflibercept (Zaltrap, Sanofi) is a recombinant human fusion protein that blocks the vascular endothelial growth factor (VEGF) pathway by preferentially binding to VEGF-A, VEGF-B and placental growth factor, which play an important role in the formation of new blood vessels in solid tumours (angiogenesis). By preventing these factors from activating their endogenous receptors, aflibercept interferes with the process by which blood vessels and capillaries expand into tumours (vascularisation), and so inhibits tumour growth. Aflibercept in combination with folinic acid/5-fluorouracil/irinotecan (FOLFIRI) (that is, in combination with irinotecan and fluorouracil-based therapy) has a UK marketing authorisation 'for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen'. The summary of product characteristics states that aflibercept should be administered as an intravenous infusion over 1\xa0hour at a dose of 4\xa0mg/kg of body weight, followed by the FOLFIRI regimen, every 2\xa0weeks until the disease progresses or unacceptable toxicity occurs.\n\nThe summary of product characteristics lists the following most common adverse reactions (according to the Common Terminology Criteria for Adverse Events v3.0) for aflibercept plus FOLFIRI in order of decreasing frequency: leukopenia, diarrhoea, neutropenia, proteinuria, increased plasma activity of aspartate aminotransferase, stomatitis, fatigue, thrombocytopenia, increased plasma activity of alanine aminotransferase, hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine and headache. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe manufacturer states that the net price of a vial of 100\xa0mg aflibercept is £295.65, and the net price of a vial of 200\xa0mg aflibercept is £591.30. The cost per patient will vary with dose adjustment and treatment duration. The manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (section\xa07) considered evidence submitted by the manufacturer of aflibercept and a review of this submission by the Evidence Review Group (ERG; section\xa08).\n\n# Clinical-effectiveness evidence\n\nThe manufacturer did a systematic literature review of studies evaluating the efficacy and safety of second-line treatments for metastatic colorectal cancer. It identified 1\xa0relevant randomised controlled trial (RCT), the VELOUR trial, from which it obtained the key clinical evidence. The VELOUR trial was a double-blind placebo-controlled phase\xa0III study that was conducted in 176\xa0centres in 28\xa0countries, including the UK. Eligible patients were adults who had inoperable metastatic colorectal cancer, and whose disease progressed on or after treatment with only 1\xa0prior oxaliplatin-based chemotherapy regimen. Investigators randomised patients in a 1:1 ratio to either aflibercept plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) (n=612) or placebo plus FOLFIRI (n=614). They stratified randomisation by patients' wellbeing and ability to perform daily activities using the Eastern Cooperative Oncology Group Performance Status (ECOG\xa0PS), and whether or not the patient had received prior therapy with bevacizumab. Patients received either aflibercept at a dose of 4\xa0mg/kg or placebo over 1\xa0hour on day\xa01, every 2\xa0weeks, both intravenously, immediately followed by FOLFIRI. During the trial, patients could stop 1\xa0study treatment (aflibercept or placebo, or FOLFIRI) but still receive the other components of the regimen. Treatment continued until disease progressed, unacceptable toxicity occurred, or the patient declined further treatment.\n\nThe primary end point in the VELOUR trial was overall survival, defined as time from randomisation to death from any cause. One of the secondary end points was progression-free survival as assessed by an independent review committee based on radiologic progression; it was determined as time from randomisation to first observation of disease progression (at least a 20% increase in the sum of the longest diameter of target tumours, the unequivocal increase in the size of non-target tumours or the appearance of 1\xa0or more new tumours), or death from any cause. In addition, disease progression determined by local investigators was recorded during the trial. Other secondary end points were objective response (complete and partial responses) according to Response Evaluation Criteria In Solid Tumors criteria version\xa01, and adverse events and abnormal laboratory findings.\n\nThe manufacturer stated that patient characteristics and disease history at baseline were well balanced between the aflibercept and placebo groups. Of the patients randomised in the study, the median age was 61\xa0years, 58.6% were men, 97.8% had a baseline ECOG\xa0PS of 0 or 1, and 2.2% had a baseline ECOG\xa0PS of 2. The marketing authorisation for aflibercept stipulates prior treatment with an oxaliplatin-containing regimen. In the VELOUR trial, 90.2% of patients randomised to aflibercept plus FOLFIRI and 89.4% of those randomised to placebo plus FOLFIRI had received prior oxaliplatin-based chemotherapy for locally advanced or metastatic disease. Approximately 10% of patients had received prior oxaliplatin-based chemotherapy in the adjuvant setting (that is, as an additional treatment given after the primary treatment). Oxaliplatin-based regimens were given in combination with bevacizumab in 30.4% of patients.\n\nThe manufacturer determined that it needed 863\xa0death events to detect a statistically significant 20% risk reduction in the aflibercept group compared with the placebo group; this determined the study cut-off date. To estimate time-to-event parameters (overall survival and progression-free survival), the manufacturer used survival analysis. It calculated hazard ratios and confidence intervals for the primary and subgroup analyses using a Cox proportional hazards model. It also established heterogeneity of treatment effect among subgroups using a Cox proportional hazards model, and provided an interaction test for each subgroup analysis. If a patient neither died nor had disease progression during the trial, the manufacturer censored the patient at the date when the tumour was last assessed or at the study cut-off date.\n\nThe median follow-up for the overall population at the time of the primary analysis was 22.28\xa0months, with the longest follow-up being 36\xa0months. At the study cut-off date, 403\xa0patients (65.8%) randomised to aflibercept and 460\xa0patients (74.9%) randomised to placebo had died. Median overall survival was estimated to be 1.44\xa0months longer for aflibercept than placebo (aflibercept 13.50\xa0months, placebo 12.06\xa0months), and the corresponding hazard ratio was 0.817 (95.34%\xa0confidence interval [CI] 0.713 to 0.937, p=0.0032), suggesting a reduction in the risk of death of 18.3% with aflibercept compared with placebo. The probabilities of overall survival at 6, 12, 18, 24 and 30\xa0months were consistently higher in the aflibercept group than in the placebo group; the probability of overall survival was 4% higher at 6\xa0months, and 85% higher at 30\xa0months.\n\nThe manufacturer noted that the Kaplan–Meier curves for overall survival separated early and continued to separate over time, and suggested that there were patients who experienced a sustained benefit after treatment with aflibercept. Because of this, the manufacturer indicated that the difference in median overall survival of 1.44\xa0months may underestimate the overall clinical benefit of adding aflibercept to FOLFIRI. In addition, the manufacturer calculated hazard ratios for overall survival by 6-month periods up to 18\xa0months after randomisation, and it combined all time points thereafter into a single hazard ratio. This analysis showed that hazard ratios improved over time, implying that the difference in overall survival increased in favour of aflibercept the longer patients received treatment. In response to a clarification request by the ERG, the manufacturer provided hazard ratios and the number of patients at risk of dying 18\xa0months after randomisation by 6-month periods. These hazard ratios continued to decrease over time (suggesting that the difference in overall survival continued to increase in favour of aflibercept), but had confidence intervals that crossed 1.00 (that is, the differences were not statistically significant).\n\nThe manufacturer estimated the mean overall survival by fitting separate parametric functions to the trial data for each treatment group, and extrapolating to provide complete curves (given that calculating the mean required all patients to have died). It modelled each treatment group separately, rather than modelling treatment as a covariate, because the log-cumulative hazard plots (used to evaluate the assumption that a hazard ratio between 2\xa0treatments remains constant over time) were not parallel and crossed. The manufacturer considered that the log-logistic function provided the best fit for overall survival for both treatment groups. The log-logistic function, however, gave a long tail (implying that some patients would live implausibly long), so the manufacturer truncated the curves at 15\xa0years after randomisation (this assumed that all patients die by 15\xa0years). Using this approach, the manufacturer estimated that aflibercept would extend mean overall survival by 4.7\xa0months compared with placebo (aflibercept 22.8\xa0months, placebo 18.1\xa0months); without truncating the survival curves, the difference in mean overall survival was 6.6\xa0months. In response to a clarification request by the ERG, the manufacturer provided estimates with the analysis truncated at 5\xa0and 10\xa0years. The manufacturer designated the results of this analysis as academic in confidence. The manufacturer also provided 'restricted' mean overall survivals for each treatment group based on actual data rather than an extrapolated model (that is, excluding patients who were alive at the end of the trial). This analysis estimated a difference in mean overall survival of 1.92\xa0months in favour of aflibercept.\n\nThe manufacturer found that aflibercept also prolonged progression-free survival compared with placebo; the difference in median progression-free survival was estimated to be 2.23\xa0months when disease progression was assessed by an independent review committee (aflibercept 6.90\xa0months, placebo 4.67\xa0months, hazard ratio 0.758 [95%\xa0CI 0.661 to 0.869]). The manufacturer also provided an estimate of 1.74\xa0months for median progression-free survival when local investigators determined disease progression. For response rate (complete and partial responses), the results favoured aflibercept, with an estimated response rate of 19.8% (95%\xa0CI 16.4 to 23.2) in the aflibercept group and 11.1% (95%\xa0CI 8.5 to 13.8) in the placebo group.\n\nThe manufacturer performed pre-specified subgroup analyses according to the following:\n\nBaseline characteristics: presence of liver metastasis, location of primary tumour, number of metastatic organs (metastases in 1\xa0organ only, or metastases in more than 1\xa0organ), prior history of hypertension.\n\nStratification variables: ECOG\xa0PS, prior bevacizumab treatment.\n\nDemographic characteristics: age (less than 65\xa0years old, or 65\xa0years or older), sex, race, geographical region.The manufacturer focused on 2\xa0subgroups in its submission: patients with liver metastases only (pre-specified), and a subgroup that excluded patients whose disease had relapsed 6\xa0months or less after starting oxaliplatin-based adjuvant therapy (post hoc). The manufacturer stated that the subgroup of patients with liver metastases only was recognised as a relevant clinical subgroup for metastatic colorectal cancer in Cetuximab for the first-line treatment of metastatic colorectal cancer (NICE technology appraisal guidance\xa0176). For the subgroup that excluded patients whose disease had relapsed 6\xa0months or less after starting oxaliplatin-based adjuvant therapy, the manufacturer performed a post hoc analysis after the results of the VELOUR trial had been compiled. The manufacturer stated that 10% of patients in the trial had cancer that had relapsed within 6\xa0months of starting oxaliplatin-based adjuvant therapy, which the manufacturer interpreted as reflecting patients with aggressive disease who would be unlikely to benefit from anti-vascular endothelial growth factor (VEGF) therapy.\n\nFor all the pre-specified subgroups, the manufacturer carried out an analysis of overall survival. It found no evidence of heterogeneity in treatment effect (non-significant interaction test), except in the subgroup of patients with liver metastases only (p value for interaction was 0.0899, statistically significant at the 10% level). The hazard ratio for this subgroup was 0.649 (95.34%\xa0CI 0.492 to 0.855) compared with a hazard ratio of 0.868 (95.34%\xa0CI 0.742 to 1.015) in patients who had no liver metastases or in whom the cancer spread to the liver and other organs (estimates of survival times are academic in confidence). In response to a clarification request by the ERG, the manufacturer provided the difference in mean overall survival for the subgroup using actual, rather than extrapolated, data; this estimate is academic in confidence. In the post hoc subgroup analysis, which excluded patients whose disease had relapsed 6\xa0months or less after starting oxaliplatin-based adjuvant therapy, the difference in median overall survival was estimated to be 1.9\xa0months in favour of aflibercept. In this subgroup, the unadjusted hazard ratio was 0.78 (95%\xa0CI 0.68 to 0.90) compared with 1.09 (95%\xa0CI 0.70 to 1.69) in patients whose disease had relapsed 6\xa0months or less after starting adjuvant therapy (p value for interaction 0.1265).\n\nFor progression-free survival, the manufacturer did not find a statistically significant subgroup effect except in patients with liver metastases only (interaction test was statistically significant at the 10% level). These results, and those of the subgroup that excluded patients whose disease had relapsed 6\xa0months or less after starting oxaliplatin-based adjuvant therapy, are academic in confidence.\n\nThe incidence of adverse events of any grade (according to the Common Terminology Criteria for Adverse Events v3.0) was similar in the aflibercept and placebo groups of the VELOUR trial (99.2% and 97.9% respectively), but the incidence of some adverse events was considerably higher in the aflibercept group (for example, 41.4% of patients receiving aflibercept had hypertension [any grade] compared with 10.7% of those receiving placebo). Grade 3–4 adverse events were reported in 83.5% of patients in the aflibercept group and 62.5% of those in the placebo group. The grade 3–4 adverse events that occurred at least twice as frequently in the aflibercept group than in the placebo group, in order of decreasing relative incidence, were: hypertension (19.3% versus 1.5%), proteinuria (7.8% versus 1.2%), hand-foot syndrome (2.8% versus 0.5%), headache (1.6% versus 0.3%), arterial thromboembolic events (1.8% versus 0.5%), weight loss (2.6% versus 0.8%), stomatitis and ulceration (13.8% versus 5.0%), diarrhoea (19.3% versus 7.8%) and decreased platelet count (3.4% versus 1.6%). Typical anti-VEGF adverse reactions and adverse reactions associated with FOLFIRI were more common in the aflibercept group. The manufacturer indicated that most of the adverse events associated with aflibercept plus FOLFIRI were reversible and manageable using current clinical practice, although some (physical weakness, infections, diarrhoea and hypertension) led to permanent discontinuation of study treatment in 26.8% of patients receiving aflibercept compared with 12.1% of those receiving placebo. Furthermore, the European Public Assessment Report notes that more patients in the aflibercept than the placebo groups had their dose of FOLFIRI reduced or their treatment cycle delayed.\n\nTo further characterise the adverse events of aflibercept, the manufacturer performed a meta-analysis by pooling safety data from 3\xa0RCTs (VELOUR, VITAL and VANILLA). The VITAL trial evaluated aflibercept plus docetaxel compared with placebo plus docetaxel in patients with non-small cell lung cancer and, in the VANILLA trial, patients with metastatic pancreatic cancer were randomised to aflibercept plus gemcitabine or placebo plus gemcitabine. Overall, the meta-analysis included data from 2662\xa0patients (1333\xa0receiving aflibercept and 1329\xa0receiving placebo). The analysis was framed so that risk ratios greater than 1 favoured placebo. The manufacturer found that, among patients treated with aflibercept, 0.4% and 0.5% had grade\xa04 hypertension and nephrotic syndrome respectively. It also found that adding aflibercept to concurrent chemotherapies did not increase the risk of venous thromboembolism, but it did increase the risk of grade 3–4 adverse reactions related to anti-VEGF therapy; the difference in this risk was statistically significant for hypertension (risk ratio [RR]\xa09.21, 95%\xa0CI 5.91 to 14.36), proteinuria (RR\xa08.37, 95%\xa0CI 4.37 to 16.06) and haemorrhage (RR\xa02.04, 95%\xa0CI 1.20 to 3.47). The incidence of adverse reactions typically associated with the background chemotherapy used in the 3\xa0RCTs also increased with the addition of aflibercept, most notably for neutropenia (including neutropenic complications), various gastrointestinal toxicities and physical weakness.\n\nData on health-related quality of life were not collected in the VELOUR trial. The manufacturer conducted the 'mCRC utilities study', an observational, cross-sectional study to estimate utility values in patients with metastatic colorectal cancer who would be eligible for treatment with aflibercept plus FOLFIRI as per the licensed indication, or who had progressed to subsequent phases of the disease. The study took place in the Netherlands and the UK, and collected EQ-5D data. The manufacturer used these data as its main source to estimate health-related quality of life for the cost-effectiveness analysis.\n\n## ERG critique\n\nThe ERG stated that the manufacturer presented a well-conducted systematic review of clinical evidence, and used a search strategy that was unlikely to have missed any relevant studies. It also stated that the manufacturer included sufficient detail about the VELOUR trial and used appropriate criteria to assess the quality of the trial. The ERG noted, however, that the manufacturer provided minimal details of its meta-analysis of aflibercept's adverse events, and of the quality of the VITAL and VANILLA trials.\n\nThe ERG indicated that VELOUR was a good quality trial and directly related to the decision problem, and that the characteristics of patients at baseline and disease history were well balanced between the aflibercept and placebo groups. However, the ERG considered that patients in the trial were potentially fitter and younger than those seen in UK practice, and so patients in clinical practice may not achieve the level of benefit reported in the trial. The ERG highlighted the following dissimilarities between the VELOUR trial and clinical practice:\n\nIn the UK, patients whose disease progresses after a break in treatment during intermittent first-line palliative chemotherapy are likely to be offered repeat treatment with the first-line chemotherapy regimen. If their disease progresses while receiving this treatment, or within 6\xa0to 8\xa0weeks of completing it, they would then move to second-line treatment. Although the manufacturer's submission does not state how many cycles of first-line oxaliplatin-based chemotherapy patients in the VELOUR trial received, the ERG indicated that the trial population may be healthier than patients in clinical practice who may have received several cycles of first-line treatment.\n\nBetween 2007 and 2009, around 72% of patients diagnosed with colorectal cancer in the UK were aged 65\xa0years or over. By contrast, in the VELOUR trial, only 33.5% of the aflibercept group and 38.9% of the placebo group were people aged 65\xa0years or over.\n\nThe proportion of patients with an ECOG\xa0PS of 2 in the VELOUR trial was 2.2%. According to the ERG's clinical adviser, this is lower than the proportion reported in other trials in the second-line setting, or in UK clinical practice.\n\nIn the VELOUR trial, 42–44% of patients had metastasis in only 1\xa0organ, which the ERG's clinical adviser considered higher than the proportion seen in clinical practice.\n\nThe ERG noted that the hazard ratios for overall survival by 6-month periods had wide confidence intervals at the later time points of the VELOUR trial because by this time many patients were no longer alive, leaving few patients at risk of dying (around 5% at 30\xa0months). The ERG stated that wide confidence intervals reflect imprecise estimates, and that interpreting hazard ratios towards the end of the trial is highly uncertain, particularly at 30\xa0months and 36\xa0months.\n\nTo estimate mean overall survival using parametric analysis, the manufacturer assumed that the proportional hazards assumption does not hold (that is, it did not accept that the hazard ratio between the 2\xa0treatment groups remained constant over time). The manufacturer stated that this was because the hazard ratios for overall survival decreased over time (treatment effect improved), and because the log-cumulative hazard plots were not parallel and crossed over one another. The ERG, conversely, considered that, while the hazard ratios decreased over time, they remained consistent with the proportional hazards assumption, although it acknowledged that using a proportional hazards approach is subject to judgement. In addition, the ERG noted that the log-cumulative hazard plots were very close to parallel. The ERG stated that rejecting the proportional hazards assumption and assuming a continued separation of the overall survival curves is highly uncertain given that no data were available beyond 36\xa0months' follow-up, and particularly that the progression-free survival curves separate then converge at around 12\xa0months. The ERG suggested that it would be reasonable to assume that the survival curves converge before 5\xa0years (that is, there is no treatment effect after 5 years), in line with clinical experience in treating metastatic colorectal cancer.\n\nThe ERG noted that the estimate of mean overall survival varied considerably depending on the parametric function the manufacturer used, indicating that the manufacturer's estimates of the difference in mean overall survival (4.7\xa0months) were not robust to the choice of distribution. The ERG requested from the manufacturer the mean estimates of overall survival for each treatment group, restricted to patients who had died before the end of the trial (that is, results based on actual data rather than an extrapolated model), which gave a difference of 1.92\xa0months in favour of aflibercept. The ERG indicated that this figure is likely to be an underestimate given that it does not take into account the patients with long survival times.\n\nThe manufacturer used the log-logistic function to estimate mean overall survival, and it truncated the curves at 15\xa0years. The ERG considered that 15\xa0years is too long for the patient population under consideration because the treatment benefit is unlikely to extend beyond 5\xa0years. The ERG requested that the manufacturer produce estimates with the analysis truncated at 5\xa0years and 10\xa0years. When the data were truncated at 5\xa0years, the results from the different functions were more consistent with each other than when the data were truncated at 15\xa0years. The ERG stated that it is unclear whether the mean based on extrapolating the curves and truncating the data at 5\xa0years, or the restricted mean based on actual data, is more valid.\n\nProgression-free survival in the VELOUR trial was a secondary end point assessed by an independent review committee. The ERG advised that independent review committees may miss symptoms other than tumour growth caused by disease progression, which may have an impact on treatment duration and associated costs. The ERG noted that, when the manufacturer explored in a sensitivity analysis disease progression determined by investigator assessment taking into account symptomatic deterioration (as would happen in clinical practice), aflibercept was found to extend median progression-free survival by 1.74\xa0months.\n\nThe ERG stated that, while there was no evidence of a statistically significant interaction at the 5% level between treatment groups for most of the baseline patient characteristics, the results of the subgroup analyses suggested that patients with less advanced disease in the VELOUR trial (ECOG\xa0PS equal to 0, number of organs with metastasis less than or equal to 1, and patients with liver metastases only) may be more likely to benefit from treatment with aflibercept than those with more advanced cancer.\n\n# Cost-effectiveness evidence\n\nThe manufacturer did not identify any published economic evaluations relevant to the decision problem. It submitted a de novo economic model to establish the cost effectiveness of aflibercept in patients with metastatic colorectal cancer who are eligible for second-line combination chemotherapy, and who were previously treated with an oxaliplatin-based regimen. The manufacturer performed subgroup analyses for patients with liver metastases only, and for a subgroup that excluded patients who had received oxaliplatin-based therapy in the adjuvant setting and whose disease relapsed within the following 6\xa0months. The manufacturer conducted the analysis from the perspective of the NHS and personal social services and chose a time horizon of 15\xa0years. It used a 2-week treatment cycle to reflect the treatment schedules of aflibercept and FOLFIRI, and applied a half-cycle correction. Costs and health effects were discounted at an annual rate of 3.5%.\n\nThe manufacturer developed a state-transition Markov cohort model simulating 3\xa0states: stable disease, progressed disease and death. The manufacturer further split the stable-disease health state into sub-states of 'on second-line treatment' and 'discontinued second-line treatment' to distinguish between patients who receive second-line treatment until their disease progresses, and those who stop second‑line treatment before their disease progresses. All simulated patients enter the model in the stable-disease health state and in the 'on second‑line treatment' sub-state. Patients can then continue treatment and remain in the 'on second-line treatment' sub-state, or move to the 'discontinued second‑line treatment' sub-state; they can instead move to the progressed-disease health state (and stop second-line treatment), or death. Patients cannot receive second-line treatment again once treatment is stopped, but they can receive further active therapy (systemic anticancer treatment, radiotherapy or surgery) or best supportive care. The manufacturer stated that the duration of second-line treatment in the model is based on the mean durations in the VELOUR trial to take into account dose delays or the discontinuation of aflibercept or FOLFIRI (for patients who were in the aflibercept group), or FOLFIRI (for patients who were in the placebo group), as observed in the trial. The manufacturer modelled adverse events as events (rather than health states) and it applied a utility decrement (disutility) for each adverse event.\n\nThe manufacturer's model included parameters for overall survival, progression-free survival and time to discontinuing second-line treatment (before or after disease progression). To estimate the survival parameters, the manufacturer fitted alternative parametric functions (Weibull, log-normal, log-logistic and exponential) to observed Kaplan–Meier data from the VELOUR trial, and extrapolated the curves beyond the trial period for overall survival and time to discontinuing treatment, but not for progression-free survival, because the disease had progressed in all patients during the trial. In extrapolating those curves, the manufacturer assumed non-proportional hazards (that is, the hazard ratios between aflibercept plus FOLFIRI and FOLFIRI alone varied over time) so it modelled each treatment group separately. The manufacturer chose the base-case survival functions based on the results of statistical tests, visual inspection of the fit to the data and the clinical plausibility of the extrapolated portion of the curve. For overall survival, the manufacturer used the log-logistic function, and assumed that the survival benefit from treatment with aflibercept plus FOLFIRI increases relative to treatment with FOLFIRI alone until around 12\xa0months after starting treatment, and then decreases over the 15-year time horizon, but does not cease at any point during the extrapolation period (that is, the overall survival curves start converging 12\xa0months after starting treatment but never fully converge later in the extrapolation period). The manufacturer used the Weibull function for progression-free survival and time to treatment discontinuation. The difference in mean progression-free survival estimated by the manufacturer was 1.2\xa0months in favour of aflibercept. Other parametric functions were explored in scenario analyses.\n\nThe manufacturer stated that the model predicted a median overall survival and a median progression-free survival similar to those from the VELOUR trial. The largest difference was for progression-free survival in the FOLFIRI group, which the model overestimated compared with the survival time observed in the trial.\n\nAdverse events in the model included grade 3–4 adverse events that affected more than 5% of patients in the VELOUR trial, together with 6\xa0rarer adverse events that the manufacturer's clinical advisory board considered important (gastrointestinal perforation, haemorrhage, febrile neutropenia, peripheral neuropathy, urinary tract infections and hand-foot syndrome). The subgroup analyses incorporated data specific to each subgroup.\n\nThe manufacturer applied utility values in the model from its 'mCRC utilities study', in which investigators assigned patients to 1\xa0of the following 3\xa0groups: patients with stable disease who are receiving second-line treatment, and patients who had previously received second-line treatment but stopped it because of an adverse event, or because their disease progressed. Because the sample size of the group of patients who had an adverse event and stopped treatment was very small, the manufacturer did not use the utility estimates from this group, and instead assumed that all patients with stable disease have the same utility, equal to the utility of patients with stable disease who are receiving second-line treatment. The manufacturer got descriptions of health states from patients using the EQ-5D system, and derived the utility weights by applying UK valuation of health states estimated using the time trade-off method. The utility estimate used in the model for patients with progressed disease was 0.708. The manufacturer assumed that the utility in the progressed-disease health state is independent of time spent in the state. The manufacturer explained that, despite the age and health of patients, the utility values used in the model are relatively high because candidates for second-line chemotherapy must be fit enough to receive treatment.\n\nThe manufacturer also identified relevant utility studies from a systematic review of the literature. It did not use the values in those studies to source the model, but used them to compare the estimates from its utility study, and noted that they were reasonably consistent. The utility estimates in the literature that the manufacturer considered relevant ranged from 0.73 to 0.81 for stable disease, and from 0.68 to 0.69 for the progressed disease. One other study, Best et al. (2010), reported utility values of 0.51 for stable metastatic disease and 0.21 for progressed metastatic disease, but the manufacturer did not consider this study relevant because the population included patients receiving adjuvant chemotherapy and patients in remission.\n\nThe manufacturer got the disutilities associated with adverse events from the published literature, and supplemented these with clinical expert opinion. To calculate the average disutility per adverse event, the manufacturer assumed that an adverse event causes the same disutility regardless of the type of cancer. This gave an average disutility per adverse event of −0.0127 for patients receiving aflibercept plus FOLFIRI, and −0.0108 for those receiving FOLFIRI alone.\n\nThe costs of aflibercept plus FOLFIRI and FOLFIRI alone did not depend on the duration of second-line treatment in the model; the manufacturer calculated them separately based on data from the VELOUR trial to reflect the dose delays (for example, because of an adverse event) and dose reductions observed in the trial. It assumed that any unused drug in a vial was discarded (wasted) for aflibercept and irinotecan (a component of FOLFIRI), but explored in scenario analyses other possibilities to model drug wastage. The cost of aflibercept in the model took into account the patient access scheme discount.\n\nTo estimate costs of caring for people with metastatic colorectal cancer ('management costs' including supportive medications, clinician and nurse visits [hospital and community], imaging, laboratory tests, hospitalisations, palliative care, and personal and social care), the manufacturer conducted a retrospective observational study, and undertook a questionnaire-based survey of 6\xa0UK clinical oncologists (both unpublished studies). In the observational study, the manufacturer collected resource-use data from patients who received oxaliplatin-based chemotherapy followed by FOLFIRI as second-line treatment, and used those data to estimate total management costs per 2-week cycle for different groups of patients (the manufacturer advised that every patient would eventually receive end-of-life care regardless of prior treatment, so it did not include resource use associated with end-of-life care in the model). The clinician survey aimed to gather data on community-based care, and on personal and social care. In this, the manufacturer elicited the average treatment practices of each oncologist to get data on managing patients with metastatic colorectal cancer. It also used the results of the survey, together with NHS reference costs, to estimate the costs associated with adverse events. The manufacturer used mean resource use for adverse events, but median resource use for community-based care, and personal and social care. The cost of subsequent therapies that patients could receive after stopping second-line treatment or experiencing disease progression was calculated based on the manufacturer's study of resource use, and was assumed to be independent of the type of second-line treatment.\n\nThe manufacturer's deterministic base-case results estimated that the addition of aflibercept to FOLFIRI provides an additional 0.243 quality-adjusted life years (QALYs). This benefit is achieved with an additional cost of £8816, resulting in an incremental cost-effectiveness ratio (ICER) of £36,294 per QALY gained for aflibercept plus FOLFIRI compared with FOLFIRI alone.\n\nThe manufacturer presented deterministic sensitivity analyses in which it varied the 20\xa0parameters with the largest impact on the ICER, one at a time. The results showed that the ICER is most sensitive to the parametric function chosen for overall survival, the utility value chosen for the progressed-disease health state, and the number of administrations assumed for second-line treatment drugs. The manufacturer explained that improving overall survival and progression-free survival increased incremental QALYs in favour of aflibercept, but also increased drug costs and the costs incurred from prolonged overall survival after disease progression.\n\nThe manufacturer carried out a probabilistic sensitivity analysis to summarise the uncertainty in the ICER. This showed that the probability of aflibercept plus FOLFIRI being cost effective when compared with FOLFIRI alone is less than 5% if the maximum acceptable ICER is £20,000 per QALY gained, and 22% at £30,000 per QALY gained.\n\nThe manufacturer investigated the structural uncertainty in the model by fitting alternative parametric functions for overall survival and progression-free survival, and by directly applying patient-level data from the VELOUR trial to model progression-free survival (given that disease had progressed in all patients during the trial). It also performed scenario analyses to test the sensitivity of the ICER to alternative assumptions around drug wastage. In these, it explored the possibility of no drug wastage, and of reducing the dose to the nearest number of whole vials for patients who would otherwise use less than 5% of the vial contents. The highest ICER from these analyses was £49,805 per QALY gained (using the Weibull function to model overall survival).\n\nThe manufacturer provided subgroup analyses to establish the cost effectiveness of aflibercept plus FOLFIRI compared with FOLFIRI alone in patients with liver metastases only, and in a subgroup that excluded those who had received oxaliplatin-based therapy in the adjuvant setting and whose disease had relapsed within the following 6\xa0months. In comparison with the deterministic base-case ICER of £36,294 per QALY gained, the ICERs were £30,474 per QALY gained (incremental costs £10,974, incremental QALYs 0.360) and £32,480 per QALY gained (incremental costs £8573, incremental QALYs 0.264) respectively. At a maximum acceptable ICER of £30,000 per QALY gained, the probability of aflibercept plus FOLFIRI being cost effective compared with FOLFIRI alone in both subgroups is around 50% (numerical values not provided in the manufacturer's submission).\n\n## ERG critique\n\nThe ERG indicated that the manufacturer's economic evaluation is consistent with the NICE reference case. It noted that the modelled population is based on data from the VELOUR trial, which relate to patients who appear fitter and younger than those seen in clinical practice. In exploratory sensitivity analyses, the ERG investigated the effect of treating a population that better reflects patients with metastatic colorectal cancer in the UK than the VELOUR trial by modelling an older population with a lower health-related quality of life.\n\nThe ERG considered that it is uncertain whether the hazard ratio for overall survival varies over time. The ERG reported that, when assuming in the manufacturer's model that the hazard ratio remains constant over time (that is, when applying the proportional hazards assumption), the ICER increased to £58,784 per QALY gained, with the difference being mainly driven by a reduction in incremental QALYs compared with the manufacturer's base case. The ERG considered that even this scenario may be relatively optimistic because the progression-free survival curves separate and then converge at around 12\xa0months, suggesting that the hazard ratio could increase over time.\n\nIn its cost-effectiveness analysis, the manufacturer assumed that the survival benefit from treatment with aflibercept plus FOLFIRI initially increases relative to treatment with FOLFIRI alone until around 12\xa0months after starting treatment, and then decreases over the rest of the time horizon, but does not cease at any point during the extrapolation period. The ERG noted that the difference in overall survival between aflibercept plus FOLFIRI and FOLFIRI alone decreases at a relatively slow rate after the initial 12\xa0months and, importantly, suggests a continuing treatment effect on overall survival during the entire 15-year horizon. The ERG explained that extrapolating overall survival data from the VELOUR trial, in which the median follow-up time was just under 2\xa0years, over a 15-year time horizon meant that the assumptions underpinning the extrapolation are key to explaining the large differences between the observed median and the extrapolated mean estimates of overall survival. The ERG stressed that extrapolating the overall survival curves beyond the trial period is highly uncertain given that no data were available for more than 3\xa0years' follow-up, and particularly that the progression-free survival curves separated and then converged at around 1\xa0year. The ERG stated that the manufacturer did not explore this uncertainty sufficiently. Specifically, the manufacturer did not explore whether the risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups could become the same from the point at which the trial ends (that is, the treatment effect of aflibercept plus FOLFIRI does not continue over the extrapolation period). In addition, it did not explore whether the overall survival curves for aflibercept plus FOLFIRI and FOLFIRI alone could converge over the extrapolation period (that is, the treatment effect of aflibercept plus FOLFIRI gradually decreases from the point at which the trial ends), similar to the convergence observed with progression-free survival (in this scenario the risk of death may be higher in the aflibercept plus FOLFIRI group during the extrapolation period than in the FOLFIRI alone group). The ERG explored these 2\xa0scenarios in its exploratory analyses.\n\nRegarding the utility estimates in the model, the ERG had concerns about the generalisability of the manufacturer's 'mCRC utilities study' because the study population appeared to be younger than UK patients, and the proportion of patients who had an ECOG\xa0PS of\xa02 was lower than that seen in UK clinical practice. Moreover, the ERG noted that the study was small, and produced counter-intuitive estimates in a subgroup analysis including UK patients only because the mean utility value for patients whose disease progressed was higher than for those who had stable disease and received second-line treatment.\n\nThe ERG was concerned that the utility estimates used in the model from the manufacturer's utility study, as well as those reported in the literature, were high when compared with values used in previous appraisals of metastatic colorectal cancer, or with general UK population norms. The ERG was particularly concerned about the utility value in the model for patients whose disease had progressed. The ERG explained that, because the model predicts longer overall survival than progression-free survival, approximately three-quarters of absolute QALY increment is accrued after disease progression. Furthermore, the ERG stated that the manufacturer's assumption that utility in the progressed-disease health state is independent of time spent in the state is clinically implausible because patients' health-related quality of life decreases as disease progresses and patients get older.\n\nThe ERG identified an error in the manufacturer's model in how disutilities associated with adverse events were applied, which reduced the disutilities in the model. Correcting this error increased the manufacturer's base-case ICER from £36,294 to £37,834 per QALY gained. The ERG applied this correction in its exploratory analyses.\n\nThe costs of aflibercept plus FOLFIRI and FOLFIRI alone did not depend on the duration of second-line treatment in the model; the manufacturer calculated them separately based on data from the VELOUR trial to reflect the dose delays (for example, because of an adverse event) and dose reductions observed in the trial. The ERG stated that an alternative way to reflect dose delays and reductions would be to apply drug costs per administration (including administration costs) directly to the proportion of patients in each health state, in line with how utility values are applied. Adjusting this increased the manufacturer's base-case ICER from £36,294 to £37,539 per QALY gained. The ERG applied this change in its exploratory analyses.\n\nThe manufacturer assumed that, because aflibercept is administered at the same time as FOLFIRI, no extra costs in terms of additional staff or inpatient admissions would be incurred. The ERG indicated that, even if given simultaneously, administering aflibercept involves preparing an additional infusion, which incurs an extra cost compared with FOLFIRI alone. The ERG highlighted that, in Cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy (NICE technology appraisal guidance\xa0242), the pharmacy preparation of cetuximab and bevacizumab was estimated to be £15 per infusion. In addition, the ERG stated that, if aflibercept is given before or after FOLFIRI, instead of at the same time, administering aflibercept will include an additional hour of infusion time compared with administering FOLFIRI alone. The ERG noted that the model is sensitive to the assumptions underlying the administration costs of aflibercept plus FOLFIRI, and it explored these assumptions in sensitivity analyses.\n\nRegarding resource use for community, and personal and social care, the manufacturer modelled the median estimate from its survey of clinical oncologists, instead of the mean. The ERG indicated that mean values are more commonly used in cost-effectiveness analyses, and that the use of medians may underestimate expected costs. The ERG noted that, when the manufacturer used the mean value in a sensitivity analysis, the base-case ICER increased from £36,294 to £41,222 per QALY gained. The ERG stated that it is unclear in this case whether the median is a better estimate than the mean because there was a small number of survey responders (n=6) and the data were skewed. The ERG noted that the model is sensitive to this parameter and it further explored this in sensitivity analyses.\n\nThe ERG advised that the results of the analysis of the liver metastases only subgroup should be interpreted cautiously. Because the parametric curves for overall survival and progression-free survival were fitted independently for each treatment group based on data for this subgroup from the VELOUR trial, and the subgroup corresponded to approximately 25% of the trial population, the ERG highlighted that the analysis may not have been powered to demonstrate a difference in treatment effect in this subgroup. For the analysis of the subgroup that excluded adjuvant chemotherapy, the ERG indicated that this analysis was performed post hoc, and so its results may be biased. The ERG's clinical advisers also stated that patients who receive adjuvant chemotherapy and whose disease relapses quickly afterwards would not be treated differently from other patients in UK clinical practice.\n\n## ERG exploratory analyses\n\nThe ERG investigated the uncertainty around how the manufacturer had chosen to extrapolate overall survival by considering other scenarios for the magnitude and duration of the overall survival benefit associated with second-line treatments. The ERG modelled the following scenarios by assuming that:\n\nThe risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same 30\xa0months after starting treatment.\n\nThe risk of death in aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same 36\xa0months after starting treatment.The ERG implemented the following scenarios to mimic the converging progression-free survival curves.\n\nThe survival curves begin converging 30\xa0months after starting treatment, and come together after a further 12\xa0months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon.\n\nThe survival curves begin converging 30\xa0months after starting treatment, and come together after a further 18\xa0months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon.\n\nThe survival curves begin converging 36\xa0months after starting treatment, and come together after a further 12\xa0months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon.\n\nThe survival curves begin converging 36\xa0months after starting treatment, and come together after a further 18\xa0months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon.In all of the above scenarios, the ERG assumed that the treatment effect of aflibercept plus FOLFIRI continues until either 30\xa0months or 36\xa0months. The ERG chose these time points because it identified them as particularly uncertain from the hazard ratios for overall survival by 6-month periods presented by the manufacturer. When the ERG assumed that the risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same beyond the trial period, the ICERs were £45,570 and £42,718 per QALY gained for a treatment effect of aflibercept plus FOLFIRI lasting until 30\xa0months or 36\xa0months respectively. In the scenario in which the ERG assumed that the survival curves begin converging 30\xa0months or 36\xa0months after starting treatment over a period of 12\xa0months or 18\xa0months, the ICERs ranged from £55,424 per QALY gained (when curves begin converging after 36\xa0months over 18\xa0months) to £66,377 per QALY gained (when curves begin converging after 30\xa0months over 12\xa0months). The ERG explained that, in this scenario, when the curves begin converging over 12\xa0months, the magnitude of the additional survival benefit from treatment with aflibercept plus FOLFIRI is assumed to taper at a higher rate than when the curves begin converging over 18\xa0months, and so convergence over 12\xa0months results in higher ICERs.\n\nTo address its concerns about some of the parameters used in the manufacturer's base-case model, the ERG performed the following sensitivity analyses, varying 1\xa0parameter at a time:\n\nApplying 2\xa0alternative utility values for patients whose disease progressed: 0.21 from Best et al. (2010) and 0.60 from Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer (NICE technology appraisal guidance\xa0118). The ERG stated that the latter may better reflect the values reported in the literature.\n\nIncluding a cost for preparing an additional infusion of aflibercept, and a cost for an additional hour of infusion time for aflibercept plus FOLFIRI compared with administering FOLFIRI alone. For the preparation cost, the ERG applied a cost of £15, in line with NICE technology appraisal guidance\xa0242 and, for the extra time for infusion, it applied £45, based on NHS reference costs. The ERG explored the impact of these 2\xa0assumptions separately and jointly.When the ERG used the lower utility values of 0.21 and 0.6, the ICER increased from £36,294 per QALY gained (base-case ICER) to £71,143 and £40,608 per QALY gained respectively. Including a cost for preparing an additional infusion of aflibercept, and a cost for an additional hour of infusion time for aflibercept plus FOLFIRI, together increased the ICER to £39,258 per QALY gained.\n\nThe ERG applied its preferred adjustments and model inputs to the manufacturer's base-case model (hereafter the 'ERG base case'). In this, the ERG corrected the error it identified in the manufacturer's model (section 3.43), and applied the acquisition and administration costs to all patients in the second-line treatment health state of the model (section 3.44). In addition, the ERG assumed that patients entered the model at the age of 70\xa0years and accounted for the impact of age on health-related quality of life by applying a utility decrement for aging. The ICER resulting from the above 3\xa0changes was £41,653 per QALY gained. The ERG then applied its preferred model inputs for the parameters it varied in one-way sensitivity analyses:\n\nan additional administration cost for aflibercept of £15\n\nmean instead of median resource use estimates (section 3.46).The ERG applied the above with or without:\n\na utility value of 0.60 for patients whose disease had progressed.When the ERG applied the 0.60 utility value, the analysis gave an ICER of £54,368 per QALY gained for aflibercept plus FOLFIRI compared with FOLFIRI alone. Without this modification (that is, using the same value in the manufacturer's base case), the ICER was £47,965 per QALY gained.\n\nThe ERG presented deterministic results for the scenario analyses (section 3.48) within its base case, and using the utility value of 0.60 for patients whose disease had progressed. It presented results for the overall population, and separately for each subgroup the manufacturer had identified. When the ERG assumed that the risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same beyond the trial period, the ICERs were £66,506 and £62,894 per QALY gained for a treatment effect of aflibercept plus FOLFIRI lasting until 30\xa0months or 36\xa0months respectively. In the scenario in which the ERG assumed that the survival curves begin converging 30\xa0months or 36\xa0months after starting treatment over a period of 12\xa0months or 18\xa0months, the ICERs ranged from £78,226 per QALY gained (when the curves begin converging after 36\xa0months over 18\xa0months) to £92,089 per QALY gained (when the curves begin converging after 30\xa0months over 12\xa0months). The ERG found that, using median resource‑use estimates from the manufacturer's survey of UK oncologists (that is, as per the manufacturer's base case), instead of mean, consistently decreased the ICERs for the scenario analyses within the ERG base case by approximately £5000 per QALY gained.\n\nFor the subgroup analyses combining the ERG's assumptions of overall survival and the ERG's alternative base case, the ICER for aflibercept plus FOLFIRI compared with FOLFIRI ranged from £46,576 to £58,257 per QALY gained for the liver metastases only subgroup, and from £57,224 to £80,187 per QALY gained for the subgroup that excluded patients who had received adjuvant oxaliplatin-based therapy and whose disease had relapsed within the following 6\xa0months.\n\n# Manufacturer's response to consultation on the appraisal consultation document\n\nTo address the Committee's considerations of the evidence described in the appraisal consultation document, the manufacturer submitted a response to the consultation, which included:\n\na revised patient access scheme discount (the details of which are commercial in confidence),\n\nutility data for the stable-disease state from an interim analysis of a phase III study (ASQoP), and\n\nproposed changes to parameters in the model considered by the Committee.\n\nThe ASQoP study was an international single-arm open-label phase III study. The primary objective of the study was to evaluate the safety of aflibercept in patients with metastatic colorectal cancer whose disease progressed following treatment with an oxaliplatin-based regimen. Its secondary objective was to establish health-related quality of life in this population. Because the study was not completed at the time of the second Committee meeting, the manufacturer provided interim results for mean EQ-5D utility values at baseline and after patients received 3\xa0and 5\xa0cycles of treatment. Data from this study were available for the stable-disease state only. The manufacturer derived a utility value of 0.78 for the stable-disease state by using a weighted average of the utility values for patients who received 3\xa0and 5\xa0cycles of treatment.\n\nIn its response, the manufacturer made the following comments on some of the parameters in the model originally considered by the Committee:\n\nThe manufacturer considered that it was more clinically plausible to assume that the hazard ratio tapers to 1.0 after the end of the trial over a short period of time than to assume that the hazard ratio immediately changes to 1.0 at the end of the trial (the Committee's preferred extrapolation scenario).\n\nThe manufacturer did not agree that the utility value chosen by the ERG for the progressed-disease state in its base case (0.6) was appropriate because it was based on a comparison with population 'norm' data that reflects the general population, which includes people with significant morbidities. The manufacturer stated that the utility value for progressed disease used in its original base case came from a relevant 'real-world' study that met the requirements of the NICE reference case. However, the manufacturer acknowledged that, according to clinical opinion, health-related quality of life declines sharply towards the end of life for patients with metastatic colorectal cancer.\n\nThe manufacturer considered that assuming a starting age of 70\xa0years in the model (as in the ERG base case) was too high according to available evidence and feedback from experts, and that a starting age of 60\xa0years was more appropriate. The manufacturer provided the average age of patients with metastatic colorectal cancer receiving second-line treatment in 4\xa0UK observational studies. It stated that these data were closer to the average age of patients in the VELOUR trial (60\xa0years) than the average age used by the ERG (70\xa0years).\n\nThe manufacturer argued that the median value, rather than the mean value, from its survey of clinical oncologists was more appropriate for estimating resource use. This was because the data on the parameter for the number of visits received by a patient from a palliative care team contained a clear outlier, which had a significant impact on the ICERs. The manufacturer further stated that the monthly cost of managing a patient whose disease had progressed used in NICE technology appraisal guidance 242 was closer to the median value than the mean.\n\nThe manufacturer revised its original base case by:\n\napplying a revised discount to the patient access scheme\n\nassuming that, 36\xa0months after starting treatment, the hazard ratio for overall survival tapers to 1.0 over a 12-month period\n\nassuming that patients enter the model at the age of 60\xa0years, and accounting for the impact of age on health-related quality of life by applying a utility decrement for aging\n\nupdating the utility value of 0.78 for the stable-disease state from the ASQoP study\n\ncorrecting the disutilities associated with adverse events (section 3.43)\n\nincluding a cost of £15 for preparing an additional infusion of aflibercept, and a cost of £45 for additional administration time (£60 in total).The manufacturer's deterministic results of the revised base case estimated that the addition of aflibercept to FOLFIRI would provide an additional 0.20\xa0QALYs. This estimated benefit would cost an additional £8500, resulting in an estimated ICER of £42,242 per QALY gained for aflibercept plus FOLFIRI compared with FOLFIRI alone. The probabilistic ICER from this analysis was estimated to be £42,197 per QALY gained, and the probability of aflibercept plus FOLFIRI being cost effective when compared with FOLFIRI alone was around 10% if the maximum acceptable ICER was £30,000 per QALY gained, and 72% at £50,000 per QALY gained.\n\nThe manufacturer performed the following scenario analyses, in which it varied one parameter at a time:\n\nassuming that, 30\xa0months after starting treatment, the hazard ratio for overall survival tapers to 1.0 over a 12-month period\n\nassuming that, 24\xa0months after starting treatment, the hazard ratio for overall survival tapers to 1.0 over a 12-month period\n\nassuming that, 36\xa0months after starting treatment, the hazard ratio changes to 1.0\n\nassuming that, 30\xa0months after starting treatment, the hazard ratio changes to 1.0\n\nassuming that patients enter the model at the age of 65\xa0years (while also applying a utility decrement for aging)\n\napplying the utility value for the stable-disease health state from the 'mCRC utilities study' (the value used in the manufacturer's original base case)\n\napplying a utility value of 0.3 during the last 2\xa0months of life\n\napplying the mean value from its survey of clinical oncologists after excluding the outlier in the data on the number of visits received by a patient from a palliative care team\n\napplying the cost of managing disease progression used in NICE technology appraisal guidance 242.The ICERs resulting from these scenario analyses ranged from £42,002 per QALY gained (when a utility value of 0.3 was applied during the last 2\xa0months of life) to £47,246 per QALY gained (when the hazard ratio for overall survival begins tapering to 1.0 24\xa0months after starting treatment over a 12-month period).\n\n## ERG critique of the manufacturer's revised base case\n\nThe ERG stated that the manufacturer's extrapolation of overall survival in its revised base case was not based on new data, and so the ERG did not consider it any more plausible than the other scenarios previously presented to the Committee.\n\nThe ERG considered that the manufacturer's assumption of a 60-year age for starting treatment in the model was unrealistic, noting that 3\xa0of the 4\xa0observational studies provided by the manufacturer reported an average starting age of 63\xa0years. However, the ERG also accepted that a starting age of 70\xa0years may be high, and that an age of 65\xa0years was a satisfactory compromise.\n\nThe ERG considered it appropriate for the manufacturer to have sourced the stable-disease utility value from the ASQoP study. However, the ERG argued that, because the manufacturer applied this value in the model for patients both on and off treatment, it would have been more appropriate to use the utility value of 0.77 for patients before they started treatment than the value for patients receiving treatment. The ERG indicated that the manufacturer's approach may have biased the utility value if patients receiving treatment were healthier than those who were not on treatment.\n\nThe ERG was concerned that, for the progressed-disease health state, the manufacturer continued to use the utility value from its 'mCRC utilities study', which the ERG considered high. Regarding the scenario analysis in which the manufacturer applied a utility value of 0.3 during the last 2\xa0months of life, the ERG stated that this was not based on empirical evidence.\n\nThe ERG agreed that the estimate from the manufacturer's survey of UK oncologists included an outlier. It considered that using the mean value after excluding this outlier (as in the manufacturer's scenario analysis) was more appropriate than using the median.\n\nTo address remaining uncertainties, the ERG altered the manufacturer's revised base case by applying the utility value before treatment from the ASQoP study for the stable-disease state; the progressed-disease utility value of 0.6; and the mean resource use estimate from the manufacturer's survey of UK oncologists after excluding the potential outlier; and assuming patients start treatment at the age of 60 or 65\xa0years. The ERG applied these changes together with each of the following extrapolation scenario:\n\nassuming a hazard ratio of 1.0 30\xa0months after starting treatment\n\nassuming a hazard ratio of 1.0 36\xa0months after starting treatment\n\nassuming that, 24\xa0months after starting treatment, the hazard ratio tapers to 1.0 over 12\xa0months\n\nassuming that, 30\xa0months after starting treatment, the hazard ratio tapers to 1.0 over 12\xa0months.When the ERG assumed that patients start treatment at the age of 60\xa0years, the resulting ICERs with the above scenarios were £54,243, £50,991, £55,139 and £51,296 per QALY gained respectively. When it assumed that patients start treatment at the age of 65 years, the ICERs were £54,890, £51,634, £55,791 and £51,941 per QALY gained respectively.\n\nThe ERG presented estimates of the difference in mean overall survival for different time horizons, while assuming a hazard ratio of 1.0 after 30 or 36\xa0months. When the ERG set the time horizon to 5, 10 and 15\xa0years, the differences in mean overall survival were 2.7–2.8, 3.2–3.5 and 3.4–3.7\xa0months respectively.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aflibercept in combination with irinotecan and fluorouracil-based therapy, having considered evidence on the nature of metastatic colorectal cancer and the value placed on the benefits of aflibercept in combination with irinotecan and fluorouracil-based therapy by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from the clinical specialists and patient experts about the nature of the condition. It heard that metastatic colorectal cancer can be debilitating, can affect a person's ability to work and lead a normal life, and can lead to premature death. The Committee noted that the illness also brings about a burden on relatives and friends. The Committee understood that the course of the disease varies, with some people's health deteriorating quickly and others' slowly. The Committee heard from patient experts that quality of life in people with the disease may be bad when it is first diagnosed because patients are usually very weak and may have many metastases, but that with treatment the quality of life may improve, as may the ability to work and socialise. The Committee understood that, in clinical practice, disease progression (in patients who already have metastatic disease) would be detected using radiological imaging, although symptoms would also be taken into account. It heard from patient experts that disease progression usually affects quality of life, but it may take a long time before it affects daily activities. The Committee heard further from patient experts that, although people would appreciate small extensions of life, they value quality of life more than length of life. The Committee noted that treatment is generally associated with unpleasant side effects, particularly high blood pressure and diarrhoea and that, while some people may be willing to tolerate the side effects, others may not. The Committee understood that clinicians are now more experienced in managing these side effects and 'optimising' treatment, although it heard from patient experts that the treatments for the side effects may themselves have side effects.\n\nThe Committee discussed the management of metastatic colorectal cancer. It heard from clinical specialists that the current treatment options for this patient population are limited, and that treatment is determined individually. The Committee was aware that, in Colorectal cancer: the diagnosis and management of colorectal cancer (NICE clinical guideline\xa0131), NICE recommends, as second-line treatment options, single-agent irinotecan or folinic acid/5-fluorouracil/irinotecan (FOLFIRI) after first‑line folinic acid/5-fluorouracil/oxaliplatin (FOLFOX), and single‑agent irinotecan after first-line capecitabine/oxaliplatin (XELOX). The Committee heard from the clinical specialists that resecting tumours surgically may be a treatment option in some patients with metastatic disease, noting that systemic therapy can make resection possible in some patients. The Committee understood that the proportion of patients with metastatic colorectal cancer who survive over 5\xa0years has increased because of successful tumour resection. The Committee noted that patients consider biologic therapies such as aflibercept to improve quality of life compared with chemotherapy.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence on the clinical effectiveness of aflibercept, noting that it was derived from the VELOUR trial. The Committee agreed that the VELOUR trial was of good quality and directly relevant to the decision problem; however, it considered that the trial had limitations. The Committee, echoing comments from a patient expert, would have liked the manufacturer to have collected and presented trial data relating to health-related quality of life. The Committee would also have liked the manufacturer to have followed and presented event data for all patients after the end of the trial as defined. The Committee discussed the initial Evidence Review Group's (ERG) concern that patients in the VELOUR trial appeared to have been fitter and younger than those seen in UK clinical practice. The Committee also heard from clinical specialists that the disease and demographic characteristics seen in patients in the VELOUR trial differed from those for patients treated in UK clinical practice; however, evidence from the VELOUR trial showed that response to treatment does not vary across patient groups. The Committee was aware that the studies provided by the manufacturer in response to consultation suggested that patients receiving second-line treatment for metastatic colorectal cancer in the UK were somewhat older than those in the VELOUR trial. The Committee agreed that the patient population in the VELOUR trial was otherwise reasonably representative of patients seen in the UK and therefore concluded that the results of the VELOUR trial are generalisable to UK clinical practice.\n\nThe Committee discussed the results for overall survival, the primary end point of the VELOUR trial. The Committee noted that, in its submission and in response to clarification requests by the ERG, the manufacturer produced a range of estimates for the difference in overall survival between the aflibercept and placebo groups of the trial. The Committee considered that the data observed directly from the trial were sufficiently mature at the study cut-off date to establish median overall survival, and agreed that the difference in median overall survival of 1.44\xa0months reflects a statistically significant but clinically small benefit. The Committee noted that the restricted mean difference of 1.92\xa0months (based on the unlikely and conservative assumption that all remaining patients die immediately at the end of the trial) was higher than the median. The Committee therefore concluded that the difference in median overall survival is likely to underestimate the mean survival benefit of aflibercept.\n\nThe Committee discussed the estimated mean survival benefit of 4.7 months derived from extrapolation, in light of the trial data. The Committee noted that, to estimate this benefit, the manufacturer extrapolated the survival curves from a trial with a median follow-up of just under 2\xa0years up to 15\xa0years. The Committee noted the comments received in the ACD consultation, and agreed to explain its concerns over the survival extrapolation in more detail. The Committee noted the marked difference between the estimated mean survival benefit of 4.7\xa0months and that of 1.44\xa0months based on median values of overall survival. The Committee understood that the manufacturer considered the extrapolated mean value to represent the magnitude of the clinical benefit of aflibercept better than the median because there were a few patients who experienced a sustained survival benefit from treatment with aflibercept. Although the Committee agreed that a small proportion of patients, with as yet undefined characteristics, appeared to derive greater benefit from aflibercept than most patients in the trial, it agreed that extrapolating the survival curves over 15\xa0years could result in highly uncertain estimates for overall survival. The Committee therefore discussed whether the manufacturer's estimates of mean overall survival were robust. It noted that, during the trial's maximum 3-year follow-up period, 66% of patients in the aflibercept group and 75% of those in the placebo group had died, and a proportion had been censored (data academic in confidence), reducing the number of patients at risk of dying to 47\xa0patients (3.8%) at 30\xa0months and 1\xa0patient (0.1%) at 36\xa0months. The Committee heard from the ERG that, because of this, the hazard ratios for overall survival for patients with follow-up nearing 36\xa0months had wide confidence intervals, reflecting imprecise and uncertain estimates. The Committee noted that, at 36\xa0months' follow-up, the Kaplan–Meier curves indicated that approximately 17% of patients randomised to aflibercept were alive but that this 17% represented only 1 patient remaining uncensored and at risk of dying, which considerably increased the uncertainty around the long-term effect on survival. The Committee noted that the cut-off date for the trial was 07 February 2011, and that the manufacturer was aware that some patients from the trial were still alive. The Committee met 18\xa0months after this date, but no further data to support the manufacturer's extrapolation were available. The Committee appreciated that estimating mean overall survival often requires extrapolating beyond a trial period, but considered that the manufacturer's extrapolation of overall survival from a population with very few patients at risk of dying after 30\xa0months' follow-up, over a further 12\xa0years, was associated with great uncertainty (see section 4.24).\n\nThe Committee discussed the mean survival benefit of 4.7\xa0months in light of the different parametric functions used by the manufacturer to estimate overall survival. The Committee was aware that, to estimate this benefit, the manufacturer used the log-logistic function, which it considered to provide the best fit to the observed data, and extrapolated the survival curves over 15\xa0years. The Committee noted that the estimates using other parametric functions ranged from 3.0\xa0months (with the Weibull function) to 5.3\xa0months (with the log-normal function). The Committee discussed which extrapolation period could be considered appropriate to estimate mean overall survival, in view of the life expectancy of patients with metastatic colorectal cancer in clinical practice. The Committee was aware that extrapolation periods should reflect the time in which all patients will have died, but that a longer than 5-year survival for patients with metastatic colorectal cancer is very unusual. It was also aware that, with surgical resection of liver metastases, survival can increase, but that a very small proportion of patients in the VELOUR trial had surgical resection of liver metastases (data designated as academic in confidence), and the Committee was not presented with information about their survival. The Committee also considered survival statistics from the US cancer registry Surveillance, Epidemiology, and End Results (SEER), which showed that 6.9% of patients with metastatic colorectal cancer survive for 5\xa0years. However, because this registry included patients who had received multiple lines of therapy, including surgical resections of tumours and therapies that may not have been considered established NHS practice, the Committee did not consider the data from the SEER registry to be a reasonable proxy for the life expectancy of the population specified in the marketing authorisation of aflibercept. The Committee agreed that a shorter extrapolation period better reflected the natural history of the disease at this stage, and yet accounted for patients who derived greater benefit from aflibercept than most patients in the VELOUR trial. It considered the robustness of the mean overall survival benefit, obtained using the log-logistic function, of 3\xa0months (5\xa0years extrapolation time), 4.7\xa0months (15\xa0years extrapolation time) and 6.6\xa0months (without truncating the survival curves). The Committee was concerned that the log-logistic function had a very 'heavy tail' (that is, a high probability of getting large values at the end of the time horizon) compared with other parametric functions, and that this is likely to have led to an overestimate of the survival benefit of aflibercept. The Committee was also concerned that the manufacturer did not characterise the uncertainty around any of the estimates. In summary, the Committee concluded that, because of the uncertainties around the survival extrapolation, the actual trial data and the life expectancy of patients at this stage of the disease, extrapolating overall survival with the log-logistic function over 15\xa0years did not provide a plausible mean overall survival benefit.\n\nThe Committee considered the relationship between progression-free survival and overall survival from the VELOUR trial. The Committee was aware that the manufacturer used disease progression assessed by an independent review committee in its base case. The difference in median progression-free survival between aflibercept and placebo using this methods was 2.23\xa0months, which was a higher value than when disease progression was determined by investigator assessment (1.74\xa0months) and higher than the mean progression-free survival (see section 3.25).The Committee considered the shapes of the Kaplan–Meier curves (reflecting the trial data) for overall survival and for progression-free survival. It noted that the curves continued to diverge during the trial period for overall survival, whereas, for progression-free survival, the curves initially diverged but then converged at around 12\xa0months, reflecting almost the same rate of progression for patients randomised to aflibercept or placebo from that time onward. The Committee heard from the clinical specialists that, because the overall survival curves continued to separate for both patients who had or had not stopped treatment, the survival curves might reflect a disease-modifying effect in that aflibercept might have altered the natural course of the disease whereby, despite the disease progressing, patients lived longer even after treatment stopped (that is, survival post disease progression was increased more than progression-free survival). The Committee discussed how the disease-modifying effect could be explained clinically. It heard that aflibercept may have delayed death by shrinking tumours, and so extended the period before the tumour grew again. However, the Committee was not presented with evidence that tumours had shrunk, and was aware that the disease had progressed in all patients during the trial. The Committee agreed that there was no robust evidence to make firm conclusions about the likely cause of the different shapes of the overall survival and progression-free survival curves, and that the magnitude of progression-free survival depended on the method used to calculate it.\n\nThe Committee considered that the subgroup analysis presented by the manufacturer for patients with liver metastases only compared with metastases not confined to the liver. The Committee noted that, in this subgroup, there was a statistically significant interaction test at the 10% level. The Committee was aware that the 10% significance level was less specific (that is, a higher chance of a positive finding) than the more conventional 5% level. The Committee agreed that there is no evidence to suggest that aflibercept would be more effective in patients with liver metastases only than in patients with metastases confined to other organs. The Committee was aware that patients with liver metastases only are more likely to be considered for surgical resection of the metastases and possibly live longer than those with widespread metastases. The Committee therefore discussed whether aflibercept can make liver metastases operable in patients with metastatic colorectal cancer. It noted that only a very small minority of patients in the VELOUR trial proceeded to have surgical resection of liver metastases after treatment with aflibercept. The Committee heard from the clinical specialist that, in approximately 20–30% of patients who have surgery to remove liver metastases, metastatic colorectal cancer can be cured. The Committee, however, was not presented with evidence about rates of resection and cure with aflibercept in the subgroup of patients with liver metastases only. The Committee also considered that resecting liver metastases to achieve a cure was more appropriate in the first-line setting than in the second-line setting. Furthermore, it heard from the manufacturer that the modelling of the subgroup did not include the costs of surgical resection. The Committee concluded that it would be appropriate to include this cost and that including it is likely to affect the incremental cost-effectiveness ratio (ICER). The Committee agreed that, given the lack of evidence, aflibercept cannot be considered an effective treatment option to make liver metastases resectable. The Committee therefore concluded that this subgroup should not be considered further.\n\nThe Committee considered the subgroup that excluded patients who had received oxaliplatin-based therapy in the adjuvant setting and whose disease had relapsed within the following 6\xa0months. The Committee heard from the clinical specialists that, in clinical practice, patients in this subgroup would not be treated differently from the overall trial population. In addition, the Committee noted that the manufacturer acknowledged that the analysis for this subgroup was planned after the trial results had been compiled (post hoc), and that the test for interaction did not show that the treatment effect in this subgroup differed from the effect in the rest of the trial population. The Committee therefore concluded that it did not need to consider further the subgroup that excluded patients whose disease had relapsed 6\xa0months or less after starting oxaliplatin-based adjuvant therapy.\n\nThe Committee discussed the adverse events associated with aflibercept. The Committee noted that more patients in the aflibercept group (27%) stopped treatment because of adverse events than in the placebo group (12%). The Committee also noted that adding aflibercept to FOLFIRI increased the adverse events typically associated with FOLFIRI, most notably neutropenia, although it heard from clinical specialists that neutropenia would not routinely be treated in clinical practice. The Committee heard from the manufacturer that the dose of FOLFIRI used in the trial was higher than the dose that is routinely used in clinical practice and might have caused some of the adverse events. The Committee was also aware that aflibercept increased the risk of hypertension, as would other anti-vascular endothelial growth factor therapies. The Committee concluded that treatment with aflibercept plus FOLFIRI was associated with a considerable burden of adverse effects, but that, being a new treatment, less is known about its adverse effects profile than for other available treatments.\n\n# Cost effectiveness\n\nThe Committee considered the structure of the model submitted by the manufacturer, and how it captured the main aspects of the condition. The Committee noted that the manufacturer chose to split the stable-disease health state into 2\xa0sub-states to capture the costs and health benefits for patients with stable disease who either receive second-line treatment with aflibercept plus FOLFIRI or FOLFIRI alone, or who have stable disease but have stopped second-line treatment for reasons other than disease progression. The Committee heard from the ERG that the manufacturer applied the same utility value to the 2\xa0sub-states of the stable-disease health state. It further heard that the acquisition and administration costs of second-line treatments in the model did not depend on the proportion of patients in each state, and that they were calculated outside the model. The Committee noted that the costs and quality-adjusted life years (QALYs) in the stable-disease health state were not specific to the 2\xa0sub-states ('on second-line treatment' and 'post second-line treatment'). The Committee concluded that overall the model adhered to the NICE reference case for assessing cost effectiveness.\n\nThe Committee discussed whether or not the 15-year time horizon used by the manufacturer in the model was appropriate. The Committee appreciated that that the choice of the time horizon is a sensitive parameter in the model given the uncertainty associated with extrapolating overall survival. The Committee was aware that the time horizon should be sufficiently long to capture all the costs and health benefits in the full population (that is, a lifetime horizon should be used). The Committee therefore concluded that a time horizon of 15\xa0years was, in principle, appropriate because all patients are likely to have died by 15\xa0years; however, the Committee agreed that, when the time horizon is much longer than the trial duration, and the life expectancy of most patients, it is particularly important to explore the assumptions underlying how overall survival is extrapolated.\n\nThe Committee discussed the manufacturer's assumptions for extrapolating overall survival in the model, and the alternative assumptions considered by the ERG in its exploratory analyses. The Committee noted that the manufacturer assumed that the survival benefit from treatment with aflibercept plus FOLFIRI increases relative to treatment with FOLFIRI alone until around 12\xa0months after starting treatment, and then decreases over the 15-year time horizon, but that the hazard ratio never reaches 1.0 (that is, a patient previously randomised to aflibercept will always have a lower risk of dying, even if not receiving aflibercept, relative to a patient previously randomised to placebo). The Committee noted that the ERG explored 2\xa0alternative scenarios:\n\nthe first assumed that the risk of death becomes the same in both treatment groups at the point at which the trial ends and continues to be the same for the remainder of the time horizon period (that is, the hazard ratio becomes 1.0 after 3\xa0years)\n\nthe second assumed that the overall survival curves for aflibercept plus FOLFIRI and FOLFIRI alone converge over the time horizon (that is, the hazard ratio gradually increases from the end of the trial until the survival curves come together, then the hazard ratio becomes 1.0 thereafter).The Committee understood that, in the ERG's second scenario, patients receiving aflibercept plus FOLFIRI need to have a higher risk of death than patients receiving FOLFIRI alone (that is, the hazard ratio may be greater than 1.0) for the curves to converge. The Committee considered that the manufacturer's assumption that the treatment benefit continues beyond the trial period and until 15\xa0years is highly uncertain given that most patients had died during the 3-year follow-up period of the trial. The Committee considered that the ERG's analysis that allows the hazard ratio to become greater than 1.0 could be considered implausible. The Committee agreed that the ERG's first scenario, which assumes equal risk of death for all patients beyond the trial period (hazard ratio equals 1.0), represents an acceptable compromise between the 2\xa0extremes of assuming continuing treatment effect (manufacturer's base case) and allowing for a reversed treatment effect (ERG's second scenario). The Committee noted that, in response to consultation, the manufacturer implemented a new scenario in its revised base case in which the hazard ratio begins to taper to 1.0 36\xa0months after starting treatment, over a 12-month period. The Committee agreed that as a means to extrapolate overall survival both its preferred scenario (that is, the ERG's first scenario) and the manufacturer's new scenario were associated with some degree of uncertainty. In the absence of further evidence to validate the manufacturer's new approach, the Committee maintained its preference for the ERG's first scenario.\n\nThe Committee considered the estimates of health-related quality of life used in the manufacturer's model, noting that it would have preferred these data to have been collected from the VELOUR trial. The Committee was aware that the manufacturer got the utility value for the stable-disease state from the 'mCRC utilities study' and revised it after consultation to a value derived from the ASQoP study because the data from this study were new, and not because the Committee questioned the validity of the original value. The Committee noted that the ERG preferred another value from the ASQoP study for the stable-disease state but, because the difference between the manufacturer's revised value (0.78) and the ERG's preferred value (0.77) was small and likely to have a negligible impact on the ICER, the Committee concluded that either value could be considered appropriate.\n\nThe Committee discussed the appropriate utility value for the progressed-disease state in the model, noting that, because approximately three-quarters of the QALY gain in the model was accrued after disease progression, the model is highly sensitive to this parameter. The Committee, having noted the mean and median time to disease progression in the manufacturer's utility study, considered that the utility value chosen by the manufacturer for the progressed-disease state did not reflect the entire duration of progressed disease but only early progressed disease, and so was likely to be an overestimate (see section 3.28). The Committee was aware of the participation bias associated with studies of this nature. Furthermore, it heard from the ERG that the manufacturer's study was small, and produced counter-intuitive estimates in 1\xa0subgroup analysis. The Committee was aware that, although the manufacturer stated that the data queries noted in its submission had been resolved, the manufacturer had yet to submit the study for peer-reviewed publication. The Committee was aware that, in its base case, the ERG used an alternative lower value of\xa00.60, which had been used in NICE technology appraisal guidance 118, and that the ERG considered this value to represent a reasonable balance of the utility values for progressed disease used in other NICE guidance, which ranged from 0.21 to 0.69. The Committee was aware that the utility value of 0.69 used in NICE technology appraisal guidance 242 for progressed disease was based on patients who had lived long enough to receive more courses of chemotherapy than patients in the VELOUR trial, and so likely reflected patients with a better health state. The Committee agreed that no utility values for progressed disease were universally accepted as valid, but that it would be important that the utility value reflected the entire progressed-disease state. The Committee was aware that the quality of life for patients with metastatic colorectal cancer deteriorates relatively slowly other than during the last few months, when it may deteriorate faster, and that exploring a utility value of 0.3 during the last 2\xa0months of life was a reasonable attempt by the manufacturer to address this. The Committee also agreed that adjusting the utility values for age was appropriate to reflect the natural deterioration in health-related quality of life in patients with the disease. The Committee concluded that the most plausible utility value for the progressed-disease health state would lie between the manufacturer's and the ERG's estimate.\n\nThe Committee discussed the costs of administering aflibercept plus FOLFIRI in the model, noting that the manufacturer assumed no extra cost for administering aflibercept in its original model. The Committee was aware that aflibercept would normally be prepared in a sterile compartment, and would therefore incur an extra cost; the Committee estimated that this cost is likely to be higher than the £15 used by the ERG. The Committee was also aware that the marketing authorisation for aflibercept stipulates that aflibercept should be administered over 1\xa0hour before the infusion with FOLFIRI, but that the cost for an additional hour of infusion time (£45) was not included in the ERG base case. The Committee acknowledged that the manufacturer's revised base case accounted for the extra preparation cost and the cost for an additional infusion time for aflibercept.\n\nThe Committee noted that, in response to consultation, the manufacturer had provided data showing that the average age of patients treated in the NHS with second-line chemotherapy for metastatic colorectal cancer was 60\xa0years in 1\xa0study and 63 years in 3\xa0others. The Committee agreed that the 70-year age of starting treatment, as initially assumed by the ERG in its base case, was therefore too high. It concluded that an age between 60 and 65\xa0years is more appropriate.\n\nThe Committee discussed the costs in the model derived from the manufacturer's survey of clinical oncologists about community-based care, and personal and social care. The Committee noted that this study was small and therefore associated with uncertainty, and did not provide evidence that the oncologists in the survey were representative of practitioners in the UK. The Committee noted that the manufacturer's model incorporated median estimates from the survey because the responses from clinicians on 1\xa0parameter (the number of visits received by a patient from a palliative care team) included an outlier, whereas the ERG argued that the mean was more appropriate. The Committee agreed that, if the sample of clinicians was appropriately homogenous and reflected similar practices, the distribution of the data collected from the survey would be largely uniform, and it would be more appropriate to use the mean rather than the median. The Committee noted that, although the manufacturer continued to use the median value in its revised base case, it presented a scenario analysis that incorporated the mean after excluding the outlier, an approach that the ERG considered appropriate. Although the Committee agreed that mean values should normally be used to estimate resource use and costs, it concluded that, in this instance, using the mean after excluding the outlier could be considered appropriate.\n\nThe Committee discussed whether aflibercept should be considered an innovative treatment. The Committee acknowledged that aflibercept represented a novel recombinant fusion protein. However, the Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee considered the criterion for short life expectancy and the evidence for life expectancy in this group of patients. The Committee noted the overall survival estimates presented by the manufacturer from the VELOUR trial with the observed median survival in the placebo group of VELOUR of 12.1\xa0months and the estimated mean overall survival of 18.1\xa0months. The Committee also noted the ERG's preferred estimate of 10.5\xa0months from the literature. The Committee concluded that patients receiving current standard NHS treatment would have an expected survival of less than 24\xa0months from the point at which they would be considered for second-line therapy and that therefore the criterion for short life expectancy was fulfilled in this appraisal.\n\nThe Committee considered the criterion that the treatment is licensed or otherwise indicated for small patient populations. The Committee noted the manufacturer's suggestion that approximately 4000 patients in England and Wales would receive second-line treatment for metastatic colorectal cancer. The Committee was concerned that aflibercept holds a marketing authorisation for treatment of a much larger population with neovascular (wet) age-related macular degeneration, but that this was a different formulation of aflibercept marketed by another company. The Committee understood that when one technology is marketed by different companies (for different indications, using different brands), these should not be added for the purpose of establishing the cumulative population to be considered in the context of life-extending treatments at the end of life, and that therefore the criterion for a small population size was fulfilled in this appraisal.\n\nThe Committee considered the criterion that treatment offers an extension to life of normally at least an additional 3\xa0months. The Committee noted the comments received in consultation on the ACD, and agreed to explain its concerns over the magnitude of the mean survival benefit more fully. The Committee noted that, based on the number of patients who had died during the trial (70.4%), 50% of those who received aflibercept lived for up to 1.44\xa0months longer than people who received placebo, and acknowledged the difficulty in finding robust mean overall survival data considering the issues with the extrapolation carried out (see section 4.7). The Committee noted that, in response to consultation, the manufacturer pointed out that the original base-case model, using the Committee's preferred assumption to extrapolate overall survival (section 4.14), predicted that aflibercept would extend life by 3.4–3.7\xa0months. The Committee discussed whether the estimates for mean overall survival produced by the model were robust indicators of what overall survival benefit can be seen in clinical practice, noting that all of the extrapolation assumptions were associated with great uncertainty. The Committee was aware that the longer the time horizon, the greater the influence of the 'tails' of the extrapolation curves, which define the difference in mean overall survival between the treatment arms, and to which the model is highly sensitive. The Committee agreed that, although there is a rationale for a 15-year time horizon in order to capture the very small number of patients who might have very prolonged survival, this introduced considerable uncertainty, and produced implausible results given that the extrapolation was based on a population with a small number of patients still at risk of dying beyond 30\xa0months. Although the use of a 15-year time horizon is, in principle, appropriate, when extrapolating the relative benefit is associated with uncertainty, the Committee considered it appropriate to consider shorter time horizons as a means to explore the uncertainty. The Committee noted that, when the model time horizon was shortened to 5\xa0years, the difference in mean overall survival decreased to 2.7–2.8\xa0months. The Committee was mindful that, when there is quantitative evidence that a treatment offers a 3-month life extension, it must also be persuaded that the estimates of life extension are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The Committee agreed that, given the considerable uncertainty around extrapolating overall survival and its implementation in the modelling, it is important to take into account what has actually been observed in the trial (see section 4.6 and 4.8) and in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled. The Committee therefore concluded that aflibercept did not meet the criteria for an end-of-life therapy as defined by NICE.\n\nThe Committee noted that, in its response to consultation on the appraisal consultation document, the manufacturer pointed out that, in NICE technology appraisal guidance 242, the Committee had considered a modelled survival benefit of 2.7–3.2\xa0months to show sufficient evidence for a 3-month survival benefit for panitumumab. The Committee was aware that, in judging whether panitumumab met the criterion for life extension, the Committee for NICE technology appraisal 242 had taken into consideration the difficulty in accommodating the cross‑over in the panitumumab trials and that the mean progression-free survival benefit for panitumumab was similar to that for cetuximab, and that the latter resulted in an overall survival benefit of 4.7\xa0months. Therefore, it had considered that there was sufficient evidence to indicate that panitumumab offers an extension to life of approximately 3\xa0months.\n\nThe Committee discussed the ICERs for aflibercept in combination with irinotecan and fluorouracil-based therapy for metastatic colorectal cancer based on the revised analyses provided in response to consultation. The Committee agreed that the cost-effectiveness analysis should assume equal risk of death for all patients beyond the trial period, and that the starting age of the modelled cohort should be between 60\xa0and 65\xa0years. The Committee noted that the manufacturer's ICER closest to these assumptions was £44,000 per QALY gained (for age 60), but would increase for the higher age bracket, if the mean value was used from the manufacturer's survey of clinical oncologists after removing the outlier and if an extrapolation function with a less heavy tail had been used. Because the manufacturer's ICERs incorporated a utility value for progressed disease deemed by the Committee to be high, the Committee considered the ICER produced by the ERG using the Committee's preferred assumptions, but which used a utility value for progressed disease of 0.6. The Committee noted that this was approximately £51,000 per QALY gained and would be higher if an extrapolation function with a less heavy tail had been used. The Committee therefore concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained, and that aflibercept in combination with irinotecan and fluorouracil-based therapy could not be considered a cost-effective use of NHS resources for patients with metastatic colorectal cancer.\n\nThe Committee noted the comments received during consultation on the appraisal consultation document that some patients appeared to gain particular benefit ('a bimodal distribution'), and which stressed the importance of offering only certain patients aflibercept. The Committee was aware that there is currently no established method in clinical practice to identify patients with metastatic colorectal cancer who could particularly benefit from treatment, and it was not presented with evidence on how these patients could be selected for treatment with aflibercept. The Committee was aware that, as a post-authorisation commitment to the European Medicines Agency, the manufacturer initiated a biomarker program encompassing 3\xa0studies to help select patients who may be more likely to benefit. The Committee agreed that the results of these studies would be useful for a future review of this appraisal.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA307\n\nAppraisal title: Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy\n\nSection\n\nKey conclusion\n\nAflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended within its marketing authorisation for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen.\n\n\n\nGiven the considerable uncertainty around extrapolating overall survival and its implementation within the model, and in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled.\n\n\n\nThe Committee concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee noted that the current treatment options for patients with metastatic colorectal cancer are limited, and that treatment is determined individually. The Committee heard that resecting tumours surgically may be a treatment option in some patients with metastatic disease, noting that systemic therapy can make resection possible in some patients.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee noted that patients consider biologic therapies such as aflibercept to improve quality of life compared with chemotherapy.\n\n\n\nThe Committee heard that, because the overall survival curves continued to separate for both patients who had or had not stopped treatment, the survival curves might reflect a disease modifying effect in that aflibercept might have altered the natural course of the disease whereby, despite the disease progressing, patients lived longer even after treatment stopped. The Committee agreed that there was no robust evidence to make firm conclusions about the likely cause of the different shapes of the overall survival and progression-free survival curves.\n\n\n\nThe Committee acknowledged that aflibercept represented a novel recombinant fusion protein. However, the Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nAflibercept in combination with FOLFIRI has a UK marketing authorisation 'for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen'.\n\n\n\nAdverse reactions\n\nThe Committee concluded that treatment with aflibercept plus FOLFIRI was associated with a considerable burden of adverse effects, but that, being a new treatment, less is known about its adverse effects profile than for other available treatments.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted that the evidence on the clinical effectiveness of aflibercept was derived from the VELOUR trial. The Committee agreed that the VELOUR trial was of good quality and directly relevant to the decision problem. However, the Committee would have liked the manufacturer to have collected and presented trial data relating to health-related quality of life, and would have liked the manufacturer to have followed and presented event data for all patients after the end of the trial as defined. The Committee concluded that the results from the VELOUR trial are generalisable to UK clinical practice.\n\n\n\nRelevance to general clinical practice in the NHS\n\nNo specific Committee considerations on the relevance to general clinical practice in the NHS.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted that, to estimate aflibercept's mean survival benefit of 4.7\xa0months, the manufacturer extrapolated the survival curves from a trial with a median follow-up of just under 2\xa0years up to 15\xa0years. Although the Committee agreed that a small proportion of patients, with as yet undefined characteristics, appeared to derive greater benefit from aflibercept than most patients in the trial, it considered that the manufacturer's extrapolation of overall survival based on a population with a very few patients at risk of dying after 30\xa0months' follow-up over a further 12\xa0years was associated with great uncertainty.\n\n\n\nThe Committee was aware that the manufacturer estimated the mean survival benefit of 4.7\xa0months by fitting the log-logistic function to the observed data, and extrapolating the survival curves over 15\xa0years. The Committee noted that the estimates using other parametric functions ranged from 3.0–5.3\xa0months. The Committee was aware that a longer than 5-year survival for patients with metastatic colorectal cancer is very unusual. Having considered the estimates obtained using different parametric functions and extrapolation periods, the Committee was concerned that the log-logistic function had a very 'heavy tail', and that this is likely to have overestimated the survival benefit of aflibercept. The Committee was also concerned that the manufacturer did not characterise the uncertainty around any of the estimates. The Committee concluded that extrapolating overall survival with the log-logistic function over 15\xa0years did not provide a plausible mean overall survival benefit.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee agreed that there was no evidence to suggest that aflibercept would be more effective in patients with liver metastases only than in patients with metastases confined to other organs. The Committee was not presented with evidence about rates of resection and cure with aflibercept in the subgroup of patients with liver metastases only. The Committee therefore agreed that aflibercept cannot be considered an effective treatment option to make liver metastases resectable, concluding that this subgroup should not be considered further.\n\n\n\nThe Committee heard from the clinical specialists that, in clinical practice, patients who had received oxaliplatin-based therapy in the adjuvant setting and relapsed within the following 6\xa0months would not be treated differently to the overall trial population. In addition, the Committee noted that the analysis for this subgroup was planned after the trial results had been compiled (post hoc), and that the test for interaction did not show that the treatment effect in this subgroup differed from the effect in the rest of the trial population. The Committee therefore concluded that it did not need to consider further the subgroup that excluded patients whose disease had relapsed 6\xa0months or less after starting oxaliplatin-based adjuvant therapy.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee agreed that the difference in median overall survival of 1.44\xa0months reflects a statistically significant but clinically small benefit.\n\n\n\nThe Committee considered that the manufacturer's extrapolation of overall survival from a population with very few patients at risk of dying after 30\xa0months' follow-up, over a further 12\xa0years, was associated with great uncertainty.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee concluded that overall the manufacturer's model adhered to the NICE reference case for assessing cost effectiveness.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered that the manufacturer's assumption that the treatment benefit continues beyond the trial period and until 15\xa0years is highly uncertain given that most patients had died during the 3-year follow-up period of the trial. The Committee considered that the ERG's analysis that allows the hazard ratio to become greater than\xa01.0 could be considered implausible. The Committee agreed that the ERG's scenario, which assumes equal risk of death for all patients beyond the trial period (hazard ratio equals\xa01.0), represents an acceptable compromise between the 2\xa0extremes of assuming continuing treatment effect (manufacturer's base case) and allowing for a reversed treatment effect (ERG's second scenario). The Committee noted that, in response to consultation, the manufacturer implemented a new scenario in its revised base case in which the hazard ratio begins to taper to 1.0 36\xa0months after starting treatment, over a 12‑month period. The Committee agreed that as a means to extrapolate overall survival both its preferred scenario (that is, the ERG's first scenario) and the manufacturer's new scenario were associated with some degree of uncertainty. In the absence of further evidence to validate the manufacturer's new approach, the Committee maintained its preference for the ERG's first scenario.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee was aware that the manufacturer got the utility value for the stable-disease state from the 'mCRC utilities study' and revised it after consultation to a value derived from the ASQoP. The Committee noted that the ERG preferred another value from the ASQoP study for the stable-disease state. The Committee concluded that either value could be considered appropriate.\n\n\n\nThe Committee considered that the utility value chosen by the manufacturer for the progressed-disease state did not reflect the entire duration of progressed disease but only early progressed disease, and so was likely to be an overestimate. The Committee was aware that, in its base case, the ERG used an alternative lower value of 0.60, which had been used in NICE technology appraisal guidance 118. The Committee agreed that no utility values for progressed disease were universally accepted as valid, but that it would be important that the utility value reflected the entire progressed-disease state. The Committee also agreed that adjusting the utility values for age was appropriate. The Committee concluded that the most plausible utility value for the progressed-disease health state would lie between the manufacturer's and the ERG's estimate.\n\n\n\nThe Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nHaving considered the clinical evidence presented by the manufacturer for the 2\xa0subgroups, the Committee concluded that it did not need to consider the cost effectiveness of the technology for any of the subgroups.\n\n\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee considered the robustness of the mean overall survival benefit, obtained using the log-logistic function, of 3\xa0months (5\xa0years extrapolation time), 4.7\xa0months (15\xa0years extrapolation time) and 6.6\xa0months (without truncating the survival curves.\n\n\n\nThe Committee was aware that the longer the time horizon, the greater the influence of the 'tails' of the extrapolation curves, which define the difference in mean overall survival between the treatment arms, and to which the model is highly sensitive.\n\n\n\nThe Committee noted that, because approximately three-quarters of the QALY gain in the model was accrued after disease progression, the model is highly sensitive to utility value for the progressed-disease state in the model.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that the manufacturer's ICER closest to its preferred assumptions was £44,000 per QALY gained (for age\xa060), but would increase for the higher age bracket, if the mean value was used from the manufacturer's survey of clinical oncologists after removing the outlier and if an extrapolation function with a less heavy tail had been used. Because the manufacturer's ICERs incorporated a utility value for progressed disease deemed by the Committee to be high, the Committee considered the ICER produced by the ERG using the Committee's preferred assumptions, but which used a utility value for progressed disease of 0.6. The Committee noted that this was approximately £51,000 per QALY gained and would be higher if an extrapolation function with a less heavy tail had been used. The Committee therefore concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence.\n\n\n\nEnd-of-life considerations\n\nThe Committee agreed that, given the considerable uncertainty around extrapolating overall survival and its implementation within the model, it is important to take into account what has actually been observed in the trial (see section 4.6 and 4.8) and, in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled. The Committee therefore concluded that aflibercept did not meet the criteria for an end-of-life therapy as defined by NICE.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues relevant to the Committee's recommendations were raised.\n\n", 'Review of guidance': 'The guidance on this technology will be considered for review in August 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveMarch 2014', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt has been incorporated into the NICE pathway on colorectal cancer along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0519-5'}	https://www.nice.org.uk/guidance/ta307	Evidence-based recommendations on aflibercept (Zaltrap) with irinotecan and fluorouracil-based therapy (FOLFIRI) for treating metastatic colorectal cancer after oxaliplatin-based chemotherapy in adults.
ade1c5d20b745202225ca640b75da18f5fd9b82a	nice	Managing medicines in care homes	Managing medicines in care homes This guideline covers good practice for managing medicines in care homes. It aims to promote the safe and effective use of medicines in care homes by advising on processes for prescribing, handling and administering medicines. It also recommends how care and services relating to medicines should be provided to people living in care homes. # Terms used in this guideline For the purposes of this guideline the term 'care home' covers the provision of 24‑hour accommodation together with either non‑nursing care (for example, a residential home) or nursing care (for example, a care home with nursing). The term 'care home provider' is used for the registered provider of care. If regulation or practice differs between different types of care homes (for example, a children's care home, an adult's care home, a non‑nursing care home or a nursing care home), then the type of care home is specified in the text. When the term 'organisations' is used, this includes all commissioners and providers (including care home providers), unless specified otherwise in the text. Commissioners are those individuals who undertake commissioning which is 'the process used by health services and local authorities to: identify the need for local services; assess this need against the services and resources available from public, private and voluntary organisations; decide priorities; and set up contracts and service agreements to buy services. As part of the commissioning process, services are regularly evaluated'. Providers are organisations that directly provide health or social care services (such as a care home). Individual people who live in care homes are referred to as 'residents' or 'care home residents' in this guideline. A 'care home' can be of any size (number of residents) or have any type of resident (children, older people, people with cognitive impairment, young disabled people, people with a learning disability), but should be a registered provider of care (for example, in England with either the CQC or Ofsted). For the purposes of this guideline, the term 'care home staff' includes registered nurses and social care practitioners working in a care home. The term 'carer' is used for an informal or unpaid carer. The term 'health and social care practitioners' is used to define the wider care team, including care home staff (registered nurses and social care practitioners working in care homes), social workers, case managers, GPs, pharmacists and community nurses. When specific recommendations are made for a particular professional group, this is specified in the recommendation, for example, 'GPs'. The term 'pharmacist' is used for all pharmacists, including primary care pharmacists, care home pharmacists and supplying pharmacists. Primary care pharmacists work in the primary care setting and may have a role working with care homes. Care home pharmacists have a dedicated role working in care homes. Supplying pharmacists work in a community pharmacy or chemist shop. When a care home resident is able to look after and take their own medicines, this is referred to as 'self-administration'. When the guideline refers to the administration of medicines, this is when care home staff check and give, or help to give, a resident their medicine(s).# Person-centred care Care home residents and health professionals (for care under the NHS) have rights and responsibilities as set out in the NHS Constitution for England, and NICE guidelines are written to reflect these. Treatment and care should take into account individual needs and preferences. Care home residents should have the opportunity to make informed decisions about their care and treatment, in partnership with their health professionals and social care practitioners. If the resident is under 16, their family or carers should also be given information and support to help the child or young person to make decisions about their treatment. Health professionals should follow the Department of Health's advice on consent. If someone does not have capacity to make decisions, health professionals should follow the code of practice that accompanies the Mental Capacity Act and the supplementary code of practice on deprivation of liberty safeguards. All health professionals should follow the recommendations in the NICE guideline on patient experience in adult NHS services and where appropriate the NICE guideline on service user experience in adult mental health, although many of the principles in that guideline apply equally to social care staff. If the resident agrees, families and carers should have the opportunity to be involved in decisions about treatment and care. Families and carers should also be given the information and support they need. The person-centred care approach is not new across sectors and resources such as Think Local, Act Personal, help to support this working. # Involving others The views of residents in care homes about who should and should not be involved in their care are important and should be respected. If the resident lacks the capacity to decide who should and should not be involved, health and social care practitioners must act in the resident's best interests, taking account of the provisions in the Mental Capacity Act 2005. Health and social care practitioners should also consider accounts from family members or carers of the resident's usual behaviour. This information, when used with an assessment of the resident concerned, will help with specific decisions about their care. It will also help to estimate the person's capacity to make a specific decision. Residents with reduced mental capacity should continue to have the opportunity to make informed decisions about those aspects of their care and personal lives for which they retain capacity. Good communication between health and social care practitioners and residents, their family members or carers (as appropriate) is essential for residents to receive the information and support they need. Evidence-based information should be offered in a form that is tailored to the needs of the individual resident. The treatment, care and information provided should be culturally appropriate and in a form that is accessible to residents who have additional needs, such as physical, cognitive or sensory disabilities, or who do not speak or read English. If the resident agrees, families and carers should have the opportunity to be involved in decisions about treatment and care. Families and carers should also be given the information and support they need, and carers should be offered an assessment of their own needs. # Keeping residents safe (safeguarding) Similar definitions exist for safeguarding of adults and children from the regulators of adult and children's services. The CQC's Essential standards of quality and safety (2010) define safeguarding adults as: 'Ensuring that people live free from harm, abuse and neglect and, in doing so, protecting their health, wellbeing and human rights'. The Department for Education's Working together to safeguard children (2013) defines safeguarding children as: 'protecting children from maltreatment; preventing impairment of children's health or development, ensuring children are growing up in circumstances consistent with the provision of safe and effective care and taking action to enable all children to have the best outcomes.' A safeguarding issue in relation to managing medicines could include the deliberate withholding of a medicine(s) without a valid reason, the incorrect use of a medicine(s) for reasons other than the benefit of a resident, deliberate attempt to harm through use of a medicine(s), or accidental harm caused by incorrect administration or a medication error.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The recommendations for good practice have been developed by the Guideline Development Group (GDG), using relevant legislation, guidance and policy as the foundation for good practice. See appendix B of the full guideline for a list of key resources used in developing this guideline. When a recommendation is aimed specifically at a person or organisation, this is clearly stated. In most cases the GDG was able to identify which person or organisation was responsible; if this is not specified it will be for organisations to consider and determine locally. The GDG agreed that arrangements will vary depending on local organisational structures, how services are commissioned and provided, and what resources are available. # Developing and reviewing policies for safe and effective use of medicines Commissioners and providers (organisations that directly provide health or social care services) should review their policies, processes and local governance arrangements, making sure that it is clear who is accountable and responsible for using medicines safely and effectively in care homes. Care home providers should have a care home medicines policy, which they review to make sure it is up to date, and is based on current legislation and the best available evidence. The policy should include written processes for: sharing information about a resident's medicines, including when they transfer between care settings ensuring that records are accurate and up to date identifying, reporting and reviewing medicines‑related problems keeping residents safe (safeguarding) accurately listing a resident's medicines (medicines reconciliation) reviewing medicines (medication review) -rdering medicines receiving, storing and disposing of medicines helping residents to look after and take their medicines themselves (self‑administration) care home staff administering medicines to residents, including staff training and competence requirements care home staff giving medicines to residents without their knowledge (covert administration) care home staff giving non-prescription and over‑the‑counter products to residents (homely remedies), if appropriate. # Supporting residents to make informed decisions and recording these decisions Health and social care practitioners (care home staff, social workers, case managers, GPs, pharmacists and community nurses) should ensure that care home residents have the same opportunities to be involved in decisions about their treatment and care as people who do not live in care homes, and that residents get the support they need to help them to take a full part in making decisions. The health professional prescribing a medicine or care home staff should record a resident's informed consent in the resident's care record. Consent does not need to be recorded each time the medicine is given but a record of the administration should be made on the medicines administration record. Care home staff (registered nurses and social care practitioners working in care homes) should record the circumstances and reasons why a resident refuses a medicine (if the resident will give a reason) in the resident's care record and medicines administration record, unless there is already an agreed plan of what to do when that resident refuses their medicines. If the resident agrees, care home staff should tell the health professional who prescribed the medicine about any ongoing refusal and inform the supplying pharmacy, to prevent further supply to the care home. Health and social care practitioners should identify and record anything that may hinder a resident giving informed consent. Things to look out for include mental health problems, lack of (mental) capacity to make decisions, health problems (such as problems with vision and hearing), difficulties with reading, speaking or understanding English and cultural differences. These should be taken into account when seeking informed consent and should be regularly reviewed. Health professionals prescribing a medicine must: assume that care home residents have the capacity to make decisions assess a resident's mental capacity in line with appropriate legislation (for example, the Mental Capacity Act 2005) if there are any concerns about whether a resident is able to give informed consent record any assessment of mental capacity in the resident's care record. Health professionals prescribing a medicine should review mental capacity, in line with the Mental Capacity Act 2005 and the Mental Capacity Act Code of Practice 2007 when a resident lacks capacity to make a specific decision. How often they do this should depend on the cause, as this may affect whether lack of capacity fluctuates or is temporary. Health and social care practitioners should ensure that residents are involved in best interest decisions, in line with the Mental Capacity Act Code of Practice 2007, and: find out about their past and present views, wishes, feelings, beliefs and values involve them, if possible, in meetings at which decisions are made about their medicines talk to people who know them well, including family members or carers (informal or unpaid carers) and friends, as well as care home staff deliver care and treatment in a way that empowers the resident to be involved in decisions and limits any restrictions to their care. # Sharing information about a resident's medicines Care home providers should have a process for managing information (information governance) covering the 5 rules set out in the Health and Social Care Information Centre's A guide to confidentiality in health and social care (2013). The process should also include the training needed by care home staff and how their skills (competency) should be assessed. Commissioners should review their commissioning arrangements with their provider organisations to ensure that any information about a resident's medicines that is transferred contains the minimum information set out in recommendation 1.7.3 in the section on accurately listing a resident's medicines. Commissioners should monitor this through their contracting arrangements. Providers of health or social care services should have processes in place for sharing, accurate information about a resident's medicines, including what is recorded and transferred when a resident moves from one care setting to another (including hospital). Providers of health or social care services should ensure that either an electronic discharge summary is sent, if possible, or a printed discharge summary is sent with the resident when care is transferred from one care setting to another. See recommendation 1.7.3 in the section on accurately listing a resident's medicines for the minimum information that should be transferred. Health and social care practitioners should ensure that all information about a resident's medicines, including who will be responsible for prescribing in the future, is accurately recorded and transferred with a resident when they move from one care setting to another. Health and social care practitioners should check that complete and accurate information about a resident's medicines has been received and recorded, and is acted on after a resident's care is transferred from one care setting to another (see recommendation 1.7.3 in the section on accurately listing a resident's medicines for the minimum information that should be transferred). Care home providers should have a process in the care home medicines policy for recording the transfer of information about residents' medicines during shift handovers and when residents move to and from care settings. Care home staff should follow the rules on confidentiality set out in the home's process on managing information about medicines (see recommendation 1.3.1) and only share enough information with health professionals that a resident visits to ensure safe care of the resident. # Ensuring that records are accurate and up to date Health and social care practitioners should ensure that records about medicines are accurate and up-to-date by following the process set out in the care home medicines policy (see recommendation 1.1.2 in the section on developing and reviewing policies for safe and effective use of medicines). The process should cover: recording information in the resident's care plan recording information in the resident's medicines administration record recording information from correspondence and messages about medicines, such as emails, letters, text messages and transcribed phone messages recording information in transfer of care letters and summaries about medicines when a resident is away from the home for a short time what to do with copies of prescriptions and any records of medicines ordered for residents. Care home providers must follow the relevant legislation to ensure that appropriate records about medicines are kept secure, for an appropriate period of time, and destroyed securely when appropriate to do so. # Identifying, reporting and reviewing medicines-related problems Commissioners and providers of health or social care services should ensure that a robust process is in place for identifying, reporting, reviewing and learning from medicines errors involving residents (see also recommendations 1.6.1 to 1.6.3 in the section on keeping residents safe). Health and social care practitioners should consider working with all relevant stakeholders to develop a locally agreed action plan, in line with other local and national strategies and governance arrangements, for improving the safety of residents and reducing medication errors in care homes. Care home staff (registered nurses and social care practitioners working in care homes) should report all suspected adverse effects from medicines to the health professional who prescribed the medicine or another health professional as soon as possible; this would usually be the GP or out-of-hours service. Staff should record the details in the resident's care plan and tell the supplying pharmacy (if the resident agrees that this information can be shared). # Keeping residents safe (safeguarding) Commissioners and providers of health or social care services should all be aware of local arrangements for notifying suspected or confirmed medicines‑related safeguarding incidents. Care home providers should have a clear process for reporting medicines‑related safeguarding incidents under local safeguarding processes and to the Care Quality Commission (CQC) (or other appropriate regulator). The process should be recorded in the care home medicines policy and should clearly state: when the CQC (or other appropriate regulator) should be notified which medicines‑related safeguarding incidents should be reported under local safeguarding processes and when that accurate details of any medicines-related safeguarding incidents are recorded as soon as possible so that the information is available for any investigation and reporting. Commissioners should ensure that reporting requirements are included in commissioning and contracting arrangements. Care home staff should contact a health professional to ensure that action is taken to safeguard any resident involved in a medicines-related safeguarding incident. They should follow a process agreed between health professional(s) and commissioners, which sets out who to contact in normal office hours and out‑of‑hours. Care home providers should record all medicines‑related safety incidents, including all 'near misses' and incidents that do not cause any harm, as a resident safety incident. Where there are notifiable safeguarding concerns these must be reported to the CQC (or other appropriate regulator). Local safeguarding processes should include the investigation of each report of a medicines-related safeguarding incident and should monitor reports for trends. Local safeguarding processes should include arrangements for feedback to care homes about reported medicines‑related incidents to promote sharing of experiences and learning. Care home staff should find out the root cause of medicines‑related incidents. Care home providers should make sure that any training needed by staff to find out the root cause of medicines‑related incidents is specified in contracts with commissioners. Care home staff should give residents and/or their family members or carers information on how to report a medicines‑related safety incident or their concerns about medicines, using the care home provider's complaints process, local authority (or local safeguarding) processes and/or a regulator's process. Care home providers should ensure that all residents can use advocacy and independent complaints services when they have concerns about medicines. # Accurately listing a resident's medicines (medicines reconciliation) The care home manager or the person responsible for a resident's transfer into a care home should coordinate the accurate listing of all the resident's medicines (medicines reconciliation) as part of a full needs assessment and care plan. The care home manager should consider the resources needed to ensure that medicines reconciliation occurs in a timely manner (see recommendation 1.1.2 in the section on developing and reviewing policies for safe and effective use of medicines). Care home providers should ensure that the following people are involved in medicines reconciliation: the resident and/or their family members or carers a pharmacist -ther health and social care practitioners involved in managing medicines for the resident, as agreed locally. Commissioners and providers of health or social care services should ensure that the following information is available for medicines reconciliation on the day that a resident transfers into or from a care home: resident's details, including full name, date of birth, NHS number, address and weight (for those aged under 16 or where appropriate, for example, frail older residents) GP's details details of other relevant contacts defined by the resident and/or their family members or carers (for example, the consultant, regular pharmacist, specialist nurse) known allergies and reactions to medicines or ingredients, and the type of reaction experienced medicines the resident is currently taking, including name, strength, form, dose, timing and frequency, how the medicine is taken (route of administration) and what for (indication), if known changes to medicines, including medicines started, stopped or dosage changed, and reason for change date and time the last dose of any 'when required' medicine was taken or any medicine given less often than once a day (weekly or monthly medicines) -ther information, including when the medicine should be reviewed or monitored, and any support the resident needs to carry on taking the medicine (adherence support) what information has been given to the resident and/or family members or carers.Providers should ensure that the details of the person completing the medicines reconciliation (name, job title) and the date are recorded. # Reviewing medicines (medication review) GPs should ensure that arrangements have been made for their patients who are residents in care homes to have medication reviews as set out in the residents' care plans (see recommendation 1.8.4). GPs should work with other health professionals to identify a named health professional who is responsible for medication reviews for each resident. This should take into account the clinical experience and skills of the health professional, how much they know about the resident and the resident's condition, and whether they can access the relevant information. Health and social care practitioners should ensure that medication reviews involve the resident and/or their family members or carers and a local team of health and social care practitioners (multidisciplinary team). This may include a: pharmacist community matron or specialist nurse, such as a community psychiatric nurse GP member of the care home staff practice nurse social care practitioner. The roles and responsibilities of each member of the team and how they work together should be carefully considered and agreed locally. Training should be provided so that they have the skills needed. Health and social care practitioners should agree how often each resident should have a multidisciplinary medication review. They should base this on the health and care needs of the resident, but the resident's safety should be the most important factor when deciding how often to do the review. The frequency of planned medication reviews should be recorded in the resident's care plan. The interval between medication reviews should be no more than 1 year. Health and social care practitioners should discuss and review the following during a medication review: the purpose of the medication review what the resident (and/or their family members or carers, as appropriate and in line with the resident's wishes) thinks about the medicines and how much they understand the resident's (and/or their family members' or carers', as appropriate and in line with the resident's wishes) concerns, questions or problems with the medicines all prescribed, over-the-counter and complementary medicines that the resident is taking or using, and what these are for how safe the medicines are, how well they work, how appropriate they are, and whether their use is in line with national guidance any monitoring tests that are needed any problems the resident has with the medicines, such as side effects or reactions, taking the medicines themselves (for example, using an inhaler) and difficulty swallowing helping the resident to take or use their medicines as prescribed (medicines adherence) any more information or support that the resident (and/or their family members or carers) may need. # Prescribing medicines GP practices should ensure that there is a clear written process for prescribing and issuing prescriptions for their patients who live in care homes. The process should cover: issuing prescriptions according to the patient medical records recording clear instructions on how a medicine should be used, including how long the resident is expected to need the medicine and, if important, how long the medicine will take to work and what it has been prescribed for (use of the term 'as directed' should be avoided) recording prescribing in the GP patient medical record and resident care record and making any changes as soon as practically possible providing any extra details the resident and/or care home staff may need about how the medicine should be taken any tests needed for monitoring prescribing the right amount of medicines to fit into the 28‑day supply cycle if appropriate, and any changes that may be needed for prescribing in the future monitoring and reviewing 'when required' and variable dose medicines issuing prescriptions when the medicines order is received from the care home. When prescribing variable dose and 'when required' medicine(s) the health professional prescribing the medicine should: note in the resident's care record the instructions for: when and how to take or use the medicine (for example, 'when low back pain is troublesome take 1 tablet') monitoring the effect they expect the medicine to have include dosage instructions on the prescription (including the maximum amount to be taken in a day and how long the medicine should be used, as appropriate) so that this can be included on the medicine's label prescribe the amount likely to be needed (for example, for 28 days or the expected length of treatment) liaise with care home staff to see how often the resident has had the medicine and how well it has worked. Health and social care practitioners should work together to make sure that everyone involved in a resident's care knows when medicines have been started, stopped or changed. Care home staff (registered nurses and social care practitioners working in care homes) should update records of medicines administration to contain accurate information about any changes to medicines. The health professional prescribing a medicine, care home provider and supplying pharmacy should follow any local processes for anticipatory medicines to ensure that residents in care homes have the same access to anticipatory medicines as those people who do not live in care homes. Health professionals prescribing medicines should use telephone, video link or online prescribing (remote prescribing) only in exceptional circumstances and when doing so should: follow guidance set out by the General Medical Council or the Nursing and Midwifery Council on assessing capacity and obtaining informed consent from residents be aware that not all care home staff have the training and skills to assist with the assessment and discussion of the resident's clinical needs that are required for safe remote prescribing ensure that care home staff understand any instructions send written confirmation of the instructions to the care home as soon as possible. Care home staff should: ensure that any change to a prescription or prescription of a new medicine by telephone is supported in writing (by fax or email) before the next or first dose is given ask that the health professional using remote prescribing changes the prescription update the medicines administration record and the care plan as soon as possible (usually within 24 hours) with any changes to medicines made by remote prescribing. Care home providers should have a process set out in the care home medicines policy for recording the details of text messages received about a resident's medicines and making sure that the resident's confidentiality is maintained. Text messaging should be used in exceptional circumstances only. # Ordering medicines Care home providers must ensure that medicines prescribed for a resident are not used by other residents. Care home providers should ensure that care home staff (registered nurses and social care practitioners working in care homes) have protected time to order medicines and check medicines delivered to the home. Care home providers should ensure that at least 2 members of the care home staff have the training and skills to order medicines, although ordering can be done by 1 member of staff. Care home providers should retain responsibility for ordering medicines from the GP practice and should not delegate this to the supplying pharmacy. Care home providers should ensure that records are kept of medicines ordered. Medicines delivered to the care home should be checked against a record of the order to make sure that all medicines ordered have been prescribed and supplied correctly. # Dispensing and supplying medicines Pharmacies and doctors supplying medicines to care home providers should ensure they have processes, such as standard operating procedures, in place for all staff who dispense and accuracy check medicines for residents, particularly those who are using monitored dosage systems. Care home providers should determine the best system for supplying medicines for each resident based on the resident's health and care needs and the aim of maintaining the resident's independence wherever possible. If needed, they should seek the support of health and social care practitioners. Supplying pharmacies should produce medicines administration records wherever possible. See also recommendation 1.14.8 in the section on care home staff administering medicines to residents. # Receiving, storing and disposing of medicines Providers of adult care homes must comply with the Misuse of Drugs Act 1971 and associated regulations when storing controlled drugs. Providers of children's homes should have robust processes for storing controlled drugs. Care home providers should include the following information in their process for storing medicines safely: how and where medicines are stored, including medicines supplied in monitored dosage systems, medicines to be taken and looked after by residents themselves (see recommendations 1.13.2 and 1.13.6 in the section on helping residents to look after and take their medicines themselves), controlled drugs, medicines to be stored in the refrigerator, skin creams, oral nutritional supplements and appliances secure storage with only authorised care home staff having access the temperatures for storing medicines and how the storage conditions should be monitored. Care home providers should assess each resident's needs for storing their medicines and should provide storage that meets the resident's needs, choices, risk assessment and type of medicines system they are using. Before disposing of a medicine that is still being prescribed for a resident, care home staff (registered nurses and social care practitioners working in care homes) should find out if it is still within its expiry date and if it is still within its shelf-life if it has been opened. When disposing of medicines and removing medicines classed as clinical waste, care home providers should have a process for the prompt disposal of: medicines that exceed requirements unwanted medicines (including medicines of any resident who has died) expired medicines (including controlled drugs). Care home providers should keep records of medicines (including controlled drugs) that have been disposed of, or are waiting for disposal. Medicines for disposal should be stored securely in a tamper-proof container within a cupboard until they are collected or taken to the pharmacy. # Helping residents to look after and take their medicines themselves (self-administration) Care home staff (registered nurses and social care practitioners working in care homes) should assume that a resident can take and look after their medicines themselves (self-administer) unless a risk assessment has indicated otherwise (see recommendation 1.13.2). Health and social care practitioners should carry out an individual risk assessment to find out how much support a resident needs to carry on taking and looking after their medicines themselves (self-administration). Risk assessment should consider: resident choice if self‑administration will be a risk to the resident or to other residents if the resident can take the correct dose of their own medicines at the right time and in the right way (for example, do they have the mental capacity and manual dexterity for self-administration?) how often the assessment will need to be repeated based upon individual resident need how the medicines will be stored the responsibilities of the care home staff, which should be written in the resident's care plan. The care home manager should coordinate the risk assessment and should help to determine who should be involved. This should be done individually for each resident and should involve the resident (and their family members or carers if the resident wishes) and care home staff with the training and skills for assessment. Other health and social care practitioners (such as the GP and pharmacist) should be involved as appropriate to help identify whether the medicines regimen could be adjusted to enable the resident to self-administer. Providers of adult care homes must ensure that records are made and kept when adult residents are supplied with medicines for taking themselves (self-administration), or when residents are reminded to take their medicines themselves. Providers of children's care homes must ensure that records are made and kept for residents living in children's homes who are able to look after and take their medicines themselves (self-administer). The following information should be recorded on the medicines administration record: that the resident is looking after and taking their medicines themselves (self-administering) whether any monitoring is needed (for example, to assess ability to self-administer or willingness to take the medicines as prescribed ) that medicine has been taken as prescribed (either by seeing this directly or by asking the resident) who has recorded that the medicine has been taken. Care home providers should ensure that medicines for self-administration are stored as identified in the resident's risk assessment (for example, in a lockable cupboard or drawer in a resident's room). Residents should be able to get any medicines that need special storage at a time when they need to take or use them (see recommendations 1.12.1 to 1.12.3 in the section on receiving, storing and disposing of medicines). Care home providers should ensure that their process for self‑administration of controlled drugs includes information about: individual risk assessment -btaining or ordering controlled drugs supplying controlled drugs storing controlled drugs recording supply of controlled drugs to residents reminding residents to take their medicines (including controlled drugs) disposal of unwanted controlled drugs. # Care home staff administering medicines to residents Care home providers should consider including the following in a medicines administration process: the 6 R's of administration: right resident right medicine right route right dose right time resident's right to refuse making a record of the administration as soon as possible what to do if the resident is having a meal what to do if the resident is asleep how to administer specific medicines such as patches, creams, inhalers, eye drops and liquids using the correct equipment depending on the formulation (for example, using oral syringes for small doses of liquid medicines) how to record and report administration errors and reactions to medicines how to record and report a resident's refusal to take a medicine(s) how to manage medicines that are prescribed 'when required' how to manage medicines when the resident is away from the care home for a short time (for example, visiting relatives) monitoring and evaluating the effects of medicines, including reactions to medicines.Care homes with nursing care should also include the correct use of infusion and injection devices (for example, syringe drivers). Care home providers should ensure that a process for administering 'when required' medicines is included in the care home medicines policy (see recommendation 1.1.2 in the section on developing and reviewing policies for safe and effective use of medicines). The following information should be included: the reasons for giving the 'when required' medicine how much to give if a variable dose has been prescribed what the medicine is expected to do the minimum time between doses if the first dose has not worked -ffering the medicine when needed and not just during 'medication rounds' when to check with the prescriber any confusion about which medicines or doses are to be given recording 'when required' medicines in the resident's care plan. Care home staff (registered nurses and social care practitioners working in care homes) should ensure that 'when required' medicines are kept in their original packaging. The care home provider, health professional prescribing the medicine and pharmacist should agree with the resident the best time for the resident to take their prescribed medicines. Busy times should be avoided. Care home providers should consider ways of avoiding disruptions during the medicines administration round, such as: having more trained and skilled care home staff on duty at that time reviewing the times for administering medicines (for example, administering once daily medicines at lunchtime rather than in the morning, if the health professional prescribing the medicine agrees that this is clinically appropriate) avoiding planned staff breaks during times of medicines administration ensuring fewer distractions for care home staff administering medicines. Care home staff must have the training and skills to use system(s) adopted in the care home for administering medicines in line with regulation 22 of the Health and Social Care Act 2008 (Regulated Activities) Regulations 2010 for adult care homes and regulation 32.3 of the Children's Homes Regulations 2015 for children's care homes. Paper-based or electronic medicines administration records should: be legible be signed by the care home staff be clear and accurate be factual have the correct date and time be completed as soon as possible after administration avoid jargon and abbreviations be easily understood by the resident, their family member or carer. Care home providers should ensure that medicines administration records (paper-based or electronic) include: the full name, date of birth and weight (if under 16 years or where appropriate, for example, frail older residents) of the resident details of any medicines the resident is taking, including the name of the medicine and its strength, form, dose, how often it is given and where it is given (route of administration) known allergies and reactions to medicines or their ingredients, and the type of reaction experienced when the medicine should be reviewed or monitored (as appropriate) any support the resident may need to carry on taking the medicine (adherence support) any special instructions about how the medicine should be taken (such as before, with or after food).See also recommendation 1.11.3 in the section on dispensing and supplying medicines. Care home providers should ensure that a new, hand-written medicines administration record is produced only in exceptional circumstances and is created by a member of care home staff with the training and skills for managing medicines and designated responsibility for medicines in the care home. The new record should be checked for accuracy and signed by a second trained and skilled member of staff before it is first used. Care home providers should ensure that all information included on the medicines administration record is up-to-date and accurate. They may need support from the health professional prescribing the medicines and the supplying pharmacy to do this. Care home staff must record medicines administration, including the date and time, on the relevant medicines administration record, as soon as possible and ensure that they: make the record only when the resident has taken their prescribed medicine complete the administration before moving on to the next resident recognise that mistakes are less likely if 1 member of staff records administration on the medicines administration record rather than 2 staff recording record 'when required' medicines only when they have been given, noting the dose given and the amount left (where possible), to make sure that there is enough in stock and to reduce waste record when and why medicines have not been given correct written mistakes with a single line through the mistake followed by the correction and a signature, date and time (correction fluid should not be used). Health professionals who are visiting the care home to administer a medicine(s) to residents should make their record of administration available to care home staff, if asked by the care home. The health professional should also consider seeing the resident with the care home staff responsible for administering medicines to the resident. Care home staff should keep a record of medicines administered by visiting health professionals on the resident's medicines administration record. Care home staff responsible for administering medicines should add a cross-reference (for example, 'see warfarin administration record') to the resident's medicines administration record when a medicine has a separate administration record. Care home staff should ensure that the resident's GP is contacted to find out about any allergies and intolerances to medicines or their ingredients. This information should be accurately recorded on the medicines administration record and shared with the team(s) providing care to the resident. Care home staff should make appropriate records of controlled drugs that have been administered to residents. The care home staff responsible for administering the controlled drug and a trained witness should sign the controlled drugs register. The staff member administering the controlled drug should also sign the medicines administration record. Care home providers should ensure that the following information is given to the resident and/or their family members or carers when the resident is temporarily away from the care home: the medicines taken with the resident clear directions and advice on how, when and how much of the medicines the resident should take time of the last and next dose of each medicine a contact for queries about the resident's medicines, such as the care home, supplying pharmacy or GP. Care home providers should have a process to ensure that the resident has the medicines they need when they are away from the care home (for example, visiting relatives). Details of the medicines taken should be recorded in the resident's care plan. Health and social care practitioners should be able to access reliable and up-to-date information about medicines. Resources may include the patient information leaflet supplied with the medicine and the following websites: Medicines and Healthcare products Regulatory Agency NHS choices Patient.co.uk Health professionals may also use the: British National Formulary (BNF) British National Formulary for Children (BNFC) Clinical Knowledge Summaries Electronic Medicines Compendium # Care home staff giving medicines to residents without their knowledge (covert administration) Health and social care practitioners should not administer medicines to a resident without their knowledge (covert administration) if the resident has capacity to make decisions about their treatment and care. Health and social care practitioners should ensure that covert administration only takes place in the context of existing legal and good practice frameworks to protect both the resident who is receiving the medicine(s) and the care home staff involved in administering the medicines. Health and social care practitioners should ensure that the process for covert administration of medicines to adult residents in care homes includes: assessing mental capacity holding a best interest meeting involving care home staff, the health professional prescribing the medicine(s), pharmacist and family member or advocate to agree whether administering medicines without the resident knowing (covertly) is in the resident's best interests recording the reasons for presuming mental incapacity and the proposed management plan planning how medicines will be administered without the resident knowing regularly reviewing whether covert administration is still needed. Commissioners and providers of care home services should consider establishing a wider policy on the covert administration of medicines across several health and social care organisations. # Care home staff giving non-prescription and over-the-counter products to residents (homely remedies) Care home providers offering non-prescription medicines or other over-the-counter-products (homely remedies) for treating minor ailments should consider having a homely remedies process, which includes the following: the name of the medicine or product and what it is for which residents should not be given certain medicines or products (for example, paracetamol should not be given as a homely remedy if a resident is already receiving prescribed paracetamol) the dose and frequency the maximum daily dose where any administration should be recorded, such as on the medicines administration record how long the medicine or product should be used before referring the resident to a GP. Care home staff who give non-prescription medicines or other over-the-counter products (homely remedies) to residents should be named in the homely remedies process. They should sign the process to confirm they have the skills to administer the homely remedy and acknowledge that they will be accountable for their actions. # Training and skills (competency) of care home staff Care home providers must ensure that designated staff administer medicines only when they have had the necessary training and are assessed as competent. Care home providers must ensure that staff who do not have the skills to administer medicines, despite completing the required training, are not allowed to administer medicines to residents. Care home providers should set up an internal and/or external learning and development programme so that care home staff can gain the necessary skills for managing and administering medicines. The programme should meet the requirements of the regulators, the residents and the training needs of care home staff. Care home providers should consider using an 'accredited learning' provider so that care home staff who are responsible for managing and administering medicines can be assessed by an external assessor. Care home staff must have induction training that is relevant to the type of home they are working in (adult care homes or children's homes). All care home staff (including registered nurses as part of their continuing professional development) involved in managing and administering medicines should successfully complete any training needed to fulfil the learning and development requirements for their role. Care home providers should ensure that all care home staff have an annual review of their knowledge, skills and competencies relating to managing and administering medicines. Care home providers should identify any other training needed by care home staff responsible for managing and administering medicines. If there is a medicines-related safety incident, this review may need to be more frequent to identify support, learning and development needs. Health professionals working in, or providing services to, care homes should work to standards set by their professional body and ensure that they have the appropriate skills, knowledge and expertise in the safe use of medicines for residents living in care homes.# Who should take action? The table below lists who should take action according to the recommendation number. Who should take action Recommendation number Commissioners Care home providers , 1.3.1, 1.3.7, 1.4.2, 1.6.2, 1.6.5, 1.6.9, 1.6.11, 1.7.2, 1.9.8, 1.10.1, 1.10.2, 1.10.3, 1.10.4, 1.10.5, 1.11.2, 1.12.1 (providers of adult care homes), 1.12.2, 1.12.3, 1.12.5, 1.12.6, 1.13.4 (providers of adult care homes), 1.13.5 (providers of children's care homes), 1.13.6, 1.13.7, 1.14.1, 1.14.2, 1.14.5, 1.14.8, 1.14.9, 1.14.10, 1.14.17, 1.14.18, 1.16.1, 1.17.1, 1.17.2, 1.17.3, 1.17.5 Providers of health or social care services Care home manager Care home staff (registered nurses and social care practitioners working in care homes) Recommendations for health and social care practitioners also apply to care home staff Health and social care practitioners (care home staff, social workers, case managers, GPs, pharmacists and community nurses) Health professionals prescribing medicines Pharmacists Recommendations for health and social care practitioners also apply to pharmacists Supplying pharmacy Health professionals who are visiting the care home to administer a medicine(s) to residents Health professionals working in, or providing services to, care homes GPs Recommendations for health and social care practitioners also apply to GPs GP practices	{'Terms used in this guideline': "For the purposes of this guideline the term 'care home' covers the provision of 24‑hour accommodation together with either non‑nursing care (for example, a residential home) or nursing care (for example, a care home with nursing).\n\nThe term 'care home provider' is used for the registered provider of care. If regulation or practice differs between different types of care homes (for example, a children's care home, an adult's care home, a non‑nursing care home or a nursing care home), then the type of care home is specified in the text.\n\nWhen the term 'organisations' is used, this includes all commissioners and providers (including care home providers), unless specified otherwise in the text. Commissioners are those individuals who undertake commissioning which is 'the process used by health services and local authorities to: identify the need for local services; assess this need against the services and resources available from public, private and voluntary organisations; decide priorities; and set up contracts and service agreements to buy services. As part of the commissioning process, services are regularly evaluated'.\n\nProviders are organisations that directly provide health or social care services (such as a care home).\n\nIndividual people who live in care homes are referred to as 'residents' or 'care home residents' in this guideline.\n\nA 'care home' can be of any size (number of residents) or have any type of resident (children, older people, people with cognitive impairment, young disabled people, people with a learning disability), but should be a registered provider of care (for example, in England with either the CQC or Ofsted).\n\nFor the purposes of this guideline, the term 'care home staff' includes registered nurses and social care practitioners working in a care home.\n\nThe term 'carer' is used for an informal or unpaid carer.\n\nThe term 'health and social care practitioners' is used to define the wider care team, including care home staff (registered nurses and social care practitioners working in care homes), social workers, case managers, GPs, pharmacists and community nurses. When specific recommendations are made for a particular professional group, this is specified in the recommendation, for example, 'GPs'.\n\nThe term 'pharmacist' is used for all pharmacists, including primary care pharmacists, care home pharmacists and supplying pharmacists. Primary care pharmacists work in the primary care setting and may have a role working with care homes. Care home pharmacists have a dedicated role working in care homes. Supplying pharmacists work in a community pharmacy or chemist shop.\n\nWhen a care home resident is able to look after and take their own medicines, this is referred to as 'self-administration'.\n\nWhen the guideline refers to the administration of medicines, this is when care home staff check and give, or help to give, a resident their medicine(s).", 'Person-centred care': "Care home residents and health professionals (for care under the NHS) have rights and responsibilities as set out in the NHS Constitution for England, and NICE guidelines are written to reflect these. Treatment and care should take into account individual needs and preferences. Care home residents should have the opportunity to make informed decisions about their care and treatment, in partnership with their health professionals and social care practitioners.\n\nIf the resident is under 16, their family or carers should also be given information and support to help the child or young person to make decisions about their treatment. Health professionals should follow the Department of Health's advice on consent.\n\nIf someone does not have capacity to make decisions, health professionals should follow the code of practice that accompanies the Mental Capacity Act and the supplementary code of practice on deprivation of liberty safeguards.\n\nAll health professionals should follow the recommendations in the NICE guideline on patient experience in adult NHS services and where appropriate the NICE guideline on service user experience in adult mental health, although many of the principles in that guideline apply equally to social care staff.\n\nIf the resident agrees, families and carers should have the opportunity to be involved in decisions about treatment and care. Families and carers should also be given the information and support they need.\n\nThe person-centred care approach is not new across sectors and resources such as Think Local, Act Personal, help to support this working.\n\n# Involving others\n\nThe views of residents in care homes about who should and should not be involved in their care are important and should be respected. If the resident lacks the capacity to decide who should and should not be involved, health and social care practitioners must act in the resident's best interests, taking account of the provisions in the Mental Capacity Act 2005.\n\nHealth and social care practitioners should also consider accounts from family members or carers of the resident's usual behaviour. This information, when used with an assessment of the resident concerned, will help with specific decisions about their care. It will also help to estimate the person's capacity to make a specific decision. Residents with reduced mental capacity should continue to have the opportunity to make informed decisions about those aspects of their care and personal lives for which they retain capacity.\n\nGood communication between health and social care practitioners and residents, their family members or carers (as appropriate) is essential for residents to receive the information and support they need. Evidence-based information should be offered in a form that is tailored to the needs of the individual resident. The treatment, care and information provided should be culturally appropriate and in a form that is accessible to residents who have additional needs, such as physical, cognitive or sensory disabilities, or who do not speak or read English.\n\nIf the resident agrees, families and carers should have the opportunity to be involved in decisions about treatment and care. Families and carers should also be given the information and support they need, and carers should be offered an assessment of their own needs.\n\n# Keeping residents safe (safeguarding)\n\nSimilar definitions exist for safeguarding of adults and children from the regulators of adult and children's services.\n\nThe CQC's Essential standards of quality and safety (2010) define safeguarding adults as: 'Ensuring that people live free from harm, abuse and neglect and, in doing so, protecting their health, wellbeing and human rights'.\n\nThe Department for Education's Working together to safeguard children (2013) defines safeguarding children as: 'protecting children from maltreatment; preventing impairment of children's health or development, ensuring children are growing up in circumstances consistent with the provision of safe and effective care and taking action to enable all children to have the best outcomes.'\n\nA safeguarding issue in relation to managing medicines could include the deliberate withholding of a medicine(s) without a valid reason, the incorrect use of a medicine(s) for reasons other than the benefit of a resident, deliberate attempt to harm through use of a medicine(s), or accidental harm caused by incorrect administration or a medication error.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations for good practice have been developed by the Guideline Development Group (GDG), using relevant legislation, guidance and policy as the foundation for good practice. See appendix\xa0B of the full guideline for a list of key resources used in developing this guideline.\n\nWhen a recommendation is aimed specifically at a person or organisation, this is clearly stated. In most cases the GDG was able to identify which person or organisation was responsible; if this is not specified it will be for organisations to consider and determine locally. The GDG agreed that arrangements will vary depending on local organisational structures, how services are commissioned and provided, and what resources are available.\n\n# Developing and reviewing policies for safe and effective use of medicines\n\nCommissioners and providers (organisations that directly provide health or social care services) should review their policies, processes and local governance arrangements, making sure that it is clear who is accountable and responsible for using medicines safely and effectively in care homes.\n\nCare home providers should have a care home medicines policy, which they review to make sure it is up to date, and is based on current legislation and the best available evidence. The policy should include written processes for:\n\nsharing information about a resident's medicines, including when they transfer between care settings\n\nensuring that records are accurate and up to date\n\nidentifying, reporting and reviewing medicines‑related problems\n\nkeeping residents safe (safeguarding)\n\naccurately listing a resident's medicines (medicines reconciliation)\n\nreviewing medicines (medication review)\n\nordering medicines\n\nreceiving, storing and disposing of medicines\n\nhelping residents to look after and take their medicines themselves (self‑administration)\n\ncare home staff administering medicines to residents, including staff training and competence requirements\n\ncare home staff giving medicines to residents without their knowledge (covert administration)\n\ncare home staff giving non-prescription and over‑the‑counter products to residents (homely remedies), if appropriate.\n\n# Supporting residents to make informed decisions and recording these decisions\n\nHealth and social care practitioners (care home staff, social workers, case managers, GPs, pharmacists and community nurses) should ensure that care home residents have the same opportunities to be involved in decisions about their treatment and care as people who do not live in care homes, and that residents get the support they need to help them to take a full part in making decisions.\n\nThe health professional prescribing a medicine or care home staff should record a resident's informed consent in the resident's care record. Consent does not need to be recorded each time the medicine is given but a record of the administration should be made on the medicines administration record.\n\nCare home staff (registered nurses and social care practitioners working in care homes) should record the circumstances and reasons why a resident refuses a medicine (if the resident will give a reason) in the resident's care record and medicines administration record, unless there is already an agreed plan of what to do when that resident refuses their medicines. If the resident agrees, care home staff should tell the health professional who prescribed the medicine about any ongoing refusal and inform the supplying pharmacy, to prevent further supply to the care home.\n\nHealth and social care practitioners should identify and record anything that may hinder a resident giving informed consent. Things to look out for include mental health problems, lack of (mental) capacity to make decisions, health problems (such as problems with vision and hearing), difficulties with reading, speaking or understanding English and cultural differences. These should be taken into account when seeking informed consent and should be regularly reviewed.\n\nHealth professionals prescribing a medicine must:\n\nassume that care home residents have the capacity to make decisions\n\nassess a resident's mental capacity in line with appropriate legislation (for example, the Mental Capacity Act 2005) if there are any concerns about whether a resident is able to give informed consent\n\nrecord any assessment of mental capacity in the resident's care record.\n\nHealth professionals prescribing a medicine should review mental capacity, in line with the Mental Capacity Act 2005 and the Mental Capacity Act Code of Practice 2007 when a resident lacks capacity to make a specific decision. How often they do this should depend on the cause, as this may affect whether lack of capacity fluctuates or is temporary.\n\nHealth and social care practitioners should ensure that residents are involved in best interest decisions, in line with the Mental Capacity Act Code of Practice 2007, and:\n\nfind out about their past and present views, wishes, feelings, beliefs and values\n\ninvolve them, if possible, in meetings at which decisions are made about their medicines\n\ntalk to people who know them well, including family members or carers (informal or unpaid carers) and friends, as well as care home staff\n\ndeliver care and treatment in a way that empowers the resident to be involved in decisions and limits any restrictions to their care.\n\n# Sharing information about a resident's medicines\n\nCare home providers should have a process for managing information (information governance) covering the 5 rules set out in the Health and Social Care Information Centre's A guide to confidentiality in health and social care (2013). The process should also include the training needed by care home staff and how their skills (competency) should be assessed.\n\nCommissioners should review their commissioning arrangements with their provider organisations to ensure that any information about a resident's medicines that is transferred contains the minimum information set out in recommendation 1.7.3 in the section on accurately listing a resident's medicines. Commissioners should monitor this through their contracting arrangements.\n\nProviders of health or social care services should have processes in place for sharing, accurate information about a resident's medicines, including what is recorded and transferred when a resident moves from one care setting to another (including hospital).\n\nProviders of health or social care services should ensure that either an electronic discharge summary is sent, if possible, or a printed discharge summary is sent with the resident when care is transferred from one care setting to another. See recommendation 1.7.3 in the section on accurately listing a resident's medicines for the minimum information that should be transferred.\n\nHealth and social care practitioners should ensure that all information about a resident's medicines, including who will be responsible for prescribing in the future, is accurately recorded and transferred with a resident when they move from one care setting to another.\n\nHealth and social care practitioners should check that complete and accurate information about a resident's medicines has been received and recorded, and is acted on after a resident's care is transferred from one care setting to another (see recommendation 1.7.3 in the section on accurately listing a resident's medicines for the minimum information that should be transferred).\n\nCare home providers should have a process in the care home medicines policy for recording the transfer of information about residents' medicines during shift handovers and when residents move to and from care settings.\n\nCare home staff should follow the rules on confidentiality set out in the home's process on managing information about medicines (see recommendation 1.3.1) and only share enough information with health professionals that a resident visits to ensure safe care of the resident.\n\n# Ensuring that records are accurate and up to date\n\nHealth and social care practitioners should ensure that records about medicines are accurate and up-to-date by following the process set out in the care home medicines policy (see recommendation 1.1.2 in the section on developing and reviewing policies for safe and effective use of medicines). The process should cover:\n\nrecording information in the resident's care plan\n\nrecording information in the resident's medicines administration record\n\nrecording information from correspondence and messages about medicines, such as emails, letters, text messages and transcribed phone messages\n\nrecording information in transfer of care letters and summaries about medicines when a resident is away from the home for a short time\n\nwhat to do with copies of prescriptions and any records of medicines ordered for residents.\n\nCare home providers must follow the relevant legislation to ensure that appropriate records about medicines are kept secure, for an appropriate period of time, and destroyed securely when appropriate to do so.\n\n# Identifying, reporting and reviewing medicines-related problems\n\nCommissioners and providers of health or social care services should ensure that a robust process is in place for identifying, reporting, reviewing and learning from medicines errors involving residents (see also recommendations 1.6.1 to 1.6.3 in the section on keeping residents safe).\n\nHealth and social care practitioners should consider working with all relevant stakeholders to develop a locally agreed action plan, in line with other local and national strategies and governance arrangements, for improving the safety of residents and reducing medication errors in care homes.\n\nCare home staff (registered nurses and social care practitioners working in care homes) should report all suspected adverse effects from medicines to the health professional who prescribed the medicine or another health professional as soon as possible; this would usually be the GP or out-of-hours service. Staff should record the details in the resident's care plan and tell the supplying pharmacy (if the resident agrees that this information can be shared).\n\n# Keeping residents safe (safeguarding)\n\nCommissioners and providers of health or social care services should all be aware of local arrangements for notifying suspected or confirmed medicines‑related safeguarding incidents.\n\nCare home providers should have a clear process for reporting medicines‑related safeguarding incidents under local safeguarding processes and to the Care Quality Commission (CQC) (or other appropriate regulator). The process should be recorded in the care home medicines policy and should clearly state:\n\nwhen the CQC (or other appropriate regulator) should be notified\n\nwhich medicines‑related safeguarding incidents should be reported under local safeguarding processes and when\n\nthat accurate details of any medicines-related safeguarding incidents are recorded as soon as possible so that the information is available for any investigation and reporting.\n\nCommissioners should ensure that reporting requirements are included in commissioning and contracting arrangements.\n\nCare home staff should contact a health professional to ensure that action is taken to safeguard any resident involved in a medicines-related safeguarding incident. They should follow a process agreed between health professional(s) and commissioners, which sets out who to contact in normal office hours and out‑of‑hours.\n\nCare home providers should record all medicines‑related safety incidents, including all 'near misses' and incidents that do not cause any harm, as a resident safety incident. Where there are notifiable safeguarding concerns these must be reported to the CQC (or other appropriate regulator).\n\nLocal safeguarding processes should include the investigation of each report of a medicines-related safeguarding incident and should monitor reports for trends.\n\nLocal safeguarding processes should include arrangements for feedback to care homes about reported medicines‑related incidents to promote sharing of experiences and learning.\n\nCare home staff should find out the root cause of medicines‑related incidents.\n\nCare home providers should make sure that any training needed by staff to find out the root cause of medicines‑related incidents is specified in contracts with commissioners.\n\nCare home staff should give residents and/or their family members or carers information on how to report a medicines‑related safety incident or their concerns about medicines, using the care home provider's complaints process, local authority (or local safeguarding) processes and/or a regulator's process.\n\nCare home providers should ensure that all residents can use advocacy and independent complaints services when they have concerns about medicines.\n\n# Accurately listing a resident's medicines (medicines reconciliation)\n\nThe care home manager or the person responsible for a resident's transfer into a care home should coordinate the accurate listing of all the resident's medicines (medicines reconciliation) as part of a full needs assessment and care plan. The care home manager should consider the resources needed to ensure that medicines reconciliation occurs in a timely manner (see recommendation\xa01.1.2 in the section on developing and reviewing policies for safe and effective use of medicines).\n\nCare home providers should ensure that the following people are involved in medicines reconciliation:\n\nthe resident and/or their family members or carers\n\na pharmacist\n\nother health and social care practitioners involved in managing medicines for the resident, as agreed locally.\n\nCommissioners and providers of health or social care services should ensure that the following information is available for medicines reconciliation on the day that a resident transfers into or from a care home:\n\nresident's details, including full name, date of birth, NHS number, address and weight (for those aged under 16 or where appropriate, for example, frail older residents)\n\nGP's details\n\ndetails of other relevant contacts defined by the resident and/or their family members or carers (for example, the consultant, regular pharmacist, specialist nurse)\n\nknown allergies and reactions to medicines or ingredients, and the type of reaction experienced\n\nmedicines the resident is currently taking, including name, strength, form, dose, timing and frequency, how the medicine is taken (route of administration) and what for (indication), if known\n\nchanges to medicines, including medicines started, stopped or dosage changed, and reason for change\n\ndate and time the last dose of any 'when required' medicine was taken or any medicine given less often than once a day (weekly or monthly medicines)\n\nother information, including when the medicine should be reviewed or monitored, and any support the resident needs to carry on taking the medicine (adherence support)\n\nwhat information has been given to the resident and/or family members or carers.Providers should ensure that the details of the person completing the medicines reconciliation (name, job title) and the date are recorded.\n\n# Reviewing medicines (medication review)\n\nGPs should ensure that arrangements have been made for their patients who are residents in care homes to have medication reviews as set out in the residents' care plans (see recommendation 1.8.4).\n\nGPs should work with other health professionals to identify a named health professional who is responsible for medication reviews for each resident. This should take into account the clinical experience and skills of the health professional, how much they know about the resident and the resident's condition, and whether they can access the relevant information.\n\nHealth and social care practitioners should ensure that medication reviews involve the resident and/or their family members or carers and a local team of health and social care practitioners (multidisciplinary team). This may include a:\n\npharmacist\n\ncommunity matron or specialist nurse, such as a community psychiatric nurse\n\nGP\n\nmember of the care home staff\n\npractice nurse\n\nsocial care practitioner. The roles and responsibilities of each member of the team and how they work together should be carefully considered and agreed locally. Training should be provided so that they have the skills needed.\n\nHealth and social care practitioners should agree how often each resident should have a multidisciplinary medication review. They should base this on the health and care needs of the resident, but the resident's safety should be the most important factor when deciding how often to do the review. The frequency of planned medication reviews should be recorded in the resident's care plan. The interval between medication reviews should be no more than 1\xa0year.\n\nHealth and social care practitioners should discuss and review the following during a medication review:\n\nthe purpose of the medication review\n\nwhat the resident (and/or their family members or carers, as appropriate and in line with the resident's wishes) thinks about the medicines and how much they understand\n\nthe resident's (and/or their family members' or carers', as appropriate and in line with the resident's wishes) concerns, questions or problems with the medicines\n\nall prescribed, over-the-counter and complementary medicines that the resident is taking or using, and what these are for\n\nhow safe the medicines are, how well they work, how appropriate they are, and whether their use is in line with national guidance\n\nany monitoring tests that are needed\n\nany problems the resident has with the medicines, such as side effects or reactions, taking the medicines themselves (for example, using an inhaler) and difficulty swallowing\n\nhelping the resident to take or use their medicines as prescribed (medicines adherence)\n\nany more information or support that the resident (and/or their family members or carers) may need.\n\n# Prescribing medicines\n\nGP practices should ensure that there is a clear written process for prescribing and issuing prescriptions for their patients who live in care homes. The process should cover:\n\nissuing prescriptions according to the patient medical records\n\nrecording clear instructions on how a medicine should be used, including how long the resident is expected to need the medicine and, if important, how long the medicine will take to work and what it has been prescribed for (use of the term 'as directed' should be avoided)\n\nrecording prescribing in the GP patient medical record and resident care record and making any changes as soon as practically possible\n\nproviding any extra details the resident and/or care home staff may need about how the medicine should be taken\n\nany tests needed for monitoring\n\nprescribing the right amount of medicines to fit into the 28‑day supply cycle if appropriate, and any changes that may be needed for prescribing in the future\n\nmonitoring and reviewing 'when required' and variable dose medicines\n\nissuing prescriptions when the medicines order is received from the care home.\n\nWhen prescribing variable dose and 'when required' medicine(s) the health professional prescribing the medicine should:\n\nnote in the resident's care record the instructions for:\n\n\n\nwhen and how to take or use the medicine (for example, 'when low back pain is troublesome take 1 tablet')\n\nmonitoring\n\nthe effect they expect the medicine to have\n\n\n\ninclude dosage instructions on the prescription (including the maximum amount to be taken in a day and how long the medicine should be used, as appropriate) so that this can be included on the medicine's label\n\nprescribe the amount likely to be needed (for example, for 28\xa0days or the expected length of treatment)\n\nliaise with care home staff to see how often the resident has had the medicine and how well it has worked.\n\nHealth and social care practitioners should work together to make sure that everyone involved in a resident's care knows when medicines have been started, stopped or changed.\n\nCare home staff (registered nurses and social care practitioners working in care homes) should update records of medicines administration to contain accurate information about any changes to medicines.\n\nThe health professional prescribing a medicine, care home provider and supplying pharmacy should follow any local processes for anticipatory medicines to ensure that residents in care homes have the same access to anticipatory medicines as those people who do not live in care homes.\n\nHealth professionals prescribing medicines should use telephone, video link or online prescribing (remote prescribing) only in exceptional circumstances and when doing so should:\n\nfollow guidance set out by the General Medical Council or the Nursing and Midwifery Council on assessing capacity and obtaining informed consent from residents\n\nbe aware that not all care home staff have the training and skills to assist with the assessment and discussion of the resident's clinical needs that are required for safe remote prescribing\n\nensure that care home staff understand any instructions\n\nsend written confirmation of the instructions to the care home as soon as possible.\n\nCare home staff should:\n\nensure that any change to a prescription or prescription of a new medicine by telephone is supported in writing (by fax or email) before the next or first dose is given\n\nask that the health professional using remote prescribing changes the prescription\n\nupdate the medicines administration record and the care plan as soon as possible (usually within 24\xa0hours) with any changes to medicines made by remote prescribing.\n\nCare home providers should have a process set out in the care home medicines policy for recording the details of text messages received about a resident's medicines and making sure that the resident's confidentiality is maintained. Text messaging should be used in exceptional circumstances only.\n\n# Ordering medicines\n\nCare home providers must ensure that medicines prescribed for a resident are not used by other residents.\n\nCare home providers should ensure that care home staff (registered nurses and social care practitioners working in care homes) have protected time to order medicines and check medicines delivered to the home.\n\nCare home providers should ensure that at least 2 members of the care home staff have the training and skills to order medicines, although ordering can be done by 1 member of staff.\n\nCare home providers should retain responsibility for ordering medicines from the GP practice and should not delegate this to the supplying pharmacy.\n\nCare home providers should ensure that records are kept of medicines ordered. Medicines delivered to the care home should be checked against a record of the order to make sure that all medicines ordered have been prescribed and supplied correctly.\n\n# Dispensing and supplying medicines\n\nPharmacies and doctors supplying medicines to care home providers should ensure they have processes, such as standard operating procedures, in place for all staff who dispense and accuracy check medicines for residents, particularly those who are using monitored dosage systems.\n\nCare home providers should determine the best system for supplying medicines for each resident based on the resident's health and care needs and the aim of maintaining the resident's independence wherever possible. If needed, they should seek the support of health and social care practitioners.\n\nSupplying pharmacies should produce medicines administration records wherever possible. See also recommendation 1.14.8 in the section on care home staff administering medicines to residents.\n\n# Receiving, storing and disposing of medicines\n\nProviders of adult care homes must comply with the Misuse of Drugs Act 1971 and associated regulations when storing controlled drugs. Providers of children's homes should have robust processes for storing controlled drugs.\n\nCare home providers should include the following information in their process for storing medicines safely:\n\nhow and where medicines are stored, including medicines supplied in monitored dosage systems, medicines to be taken and looked after by residents themselves (see recommendations 1.13.2 and 1.13.6 in the section on helping residents to look after and take their medicines themselves), controlled drugs, medicines to be stored in the refrigerator, skin creams, oral nutritional supplements and appliances\n\nsecure storage with only authorised care home staff having access\n\nthe temperatures for storing medicines and how the storage conditions should be monitored.\n\nCare home providers should assess each resident's needs for storing their medicines and should provide storage that meets the resident's needs, choices, risk assessment and type of medicines system they are using.\n\nBefore disposing of a medicine that is still being prescribed for a resident, care home staff (registered nurses and social care practitioners working in care homes) should find out if it is still within its expiry date and if it is still within its shelf-life if it has been opened.\n\nWhen disposing of medicines and removing medicines classed as clinical waste, care home providers should have a process for the prompt disposal of:\n\nmedicines that exceed requirements\n\nunwanted medicines (including medicines of any resident who has died)\n\nexpired medicines (including controlled drugs).\n\nCare home providers should keep records of medicines (including controlled drugs) that have been disposed of, or are waiting for disposal. Medicines for disposal should be stored securely in a tamper-proof container within a cupboard until they are collected or taken to the pharmacy.\n\n# Helping residents to look after and take their medicines themselves (self-administration)\n\nCare home staff (registered nurses and social care practitioners working in care homes) should assume that a resident can take and look after their medicines themselves (self-administer) unless a risk assessment has indicated otherwise (see recommendation 1.13.2).\n\nHealth and social care practitioners should carry out an individual risk assessment to find out how much support a resident needs to carry on taking and looking after their medicines themselves (self-administration). Risk assessment should consider:\n\nresident choice\n\nif self‑administration will be a risk to the resident or to other residents\n\nif the resident can take the correct dose of their own medicines at the right time and in the right way (for example, do they have the mental capacity and manual dexterity for self-administration?)\n\nhow often the assessment will need to be repeated based upon individual resident need\n\nhow the medicines will be stored\n\nthe responsibilities of the care home staff, which should be written in the resident's care plan.\n\nThe care home manager should coordinate the risk assessment and should help to determine who should be involved. This should be done individually for each resident and should involve the resident (and their family members or carers if the resident wishes) and care home staff with the training and skills for assessment. Other health and social care practitioners (such as the GP and pharmacist) should be involved as appropriate to help identify whether the medicines regimen could be adjusted to enable the resident to self-administer.\n\nProviders of adult care homes must ensure that records are made and kept when adult residents are supplied with medicines for taking themselves (self-administration), or when residents are reminded to take their medicines themselves.\n\nProviders of children's care homes must ensure that records are made and kept for residents living in children's homes who are able to look after and take their medicines themselves (self-administer). The following information should be recorded on the medicines administration record:\n\nthat the resident is looking after and taking their medicines themselves (self-administering)\n\nwhether any monitoring is needed (for example, to assess ability to self-administer or willingness to take the medicines as prescribed [adherence])\n\nthat medicine has been taken as prescribed (either by seeing this directly or by asking the resident)\n\nwho has recorded that the medicine has been taken.\n\nCare home providers should ensure that medicines for self-administration are stored as identified in the resident's risk assessment (for example, in a lockable cupboard or drawer in a resident's room). Residents should be able to get any medicines that need special storage at a time when they need to take or use them (see recommendations 1.12.1 to 1.12.3 in the section on receiving, storing and disposing of medicines).\n\nCare home providers should ensure that their process for self‑administration of controlled drugs includes information about:\n\nindividual risk assessment\n\nobtaining or ordering controlled drugs\n\nsupplying controlled drugs\n\nstoring controlled drugs\n\nrecording supply of controlled drugs to residents\n\nreminding residents to take their medicines (including controlled drugs)\n\ndisposal of unwanted controlled drugs.\n\n# Care home staff administering medicines to residents\n\nCare home providers should consider including the following in a medicines administration process:\n\nthe 6 R's of administration:\n\n\n\nright resident\n\nright medicine\n\nright route\n\nright dose\n\nright time\n\nresident's right to refuse\n\n\n\nmaking a record of the administration as soon as possible\n\nwhat to do if the resident is having a meal\n\nwhat to do if the resident is asleep\n\nhow to administer specific medicines such as patches, creams, inhalers, eye drops and liquids\n\nusing the correct equipment depending on the formulation (for example, using oral syringes for small doses of liquid medicines)\n\nhow to record and report administration errors and reactions to medicines\n\nhow to record and report a resident's refusal to take a medicine(s)\n\nhow to manage medicines that are prescribed 'when required'\n\nhow to manage medicines when the resident is away from the care home for a short time (for example, visiting relatives)\n\nmonitoring and evaluating the effects of medicines, including reactions to medicines.Care homes with nursing care should also include the correct use of infusion and injection devices (for example, syringe drivers).\n\nCare home providers should ensure that a process for administering 'when required' medicines is included in the care home medicines policy (see recommendation 1.1.2 in the section on developing and reviewing policies for safe and effective use of medicines). The following information should be included:\n\nthe reasons for giving the 'when required' medicine\n\nhow much to give if a variable dose has been prescribed\n\nwhat the medicine is expected to do\n\nthe minimum time between doses if the first dose has not worked\n\noffering the medicine when needed and not just during 'medication rounds'\n\nwhen to check with the prescriber any confusion about which medicines or doses are to be given\n\nrecording 'when required' medicines in the resident's care plan.\n\nCare home staff (registered nurses and social care practitioners working in care homes) should ensure that 'when required' medicines are kept in their original packaging.\n\nThe care home provider, health professional prescribing the medicine and pharmacist should agree with the resident the best time for the resident to take their prescribed medicines. Busy times should be avoided.\n\nCare home providers should consider ways of avoiding disruptions during the medicines administration round, such as:\n\nhaving more trained and skilled care home staff on duty at that time\n\nreviewing the times for administering medicines (for example, administering once daily medicines at lunchtime rather than in the morning, if the health professional prescribing the medicine agrees that this is clinically appropriate)\n\navoiding planned staff breaks during times of medicines administration\n\nensuring fewer distractions for care home staff administering medicines.\n\nCare home staff must have the training and skills to use system(s) adopted in the care home for administering medicines in line with regulation 22 of the Health and Social Care Act 2008 (Regulated Activities) Regulations 2010 for adult care homes and regulation 32.3 of the Children's Homes Regulations 2015 for children's care homes.\n\nPaper-based or electronic medicines administration records should:\n\nbe legible\n\nbe signed by the care home staff\n\nbe clear and accurate\n\nbe factual\n\nhave the correct date and time\n\nbe completed as soon as possible after administration\n\navoid jargon and abbreviations\n\nbe easily understood by the resident, their family member or carer.\n\nCare home providers should ensure that medicines administration records (paper-based or electronic) include:\n\nthe full name, date of birth and weight (if under 16\xa0years or where appropriate, for example, frail older residents) of the resident\n\ndetails of any medicines the resident is taking, including the name of the medicine and its strength, form, dose, how often it is given and where it is given (route of administration)\n\nknown allergies and reactions to medicines or their ingredients, and the type of reaction experienced\n\nwhen the medicine should be reviewed or monitored (as appropriate)\n\nany support the resident may need to carry on taking the medicine (adherence support)\n\nany special instructions about how the medicine should be taken (such as before, with or after food).See also recommendation 1.11.3 in the section on dispensing and supplying medicines.\n\nCare home providers should ensure that a new, hand-written medicines administration record is produced only in exceptional circumstances and is created by a member of care home staff with the training and skills for managing medicines and designated responsibility for medicines in the care home. The new record should be checked for accuracy and signed by a second trained and skilled member of staff before it is first used.\n\nCare home providers should ensure that all information included on the medicines administration record is up-to-date and accurate. They may need support from the health professional prescribing the medicines and the supplying pharmacy to do this.\n\nCare home staff must record medicines administration, including the date and time, on the relevant medicines administration record, as soon as possible and ensure that they:\n\nmake the record only when the resident has taken their prescribed medicine\n\ncomplete the administration before moving on to the next resident\n\nrecognise that mistakes are less likely if 1 member of staff records administration on the medicines administration record rather than 2 staff recording\n\nrecord 'when required' medicines only when they have been given, noting the dose given and the amount left (where possible), to make sure that there is enough in stock and to reduce waste\n\nrecord when and why medicines have not been given\n\ncorrect written mistakes with a single line through the mistake followed by the correction and a signature, date and time (correction fluid should not be used).\n\nHealth professionals who are visiting the care home to administer a medicine(s) to residents should make their record of administration available to care home staff, if asked by the care home. The health professional should also consider seeing the resident with the care home staff responsible for administering medicines to the resident.\n\nCare home staff should keep a record of medicines administered by visiting health professionals on the resident's medicines administration record.\n\nCare home staff responsible for administering medicines should add a cross-reference (for example, 'see warfarin administration record') to the resident's medicines administration record when a medicine has a separate administration record.\n\nCare home staff should ensure that the resident's GP is contacted to find out about any allergies and intolerances to medicines or their ingredients. This information should be accurately recorded on the medicines administration record and shared with the team(s) providing care to the resident.\n\nCare home staff should make appropriate records of controlled drugs that have been administered to residents. The care home staff responsible for administering the controlled drug and a trained witness should sign the controlled drugs register. The staff member administering the controlled drug should also sign the medicines administration record.\n\nCare home providers should ensure that the following information is given to the resident and/or their family members or carers when the resident is temporarily away from the care home:\n\nthe medicines taken with the resident\n\nclear directions and advice on how, when and how much of the medicines the resident should take\n\ntime of the last and next dose of each medicine\n\na contact for queries about the resident's medicines, such as the care home, supplying pharmacy or GP.\n\nCare home providers should have a process to ensure that the resident has the medicines they need when they are away from the care home (for example, visiting relatives). Details of the medicines taken should be recorded in the resident's care plan.\n\nHealth and social care practitioners should be able to access reliable and up-to-date information about medicines. Resources may include the patient information leaflet supplied with the medicine and the following websites:\n\nMedicines and Healthcare products Regulatory Agency\n\nNHS choices\n\nPatient.co.uk\n \n Health professionals may also use the:\n\nBritish National Formulary (BNF)\n\nBritish National Formulary for Children (BNFC)\n\nClinical Knowledge Summaries\n\nElectronic Medicines Compendium\n\n# Care home staff giving medicines to residents without their knowledge (covert administration)\n\nHealth and social care practitioners should not administer medicines to a resident without their knowledge (covert administration) if the resident has capacity to make decisions about their treatment and care.\n\nHealth and social care practitioners should ensure that covert administration only takes place in the context of existing legal and good practice frameworks to protect both the resident who is receiving the medicine(s) and the care home staff involved in administering the medicines.\n\nHealth and social care practitioners should ensure that the process for covert administration of medicines to adult residents in care homes includes:\n\nassessing mental capacity\n\nholding a best interest meeting involving care home staff, the health professional prescribing the medicine(s), pharmacist and family member or advocate to agree whether administering medicines without the resident knowing (covertly) is in the resident's best interests\n\nrecording the reasons for presuming mental incapacity and the proposed management plan\n\nplanning how medicines will be administered without the resident knowing\n\nregularly reviewing whether covert administration is still needed.\n\nCommissioners and providers of care home services should consider establishing a wider policy on the covert administration of medicines across several health and social care organisations.\n\n# Care home staff giving non-prescription and over-the-counter products to residents (homely remedies)\n\nCare home providers offering non-prescription medicines or other over-the-counter-products (homely remedies) for treating minor ailments should consider having a homely remedies process, which includes the following:\n\nthe name of the medicine or product and what it is for\n\nwhich residents should not be given certain medicines or products (for example, paracetamol should not be given as a homely remedy if a resident is already receiving prescribed paracetamol)\n\nthe dose and frequency\n\nthe maximum daily dose\n\nwhere any administration should be recorded, such as on the medicines administration record\n\nhow long the medicine or product should be used before referring the resident to a GP.\n\nCare home staff who give non-prescription medicines or other over-the-counter products (homely remedies) to residents should be named in the homely remedies process. They should sign the process to confirm they have the skills to administer the homely remedy and acknowledge that they will be accountable for their actions.\n\n# Training and skills (competency) of care home staff\n\nCare home providers must ensure that designated staff administer medicines only when they have had the necessary training and are assessed as competent. Care home providers must ensure that staff who do not have the skills to administer medicines, despite completing the required training, are not allowed to administer medicines to residents.\n\nCare home providers should set up an internal and/or external learning and development programme so that care home staff can gain the necessary skills for managing and administering medicines. The programme should meet the requirements of the regulators, the residents and the training needs of care home staff.\n\nCare home providers should consider using an 'accredited learning' provider so that care home staff who are responsible for managing and administering medicines can be assessed by an external assessor.\n\nCare home staff must have induction training that is relevant to the type of home they are working in (adult care homes or children's homes). All care home staff (including registered nurses as part of their continuing professional development) involved in managing and administering medicines should successfully complete any training needed to fulfil the learning and development requirements for their role.\n\nCare home providers should ensure that all care home staff have an annual review of their knowledge, skills and competencies relating to managing and administering medicines. Care home providers should identify any other training needed by care home staff responsible for managing and administering medicines. If there is a medicines-related safety incident, this review may need to be more frequent to identify support, learning and development needs.\n\nHealth professionals working in, or providing services to, care homes should work to standards set by their professional body and ensure that they have the appropriate skills, knowledge and expertise in the safe use of medicines for residents living in care homes.", 'Who should take action?': "The table below lists who should take action according to the recommendation number.\n\nWho should take action\n\nRecommendation number\n\nCommissioners\n\n, 1.3.2, 1.5.1, 1.6.1, 1.6.3, 1.7.3, 1.15.4\n\nCare home providers\n\n, 1.3.1, 1.3.7, 1.4.2, 1.6.2, 1.6.5, 1.6.9, 1.6.11, 1.7.2, 1.9.8, 1.10.1, 1.10.2, 1.10.3, 1.10.4, 1.10.5, 1.11.2, 1.12.1 (providers of adult care homes), 1.12.2, 1.12.3, 1.12.5, 1.12.6, 1.13.4 (providers of adult care homes), 1.13.5 (providers of children's care homes), 1.13.6, 1.13.7, 1.14.1, 1.14.2, 1.14.5, 1.14.8, 1.14.9, 1.14.10, 1.14.17, 1.14.18, 1.16.1, 1.17.1, 1.17.2, 1.17.3, 1.17.5\n\nProviders of health or social care services\n\n, 1.3.4, 1.5.1, 1.6.1, 1.7.3\n\nCare home manager\n\n, 1.13.3\n\nCare home staff (registered nurses and social care practitioners working in care homes)\n\nRecommendations for health and social care practitioners also apply to care home staff\n\n, 1.2.3, 1.3.8, 1.5.3, 1.6.4, 1.6.8, 1.6.10, 1.9.4, 1.9.7, 1.12.4, 1.13.1, 1.14.3, 1.14.6, 1.14.7, 1.14.11, 1.14.13, 1.14.14, 1.14.15, 1.14.16, 1.16.2, 1.17.4\n\nHealth and social care practitioners (care home staff, social workers, case managers, GPs, pharmacists and community nurses)\n\n, 1.2.4, 1.2.7, 1.3.5, 1.3.6, 1.4.1, 1.5.2, 1.8.3, 1.8.4, 1.8.5, 1.9.3, 1.13.2, 1.14.19, 1.15.1, 1.15.2, 1.15.3\n\nHealth professionals prescribing medicines\n\n, 1.9.2, 1.9.5, 1.14.4\n\nPharmacists\n\nRecommendations for health and social care practitioners also apply to pharmacists\n\n\n\nSupplying pharmacy\n\n\n\nHealth professionals who are visiting the care home to administer a medicine(s) to residents\n\n\n\nHealth professionals working in, or providing services to, care homes\n\n\n\nGPs\n\nRecommendations for health and social care practitioners also apply to GPs\n\n, 1.8.2\n\nGP practices\n\n"}	https://www.nice.org.uk/guidance/sc1	This guideline covers good practice for managing medicines in care homes. It aims to promote the safe and effective use of medicines in care homes by advising on processes for prescribing, handling and administering medicines. It also recommends how care and services relating to medicines should be provided to people living in care homes.
ec187117c0e0c4ac4f76fab7280774cd64c5587f	nice	Psychosis and schizophrenia in adults: prevention and management	Psychosis and schizophrenia in adults: prevention and management This guideline covers recognising and managing psychosis and schizophrenia in adults. It aims to improve care through early recognition and treatment, and by focusing on long-term recovery. It also recommends checking for coexisting health problems and providing support for family members and carers. # Introduction This guideline covers the treatment and management of psychosis and schizophrenia and related disorders in adults (18 years and older) with onset before 60 years. The term 'psychosis' is used in this guideline to refer to the group of psychotic disorders that includes schizophrenia, schizoaffective disorder, schizophreniform disorder and delusional disorder. The recognition, treatment and management of affective psychoses (such as bipolar disorder or unipolar psychotic depression) are covered by other NICE guidelines. The guideline does not address the specific treatment of young people under the age of 18 years, except those who are receiving treatment and support from early intervention in psychosis services; there is a separate NICE guideline on psychosis and schizophrenia in children and young people. Psychosis and the specific diagnosis of schizophrenia represent a major psychiatric disorder (or cluster of disorders) in which a person's perception, thoughts, mood and behaviour are significantly altered. The symptoms of psychosis and schizophrenia are usually divided into 'positive symptoms', including hallucinations (perception in the absence of any stimulus) and delusions (fixed or falsely held beliefs), and 'negative symptoms' (such as emotional apathy, lack of drive, poverty of speech, social withdrawal and self-neglect). Each person will have a unique combination of symptoms and experiences. Typically there is a prodromal period, which precedes a first episode of psychosis and can last from a few days to around 18 months. The prodromal period is often characterised by some deterioration in personal functioning. Changes include the emergence of transient (of short duration) and/or attenuated (of lower intensity) psychotic symptoms, memory and concentration problems, unusual behaviour and ideas, disturbed communication and affect, and social withdrawal, apathy and reduced interest in daily activities. The prodromal period is usually followed by an acute episode marked by hallucinations, delusions and behavioural disturbances, usually accompanied by agitation and distress. Following resolution of the acute episode, usually after pharmacological, psychological and other interventions, symptoms diminish and often disappear for many people, although sometimes a number of negative symptoms remain. This phase, which can last for many years, may be interrupted by recurrent acute episodes that may need additional pharmacological, psychological and other interventions, as in previous episodes. Although this is a common pattern, the course of schizophrenia varies considerably. Some people may have positive symptoms very briefly; others may experience them for many years. Others have no prodromal period, the disorder beginning suddenly with an acute episode. Over a lifetime, about 1% of the population will develop psychosis and schizophrenia. The first symptoms tend to start in young adulthood, at a time when a person would usually make the transition to independent living, but can occur at any age. The symptoms and behaviour associated with psychosis and schizophrenia can have a distressing impact on the individual, family and friends. Psychosis and schizophrenia are associated with considerable stigma, fear and limited public understanding. The first few years after onset can be particularly upsetting and chaotic, and there is a higher risk of suicide. Once an acute episode is over, there are often other problems such as social exclusion, with reduced opportunities to get back to work or study, and problems forming new relationships. In the last decade, there has been a new emphasis on services for early detection and intervention, and a focus on long-term recovery and promoting people's choices about the management of their condition. There is evidence that most people will recover, although some will have persisting difficulties or remain vulnerable to future episodes. Not everyone will accept help from statutory services. In the longer term, most people will find ways to manage acute problems, and compensate for any remaining difficulties. Carers, relatives and friends of people with psychosis and schizophrenia are important both in the process of assessment and engagement, and in the long-term successful delivery of effective treatments. This guideline uses the term 'carer' to apply to everyone who has regular close contact with people with psychosis and schizophrenia, including advocates, friends or family members, although some family members may choose not to be carers. Psychosis and schizophrenia are commonly associated with a number of other conditions, such as depression, anxiety, post-traumatic stress disorder, personality disorder and substance misuse. This guideline does not cover these conditions. NICE has produced separate guidance on the management of these conditions (see the NICE topic page on mental health and behavioural conditions). The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Care across all phases ## Service user experience Use this guideline in conjunction with the NICE guideline on service user experience in adult mental health to improve the experience of care for people with psychosis or schizophrenia using mental health services, and: work in partnership with people with schizophrenia and their carers -ffer help, treatment and care in an atmosphere of hope and optimism take time to build supportive and empathic relationships as an essential part of care. ## Race, culture and ethnicity The NICE guideline on service user experience in adult mental health includes recommendations on communication relevant to this section. Healthcare professionals inexperienced in working with people with psychosis or schizophrenia from diverse ethnic and cultural backgrounds should seek advice and supervision from healthcare professionals who are experienced in working transculturally. Healthcare professionals working with people with psychosis or schizophrenia should ensure they are competent in: assessment skills for people from diverse ethnic and cultural backgrounds using explanatory models of illness for people from diverse ethnic and cultural backgrounds explaining the causes of psychosis or schizophrenia and treatment options addressing cultural and ethnic differences in treatment expectations and adherence addressing cultural and ethnic differences in beliefs regarding biological, social and family influences on the causes of abnormal mental states negotiating skills for working with families of people with psychosis or schizophrenia conflict management and conflict resolution. Mental health services should work with local voluntary black, Asian and minority ethnic groups to jointly ensure that culturally appropriate psychological and psychosocial treatment, consistent with this guideline and delivered by competent practitioners, is provided to people from diverse ethnic and cultural backgrounds. ## Physical health People with psychosis or schizophrenia, especially those taking antipsychotics, should be offered a combined healthy eating and physical activity programme by their mental healthcare provider.Our 2019 review of the STEPWISE trial did not change this recommendation. If a person has rapid or excessive weight gain, abnormal lipid levels or problems with blood glucose management, offer interventions in line with relevant NICE guidance (see the NICE guidelines on obesity, cardiovascular disease: risk assessment and reduction, including lipid modification and preventing type 2 diabetes). Offer people with psychosis or schizophrenia who smoke help to stop smoking, even if previous attempts have been unsuccessful. Be aware of the potential significant impact of reducing cigarette smoking on the metabolism of other drugs, particularly clozapine and olanzapine. Consider one of the following to help people stop smoking: nicotine replacement therapy (usually a combination of transdermal patches with a short-acting product such as an inhalator, gum, lozenges or spray) for people with psychosis or schizophrenia or bupropion for people with a diagnosis of schizophrenia or varenicline for people with psychosis or schizophrenia. Warn people taking bupropion or varenicline that there is an increased risk of adverse neuropsychiatric symptoms and monitor them regularly, particularly in the first 2 to 3 weeks. For people in inpatient settings who do not want to stop smoking, offer nicotine replacement therapy to help them to reduce or temporarily stop smoking. Routinely monitor weight, and cardiovascular and metabolic indicators of morbidity in people with psychosis and schizophrenia. These should be audited in the annual team report. Trusts should ensure compliance with quality standards on the monitoring and treatment of cardiovascular and metabolic disease in people with psychosis or schizophrenia through board-level performance indicators. ## Comprehensive services provision All teams providing services for people with psychosis or schizophrenia should offer a comprehensive range of interventions consistent with this guideline. ## Support for carers Offer carers of people with psychosis or schizophrenia an assessment (provided by mental health services) of their own needs and discuss with them their strengths and views. Develop a care plan to address any identified needs, give a copy to the carer and their GP and ensure it is reviewed annually. See the NICE guideline on supporting adult carers. Advise carers about their right to a carer's assessment (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of carers). Give carers written and verbal information in an accessible format about: diagnosis and management of psychosis and schizophrenia positive outcomes and recovery types of support for carers role of teams and services getting help in a crisis. When providing information, offer the carer support if necessary. As early as possible negotiate with service users and carers about how information about the service user will be shared. When discussing rights to confidentiality, emphasise the importance of sharing information about risks and the need for carers to understand the service user's perspective. Foster a collaborative approach that supports both service users and carers, and respects their individual needs and interdependence. Review regularly how information is shared, especially if there are communication and collaboration difficulties between the service user and carer. Include carers in decision-making if the service user agrees. Offer a carer-focused education and support programme, which may be part of a family intervention for psychosis and schizophrenia, as early as possible to all carers. The intervention should: be available as needed have a positive message about recovery. ## Peer support and self-management Consider peer support for people with psychosis or schizophrenia to help improve service user experience and quality of life. Peer support should be delivered by a trained peer support worker who has recovered from psychosis or schizophrenia and remains stable. Peer support workers should receive support from their whole team, and support and mentorship from experienced peer workers. Consider a manualised self-management programme delivered face-to-face with service users, as part of the treatment and management of psychosis or schizophrenia. Peer support and self-management programmes should include information and advice about: psychosis and schizophrenia effective use of medication identifying and managing symptoms accessing mental health and other support services coping with stress and other problems what to do in a crisis building a social support network preventing relapse and setting personal recovery goals. # Preventing psychosis ## Referral from primary care If a person is distressed, has a decline in social functioning and has: transient or attenuated psychotic symptoms or -ther experiences or behaviour suggestive of possible psychosis or a first-degree relative with psychosis or schizophrenia refer them for assessment without delay to a specialist mental health service or an early intervention in psychosis service because they may be at increased risk of developing psychosis. ## Specialist assessment A consultant psychiatrist or a trained specialist with experience in at-risk mental states should carry out the assessment. ## Treatment options to prevent psychosis If a person is considered to be at increased risk of developing psychosis (as described in recommendation 1.2.1.1): -ffer individual cognitive behavioural therapy (CBT) with or without family intervention (delivered as described in section 1.3.7) and -ffer interventions recommended in NICE guidance for people with any of the anxiety disorders, depression, emerging personality disorder or substance misuse. Do not offer antipsychotic medication: to people considered to be at increased risk of developing psychosis (as described in recommendation 1.2.1.1) or with the aim of decreasing the risk of or preventing psychosis. ## Monitoring and follow-up If, after treatment (as described in recommendation 1.2.3.1), the person continues to have symptoms, impaired functioning or is distressed, but a clear diagnosis of psychosis cannot be made, monitor the person regularly for changes in symptoms and functioning for up to 3 years using a structured and validated assessment tool. Determine the frequency and duration of monitoring by the: severity and frequency of symptoms level of impairment and/or distress and degree of family disruption or concern. If a person asks to be discharged from the service, offer follow-up appointments and the option to self-refer in the future. Ask the person's GP to continue monitoring changes in their mental state. # First episode psychosis ## Early intervention in psychosis services Early intervention in psychosis services should be accessible to all people with a first episode or first presentation of psychosis, irrespective of the person's age or the duration of untreated psychosis. People presenting to early intervention in psychosis services should be assessed without delay. If the service cannot provide urgent intervention for people in a crisis, refer the person to a crisis resolution and home treatment team (with support from early intervention in psychosis services). Referral may be from primary or secondary care (including other community services) or a self- or carer-referral. Early intervention in psychosis services should aim to provide a full range of pharmacological, psychological, social, occupational and educational interventions for people with psychosis, consistent with this guideline. Consider extending the availability of early intervention in psychosis services beyond 3 years if the person has not made a stable recovery from psychosis or schizophrenia. ## Primary care Do not start antipsychotic medication for a first presentation of sustained psychotic symptoms in primary care unless it is done in consultation with a consultant psychiatrist. ## Assessment and care planning Carry out a comprehensive multidisciplinary assessment of people with psychotic symptoms in secondary care. This should include assessment by a psychiatrist, a psychologist or a professional with expertise in the psychological treatment of people with psychosis or schizophrenia. The assessment should address the following domains: psychiatric (mental health problems, risk of harm to self or others, alcohol consumption and prescribed and non-prescribed drug history) medical, including medical history and full physical examination to identify physical illness (including organic brain disorders) and prescribed drug treatments that may result in psychosis physical health and wellbeing (including weight, smoking, nutrition, physical activity and sexual health) psychological and psychosocial, including social networks, relationships and history of trauma developmental (social, cognitive and motor development and skills, including coexisting neurodevelopmental conditions) social (accommodation, culture and ethnicity, leisure activities and recreation, and responsibilities for children or as a carer) -ccupational and educational (attendance at college, educational attainment, employment and activities of daily living) quality of life economic status. Assess for post-traumatic stress disorder and other reactions to trauma because people with psychosis or schizophrenia are likely to have experienced previous adverse events or trauma associated with the development of the psychosis or as a result of the psychosis itself. For people who show signs of post-traumatic stress, follow the recommendations in the NICE guideline on post-traumatic stress disorder. Routinely monitor for other coexisting conditions, including depression, anxiety and substance misuse particularly in the early phases of treatment. Write a care plan in collaboration with the service user as soon as possible following assessment, based on a psychiatric and psychological formulation, and a full assessment of their physical health. Send a copy of the care plan to the primary healthcare professional who made the referral and the service user. For people who are unable to attend mainstream education, training or work, facilitate alternative educational or occupational activities according to their individual needs and capacity to engage with such activities, with an ultimate goal of returning to mainstream education, training or employment. ## Treatment options For people with first episode psychosis offer: -ral antipsychotic medication (see sections 1.3.5 and 1.3.6) in conjunction with psychological interventions (family intervention and individual CBT, delivered as described in section 1.3.7). Advise people who want to try psychological interventions alone that these are more effective when delivered in conjunction with antipsychotic medication. If the person still wants to try psychological interventions alone: -ffer family intervention and CBT agree a time (1 month or less) to review treatment options, including introducing antipsychotic medication continue to monitor symptoms, distress, impairment and level of functioning (including education, training and employment) regularly. If the person's symptoms and behaviour suggest an affective psychosis or disorder, including bipolar disorder and unipolar psychotic depression, follow the recommendations in the NICE guidelines on bipolar disorder or depression. ## Choice of antipsychotic medication The choice of antipsychotic medication should be made by the service user and healthcare professional together, taking into account the views of the carer if the service user agrees. Provide information and discuss the likely benefits and possible side effects of each drug, including: metabolic (including weight gain and diabetes) extrapyramidal (including akathisia, dyskinesia and dystonia) cardiovascular (including prolonging the QT interval) hormonal (including increasing plasma prolactin) -ther (including unpleasant subjective experiences). ## How to use antipsychotic medication Before starting antipsychotic medication, undertake and record the following baseline investigations: weight (plotted on a chart) waist circumference pulse and blood pressure fasting blood glucose or glycosylated haemoglobin (HbA1c) blood lipid profile and prolactin levels assessment of any movement disorders assessment of nutritional status, diet and level of physical activity. Before starting antipsychotic medication, offer the person with psychosis or schizophrenia an electrocardiogram (ECG) if: specified in the summary of product characteristics (SPC) a physical examination has identified specific cardiovascular risk (such as diagnosis of high blood pressure) there is a personal history of cardiovascular disease or the service user is being admitted as an inpatient. Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Include the following: Discuss and record the side effects that the person is most willing to tolerate. Record the indications and expected benefits and risks of oral antipsychotic medication, and the expected time for a change in symptoms and appearance of side effects. At the start of treatment give a dose at the lower end of the licensed range and slowly titrate upwards within the dose range given in the British national formulary (BNF) or SPC. Justify and record reasons for dosages outside the range given in the BNF or SPC. Record the rationale for continuing, changing or stopping medication, and the effects of such changes. Carry out a trial of the medication at optimum dosage for 4 to 6 weeks. Monitor and record the following regularly and systematically throughout treatment, but especially during titration: response to treatment, including changes in symptoms and behaviour side effects of treatment, taking into account overlap between certain side effects and clinical features of schizophrenia (for example, the overlap between akathisia and agitation or anxiety) and impact on functioning the emergence of movement disorders weight, weekly for the first 6 weeks, then at 12 weeks, at 1 year and then annually (plotted on a chart) waist circumference annually (plotted on a chart) pulse and blood pressure at 12 weeks, at 1 year and then annually fasting blood glucose or HbA1c, and blood lipid levels at 12 weeks, at 1 year and then annually adherence -verall physical health. The secondary care team should maintain responsibility for monitoring service users' physical health and the effects of antipsychotic medication for at least the first 12 months or until the person's condition has stabilised, whichever is longer. Thereafter, the responsibility for this monitoring may be transferred to primary care under shared care arrangements. Discuss any non-prescribed therapies the service user wishes to use (including complementary therapies) with the service user, and carer if appropriate. Discuss the safety and efficacy of the therapies, and possible interference with the therapeutic effects of prescribed medication and psychological treatments. Discuss the use of alcohol, tobacco, prescription and non-prescription medication and illicit drugs with the service user, and carer if appropriate. Discuss their possible interference with the therapeutic effects of prescribed medication and psychological treatments. 'As required' (p.r.n.) prescriptions of antipsychotic medication should be made as described in recommendation 1.3.6.3. Review clinical indications, frequency of administration, therapeutic benefits and side effects each week or as appropriate. Check whether 'p.r.n.' prescriptions have led to a dosage above the maximum specified in the BNF or SPC. Do not use a loading dose of antipsychotic medication (often referred to as 'rapid neuroleptisation'). Do not initiate regular combined antipsychotic medication, except for short periods (for example, when changing medication). If prescribing chlorpromazine, warn of its potential to cause skin photosensitivity. Advise using sunscreen if necessary. ## How to deliver psychological interventions CBT should be delivered on a one-to-one basis over at least 16 planned sessions and: follow a treatment manual (with evidence of efficacy from a clinical trial, if possible) so that: people can establish links between their thoughts, feelings or actions and their current or past symptoms, and/or functioning the re-evaluation of people's perceptions, beliefs or reasoning relates to the target symptoms also include at least one of the following components: people monitoring their own thoughts, feelings or behaviours with respect to their symptoms or recurrence of symptoms promoting alternative ways of coping with the target symptom reducing distress improving functioning. Family intervention should: include the person with psychosis or schizophrenia if practical be carried out for between 3 months and 1 year include at least 10 planned sessions take account of the whole family's preference for either single-family intervention or multi-family group intervention take account of the relationship between the main carer and the person with psychosis or schizophrenia have a specific supportive, educational or treatment function and include negotiated problem solving or crisis management work. ## Monitoring and reviewing psychological interventions When providing psychological interventions, routinely and systematically monitor a range of outcomes across relevant areas, including service user satisfaction and, if appropriate, carer satisfaction. Healthcare teams working with people with psychosis or schizophrenia should identify a lead healthcare professional within the team whose responsibility is to monitor and review: access to and engagement with psychological interventions decisions to offer psychological interventions and equality of access across different ethnic groups. ## Competencies for delivering psychological interventions Healthcare professionals providing psychological interventions should: have an appropriate level of competence in delivering the intervention to people with psychosis or schizophrenia be regularly supervised during psychological therapy by a competent therapist and supervisor. Trusts should provide access to training that equips healthcare professionals with the competencies required to deliver the psychological therapy interventions recommended in this guideline. # Subsequent acute episodes of psychosis or schizophrenia and referral in crisis ## Service-level interventions Offer crisis resolution and home treatment teams as a first-line service to support people with psychosis or schizophrenia during an acute episode in the community if the severity of the episode, or the level of risk to self or others, exceeds the capacity of the early intervention in psychosis services or other community teams to effectively manage it. Crisis resolution and home treatment teams should be the single point of entry to all other acute services in the community and in hospitals. Consider acute community treatment within crisis resolution and home treatment teams before admission to an inpatient unit and as a means to enable timely discharge from inpatient units. Crisis houses or acute day facilities may be considered in addition to crisis resolution and home treatment teams depending on the person's preference and need. If a person with psychosis or schizophrenia needs hospital care, think about the impact on the person, their carers and other family members, especially if the inpatient unit is a long way from where they live. If hospital admission is unavoidable, ensure that the setting is suitable for the person's age, gender and level of vulnerability, support their carers and follow the recommendations in the NICE guideline on service user experience in adult mental health. ## Treatment options For people with an acute exacerbation or recurrence of psychosis or schizophrenia, offer: -ral antipsychotic medication (see sections 1.3.5 and 1.3.6) in conjunction with psychological interventions (family intervention and individual CBT, delivered as described in section 1.3.7). ## Pharmacological interventions For people with an acute exacerbation or recurrence of psychosis or schizophrenia, offer oral antipsychotic medication or review existing medication. The choice of drug should be influenced by the same criteria recommended for starting treatment (see sections 1.3.5 and 1.3.6). Take into account the clinical response and side effects of the service user's current and previous medication. ## Psychological and psychosocial interventions Offer CBT to all people with psychosis or schizophrenia (delivered as described in recommendation 1.3.7.1). This can be started either during the acute phase or later, including in inpatient settings. Offer family intervention to all families of people with psychosis or schizophrenia who live with or are in close contact with the service user (delivered as described in recommendation 1.3.7.2). This can be started either during the acute phase or later, including in inpatient settings. Consider offering arts therapies to all people with psychosis or schizophrenia, particularly for the alleviation of negative symptoms. This can be started either during the acute phase or later, including in inpatient settings. Arts therapies should be provided by a Health and Care Professions Council registered arts therapist with previous experience of working with people with psychosis or schizophrenia. The intervention should be provided in groups unless difficulties with acceptability and access and engagement indicate otherwise. Arts therapies should combine psychotherapeutic techniques with activity aimed at promoting creative expression, which is often unstructured and led by the service user. Aims of arts therapies should include: enabling people with psychosis or schizophrenia to experience themselves differently and to develop new ways of relating to others helping people to express themselves and to organise their experience into a satisfying aesthetic form helping people to accept and understand feelings that may have emerged during the creative process (including, in some cases, how they came to have these feelings) at a pace suited to the person. When psychological treatments, including arts therapies, are started in the acute phase (including in inpatient settings), the full course should be continued after discharge without unnecessary interruption. Do not routinely offer counselling and supportive psychotherapy (as specific interventions) to people with psychosis or schizophrenia. However, take service user preferences into account, especially if other more efficacious psychological treatments, such as CBT, family intervention and arts therapies, are not available locally. Do not offer adherence therapy (as a specific intervention) to people with psychosis or schizophrenia. Do not routinely offer social skills training (as a specific intervention) to people with psychosis or schizophrenia. ## Behaviour that challenges Occasionally people with psychosis or schizophrenia pose an immediate risk to themselves or others during an acute episode and may need rapid tranquillisation. The management of immediate risk should follow the relevant NICE guidelines (see recommendations 1.4.5.2 and 1.4.5.5). Follow the recommendations in the NICE guideline on violence and aggression when facing imminent violence or when considering rapid tranquillisation. After rapid tranquillisation, offer the person with psychosis or schizophrenia the opportunity to discuss their experiences. Provide them with a clear explanation of the decision to use urgent sedation. Record this in their notes. Ensure that the person with psychosis or schizophrenia has the opportunity to write an account of their experience of rapid tranquillisation in their notes. Follow the recommendations in the NICE guideline on self-harm when managing acts of self-harm in people with psychosis or schizophrenia. ## Early post-acute period After each acute episode, encourage people with psychosis or schizophrenia to write an account of their illness in their notes. Healthcare professionals may consider using psychoanalytic and psychodynamic principles to help them understand the experiences of people with psychosis or schizophrenia and their interpersonal relationships. Inform the service user that there is a high risk of relapse if they stop medication in the next 1 to 2 years. If withdrawing antipsychotic medication, undertake gradually and monitor regularly for signs and symptoms of relapse. After withdrawal from antipsychotic medication, continue monitoring for signs and symptoms of relapse for at least 2 years. # Promoting recovery and possible future care ## General principles Continue treatment and care in early intervention in psychosis services or refer the person to a specialist integrated community-based team. This team should: -ffer the full range of psychological, pharmacological, social and occupational interventions recommended in this guideline be competent to provide all interventions offered place emphasis on engagement rather than risk management provide treatment and care in the least restrictive and stigmatising environment possible and in an atmosphere of hope and optimism in line with the NICE guideline on service user experience in adult mental health. Consider intensive case management for people with psychosis or schizophrenia who are likely to disengage from treatment or services. Review antipsychotic medication annually, including observed benefits and any side effects. ## Return to primary care Offer people with psychosis or schizophrenia whose symptoms have responded effectively to treatment and remain stable the option to return to primary care for further management. If a service user wishes to do this, record this in their notes and coordinate transfer of responsibilities through the care programme approach. ## Primary care Develop and use practice case registers to monitor the physical and mental health of people with psychosis or schizophrenia in primary care. GPs and other primary healthcare professionals should monitor the physical health of people with psychosis or schizophrenia when responsibility for monitoring is transferred from secondary care, and then at least annually. The health check should be comprehensive, focusing on physical health problems that are common in people with psychosis and schizophrenia. Include all the checks in recommendation 1.3.6.1 and refer to relevant NICE guidance on monitoring for cardiovascular disease, diabetes, obesity and respiratory disease. A copy of the results should be sent to the care coordinator and psychiatrist, and put in the secondary care notes. Identify people with psychosis or schizophrenia who have high blood pressure, have abnormal lipid levels, are obese or at risk of obesity, have diabetes or are at risk of diabetes (as indicated by abnormal blood glucose levels), or are physically inactive, at the earliest opportunity following relevant NICE guidelines on cardiovascular disease: risk assessment and reduction, including lipid modification, preventing type 2 diabetes, obesity, hypertension, prevention of cardiovascular disease and physical activity. Treat people with psychosis or schizophrenia who have diabetes and/or cardiovascular disease in primary care according to the appropriate NICE guidance (for example, see the NICE guidelines on lipid modification, type 1 diabetes and type 2 diabetes). Healthcare professionals in secondary care should ensure, as part of the care programme approach, that people with psychosis or schizophrenia receive physical healthcare from primary care as described in recommendations 1.5.3.1 to 1.5.3.4. When a person with an established diagnosis of psychosis or schizophrenia presents with a suspected relapse (for example, with increased psychotic symptoms or a significant increase in the use of alcohol or other substances), primary healthcare professionals should refer to the crisis section of the care plan. Consider referral to the key clinician or care coordinator identified in the crisis plan. For a person with psychosis or schizophrenia being cared for in primary care, consider referral to secondary care again if there is: poor response to treatment non-adherence to medication intolerable side effects from medication comorbid substance misuse risk to self or others. When re-referring people with psychosis or schizophrenia to mental health services, take account of service user and carer requests, especially for: review of the side effects of existing treatments psychological treatments or other interventions. When a person with psychosis or schizophrenia is planning to move to the catchment area of a different NHS trust, a meeting should be arranged between the services involved and the service user to agree a transition plan before transfer. The person's current care plan should be sent to the new secondary care and primary care providers. ## Psychological interventions Offer CBT to assist in promoting recovery in people with persisting positive and negative symptoms and for people in remission. Deliver CBT as described in recommendation 1.3.7.1. Offer family intervention to families of people with psychosis or schizophrenia who live with or are in close contact with the service user. Deliver family intervention as described in recommendation 1.3.7.2. Family intervention may be particularly useful for families of people with psychosis or schizophrenia who have: recently relapsed or are at risk of relapse persisting symptoms. Consider offering arts therapies to assist in promoting recovery, particularly in people with negative symptoms. ## Pharmacological interventions The choice of drug should be influenced by the same criteria recommended for starting treatment (see sections 1.3.5 and 1.3.6). Do not use targeted, intermittent dosage maintenance strategies (use of antipsychotic medication only during periods of incipient relapse or symptom exacerbation) routinely. However, consider them for people with psychosis or schizophrenia who are unwilling to accept a continuous maintenance regimen or if there is another contraindication to maintenance therapy, such as side-effect sensitivity. Consider offering depot/long-acting injectable antipsychotic medication to people with psychosis or schizophrenia: who would prefer such treatment after an acute episode where avoiding covert non-adherence (either intentional or unintentional) to antipsychotic medication is a clinical priority within the treatment plan. ## Using depot/long-acting injectable antipsychotic medication When initiating depot/long-acting injectable antipsychotic medication: take into account the service user's preferences and attitudes towards the mode of administration (regular intramuscular injections) and organisational procedures (for example, home visits and location of clinics) take into account the same criteria recommended for the use of oral antipsychotic medication (see sections 1.3.5 and 1.3.6), particularly in relation to the risks and benefits of the drug regimen prescribe according to the procedures set out in the BNF or SPC. ## Interventions for people whose illness has not responded adequately to treatment For people with schizophrenia whose illness has not responded adequately to pharmacological or psychological treatment: Review the diagnosis. Establish that there has been adherence to antipsychotic medication, prescribed at an adequate dose and for the correct duration. Review engagement with and use of psychological treatments and ensure that these have been offered according to this guideline. If family intervention has been undertaken suggest CBT; if CBT has been undertaken suggest family intervention for people in close contact with their families. Consider other causes of non-response, such as comorbid substance misuse (including alcohol), the concurrent use of other prescribed medication or physical illness. Offer clozapine to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least 2 different antipsychotic drugs. At least 1 of the drugs should be a non-clozapine second-generation antipsychotic. For people with schizophrenia whose illness has not responded adequately to clozapine at an optimised dose, healthcare professionals should consider recommendation 1.5.7.1 (including measuring therapeutic drug levels) before adding a second antipsychotic to augment treatment with clozapine. An adequate trial of such an augmentation may need to be up to 8 to 10 weeks. Choose a drug that does not compound the common side effects of clozapine. ## Employment, education and occupational activities Offer supported employment programmes to people with psychosis or schizophrenia who wish to find or return to work. Consider other occupational or educational activities, including pre-vocational training, for people who are unable to work or unsuccessful in finding employment. Mental health services should work in partnership with local stakeholders, including those representing black, Asian and minority ethnic groups, to enable people with mental health problems, including psychosis or schizophrenia, to stay in work or education and to access new employment (including self-employment), volunteering and educational opportunities. Routinely record the daytime activities of people with psychosis or schizophrenia in their care plans, including occupational outcomes. # Recommendations for research The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research are detailed in the full guideline. # Peer support interventions What is the clinical and cost effectiveness of peer support interventions in people with psychosis and schizophrenia? ## Why this is important Service users have supported the development of peer support interventions, which have recently proliferated in the UK, but current evidence for these interventions in people with psychotic disorders is not strong and the studies are mainly of very low quality. Moreover the content of the programmes has varied considerably, some using structured interventions, others providing more informal support. There is therefore an urgent need for high-quality evidence in this area. The programme of research would be in several stages. First, there should be development work to establish what specifically service users want from peer support workers, as opposed to what they want from professionals, and what the conditions are for optimal delivery of the intervention. This development work should be co-produced by exploring the views of service users, experienced peer support workers and developers of peer support interventions, and suitable outcome measures should be identified reflecting the aims of peer support. Second, the intervention, delivered as far as possible under the optimal conditions, should be tested in a high-quality trial. Further research should test structured and manualised formats versus unstructured formats (in which service user and peer decide together what to cover in the session). Benefits and adverse effects experienced by peer support workers should also be measured. # People who choose not to take antipsychotic medication What is the clinical and cost effectiveness of psychological intervention alone, compared with treatment as usual, in people with psychosis or schizophrenia who choose not to take antipsychotic medication? ## Why this is important The development of alternative treatment strategies is important for the high proportion of people with psychosis and schizophrenia who choose not to take antipsychotic medication, or discontinue it because of adverse effects or lack of efficacy. There is evidence that psychological interventions (CBT and family intervention) as an adjunct to antipsychotic medication are effective in the treatment of psychosis and schizophrenia and are cost saving. However, there is little evidence for family intervention or CBT alone, without antipsychotic medication. The programme of research should compare the clinical and cost effectiveness of psychological intervention alone (CBT and/or family intervention) with treatment as usual for people with psychosis or schizophrenia who choose not to take antipsychotic medication, using an adequately powered study with a randomised controlled design. Key outcomes should include symptoms, relapse rates, quality of life, treatment acceptability, social functioning and the cost effectiveness of the interventions. # The physical health benefits of discontinuing antipsychotic medication What are the short- and long-term benefits to physical health of guided medication discontinuation and/or reduction in first episode psychosis and can this be achieved without major risks? ## Why this is important There is growing concern about the long-term health risks, increased mortality and cortical grey matter loss linked to cumulative neuroleptic exposure in people with psychosis. The majority of young adults discontinue their medication in an unplanned way because of these risks. A Dutch moderately-sized open trial has reported successful discontinuation of medication in 20% of people without serious relapse; at 7-year follow-up there was continuous benefit for guided reduction in terms of side effects, functioning and employment, with no long-term risks. If replicated, this would mark a significant breakthrough in reducing the long-term physical health risks associated with antipsychotic treatment and improving outcomes. The programme of research should use an adequately powered, multicentre, double-blind, randomised controlled design to test the physical health benefits, risks and costs of discontinuing or reducing antipsychotic medication among young adults with first episode psychosis who have achieved remission. The primary outcomes should be quality of life and metabolic disorder, including weight gain; secondary outcomes should include side effects, serious relapse, acceptability and user preference. # Maintaining the benefits of early intervention in psychosis services after discharge How can the benefits of early intervention in psychosis services be maintained once service users are discharged after 3 years? ## Why this is important Early intervention in psychosis services deliver evidence-based interventions in a positive, youth-friendly setting, improve outcomes, are cost effective and have high service user acceptability and engagement. Once people are transferred to primary care or community mental health services these gains are diminished. The guideline recommends that trusts consider extending these services. However, the extent to which gains would be maintained and who would benefit most is not known. The successful element of early intervention in psychosis services might be incorporated into mainstream services for psychosis, but how this would function, and its cost effectiveness, needs to be determined. The suggested programme of research should use an adequately powered, multi-centre randomised trial comparing extending early intervention in psychosis services (for example, for 2 years) versus providing augmented (step-down) care in community mental health services versus treatment as usual to determine whether the gains of early intervention can be maintained and which service users would benefit most under each condition. The primary outcome should be treatment or service engagement and secondary outcomes should include relapse, readmission, functioning and user preference. # Interventions for PTSD symptoms in people with psychosis and schizophrenia What is the benefit of a CBT-based trauma reprocessing intervention on PTSD symptoms in people with psychosis and schizophrenia? ## Why this is important PTSD symptoms have been documented in approximately one-third of people with psychosis and schizophrenia. The absence of PTSD symptoms in this context predicts better mental health outcomes, lower service use and improved life satisfaction. Two-thirds of the traumatic intrusions, observed in first episode and established psychosis, relate to symptoms of psychosis and its treatment (including detention). One study has demonstrated proof-of-principle in first episode psychosis for trauma reprocessing, focusing on psychosis-related intrusions. Replication of the study will fill a major gap in treatment for this population and may have other benefits on psychotic symptoms and service use. The suggested programme of research would use an adequately powered, multi-centre randomised trial to test whether a CBT-based trauma reprocessing intervention can reduce PTSD symptoms and related distress in people with psychosis and schizophrenia. The trial should be targeted at those with high levels of PTSD symptoms, particularly traumatic intrusions, following first episode psychosis. The follow-up should be up to 2 years and the intervention should include 'booster' elements, extra sessions of CBT-based trauma reprocessing interventions, and a health economic evaluation.	{'Introduction': "This guideline covers the treatment and management of psychosis and schizophrenia and related disorders in adults (18 years and older) with onset before 60 years. The term 'psychosis' is used in this guideline to refer to the group of psychotic disorders that includes schizophrenia, schizoaffective disorder, schizophreniform disorder and delusional disorder. The recognition, treatment and management of affective psychoses (such as bipolar disorder or unipolar psychotic depression) are covered by other NICE guidelines. The guideline does not address the specific treatment of young people under the age of 18\xa0years, except those who are receiving treatment and support from early intervention in psychosis services; there is a separate NICE guideline on psychosis and schizophrenia in children and young people.\n\nPsychosis and the specific diagnosis of schizophrenia represent a major psychiatric disorder (or cluster of disorders) in which a person's perception, thoughts, mood and behaviour are significantly altered. The symptoms of psychosis and schizophrenia are usually divided into 'positive symptoms', including hallucinations (perception in the absence of any stimulus) and delusions (fixed or falsely held beliefs), and 'negative symptoms' (such as emotional apathy, lack of drive, poverty of speech, social withdrawal and self-neglect). Each person will have a unique combination of symptoms and experiences.\n\nTypically there is a prodromal period, which precedes a first episode of psychosis and can last from a few days to around 18\xa0months. The prodromal period is often characterised by some deterioration in personal functioning. Changes include the emergence of transient (of short duration) and/or attenuated (of lower intensity) psychotic symptoms, memory and concentration problems, unusual behaviour and ideas, disturbed communication and affect, and social withdrawal, apathy and reduced interest in daily activities. The prodromal period is usually followed by an acute episode marked by hallucinations, delusions and behavioural disturbances, usually accompanied by agitation and distress. Following resolution of the acute episode, usually after pharmacological, psychological and other interventions, symptoms diminish and often disappear for many people, although sometimes a number of negative symptoms remain. This phase, which can last for many years, may be interrupted by recurrent acute episodes that may need additional pharmacological, psychological and other interventions, as in previous episodes.\n\nAlthough this is a common pattern, the course of schizophrenia varies considerably. Some people may have positive symptoms very briefly; others may experience them for many years. Others have no prodromal period, the disorder beginning suddenly with an acute episode.\n\nOver a lifetime, about 1% of the population will develop psychosis and schizophrenia. The first symptoms tend to start in young adulthood, at a time when a person would usually make the transition to independent living, but can occur at any age. The symptoms and behaviour associated with psychosis and schizophrenia can have a distressing impact on the individual, family and friends.\n\nPsychosis and schizophrenia are associated with considerable stigma, fear and limited public understanding. The first few years after onset can be particularly upsetting and chaotic, and there is a higher risk of suicide. Once an acute episode is over, there are often other problems such as social exclusion, with reduced opportunities to get back to work or study, and problems forming new relationships.\n\nIn the last decade, there has been a new emphasis on services for early detection and intervention, and a focus on long-term recovery and promoting people's choices about the management of their condition. There is evidence that most people will recover, although some will have persisting difficulties or remain vulnerable to future episodes. Not everyone will accept help from statutory services. In the longer term, most people will find ways to manage acute problems, and compensate for any remaining difficulties.\n\nCarers, relatives and friends of people with psychosis and schizophrenia are important both in the process of assessment and engagement, and in the long-term successful delivery of effective treatments. This guideline uses the term 'carer' to apply to everyone who has regular close contact with people with psychosis and schizophrenia, including advocates, friends or family members, although some family members may choose not to be carers.\n\nPsychosis and schizophrenia are commonly associated with a number of other conditions, such as depression, anxiety, post-traumatic stress disorder, personality disorder and substance misuse. This guideline does not cover these conditions. NICE has produced separate guidance on the management of these conditions (see the NICE topic page on mental health and behavioural conditions).\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Care across all phases\n\n## Service user experience\n\nUse this guideline in conjunction with the NICE guideline on service user experience in adult mental health to improve the experience of care for people with psychosis or schizophrenia using mental health services, and:\n\nwork in partnership with people with schizophrenia and their carers\n\noffer help, treatment and care in an atmosphere of hope and optimism\n\ntake time to build supportive and empathic relationships as an essential part of care. [2009; amended 2014]\n\n## Race, culture and ethnicity\n\nThe NICE guideline on service user experience in adult mental health includes recommendations on communication relevant to this section.\n\nHealthcare professionals inexperienced in working with people with psychosis or schizophrenia from diverse ethnic and cultural backgrounds should seek advice and supervision from healthcare professionals who are experienced in working transculturally. \n\nHealthcare professionals working with people with psychosis or schizophrenia should ensure they are competent in:\n\nassessment skills for people from diverse ethnic and cultural backgrounds\n\nusing explanatory models of illness for people from diverse ethnic and cultural backgrounds\n\nexplaining the causes of psychosis or schizophrenia and treatment options\n\naddressing cultural and ethnic differences in treatment expectations and adherence\n\naddressing cultural and ethnic differences in beliefs regarding biological, social and family influences on the causes of abnormal mental states\n\nnegotiating skills for working with families of people with psychosis or schizophrenia\n\nconflict management and conflict resolution. \n\nMental health services should work with local voluntary black, Asian and minority ethnic groups to jointly ensure that culturally appropriate psychological and psychosocial treatment, consistent with this guideline and delivered by competent practitioners, is provided to people from diverse ethnic and cultural backgrounds. \n\n## Physical health\n\nPeople with psychosis or schizophrenia, especially those taking antipsychotics, should be offered a combined healthy eating and physical activity programme by their mental healthcare provider.Our 2019 review of the STEPWISE trial did not change this recommendation. \n\nIf a person has rapid or excessive weight gain, abnormal lipid levels or problems with blood glucose management, offer interventions in line with relevant NICE guidance (see the NICE guidelines on obesity, cardiovascular disease: risk assessment and reduction, including lipid modification and preventing type 2 diabetes). \n\nOffer people with psychosis or schizophrenia who smoke help to stop smoking, even if previous attempts have been unsuccessful. Be aware of the potential significant impact of reducing cigarette smoking on the metabolism of other drugs, particularly clozapine and olanzapine. \n\nConsider one of the following to help people stop smoking:\n\nnicotine replacement therapy (usually a combination of transdermal patches with a short-acting product such as an inhalator, gum, lozenges or spray) for people with psychosis or schizophrenia or\n\nbupropion for people with a diagnosis of schizophrenia or\n\nvarenicline for people with psychosis or schizophrenia. Warn people taking bupropion or varenicline that there is an increased risk of adverse neuropsychiatric symptoms and monitor them regularly, particularly in the first 2 to 3\xa0weeks. \n\nFor people in inpatient settings who do not want to stop smoking, offer nicotine replacement therapy to help them to reduce or temporarily stop smoking. \n\nRoutinely monitor weight, and cardiovascular and metabolic indicators of morbidity in people with psychosis and schizophrenia. These should be audited in the annual team report. \n\nTrusts should ensure compliance with quality standards on the monitoring and treatment of cardiovascular and metabolic disease in people with psychosis or schizophrenia through board-level performance indicators. \n\n## Comprehensive services provision\n\nAll teams providing services for people with psychosis or schizophrenia should offer a comprehensive range of interventions consistent with this guideline. \n\n## Support for carers\n\nOffer carers of people with psychosis or schizophrenia an assessment (provided by mental health services) of their own needs and discuss with them their strengths and views. Develop a care plan to address any identified needs, give a copy to the carer and their GP and ensure it is reviewed annually. See the NICE guideline on supporting adult carers. \n\nAdvise carers about their right to a carer's assessment (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of carers). \n\nGive carers written and verbal information in an accessible format about:\n\ndiagnosis and management of psychosis and schizophrenia\n\npositive outcomes and recovery\n\ntypes of support for carers\n\nrole of teams and services\n\ngetting help in a crisis. When providing information, offer the carer support if necessary. \n\nAs early as possible negotiate with service users and carers about how information about the service user will be shared. When discussing rights to confidentiality, emphasise the importance of sharing information about risks and the need for carers to understand the service user's perspective. Foster a collaborative approach that supports both service users and carers, and respects their individual needs and interdependence. \n\nReview regularly how information is shared, especially if there are communication and collaboration difficulties between the service user and carer. \n\nInclude carers in decision-making if the service user agrees. \n\nOffer a carer-focused education and support programme, which may be part of a family intervention for psychosis and schizophrenia, as early as possible to all carers. The intervention should:\n\nbe available as needed\n\nhave a positive message about recovery. \n\n## Peer support and self-management\n\nConsider peer support for people with psychosis or schizophrenia to help improve service user experience and quality of life. Peer support should be delivered by a trained peer support worker who has recovered from psychosis or schizophrenia and remains stable. Peer support workers should receive support from their whole team, and support and mentorship from experienced peer workers. \n\nConsider a manualised self-management programme delivered face-to-face with service users, as part of the treatment and management of psychosis or schizophrenia. \n\nPeer support and self-management programmes should include information and advice about:\n\npsychosis and schizophrenia\n\neffective use of medication\n\nidentifying and managing symptoms\n\naccessing mental health and other support services\n\ncoping with stress and other problems\n\nwhat to do in a crisis\n\nbuilding a social support network\n\npreventing relapse and setting personal recovery goals. \n\n# Preventing psychosis\n\n## Referral from primary care\n\nIf a person is distressed, has a decline in social functioning and has:\n\ntransient or attenuated psychotic symptoms or\n\nother experiences or behaviour suggestive of possible psychosis or\n\na first-degree relative with psychosis or schizophrenia refer them for assessment without delay to a specialist mental health service or an early intervention in psychosis service because they may be at increased risk of developing psychosis. \n\n## Specialist assessment\n\nA consultant psychiatrist or a trained specialist with experience in at-risk mental states should carry out the assessment. \n\n## Treatment options to prevent psychosis\n\nIf a person is considered to be at increased risk of developing psychosis (as described in recommendation 1.2.1.1):\n\noffer individual cognitive behavioural therapy (CBT) with or without family intervention (delivered as described in section 1.3.7) and\n\noffer interventions recommended in NICE guidance for people with any of the anxiety disorders, depression, emerging personality disorder or substance misuse. \n\nDo not offer antipsychotic medication:\n\nto people considered to be at increased risk of developing psychosis (as described in recommendation 1.2.1.1) or\n\nwith the aim of decreasing the risk of or preventing psychosis. \n\n## Monitoring and follow-up\n\nIf, after treatment (as described in recommendation 1.2.3.1), the person continues to have symptoms, impaired functioning or is distressed, but a clear diagnosis of psychosis cannot be made, monitor the person regularly for changes in symptoms and functioning for up to 3\xa0years using a structured and validated assessment tool. Determine the frequency and duration of monitoring by the:\n\nseverity and frequency of symptoms\n\nlevel of impairment and/or distress and\n\ndegree of family disruption or concern. \n\nIf a person asks to be discharged from the service, offer follow-up appointments and the option to self-refer in the future. Ask the person's GP to continue monitoring changes in their mental state. \n\n# First episode psychosis\n\n## Early intervention in psychosis services\n\nEarly intervention in psychosis services should be accessible to all people with a first episode or first presentation of psychosis, irrespective of the person's age or the duration of untreated psychosis. \n\nPeople presenting to early intervention in psychosis services should be assessed without delay. If the service cannot provide urgent intervention for people in a crisis, refer the person to a crisis resolution and home treatment team (with support from early intervention in psychosis services). Referral may be from primary or secondary care (including other community services) or a self- or carer-referral. \n\nEarly intervention in psychosis services should aim to provide a full range of pharmacological, psychological, social, occupational and educational interventions for people with psychosis, consistent with this guideline. \n\nConsider extending the availability of early intervention in psychosis services beyond 3\xa0years if the person has not made a stable recovery from psychosis or schizophrenia. \n\n## Primary care\n\nDo not start antipsychotic medication for a first presentation of sustained psychotic symptoms in primary care unless it is done in consultation with a consultant psychiatrist. [2009; amended 2014]\n\n## Assessment and care planning\n\nCarry out a comprehensive multidisciplinary assessment of people with psychotic symptoms in secondary care. This should include assessment by a psychiatrist, a psychologist or a professional with expertise in the psychological treatment of people with psychosis or schizophrenia. The assessment should address the following domains:\n\npsychiatric (mental health problems, risk of harm to self or others, alcohol consumption and prescribed and non-prescribed drug history)\n\nmedical, including medical history and full physical examination to identify physical illness (including organic brain disorders) and prescribed drug treatments that may result in psychosis\n\nphysical health and wellbeing (including weight, smoking, nutrition, physical activity and sexual health)\n\npsychological and psychosocial, including social networks, relationships and history of trauma\n\ndevelopmental (social, cognitive and motor development and skills, including coexisting neurodevelopmental conditions)\n\nsocial (accommodation, culture and ethnicity, leisure activities and recreation, and responsibilities for children or as a carer)\n\noccupational and educational (attendance at college, educational attainment, employment and activities of daily living)\n\nquality of life\n\neconomic status. [2009; amended 2014]\n\nAssess for post-traumatic stress disorder and other reactions to trauma because people with psychosis or schizophrenia are likely to have experienced previous adverse events or trauma associated with the development of the psychosis or as a result of the psychosis itself. For people who show signs of post-traumatic stress, follow the recommendations in the NICE guideline on post-traumatic stress disorder. \n\nRoutinely monitor for other coexisting conditions, including depression, anxiety and substance misuse particularly in the early phases of treatment. [2009; amended 2014]\n\nWrite a care plan in collaboration with the service user as soon as possible following assessment, based on a psychiatric and psychological formulation, and a full assessment of their physical health. Send a copy of the care plan to the primary healthcare professional who made the referral and the service user. [2009; amended 2014]\n\nFor people who are unable to attend mainstream education, training or work, facilitate alternative educational or occupational activities according to their individual needs and capacity to engage with such activities, with an ultimate goal of returning to mainstream education, training or employment. \n\n## Treatment options\n\nFor people with first episode psychosis offer:\n\noral antipsychotic medication (see sections 1.3.5 and 1.3.6) in conjunction with\n\npsychological interventions (family intervention and individual CBT, delivered as described in section 1.3.7). \n\nAdvise people who want to try psychological interventions alone that these are more effective when delivered in conjunction with antipsychotic medication. If the person still wants to try psychological interventions alone:\n\noffer family intervention and CBT\n\nagree a time (1\xa0month or less) to review treatment options, including introducing antipsychotic medication\n\ncontinue to monitor symptoms, distress, impairment and level of functioning (including education, training and employment) regularly. \n\nIf the person's symptoms and behaviour suggest an affective psychosis or disorder, including bipolar disorder and unipolar psychotic depression, follow the recommendations in the NICE guidelines on bipolar disorder or depression. \n\n## Choice of antipsychotic medication\n\nThe choice of antipsychotic medication should be made by the service user and healthcare professional together, taking into account the views of the carer if the service user agrees. Provide information and discuss the likely benefits and possible side effects of each drug, including:\n\nmetabolic (including weight gain and diabetes)\n\nextrapyramidal (including akathisia, dyskinesia and dystonia)\n\ncardiovascular (including prolonging the QT interval)\n\nhormonal (including increasing plasma prolactin)\n\nother (including unpleasant subjective experiences). [2009; amended 2014]\n\n## How to use antipsychotic medication\n\nBefore starting antipsychotic medication, undertake and record the following baseline investigations:\n\nweight (plotted on a chart)\n\nwaist circumference\n\npulse and blood pressure\n\nfasting blood glucose or glycosylated haemoglobin (HbA1c)\n\nblood lipid profile and prolactin levels\n\nassessment of any movement disorders\n\nassessment of nutritional status, diet and level of physical activity. \n\nBefore starting antipsychotic medication, offer the person with psychosis or schizophrenia an electrocardiogram (ECG) if:\n\nspecified in the summary of product characteristics (SPC)\n\na physical examination has identified specific cardiovascular risk (such as diagnosis of high blood pressure)\n\nthere is a personal history of cardiovascular disease or\n\nthe service user is being admitted as an inpatient. \n\nTreatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Include the following:\n\nDiscuss and record the side effects that the person is most willing to tolerate.\n\nRecord the indications and expected benefits and risks of oral antipsychotic medication, and the expected time for a change in symptoms and appearance of side effects.\n\nAt the start of treatment give a dose at the lower end of the licensed range and slowly titrate upwards within the dose range given in the British national formulary (BNF) or SPC.\n\nJustify and record reasons for dosages outside the range given in the BNF or SPC.\n\nRecord the rationale for continuing, changing or stopping medication, and the effects of such changes.\n\nCarry out a trial of the medication at optimum dosage for 4 to 6\xa0weeks. [2009; amended 2014]\n\nMonitor and record the following regularly and systematically throughout treatment, but especially during titration:\n\nresponse to treatment, including changes in symptoms and behaviour\n\nside effects of treatment, taking into account overlap between certain side effects and clinical features of schizophrenia (for example, the overlap between akathisia and agitation or anxiety) and impact on functioning\n\nthe emergence of movement disorders\n\nweight, weekly for the first 6\xa0weeks, then at 12\xa0weeks, at 1\xa0year and then annually (plotted on a chart)\n\nwaist circumference annually (plotted on a chart)\n\npulse and blood pressure at 12\xa0weeks, at 1\xa0year and then annually\n\nfasting blood glucose or HbA1c, and blood lipid levels at 12\xa0weeks, at 1\xa0year and then annually\n\nadherence\n\noverall physical health. \n\nThe secondary care team should maintain responsibility for monitoring service users' physical health and the effects of antipsychotic medication for at least the first 12\xa0months or until the person's condition has stabilised, whichever is longer. Thereafter, the responsibility for this monitoring may be transferred to primary care under shared care arrangements. \n\nDiscuss any non-prescribed therapies the service user wishes to use (including complementary therapies) with the service user, and carer if appropriate. Discuss the safety and efficacy of the therapies, and possible interference with the therapeutic effects of prescribed medication and psychological treatments. \n\nDiscuss the use of alcohol, tobacco, prescription and non-prescription medication and illicit drugs with the service user, and carer if appropriate. Discuss their possible interference with the therapeutic effects of prescribed medication and psychological treatments. \n\n'As required' (p.r.n.) prescriptions of antipsychotic medication should be made as described in recommendation 1.3.6.3. Review clinical indications, frequency of administration, therapeutic benefits and side effects each week or as appropriate. Check whether 'p.r.n.' prescriptions have led to a dosage above the maximum specified in the BNF or SPC. \n\nDo not use a loading dose of antipsychotic medication (often referred to as 'rapid neuroleptisation'). \n\nDo not initiate regular combined antipsychotic medication, except for short periods (for example, when changing medication). \n\nIf prescribing chlorpromazine, warn of its potential to cause skin photosensitivity. Advise using sunscreen if necessary. \n\n## How to deliver psychological interventions\n\nCBT should be delivered on a one-to-one basis over at least 16 planned sessions and:\n\nfollow a treatment manual (with evidence of efficacy from a clinical trial, if possible) so that:\n\n\n\npeople can establish links between their thoughts, feelings or actions and their current or past symptoms, and/or functioning\n\nthe re-evaluation of people's perceptions, beliefs or reasoning relates to the target symptoms\n\n\n\nalso include at least one of the following components:\n\n\n\npeople monitoring their own thoughts, feelings or behaviours with respect to their symptoms or recurrence of symptoms\n\npromoting alternative ways of coping with the target symptom\n\nreducing distress\n\nimproving functioning. \n\n\n\nFamily intervention should:\n\ninclude the person with psychosis or schizophrenia if practical\n\nbe carried out for between 3\xa0months and 1\xa0year\n\ninclude at least 10 planned sessions\n\ntake account of the whole family's preference for either single-family intervention or multi-family group intervention\n\ntake account of the relationship between the main carer and the person with psychosis or schizophrenia\n\nhave a specific supportive, educational or treatment function and include negotiated problem solving or crisis management work. \n\n## Monitoring and reviewing psychological interventions\n\nWhen providing psychological interventions, routinely and systematically monitor a range of outcomes across relevant areas, including service user satisfaction and, if appropriate, carer satisfaction. \n\nHealthcare teams working with people with psychosis or schizophrenia should identify a lead healthcare professional within the team whose responsibility is to monitor and review:\n\naccess to and engagement with psychological interventions\n\ndecisions to offer psychological interventions and equality of access across different ethnic groups. \n\n## Competencies for delivering psychological interventions\n\nHealthcare professionals providing psychological interventions should:\n\nhave an appropriate level of competence in delivering the intervention to people with psychosis or schizophrenia\n\nbe regularly supervised during psychological therapy by a competent therapist and supervisor. \n\nTrusts should provide access to training that equips healthcare professionals with the competencies required to deliver the psychological therapy interventions recommended in this guideline. \n\n# Subsequent acute episodes of psychosis or schizophrenia and referral in crisis\n\n## Service-level interventions\n\nOffer crisis resolution and home treatment teams as a first-line service to support people with psychosis or schizophrenia during an acute episode in the community if the severity of the episode, or the level of risk to self or others, exceeds the capacity of the early intervention in psychosis services or other community teams to effectively manage it. \n\nCrisis resolution and home treatment teams should be the single point of entry to all other acute services in the community and in hospitals. \n\nConsider acute community treatment within crisis resolution and home treatment teams before admission to an inpatient unit and as a means to enable timely discharge from inpatient units. Crisis houses or acute day facilities may be considered in addition to crisis resolution and home treatment teams depending on the person's preference and need. \n\nIf a person with psychosis or schizophrenia needs hospital care, think about the impact on the person, their carers and other family members, especially if the inpatient unit is a long way from where they live. If hospital admission is unavoidable, ensure that the setting is suitable for the person's age, gender and level of vulnerability, support their carers and follow the recommendations in the NICE guideline on service user experience in adult mental health. \n\n## Treatment options\n\nFor people with an acute exacerbation or recurrence of psychosis or schizophrenia, offer:\n\noral antipsychotic medication (see sections\xa01.3.5 and 1.3.6) in conjunction with\n\npsychological interventions (family intervention and individual CBT, delivered as described in section 1.3.7). \n\n## Pharmacological interventions\n\nFor people with an acute exacerbation or recurrence of psychosis or schizophrenia, offer oral antipsychotic medication or review existing medication. The choice of drug should be influenced by the same criteria recommended for starting treatment (see sections\xa01.3.5 and 1.3.6). Take into account the clinical response and side effects of the service user's current and previous medication. [2009; amended 2014]\n\n## Psychological and psychosocial interventions\n\nOffer CBT to all people with psychosis or schizophrenia (delivered as described in recommendation 1.3.7.1). This can be started either during the acute phase or later, including in inpatient settings. \n\nOffer family intervention to all families of people with psychosis or schizophrenia who live with or are in close contact with the service user (delivered as described in recommendation 1.3.7.2). This can be started either during the acute phase or later, including in inpatient settings. \n\nConsider offering arts therapies to all people with psychosis or schizophrenia, particularly for the alleviation of negative symptoms. This can be started either during the acute phase or later, including in inpatient settings. \n\nArts therapies should be provided by a Health and Care Professions Council registered arts therapist with previous experience of working with people with psychosis or schizophrenia. The intervention should be provided in groups unless difficulties with acceptability and access and engagement indicate otherwise. Arts therapies should combine psychotherapeutic techniques with activity aimed at promoting creative expression, which is often unstructured and led by the service user. Aims of arts therapies should include:\n\nenabling people with psychosis or schizophrenia to experience themselves differently and to develop new ways of relating to others\n\nhelping people to express themselves and to organise their experience into a satisfying aesthetic form\n\nhelping people to accept and understand feelings that may have emerged during the creative process (including, in some cases, how they came to have these feelings) at a pace suited to the person. \n\nWhen psychological treatments, including arts therapies, are started in the acute phase (including in inpatient settings), the full course should be continued after discharge without unnecessary interruption. \n\nDo not routinely offer counselling and supportive psychotherapy (as specific interventions) to people with psychosis or schizophrenia. However, take service user preferences into account, especially if other more efficacious psychological treatments, such as CBT, family intervention and arts therapies, are not available locally. \n\nDo not offer adherence therapy (as a specific intervention) to people with psychosis or schizophrenia. \n\nDo not routinely offer social skills training (as a specific intervention) to people with psychosis or schizophrenia. \n\n## Behaviour that challenges\n\nOccasionally people with psychosis or schizophrenia pose an immediate risk to themselves or others during an acute episode and may need rapid tranquillisation. The management of immediate risk should follow the relevant NICE guidelines (see recommendations 1.4.5.2 and 1.4.5.5). \n\nFollow the recommendations in the NICE guideline on violence and aggression when facing imminent violence or when considering rapid tranquillisation. \n\nAfter rapid tranquillisation, offer the person with psychosis or schizophrenia the opportunity to discuss their experiences. Provide them with a clear explanation of the decision to use urgent sedation. Record this in their notes. \n\nEnsure that the person with psychosis or schizophrenia has the opportunity to write an account of their experience of rapid tranquillisation in their notes. \n\nFollow the recommendations in the NICE guideline on self-harm when managing acts of self-harm in people with psychosis or schizophrenia. \n\n## Early post-acute period\n\nAfter each acute episode, encourage people with psychosis or schizophrenia to write an account of their illness in their notes. \n\nHealthcare professionals may consider using psychoanalytic and psychodynamic principles to help them understand the experiences of people with psychosis or schizophrenia and their interpersonal relationships. \n\nInform the service user that there is a high risk of relapse if they stop medication in the next 1 to 2\xa0years. \n\nIf withdrawing antipsychotic medication, undertake gradually and monitor regularly for signs and symptoms of relapse. \n\nAfter withdrawal from antipsychotic medication, continue monitoring for signs and symptoms of relapse for at least 2\xa0years. \n\n# Promoting recovery and possible future care\n\n## General principles\n\nContinue treatment and care in early intervention in psychosis services or refer the person to a specialist integrated community-based team. This team should:\n\noffer the full range of psychological, pharmacological, social and occupational interventions recommended in this guideline\n\nbe competent to provide all interventions offered\n\nplace emphasis on engagement rather than risk management\n\nprovide treatment and care in the least restrictive and stigmatising environment possible and in an atmosphere of hope and optimism in line with the NICE guideline on service user experience in adult mental health. \n\nConsider intensive case management for people with psychosis or schizophrenia who are likely to disengage from treatment or services. \n\nReview antipsychotic medication annually, including observed benefits and any side effects. \n\n## Return to primary care\n\nOffer people with psychosis or schizophrenia whose symptoms have responded effectively to treatment and remain stable the option to return to primary care for further management. If a service user wishes to do this, record this in their notes and coordinate transfer of responsibilities through the care programme approach. \n\n## Primary care\n\nDevelop and use practice case registers to monitor the physical and mental health of people with psychosis or schizophrenia in primary care. \n\nGPs and other primary healthcare professionals should monitor the physical health of people with psychosis or schizophrenia when responsibility for monitoring is transferred from secondary care, and then at least annually. The health check should be comprehensive, focusing on physical health problems that are common in people with psychosis and schizophrenia. Include all the checks in recommendation 1.3.6.1 and refer to relevant NICE guidance on monitoring for cardiovascular disease, diabetes, obesity and respiratory disease. A copy of the results should be sent to the care coordinator and psychiatrist, and put in the secondary care notes. \n\nIdentify people with psychosis or schizophrenia who have high blood pressure, have abnormal lipid levels, are obese or at risk of obesity, have diabetes or are at risk of diabetes (as indicated by abnormal blood glucose levels), or are physically inactive, at the earliest opportunity following relevant NICE guidelines on cardiovascular disease: risk assessment and reduction, including lipid modification, preventing type 2 diabetes, obesity, hypertension, prevention of cardiovascular disease and physical activity. \n\nTreat people with psychosis or schizophrenia who have diabetes and/or cardiovascular disease in primary care according to the appropriate NICE guidance (for example, see the NICE guidelines on lipid modification, type 1 diabetes and type 2 diabetes). \n\nHealthcare professionals in secondary care should ensure, as part of the care programme approach, that people with psychosis or schizophrenia receive physical healthcare from primary care as described in recommendations 1.5.3.1 to 1.5.3.4. \n\nWhen a person with an established diagnosis of psychosis or schizophrenia presents with a suspected relapse (for example, with increased psychotic symptoms or a significant increase in the use of alcohol or other substances), primary healthcare professionals should refer to the crisis section of the care plan. Consider referral to the key clinician or care coordinator identified in the crisis plan. \n\nFor a person with psychosis or schizophrenia being cared for in primary care, consider referral to secondary care again if there is:\n\npoor response to treatment\n\nnon-adherence to medication\n\nintolerable side effects from medication\n\ncomorbid substance misuse\n\nrisk to self or others. \n\nWhen re-referring people with psychosis or schizophrenia to mental health services, take account of service user and carer requests, especially for:\n\nreview of the side effects of existing treatments\n\npsychological treatments or other interventions. \n\nWhen a person with psychosis or schizophrenia is planning to move to the catchment area of a different NHS trust, a meeting should be arranged between the services involved and the service user to agree a transition plan before transfer. The person's current care plan should be sent to the new secondary care and primary care providers. \n\n## Psychological interventions\n\nOffer CBT to assist in promoting recovery in people with persisting positive and negative symptoms and for people in remission. Deliver CBT as described in recommendation 1.3.7.1. \n\nOffer family intervention to families of people with psychosis or schizophrenia who live with or are in close contact with the service user. Deliver family intervention as described in recommendation 1.3.7.2. \n\nFamily intervention may be particularly useful for families of people with psychosis or schizophrenia who have:\n\nrecently relapsed or are at risk of relapse\n\npersisting symptoms. \n\nConsider offering arts therapies to assist in promoting recovery, particularly in people with negative symptoms. \n\n## Pharmacological interventions\n\nThe choice of drug should be influenced by the same criteria recommended for starting treatment (see sections 1.3.5 and 1.3.6). \n\nDo not use targeted, intermittent dosage maintenance strategies (use of antipsychotic medication only during periods of incipient relapse or symptom exacerbation) routinely. However, consider them for people with psychosis or schizophrenia who are unwilling to accept a continuous maintenance regimen or if there is another contraindication to maintenance therapy, such as side-effect sensitivity. \n\nConsider offering depot/long-acting injectable antipsychotic medication to people with psychosis or schizophrenia:\n\nwho would prefer such treatment after an acute episode\n\nwhere avoiding covert non-adherence (either intentional or unintentional) to antipsychotic medication is a clinical priority within the treatment plan. \n\n## Using depot/long-acting injectable antipsychotic medication\n\nWhen initiating depot/long-acting injectable antipsychotic medication:\n\ntake into account the service user's preferences and attitudes towards the mode of administration (regular intramuscular injections) and organisational procedures (for example, home visits and location of clinics)\n\ntake into account the same criteria recommended for the use of oral antipsychotic medication (see sections 1.3.5 and 1.3.6), particularly in relation to the risks and benefits of the drug regimen\n\nprescribe according to the procedures set out in the BNF or SPC. \n\n## Interventions for people whose illness has not responded adequately to treatment\n\nFor people with schizophrenia whose illness has not responded adequately to pharmacological or psychological treatment:\n\nReview the diagnosis.\n\nEstablish that there has been adherence to antipsychotic medication, prescribed at an adequate dose and for the correct duration.\n\nReview engagement with and use of psychological treatments and ensure that these have been offered according to this guideline. If family intervention has been undertaken suggest CBT; if CBT has been undertaken suggest family intervention for people in close contact with their families.\n\nConsider other causes of non-response, such as comorbid substance misuse (including alcohol), the concurrent use of other prescribed medication or physical illness. \n\nOffer clozapine to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least 2 different antipsychotic drugs. At least 1 of the drugs should be a non-clozapine second-generation antipsychotic. \n\nFor people with schizophrenia whose illness has not responded adequately to clozapine at an optimised dose, healthcare professionals should consider recommendation 1.5.7.1 (including measuring therapeutic drug levels) before adding a second antipsychotic to augment treatment with clozapine. An adequate trial of such an augmentation may need to be up to 8 to 10\xa0weeks. Choose a drug that does not compound the common side effects of clozapine. \n\n## Employment, education and occupational activities\n\nOffer supported employment programmes to people with psychosis or schizophrenia who wish to find or return to work. Consider other occupational or educational activities, including pre-vocational training, for people who are unable to work or unsuccessful in finding employment. \n\nMental health services should work in partnership with local stakeholders, including those representing black, Asian and minority ethnic groups, to enable people with mental health problems, including psychosis or schizophrenia, to stay in work or education and to access new employment (including self-employment), volunteering and educational opportunities. [2009; amended 2014]\n\nRoutinely record the daytime activities of people with psychosis or schizophrenia in their care plans, including occupational outcomes. ", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research are detailed in the full guideline.\n\n# Peer support interventions\n\nWhat is the clinical and cost effectiveness of peer support interventions in people with psychosis and schizophrenia?\n\n## Why this is important\n\nService users have supported the development of peer support interventions, which have recently proliferated in the UK, but current evidence for these interventions in people with psychotic disorders is not strong and the studies are mainly of very low quality. Moreover the content of the programmes has varied considerably, some using structured interventions, others providing more informal support. There is therefore an urgent need for high-quality evidence in this area.\n\nThe programme of research would be in several stages. First, there should be development work to establish what specifically service users want from peer support workers, as opposed to what they want from professionals, and what the conditions are for optimal delivery of the intervention. This development work should be co-produced by exploring the views of service users, experienced peer support workers and developers of peer support interventions, and suitable outcome measures should be identified reflecting the aims of peer support. Second, the intervention, delivered as far as possible under the optimal conditions, should be tested in a high-quality trial. Further research should test structured and manualised formats versus unstructured formats (in which service user and peer decide together what to cover in the session). Benefits and adverse effects experienced by peer support workers should also be measured.\n\n# People who choose not to take antipsychotic medication\n\nWhat is the clinical and cost effectiveness of psychological intervention alone, compared with treatment as usual, in people with psychosis or schizophrenia who choose not to take antipsychotic medication?\n\n## Why this is important\n\nThe development of alternative treatment strategies is important for the high proportion of people with psychosis and schizophrenia who choose not to take antipsychotic medication, or discontinue it because of adverse effects or lack of efficacy. There is evidence that psychological interventions (CBT and family intervention) as an adjunct to antipsychotic medication are effective in the treatment of psychosis and schizophrenia and are cost saving. However, there is little evidence for family intervention or CBT alone, without antipsychotic medication.\n\nThe programme of research should compare the clinical and cost effectiveness of psychological intervention alone (CBT and/or family intervention) with treatment as usual for people with psychosis or schizophrenia who choose not to take antipsychotic medication, using an adequately powered study with a randomised controlled design. Key outcomes should include symptoms, relapse rates, quality of life, treatment acceptability, social functioning and the cost effectiveness of the interventions.\n\n# The physical health benefits of discontinuing antipsychotic medication\n\nWhat are the short- and long-term benefits to physical health of guided medication discontinuation and/or reduction in first episode psychosis and can this be achieved without major risks?\n\n## Why this is important\n\nThere is growing concern about the long-term health risks, increased mortality and cortical grey matter loss linked to cumulative neuroleptic exposure in people with psychosis. The majority of young adults discontinue their medication in an unplanned way because of these risks. A Dutch moderately-sized open trial has reported successful discontinuation of medication in 20% of people without serious relapse; at 7-year follow-up there was continuous benefit for guided reduction in terms of side effects, functioning and employment, with no long-term risks. If replicated, this would mark a significant breakthrough in reducing the long-term physical health risks associated with antipsychotic treatment and improving outcomes.\n\nThe programme of research should use an adequately powered, multicentre, double-blind, randomised controlled design to test the physical health benefits, risks and costs of discontinuing or reducing antipsychotic medication among young adults with first episode psychosis who have achieved remission. The primary outcomes should be quality of life and metabolic disorder, including weight gain; secondary outcomes should include side effects, serious relapse, acceptability and user preference.\n\n# Maintaining the benefits of early intervention in psychosis services after discharge\n\nHow can the benefits of early intervention in psychosis services be maintained once service users are discharged after 3\xa0years?\n\n## Why this is important\n\nEarly intervention in psychosis services deliver evidence-based interventions in a positive, youth-friendly setting, improve outcomes, are cost effective and have high service user acceptability and engagement. Once people are transferred to primary care or community mental health services these gains are diminished. The guideline recommends that trusts consider extending these services. However, the extent to which gains would be maintained and who would benefit most is not known. The successful element of early intervention in psychosis services might be incorporated into mainstream services for psychosis, but how this would function, and its cost effectiveness, needs to be determined.\n\nThe suggested programme of research should use an adequately powered, multi-centre randomised trial comparing extending early intervention in psychosis services (for example, for 2\xa0years) versus providing augmented (step-down) care in community mental health services versus treatment as usual to determine whether the gains of early intervention can be maintained and which service users would benefit most under each condition. The primary outcome should be treatment or service engagement and secondary outcomes should include relapse, readmission, functioning and user preference.\n\n# Interventions for PTSD symptoms in people with psychosis and schizophrenia\n\nWhat is the benefit of a CBT-based trauma reprocessing intervention on PTSD symptoms in people with psychosis and schizophrenia?\n\n## Why this is important\n\nPTSD symptoms have been documented in approximately one-third of people with psychosis and schizophrenia. The absence of PTSD symptoms in this context predicts better mental health outcomes, lower service use and improved life satisfaction. Two-thirds of the traumatic intrusions, observed in first episode and established psychosis, relate to symptoms of psychosis and its treatment (including detention). One study has demonstrated proof-of-principle in first episode psychosis for trauma reprocessing, focusing on psychosis-related intrusions. Replication of the study will fill a major gap in treatment for this population and may have other benefits on psychotic symptoms and service use.\n\nThe suggested programme of research would use an adequately powered, multi-centre randomised trial to test whether a CBT-based trauma reprocessing intervention can reduce PTSD symptoms and related distress in people with psychosis and schizophrenia. The trial should be targeted at those with high levels of PTSD symptoms, particularly traumatic intrusions, following first episode psychosis. The follow-up should be up to 2\xa0years and the intervention should include 'booster' elements, extra sessions of CBT-based trauma reprocessing interventions, and a health economic evaluation."}	https://www.nice.org.uk/guidance/cg178	This guideline covers recognising and managing psychosis and schizophrenia in adults. It aims to improve care through early recognition and treatment, and by focusing on long-term recovery. It also recommends checking for coexisting health problems and providing support for family members and carers.
f4a15c706e7d99c8948d873d7370669b77a1ac6e	nice	Domestic violence and abuse: multi-agency working	Domestic violence and abuse: multi-agency working This guideline covers planning and delivering multi-agency services for domestic violence and abuse. It aims to help identify, prevent and reduce domestic violence and abuse among women and men in heterosexual or same-sex relationships, and among young people. # Introduction # What is this guidance about? This guidance aims to help identify, prevent and reduce domestic violence and abuse. Violence and abuse perpetrated on children by adults ('child abuse') is not dealt with in this guidance, but it does include support for children who are affected by domestic violence and abuse. Domestic violence and abuse is a complex issue that needs sensitive handling by a range of health and social care professionals. The cost, in both human and economic terms, is so significant that even marginally effective interventions are cost effective. Women and men can experience this type of violence in heterosexual and same-sex relationships. The prevalence of physical assaults from a partner or adult family member is higher among heterosexual women than among men. Moreover, heterosexual women experience more repeated physical violence, more severe violence, much more sexual violence, more coercive control, more injuries and more fear of their partner. The recommendations cover the broad spectrum of domestic violence and abuse, including violence perpetrated on men, on those in same-sex relationships and on young people. Working in a multi-agency partnership is the most effective way to approach the issue at both an operational and strategic level. Initial and ongoing training and organisational support is also needed. There was not sufficient evidence to make recommendations on primary prevention programmes. Most of the evidence about this relates to interventions in educational settings and these are outside the scope of this guidance unless they are delivered by a health or social care professional. Prevention is an important area for future research (see Recommendations for research). The guidance is for health and social care commissioners, specialist domestic violence and abuse staff and others whose work may bring them into contact with people who experience or perpetrate domestic violence and abuse. (For details, see Who should take action?) In addition it may be of interest to members of the public. See About this guidance for details of how the guidance was developed and its current status.# Recommendations # Recommendation 1 Plan services based on an assessment of need and service mapping Strategic partnerships (see Who should take action?) should assess the need for domestic violence and abuse services as part of the joint strategic needs assessment. Consult with women, men and young people who have experienced domestic violence and abuse as part of this assessment. Commissioners of domestic violence and abuse services and related services should be aware of the importance of consulting communities that are rarely heard on this matter. Local commissioners of domestic violence and abuse services and related services should undertake a comprehensive mapping exercise to identify all local services and partnerships that work in domestic violence and abuse. (For example, this could include: ambulance services, housing, the police, health, criminal justice, education, probation, safeguarding and social care services. It could also include other specialist statutory, community and voluntary services, such as drug and alcohol services.) Map services against the Home Office-endorsed Coordinated Community Response Model and identify any gaps. Local commissioners (see above) should use the results of the needs assessment and mapping exercise to inform commissioning. They should develop referral pathways that aim to meet the health and social care needs of all those affected by domestic violence and abuse. This includes people with protected characteristics and those who face particular barriers trying to access domestic violence and abuse support services (see recommendations 4 and 9). Regional and national commissioners of domestic violence and abuse services and related services should work with local commissioners to ensure service support extends across local authority boundaries, where necessary, for services such as prisons that cover broader geographical areas. Regional and national commissioners (see above) should work with local commissioners to provide specialist services across local authority boundaries where there is not enough local need to justify setting them up within a particular local authority area. (This could include services to help prevent forced marriages, to help men, and lesbian, gay, bisexual or trans people affected by domestic violence, or for people subjected to 'honour' violence or stalking.) Strategic partnerships should use the results of mapping in the joint strategic needs assessment and other strategic planning tools. They should also make the results widely available to all relevant services and the general public – for example, by publishing a directory of local and national services. # Recommendation 2 Participate in a local strategic multi-agency partnership to prevent domestic violence and abuse Local authorities, health services and their strategic partners (including the voluntary and community sectors) should: Ensure senior officers from the following services participate in a local strategic partnership to prevent domestic violence and abuse, along with representatives of frontline practitioners and service users or their representatives: health services and the local authority (including the chairs of local safeguarding boards for adults and children) public health sexual violence services housing schools and colleges police and crime commissioners community safety partnerships criminal justice agencies (including probation) the Children and Family Court Advisory and Support Service specialist voluntary, community and private sector organisations. Ensure health and social care practitioners are actively involved in both operational and strategic multi-agency initiatives (for example, multi-agency risk assessment conferences). Regularly review membership of the partnership to ensure it is relevant and inclusive. # Recommendation 3 Develop an integrated commissioning strategy Local strategic partnerships on domestic violence and abuse, commissioners, clinical commissioning groups and local authorities should: Establish an integrated commissioning strategy. This should include input from domestic violence and abuse services, other relevant services and from people who have experienced domestic violence and abuse. The strategy should: meet the health and social care needs of those who experience domestic violence and abuse (including young people) meet the needs of children and young people who are affected by domestic violence and abuse address the perpetrator's behaviour and health needs meet the needs of all local communities. Ensure the strategy is based on the following principles: aligned or, where possible, integrated budgets and other resources -ne partner takes the strategic lead and oversees delivery on behalf of the local strategic partnership services address all levels of risk and all degrees of severity of domestic violence and abuse services are based on evidence-based commissioning principles and the local needs assessment and mapping exercise (see recommendation 1). agencies work together to deliver services. Monitor implementation of the strategy and evaluate its effectiveness for different groups. Include both quantitative data on outcomes and qualitative data (such as feedback from service users). # Recommendation 4 Commission integrated care pathways Commissioners of health and social care services should: Ensure there are integrated care pathways for identifying, referring (either externally or internally) and providing interventions to support people who experience domestic violence and abuse, and to manage those who perpetrate it. Ensure people who misuse alcohol or drugs or who have mental health problems and are affected by domestic violence and abuse are also referred to the relevant health, social care and domestic violence and abuse services. Ensure all service pathways have consistent, robust mechanisms for assessing the risks facing adults who experience domestic violence and abuse and any children who may be affected. This includes ensuring those affected by, and the perpetrators of, the violence and abuse are kept separate from each other when receiving support. # Recommendation 5 Create an environment for disclosing domestic violence and abuse Health and social care service managers and managers of specialist domestic violence and abuse services and related services (see Who should take action?) should: Clearly display information in waiting areas and other suitable places about the support on offer for those affected by domestic violence and abuse. This includes contact details of relevant local and national helplines. It could also include information for groups who may find it more difficult to disclose that they are experiencing violence and abuse (see recommendation 9). Ensure the information on where to get support is available in a range of formats and locally used languages. The former could include braille and audio versions and the use of large font sizes. There may also be more discreet ways of conveying information, for example, by providing pens or key rings with a helpline number. Take steps to ensure people who use the service are given maximum privacy, for example, by arranging the reception area so that people cannot be overheard. Establish a referral pathway to specialist domestic violence and abuse agencies (or the equivalent in a health or social care setting). This should include age-appropriate options and options for groups that may have difficulties accessing services, or are reluctant to do so (see recommendation 9). Ensure frontline staff know about the services, policies and procedures of relevant local agencies in relation to domestic violence and abuse. Provide ongoing training and regular supervision for staff who may be asking people about domestic violence and abuse. This should aim to sustain and monitor good practice. Establish clear policies and procedures for staff who have been affected by domestic violence and abuse. Ensure staff have the opportunity to address issues relating to their own personal experiences, as well as those that may arise after contact with patients or service users. # Recommendation 6 Ensure trained staff ask people about domestic violence and abuse Health and social care service managers and professionals should: Ensure frontline staff in all services are trained to recognise the indicators of domestic violence and abuse and can ask relevant questions to help people disclose their past or current experiences of such violence or abuse. The enquiry should be made in private on a one-to-one basis in an environment where the person feels safe, and in a kind, sensitive manner. Ensure people who may be experiencing domestic violence and abuse can be seen on their own (a person may have multiple abusers and friends or family members may be colluding in the abuse). Ensure trained staff in antenatal, postnatal, reproductive care, sexual health, alcohol or drug misuse, mental health, children's and vulnerable adults' services ask service users whether they have experienced domestic violence and abuse. This should be a routine part of good clinical practice, even where there are no indicators of such violence and abuse. Ensure staff know, or have access to, information about the services, policies and procedures of all relevant local agencies for people who experience or perpetrate domestic violence and abuse. Ensure all services have formal referral pathways in place for domestic violence and abuse. These should support: people who disclose that they have been subjected to it; the perpetrators; and children who have been affected by it (see recommendation 4). # Recommendation 7 Adopt clear protocols and methods for information sharing Commissioners and service providers involved with those who experience or perpetrate domestic violence and abuse (see Who should take action?) should: Take note of the Data Protection Act and professional guidelines that address confidentiality and information sharing in health services. This includes guidelines on how to apply the Caldicott guardian principles to domestic violence, see Caldicott guidelines. It also includes guidelines on: seeking consent from people to share their information, letting them know when, and with whom, information is being shared, and knowing when information can be shared without consent. Develop or adapt clear protocols and methods for sharing information, both within and between agencies, about people at risk of, experiencing, or perpetrating domestic violence and abuse. Clearly define the range of information that can be shared and with whom (this includes sharing information with health or children's services on a perpetrator's criminal history.) Ensure protocols and methods encourage staff to: Remember their professional duty of confidentiality. Determine when the duty of confidentiality might have to be breached: information should be shared only with the person's consent unless they are at serious risk, and within agreed multi-agency information-sharing protocols. Note that information sharing without consent risks losing trust and may endanger a person's safety. Weigh the risks of sharing information or not by determining whether you are sharing with the aim of protecting someone. It is acceptable to share information if that is the case and you are not sharing data just to alert another agency to a problem. Distinguish between anonymised data and personal data: the former does not need individual consent, but there should be a protocol in place for sharing such data. Distinguish between situations that involve only adults and those where children are involved: information sharing without consent, or where consent is not given, is necessary when children's safety is at risk. Ensure information-sharing methods are secure and will not put anyone involved at risk. Ensure the protocols and methods are regularly monitored. Identify and train key contacts responsible for advising on the safe sharing of domestic violence and abuse-related information. Ensure all staff who need to share information are trained to use the protocols so that they do not decline to cooperate because of being overcautious or for fear of reprisal. Ensure any information shared is acknowledged by a person, rather than by an automatically generated response. # Recommendation 8 Tailor support to meet people's needs Managers and staff working in domestic violence and abuse services and staff in all health and social care settings (see Who should take action?) should: Prioritise people's safety. Refer people from general services to domestic violence and abuse (and other specialist) services if they need additional support. Regularly assess what type of service someone needs – immediately and in the longer term. Think about referring someone to specialist domestic violence and abuse services if they need immediate support. This includes advocacy, floating support and outreach support and refuges. It also includes housing workers, independent domestic violence advisers or a multi-agency risk assessment conference for high-risk clients. Think about referring someone to floating or outreach advocacy support or to a skill-building programme if they need longer-term support. Also explore whether they would like to be referred to a local support group. If there are indications that someone has alcohol or drug misuse or mental health problems, also refer them to the relevant alcohol or drug misuse or mental health services (see recommendation 13). # Recommendation 9 Help people who find it difficult to access services Commissioners and service providers in the statutory, private, voluntary and community sectors (see Who should take action?) should: Help people who may find domestic violence and abuse services inaccessible or difficult to use. This includes: people from black and minority ethnic groups or with disabilities, older people, trans people and lesbian, gay or bisexual people. It also includes people with no recourse to public funds. Identify any barriers people from these groups may face when trying to get help. Do this in consultation with local groups that have an equality remit (including organisations representing the interests of specific groups), and in line with statutory requirements. Introduce a strategy to overcome these barriers. Train staff in direct contact with people affected by domestic violence and abuse to understand equality and diversity issues. This includes those working with people who perpetrate this type of violence and abuse. Specifically: Ensure assumptions about people's beliefs and values (for example, in relation to 'honour') do not stop staff identifying and responding to domestic violence and abuse. Ensure staff know where to seek specialist advice, for example, for people with no recourse to public funds or for people with HIV. Ensure staff are aware that lesbian, gay, bisexual and trans people are also at risk of forced marriage and that 'honour'-based violence might be triggered by someone's gender identity or sexuality. Ensure interpreting services are confidential (often a concern in small communities where a minority language is spoken). Ensure professional interpreters are used. Do not use family members or friends. In some areas this will mean using a national interpreting service or one based in another locality. # Recommendation 10 Identify and, where necessary, refer children and young people affected by domestic violence and abuse Providers of services where children and young people affected by domestic violence and abuse may be identified and those responsible for safeguarding children (see Who should take action?) should: Ensure staff can recognise the indicators of domestic violence and abuse and understand how it affects children and young people. Ensure staff are trained and confident to discuss domestic violence and abuse with children and young people who are affected by or experiencing it directly. The violence and abuse may be happening in their own intimate relationships or among adults they know or live with. Put clear information-sharing protocols in place to ensure staff gather and share information and have a clear picture of the child or young person's circumstances, risks and needs. Develop or adapt and implement clear referral pathways to local services that can support children and young people affected by domestic violence and abuse. Ensure staff know how to refer children and young people to child protection services. They should also know how to contact safeguarding leads, senior clinicians or managers to discuss whether or not a referral would be appropriate. Ensure staff know about the services, policies and procedures of all relevant local agencies for children and young people in relation to domestic violence and abuse. Involve children and young people in developing and evaluating local policies and services dealing with domestic violence and abuse. Monitor these policies and services with regard to children's and young people's needs. # Recommendation 11 Provide specialist domestic violence and abuse services for children and young people Those responsible for safeguarding children, and commissioners and providers of specialist services for children and young people affected by domestic violence and abuse (see Who should take action?) should: Address the emotional, psychological and physical harms arising from a child or young person being affected by domestic violence and abuse, as well as their safety. This includes the wider educational, behavioural and social effects. Provide a coordinated package of care and support that takes individual preferences and needs into account. Ensure the support matches the child's developmental stage (for example, infant, pre-adolescent or adolescent). Interventions should be timely and should continue over a long enough period to achieve lasting effects. Recognise that long-term interventions are more effective. Provide interventions that aim to strengthen the relationship between the child or young person and their non-abusive parent or carer. This may involve individual or group sessions, or both. The sessions should include advocacy, therapy and other support that addresses the impact of domestic violence and abuse on parenting. Sessions should be delivered to children and their non-abusive parent or carer in parallel, or together. Provide support and services for children and young people experiencing domestic violence and abuse in their own intimate relationships. # Recommendation 12 Provide specialist advice, advocacy and support as part of a comprehensive referral pathway Health and social care commissioners, health and wellbeing boards and practitioners in specialist domestic and sexual violence services (see Who should take action?) should: Provide all those currently (or recently) affected by domestic violence and abuse with advocacy and advice services tailored to their level of risk and specific needs. This includes providing support in different languages, as necessary. Ensure practitioners are aware of how discrimination, prejudice and other issues, such as insecure immigration status, may have affected the risk that people using their services face. Ensure specialist support services meet national standards of good practice. Ensure specialist advice, advocacy and support forms part of a comprehensive referral pathway (see recommendation 4). Ensure the support is offered (although not necessarily delivered) in settings where people may be identified or may disclose that domestic violence and abuse is occurring. Examples include: accident and emergency departments, general practices, refuges, sexual health clinics and maternity, mental health, rape crisis, sexual violence, alcohol or drug misuse and abortion services. # Recommendation 13 Provide people who experience domestic violence and abuse and have a mental health condition with evidence-based treatment for that condition Health, police and crime commissioners, health and social care providers and practitioners in primary, mental health and related care services (see Who should take action?) should: Where people who experience domestic violence and abuse have a mental health condition (either pre-existing or as a consequence of the violence and abuse), provide evidence-based treatment for the condition. Ensure mental health interventions are provided by professionals trained in how to address domestic violence and abuse. Interventions may include psychological therapy (for example, trauma-focused cognitive behavioural therapy), medication and support, in accordance with national guidelines. Ensure any treatment programme includes an ongoing assessment of the risk of further domestic violence and abuse, collaborative safety planning and the offer of a referral to specialist domestic violence and abuse support services. It must also take into account the person's preferences and whether the violence and abuse is ongoing or historic. # Recommendation 14 Commission and evaluate tailored interventions for people who perpetrate domestic violence and abuse Health and wellbeing boards and commissioners who commission perpetrator interventions should: Commission robust evaluations of the interventions to inform future commissioning. Identify, and link with, existing initiatives that work with people who perpetrate domestic violence and abuse. Commission tailored interventions for people who perpetrate domestic violence and abuse, in accordance with national standards and based on the local needs assessment (see recommendation 1). Ensure interventions primarily aim to increase the safety of the perpetrator's partner and children (if they have any). Ensure this is monitored and reported. In addition, staff should report on the perpetrators' attitudinal change, their understanding of violence and accountability, and their ability and willingness to seek help. Link perpetrator services with services providing specialist support for those experiencing domestic violence and abuse (including children and young people). For example, link ongoing risk assessments of the perpetrator with safety planning and support provided by specialist services. See also recommendations 2–4. # Recommendation 15 Provide specific training for health and social care professionals in how to respond to domestic violence and abuse Organisations responsible for training and registration standards and providers of health and social care training (see Who should take action?) should provide different levels of training for different groups of professionals, as follows. Training to provide a universal response should give staff a basic understanding of the dynamics of domestic violence and abuse and its links to mental health and alcohol and drug misuse, along with their legal duties. In addition, it should cover the concept of shame that is associated with 'honour'-based violence and an awareness of diversity and equality issues. It should also ensure staff know what to do next: Level 1 Staff should be trained to respond to a disclosure of domestic violence and abuse sensitively and in a way that ensures people's safety. They should also be able to direct people to specialist services. This level of training is for: physiotherapists, speech therapists, dentists, youth workers, care assistants, receptionists, interpreters and non-specialist voluntary and community sector workers. Level 2 Staff should be trained to ask about domestic violence and abuse in a way that makes it easier for people to disclose it. This involves an understanding of the epidemiology of domestic violence and abuse, how it affects people's lives and the role of professionals in intervening safely. Staff should also be able to respond with empathy and understanding, assess someone's immediate safety and offer referral to specialist services. Typically this level of training is for: nurses, accident and emergency doctors, adult social care staff, ambulance staff, children's centre staff, children and family social care staff, GPs, mental health professionals, midwives, health visitors, paediatricians, health and social care professionals in education (including school nurses), prison staff and alcohol and drug misuse workers. In some cases, it will also be relevant for youth workers. Training to provide a specialist response should equip staff with a more detailed understanding of domestic violence and abuse and more specialist skills: Level 3 Staff should be trained to provide an initial response that includes risk identification and assessment, safety planning and continued liaison with specialist support services. Typically this is for: child safeguarding social workers, safeguarding nurses, midwives and health visitors with additional domestic violence and abuse training, multi-agency risk assessment conference representatives and adult safeguarding staff. Level 4 Staff should be trained to give expert advice and support to people experiencing domestic violence and abuse. This is for specialists in domestic violence and abuse. For example, domestic violence advocates or support workers, independent domestic violence advisers or independent sexual violence advisers, refuge staff, domestic violence and abuse and sexual violence counsellors and therapists, and children's workers. Other training to raise awareness of, and address misconceptions about, domestic violence and abuse issues and the skills, specialist services and training needed to provide people with effective support. This is for: commissioners, managers and others in strategic roles within health and social care services. Organisations responsible for training and registration standards and providers of health and social care training should ensure: The higher levels of training include increasing amounts of face-to-face interaction, although level 1 training can be delivered mostly online or by distance learning. Face-to-face training covers the practicalities of enabling someone to disclose that they are affected by domestic violence and abuse and how to respond. # Recommendation 16 GP practices and other agencies should include training on, and a referral pathway for, domestic violence and abuse NHS England, commissioners and GPs should commission integrated training and referral pathways for domestic violence and abuse. This should include education for clinicians and administrative staff in GP practices on how to make it easier for people to disclose domestic violence and abuse. It should also include education for clinicians on how to provide immediate support after a disclosure and how to make referrals to specialist agencies. Managers of specialist domestic violence and abuse services, clinical commissioning groups and public health departments should work in partnership with voluntary and community agencies to develop training and referral pathways for domestic violence and abuse. # Recommendation 17 Pre-qualifying training and continuing professional development for health and social care professionals should include domestic violence and abuse Organisations responsible for training and registration standards and providers of health and social care training (see Who should take action?) should: Ensure training about domestic violence and abuse is part of the undergraduate or pre-qualifying curriculum, and part of the continuing professional development, for health and social care professionals who come into contact with service users. It should be delivered in partnership with local specialist domestic violence and abuse services and include face-to-face contact, even if it is mainly delivered online. Implement a rolling training programme that recognises the turnover of staff and the need for follow-up. The training strategy should: be clear about the level of competency needed for each role (see recommendation 15) refer to existing accredited materials from specialist organisations working in domestic violence and abuse, if they are suitable ensure the content on domestic violence and abuse is linked to child welfare, safeguarding and adult protection services, and vice versa follow the recommended content for each level (see recommendation 15). # Who should take action? # Introduction The guidance is for everyone working in health and social care whose work brings them into contact with people who experience or perpetrate domestic violence and abuse. This includes: people working in criminal justice settings and detention centres, health and social care commissioners, including clinical commissioning groups and local authorities, and staff working for specialist domestic violence and abuse services. The latter could be working in local authorities, the NHS and other organisations in the public, private, voluntary and community sectors. The guidance is also aimed at local strategic partnerships and health and wellbeing boards. In addition, it will be of interest to people affected by domestic violence and abuse, including those who perpetrate it, those who experience it, their families or carers and other members of the public. # Who should do what at a glance Who should take action Recommendation NHS England Organisations that coordinate or offer training, or that register and set standards for professionals Health services, local authorities and strategic partnerships (including health and wellbeing boards) Local safeguarding children boards and other local partnerships with a responsibility for safeguarding children Commissioners Heads and managers of health and social care services Service providers Health and social care staff # Who should take action in detail ## Recommendation 1 Local, regional and national commissioners of domestic violence and abuse services and related services; strategic partnerships, for example, health and wellbeing boards, local domestic violence partnerships; community safety partnerships ## Recommendation 2 Local authorities, health services and their strategic partners (including those in the voluntary and community sectors) ## Recommendation 3 Local strategic partnerships on domestic violence and abuse; commissioners, including clinical commissioning groups and local authorities ## Recommendation 4 Commissioners of health and social care services ## Recommendation 5 Health and social care service managers in the statutory, voluntary, community and private sectors; specialist domestic violence and abuse services and related services. The latter includes: criminal justice, early years and youth services, housing, the police, prison and probation services, schools and colleges, and services for older people ## Recommendation 6 Health and social care service managers and professionals ## Recommendation 7 Health, social care, education, criminal justice, probation and voluntary and community sector commissioners and service providers involved with those who experience or perpetrate domestic violence and abuse ## Recommendation 8 Managers of domestic violence and abuse services; staff in all health and social care settings, including the public, voluntary and community sectors, and those they work with. The latter includes: criminal justice, including prisons, early years and youth services, housing, the police, schools and colleges, and services for older people ## Recommendation 9 Health and social care commissioners and service providers in the public, voluntary and community sector; managers and commissioners of interpreting services ## Recommendation 10 Local safeguarding children boards and other local partnerships with a responsibility for safeguarding children; providers of services where children and young people who are affected by domestic violence and abuse may be identified in the public, community and voluntary sectors. The latter includes: accident and emergency departments, child and adolescent mental health services, dental services, GP practices, health visiting, maternity services, sexual health services and other health services; early years services, schools and colleges, school nursing services; social care; specialist paediatric services for child safeguarding and looked after children; alcohol and drug misuse services; youth services; youth justice services ## Recommendation 11 Local safeguarding children boards and other local partnerships with a responsibility for safeguarding children; commissioners and providers of specialist services for children and young people who are affected by domestic violence and abuse in the public, community and voluntary sectors. The latter includes: child and adolescent mental health, health visiting, sexual health, social care and specialist paediatric services for child safeguarding and looked after children, and youth services ## Recommendation 12 Health and social care commissioners (including clinical commissioning groups, local authority commissioners and police and crime commissioners); health and wellbeing boards; frontline practitioners in specialist domestic and sexual violence services (for example, domestic violence and abuse advisers, people working in refuges or outreach services) ## Recommendation 13 Clinical commissioning groups and specialist commissioners; police and crime commissioners; health and wellbeing boards; providers of primary care and mental health care services in the private, voluntary and community sectors. The latter includes: health and social care professionals working in alcohol and drug misuse services, detention centres and criminal justice settings ## Recommendation 14 Health and wellbeing boards; commissioners of tailored interventions for people who perpetrate domestic violence and abuse ## Recommendation 15 Royal colleges and professional organisations responsible for setting training and registration standards for clinical, social workers and social care staff; commissioners; Health Education England; heads of health, social care and related services; universities and other providers of health and social care training, including interpreting ## Recommendation 16 NHS England, commissioners and service managers working in specialist domestic violence and abuse services, GPs ## Recommendation 17 Royal colleges and professional organisations responsible for setting training and registration standards for relevant clinical, social workers and social care staff; heads of health, social care and related services; universities and other providers of health and social care training for professionals who come into contact with service users, including interpreters# Context # Introduction At least 1.2 million women and 784,000 men aged 16 to 59 in England and Wales experienced domestic abuse in 2010/11 – 7.4% of women and 4.8% of men. (Domestic violence and abuse here is defined as: physical abuse, threats, non-physical abuse, sexual assault or stalking perpetrated by a partner, ex-partner or family member.) At least 29.9% of women and 17.0% of men in England and Wales have, at some point, experienced it (Smith et al. 2012). These figures are likely to be an underestimate, because all types of domestic violence and abuse are under-reported in health and social research, to the police and other services. Both men and women may perpetrate or experience domestic violence and abuse. However, it is more commonly inflicted on women by men. This is particularly true for severe and repeated violence and sexual assault. Lesbian and bisexual women experience domestic violence and abuse at a similar rate to women in general (1 in 4), although a third of this is associated with male perpetrators (Hunt and Fish. 2008). Compared with 17% of men in general, 49% of gay and bisexual men have experienced at least 1 incident of domestic violence and abuse since the age of 16. This includes domestic violence and abuse within same-sex relationships (Stonewall Gay and Bisexual Men's Health Survey 2012). A focus on specific incidents and episodes is of limited value in understanding the experience of domestic abuse. # Associated risk factors The risk of experiencing domestic violence or abuse is increased if someone: is female is aged 16–24 (women) or 16–19 (men) (Smith et al. 2011) has a long-term illness or disability – this almost doubles the risk (Smith et al. 2011) has a mental health problem (Trevillion et al. 2012) is a woman who is separated (Smith et al. 2011) – there is an elevated risk of abuse around the time of separation (Richards 2004).The risk is also increased if a woman is pregnant or has recently given birth. Although pregnancy appears to offer protection for some women (Bowen et al. 2005) for others it increases the risk (Harrykissoon et al. 2002). In addition, there is a strong correlation between postnatal depression and domestic violence and abuse. The majority of trans people (80%) experience emotional, physical or sexual abuse from a partner or ex-partner (Roch et al. 2010). Just under 40% (38.4%) of bisexual, gay and lesbian people class themselves as having experienced domestic violence and abuse. However, many more respondents reported behaviours that could be classed as domestic violence and abuse (Donovan et al. 2006). The role played by alcohol or drug misuse in domestic violence and abuse is poorly understood. Research has indicated that 21% of people experiencing partner abuse in the past year thought the perpetrator was under the influence of alcohol and 8% under the influence of illicit drugs (Smith et al. 2012). People are thought to be at increased risk of substance dependency as a consequence of being the victim of domestic violence (Humphreys et. al. 2005). # Partner abuse among adults Partner abuse is the most prevalent form of domestic abuse. At least 26.6% of women and 14% of men have, at some point, experienced this since they were 16 (Smith et al. 2012). The prevalence is consistently higher among people in healthcare settings (Feder et al 2009). Women are more likely than men to experience repeated partner abuse, partner abuse over a longer period of time, violence and more severe abuse (Smith et al. 2010). Women's reports of partner abuse are also more likely to indicate that it is part of a system of fear and coercive control (Hester and Westmarland 2005; Hester 2013). Men are less likely to report abuse to the police, and more likely to say this is because they consider it too trivial or not worth reporting (Smith et al. 2010). Each year since 1995, approximately half of all women aged 16 or older murdered in England and Wales were killed by their partner or ex-partner. Around 12% of men murdered each year from 1995 were killed by their partner or ex-partner (Smith et al. 2012; Thompson 2010). # Partner abuse among young people Partner violence is also prevalent in young people's relationships. In the UK in 2009, 72% of girls and 51% of boys aged 13 to 16 reported experiencing emotional violence in an intimate partner relationship, 31% of girls and 16% of boys reported sexual violence, and 25% of girls and 18% of boys experienced physical violence (Meltzer et al. 2009). Some form of severe domestic violence and abuse inflicted on them by a partner (Barter et al. 2009) was reported by 1 in 6 girls. In line with research among adults, girls described more abuse, and more severe abuse, more direct intimidation and control, and more negative impacts. Young people in same sex relationships were at greater risk than those in heterosexual relationships. # Domestic violence and abuse between parents Domestic violence and abuse between parents is the most frequently reported form of trauma for children (Meltzer et al. 2009). In the UK, 24.8% of those aged 18 to 24 reported that they experienced domestic violence and abuse during their childhood. Around 3% of those aged under 17 reported exposure to it in the past 12 months (Radford et al. 2011). The impact of living in a household where there is a regime of intimidation, control and violence differs by children's developmental age. However, whatever their age, it has an impact on their mental, emotional and psychological health and their social and educational development. It also affects their likelihood of experiencing or becoming a perpetrator of domestic violence and abuse as an adult, as well as exposing them directly to physical harm (Stanley 2011; Holt et al. 2008). There is a strong association between domestic violence and abuse and other forms of child maltreatment: it was a feature of family life in 63% of the serious case reviews carried out between 2009 and 2011 (Brandon et al. 2012). # 'Honour'-based violence and forced marriage It is difficult to estimate the prevalence of so-called 'honour'-based violence and forced marriage, but we do know that the incidences of both are under-reported. Both can occur in Christian, Jewish, Sikh, Hindu, Muslim and other communities. They are probably more common in some groups, for example, some Pakistani, Kurdish, and Gypsy and Traveller communities, reflecting a more oppressive patriarchal ideology. (Home Affairs Select Committee 2008; Brandon and Hafez 2008). Both often involve wider family members and affect men, as well as women: 22% of the 1468 cases looked at by the Forced Marriage Unit involved a male being forced to marry. It is estimated that between 5000 and 8000 cases of forced marriage were reported to local and national organisations in England in 2008. In 41% of cases reported to local organisations the person forced to marry was younger than 18 (Kazmirski et al. 2009). # Abuse of older people More than 250,000 older people (aged 66 and older) living in England in private households reported experiencing maltreatment from a family member, close friend or care workers in the past year (O'Keefe et al. 2007). Maltreatment included neglect and psychological, physical, sexual and financial abuse. Of those experiencing maltreatment, 51% experienced it from a partner, 49% from another family member, 5% from a close friend and 13% from a care worker. Women were more likely to experience maltreatment than men (3.8% of women and 1.1% of men in the past year), and men were more often the perpetrators. # Abuse of parents by children The prevalence of abuse of parents by their children is very difficult to ascertain and 'still lies in a veil of secrecy' (Kennair and Mellor 2007). It is 'a pattern of behaviour that uses verbal, financial, physical or emotional means to practise power and exert control over a parent' (Holt 2012). It is more commonly experienced by mothers than fathers – and is more common among single parents. It can bring stress, fear, shame and guilt, as well as physical, emotional and psychological harm to the person who experiences it. Those inflicting the abuse may feel inadequate, hopeless and alone (Holt 2012; Kennair and Mellor 2007). A large proportion of those inflicting the abuse will themselves have been physically or sexually abused or have witnessed abuse. # Public sector costs The public service burden of domestic abuse is considerable. A high proportion of women attending accident and emergency departments, primary care, family planning, reproductive and sexual health settings are likely to have experienced domestic violence and abuse at some point (Alhabib et al. 2010; Feder et al. 2009). In addition, between 25 and 56% of female psychiatric patients report experiencing domestic violence and abuse in their lifetime (Oram et al. 2013). Domestic violence and abuse cost the UK an estimated £15.7 billion in 2008 (Walby 2009). This included: just over £9.9 billon in 'human and emotional' costs more than £3.8 billion for the criminal justice system, civil legal services, healthcare, social services, housing and refuges more than £1.9 billion for the economy (based on time off work for injuries).# Considerations The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations, as follows. Please note: this section does not contain recommendations (see Recommendations.) # General The PDG agreed that domestic violence and abuse occurs in all communities. The PDG was clear that both women and men can experience domestic violence in heterosexual and same sex relationships. The likelihood of ever experiencing a physical assault from a partner or adult family member is higher among heterosexual women than men. Moreover, heterosexual women experience more repeated physical violence, more severe violence, much more sexual violence, more coercive control, more injuries and more fear of their partner than heterosexual men. Although domestic violence and abuse research and services mainly focus on intimate partners, this type of violence and abuse takes many forms. Examples include: forced marriage, violence connected to 'honour', violence against adults by their children, abuse of older people and other intra-familial abuse. However, evidence of effective interventions in these areas is lacking. The PDG recognised the important role that the experiences, views and preferences of those who have experienced domestic violence should have in the development of policy and services. However, it did not hear evidence from them directly; this was largely outside the scope of the evidence reviews due to a focus on evaluation of interventions and the quality appraisal system used. However, the PDG did receive very helpful expert evidence and reports from people working in the specialist domestic violence sector and directly with service users. Such organisations were also represented by PDG members. The PDG agreed that, rather than use the terms 'victim' or 'survivor', the Group would refer to 'people who have experienced domestic violence and abuse'. The PDG thought it likely that domestic violence and abuse services could also benefit the extended family and friends of people who directly experience domestic violence and abuse. However, these effects have not been studied. The PDG was aware that much of the expertise and support for people who experience domestic violence and abuse lies in the voluntary and community sector, where funding and capacity is generally limited. The PDG was aware that domestic violence and abuse is often one of several problems that a couple or family may face. For example, it may be combined with poverty, drug and alcohol misuse or mental health problems. Most of the evidence relates to male violence against women and children in heterosexual relationships. However, the PDG noted that domestic violence and abuse affects: bisexual, gay, lesbian and trans relationships, and reconstituted (or step) and more complex families. In such cases, the Group noted that people may face particular barriers to accessing support and may have specific needs. # Children who are affected by domestic violence and abuse The PDG recognised the wide range of ill-effects that exposure to domestic violence and abuse can have on children and young people, including the effect on their social, emotional, psychological and educational wellbeing and development. It also recognised that providing effective interventions and support may reduce the likelihood of them being affected by, or perpetrating, domestic violence and abuse in adulthood. The PDG noted the importance of working concurrently with both the non-abusive parent or carer and child, rather than just focusing on the parent. Research on the effectiveness of parent/carer-child interventions has focused exclusively on mothers. Given the profile of domestic violence and abuse, that is where the biggest need for services is likely to be, but provision is needed for all families. The PDG agreed that evaluation of programmes where the father is the non-abusive carer will be especially important in light of the current lack of evidence about effective interventions. The PDG noted that domestic violence and abuse – and children's exposure to it – often continues beyond the end of the adults' relationship. The evidence linking effectiveness to the length of interventions for children is unclear. But it appears that longer interventions are more effective. This may be particularly true in complex cases. The PDG did not consider evidence on the timeliness of interventions for children, but the Group was aware of a developing body of literature in this area. The PDG noted the importance of ensuring services are appropriate to the age, gender and developmental stage of the child or young person. For example, teenagers may not want to be seen at the same time as their non-abusive parent or carer. # Identifying domestic violence or abuse The PDG was aware that there is an ongoing debate about the effectiveness and desirability of screening, routine and targeted enquiries to identify people who are experiencing domestic violence and abuse. Currently there is insufficient evidence to recommend screening or routine enquiry in healthcare settings. Nevertheless, the PDG recognised that asking patients routinely about abuse in some specialised health care settings was considered good practice by professionals in those fields. The PDG acknowledged that people experiencing domestic violence and abuse may choose not to disclose it when asked by a healthcare or other professional. Or, if they do disclose, they do not want to be pressurised to give more details of the abuse or take a specific course of action (Feder 2006). The PDG noted that healthcare professionals not trained to identify domestic violence and abuse may mislabel and misdiagnose people's problems, leading to inappropriate plans or ineffective remedies. (For example, specialists may be ordering unnecessary and expensive investigations and GPs may be prescribing inappropriate anxiolytics and antidepressants.) # Specialist support, advocacy, advice and skill building There is no universally accepted understanding of what 'advocacy' means in the context of domestic violence and abuse. The PDG kept the term because it has been applied to a range of interventions that have been evaluated in research studies. A definition of advocacy was agreed for the purposes of this guidance. The PDG noted that skill-building approaches might be of particular use in refuge settings, although they are also an intrinsic part of the advocacy and support role. # Programmes for people who perpetrate domestic violence and abuse There is a lack of consistent evidence on the effectiveness of programmes for people who perpetrate domestic violence and abuse. The PDG noted that some evaluations take account of the partner's health and wellbeing and include their perception of any changes in the perpetrator's behaviour. However, these tend to be small-scale, uncontrolled studies. The cost effectiveness analyses concluded that interventions with people who have experienced domestic violence and abuse are likely to be cost effective. However, this conclusion could not be extrapolated to interventions with perpetrators and the PDG was split on whether interventions with perpetrators should be recommended. However, members agreed that such interventions are an important part of domestic violence and abuse services and, provided they are supported by robust evaluation to inform future commissioning decisions, should be recommended. The PDG noted that national programmes dealing with behaviour-change among perpetrators are aimed at heterosexuals. Members were unclear whether or not these programmes would also be effective for other groups. # Prevention Members of the PDG (and stakeholders) were disappointed that the review did not find sufficient evidence to make recommendations on primary prevention programmes. This was partly because it looked only at health and social care – and currently most primary prevention interventions are delivered in education settings. However, the PDG agreed that prevention is an important area for future research (see Recommendations for research). # Training The PDG discussed the relationship between training to support people affected by domestic violence and abuse and child safeguarding training. Overall, members agreed that there were obvious links between them. However, they did not necessarily think they should be combined. Members recommended that this question should be addressed in future research (see Recommendations for research). # Health economics The economic modelling showed that effectiveness and cost-effectiveness in the medium to long term was less certain than in the shorter term. This was partly due to the short follow-up period applied to the studies used as the basis of the model. It was also due to the lack of longitudinal studies. However, even using conservative assumptions, it seems likely that the interventions will be cost-effective in the long term by stopping the violence and improving the mental health of all those involved. The PDG was aware that lack of evidence about the medium- and long-term consequence of interventions meant the economic models would underestimate their cost effectiveness. For example, a reduction in the incidence of post-trauma-related stress disorder is likely to lead to additional benefits, such as being less depressed or having improved self-esteem. However, limited data on these benefits meant they could not be estimated in the model. Although the systematic review of cost-effectiveness studies only found one analysis (Devine 2012) and the economic modelling focused on 2 interventions, the findings are also relevant for interventions with similar benefits and similar (or lower) costs. The PDG noted that the potential health and non-health benefits of these interventions would outweigh the costs when the positive impacts on people experiencing the violence and abuse, their families and wider society were considered.# Recommendations for research The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects. How effective are programmes that aim to prevent domestic violence and abuse from ever happening in the first place? This includes media-based public health awareness campaigns. It also includes social movements to establish people's rights, and community-building and primary prevention activities that tackle underlying assumptions in society. (Examples of the latter might include the role and status of women.) How effective are combinations of interventions to deal with domestic violence and abuse in the short, medium and long term? Are the outcomes sustainable and do they have a beneficial effect on quality of life and health in the longer term? How effective are the following interventions in the short, medium and long term, across various levels of risk and including diverse and marginalised groups: advocacy domestic abuse recovery programmes perpetrator programmes psychological or social interventions modified for domestic violence and abuse, including programmes for those who have suffered multiple forms of abuse and those who are still experiencing it interventions for primary carers apart from mothers (for example, fathers, grandparents) interventions for other family members? What are the most appropriate ways to collect and manage data about domestic violence and abuse across the health, social care and criminal justice sectors? Is there value in collecting anonymised aggregate data, or is there a more useful method of data capture? What type of interventions (including training and referral pathways), in diverse health care settings, provide the most effective support for practitioners working with people who are experiencing, or have experienced, domestic violence and abuse? More detail identified during development of this guidance is provided in Gaps in the evidence.# Related NICE guidance Common mental health disorders. NICE clinical guideline 123 (2011) Depression in adults (update). NICE clinical guideline 90 (2009) Alcohol dependence and harmful alcohol use. NICE clinical guideline 115 (2011) Pregnancy and complex social factors. NICE clinical guideline 110 (2010) Looked-after children and young people. NICE public health guidance 28 (2010) Alcohol-use disorders: preventing harmful drinking. NICE public health guidance 24 (2010) When to suspect child maltreatment. NICE clinical guideline 89 (2009) Antisocial personality disorder. NICE clinical guideline 77 (2009) Antenatal care. NICE clinical guideline 62 (2008) Antenatal and postnatal mental health. NICE clinical guideline 45 (2007) Postnatal care. NICE clinical guideline 37 (2006) Post-traumatic stress disorder (PTSD). NICE clinical guideline 26 (2005)# Glossary # Advocacy In general, advocacy for people who have experienced domestic violence includes: legal, housing and financial advice access to and use of community resources such as refuges, emergency housing and psychological interventions safety planning advice. The activities may differ according to the level of risk facing the person. Crisis advocacy involves working with the person for a limited period of time (they may then be referred on to more specialised agencies). Practitioners providing advocacy can also provide ongoing support and informal counselling. The intensity of the advocacy provided may vary. It may last for a year – or longer, if the person is particularly vulnerable. # Coercive behaviour Coercive behaviour is an act, or a pattern of acts, involving assault, threats, humiliation and intimidation or other abuse, to harm, punish or frighten someone. This includes so-called 'honour'-based violence and forced marriage. People who experience domestic violence can be male or female and from any ethnic group. (Home Office Ending violence against women and girls in the UK .) # Controlling behaviour Controlling behaviour involves a range of acts designed to make a person subordinate or dependent. This could range from isolating them from sources of support to exploiting them for personal gain. It can also involve depriving them of the means to be independent, including stopping them from leaving and regulating their everyday behaviour. (Home Office New definition of domestic violence, 18 September 2012). # Children and young people affected by domestic violence and abuse Children (aged under 16) and young people (aged 16 to 18) can experience domestic violence and abuse: when they are affected by it; this includes fearing, hearing or seeing it within their families, or worrying about its effects on someone else within their own intimate relationships. Young people may also perpetrate domestic violence and abuse in their own intimate relationships and on their parents or carers. # Disclosure For the purpose of this guidance, disclosure is defined as any occasion when an adult or child who has experienced or perpetrated domestic violence or abuse informs a health or social care worker or any other third party. # Domestic violence and abuse The term 'domestic violence and abuse' is used to mean: any incident or pattern of incidents of controlling, coercive or threatening behaviour, violence or abuse between those aged 16 or over who are, or have been, intimate partners or are family members. This includes: psychological, physical, sexual, financial and emotional abuse. It also includes 'honour'-based violence and forced marriage. For the purposes of this document, it does not include female genital mutilation, which may be referred to NICE as a future topic. # Elder abuse or maltreatment Action or neglect, within a relationship in which there is an expectation of trust, that causes harm or distress to a person older than 60. The abuse can take various forms: physical, verbal, psychological, sexual and financial. # Floating support In the context of this guidance, floating support is a housing service designed to prevent tenancy breakdowns. Floating support can also provide help with: keeping safe and security measures accessing legal advice and options welfare benefits budgeting and debts life skills resettlement or re-housing accessing community services form filling pre-tenancy support training, education and employment # Forced marriage A forced marriage is one in which one or both spouses do not (or, in the case of some adults with learning or physical disabilities, cannot) consent to the marriage but are forced into it using physical, psychological, financial, sexual or emotional pressure. ('Handling cases of forced marriage', HM Government 2008). It is distinct from an arranged marriage that both partners enter into freely. # 'Honour'-based violence or 'honour' violence A crime or incident committed (or possibly committed) to protect or defend the perceived 'honour' of a family or community. Often this term is enclosed in quote marks, or prefaced with 'so-called', to emphasise that the concept of honour in these cases is contested and that it is generally invoked as a means of power and control. # Independent domestic violence advisers (IDVAs) Also known as independent domestic violence advocates, IDVAs work primarily with people at high risk of domestic violence and abuse, independently of any one agency, to secure their safety and the safety of their children. Serving as the primary point of contact, IDVAs normally work with their clients from the point of crisis to assess the level of risk, discuss the options and develop plans that address their immediate safety, as well as longer-term solutions. In many areas they are funded by the local community safety partnership, in some areas they are funded by the police or local authorities. # Indicators Indicators are presenting problems or conditions that are associated with domestic violence and abuse. They can include: symptoms of depression, anxiety, post-traumatic stress disorder, sleep disorders suicidal tendencies or self-harming alcohol or other substance use unexplained chronic gastrointestinal symptoms unexplained reproductive symptoms, including pelvic pain and sexual dysfunction adverse reproductive outcomes, including multiple unintended pregnancies or terminations, delayed pregnancy care, miscarriage, premature labour and stillbirth unexplained genitourinary symptoms, including frequent bladder or kidney infections vaginal bleeding or sexually transmitted infections chronic pain (unexplained) traumatic injury, particularly if repeated and with vague or implausible explanations problems with the central nervous system – headaches, cognitive problems, hearing loss repeated health consultations with no clear diagnosis intrusive 'other person' in consultations including partner or husband, parent, grandparent or an adult child (for elder abuse). (Adapted from Black 2011.) # Multi-agency risk assessment conferences (MARACs) Regular meetings at which information about people experiencing domestic violence or abuse and who are at high risk (those at risk of homicide or serious harm) is shared between local agencies. Whenever possible, the person who experiences the violence is represented by an independent domestic violence adviser or advocate (IDVA). Participants aim to draw up a coordinated safety plan to support the person. In many areas they are funded by the local community safety partnership, in some areas they are funded by the police or local authorities. # No recourse to public funds 'No recourse to public funds' is a term used for people who are not entitled to welfare benefits, home office asylum support, public housing and other public funds and services. The term derives from the 'no recourse to public funds' condition applied to certain immigration statuses. 'Public funds' refers to a range of benefits including housing support, carer's allowance, child benefit, disability living allowance, housing benefit, income support and social fund payments. # Parenting support Interventions that aim to improve parents' understanding of how domestic violence and abuse affects children and how to protect them. Most of the interventions found to be effective focus on non-abusive mothers and on strengthening the mother–child bond. # People who experience domestic violence and abuse Throughout this guidance, 'people who experience domestic violence and abuse' refers to those who are victims or survivors of the violence and abuse. # Protected characteristics The Equality Act (2010) makes it illegal to discriminate against anyone because of: age being or becoming a transsexual person being married or in a civil partnership being pregnant or having a child disability race including colour, nationality, ethnic or national origin religion, belief or lack of religion/belief sex sexual orientation. These are called 'protected characteristics'. # Refuge or shelter Residential service – a safe house – provided for adults (usually women) and children who are experiencing domestic violence and abuse. # Risk identification and assessment This process is undertaken with people who have disclosed that they are the victims of domestic violence and abuse. The aim is to evaluate their risk of further harm. Practitioners with level 2 training assess their immediate safety, for example, whether it is safe for the person to go home. Practitioners with level 3 training identify the risks faced in more detail to inform safety planning, referrals to specialist support services and to aid any police investigation. Almost all police forces in England and Wales use the DASH (domestic abuse, stalking and harassment and 'honour'-based violence) risk identification tool and guidance. A multi-sectoral version, CAADA-DASH, is used by independent domestic violence advisers, some domestic violence advocates and support workers, other specialist domestic abuse services and some health and social care practitioners. # Safety planning An intervention to help people judge their risk of violence, identify the warning signs and develop plans on what to do when violence is imminent or is happening. # Skill building Training and education to improve the skills of people who have experienced domestic violence and abuse. Typically it covers: problem solving and decision making, resilience and coping, financial skills, and understanding the dynamics of domestic violence and abuse. Sometimes it also includes other components; for example, relaxation and parenting skills. # Therapy A structured psychological or psychiatric treatment delivered by professional clinicians, such as psychologists. Therapeutic interventions may be delivered in an individual or group format. # Trans people Trans is an umbrella term. It includes cross-dressers, transgender and transsexual people as well as anyone else who is in any way gender-variant.# References Alhabib S, Nur U, Jones R (2010) Domestic violence against women: systematic review of prevalence studies. Journal of Family Violence 25: 369–82 Barter C, McCarry M, Berridge D et al. (2009) Partner exploitation and violence in teenage intimate relationships. London: NSPCC Black MC (2011) Intimate partner violence and adverse health consequences: implications for clinicians. American Journal of Lifestyle Medicine 5: 428–39 Bowen E, Heron J, Waylen A et al. (2005) Domestic violence risk during and after pregnancy: findings from a British longitudinal study. BJOG: An International Journal of Obstetrics and Gynaecology 112: 1083–9 Brandon J, Hafez S (2008) Crimes of the community – honour-based violence in the UK. London: Centre for Social Cohesion Brandon M, Sidebotham P, Bailey S et al. (2012) New learning from serious case reviews: a two year report for 2009–11. London: Department for Education Devine A, Spencer A, Eldridge S et al. (2010) Cost-effectiveness of Identification and Referral to Improve Safety (IRIS), a domestic violence training and support programme for primary care: a modelling study based on a randomised controlled trial. BMJ Open 2: e001008 Dick S (2008) Homophobic hate crime The Gay British Crime Survey. London: Stonewall Donovan C, Hester M, Holmes J et al. (2006) Comparing domestic abuse in same sex and heterosexual relationships Feder GS, Hutson M, Ramsay J et al. (2006) Women exposed to intimate partner violence: expectations and experiences when they encounter health care professionals: a meta-analysis of qualitative studies. Archives of Internal Medicine 166: 22–37 Feder G, Ramsay J, Dunne D et al. (2009) How far does screening women for domestic (partner) violence in different health-care settings meet criteria for a screening programme? Systematic reviews of nine UK National Screening Committee criteria. Health Technology Assessment 13 (16) Harrykissoon SD, Vaughn IR, Wiemann CM (2002) Prevalence and patterns of intimate partner violence among adolescent mothers during the postpartum period. Archives of Paediatrics and Adolescent Medicine 156: 325–30 Hester M (2013) Who does what to whom? Gender and domestic violence perpetrators in English police records. European Journal of Criminology 10: 623–637 Hester M, Westmarland N (2005) Tackling domestic violence: effective interventions and approaches. London: Home Office Research, Development and Statistics Directorate Holt A (2012) Adolescent-to-parent abuse: current understandings in research, policy and practice. Bristol: The Policy Press Holt S, Buckley H, Whelan S (2008) The impact of exposure to domestic violence on children and young people: a review of the literature. Child Abuse and Neglect 32: 797–810 Home Affairs Select Committee (2008) Domestic violence, forced marriage and 'honour'-based violence. London: House of Commons Humphreys C, Regan L, River D et al (2005) Domestic Violence and Substance Use: Tackling Complexity. British Journal of Social Work 35: 1303–20 Hunt R, Fish J (2008) Prescription for change: lesbian and bisexual women's health check. London: Stonewall Kazmirski A, Keogh P, Kumari V et al. (2009) Forced marriage – prevalence and service response. London: Department for Children, Schools and Families Kennair N, Mellor D (2007) Parent abuse: a review. Child Psychiatry & Human Development 38: 203–19 Meltzer H, Doos L, Vostanis P et al. (2009) The mental health of children who witness domestic violence. Child and Family Social Work 14: 491–501 Murphy CM, Ting L (2010) The effects of treatment for substance use problems on intimate partner violence: A review of empirical data. Aggression and Violent Behavior 15: 325–33 Norman R, Spencer A, Eldridge S et al. (2010) Cost-effectiveness of a programme to detect and provide better care for female victims of intimate partner violence. Journal of Health Services Research and Policy 15: 143–9 O'Keefe M, Hills A, Doyle M et al. (2007) UK study of abuse and neglect of older people. London: Department of Health Oram S, Trevillion K, Feder G et al. (2013) Prevalence of experiences of domestic violence among psychiatric patients: systematic review. The British Journal of Psychiatry 202: 94–9 Radford L, Corral S, Bradley C et al. (2011) Child abuse and neglect in the UK today. London: NSPCC Richards L (2004) Getting away with it: a strategic overview of domestic violence, sexual assault and serious incident analysis. London: Metropolitan Police Service Roch A, Morton J, Ritchie G et al. (2010) Abuse out of sight out of mind: transgender people's experiences of domestic abuse. LGBT Youth Scotland and the Equality Network Smith K (ed), Coleman K, Eder S et al. (2011) Homicides, firearm offences and intimate violence 2009/10: supplementary volume 2 to Crime in England and Wales 2009/10 (2nd edition). London: Home Office Smith K (ed), Flatley J (ed), Coleman K et al. (2010) Homicides, firearm offences and intimate violence 2008/09: supplementary volume 2 to Crime in England and Wales 2008/09 (3rd edition). London: Home Office Smith K (ed), Osborne S, Lau I et al. (2012) Homicides, firearm offences and intimate violence 2010/11: supplementary volume 2 to Crime in England and Wales 2010/11. London: Home Office Stanley N (2011) Children experiencing domestic violence: a research review. Dartington: Research in Practice Stonewall (2012) Gay and Bisexual Men's Health Survey 2012 Thompson G (2010) Domestic violence statistics Trevillion K, Oram S, Feder G et al. (2012) Experiences of domestic violence and mental disorders: a systematic review and meta-analysis. PLoS ONE 7: e51740. Walby S (2009) The cost of domestic violence: up-date 2009 .# Summary of the methods used to develop this guidance # Introduction The review and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Programme Development Group (PDG) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations. All supporting documents are listed in About this guidance. # Guidance development The stages involved in developing public health guidance are outlined in the box below. . Draft scope released for consultation . Stakeholder meeting about the draft scope . Stakeholder comments used to revise the scope . Final scope and responses to comments published on website . Evidence reviews and economic modelling undertaken and submitted to PDG . PDG produces draft recommendations . Draft guidance (and evidence) released for consultation and for field testing . PDG amends recommendations . Final guidance published on website . Responses to comments published on website # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were: . What types of intervention or approach are effective and cost effective in preventing domestic violence from ever happening in the first place (that is, primary prevention)? . What types of intervention or approach are effective and cost effective in helping all those working in health and social care to safely identify and, if appropriate, intervene to prevent domestic violence? Examples may include collaborative partnerships, advice and information-sharing protocols and specialised training, both on-the-job and pre-entry. . What types of intervention or approach are effective and cost effective in helping all those working in health and social care to respond to domestic violence? This may include interventions and approaches to assess and improve someone's safety, reduce the risk of harm, support their recovery and prevent a perpetrator reoffending. It may also include collaborative partnerships and advice and information-sharing protocols. . What types of intervention and approach are effective and cost effective in identifying and responding to children who are exposed to domestic violence in the various settings identified? (That is, the violence is not perpetrated on them directly but they witness or experience it.) Interventions could include collaborative partnerships and advice and information-sharing protocols. . What are the most effective and cost-effective types of partnership and partnership approaches for assessing and responding to domestic violence? These questions were made more specific for the review (see review for further details). # Reviewing the evidence ## Effectiveness reviews One review of effectiveness was conducted. A number of databases were searched in May 2012 for randomised controlled trials (RCT), case-control studies, interrupted time series, cohort studies, cross-sectional studies, observational studies, systematic reviews and qualitative studies. See the review for details of the databases searched. A range of websites were searched manually for relevant grey literature. In addition, the citation lists of all studies included in the review were searched and PDG members provided and discussed key literature 'virtually' with the external contractor. NICE also issued a call for evidence. Studies from countries in the Organisation for Economic Co-operation and Development (OECD) were included in the effectiveness review if they: evaluated an intervention or approach to identify, prevent, reduce or respond to domestic violence and abuse between adults and young people who were, or had been, intimate partners evaluated an intervention or approach to identify, prevent, reduce or respond to the abuse of older people by a family member focused on healthcare, social care or specialised services that deal with domestic violence and abuse. Studies were excluded if they: focused on children who directly experienced domestic violence and abuse and perpetrators whose violence is directed at children focussed on female genital mutilation, violence perpetrated against older vulnerable people by paid carers or violence in occupational settings included interventions not linked to health and social care. See the review for details of the inclusion and exclusion criteria. ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in Methods for the development of NICE public health guidance. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution. Studies graded (−) were excluded from the review. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled, or not adequately described, are unlikely to alter the conclusions. − Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. The evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable). ## Summarising the evidence and making evidence statements The review data were summarised in evidence tables (see full review). The findings from the review and expert reports were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see About this guidance). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope. # Cost effectiveness There was a systematic review of economic evaluations and an economic modelling exercise. ## Review of economic evaluations A search was undertaken using a search strategy developed by the review team. Studies were included if they focused on: full economic evaluations of relevant types of intervention high quality costing studies relevant to the UK. Studies were categorised according to study type, methodological rigour and quality. ## Economic modelling A number of assumptions were made that could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details). Economic models were constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in: Economic analysis of interventions to reduce the incidence and harm of domestic violence and abuse. # Fieldwork Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with commissioners and practitioners, including directors of public health and mental health and substance misuse services who are involved in domestic violence and abuse services. They included: commissioners, primary and secondary health care professionals, police officers, public health specialists, specialist domestic violence staff and other representatives from local authorities and voluntary sector groups. The fieldwork comprised: focus groups and 20 in-depth interviews carried out in Birmingham, Bristol, Liverpool and London by Word of Mouth. The 10 focus groups and 20 in-depth interviews were commissioned to ensure there was ample geographical coverage. The main issues arising are set out in section 10 under fieldwork findings. Or see Field testing NICE guidance on domestic violence and abuse: how social care, health services and those they work with can identify, prevent, and reduce domestic violence. # How the PDG formulated the recommendations At its meetings in 2012/3 the Programme Development Group (PDG) considered the evidence, expert reports and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guidance. The PDG developed recommendations through informal consensus, based on the following criteria: Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. Where evidence was lacking, the PDG also considered whether a recommendation should only be implemented as part of a research programme. Where possible, recommendations were linked to an evidence statement(s) (see The evidence for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).# The evidence The evidence statements from 1 review are provided by an external contractor (see Evidence). This section lists how the evidence statements and expert reports link to the relevant recommendations and sets out a brief summary of findings from the economic analysis and the fieldwork. The evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document. Evidence statement number 1 indicates that the linked statement is numbered 1 in the review 'Review of interventions to identify, prevent, reduce and respond to domestic violence and abuse'. Evidence statement ER1 indicates that the evidence is in the expert report 1 'Current health and social care interventions on domestic violence and abuse'. The review, expert reports and economic analysis are available online. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: ER1 Recommendation 2: evidence statement 30–33 Recommendation 3: evidence statements 30–33 Recommendation 4: evidence statements 9, 30–-33 Recommendation 5: evidence statements 3, 8, 9; ER2–5 Recommendation 6: evidence statements 11–14 Recommendation 7: evidence statements 3, 33 Recommendation 8: evidence statements 8–10, 31 Recommendation 9: evidence statement 33; ER2–5 Recommendation 10: evidence statements 8, 9, 30–33 Recommendation 11: evidence statements 27–29 Recommendation 12: evidence statements 10–12, 27, 28 Recommendation 13: evidence statements 13, 14 Recommendation 14: evidence statements 15, 17; ER2 Recommendation 15: evidence statements 8–10, 30 Recommendation 16: evidence statements 8,9, 31–33 Recommendation 17: evidence statements 8, 9, 30 # Review of economic evaluation Two papers were included in the review. These reported findings from a pilot intervention to prevent domestic violence (Norman et al. 2010) and a cluster RCT of the intervention (Devine et al. 2012).This multi-faceted intervention included: education of doctors about domestic violence and abuse; improved cross-system collaboration; use of electronic prompts for doctors to ask about intimate partner violence; use of prompts to encourage doctors to refer people who have experienced domestic violence to domestic violence and abuse advocates and to psychologists. Moderate evidence from the UK perspective suggested that the interventions were cost effective, with an incremental cost–effectiveness ratio of £2450 when an additional quality-adjusted life year was valued at £20,000. # Economic modelling Two interventions were modelled: the use of independent domestic violence services and cognitive trauma therapy for battered women. Overall, the independent domestic violence adviser service intervention was found to be cost saving (that is, it both saves resources and improves quality of life) compared with no intervention. The overall message is that the cost of domestic violence and abuse is so significant that even marginally effective interventions are cost effective. Cognitive trauma therapy for battered women saved £15 million by reducing the harm from domestic violence, compared with no intervention. The results are subject to uncertainty and assumptions made in both models. The key assumptions were explored in a series of sensitivity analyses. These analyses demonstrated that the interventions are cost effective, even when the costs and effects of the interventions varied. Full details can be found in the Economic analysis of interventions to reduce the incidence and harm of domestic violence and abuse. # Fieldwork findings Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, go to Fieldwork and Field testing NICE guidance on domestic violence and abuse: how social care, health services and those they work with can identify, prevent, and reduce domestic violence. Fieldwork participants who come into contact with people who experience, or perpetrate, domestic violence and abuse were fairly positive about the recommendations and their potential to help identify, prevent and reduce this violence and abuse. Many welcomed the holistic (multi-agency and multi-sector) approach and the comprehensive scope of the guidance (covering everything from strategy development to service delivery). The inclusion of a key role for public health – including NHS services – was especially welcomed, because participants felt that domestic violence and abuse has not been seen as a priority by the health sector in the past. If the recommendations are implemented, participants felt that the overall standard of domestic violence and abuse service provision was likely to improve. (According to participants, current provision varies by locality, due to the uncertain and short-term nature of funding arrangements.) However, recent changes in the commissioning of health and social care services were reported to have created confusion, with many participants saying that it is difficult to identify the relevant commissioners in their area. Some suggested that the guidance should more clearly identify accountable agencies and partnerships.# Gaps in the evidence The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence and expert comment. These gaps are set out below. . There is a lack of research on: a) working with men who experience domestic violence and abuse b) 'honour'-based violence or forced marriage c) interventions to prevent elder abuse d) lesbian, gay, bisexual and trans people's experiences of domestic violence and abuse e) the differences in outcomes of interventions for women and men f) dating violence and intimate partner violence among adolescents g) tailored approaches for women facing different levels of risk h) whole-family interventions in response to domestic violence i) violence and abuse directed at parents, carers or siblings by children and young people j) stalking. . There is a lack of evidence on identifying people affected by domestic violence or abuse in social care settings and integrated approaches to identifying people across various health and social care settings. There is also a lack of evidence on integrated approaches to identifying coexisting issues, such as the links between domestic violence and substance use or mental health issues. . There is a lack of evidence on prevention interventions due to methodological issues including: short follow up, lack of comparisons of different interventions, lack of behavioural measures and reliance on self-reporting. In addition, most studies measured attitudes and knowledge, or exposure to educational materials and messages, rather than behavioural outcomes. Many included women who were already using refuge or shelter services, so the findings may not be applicable to those who are not using them. . There is a lack of large, robust studies of advocacy, skill development, counselling and other therapeutic approaches for people who have experienced domestic violence or abuse. . There is a lack of large, robust studies of interventions for people who perpetrate abuse. The majority were non-experimental (primarily before-and-after studies).Often they did not include a comparison group, had relatively small sample sizes, reported high rates of attrition and lacked follow up beyond programme completion. . There is a lack of high quality studies measuring the effects of multi-faceted and multi-sectorial approaches to the prevention of domestic violence. The majority were before and after, or qualitative studies providing narrative reports. Methodological weaknesses included: scant information on data collection, methods and analysis and small sample size (particularly for qualitative studies). . There is a lack of research on the impact of partnership working among agencies serving men or a range of subgroups of women experiencing violence. No studies discussed the effectiveness of partnership working for lesbian women who experience domestic violence. The Committee made 4 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in Recommendations for research.# About this guidance # Why has this guidance been produced? In 2008, the Department of Health (DH) asked the National Institute for Health and Care Excellence (NICE) to produce guidance on how to identify, prevent and reduce domestic violence and abuse. (See the scope.) The PDG felt that the review did not find sufficient evidence for them to make recommendations on primary and secondary prevention programmes. This was partly because it looked only at health and social care settings and most primary prevention interventions are delivered in education settings. There were other measures and interventions for which no evidence, or insufficient evidence, was identified. Their absence from the recommendations is a result of this lack of evidence and should not be taken as a judgement on whether they are effective. Violence and abuse can be perpetrated on children by adults ('child abuse'), but that is not dealt with in this guidance. NICE has produced guidance on child maltreatment. # How was this guidance developed? This guidance was developed jointly by NICE and the Social Care Institute for Excellence (SCIE). SCIE provided particular input into discussions about what the guidance should cover. The recommendations are based on the best available evidence. They were developed by the Programme Development Group (PDG). Members of the PDG are listed in Membership of the Programme Development Group and the NICE project team. For information on how NICE public health guidance is developed, see the NICE public health guidance process and methods guides. # What evidence is the guidance based on? The evidence the PDG considered included: evidence review review of economic evaluations and economic modelling expert reports fieldwork report. In some cases the evidence was insufficient and the PDG has made recommendations for future research. See Recommendations for research and Gaps in the evidence respectively. # Status of this guidance The draft guidance, including the recommendations, was released for consultation in August 2013 At its meeting in November 2013, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in February 2014 The guidance is available on NICE's website. The recommendations are also available in a pathway for professionals whose remit includes public health and for interested members of the public. # Implementation NICE guidance can help: Commissioners and providers of NHS services to meet the quality requirements of the DH's Operating framework for 2012/13. It can also help them to deliver against domain 1 of the NHS outcomes framework (preventing people from dying prematurely). Local health and wellbeing boards to deliver on their requirements within Healthy lives, healthy people (2010). Local authorities, NHS services and local organisations determine how to improve health outcomes and reduce health inequalities during the joint strategic needs assessment process. NICE has developed tools to help organisations put this guidance into practice. All healthcare professionals should ensure people have a high quality experience of the NHS by following NICE's recommendations in Patient experience in adult NHS services. All health and social care providers working with people using adult NHS mental health services should follow NICE's recommendations in Service user experience in adult mental health. # Updating the recommendations This guidance will be reviewed 3 years after publication to determine whether all or part of it should be updated. Information on the progress of any update will be posted on the NICE website. # Your responsibility This guidance represents the views of the Institute and was arrived at after careful consideration of the evidence available. Those working in the NHS, local authorities, the wider public, voluntary and community sectors and the private sector should take it into account when carrying out their professional, managerial or voluntary duties. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity, and foster good relations. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. # Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0475-4	{'Introduction': "# What is this guidance about?\n\nThis guidance aims to help identify, prevent and reduce domestic violence and abuse. Violence and abuse perpetrated on children by adults ('child abuse') is not dealt with in this guidance, but it does include support for children who are affected by domestic violence and abuse.\n\nDomestic violence and abuse is a complex issue that needs sensitive handling by a range of health and social care professionals. The cost, in both human and economic terms, is so significant that even marginally effective interventions are cost effective.\n\nWomen and men can experience this type of violence in heterosexual and same-sex relationships. The prevalence of physical assaults from a partner or adult family member is higher among heterosexual women than among men. Moreover, heterosexual women experience more repeated physical violence, more severe violence, much more sexual violence, more coercive control, more injuries and more fear of their partner.\n\nThe recommendations cover the broad spectrum of domestic violence and abuse, including violence perpetrated on men, on those in same-sex relationships and on young people.\n\nWorking in a multi-agency partnership is the most effective way to approach the issue at both an operational and strategic level. Initial and ongoing training and organisational support is also needed.\n\nThere was not sufficient evidence to make recommendations on primary prevention programmes. Most of the evidence about this relates to interventions in educational settings and these are outside the scope of this guidance unless they are delivered by a health or social care professional. Prevention is an important area for future research (see Recommendations for research).\n\nThe guidance is for health and social care commissioners, specialist domestic violence and abuse staff and others whose work may bring them into contact with people who experience or perpetrate domestic violence and abuse. (For details, see Who should take action?) In addition it may be of interest to members of the public.\n\nSee About this guidance for details of how the guidance was developed and its current status.", 'Recommendations ': "# Recommendation 1 Plan services based on an assessment of need and service mapping\n\nStrategic partnerships (see Who should take action?) should assess the need for domestic violence and abuse services as part of the joint strategic needs assessment. Consult with women, men and young people who have experienced domestic violence and abuse as part of this assessment. Commissioners of domestic violence and abuse services and related services should be aware of the importance of consulting communities that are rarely heard on this matter.\n\nLocal commissioners of domestic violence and abuse services and related services should undertake a comprehensive mapping exercise to identify all local services and partnerships that work in domestic violence and abuse. (For example, this could include: ambulance services, housing, the police, health, criminal justice, education, probation, safeguarding and social care services. It could also include other specialist statutory, community and voluntary services, such as drug and alcohol services.) Map services against the Home Office-endorsed Coordinated Community Response Model and identify any gaps.\n\nLocal commissioners (see above) should use the results of the needs assessment and mapping exercise to inform commissioning. They should develop referral pathways that aim to meet the health and social care needs of all those affected by domestic violence and abuse. This includes people with protected characteristics and those who face particular barriers trying to access domestic violence and abuse support services (see recommendations 4 and 9).\n\nRegional and national commissioners of domestic violence and abuse services and related services should work with local commissioners to ensure service support extends across local authority boundaries, where necessary, for services such as prisons that cover broader geographical areas.\n\nRegional and national commissioners (see above) should work with local commissioners to provide specialist services across local authority boundaries where there is not enough local need to justify setting them up within a particular local authority area. (This could include services to help prevent forced marriages, to help men, and lesbian, gay, bisexual or trans people affected by domestic violence, or for people subjected to 'honour' violence or stalking.)\n\nStrategic partnerships should use the results of mapping in the joint strategic needs assessment and other strategic planning tools. They should also make the results widely available to all relevant services and the general public – for example, by publishing a directory of local and national services.\n\n# Recommendation 2 Participate in a local strategic multi-agency partnership to prevent domestic violence and abuse\n\nLocal authorities, health services and their strategic partners (including the voluntary and community sectors) should:\n\nEnsure senior officers from the following services participate in a local strategic partnership to prevent domestic violence and abuse, along with representatives of frontline practitioners and service users or their representatives:\n\n\n\nhealth services and the local authority (including the chairs of local safeguarding boards for adults and children)\n\npublic health\n\nsexual violence services\n\nhousing\n\nschools and colleges\n\npolice and crime commissioners\n\ncommunity safety partnerships\n\ncriminal justice agencies (including probation)\n\nthe Children and Family Court Advisory and Support Service\n\nspecialist voluntary, community and private sector organisations.\n\n\n\nEnsure health and social care practitioners are actively involved in both operational and strategic multi-agency initiatives (for example, multi-agency risk assessment conferences).\n\nRegularly review membership of the partnership to ensure it is relevant and inclusive.\n\n# Recommendation 3 Develop an integrated commissioning strategy\n\nLocal strategic partnerships on domestic violence and abuse, commissioners, clinical commissioning groups and local authorities should:\n\nEstablish an integrated commissioning strategy. This should include input from domestic violence and abuse services, other relevant services and from people who have experienced domestic violence and abuse. The strategy should:\n\n\n\nmeet the health and social care needs of those who experience domestic violence and abuse (including young people)\n\nmeet the needs of children and young people who are affected by domestic violence and abuse\n\naddress the perpetrator's behaviour and health needs\n\nmeet the needs of all local communities.\n\n\n\nEnsure the strategy is based on the following principles:\n\n\n\naligned or, where possible, integrated budgets and other resources\n\none partner takes the strategic lead and oversees delivery on behalf of the local strategic partnership\n\nservices address all levels of risk and all degrees of severity of domestic violence and abuse\n\nservices are based on evidence-based commissioning principles and the local needs assessment and mapping exercise (see recommendation 1).\n\nagencies work together to deliver services.\n\n\n\nMonitor implementation of the strategy and evaluate its effectiveness for different groups. Include both quantitative data on outcomes and qualitative data (such as feedback from service users).\n\n# Recommendation 4 Commission integrated care pathways\n\nCommissioners of health and social care services should:\n\nEnsure there are integrated care pathways for identifying, referring (either externally or internally) and providing interventions to support people who experience domestic violence and abuse, and to manage those who perpetrate it.\n\nEnsure people who misuse alcohol or drugs or who have mental health problems and are affected by domestic violence and abuse are also referred to the relevant health, social care and domestic violence and abuse services.\n\nEnsure all service pathways have consistent, robust mechanisms for assessing the risks facing adults who experience domestic violence and abuse and any children who may be affected. This includes ensuring those affected by, and the perpetrators of, the violence and abuse are kept separate from each other when receiving support.\n\n# Recommendation 5 Create an environment for disclosing domestic violence and abuse\n\nHealth and social care service managers and managers of specialist domestic violence and abuse services and related services (see Who should take action?) should:\n\nClearly display information in waiting areas and other suitable places about the support on offer for those affected by domestic violence and abuse. This includes contact details of relevant local and national helplines. It could also include information for groups who may find it more difficult to disclose that they are experiencing violence and abuse (see recommendation 9).\n\nEnsure the information on where to get support is available in a range of formats and locally used languages. The former could include braille and audio versions and the use of large font sizes. There may also be more discreet ways of conveying information, for example, by providing pens or key rings with a helpline number.\n\nTake steps to ensure people who use the service are given maximum privacy, for example, by arranging the reception area so that people cannot be overheard.\n\nEstablish a referral pathway to specialist domestic violence and abuse agencies (or the equivalent in a health or social care setting). This should include age-appropriate options and options for groups that may have difficulties accessing services, or are reluctant to do so (see recommendation 9).\n\nEnsure frontline staff know about the services, policies and procedures of relevant local agencies in relation to domestic violence and abuse.\n\nProvide ongoing training and regular supervision for staff who may be asking people about domestic violence and abuse. This should aim to sustain and monitor good practice.\n\nEstablish clear policies and procedures for staff who have been affected by domestic violence and abuse. Ensure staff have the opportunity to address issues relating to their own personal experiences, as well as those that may arise after contact with patients or service users.\n\n# Recommendation 6 Ensure trained staff ask people about domestic violence and abuse\n\nHealth and social care service managers and professionals should:\n\nEnsure frontline staff in all services are trained to recognise the indicators of domestic violence and abuse and can ask relevant questions to help people disclose their past or current experiences of such violence or abuse. The enquiry should be made in private on a one-to-one basis in an environment where the person feels safe, and in a kind, sensitive manner.\n\nEnsure people who may be experiencing domestic violence and abuse can be seen on their own (a person may have multiple abusers and friends or family members may be colluding in the abuse).\n\nEnsure trained staff in antenatal, postnatal, reproductive care, sexual health, alcohol or drug misuse, mental health, children's and vulnerable adults' services ask service users whether they have experienced domestic violence and abuse. This should be a routine part of good clinical practice, even where there are no indicators of such violence and abuse.\n\nEnsure staff know, or have access to, information about the services, policies and procedures of all relevant local agencies for people who experience or perpetrate domestic violence and abuse.\n\nEnsure all services have formal referral pathways in place for domestic violence and abuse. These should support: people who disclose that they have been subjected to it; the perpetrators; and children who have been affected by it (see recommendation 4).\n\n# Recommendation 7 Adopt clear protocols and methods for information sharing\n\nCommissioners and service providers involved with those who experience or perpetrate domestic violence and abuse (see Who should take action?) should:\n\nTake note of the Data Protection Act and professional guidelines that address confidentiality and information sharing in health services. This includes guidelines on how to apply the Caldicott guardian principles to domestic violence, see Caldicott guidelines. It also includes guidelines on: seeking consent from people to share their information, letting them know when, and with whom, information is being shared, and knowing when information can be shared without consent.\n\nDevelop or adapt clear protocols and methods for sharing information, both within and between agencies, about people at risk of, experiencing, or perpetrating domestic violence and abuse. Clearly define the range of information that can be shared and with whom (this includes sharing information with health or children's services on a perpetrator's criminal history.)\n\nEnsure protocols and methods encourage staff to:\n\n\n\nRemember their professional duty of confidentiality.\n\nDetermine when the duty of confidentiality might have to be breached: information should be shared only with the person's consent unless they are at serious risk, and within agreed multi-agency information-sharing protocols.\n\nNote that information sharing without consent risks losing trust and may endanger a person's safety.\n\nWeigh the risks of sharing information or not by determining whether you are sharing with the aim of protecting someone. It is acceptable to share information if that is the case and you are not sharing data just to alert another agency to a problem.\n\nDistinguish between anonymised data and personal data: the former does not need individual consent, but there should be a protocol in place for sharing such data.\n\nDistinguish between situations that involve only adults and those where children are involved: information sharing without consent, or where consent is not given, is necessary when children's safety is at risk.\n\n\n\nEnsure information-sharing methods are secure and will not put anyone involved at risk.\n\nEnsure the protocols and methods are regularly monitored.\n\nIdentify and train key contacts responsible for advising on the safe sharing of domestic violence and abuse-related information.\n\nEnsure all staff who need to share information are trained to use the protocols so that they do not decline to cooperate because of being overcautious or for fear of reprisal.\n\nEnsure any information shared is acknowledged by a person, rather than by an automatically generated response.\n\n# Recommendation 8 Tailor support to meet people's needs\n\nManagers and staff working in domestic violence and abuse services and staff in all health and social care settings (see Who should take action?) should:\n\nPrioritise people's safety.\n\nRefer people from general services to domestic violence and abuse (and other specialist) services if they need additional support.\n\nRegularly assess what type of service someone needs – immediately and in the longer term.\n\nThink about referring someone to specialist domestic violence and abuse services if they need immediate support. This includes advocacy, floating support and outreach support and refuges. It also includes housing workers, independent domestic violence advisers or a multi-agency risk assessment conference for high-risk clients.\n\nThink about referring someone to floating or outreach advocacy support or to a skill-building programme if they need longer-term support. Also explore whether they would like to be referred to a local support group.\n\nIf there are indications that someone has alcohol or drug misuse or mental health problems, also refer them to the relevant alcohol or drug misuse or mental health services (see recommendation 13).\n\n# Recommendation 9 Help people who find it difficult to access services\n\nCommissioners and service providers in the statutory, private, voluntary and community sectors (see Who should take action?) should:\n\nHelp people who may find domestic violence and abuse services inaccessible or difficult to use. This includes: people from black and minority ethnic groups or with disabilities, older people, trans people and lesbian, gay or bisexual people. It also includes people with no recourse to public funds.\n\nIdentify any barriers people from these groups may face when trying to get help. Do this in consultation with local groups that have an equality remit (including organisations representing the interests of specific groups), and in line with statutory requirements.\n\nIntroduce a strategy to overcome these barriers.\n\nTrain staff in direct contact with people affected by domestic violence and abuse to understand equality and diversity issues. This includes those working with people who perpetrate this type of violence and abuse. Specifically:\n\n\n\nEnsure assumptions about people's beliefs and values (for example, in relation to 'honour') do not stop staff identifying and responding to domestic violence and abuse.\n\nEnsure staff know where to seek specialist advice, for example, for people with no recourse to public funds or for people with HIV.\n\nEnsure staff are aware that lesbian, gay, bisexual and trans people are also at risk of forced marriage and that 'honour'-based violence might be triggered by someone's gender identity or sexuality.\n\nEnsure interpreting services are confidential (often a concern in small communities where a minority language is spoken).\n\nEnsure professional interpreters are used. Do not use family members or friends. In some areas this will mean using a national interpreting service or one based in another locality.\n\n\n\n# Recommendation 10 Identify and, where necessary, refer children and young people affected by domestic violence and abuse\n\nProviders of services where children and young people affected by domestic violence and abuse may be identified and those responsible for safeguarding children (see Who should take action?) should:\n\nEnsure staff can recognise the indicators of domestic violence and abuse and understand how it affects children and young people.\n\nEnsure staff are trained and confident to discuss domestic violence and abuse with children and young people who are affected by or experiencing it directly. The violence and abuse may be happening in their own intimate relationships or among adults they know or live with.\n\nPut clear information-sharing protocols in place to ensure staff gather and share information and have a clear picture of the child or young person's circumstances, risks and needs.\n\nDevelop or adapt and implement clear referral pathways to local services that can support children and young people affected by domestic violence and abuse.\n\nEnsure staff know how to refer children and young people to child protection services. They should also know how to contact safeguarding leads, senior clinicians or managers to discuss whether or not a referral would be appropriate.\n\nEnsure staff know about the services, policies and procedures of all relevant local agencies for children and young people in relation to domestic violence and abuse.\n\nInvolve children and young people in developing and evaluating local policies and services dealing with domestic violence and abuse.\n\nMonitor these policies and services with regard to children's and young people's needs.\n\n# Recommendation 11 Provide specialist domestic violence and abuse services for children and young people\n\nThose responsible for safeguarding children, and commissioners and providers of specialist services for children and young people affected by domestic violence and abuse (see Who should take action?) should:\n\nAddress the emotional, psychological and physical harms arising from a child or young person being affected by domestic violence and abuse, as well as their safety. This includes the wider educational, behavioural and social effects.\n\nProvide a coordinated package of care and support that takes individual preferences and needs into account.\n\nEnsure the support matches the child's developmental stage (for example, infant, pre-adolescent or adolescent). Interventions should be timely and should continue over a long enough period to achieve lasting effects. Recognise that long-term interventions are more effective.\n\nProvide interventions that aim to strengthen the relationship between the child or young person and their non-abusive parent or carer. This may involve individual or group sessions, or both. The sessions should include advocacy, therapy and other support that addresses the impact of domestic violence and abuse on parenting. Sessions should be delivered to children and their non-abusive parent or carer in parallel, or together.\n\nProvide support and services for children and young people experiencing domestic violence and abuse in their own intimate relationships.\n\n# Recommendation 12 Provide specialist advice, advocacy and support as part of a comprehensive referral pathway\n\nHealth and social care commissioners, health and wellbeing boards and practitioners in specialist domestic and sexual violence services (see Who should take action?) should:\n\nProvide all those currently (or recently) affected by domestic violence and abuse with advocacy and advice services tailored to their level of risk and specific needs. This includes providing support in different languages, as necessary.\n\nEnsure practitioners are aware of how discrimination, prejudice and other issues, such as insecure immigration status, may have affected the risk that people using their services face.\n\nEnsure specialist support services meet national standards of good practice.\n\nEnsure specialist advice, advocacy and support forms part of a comprehensive referral pathway (see recommendation 4).\n\nEnsure the support is offered (although not necessarily delivered) in settings where people may be identified or may disclose that domestic violence and abuse is occurring. Examples include: accident and emergency departments, general practices, refuges, sexual health clinics and maternity, mental health, rape crisis, sexual violence, alcohol or drug misuse and abortion services.\n\n# Recommendation 13 Provide people who experience domestic violence and abuse and have a mental health condition with evidence-based treatment for that condition\n\nHealth, police and crime commissioners, health and social care providers and practitioners in primary, mental health and related care services (see Who should take action?) should:\n\nWhere people who experience domestic violence and abuse have a mental health condition (either pre-existing or as a consequence of the violence and abuse), provide evidence-based treatment for the condition.\n\nEnsure mental health interventions are provided by professionals trained in how to address domestic violence and abuse. Interventions may include psychological therapy (for example, trauma-focused cognitive behavioural therapy), medication and support, in accordance with national guidelines.\n\nEnsure any treatment programme includes an ongoing assessment of the risk of further domestic violence and abuse, collaborative safety planning and the offer of a referral to specialist domestic violence and abuse support services. It must also take into account the person's preferences and whether the violence and abuse is ongoing or historic.\n\n# Recommendation 14 Commission and evaluate tailored interventions for people who perpetrate domestic violence and abuse\n\nHealth and wellbeing boards and commissioners who commission perpetrator interventions should:\n\nCommission robust evaluations of the interventions to inform future commissioning.\n\nIdentify, and link with, existing initiatives that work with people who perpetrate domestic violence and abuse.\n\nCommission tailored interventions for people who perpetrate domestic violence and abuse, in accordance with national standards and based on the local needs assessment (see recommendation 1).\n\nEnsure interventions primarily aim to increase the safety of the perpetrator's partner and children (if they have any). Ensure this is monitored and reported. In addition, staff should report on the perpetrators' attitudinal change, their understanding of violence and accountability, and their ability and willingness to seek help.\n\nLink perpetrator services with services providing specialist support for those experiencing domestic violence and abuse (including children and young people). For example, link ongoing risk assessments of the perpetrator with safety planning and support provided by specialist services.\n\nSee also recommendations 2–4.\n\n# Recommendation 15 Provide specific training for health and social care professionals in how to respond to domestic violence and abuse\n\nOrganisations responsible for training and registration standards and providers of health and social care training (see Who should take action?) should provide different levels of training for different groups of professionals, as follows.\n\nTraining to provide a universal response should give staff a basic understanding of the dynamics of domestic violence and abuse and its links to mental health and alcohol and drug misuse, along with their legal duties. In addition, it should cover the concept of shame that is associated with 'honour'-based violence and an awareness of diversity and equality issues. It should also ensure staff know what to do next:\n\n\n\nLevel 1 Staff should be trained to respond to a disclosure of domestic violence and abuse sensitively and in a way that ensures people's safety. They should also be able to direct people to specialist services. This level of training is for: physiotherapists, speech therapists, dentists, youth workers, care assistants, receptionists, interpreters and non-specialist voluntary and community sector workers.\n\nLevel 2 Staff should be trained to ask about domestic violence and abuse in a way that makes it easier for people to disclose it. This involves an understanding of the epidemiology of domestic violence and abuse, how it affects people's lives and the role of professionals in intervening safely. Staff should also be able to respond with empathy and understanding, assess someone's immediate safety and offer referral to specialist services. Typically this level of training is for: nurses, accident and emergency doctors, adult social care staff, ambulance staff, children's centre staff, children and family social care staff, GPs, mental health professionals, midwives, health visitors, paediatricians, health and social care professionals in education (including school nurses), prison staff and alcohol and drug misuse workers. In some cases, it will also be relevant for youth workers.\n\n\n\nTraining to provide a specialist response should equip staff with a more detailed understanding of domestic violence and abuse and more specialist skills:\n\n\n\nLevel 3 Staff should be trained to provide an initial response that includes risk identification and assessment, safety planning and continued liaison with specialist support services. Typically this is for: child safeguarding social workers, safeguarding nurses, midwives and health visitors with additional domestic violence and abuse training, multi-agency risk assessment conference representatives and adult safeguarding staff.\n\nLevel 4 Staff should be trained to give expert advice and support to people experiencing domestic violence and abuse. This is for specialists in domestic violence and abuse. For example, domestic violence advocates or support workers, independent domestic violence advisers or independent sexual violence advisers, refuge staff, domestic violence and abuse and sexual violence counsellors and therapists, and children's workers.\n\n\n\nOther training to raise awareness of, and address misconceptions about, domestic violence and abuse issues and the skills, specialist services and training needed to provide people with effective support. This is for: commissioners, managers and others in strategic roles within health and social care services.\n\nOrganisations responsible for training and registration standards and providers of health and social care training should ensure:\n\nThe higher levels of training include increasing amounts of face-to-face interaction, although level 1 training can be delivered mostly online or by distance learning.\n\nFace-to-face training covers the practicalities of enabling someone to disclose that they are affected by domestic violence and abuse and how to respond.\n\n# Recommendation 16 GP practices and other agencies should include training on, and a referral pathway for, domestic violence and abuse\n\nNHS England, commissioners and GPs should commission integrated training and referral pathways for domestic violence and abuse. This should include education for clinicians and administrative staff in GP practices on how to make it easier for people to disclose domestic violence and abuse. It should also include education for clinicians on how to provide immediate support after a disclosure and how to make referrals to specialist agencies.\n\nManagers of specialist domestic violence and abuse services, clinical commissioning groups and public health departments should work in partnership with voluntary and community agencies to develop training and referral pathways for domestic violence and abuse.\n\n# Recommendation 17 Pre-qualifying training and continuing professional development for health and social care professionals should include domestic violence and abuse\n\nOrganisations responsible for training and registration standards and providers of health and social care training (see Who should take action?) should:\n\nEnsure training about domestic violence and abuse is part of the undergraduate or pre-qualifying curriculum, and part of the continuing professional development, for health and social care professionals who come into contact with service users. It should be delivered in partnership with local specialist domestic violence and abuse services and include face-to-face contact, even if it is mainly delivered online.\n\nImplement a rolling training programme that recognises the turnover of staff and the need for follow-up. The training strategy should:\n\n\n\nbe clear about the level of competency needed for each role (see recommendation 15)\n\nrefer to existing accredited materials from specialist organisations working in domestic violence and abuse, if they are suitable\n\nensure the content on domestic violence and abuse is linked to child welfare, safeguarding and adult protection services, and vice versa\n\nfollow the recommended content for each level (see recommendation 15).\n\n", 'Who should take action?': '# Introduction\n\nThe guidance is for everyone working in health and social care whose work brings them into contact with people who experience or perpetrate domestic violence and abuse.\n\nThis includes: people working in criminal justice settings and detention centres, health and social care commissioners, including clinical commissioning groups and local authorities, and staff working for specialist domestic violence and abuse services. The latter could be working in local authorities, the NHS and other organisations in the public, private, voluntary and community sectors. The guidance is also aimed at local strategic partnerships and health and wellbeing boards.\n\nIn addition, it will be of interest to people affected by domestic violence and abuse, including those who perpetrate it, those who experience it, their families or carers and other members of the public.\n\n# Who should do what at a glance\n\nWho should take action\n\nRecommendation\n\nNHS England\n\n\n\nOrganisations that coordinate or offer training, or that register and set standards for professionals\n\n, 17\n\nHealth services, local authorities and strategic partnerships (including health and wellbeing boards)\n\n, 2, 3, 12, 13, 14\n\nLocal safeguarding children boards and other local partnerships with a responsibility for safeguarding children\n\n, 11\n\nCommissioners\n\n, 3, 4, 7, 9, 11, 12, 13, 14, 15, 16, 17\n\nHeads and managers of health and social care services\n\n, 6, 15, 17\n\nService providers\n\n, 7, 8, 9, 10, 11, 13, 16\n\nHealth and social care staff\n\n, 8, 12, 13\n\n# Who should take action in detail\n\n## Recommendation 1\n\nLocal, regional and national commissioners of domestic violence and abuse services and related services; strategic partnerships, for example, health and wellbeing boards, local domestic violence partnerships; community safety partnerships\n\n## Recommendation 2\n\nLocal authorities, health services and their strategic partners (including those in the voluntary and community sectors)\n\n## Recommendation 3\n\nLocal strategic partnerships on domestic violence and abuse; commissioners, including clinical commissioning groups and local authorities\n\n## Recommendation 4\n\nCommissioners of health and social care services\n\n## Recommendation 5\n\nHealth and social care service managers in the statutory, voluntary, community and private sectors; specialist domestic violence and abuse services and related services. The latter includes: criminal justice, early years and youth services, housing, the police, prison and probation services, schools and colleges, and services for older people\n\n## Recommendation 6\n\nHealth and social care service managers and professionals\n\n## Recommendation 7\n\nHealth, social care, education, criminal justice, probation and voluntary and community sector commissioners and service providers involved with those who experience or perpetrate domestic violence and abuse\n\n## Recommendation 8\n\nManagers of domestic violence and abuse services; staff in all health and social care settings, including the public, voluntary and community sectors, and those they work with. The latter includes: criminal justice, including prisons, early years and youth services, housing, the police, schools and colleges, and services for older people\n\n## Recommendation 9\n\nHealth and social care commissioners and service providers in the public, voluntary and community sector; managers and commissioners of interpreting services\n\n## Recommendation 10\n\nLocal safeguarding children boards and other local partnerships with a responsibility for safeguarding children; providers of services where children and young people who are affected by domestic violence and abuse may be identified in the public, community and voluntary sectors. The latter includes: accident and emergency departments, child and adolescent mental health services, dental services, GP practices, health visiting, maternity services, sexual health services and other health services; early years services, schools and colleges, school nursing services; social care; specialist paediatric services for child safeguarding and looked after children; alcohol and drug misuse services; youth services; youth justice services\n\n## Recommendation 11\n\nLocal safeguarding children boards and other local partnerships with a responsibility for safeguarding children; commissioners and providers of specialist services for children and young people who are affected by domestic violence and abuse in the public, community and voluntary sectors. The latter includes: child and adolescent mental health, health visiting, sexual health, social care and specialist paediatric services for child safeguarding and looked after children, and youth services\n\n## Recommendation 12\n\nHealth and social care commissioners (including clinical commissioning groups, local authority commissioners and police and crime commissioners); health and wellbeing boards; frontline practitioners in specialist domestic and sexual violence services (for example, domestic violence and abuse advisers, people working in refuges or outreach services)\n\n## Recommendation 13\n\nClinical commissioning groups and specialist commissioners; police and crime commissioners; health and wellbeing boards; providers of primary care and mental health care services in the private, voluntary and community sectors. The latter includes: health and social care professionals working in alcohol and drug misuse services, detention centres and criminal justice settings\n\n## Recommendation 14\n\nHealth and wellbeing boards; commissioners of tailored interventions for people who perpetrate domestic violence and abuse\n\n## Recommendation 15\n\nRoyal colleges and professional organisations responsible for setting training and registration standards for clinical, social workers and social care staff; commissioners; Health Education England; heads of health, social care and related services; universities and other providers of health and social care training, including interpreting\n\n## Recommendation 16\n\nNHS England, commissioners and service managers working in specialist domestic violence and abuse services, GPs\n\n## Recommendation 17\n\nRoyal colleges and professional organisations responsible for setting training and registration standards for relevant clinical, social workers and social care staff; heads of health, social care and related services; universities and other providers of health and social care training for professionals who come into contact with service users, including interpreters', 'Context': "# Introduction\n\nAt least 1.2\xa0million women and 784,000 men aged 16 to 59 in England and Wales experienced domestic abuse in 2010/11 – 7.4% of women and 4.8% of men. (Domestic violence and abuse here is defined as: physical abuse, threats, non-physical abuse, sexual assault or stalking perpetrated by a partner, ex-partner or family member.) At least 29.9% of women and 17.0% of men in England and Wales have, at some point, experienced it (Smith et al. 2012).\n\nThese figures are likely to be an underestimate, because all types of domestic violence and abuse are under-reported in health and social research, to the police and other services.\n\nBoth men and women may perpetrate or experience domestic violence and abuse. However, it is more commonly inflicted on women by men. This is particularly true for severe and repeated violence and sexual assault.\n\nLesbian and bisexual women experience domestic violence and abuse at a similar rate to women in general (1 in 4), although a third of this is associated with male perpetrators (Hunt and Fish. 2008). Compared with 17% of men in general, 49% of gay and bisexual men have experienced at least 1 incident of domestic violence and abuse since the age of 16. This includes domestic violence and abuse within same-sex relationships (Stonewall Gay and Bisexual Men's Health Survey 2012). A focus on specific incidents and episodes is of limited value in understanding the experience of domestic abuse.\n\n# Associated risk factors\n\nThe risk of experiencing domestic violence or abuse is increased if someone:\n\nis female\n\nis aged 16–24 (women) or 16–19 (men) (Smith et al. 2011)\n\nhas a long-term illness or disability – this almost doubles the risk (Smith et al. 2011)\n\nhas a mental health problem (Trevillion et al. 2012)\n\nis a woman who is separated (Smith et al. 2011) – there is an elevated risk of abuse around the time of separation (Richards 2004).The risk is also increased if a woman is pregnant or has recently given birth. Although pregnancy appears to offer protection for some women (Bowen et al. 2005) for others it increases the risk (Harrykissoon et al. 2002). In addition, there is a strong correlation between postnatal depression and domestic violence and abuse.\n\nThe majority of trans people (80%) experience emotional, physical or sexual abuse from a partner or ex-partner (Roch et al. 2010).\n\nJust under 40% (38.4%) of bisexual, gay and lesbian people class themselves as having experienced domestic violence and abuse. However, many more respondents reported behaviours that could be classed as domestic violence and abuse (Donovan et al. 2006).\n\nThe role played by alcohol or drug misuse in domestic violence and abuse is poorly understood. Research has indicated that 21% of people experiencing partner abuse in the past year thought the perpetrator was under the influence of alcohol and 8% under the influence of illicit drugs (Smith et al. 2012). People are thought to be at increased risk of substance dependency as a consequence of being the victim of domestic violence (Humphreys et. al. 2005).\n\n# Partner abuse among adults\n\nPartner abuse is the most prevalent form of domestic abuse. At least 26.6% of women and 14% of men have, at some point, experienced this since they were 16 (Smith et al. 2012). The prevalence is consistently higher among people in healthcare settings (Feder et al 2009).\n\nWomen are more likely than men to experience repeated partner abuse, partner abuse over a longer period of time, violence and more severe abuse (Smith et al. 2010). Women's reports of partner abuse are also more likely to indicate that it is part of a system of fear and coercive control (Hester and Westmarland 2005; Hester 2013).\n\nMen are less likely to report abuse to the police, and more likely to say this is because they consider it too trivial or not worth reporting (Smith et al. 2010).\n\nEach year since 1995, approximately half of all women aged 16 or older murdered in England and Wales were killed by their partner or ex-partner. Around 12% of men murdered each year from 1995 were killed by their partner or ex-partner (Smith et al. 2012; Thompson 2010).\n\n# Partner abuse among young people\n\nPartner violence is also prevalent in young people's relationships. In the UK in 2009, 72% of girls and 51% of boys aged 13 to 16 reported experiencing emotional violence in an intimate partner relationship, 31% of girls and 16% of boys reported sexual violence, and 25% of girls and 18% of boys experienced physical violence (Meltzer et al. 2009). Some form of severe domestic violence and abuse inflicted on them by a partner (Barter et al. 2009) was reported by 1 in 6 girls.\n\nIn line with research among adults, girls described more abuse, and more severe abuse, more direct intimidation and control, and more negative impacts.\n\nYoung people in same sex relationships were at greater risk than those in heterosexual relationships.\n\n# Domestic violence and abuse between parents\n\nDomestic violence and abuse between parents is the most frequently reported form of trauma for children (Meltzer et al. 2009). In the UK, 24.8% of those aged 18 to 24 reported that they experienced domestic violence and abuse during their childhood. Around 3% of those aged under 17 reported exposure to it in the past 12\xa0months (Radford et al. 2011).\n\nThe impact of living in a household where there is a regime of intimidation, control and violence differs by children's developmental age. However, whatever their age, it has an impact on their mental, emotional and psychological health and their social and educational development. It also affects their likelihood of experiencing or becoming a perpetrator of domestic violence and abuse as an adult, as well as exposing them directly to physical harm (Stanley 2011; Holt et al. 2008).\n\nThere is a strong association between domestic violence and abuse and other forms of child maltreatment: it was a feature of family life in 63% of the serious case reviews carried out between 2009 and 2011 (Brandon et al. 2012).\n\n# 'Honour'-based violence and forced marriage\n\nIt is difficult to estimate the prevalence of so-called 'honour'-based violence and forced marriage, but we do know that the incidences of both are under-reported. Both can occur in Christian, Jewish, Sikh, Hindu, Muslim and other communities. They are probably more common in some groups, for example, some Pakistani, Kurdish, and Gypsy and Traveller communities, reflecting a more oppressive patriarchal ideology. (Home Affairs Select Committee 2008; Brandon and Hafez 2008).\n\nBoth often involve wider family members and affect men, as well as women: 22% of the 1468 cases looked at by the Forced Marriage Unit involved a male being forced to marry. It is estimated that between 5000 and 8000 cases of forced marriage were reported to local and national organisations in England in 2008. In 41% of cases reported to local organisations the person forced to marry was younger than 18 (Kazmirski et al. 2009).\n\n# Abuse of older people\n\nMore than 250,000 older people (aged 66 and older) living in England in private households reported experiencing maltreatment from a family member, close friend or care workers in the past year (O'Keefe et al. 2007). Maltreatment included neglect and psychological, physical, sexual and financial abuse.\n\nOf those experiencing maltreatment, 51% experienced it from a partner, 49% from another family member, 5% from a close friend and 13% from a care worker. Women were more likely to experience maltreatment than men (3.8% of women and 1.1% of men in the past year), and men were more often the perpetrators.\n\n# Abuse of parents by children\n\nThe prevalence of abuse of parents by their children is very difficult to ascertain and 'still lies in a veil of secrecy' (Kennair and Mellor 2007). It is 'a pattern of behaviour that uses verbal, financial, physical or emotional means to practise power and exert control over a parent' (Holt 2012). It is more commonly experienced by mothers than fathers – and is more common among single parents.\n\nIt can bring stress, fear, shame and guilt, as well as physical, emotional and psychological harm to the person who experiences it. Those inflicting the abuse may feel inadequate, hopeless and alone (Holt 2012; Kennair and Mellor 2007). A large proportion of those inflicting the abuse will themselves have been physically or sexually abused or have witnessed abuse.\n\n# Public sector costs\n\nThe public service burden of domestic abuse is considerable. A high proportion of women attending accident and emergency departments, primary care, family planning, reproductive and sexual health settings are likely to have experienced domestic violence and abuse at some point (Alhabib et al. 2010; Feder et al. 2009). In addition, between 25 and 56% of female psychiatric patients report experiencing domestic violence and abuse in their lifetime (Oram et al. 2013).\n\nDomestic violence and abuse cost the UK an estimated £15.7\xa0billion in 2008 (Walby 2009). This included:\n\njust over £9.9\xa0billon in 'human and emotional' costs\n\nmore than £3.8\xa0billion for the criminal justice system, civil legal services, healthcare, social services, housing and refuges\n\nmore than £1.9\xa0billion for the economy (based on time off work for injuries).", 'Considerations': "The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations, as follows. Please note: this section does not contain recommendations (see Recommendations.)\n\n# General\n\nThe PDG agreed that domestic violence and abuse occurs in all communities.\n\nThe PDG was clear that both women and men can experience domestic violence in heterosexual and same sex relationships. The likelihood of ever experiencing a physical assault from a partner or adult family member is higher among heterosexual women than men. Moreover, heterosexual women experience more repeated physical violence, more severe violence, much more sexual violence, more coercive control, more injuries and more fear of their partner than heterosexual men.\n\nAlthough domestic violence and abuse research and services mainly focus on intimate partners, this type of violence and abuse takes many forms. Examples include: forced marriage, violence connected to 'honour', violence against adults by their children, abuse of older people and other intra-familial abuse. However, evidence of effective interventions in these areas is lacking.\n\nThe PDG recognised the important role that the experiences, views and preferences of those who have experienced domestic violence should have in the development of policy and services. However, it did not hear evidence from them directly; this was largely outside the scope of the evidence reviews due to a focus on evaluation of interventions and the quality appraisal system used. However, the PDG did receive very helpful expert evidence and reports from people working in the specialist domestic violence sector and directly with service users. Such organisations were also represented by PDG members.\n\nThe PDG agreed that, rather than use the terms 'victim' or 'survivor', the Group would refer to 'people who have experienced domestic violence and abuse'.\n\nThe PDG thought it likely that domestic violence and abuse services could also benefit the extended family and friends of people who directly experience domestic violence and abuse. However, these effects have not been studied.\n\nThe PDG was aware that much of the expertise and support for people who experience domestic violence and abuse lies in the voluntary and community sector, where funding and capacity is generally limited.\n\nThe PDG was aware that domestic violence and abuse is often one of several problems that a couple or family may face. For example, it may be combined with poverty, drug and alcohol misuse or mental health problems. Most of the evidence relates to male violence against women and children in heterosexual relationships. However, the PDG noted that domestic violence and abuse affects: bisexual, gay, lesbian and trans relationships, and reconstituted (or step) and more complex families. In such cases, the Group noted that people may face particular barriers to accessing support and may have specific needs.\n\n# Children who are affected by domestic violence and abuse\n\nThe PDG recognised the wide range of ill-effects that exposure to domestic violence and abuse can have on children and young people, including the effect on their social, emotional, psychological and educational wellbeing and development. It also recognised that providing effective interventions and support may reduce the likelihood of them being affected by, or perpetrating, domestic violence and abuse in adulthood.\n\nThe PDG noted the importance of working concurrently with both the non-abusive parent or carer and child, rather than just focusing on the parent. Research on the effectiveness of parent/carer-child interventions has focused exclusively on mothers. Given the profile of domestic violence and abuse, that is where the biggest need for services is likely to be, but provision is needed for all families. The PDG agreed that evaluation of programmes where the father is the non-abusive carer will be especially important in light of the current lack of evidence about effective interventions.\n\nThe PDG noted that domestic violence and abuse – and children's exposure to it – often continues beyond the end of the adults' relationship.\n\nThe evidence linking effectiveness to the length of interventions for children is unclear. But it appears that longer interventions are more effective. This may be particularly true in complex cases.\n\nThe PDG did not consider evidence on the timeliness of interventions for children, but the Group was aware of a developing body of literature in this area.\n\nThe PDG noted the importance of ensuring services are appropriate to the age, gender and developmental stage of the child or young person. For example, teenagers may not want to be seen at the same time as their non-abusive parent or carer.\n\n# Identifying domestic violence or abuse\n\nThe PDG was aware that there is an ongoing debate about the effectiveness and desirability of screening, routine and targeted enquiries to identify people who are experiencing domestic violence and abuse. Currently there is insufficient evidence to recommend screening or routine enquiry in healthcare settings. Nevertheless, the PDG recognised that asking patients routinely about abuse in some specialised health care settings was considered good practice by professionals in those fields. The PDG acknowledged that people experiencing domestic violence and abuse may choose not to disclose it when asked by a healthcare or other professional. Or, if they do disclose, they do not want to be pressurised to give more details of the abuse or take a specific course of action (Feder 2006).\n\nThe PDG noted that healthcare professionals not trained to identify domestic violence and abuse may mislabel and misdiagnose people's problems, leading to inappropriate plans or ineffective remedies. (For example, specialists may be ordering unnecessary and expensive investigations and GPs may be prescribing inappropriate anxiolytics and antidepressants.)\n\n# Specialist support, advocacy, advice and skill building\n\nThere is no universally accepted understanding of what 'advocacy' means in the context of domestic violence and abuse. The PDG kept the term because it has been applied to a range of interventions that have been evaluated in research studies. A definition of advocacy was agreed for the purposes of this guidance.\n\nThe PDG noted that skill-building approaches might be of particular use in refuge settings, although they are also an intrinsic part of the advocacy and support role.\n\n# Programmes for people who perpetrate domestic violence and abuse\n\nThere is a lack of consistent evidence on the effectiveness of programmes for people who perpetrate domestic violence and abuse. The PDG noted that some evaluations take account of the partner's health and wellbeing and include their perception of any changes in the perpetrator's behaviour. However, these tend to be small-scale, uncontrolled studies.\n\nThe cost effectiveness analyses concluded that interventions with people who have experienced domestic violence and abuse are likely to be cost effective. However, this conclusion could not be extrapolated to interventions with perpetrators and the PDG was split on whether interventions with perpetrators should be recommended. However, members agreed that such interventions are an important part of domestic violence and abuse services and, provided they are supported by robust evaluation to inform future commissioning decisions, should be recommended.\n\nThe PDG noted that national programmes dealing with behaviour-change among perpetrators are aimed at heterosexuals. Members were unclear whether or not these programmes would also be effective for other groups.\n\n# Prevention\n\nMembers of the PDG (and stakeholders) were disappointed that the review did not find sufficient evidence to make recommendations on primary prevention programmes. This was partly because it looked only at health and social care – and currently most primary prevention interventions are delivered in education settings. However, the PDG agreed that prevention is an important area for future research (see Recommendations for research).\n\n# Training\n\nThe PDG discussed the relationship between training to support people affected by domestic violence and abuse and child safeguarding training. Overall, members agreed that there were obvious links between them. However, they did not necessarily think they should be combined. Members recommended that this question should be addressed in future research (see Recommendations for research).\n\n# Health economics\n\nThe economic modelling showed that effectiveness and cost-effectiveness in the medium to long term was less certain than in the shorter term. This was partly due to the short follow-up period applied to the studies used as the basis of the model. It was also due to the lack of longitudinal studies. However, even using conservative assumptions, it seems likely that the interventions will be cost-effective in the long term by stopping the violence and improving the mental health of all those involved.\n\nThe PDG was aware that lack of evidence about the medium- and long-term consequence of interventions meant the economic models would underestimate their cost effectiveness. For example, a reduction in the incidence of post-trauma-related stress disorder is likely to lead to additional benefits, such as being less depressed or having improved self-esteem. However, limited data on these benefits meant they could not be estimated in the model.\n\nAlthough the systematic review of cost-effectiveness studies only found one analysis (Devine 2012) and the economic modelling focused on 2 interventions, the findings are also relevant for interventions with similar benefits and similar (or lower) costs. The PDG noted that the potential health and non-health benefits of these interventions would outweigh the costs when the positive impacts on people experiencing the violence and abuse, their families and wider society were considered.", 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.\n\nHow effective are programmes that aim to prevent domestic violence and abuse from ever happening in the first place? This includes media-based public health awareness campaigns. It also includes social movements to establish people's rights, and community-building and primary prevention activities that tackle underlying assumptions in society. (Examples of the latter might include the role and status of women.)\n\nHow effective are combinations of interventions to deal with domestic violence and abuse in the short, medium and long term? Are the outcomes sustainable and do they have a beneficial effect on quality of life and health in the longer term?\n\nHow effective are the following interventions in the short, medium and long term, across various levels of risk and including diverse and marginalised groups:\n\nadvocacy\n\ndomestic abuse recovery programmes\n\nperpetrator programmes\n\npsychological or social interventions modified for domestic violence and abuse, including programmes for those who have suffered multiple forms of abuse and those who are still experiencing it\n\ninterventions for primary carers apart from mothers (for example, fathers, grandparents)\n\ninterventions for other family members?\n\nWhat are the most appropriate ways to collect and manage data about domestic violence and abuse across the health, social care and criminal justice sectors? Is there value in collecting anonymised aggregate data, or is there a more useful method of data capture?\n\nWhat type of interventions (including training and referral pathways), in diverse health care settings, provide the most effective support for practitioners working with people who are experiencing, or have experienced, domestic violence and abuse?\n\nMore detail identified during development of this guidance is provided in Gaps in the evidence.", 'Related NICE guidance': 'Common mental health disorders. NICE clinical guideline 123 (2011)\n\nDepression in adults (update). NICE clinical guideline 90 (2009)\n\nAlcohol dependence and harmful alcohol use. NICE clinical guideline 115 (2011)\n\nPregnancy and complex social factors. NICE clinical guideline 110 (2010)\n\nLooked-after children and young people. NICE public health guidance 28 (2010)\n\nAlcohol-use disorders: preventing harmful drinking. NICE public health guidance 24 (2010)\n\nWhen to suspect child maltreatment. NICE clinical guideline 89 (2009)\n\nAntisocial personality disorder. NICE clinical guideline 77 (2009)\n\nAntenatal care. NICE clinical guideline 62 (2008)\n\nAntenatal and postnatal mental health. NICE clinical guideline 45 (2007)\n\nPostnatal care. NICE clinical guideline 37 (2006)\n\nPost-traumatic stress disorder (PTSD). NICE clinical guideline 26 (2005)', 'Glossary ': "# Advocacy\n\nIn general, advocacy for people who have experienced domestic violence includes:\n\nlegal, housing and financial advice\n\naccess to and use of community resources such as refuges, emergency housing and psychological interventions\n\nsafety planning advice.\n\nThe activities may differ according to the level of risk facing the person. Crisis advocacy involves working with the person for a limited period of time (they may then be referred on to more specialised agencies).\n\nPractitioners providing advocacy can also provide ongoing support and informal counselling. The intensity of the advocacy provided may vary. It may last for a year – or longer, if the person is particularly vulnerable.\n\n# Coercive behaviour\n\nCoercive behaviour is an act, or a pattern of acts, involving assault, threats, humiliation and intimidation or other abuse, to harm, punish or frighten someone. This includes so-called 'honour'-based violence and forced marriage. People who experience domestic violence can be male or female and from any ethnic group. (Home Office Ending violence against women and girls in the UK [accessed 6 November 2012].)\n\n# Controlling behaviour\n\nControlling behaviour involves a range of acts designed to make a person subordinate or dependent. This could range from isolating them from sources of support to exploiting them for personal gain. It can also involve depriving them of the means to be independent, including stopping them from leaving and regulating their everyday behaviour. (Home Office New definition of domestic violence, 18 September 2012).\n\n# Children and young people affected by domestic violence and abuse\n\nChildren (aged under 16) and young people (aged 16 to 18) can experience domestic violence and abuse:\n\nwhen they are affected by it; this includes fearing, hearing or seeing it within their families, or worrying about its effects on someone else\n\nwithin their own intimate relationships.\n\nYoung people may also perpetrate domestic violence and abuse in their own intimate relationships and on their parents or carers.\n\n# Disclosure\n\nFor the purpose of this guidance, disclosure is defined as any occasion when an adult or child who has experienced or perpetrated domestic violence or abuse informs a health or social care worker or any other third party.\n\n# Domestic violence and abuse\n\nThe term 'domestic violence and abuse' is used to mean: any incident or pattern of incidents of controlling, coercive or threatening behaviour, violence or abuse between those aged 16 or over who are, or have been, intimate partners or are family members. This includes: psychological, physical, sexual, financial and emotional abuse. It also includes 'honour'-based violence and forced marriage. For the purposes of this document, it does not include female genital mutilation, which may be referred to NICE as a future topic.\n\n# Elder abuse or maltreatment\n\nAction or neglect, within a relationship in which there is an expectation of trust, that causes harm or distress to a person older than 60. The abuse can take various forms: physical, verbal, psychological, sexual and financial.\n\n# Floating support\n\nIn the context of this guidance, floating support is a housing service designed to prevent tenancy breakdowns. Floating support can also provide help with:\n\nkeeping safe and security measures\n\naccessing legal advice and options\n\nwelfare benefits\n\nbudgeting and debts\n\nlife skills\n\nresettlement or re-housing\n\naccessing community services\n\nform filling\n\npre-tenancy support\n\ntraining, education and employment\n\n# Forced marriage\n\nA forced marriage is one in which one or both spouses do not (or, in the case of some adults with learning or physical disabilities, cannot) consent to the marriage but are forced into it using physical, psychological, financial, sexual or emotional pressure. ('Handling cases of forced marriage', HM Government 2008). It is distinct from an arranged marriage that both partners enter into freely.\n\n# 'Honour'-based violence or 'honour' violence\n\nA crime or incident committed (or possibly committed) to protect or defend the perceived 'honour' of a family or community. Often this term is enclosed in quote marks, or prefaced with 'so-called', to emphasise that the concept of honour in these cases is contested and that it is generally invoked as a means of power and control.\n\n# Independent domestic violence advisers (IDVAs)\n\nAlso known as independent domestic violence advocates, IDVAs work primarily with people at high risk of domestic violence and abuse, independently of any one agency, to secure their safety and the safety of their children. Serving as the primary point of contact, IDVAs normally work with their clients from the point of crisis to assess the level of risk, discuss the options and develop plans that address their immediate safety, as well as longer-term solutions. In many areas they are funded by the local community safety partnership, in some areas they are funded by the police or local authorities.\n\n# Indicators\n\nIndicators are presenting problems or conditions that are associated with domestic violence and abuse. They can include:\n\nsymptoms of depression, anxiety, post-traumatic stress disorder, sleep disorders\n\nsuicidal tendencies or self-harming\n\nalcohol or other substance use\n\nunexplained chronic gastrointestinal symptoms\n\nunexplained reproductive symptoms, including pelvic pain and sexual dysfunction\n\nadverse reproductive outcomes, including multiple unintended pregnancies or terminations, delayed pregnancy care, miscarriage, premature labour and stillbirth\n\nunexplained genitourinary symptoms, including frequent bladder or kidney infections\n\nvaginal bleeding or sexually transmitted infections\n\nchronic pain (unexplained)\n\ntraumatic injury, particularly if repeated and with vague or implausible explanations\n\nproblems with the central nervous system – headaches, cognitive problems, hearing loss\n\nrepeated health consultations with no clear diagnosis\n\nintrusive 'other person' in consultations including partner or husband, parent, grandparent or an adult child (for elder abuse).\n\n(Adapted from Black 2011.)\n\n# Multi-agency risk assessment conferences (MARACs)\n\nRegular meetings at which information about people experiencing domestic violence or abuse and who are at high risk (those at risk of homicide or serious harm) is shared between local agencies. Whenever possible, the person who experiences the violence is represented by an independent domestic violence adviser or advocate (IDVA). Participants aim to draw up a coordinated safety plan to support the person. In many areas they are funded by the local community safety partnership, in some areas they are funded by the police or local authorities.\n\n# No recourse to public funds\n\n'No recourse to public funds' is a term used for people who are not entitled to welfare benefits, home office asylum support, public housing and other public funds and services. The term derives from the 'no recourse to public funds' condition applied to certain immigration statuses. 'Public funds' refers to a range of benefits including housing support, carer's allowance, child benefit, disability living allowance, housing benefit, income support and social fund payments.\n\n# Parenting support\n\nInterventions that aim to improve parents' understanding of how domestic violence and abuse affects children and how to protect them. Most of the interventions found to be effective focus on non-abusive mothers and on strengthening the mother–child bond.\n\n# People who experience domestic violence and abuse\n\nThroughout this guidance, 'people who experience domestic violence and abuse' refers to those who are victims or survivors of the violence and abuse.\n\n# Protected characteristics\n\nThe Equality Act (2010) makes it illegal to discriminate against anyone because of:\n\nage\n\nbeing or becoming a transsexual person\n\nbeing married or in a civil partnership\n\nbeing pregnant or having a child\n\ndisability\n\nrace including colour, nationality, ethnic or national origin\n\nreligion, belief or lack of religion/belief\n\nsex\n\nsexual orientation.\n\nThese are called 'protected characteristics'.\n\n# Refuge or shelter\n\nResidential service – a safe house – provided for adults (usually women) and children who are experiencing domestic violence and abuse.\n\n# Risk identification and assessment\n\nThis process is undertaken with people who have disclosed that they are the victims of domestic violence and abuse. The aim is to evaluate their risk of further harm. Practitioners with level\xa02 training assess their immediate safety, for example, whether it is safe for the person to go home. Practitioners with level\xa03 training identify the risks faced in more detail to inform safety planning, referrals to specialist support services and to aid any police investigation. Almost all police forces in England and Wales use the DASH (domestic abuse, stalking and harassment and 'honour'-based violence) risk identification tool and guidance. A multi-sectoral version, CAADA-DASH, is used by independent domestic violence advisers, some domestic violence advocates and support workers, other specialist domestic abuse services and some health and social care practitioners.\n\n# Safety planning\n\nAn intervention to help people judge their risk of violence, identify the warning signs and develop plans on what to do when violence is imminent or is happening.\n\n# Skill building\n\nTraining and education to improve the skills of people who have experienced domestic violence and abuse. Typically it covers: problem solving and decision making, resilience and coping, financial skills, and understanding the dynamics of domestic violence and abuse. Sometimes it also includes other components; for example, relaxation and parenting skills.\n\n# Therapy\n\nA structured psychological or psychiatric treatment delivered by professional clinicians, such as psychologists. Therapeutic interventions may be delivered in an individual or group format.\n\n# Trans people\n\nTrans is an umbrella term. It includes cross-dressers, transgender and transsexual people as well as anyone else who is in any way gender-variant.", 'References': "Alhabib S, Nur U, Jones R (2010) Domestic violence against women: systematic review of prevalence studies. Journal of Family Violence 25: 369–82\n\nBarter C, McCarry M, Berridge D et al. (2009) Partner exploitation and violence in teenage intimate relationships. London: NSPCC\n\nBlack MC (2011) Intimate partner violence and adverse health consequences: implications for clinicians. American Journal of Lifestyle Medicine 5: 428–39\n\nBowen E, Heron J, Waylen A et al. (2005) Domestic violence risk during and after pregnancy: findings from a British longitudinal study. BJOG: An International Journal of Obstetrics and Gynaecology 112: 1083–9\n\nBrandon J, Hafez S (2008) Crimes of the community – honour-based violence in the UK. London: Centre for Social Cohesion\n\nBrandon M, Sidebotham P, Bailey S et al. (2012) New learning from serious case reviews: a two year report for 2009–11. London: Department for Education\n\nDevine A, Spencer A, Eldridge S et al. (2010) Cost-effectiveness of Identification and Referral to Improve Safety (IRIS), a domestic violence training and support programme for primary care: a modelling study based on a randomised controlled trial. BMJ Open 2: e001008\n\nDick S (2008) Homophobic hate crime The Gay British Crime Survey. London: Stonewall\n\nDonovan C, Hester M, Holmes J et al. (2006) Comparing domestic abuse in same sex and heterosexual relationships [online]\n\nFeder GS, Hutson M, Ramsay J et al. (2006) Women exposed to intimate partner violence: expectations and experiences when they encounter health care professionals: a meta-analysis of qualitative studies. Archives of Internal Medicine 166: 22–37\n\nFeder G, Ramsay J, Dunne D et al. (2009) How far does screening women for domestic (partner) violence in different health-care settings meet criteria for a screening programme? Systematic reviews of nine UK National Screening Committee criteria. Health Technology Assessment 13 (16)\n\nHarrykissoon SD, Vaughn IR, Wiemann CM (2002) Prevalence and patterns of intimate partner violence among adolescent mothers during the postpartum period. Archives of Paediatrics and Adolescent Medicine 156: 325–30\n\nHester M (2013) Who does what to whom? Gender and domestic violence perpetrators in English police records. European Journal of Criminology 10: 623–637\n\nHester M, Westmarland N (2005) Tackling domestic violence: effective interventions and approaches. London: Home Office Research, Development and Statistics Directorate\n\nHolt A (2012) Adolescent-to-parent abuse: current understandings in research, policy and practice. Bristol: The Policy Press\n\nHolt S, Buckley H, Whelan S (2008) The impact of exposure to domestic violence on children and young people: a review of the literature. Child Abuse and Neglect 32: 797–810\n\nHome Affairs Select Committee (2008) Domestic violence, forced marriage and 'honour'-based violence. London: House of Commons\n\nHumphreys C, Regan L, River D et al (2005) Domestic Violence and Substance Use: Tackling Complexity. British Journal of Social Work 35: 1303–20\n\nHunt R, Fish J (2008) Prescription for change: lesbian and bisexual women's health check. London: Stonewall\n\nKazmirski A, Keogh P, Kumari V et al. (2009) Forced marriage – prevalence and service response. London: Department for Children, Schools and Families\n\nKennair N, Mellor D (2007) Parent abuse: a review. Child Psychiatry & Human Development 38: 203–19\n\nMeltzer H, Doos L, Vostanis P et al. (2009) The mental health of children who witness domestic violence. Child and Family Social Work 14: 491–501\n\nMurphy CM, Ting L (2010) The effects of treatment for substance use problems on intimate partner violence: A review of empirical data. Aggression and Violent Behavior 15: 325–33\n\nNorman R, Spencer A, Eldridge S et al. (2010) Cost-effectiveness of a programme to detect and provide better care for female victims of intimate partner violence. Journal of Health Services Research and Policy 15: 143–9\n\nO'Keefe M, Hills A, Doyle M et al. (2007) UK study of abuse and neglect of older people. London: Department of Health\n\nOram S, Trevillion K, Feder G et al. (2013) Prevalence of experiences of domestic violence among psychiatric patients: systematic review. The British Journal of Psychiatry 202: 94–9\n\nRadford L, Corral S, Bradley C et al. (2011) Child abuse and neglect in the UK today. London: NSPCC\n\nRichards L (2004) Getting away with it: a strategic overview of domestic violence, sexual assault and serious incident analysis. London: Metropolitan Police Service\n\nRoch A, Morton J, Ritchie G et al. (2010) Abuse out of sight out of mind: transgender people's experiences of domestic abuse. LGBT Youth Scotland and the Equality Network [online]\n\nSmith K (ed), Coleman K, Eder S et al. (2011) Homicides, firearm offences and intimate violence 2009/10: supplementary volume 2 to Crime in England and Wales 2009/10 (2nd edition). London: Home Office\n\nSmith K (ed), Flatley J (ed), Coleman K et al. (2010) Homicides, firearm offences and intimate violence 2008/09: supplementary volume 2 to Crime in England and Wales 2008/09 (3rd edition). London: Home Office\n\nSmith K (ed), Osborne S, Lau I et al. (2012) Homicides, firearm offences and intimate violence 2010/11: supplementary volume 2 to Crime in England and Wales 2010/11. London: Home Office\n\nStanley N (2011) Children experiencing domestic violence: a research review. Dartington: Research in Practice\n\nStonewall (2012) Gay and Bisexual Men's Health Survey 2012 [online]\n\nThompson G (2010) Domestic violence statistics [online]\n\nTrevillion K, Oram S, Feder G et al. (2012) Experiences of domestic violence and mental disorders: a systematic review and meta-analysis. PLoS ONE 7: e51740.\n\nWalby S (2009) The cost of domestic violence: up-date 2009 [online].", 'Summary of the methods used to develop this guidance': "# Introduction\n\nThe review and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in About this guidance.\n\n# Guidance development\n\nThe stages involved in developing public health guidance are outlined in the box below.\n\n. Draft scope released for consultation\n\n. Stakeholder meeting about the draft scope\n\n. Stakeholder comments used to revise the scope\n\n. Final scope and responses to comments published on website\n\n. Evidence reviews and economic modelling undertaken and submitted to PDG\n\n. PDG produces draft recommendations\n\n. Draft guidance (and evidence) released for consultation and for field testing\n\n. PDG amends recommendations\n\n. Final guidance published on website\n\n. Responses to comments published on website\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were:\n\n. What types of intervention or approach are effective and cost effective in preventing domestic violence from ever happening in the first place (that is, primary prevention)?\n\n. What types of intervention or approach are effective and cost effective in helping all those working in health and social care to safely identify and, if appropriate, intervene to prevent domestic violence? Examples may include collaborative partnerships, advice and information-sharing protocols and specialised training, both on-the-job and pre-entry.\n\n. What types of intervention or approach are effective and cost effective in helping all those working in health and social care to respond to domestic violence? This may include interventions and approaches to assess and improve someone's safety, reduce the risk of harm, support their recovery and prevent a perpetrator reoffending. It may also include collaborative partnerships and advice and information-sharing protocols.\n\n. What types of intervention and approach are effective and cost effective in identifying and responding to children who are exposed to domestic violence in the various settings identified? (That is, the violence is not perpetrated on them directly but they witness or experience it.) Interventions could include collaborative partnerships and advice and information-sharing protocols.\n\n. What are the most effective and cost-effective types of partnership and partnership approaches for assessing and responding to domestic violence?\n\nThese questions were made more specific for the review (see review for further details).\n\n# Reviewing the evidence\n\n## Effectiveness reviews\n\nOne review of effectiveness was conducted.\n\nA number of databases were searched in May\xa02012 for randomised controlled trials (RCT), case-control studies, interrupted time series, cohort studies, cross-sectional studies, observational studies, systematic reviews and qualitative studies. See the review for details of the databases searched.\n\nA range of websites were searched manually for relevant grey literature.\n\nIn addition, the citation lists of all studies included in the review were searched and PDG members provided and discussed key literature 'virtually' with the external contractor. NICE also issued a call for evidence.\n\nStudies from countries in the Organisation for Economic Co-operation and Development (OECD) were included in the effectiveness review if they:\n\nevaluated an intervention or approach to identify, prevent, reduce or respond to domestic violence and abuse between adults and young people who were, or had been, intimate partners\n\nevaluated an intervention or approach to identify, prevent, reduce or respond to the abuse of older people by a family member\n\nfocused on healthcare, social care or specialised services that deal with domestic violence and abuse.\n\nStudies were excluded if they:\n\nfocused on children who directly experienced domestic violence and abuse and perpetrators whose violence is directed at children\n\nfocussed on female genital mutilation, violence perpetrated against older vulnerable people by paid carers or violence in occupational settings\n\nincluded interventions not linked to health and social care.\n\nSee the review for details of the inclusion and exclusion criteria.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in Methods for the development of NICE public health guidance. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution. Studies graded (−) were excluded from the review.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled, or not adequately described, are unlikely to alter the conclusions.\n\n− Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nThe evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable).\n\n## Summarising the evidence and making evidence statements\n\nThe review data were summarised in evidence tables (see full review).\n\nThe findings from the review and expert reports were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see About this guidance). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Cost effectiveness\n\nThere was a systematic review of economic evaluations and an economic modelling exercise.\n\n## Review of economic evaluations\n\nA search was undertaken using a search strategy developed by the review team. Studies were included if they focused on:\n\nfull economic evaluations of relevant types of intervention\n\nhigh quality costing studies relevant to the UK.\n\nStudies were categorised according to study type, methodological rigour and quality.\n\n## Economic modelling\n\nA number of assumptions were made that could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details).\n\nEconomic models were constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in: Economic analysis of interventions to reduce the incidence and harm of domestic violence and abuse.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice.\n\nIt was conducted with commissioners and practitioners, including directors of public health and mental health and substance misuse services who are involved in domestic violence and abuse services. They included: commissioners, primary and secondary health care professionals, police officers, public health specialists, specialist domestic violence staff and other representatives from local authorities and voluntary sector groups.\n\nThe fieldwork comprised:\n\nfocus groups and 20 in-depth interviews carried out in Birmingham, Bristol, Liverpool and London by Word of Mouth.\n\nThe 10 focus groups and 20 in-depth interviews were commissioned to ensure there was ample geographical coverage. The main issues arising are set out in section 10 under fieldwork findings. Or see Field testing NICE guidance on domestic violence and abuse: how social care, health services and those they work with can identify, prevent, and reduce domestic violence.\n\n# How the PDG formulated the recommendations\n\nAt its meetings in 2012/3 the Programme Development Group (PDG) considered the evidence, expert reports and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nThe PDG developed recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere evidence was lacking, the PDG also considered whether a recommendation should only be implemented as part of a research programme.\n\nWhere possible, recommendations were linked to an evidence statement(s) (see The evidence for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).", 'The evidence ': "The evidence statements from 1 review are provided by an external contractor (see Evidence). This section lists how the evidence statements and expert reports link to the relevant recommendations and sets out a brief summary of findings from the economic analysis and the fieldwork.\n\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document.\n\nEvidence statement number 1 indicates that the linked statement is numbered 1 in the review 'Review of interventions to identify, prevent, reduce and respond to domestic violence and abuse'. Evidence statement ER1 indicates that the evidence is in the expert report 1 'Current health and social care interventions on domestic violence and abuse'.\n\nThe review, expert reports and economic analysis are available online. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: ER1\n\nRecommendation 2: evidence statement 30–33\n\nRecommendation 3: evidence statements 30–33\n\nRecommendation 4: evidence statements 9, 30–-33\n\nRecommendation 5: evidence statements 3, 8, 9; ER2–5\n\nRecommendation 6: evidence statements 11–14\n\nRecommendation 7: evidence statements 3, 33\n\nRecommendation 8: evidence statements 8–10, 31\n\nRecommendation 9: evidence statement 33; ER2–5\n\nRecommendation 10: evidence statements 8, 9, 30–33\n\nRecommendation 11: evidence statements 27–29\n\nRecommendation 12: evidence statements 10–12, 27, 28\n\nRecommendation 13: evidence statements 13, 14\n\nRecommendation 14: evidence statements 15, 17; ER2\n\nRecommendation 15: evidence statements 8–10, 30\n\nRecommendation 16: evidence statements 8,9, 31–33\n\nRecommendation 17: evidence statements 8, 9, 30\n\n# Review of economic evaluation\n\nTwo papers were included in the review. These reported findings from a pilot intervention to prevent domestic violence (Norman et al. 2010) and a cluster RCT of the intervention (Devine et al. 2012).This multi-faceted intervention included: education of doctors about domestic violence and abuse; improved cross-system collaboration; use of electronic prompts for doctors to ask about intimate partner violence; use of prompts to encourage doctors to refer people who have experienced domestic violence to domestic violence and abuse advocates and to psychologists.\n\nModerate evidence from the UK perspective suggested that the interventions were cost effective, with an incremental cost–effectiveness ratio of £2450 when an additional quality-adjusted life year was valued at £20,000.\n\n# Economic modelling\n\nTwo interventions were modelled: the use of independent domestic violence services and cognitive trauma therapy for battered women.\n\nOverall, the independent domestic violence adviser service intervention was found to be cost saving (that is, it both saves resources and improves quality of life) compared with no intervention. The overall message is that the cost of domestic violence and abuse is so significant that even marginally effective interventions are cost effective.\n\nCognitive trauma therapy for battered women saved £15\xa0million by reducing the harm from domestic violence, compared with no intervention.\n\nThe results are subject to uncertainty and assumptions made in both models.\n\nThe key assumptions were explored in a series of sensitivity analyses. These analyses demonstrated that the interventions are cost effective, even when the costs and effects of the interventions varied.\n\nFull details can be found in the Economic analysis of interventions to reduce the incidence and harm of domestic violence and abuse.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, go to Fieldwork and Field testing NICE guidance on domestic violence and abuse: how social care, health services and those they work with can identify, prevent, and reduce domestic violence.\n\nFieldwork participants who come into contact with people who experience, or perpetrate, domestic violence and abuse were fairly positive about the recommendations and their potential to help identify, prevent and reduce this violence and abuse.\n\nMany welcomed the holistic (multi-agency and multi-sector) approach and the comprehensive scope of the guidance (covering everything from strategy development to service delivery). The inclusion of a key role for public health – including NHS services – was especially welcomed, because participants felt that domestic violence and abuse has not been seen as a priority by the health sector in the past.\n\nIf the recommendations are implemented, participants felt that the overall standard of domestic violence and abuse service provision was likely to improve. (According to participants, current provision varies by locality, due to the uncertain and short-term nature of funding arrangements.)\n\nHowever, recent changes in the commissioning of health and social care services were reported to have created confusion, with many participants saying that it is difficult to identify the relevant commissioners in their area. Some suggested that the guidance should more clearly identify accountable agencies and partnerships.", 'Gaps in the evidence': "The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence and expert comment. These gaps are set out below.\n\n. There is a lack of research on:\n\na) working with men who experience domestic violence and abuse\n\nb) 'honour'-based violence or forced marriage\n\nc) interventions to prevent elder abuse\n\nd) lesbian, gay, bisexual and trans people's experiences of domestic violence and abuse\n\ne) the differences in outcomes of interventions for women and men\n\nf) dating violence and intimate partner violence among adolescents\n\ng) tailored approaches for women facing different levels of risk\n\nh) whole-family interventions in response to domestic violence\n\ni) violence and abuse directed at parents, carers or siblings by children and young people\n\nj) stalking.\n\n. There is a lack of evidence on identifying people affected by domestic violence or abuse in social care settings and integrated approaches to identifying people across various health and social care settings. There is also a lack of evidence on integrated approaches to identifying coexisting issues, such as the links between domestic violence and substance use or mental health issues.\n\n. There is a lack of evidence on prevention interventions due to methodological issues including: short follow up, lack of comparisons of different interventions, lack of behavioural measures and reliance on self-reporting. In addition, most studies measured attitudes and knowledge, or exposure to educational materials and messages, rather than behavioural outcomes. Many included women who were already using refuge or shelter services, so the findings may not be applicable to those who are not using them.\n\n. There is a lack of large, robust studies of advocacy, skill development, counselling and other therapeutic approaches for people who have experienced domestic violence or abuse.\n\n. There is a lack of large, robust studies of interventions for people who perpetrate abuse. The majority were non-experimental (primarily before-and-after studies).Often they did not include a comparison group, had relatively small sample sizes, reported high rates of attrition and lacked follow up beyond programme completion.\n\n. There is a lack of high quality studies measuring the effects of multi-faceted and multi-sectorial approaches to the prevention of domestic violence. The majority were before and after, or qualitative studies providing narrative reports. Methodological weaknesses included: scant information on data collection, methods and analysis and small sample size (particularly for qualitative studies).\n\n. There is a lack of research on the impact of partnership working among agencies serving men or a range of subgroups of women experiencing violence. No studies discussed the effectiveness of partnership working for lesbian women who experience domestic violence.\n\nThe Committee made 4 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in Recommendations for research.", 'About this guidance': "# Why has this guidance been produced?\n\nIn 2008, the Department of Health (DH) asked the National Institute for Health and Care Excellence (NICE) to produce guidance on how to identify, prevent and reduce domestic violence and abuse. (See the scope.)\n\nThe PDG felt that the review did not find sufficient evidence for them to make recommendations on primary and secondary prevention programmes. This was partly because it looked only at health and social care settings and most primary prevention interventions are delivered in education settings.\n\nThere were other measures and interventions for which no evidence, or insufficient evidence, was identified. Their absence from the recommendations is a result of this lack of evidence and should not be taken as a judgement on whether they are effective.\n\nViolence and abuse can be perpetrated on children by adults ('child abuse'), but that is not dealt with in this guidance. NICE has produced guidance on child maltreatment.\n\n# How was this guidance developed?\n\nThis guidance was developed jointly by NICE and the Social Care Institute for Excellence (SCIE). SCIE provided particular input into discussions about what the guidance should cover.\n\nThe recommendations are based on the best available evidence. They were developed by the Programme Development Group (PDG).\n\nMembers of the PDG are listed in Membership of the Programme Development Group and the NICE project team.\n\nFor information on how NICE public health guidance is developed, see the NICE public health guidance process and methods guides.\n\n# What evidence is the guidance based on?\n\nThe evidence the PDG considered included:\n\nevidence review\n\nreview of economic evaluations and economic modelling\n\nexpert reports\n\nfieldwork report.\n\nIn some cases the evidence was insufficient and the PDG has made recommendations for future research. See Recommendations for research and Gaps in the evidence respectively.\n\n# Status of this guidance\n\nThe draft guidance, including the recommendations, was released for consultation in August 2013 At its meeting in November 2013, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in February 2014\n\nThe guidance is available on NICE's website. The recommendations are also available in a pathway for professionals whose remit includes public health and for interested members of the public.\n\n# Implementation\n\nNICE guidance can help:\n\nCommissioners and providers of NHS services to meet the quality requirements of the DH's Operating framework for 2012/13. It can also help them to deliver against domain 1 of the NHS outcomes framework (preventing people from dying prematurely).\n\nLocal health and wellbeing boards to deliver on their requirements within Healthy lives, healthy people (2010).\n\nLocal authorities, NHS services and local organisations determine how to improve health outcomes and reduce health inequalities during the joint strategic needs assessment process.\n\nNICE has developed tools to help organisations put this guidance into practice.\n\nAll healthcare professionals should ensure people have a high quality experience of the NHS by following NICE's recommendations in Patient experience in adult NHS services.\n\nAll health and social care providers working with people using adult NHS mental health services should follow NICE's recommendations in Service user experience in adult mental health.\n\n# Updating the recommendations\n\nThis guidance will be reviewed 3 years after publication to determine whether all or part of it should be updated. Information on the progress of any update will be posted on the NICE website.\n\n# Your responsibility\n\nThis guidance represents the views of the Institute and was arrived at after careful consideration of the evidence available. Those working in the NHS, local authorities, the wider public, voluntary and community sectors and the private sector should take it into account when carrying out their professional, managerial or voluntary duties.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity, and foster good relations. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\n# Copyright\n\n© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0475-4"}	https://www.nice.org.uk/guidance/ph50	This guideline covers planning and delivering multi-agency services for domestic violence and abuse. It aims to help identify, prevent and reduce domestic violence and abuse among women and men in heterosexual or same-sex relationships, and among young people.
2f85d6ec392675d75b60506cc999bf8e19e39343	nice	Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma	Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma Evidence-based recommendations on pixantrone (Pixuvri) for treating relapsed or refractory aggressive non-Hodgkin's B-cell lymphoma in adults. # Guidance Pixantrone monotherapy is recommended as an option for treating adults with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma only if: the person has previously been treated with rituximab and the person is receiving third- or fourth-line treatment and the manufacturer provides pixantrone with the discount agreed in the patient access scheme. People currently receiving treatment initiated within the NHS with pixantrone monotherapy that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.# The technology Pixantrone (Pixuvri, Cell Therapeutics) is an aza‑anthracenedione analogue and inhibitor of topoisomerase II. The recommended dosage is pixantrone 50 mg/m2 on days 1, 8 and 15 of each 28-day cycle for up to 6 cycles. It is administered intravenously. Pixantrone has a conditional marketing authorisation 'as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B‑cell lymphomas (NHL). The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy'. The European public assessment report noted pixantrone had a reduced benefit in patients pretreated with rituximab. The marketing authorisation is linked to results being provided from the phase III PIX306 trial, which is investigating pixantrone plus rituximab compared with gemcitabine plus rituximab in patients with relapsed or refractory aggressive non-Hodgkin's B‑cell lymphomas who have previously received a rituximab-containing regimen. Results are expected in 2015. The summary of product characteristics states that the most common toxicity with pixantrone is bone marrow suppression (particularly the neutrophil lineage) and that other toxicities such as nausea, vomiting and diarrhoea are generally infrequent, mild, reversible, manageable and as expected in patients treated with cytotoxic agents. Although the occurrence of cardiac toxicity indicated by congestive heart failure appears to be lower than that expected with related drugs like anthracyclines, the summary of product characteristics recommends monitoring left ventricular ejection fraction. For full details of adverse reactions and contraindications, see the summary of product characteristics. Pixantrone is priced at £553.50 per 20‑ml vial containing 29 mg free base pixantrone, which is equivalent to 50 mg pixantrone dimaleate (excluding VAT; 'British national formulary' edition 66). The estimated cost of a course of treatment is £19,926 (costs calculated over 4 cycles using an average of 3 vials per dose based on the median length of treatment in the PIX301 trial, described in section 3.2). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of pixantrone has agreed a patient access scheme with the Department of Health that makes pixantrone available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of pixantrone and a review of the submissions by the Evidence Review Group (ERG; section 9). The manufacturer submitted additional evidence (about the patient population, trial design and clinical effectiveness, a revised model, and support for consideration of end-of-life criteria) after consultation on the appraisal consultation document. The submission and the additional evidence did not incorporate a patient access scheme. The manufacturer later made a confidential simple discount patient access scheme submission in July 2013, which was superseded by an updated patient access scheme submitted in November 2013. The Committee's considerations and decision-making are based on the November 2013 patient access scheme. # Clinical effectiveness ## Manufacturer's original submission The manufacturer's systematic review identified 1 randomised controlled trial, which was included in its original submission. No other relevant randomised controlled trials or non-randomised controlled trials were identified. The manufacturer also included some supporting cardiotoxicity data from a randomised phase II study that did not meet the inclusion criteria of the literature review (because it evaluated pixantrone in combination with other drugs, not as monotherapy). PIX301 is a randomised, controlled, open-label phase III study conducted in 66 centres, including the USA and Europe. Eligible patients were adults with aggressive de novo or transformed non-Hodgkin's lymphoma that had relapsed after 2 or more chemotherapy regimens, including at least 1 standard anthracycline-containing regimen with a response that had lasted at least 24 weeks. Seventy patients were randomised to pixantrone and 70 patients to a physician's choice of single-agent comparators. The full publication of PIX301 described how 67 patients went on to receive vinorelbine (n=11), oxaliplatin (n=30), ifosfamide (n=12), etoposide (n=9), mitoxantrone (n=4) or gemcitabine (n=1). Pixantrone was administered at a dosage of 85 mg/m2 on days 1, 8 and 15 of a 28‑day cycle for up to 6 cycles. Comparators were administered at predefined standard dosages for up to 6 cycles. Follow-up was for 18 months after completing study treatment. The primary outcome was complete and unconfirmed complete response, which was determined by a blinded independent assessment panel. Secondary outcomes were overall survival, response lasting at least 4 months and progression-free survival. Other predefined end points were overall response rate, time to response, time to complete response, duration of response and relative dose intensity. Health-related quality of life was not assessed. The primary analysis was the intention-to-treat population. Secondary analyses included a prespecified analysis of the response and survival end points for the histologically confirmed intention-to-treat population (that is, if the lymphoma had been classified according to retrospective independent central pathological assessment). It was initially planned that 320 patients would be recruited to PIX301 but study enrolment was closed early because of slow accrual. The manufacturer's original submission stated that, with a final enrolment of 140 patients, the study was considered to be sufficiently powered (about 80%) to detect a 15% difference in the complete or unconfirmed complete response rate, assuming a rate of at least 18% in the pixantrone arm. In contrast, the full publication of PIX301 reported that the study was originally powered to detect a difference of 10% in the proportion of patients who achieved a complete or unconfirmed complete response. The publication further stated that, according to the original sample size assumptions, a sample of 70 patients per group would have about 40% power. It added that, to achieve 81% power with 70 patients per group, the true proportion of patients with a complete or unconfirmed complete response would have to be 22% in the pixantrone group and 5% in the comparator group. The manufacturer's original submission reported that baseline demographic and disease characteristics were similar in the 2 arms. Previous treatment for non-Hodgkin's lymphoma was broadly similar for both groups, including number of chemotherapy regimens (median 8 regimens in both arms). Aggressive histological features were identified onsite in all patients before treatment was given and confirmed by central independent pathological review in 54 (77%) of 70 patients in the pixantrone arm and 50 (71%) of 70 patients in the comparator arm receiving treatment of physician's choice. Of the remaining 36 patients, reasons for non-confirmation were low-grade histology (n=13), lack of consensus (n=10), shortage of specimen (n=6), confirmation of a non-aggressive subtype other than non-Hodgkin's lymphoma (n=5), and the specimen reviewed by only 1 pathologist (n=2). Out of 140 patients, 36 patients completed 6 cycles of protocol treatment, and 104 patients discontinued early. The most common reason for early discontinuation in both groups was disease progression or relapse. After completing study treatment, 95 patients entered follow-up and 26 of these completed 18 months of follow-up. The manufacturer's original submission reported that, at the end of treatment, confirmed and unconfirmed response rates for the intention-to-treat population (70 patients in each arm) were statistically significantly higher for the pixantrone group than the comparator group receiving treatment of physician's choice (20% compared with 5.7%; p=0.021). This was also the case at the end of the study after 18 months of follow-up (24.3% compared with 7.1%; p=0.009). The manufacturer's original submission described the results for progression-free and overall survival in the intention-to-treat population. Median progression-free survival was statistically significantly longer for the group receiving pixantrone than the comparator group receiving treatment of physician's choice at 5.3 months compared with 2.6 months (hazard ratio 0.60 and 95% confidence interval 0.42 to 0.82; p=0.005). However, there was no statistically significant difference in median overall survival between the 2 groups (10.2 months in the pixantrone arm compared with 7.6 months in the comparator arm receiving treatment of physician's choice (hazard ratio 0.79 ; p=0.251). In addition to the results for the intention-to-treat population of PIX301, the manufacturer included clinical-effectiveness data for several post-hoc subgroups in its original submission for patients with aggressive B‑cell lymphoma (classed as diffuse large B‑cell lymphoma, transformed indolent lymphoma or follicular lymphoma ): Disease confirmed by onsite pathological review (all lines of treatment, and third- or fourth-line treatment only). Disease confirmed by central independent pathological review (all lines of treatment, and third- or fourth-line treatment only). Disease confirmed by central independent pathological review in patients who had previously received rituximab treatment.The manufacturer also presented the results for a subgroup of patients with diffuse large B‑cell lymphoma confirmed by onsite pathological review (over 80% of the total number of patients with aggressive B‑cell lymphoma). The results of the subgroup analyses that were incorporated into the manufacturer's original economic model are described below. The results of other subgroup analyses included in the manufacturer's original submission have been previously reported in the appraisal consultation document. In its original submission, the manufacturer considered the post-hoc subgroup of patients with aggressive B‑cell lymphoma confirmed by onsite pathological review to be similar to the population eligible for treatment according to pixantrone's European marketing authorisation, and indicated that this formed the basis of the population in the original base case of its cost-effectiveness analysis (however, it should be noted that the manufacturer stated that its economic evaluation focused on those who had received 2 or 3 previous therapies; see section 3.20 for details). This subgroup excluded patients with peripheral T‑cell lymphoma not otherwise characterised and other disease subtypes not included in pixantrone's European marketing authorisation. Compared with the group that received treatment of physician's choice (n=62), complete or unconfirmed complete response rates at the end of the study in the pixantrone group (n=64) were statistically significantly higher (23.4% compared with 8.1%; p=0.027). Overall response rates were also statistically significantly higher in the pixantrone group (40.6% compared with 16.1%; p=0.003). Median progression-free survival was statistically significantly longer in patients who had received pixantrone than those who had received a comparator drug (5.7 months compared with 2.5 months, hazard ratio 0.56 ; p=0.002). The manufacturer advised that median overall survival was not included because the aggressive B‑cell lymphoma analyses were exploratory. In its original submission, the manufacturer presented a further analysis of patients with aggressive B‑cell lymphoma confirmed by onsite pathological review who received pixantrone (n=50) or a comparator (n=49) as third- or fourth-line treatment, which it stated was more closely aligned with pixantrone's marketing authorisation. It is not clear from the manufacturer's submission how this population differs from that in the base case of its cost-effectiveness analyses (see section 3.20 for details). The group receiving pixantrone had a statistically significantly higher complete response or unconfirmed complete response rate (28.0% compared with 4.0%; p=0.002) and overall response rate (48.0% compared with 12.2%; p<0.001), and statistically significantly longer progression-free survival (5.8 months compared with 2.8 months, hazard ratio not stated; p=0.002) than the comparator group receiving treatment of physician's choice. Median overall survival in this population was numerically higher in the pixantrone arm than the comparator arm but this difference was not statistically significant (13.9 months compared with 7.8 months, hazard ratio 0.76 ; p=0.275). The manufacturer's submission did not state whether the results were for end of treatment or end of study. In addition to the histologically defined subgroups of the PIX301 population in its original submission, the manufacturer also supplied subgroup analyses that showed the influence of previous rituximab treatment on pixantrone's efficacy in the subgroup of patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review. In this subgroup of patients who had previously received rituximab, there was no statistically significant difference between pixantrone (n=30) and the comparator arm (n=26) in the proportion of patients who had a complete or unconfirmed complete response at the end of treatment (16.7% compared with 7.7%; p=0.431). Median progression-free survival was longer in the pixantrone group than in the comparator group receiving treatment of physician's choice for this subgroup of patients but the difference did not reach statistical significance (3.5 months compared with 2.3 months, hazard ratio 0.66 ). Similarly, median overall survival was longer in the pixantrone group than in the comparator group receiving treatment of physician's choice but the between-group difference was not statistically significant (6.0 months compared with 4.6 months, hazard ratio 0.85 ). The manufacturer's original submission described the adverse events in PIX301 for 68 patients in the pixantrone group and 67 patients in the comparator group who received treatment of physician's choice. One dose reduction was allowed for patients who had neutropenia during treatment, and reductions were similar in the pixantrone and comparator groups (18% compared with 15%). Dose delay was more frequent with pixantrone (40% compared with 22%). A similar number of patients had an adverse event of any grade but there was a higher incidence of grade 3 and 4 adverse events in the pixantrone group than in the comparator group (76.5% compared with 52.2%). Neutropenia occurred more frequently in the pixantrone group and was the most common adverse event of any grade (50.0% compared with 23.9%) and the most common grade 3 or 4 adverse event (41.2% compared with 19.4%). Grade 3 or 4 febrile neutropenia was also more common in the pixantrone group than in the comparator group (7.4% compared with 3.0%), and more patients in the pixantrone group than in the comparator group received an immunostimulant (51.5% compared with 26.9%). The manufacturer reported that severity of neutropenia did not increase with increasing cycle number and that the overall rates of grade 3 and 4 infections were similar in the 2 groups. It further stated that the common adverse events were similar to those expected in a heavily pretreated patient population, which reflected pixantrone's intended use in clinical practice in England and Wales (that is, third and subsequent lines of treatment). Approximately 40% of patients in both treatment arms presented with a history of cardiac disease at study enrolment, and cardiac risk factors were also similar in the 2 groups. The manufacturer stated that pixantrone is an innovative treatment because it has been specifically designed to reduce cardiotoxicity associated with anthracyclines without compromising efficacy. More cardiac adverse events occurred in the pixantrone group (24 patients than in the comparator group who received treatment of physician's choice (14 patients ). Thirteen (19.1%) patients in the pixantrone group experienced decreased left ventricular ejection fraction compared with 7 patients in the comparator group. The manufacturer provided supporting cardiotoxicity data from the randomised open-label phase II PIX203 trial, which closed before enrolment completed. This trial compared the combination of cyclophosphamide, pixantrone, vincristine, prednisone and rituximab with the standard of care (that is, rituximab in combination with a regimen of cyclophosphamide, doxorubicin, vincristine and prednisone) as first-line treatment in patients with diffuse large B‑cell lymphoma. The cardiotoxicity results of PIX203 broadly supported those of PIX301. ## Manufacturer's additional evidence in response to consultation on the first appraisal consultation document In response to consultation on the first appraisal consultation document, the manufacturer requested and received permission from NICE to submit additional evidence. The additional evidence contained the results for 4 subgroups and showed the effect of treatment in patients who had previously received rituximab. Two of the subgroups were patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review for all lines of therapy, and the other 2 subgroups were patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment. During the second Committee meeting, the manufacturer clarified that the subgroups of all patients regardless of rituximab status (those patients who had previously received rituximab plus those who had not) were labelled as 'without rituximab' in its response to consultation. In its additional evidence, the manufacturer presented amended results for the subgroup of patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review and had previously received rituximab (see section 3.11). Complete or unconfirmed complete response rates were higher in the pixantrone arm than in the comparator arm (20% compared with 11%) but this difference was not statistically significant. Results for progression-free survival and overall survival were as before, except for median progression-free survival in the comparator arm, which the manufacturer confirmed was an error. In its consultation response, the manufacturer also reiterated data for the subgroup of all patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review regardless of whether they had previously received rituximab or not (n=50 in the pixantrone group, n=47 in the comparator group). At the end of the study, there was no statistically significant difference in complete or unconfirmed complete response rates between the pixantrone and comparator groups (9 patients compared with 4 patients; p=0.236). However, the overall response rate was statistically significantly higher in the pixantrone group (18 patients compared with 8 patients; p=0.041). Median progression-free survival was statistically significantly longer in the pixantrone arm than in the comparator arm (5.6 months compared with 2.5 months, hazard ratio 0.51 ; p value not stated) but there was no statistically significant difference in median overall survival between the 2 groups (8.1 months compared with 6.3 months, hazard ratio 0.72 ; p value not stated). In its additional evidence, the manufacturer reiterated subgroup analyses for all patients (that is, patients who had previously received rituximab plus those who had not) with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment with pixantrone (n=39) or treatment of physician's choice (n=39). Compared with the group receiving treatment of physician's choice, the pixantrone group had a statistically significantly higher complete or unconfirmed complete response rate (23.1% compared with 5.1%; p=0.047) and overall response rate (43.6% compared with 12.8%; p=0.005). Median progression-free survival was statistically significantly longer with pixantrone than with treatment of physician's choice (5.7 months compared with 2.8 months, hazard ratio 0.44 ) but there was no statistically significant difference in median overall survival between treatment groups (11.9 months with pixantrone compared with 7.0 months with treatment of physician's choice, hazard ratio 0.67 ). In its additional evidence, the manufacturer also provided results for a subgroup described as patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment who had previously received rituximab (n=25 in both study arms), but confirmed at the second Committee meeting that this population was in fact a subgroup of patients whose disease had been confirmed by onsite (not central) pathological review. The correct population (that is, with pathology confirmed by central independent review), whose results had previously been included as part of the manufacturer's clarification response, showed an increase in complete response or unconfirmed complete response in the pixantrone arm (n=20) compared with the comparator arm (n=18; 30% compared with 5.6%; p=0.093). There was no statistically significant difference between treatment arms in median progression-free survival (5.4 months in the pixantrone group and 2.8 months in the comparator group, hazard ratio 0.52 ). Similarly, there was no statistically significant difference in median or mean overall survival between treatment arms (hazard ratio 0.76 ). Median overall survival was 7.5 months in the pixantrone group and 5.4 months in the comparator group. Mean overall survival was 9.9 months in the pixantrone arm and 7.9 months in the comparator group (difference of 2.0 months). # Cost effectiveness The manufacturer did not identify any published economic evaluations or costing studies that were relevant to the decision problem. Consequently, it submitted a de novo economic analysis that assessed the cost effectiveness of pixantrone compared with treatment of physician's choice in treating multiply relapsed or refractory aggressive B‑cell lymphoma, which was later revised as part of the manufacturer's response to consultation (see section 3.31 for details of changes in the revised model). Further minor updates were made in the manufacturer's model that formed part of a patient access scheme submission which was submitted in July 2013. In November 2013, this was superseded by another patient access scheme submission, which applied a further simple discount to the model (see sections 3.34–3.38 for details). ## Manufacturer's submission The manufacturer advised that the base-case model considered patients who had received 2 or 3 prior therapies and whose disease was sensitive to treatment with anthracyclines because this population was consistent with pixantrone's European marketing authorisation for treating multiply relapsed or refractory aggressive non-Hodgkin's lymphoma (the marketing authorisation notes that a treatment benefit has not been established 'when used as fifth line or greater chemotherapy in patients who are refractory to last therapy'). The clinical data for this population were derived from PIX301. The analysis was conducted from an NHS and personal and social services perspective and a lifetime horizon of 23 years was used. Weekly cycles were chosen to capture the 4‑week treatment cycles of pixantrone and 3‑week treatment cycles of some of the comparator treatments and a half-cycle correction was applied. Costs and benefits were discounted at 3.5% per annum. The manufacturer created a semi-Markov model that contained 3 health states: stable or no progression, progressive or relapsed disease, and death. The stable or no progression health state had 2 distinct subpopulations. The first of these was patients on initial third- or fourth-line treatment. The second was patients who had discontinued third- or fourth-line treatment (because of complete response, adverse event, completion of 6 months' treatment or a non-clinical reason) but had not experienced progression. All patients entered the model in the on-treatment subpopulation within the stable or no progression health state. During each cycle, patients could remain in the on-treatment subpopulation of this health state, discontinue treatment and move into the other subpopulation in this health state, progress and move into the progressive disease health state, or die. Patients who discontinued treatment before progression remained at risk of progression or death. Following progression, patients were at risk of death and unable to return to the stable or no progression health state. It was assumed that the original treatment was stopped following disease progression and patients received further treatment or palliative care. Adverse events were captured as events within the model by applying a utility decrement (disutility). The manufacturer outlined how the transition between health states was calculated from the clinical data for any given weekly cycle. It noted that semi-Markov models allow the use of a partition approach, which has been used extensively in oncology because it is particularly suited to progressive conditions that have ongoing risks that may vary over time. The distribution of the patient group between the different health states was estimated by calculating the area under the survival curves at each cycle. The progression-free survival curve defined the stable or no progression state, while the progressed state was defined by subtracting those patients who remained progression free from all surviving patients. Clinical parameters for progression-free survival and overall survival were incorporated into the base case of the manufacturer's economic model by statistical analysis of patient-level data from the aggressive B‑cell population of PIX301. Predictive equations for progression-free survival and overall survival were derived by fitting the patient-level data and extrapolating beyond the data from PIX301 (around 2 years). A log-normal distribution was used in the base case for both progression-free survival and overall survival. Further clinical parameters were incorporated into the base case of the manufacturer's economic model. The cycle probability of treatment discontinuation distinguished between patients remaining on initial treatment and those who discontinued while stable. The frequency and duration of adverse events (grades 2–4) before progression while taking initial treatment were based on PIX301. Grade 3 and 4 adverse events occurring in at least 5% of the total patient population were considered to have cost and utility consequences. Some grade 2, and rarer grade 3 and 4, adverse events were included if considered important by clinical specialists in England. Other data from PIX301 that were used to inform the model were mean dose for the comparator treatments plus sex and body surface area. There were no patient-reported outcomes in PIX301 and the manufacturer did not identify any utility data for any line of treatment in aggressive non-Hodgkin's lymphoma in its systematic literature review for studies on health-related quality of life. Utility data were identified from published sources for similar patient populations, and for disease areas with similar expected survival, disease progression, nature of the disease and quality of life. These were diffuse large B‑cell lymphoma, chronic myelogenous leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, renal cell carcinoma and melanoma. For its original model, the manufacturer considered the self-reported quality of life in older patients with aggressive diffuse large B‑cell lymphoma to give the estimation closest to the PIX301 trial population and used these values (pre-progression 0.81, post-progression 0.60) in its base-case analysis. The manufacturer did not provide a rationale for this decision. Utility values were assumed to depend only on the health state and any adverse events experienced, but not the treatment arm. Based on expert clinical opinion, the manufacturer assumed no difference in baseline health-related quality of life between the 2 subpopulations in the stable or no progression health state. All stable/no progression patients were assumed to have similar quality of life (that is, there was no difference according to complete response, partial response or stable disease). The manufacturer determined disutilities associated with each adverse event that was included in the original model from relevant literature from other oncology indications. If no utility decrements were available, the maximum value of the range identified was assumed by the manufacturer to keep the calculations conservative (that is, so that pixantrone was not favoured). Adverse events were modelled by the manufacturer as events rather than as health states and were assumed to be time independent because adverse events are likely to be experienced at different stages of treatment. Any grade 1–4 adverse event that occurred in less than 5% of the trial population was assumed to have no impact on quality of life. After consulting some clinical specialists in England, the manufacturer included some rarer grade 3 and 4 adverse events and some grade 2 adverse events that the clinical specialists considered to be important. Because no disutility values were available specifically for grade 2 and grade 3 or 4 adverse events, they were assumed to be the same for each grade. Within a health state, disutilities relating to an adverse event were applied to the proportion of patients assumed to experience the adverse event as weighted average disutilities. For each treatment, the manufacturer calculated a weighted average of grade-specific disutilities that were weighted by the number of effects of that particular grade. The disutility for each adverse event was then applied for the duration of that specific type of effect. The manufacturer's model limited the consideration of adverse events to patients on original treatment upon entering the model (pixantrone or treatment of physician's choice). Costs captured in the manufacturer's model included drugs and their administration, plus those associated with health state and disease management, including adverse events. Drug and administration costs in the original model were calculated based on average dose per administration from the PIX301 trial using the British national formulary (BNF) edition 62 (published in September 2011) and the NHS reference costs. No patient access scheme was incorporated in the original model. From the second attendance onwards, administration costs were £206 for each attendance for all drugs except etoposide 50 mg (£163). At clarification, the manufacturer corrected an error in the vial price, which had been mistakenly quoted as £343.80 (based on the vial size given for pixantrone base) instead of £553.50 (equivalent to 50 mg pixantrone dimaleate). It advised that this error had a minimal impact on the cost-effectiveness estimates (which increased by 0.3%) because the drug costs in the model had been calculated based on cost per administration. The total number of administrations varied according to the dosing schedule for each drug. Drug wastage was incorporated in the base case. Personal and social services costs were £476.42 per 28 days for stable health state on treatment, £119.10 for stable health state on palliative care and £1993.89 for progressive health state. Disease management costs (comprising healthcare professional contact, disease follow-up and hospital-related costs) were different for active treatment and palliative care. For active treatment, health professional contact costs were £788.96 on treatment and £220.38 after treatment (per 28 days), disease follow-up costs were £86.63 per 28 days and annual hospital-related costs were £2357.28. For palliative care, health professional contact costs were £990.74 per 28 days, disease follow-up costs were £18.44 per 28 days and annual hospital-related costs were £1982.03. End-of-life care was excluded from the calculations because it affected only the last few weeks of life and estimates would be similar for pixantrone and its comparators. Within a health state, costs for managing an adverse event were applied to the proportion of patients assumed to experience the adverse event. The manufacturer advised that the predicted median progression-free survival and predicted median overall survival were similar to the results reported in PIX301. Compared with the clinical trial results, the manufacturer noted that the original model slightly underestimated the median overall survival with pixantrone (13.1 months compared with 13.8 months) while overestimating it for the comparator (9.2 months compared with 7.6 months). It reported that, conversely, the original model overestimated the median progression-free survival for the pixantrone arm (7.8 months compared with 6.4 months) and slightly underestimated it for the comparator arm (3.2 months compared with 3.5 months). Using the original model, the manufacturer's base-case analyses for pixantrone compared with treatment of physician's choice in patients with aggressive B‑cell lymphoma confirmed by onsite pathological review (third- or fourth-line treatment) produced a deterministic incremental cost-effectiveness ratio (ICER) of £28,423 per quality-adjusted life year (QALY) gained. Incremental costs were £17,638 and incremental QALYs were 0.62. Using the correct vial price supplied at clarification increased the ICER to £28,503 per QALY gained. No probabilistic base-case ICER was presented. All economic analysis results generated using the manufacturer's original model have been superseded by those using the model provided with the patient access scheme submission submitted in November 2013 (see sections 3.34–3.38). ## Manufacturer's additional evidence in response to consultation on the first appraisal consultation document In response to the first appraisal consultation document, the manufacturer provided a revised economic model, which contained these amendments: The adverse-event disutilities used in the ERG's exploratory analyses were incorporated. Drug costs for comparator treatments were taken from the NHS Commercial Medicines Unit's Electronic Marketing Information Tool (eMIT) database instead of the BNF in line with NICE's Guide to the methods of technology appraisal (2013). Utility values were changed from self-reported quality of life in older patients with aggressive diffuse large B‑cell lymphoma (0.81 for the pre-progression health state, 0.60 for the post-progression health state) to those for second- and subsequent-line treatment of renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). This was in response to the Committee's conclusion in the first Committee meeting that the original utility values had overestimated quality of life for patients with multiply relapsed or refractory non-Hodgkin's lymphoma.The revised model did not incorporate a patient access scheme. Using its revised model, the manufacturer provided cost-effectiveness estimates of pixantrone compared with treatment of physician's choice for several subgroups, including patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment and had previously had rituximab. The deterministic ICER for this subgroup was £45,282 per QALY gained (incremental costs £9170; incremental QALYs 0.20). No probabilistic ICER was provided. All economic analysis results generated using the manufacturer's revised model have been superseded by those using the model provided with the patient access scheme submission submitted in November 2013 (see sections 3.34–3.38). ## Manufacturer's patient access scheme submissions The manufacturer agreed a patient access scheme in July 2013, which was a confidential simple discount on the list price of pixantrone. It further updated its economic model so that costs for treating adverse events and the cost for methotrexate were in line with the Committee's preferred values decided at the second Committee meeting. All economic analysis results generated using the manufacturer's model provided with the patient access scheme submitted in July 2013 have been superseded by those using the model provided with the patient access scheme submission submitted in November 2013 (see sections 3.34–3.38). In response to the second appraisal consultation document, the manufacturer submitted a patient access scheme in November 2013 that contained an additional discount to the patient access scheme proposed in July 2013. The November 2013 patient access scheme is a simple discount on the list price of pixantrone, and the economic model was further updated with this additional discount as part of this submission. The manufacturer advised that the patient access scheme would apply to patients with histologically confirmed aggressive non-Hodgkin's B‑cell lymphoma who had previously received rituximab and would be receiving pixantrone as a third- or fourth-line treatment. The manufacturer made no other revisions to the economic model. The manufacturer provided cost-effectiveness estimates incorporating the patient access scheme submitted in November 2013 for pixantrone compared with treatment of physician's choice for patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment and had previously received rituximab. This additional discount reduced the deterministic ICER to £18,462 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.20). The manufacturer tested the robustness of the model using one-way sensitivity analyses and reported that the key drivers of the cost-effectiveness estimates produced using its economic model were the parametric fitting methodology for progression-free survival and overall survival, and the utility estimate for the stable or no progression health state. The manufacturer noted that the ICER was sensitive to changes in the estimates for progression-free survival. In its base-case patient access scheme submission provided in November 2013, the manufacturer used the same utility values as the revised version of the model, which were for patients receiving second- and subsequent-line treatment for renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). The manufacturer provided alternative utility scenarios using data from published sources for similar patient populations, and for disease areas with similar characteristics. These were second-line treatment in patients with chronic myelogenous leukaemia, third-line treatment in patients with chronic lymphocytic leukaemia, first-line maintenance treatment in patients with follicular lymphoma, first-line treatment in patients with metastatic renal cell carcinoma, self-reported quality of life during chemotherapy in elderly patients with aggressive non-Hodgkin's lymphoma and second-line treatment in patients with malignant melanoma. The ICERs ranged from £14,607 per QALY gained to £18,871 per QALY gained. To explore uncertainty, the manufacturer undertook a probabilistic sensitivity analysis that incorporated the patient access scheme submitted in November 2013. The probabilistic mean ICER was £22,024 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.18). However the manufacturer asserted that there was structural uncertainty inherent in the probabilistic sensitivity analysis that reduced the advantage of pixantrone and skewed the probabilistic results. It explained that the model assumed that overall survival and progression-free survival were independent, leading to the survival curves crossing (that is, more patients were in the progression-free survival state than alive) and the model artificially reduced progression-free survival to avoid this, and that this applied to around 30% of the simulations. In order to illustrate the structural uncertainty arising from the probabilistic ICER, the manufacturer provided additional analyses; for example, if it is assumed that overall survival and progression-free survival are not independent (by assuming the same random numbers for progression-free survival and overall survival using the Cholesky decomposition), the probabilistic mean ICER is £9938 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.21). The manufacturer also noted that the joint uncertainty of incremental QALYs and incremental costs did not follow a normal distribution, and reported that the median probabilistic ICER was £14,692 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.18). The manufacturer reported that pixantrone was more likely to be cost effective compared with treatment of physician's choice in patients with aggressive B‑cell lymphoma confirmed by central pathological review who were receiving third- or fourth-line treatment at a maximum acceptable ICER of £25,000 per QALY gained. # Evidence Review Group's comments The ERG considered the evidence included by the manufacturer to be relevant to the decision problem in its analysis. No additional relevant trials were identified and the ERG found that the manufacturer's systematic review followed standard practices. The ERG had concerns about the generalisability of the PIX301 population to clinical practice in England and Wales, particularly the potential effect of previous rituximab treatment on the response to pixantrone because rituximab is given as part of standard first-line treatment in the UK. The ERG noted that about 50% of patients in PIX301 had previously received treatment with a biological agent (for example, rituximab). The ERG considered the clinical benefit of pixantrone in patients who have previously been treated with rituximab to be a key area of uncertainty, given that there were no statistically significant differences between the pixantrone and comparator arms for complete or unconfirmed complete response, progression-free survival or overall survival in the subgroup of patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who had previously received rituximab. The ERG considered whether the treatments of physician's choice in PIX301 represented clinical practice in England and Wales. Following input from its clinical specialists, the ERG noted that there is no consensus on which chemotherapy regimens should be used after second-line treatment fails and that there is a lack of comparative data on their clinical effectiveness. The ERG concluded that this meant the choice of treatment in the comparator arm of PIX301 was unlikely to be a key issue. It also concluded that the small number of patients receiving each treatment meant that the choice of treatment in the comparator group could not be reliably analysed. The ERG was concerned about the statistical power of PIX301 to detect a difference between treatment groups. According to the manufacturer's revised power calculation, 81% power with 70 patients per group (the intention-to-treat population) would be achieved if the true proportion of patients with complete or unconfirmed complete response was 22% in the pixantrone group and 5% in the comparator group. However, the observed proportions of patients with a complete or unconfirmed complete response in the intention-to-treat population were 20.0% in the pixantrone group and 5.7% in the comparator group. The ERG noted that the difference between groups did not always reach statistical significance, and that results of the analyses in the subgroups confirmed by central independent pathological review should be interpreted with caution because they are likely to be underpowered to detect a difference between treatment groups. For these reasons, the ERG had reservations about whether pixantrone had been shown to have superior efficacy in PIX301. The ERG was concerned about the reliability of the diagnosis of aggressive non-Hodgkin's lymphoma at study entry. It noted that central independent pathological review by consensus was undertaken retrospectively (that is, after the trial), rather than at enrolment, and that aggressive disease was subsequently confirmed in only 104 of the 140 patients who were randomised. Consequently, it felt that results from the full trial population might not reflect the benefit of pixantrone in patients with aggressive B‑cell lymphoma. The ERG acknowledged that the manufacturer said it had not been practical to confirm aggressive disease by central independent pathological review at enrolment, but considered it was important to evaluate data from the subgroup of patients with disease confirmed by central independent pathological review. The ERG noted that, as a subgroup analysis, the statistical power of PIX301 would be less than the intention-to-treat population. The ERG considered the different patient populations in the subgroup analyses presented by the manufacturer. The ERG viewed the data from the post-hoc subgroup of patients with aggressive non-Hodgkin's B‑cell lymphoma that was histologically confirmed by central independent pathological review to be more relevant to the marketing authorisation and the decision problem in the NICE scope than the other 2 subgroups categorised according to type of lymphoma determined by onsite pathological review (patients with aggressive non-Hodgkin's B‑cell lymphoma and patients with diffuse large B‑cell lymphoma). The ERG noted that retrospective central independent pathological review revealed 23% of patients receiving pixantrone and 29% of patients receiving a comparator in the intention-to-treat population had disease that was not subsequently confirmed as being aggressive. The ERG was aware that disease severity is an important factor in deciding treatment strategy because patients without aggressive disease are likely to have a more favourable response than those with aggressive disease. The ERG considered the statistical robustness of the subgroup analyses. It observed that the comparative clinical-effectiveness results for most of the subgroups were based on post-hoc subgroup analyses. It also noted that the number of patients in the analysis was generally small, increasing uncertainty around the results. For subgroups based on retrospective histological confirmation of aggressive disease and previous rituximab treatment, the ERG noted the potential for unbalanced groups because randomisation had not been stratified by these factors. The ERG concluded that the results of the subgroup analyses should be interpreted with caution. The ERG considered the adverse events reported to occur more often in the pixantrone group than the comparator group receiving treatment of physician's choice to be consistent with the common adverse events associated with pixantrone reported in the summary of product characteristics. Overall, the ERG considered the manufacturer's original model to be in line with current best practice recommendations, generally well constructed and largely transparent. The ERG considered that an important limitation of the manufacturer's original base-case analysis was that it used data from patients whose disease had not been histologically confirmed as aggressive. The ERG indicated that the subgroup of patients with aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review for all lines of treatment in PIX301 was the most informative to the decision problem because it excluded patients who were later found to have disease that was irrelevant to the decision problem (for example, indolent disease). However, the ERG noted that the manufacturer's estimate of cost effectiveness in this patient population was highly uncertain because it used post-hoc subgroup data and because the subgroups were not powered to detect a difference in efficacy between treatment with pixantrone and the comparators. The ERG considered the utility weights used by the manufacturer in its original economic model to be potentially inappropriate. It noted that the utility values were from a population of patients receiving first-line treatment for aggressive non-Hodgkin's lymphoma and were derived from a study that had initially been rejected by the manufacturer in its systematic review. It further noted that the manufacturer's reported utility values were higher than those that have been derived for healthy older patients in the UK. The ERG noted that the results of the manufacturer's original economic model may potentially be biased towards pixantrone because of an overestimation of pixantrone's relative progression-free survival benefit compared with treatment of physician's choice for the populations with aggressive B‑cell lymphoma (whether confirmed by onsite or central independent pathological review). Clinical specialist opinion received by the ERG expressed concern that the data used in the model may not be sufficient to reach reasonable conclusions about the clinical or cost effectiveness of pixantrone. The ERG identified other areas of inaccuracy or uncertainty in the assumptions and parameter estimates used in the manufacturer's original model and indicated the most significant of these were structural assumptions made about treatment discontinuation, disutility, and the cost parameters used: The potential double-counting of treatment discontinuation because of disease progression. Excluding adverse event disutilities for patients on further lines of treatment. Discrepancies between the manufacturer's and ERG's interpretation of the literature on disutilities for adverse events. Using weighted average adverse event rates to inform costs and disutilities associated with adverse events for patients on original treatment. Missing data from data used to inform average adverse event costs. Excluding costs associated with treating leukopenia and thrombocytopenia. Using costs from BNF 62 (published September 2011) rather than BNF 64 (published September 2012). The ERG critiqued the manufacturer's additional evidence submitted in response to the first consultation. Although there were some uncertainties in the definition and labelling of the manufacturer's subgroups, the ERG was able to validate the terminology used and check that the changes the manufacturer had made to its model were appropriate. The ERG indicated that, based on the European marketing authorisation and clinical practice in England and Wales, it was important to evaluate patients with aggressive B‑cell lymphoma confirmed by retrospective central independent pathological review who had previously received rituximab. However, it noted that it was also appropriate to evaluate a subgroup of these patients receiving third- or fourth-line treatment. The ERG critiqued the manufacturer's patient access scheme submission. It validated the changes made to the economic model in the July 2013 and November 2013 submissions and agreed that the subgroup of patients covered by the patient access scheme was characteristic of patients in England and Wales who were likely to be eligible for treatment with pixantrone. The ERG validated the manufacturer's deterministic and probabilistic sensitivity analyses on the updated base case in the patient access scheme submitted in November 2013, which were conducted in the same way as in the manufacturer's original submission. The ERG had commented in its critique of the manufacturer's original submission that the manufacturer's assessment of uncertainty was very detailed and that the probabilistic and one-way sensitivity analyses, including various scenario analyses, were satisfactorily reported. The ERG commented that the absence of utility data in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma results in a great deal of uncertainty. The ERG stated that although the utility values derived from patients receiving second-line treatment for renal cell carcinoma were less favourable than those used in the manufacturer's original submission, they may still overestimate the utility of patients with aggressive non-Hodgkin's B‑cell lymphoma receiving third- or fourth-line treatment. The ERG stated that the manufacturer's original base-case cost-effectiveness results (before inclusion of any patient access scheme) were generated deterministically rather than probabilistically (that is, mean values rather than distributions were used to inform the value of each parameter). However, the ERG noted that probabilistic cost-effectiveness results could be assessed using the manufacturer's original model. It noted a wide range in the 95% confidence interval for the mean probabilistic ICER. The ERG considered this showed substantial uncertainty in the manufacturer's cost-effectiveness results. Using the manufacturer's original model (before inclusion of any patient access scheme), the ERG carried out exploratory sensitivity analyses to investigate the impact of alternative assumptions or parameters on the manufacturer's cost-effectiveness results. The ERG judged the population with aggressive B‑cell lymphoma confirmed by central independent pathological review for all lines of treatment in PIX301 to be the most relevant to the decision problem (because it excluded patients who were later found to have disease that was not relevant to the decision problem ) and used it in all its exploratory analyses with the original model. Because it had concluded that the utility values used by the manufacturer in its original model (before inclusion of any patient access scheme) may have been inappropriate, the ERG investigated how alternative utility values affected the manufacturer's original base case. The ERG presented a markedly increased ICER for pixantrone compared with treatment of physician's choice when it used utility data from chronic lymphocytic leukaemia patients receiving third- or later-line treatment to inform the utility of progression-free survival and progressive disease (0.428 for the pre-progression health state and 0.279 for the post-progression health state). The ERG discussed the probabilistic cost-effectiveness results generated by the manufacturer using the patient access scheme submitted in November 2013, and validated the changes by the manufacturer to the economic model. The ERG commented that the manufacturer's probabilistic analysis showed that, after incorporating the patient access scheme, the probability of pixantrone being cost-effective compared with treatment of physician's choice was 49.3% at up to £20,000 per QALY gained and 55.7% at up to £30,000 per QALY gained. The ERG considered it important to note that, although 68% of probabilistic iterations showed a greater benefit for pixantrone than treatment of physician's choice, around 32% of probabilistic iterations indicated that patients treated with pixantrone fared worse than those who received treatment of physician's choice. Full details of all the evidence are in the evaluation report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pixantrone, having considered evidence on the nature of multiply relapsed or refractory non-Hodgkin's B‑cell lymphoma and the value placed on the benefits of pixantrone by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee discussed the treatment pathway for multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It heard from the clinical specialists that rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (also known as R‑CHOP) was the standard first-line treatment in England and Wales, and that most patients would also receive a rituximab-containing regimen second line. If their disease did not relapse within 6 months of first-line treatment, patients would be treated with rituximab. The Committee also noted that the clinical specialists stated that people treated with rituximab were less likely to respond to any subsequent treatment. The Committee heard that a platinum-based regimen was offered as second-line treatment but that there was no consensus on third- or fourth-line treatment. The Committee heard from the clinical specialists and the patient expert that the aim of treatment at this disease stage was to reduce the impact of symptoms on quality of life, as well as extending life, and could include chemotherapy or participating in clinical trials. The clinical specialists highlighted that fifth-line options include palliative care or participating in clinical trials. The Committee also noted that the marketing authorisation states that the benefit of pixantrone treatment has not been established in patients when used as fifth-line or further chemotherapy in patients whose disease is refractory to last therapy. The Committee heard from the patient expert about the impact of multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma on daily life and that the symptoms of the disease can reduce quality of life. It heard that patients are normally told at the start of their treatment that they are being treated with curative intent and that experiencing multiple relapses can be devastating; consequently, they would value any new treatment that could offer symptom relief, have a positive impact on quality of life and increase survival. The Committee acknowledged the demands that living with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma can place on patients and accepted that a treatment option for these patients is important. # Clinical effectiveness The Committee reviewed the suitability of the clinical trial evidence submitted by the manufacturer and expressed several concerns about the PIX301 trial. It considered PIX301 to be underpowered because it had failed to recruit the planned number of patients. It also noted that European regulators prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response. The Committee heard from the clinical specialists that although this end point would have been acceptable when the trial began in 2004, positron emission tomography (PET) scans have made unconfirmed complete response obsolete in trials that have begun more recently. The Committee also heard from the clinical specialists that they considered studies that were powered to detect a difference in overall survival to be more useful for clinical decision-making. The Committee concluded that these fundamental concerns about the design of PIX301 meant that there was considerable uncertainty in the validity and robustness of its results. The Committee discussed the relationship between the marketing authorisation, the PIX301 population and clinical practice in England and Wales. The Committee was aware that the intention-to-treat population included around 10% of patients who did not have aggressive B‑cell lymphoma, making them ineligible for treatment with pixantrone according to the terms of the marketing authorisation. The Committee further noted that the marketing authorisation is for multiply relapsed or refractory disease (that is, it is approved for patients who have received at least 2 previous lines of treatment) and that this does not necessarily restrict its use to third- and fourth-line treatment. However, it also noted the comments received during consultation stating that patients receiving fifth-line or further treatment would likely have palliative treatment or participate in a clinical trial. The Committee was persuaded that pixantrone would most likely be used, within its marketing authorisation, as a third- or fourth-line treatment in clinical practice in England and Wales. The Committee concluded that, when assessing the PIX301 results, it would be more appropriate to consider the population with aggressive B‑cell lymphoma who had received third- or fourth-line treatment. The Committee discussed how the tumour histologies were determined in the PIX301 population and whether this was generalisable to clinical practice in England and Wales. It was aware that tumour histology in the intention-to-treat population of PIX301 had been determined by onsite review by a single pathologist. The Committee heard from the clinical specialists that this was not representative of clinical practice in England and Wales, in which multidisciplinary team review is routine and specimens are examined by 2 or 3 pathologists. It noted that the Evidence Review Group (ERG) had also been advised by clinical specialists that a population with disease confirmed by central independent pathological review was more relevant to clinical practice in England and Wales. It also noted that a considerable proportion of patients were excluded after the central independent pathological review (for example, if indolent disease had been confirmed). The Committee concluded that it would be more appropriate to consider the PIX301 population with tumour histology confirmed by retrospective central independent pathological review by consensus than by onsite review by a single pathologist. The Committee discussed whether the comparator arm (treatment of physician's choice) in PIX301 was relevant to clinical practice in England and Wales. It heard from clinical specialists that, apart from PIX301, there was no evidence base for selecting a third- or fourth-line treatment for multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma and that there was wide variation in the treatments used in clinical practice in England and Wales. The Committee concluded that all of the comparators used in the treatment of physician's choice arm in PIX301 were clinically relevant (although there was some uncertainty in the proportions in PIX301 compared with clinical practice in England and Wales), and the comparator arm was therefore acceptable for decision-making. The Committee discussed the generalisability of previous treatments received by the PIX301 population to clinical practice in England and Wales. The Committee heard from the clinical specialists that rituximab is an integral part of standard first-line treatment in the NHS and is also often used as a second-line treatment. The Committee noted that the manufacturer's subgroup analyses showed a reduced benefit of pixantrone in patients who had previously received rituximab, and that many of the results showed no statistically significant difference between treatment arms (see sections 3.11 and 3.16–3.18). It also noted a clinical specialist's concern that statistical significance was not reached for the parameters complete or unconfirmed complete response, progression-free survival and overall survival for this subgroup. The Committee accepted the non statistically significant results because of the positive trend in all 3 outcomes for this subgroup. It was aware from comments received during consultation that this reduced benefit applied to other drugs in clinical development and was not specific to pixantrone. It was also aware of the obligation to the European Medicines Agency in pixantrone's European marketing authorisation requiring a trial to confirm the clinical benefit in patients who have previously received rituximab. However, the Committee acknowledged the comments received in response to consultation that the complete response rates with pixantrone in PIX301 were among the highest reported to date in trials for patients with diffuse large B‑cell lymphoma who had previously received rituximab. The Committee concluded that it was appropriate to evaluate the subgroup of patients in PIX301 who had previously received rituximab because this would apply to almost all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales. The Committee considered the clinical-effectiveness results for the whole intention-to-treat trial population and all the post-hoc subgroups. It noted that in the intention-to-treat population, PIX301 was inadequately powered to detect a difference between treatment groups because it had accrued less than half of the planned 320 patients. It noted that the difference in response rates, progression-free survival and overall survival between treatment groups did not always reach statistical significance in the intention-to-treat population (see section 3.17) and the post-hoc subgroups, and that there was no statistically significant difference in overall survival between treatment arms for any groups presented by the manufacturer. The Committee had reservations about whether superior efficacy of pixantrone had been shown for the intention-to-treat trial population. The Committee then discussed the clinical effectiveness for the subgroup of patients it considered to be most appropriate for decision making (those receiving third- or fourth-line treatment and who had previously received rituximab ). It concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice, and that the mean survival advantage of pixantrone compared with treatment of physician's choice was 2.0 months. However, these results were not statistically significant (see section 3.18). The Committee also concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in the Committee's preferred subgroup. The Committee discussed the adverse events associated with pixantrone. It noted the manufacturer's assertion that pixantrone was associated with less cardiotoxicity than anthracyclines. The Committee was aware that the final scope issued by NICE did not include any anthracyclines as comparators and that mitoxantrone was the only anthracenedione out of the 6 comparators. It heard from clinical specialists that doxorubicin (an anthracycline) was used as first-line treatment, and that none of the comparators for third- or fourth-line treatment were associated with the similarly raised cardiovascular risk associated with anthracyclines. The Committee was aware that there were more cardiac adverse events in the pixantrone group than in the comparator group, who received treatment of physician's choice (35% compared with 21%). However, it heard from the clinical specialists that efficacy is considered key in this patient population and that, because of its cardiovascular safety profile compared with anthracyclines, pixantrone offered an opportunity for response in patients who had previously shown sensitivity to anthracyclines but who could not receive further lines of anthracycline treatment after relapse because they had reached the maximum lifetime dose. It concluded that pixantrone had an acceptable adverse-effect profile although it was associated with more cardiotoxicity than treatments such as oxaliplatin and gemcitabine that are routinely used in this population in clinical practice in England and Wales. # Cost effectiveness The Committee discussed the manufacturer's general approach to developing the submitted pixantrone economic models. It noted that the ERG considered the manufacturer's approach to follow current best practice and was largely transparent. The Committee concluded that the outlined structure of the models adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pixantrone. The Committee considered the manufacturer's cost-effectiveness analyses that included the patient access scheme for the Committee's preferred patient subgroup (that is, the subgroup with aggressive B‑cell lymphoma confirmed by central independent pathological review for third- or fourth-line treatment and who had previously received rituximab ). In particular the Committee discussed how quality of life had been incorporated into the manufacturer's economic modelling. It was aware that the base-case analysis in the manufacturer's patient access scheme submitted in November 2013 used utility values for patients receiving second- and subsequent-line treatment for renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). It noted the absence of published utility values in the relevant patient population and that the manufacturer intends to fund additional research in this area. The Committee noted that the utility value for the pre-progression health state (0.76) was similar to that expected for a healthy older population in the UK, and it considered that the quality of life of patients receiving third- or fourth-line treatment for aggressive non-Hodgkin's B‑cell lymphoma could be lower than this. The Committee then reviewed the utility values selected by the ERG for its exploratory analyses using the manufacturer's original model and the revised model supplied with the patient access scheme submission, which were for patients receiving final-line treatment for chronic lymphocytic leukaemia (0.428 for the pre-progression health state and 0.279 for the post-progression health state). The Committee heard from the clinical specialists that there were differences between the 2 conditions that could mean these utility values were too low, and decided that the ERG's utility values were likely to underestimate the quality of life for this population. Having excluded the ERG's low utility values, the Committee considered that the manufacturer's deterministic sensitivity analysis on the base case in the patient access scheme submission using various utility values (see section 3.37) showed that utility values were not a key driver of cost effectiveness. The Committee concluded that, although there was some uncertainty as to the true utility value, the utility values used in the manufacturer's revised model with the patient access scheme were acceptable for use in the Committee's decision-making. The Committee considered the incremental cost-effectiveness ratios (ICERs) and considered those presented in the manufacturer's most recent cost-effectiveness analyses, which included the patient access scheme for the Committee's preferred patient subgroup. For the comparison of pixantrone with treatment of physician's choice, it noted that the manufacturer's deterministic and mean probabilistic ICERs incorporating the patient access scheme for this population were £18,500 and £22,000 per quality-adjusted life year (QALY) gained respectively. The Committee noted that the ERG had validated the changes made to the manufacturer's model as part of the patient access scheme submission in November 2013. The Committee concluded that the manufacturer's analysis was appropriate for its decision-making. The Committee discussed the amount of uncertainty in the cost-effectiveness estimates for the Committee's preferred subgroup of patients, that is people with aggressive B‑cell lymphoma confirmed by central pathological review receiving third- or fourth-line treatment and who have previously received rituximab. The Committee was persuaded that the manufacturer's mean probabilistic ICER of £22,000 per QALY gained could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. It was aware that the median probabilistic ICER was £14,700 per QALY gained and that the probabilistic ICER reduced to £10,000 per QALY gained when assuming that progression-free survival and overall survival did not change independently of each other. The Committee noted that the manufacturer's exploratory probabilistic sensitivity analysis showed that the probability of pixantrone being cost effective compared with treatment of physician's choice was 56% at a maximum acceptable ICER of £30,000 per QALY gained, and approximately 50% at a maximum acceptable ICER of £20,000 per QALY gained. Additionally, although pixantrone was less clinically effective in 32% of simulations, it was less expensive than treatment of physician's choice in a high proportion of these at a maximum acceptable ICER of £20,000 per QALY gained. The Committee therefore agreed that the probability of pixantrone being cost-effective compared with treatment of physician's choice was acceptable. The Committee concluded that the most plausible ICER was likely to be less than £22,000 per QALY gained, and it concluded that pixantrone was recommended as a cost-effective use of NHS resources. The Committee discussed whether pixantrone was innovative in its potential to make a significant and substantial impact on health-related benefits. It observed that pixantrone is the first drug that has been tested in a randomised phase III trial in patients with multiply relapsed or refractory aggressive non-Hodgkin's lymphoma. It examined whether pixantrone had the potential to make a significant and substantial impact on health-related benefits but heard from the clinical specialists that it was uncertain whether pixantrone could be considered a step change in treatment. On the basis of currently available evidence, the Committee did not consider pixantrone to be a step change in managing multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. The Committee observed that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The Committee concluded that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates. The Committee understood that pixantrone's conditional marketing authorisation is linked to results from the ongoing PIX306 study, which should be available in 2015. It noted that this larger randomised phase III study (n=350) will compare the effectiveness of pixantrone plus rituximab with gemcitabine plus rituximab in patients with relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma who have already received a rituximab-containing regimen. Given the relevance of the patient population (because virtually all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales will have previously received rituximab ), the Committee recommended that the technology appraisal guidance on pixantrone for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma should be considered for review by NICE once the PIX306 results are available in 2015. The Committee considered whether NICE's duties under the equality legislation required it to alter or to add to its recommendations. It noted that no equality issues had been raised during scoping, in any of the consultees' submissions, during consultation or during the Committee meetings. The Committee concluded that its decision on the use of pixantrone does not have a particular impact on any group with a protected characteristic in the equality legislation and that there was no need to alter or add to its recommendations. # Summary of Appraisal Committee's key conclusions TA306 Appraisal title: Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma Section Key conclusion Pixantrone monotherapy is recommended as an option for treating adults with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma only if: the person has previously been treated with rituximab and the person is receiving third- or fourth-line treatment and the manufacturer provides pixantrone with the discount agreed in the patient access scheme. The Committee concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant. The Committee noted that using the revised model that incorporated the patient access scheme, the manufacturer's deterministic ICER was £18,500 per quality-adjusted life year (QALY) gained and that the mean probabilistic ICER was £22,000 per QALY gained. The Committee agreed that the probability of pixantrone being cost effective compared with treatment of physician's choice was acceptable and that the most plausible ICER was likely to be less than £22,000 per QALY gained. It therefore concluded that pixantrone could be recommended as a cost-effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments The Committee heard from the clinical specialists and the patient expert that the aim of treatment at this disease stage was to reduce the impact of symptoms on quality of life, as well as extending life, and could include chemotherapy and participating in clinical trials. The Committee heard from the patient expert that patients would value any new treatment that could offer symptom relief, have a positive impact on quality of life and increase survival. The Committee acknowledged the demands that living with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma can place on patients and accepted that a treatment option for these patients is important. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Pixantrone (Pixuvri, Cell Therapeutics) is an aza‑anthracenedione analogue and inhibitor of topoisomerase II. The Committee concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in clinical practice to treat multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant. The Committee examined whether pixantrone had the potential to make a significant and substantial impact on health-related benefits. On the basis of currently available evidence, the Committee concluded that using pixantrone would not be a step change in managing multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma and that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates. What is the position of the treatment in the pathway of care for the condition? Pixantrone has a conditional marketing authorisation 'as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B‑cell lymphomas (NHL). The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy'. In light of consultee and commentator responses to consultation, the Committee considered that it was appropriate to restrict its assessment of pixantrone to third- and fourth-line treatment. The Committee concluded that the subgroup in PIX301 with aggressive B‑cell lymphoma confirmed by central independent pathological review receiving third- or fourth-line treatment and who had previously received rituximab was the most appropriate for decision-making. Adverse reactions The summary of product characteristics states that the most common toxicity with pixantrone is bone marrow suppression (particularly the neutrophil lineage) and that other toxicities such as nausea, vomiting and diarrhoea are generally infrequent, mild, reversible, manageable and as expected in patients treated with cytotoxic agents. Although the occurrence of cardiac toxicity indicated by congestive heart failure appears to be lower than that expected with related drugs like anthracyclines, the summary of product characteristics recommends monitoring left ventricular ejection fraction. The Committee concluded that pixantrone had an acceptable adverse-event profile although it was associated with more cardiotoxicity than treatments such as oxaliplatin and gemcitabine that are routinely used in this population in clinical practice in England and Wales. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee considered that the PIX301 trial was underpowered because it had failed to recruit the planned number of patients. It also noted that European regulators prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response. The Committee considered that although the PIX301 study had included a high proportion of patients who would be eligible for treatment under the terms of the marketing authorisation, the intention-to-treat population was not appropriate for evaluation and decision-making. The Committee concluded that these fundamental concerns about the design of PIX301 meant that there was considerable uncertainty in the validity and robustness of its results. Relevance to general clinical practice in the NHS Because tumour specimens would be examined by 2 or 3 pathologists in clinical practice in England and Wales, the Committee concluded that it would be more appropriate to consider results from the PIX301 trial using a population with tumour histology confirmed by retrospective central independent pathological review by consensus than by onsite review by a single pathologist. Uncertainties generated by the evidence The Committee was concerned that only just over half of patients in the PIX301 trial had previously received rituximab because it heard from the clinical specialists that rituximab is an integral part of standard first-line treatment in the NHS and also often used as a second-line treatment. It was aware of the obligation to the European Medicines Agency in pixantrone's marketing authorisation requiring a trial to confirm the clinical benefit in patients who have previously received rituximab. The Committee noted a reduced benefit of pixantrone in the subgroup of patients who had previously received rituximab, but concluded that it was appropriate to evaluate this subgroup because this would apply to almost all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee was aware that the intention-to-treat population included patients whose tumour histology would make them ineligible for treatment with pixantrone according to the terms of the European marketing authorisation. The Committee concluded that the subgroup of patients in PIX301 with aggressive B‑cell lymphoma confirmed by central independent pathological review receiving third- or fourth-line treatment and who had previously received rituximab was the most appropriate for decision-making. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that for the subgroup of patients it considered to be most appropriate for decision making (those receiving third- or fourth-line treatment and who had previously received rituximab) there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice, and that the mean survival advantage of pixantrone compared with treatment of physician's choice was 2.0 months. However, these results were not statistically significant. The Committee concluded that there was limited and non-robust evidence to show pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. Evidence for cost effectiveness Availability and nature of evidence The Committee concluded that the outlined structure of the models adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pixantrone. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee was persuaded that the manufacturer's mean probabilistic ICER of £22,000 per QALY gained could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee was aware that the utility value used by the manufacturer in its revised model incorporating the patient access scheme for the pre-progression health state was similar to that expected for an older population in the UK. The Committee considered that the quality of life of patients receiving third- or fourth-line treatment for aggressive non-Hodgkin's B‑cell lymphoma could be lower than this. The Committee concluded that, although there was some uncertainty as to the true utility value, the utility values used in the manufacturer's revised model that was part of the patient access scheme submission were appropriate for use in the Committee's decision-making. The Committee observed that there were no additional gains in health-related quality of life over those already included in the QALY calculations and concluded that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates. Are there specific groups of people for whom the technology is particularly cost effective? The patient access scheme applies to patients with histologically confirmed aggressive non-Hodgkin's B‑cell lymphoma who have previously received rituximab and are receiving pixantrone as a third- or fourth-line treatment. What are the key drivers of cost effectiveness? The Committee concluded that there was limited and non-robust evidence to show pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant. The patient access scheme reduced the mean probabilistic ICER to £22,000 per QALY gained. The Committee was persuaded that this ICER could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. Most likely cost-effectiveness estimate (given as an ICER) The Committee noted that, for the subgroup of patients with aggressive B‑cell lymphoma confirmed by central independent pathological review for third- or fourth-line treatment and who had previously received rituximab, the manufacturer's deterministic ICER incorporating the patient access scheme was £18,500 per QALY gained and the manufacturer's mean probabilistic ICER was £22,000 per QALY gained. The Committee noted that the exploratory analysis showed a high level of uncertainty around the ICER. However, the Committee was persuaded that this analysis could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. The Committee concluded that because the probabilistic ICER was likely to be less than £22,000 per QALY gained pixantrone was recommended as a cost-effective use of NHS resources. Additional factors taken into account Patient access schemes (PPRS) The manufacturer of pixantrone has agreed a patient access scheme with the Department of Health that makes pixantrone available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. End-of-life considerations Not appropriate. Equalities considerations and social value judgements The Committee concluded that its decision on the use of pixantrone does not have a particular impact on any group with a protected characteristic in the equality legislation and that there was no need to alter or add to its recommendations. # Related NICE guidance Details are correct at the time of publication. Further information is available on the NICE website. Rituximab for aggressive non-Hodgkin's lymphoma. NICE technology appraisal guidance 65 (2003). Improving outcomes in haematological cancers. NICE cancer service guidance (2003).# Review of guidance The guidance on this technology will be considered for review when the PIX306 trial results are available and at the latest in November 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveFebruary 2014# Changes after publication April 2014: Wording changes in sections 4.8 and 4.9.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It has been incorporated into the NICE pathway on blood and bone marrow cancers along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0448-8	{'Guidance': "Pixantrone monotherapy is recommended as an option for treating adults with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma only if:\n\nthe person has previously been treated with rituximab and\n\nthe person is receiving third- or fourth-line treatment and\n\nthe manufacturer provides pixantrone with the discount agreed in the patient access scheme.\n\nPeople currently receiving treatment initiated within the NHS with pixantrone monotherapy that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.", 'The technology': "Pixantrone (Pixuvri, Cell Therapeutics) is an aza‑anthracenedione analogue and inhibitor of topoisomerase\xa0II. The recommended dosage is pixantrone 50\xa0mg/m2 on days\xa01, 8\xa0and 15\xa0of each 28-day cycle for up to 6\xa0cycles. It is administered intravenously. Pixantrone has a conditional marketing authorisation 'as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B‑cell lymphomas (NHL). The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy'. The European public assessment report noted pixantrone had a reduced benefit in patients pretreated with rituximab. The marketing authorisation is linked to results being provided from the phase\xa0III PIX306 trial, which is investigating pixantrone plus rituximab compared with gemcitabine plus rituximab in patients with relapsed or refractory aggressive non-Hodgkin's B‑cell lymphomas who have previously received a rituximab-containing regimen. Results are expected in 2015.\n\nThe summary of product characteristics states that the most common toxicity with pixantrone is bone marrow suppression (particularly the neutrophil lineage) and that other toxicities such as nausea, vomiting and diarrhoea are generally infrequent, mild, reversible, manageable and as expected in patients treated with cytotoxic agents. Although the occurrence of cardiac toxicity indicated by congestive heart failure appears to be lower than that expected with related drugs like anthracyclines, the summary of product characteristics recommends monitoring left ventricular ejection fraction. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nPixantrone is priced at £553.50 per 20‑ml vial containing 29\xa0mg free base pixantrone, which is equivalent to 50\xa0mg pixantrone dimaleate (excluding VAT; 'British national formulary' [BNF] edition 66). The estimated cost of a course of treatment is £19,926 (costs calculated over 4\xa0cycles using an average of 3\xa0vials per dose based on the median length of treatment in the PIX301 trial, described in section\xa03.2). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of pixantrone has agreed a patient access scheme with the Department of Health that makes pixantrone available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (section\xa08) considered evidence submitted by the manufacturer of pixantrone and a review of the submissions by the Evidence Review Group (ERG; section\xa09). The manufacturer submitted additional evidence (about the patient population, trial design and clinical effectiveness, a revised model, and support for consideration of end-of-life criteria) after consultation on the appraisal consultation document. The submission and the additional evidence did not incorporate a patient access scheme. The manufacturer later made a confidential simple discount patient access scheme submission in July 2013, which was superseded by an updated patient access scheme submitted in November 2013. The Committee's considerations and decision-making are based on the November 2013 patient access scheme.\n\n# Clinical effectiveness\n\n## Manufacturer's original submission\n\nThe manufacturer's systematic review identified 1\xa0randomised controlled trial, which was included in its original submission. No other relevant randomised controlled trials or non-randomised controlled trials were identified. The manufacturer also included some supporting cardiotoxicity data from a randomised phase\xa0II study that did not meet the inclusion criteria of the literature review (because it evaluated pixantrone in combination with other drugs, not as monotherapy).\n\nPIX301 is a randomised, controlled, open-label phase\xa0III study conducted in 66\xa0centres, including the USA and Europe. Eligible patients were adults with aggressive de novo or transformed non-Hodgkin's lymphoma that had relapsed after 2\xa0or more chemotherapy regimens, including at least 1\xa0standard anthracycline-containing regimen with a response that had lasted at least 24\xa0weeks. Seventy patients were randomised to pixantrone and 70\xa0patients to a physician's choice of single-agent comparators. The full publication of PIX301 described how 67\xa0patients went on to receive vinorelbine (n=11), oxaliplatin (n=30), ifosfamide (n=12), etoposide (n=9), mitoxantrone (n=4) or gemcitabine (n=1). Pixantrone was administered at a dosage of 85\xa0mg/m2 on days\xa01, 8\xa0and 15\xa0of a 28‑day cycle for up to 6\xa0cycles. Comparators were administered at predefined standard dosages for up to 6\xa0cycles. Follow-up was for 18\xa0months after completing study treatment.\n\nThe primary outcome was complete and unconfirmed complete response, which was determined by a blinded independent assessment panel. Secondary outcomes were overall survival, response lasting at least 4\xa0months and progression-free survival. Other predefined end points were overall response rate, time to response, time to complete response, duration of response and relative dose intensity. Health-related quality of life was not assessed. The primary analysis was the intention-to-treat population. Secondary analyses included a prespecified analysis of the response and survival end points for the histologically confirmed intention-to-treat population (that is, if the lymphoma had been classified according to retrospective independent central pathological assessment).\n\nIt was initially planned that 320\xa0patients would be recruited to PIX301 but study enrolment was closed early because of slow accrual. The manufacturer's original submission stated that, with a final enrolment of 140\xa0patients, the study was considered to be sufficiently powered (about 80%) to detect a 15% difference in the complete or unconfirmed complete response rate, assuming a rate of at least 18% in the pixantrone arm. In contrast, the full publication of PIX301 reported that the study was originally powered to detect a difference of 10% in the proportion of patients who achieved a complete or unconfirmed complete response. The publication further stated that, according to the original sample size assumptions, a sample of 70\xa0patients per group would have about 40% power. It added that, to achieve 81% power with 70\xa0patients per group, the true proportion of patients with a complete or unconfirmed complete response would have to be 22% in the pixantrone group and 5% in the comparator group.\n\nThe manufacturer's original submission reported that baseline demographic and disease characteristics were similar in the 2\xa0arms. Previous treatment for non-Hodgkin's lymphoma was broadly similar for both groups, including number of chemotherapy regimens (median 8\xa0regimens [range 2–9] in both arms). Aggressive histological features were identified onsite in all patients before treatment was given and confirmed by central independent pathological review in 54 (77%) of 70\xa0patients in the pixantrone arm and 50 (71%) of 70\xa0patients in the comparator arm receiving treatment of physician's choice. Of the remaining 36\xa0patients, reasons for non-confirmation were low-grade histology (n=13), lack of consensus (n=10), shortage of specimen (n=6), confirmation of a non-aggressive subtype other than non-Hodgkin's lymphoma (n=5), and the specimen reviewed by only 1\xa0pathologist (n=2). Out of 140\xa0patients, 36\xa0patients completed 6\xa0cycles of protocol treatment, and 104\xa0patients discontinued early. The most common reason for early discontinuation in both groups was disease progression or relapse. After completing study treatment, 95\xa0patients entered follow-up and 26 of these completed 18\xa0months of follow-up.\n\nThe manufacturer's original submission reported that, at the end of treatment, confirmed and unconfirmed response rates for the intention-to-treat population (70\xa0patients in each arm) were statistically significantly higher for the pixantrone group than the comparator group receiving treatment of physician's choice (20% compared with 5.7%; p=0.021). This was also the case at the end of the study after 18\xa0months of follow-up (24.3% compared with 7.1%; p=0.009).\n\nThe manufacturer's original submission described the results for progression-free and overall survival in the intention-to-treat population. Median progression-free survival was statistically significantly longer for the group receiving pixantrone than the comparator group receiving treatment of physician's choice at 5.3\xa0months compared with 2.6\xa0months (hazard ratio 0.60 and 95% confidence interval [CI] 0.42 to 0.82; p=0.005). However, there was no statistically significant difference in median overall survival between the 2\xa0groups (10.2\xa0months in the pixantrone arm compared with 7.6\xa0months in the comparator arm receiving treatment of physician's choice (hazard ratio 0.79 [95%\xa0CI 0.53 to 1.18]; p=0.251).\n\nIn addition to the results for the intention-to-treat population of PIX301, the manufacturer included clinical-effectiveness data for several post-hoc subgroups in its original submission for patients with aggressive B‑cell lymphoma (classed as diffuse large B‑cell lymphoma, transformed indolent lymphoma or follicular lymphoma [grade\xa0III]):\n\nDisease confirmed by onsite pathological review (all lines of treatment, and third- or fourth-line treatment only).\n\nDisease confirmed by central independent pathological review (all lines of treatment, and third- or fourth-line treatment only).\n\nDisease confirmed by central independent pathological review in patients who had previously received rituximab treatment.The manufacturer also presented the results for a subgroup of patients with diffuse large B‑cell lymphoma confirmed by onsite pathological review (over 80% of the total number of patients with aggressive B‑cell lymphoma). The results of the subgroup analyses that were incorporated into the manufacturer's original economic model are described below. The results of other subgroup analyses included in the manufacturer's original submission have been previously reported in the appraisal consultation document.\n\nIn its original submission, the manufacturer considered the post-hoc subgroup of patients with aggressive B‑cell lymphoma confirmed by onsite pathological review to be similar to the population eligible for treatment according to pixantrone's European marketing authorisation, and indicated that this formed the basis of the population in the original base case of its cost-effectiveness analysis (however, it should be noted that the manufacturer stated that its economic evaluation focused on those who had received 2\xa0or 3\xa0previous therapies; see section\xa03.20 for details). This subgroup excluded patients with peripheral T‑cell lymphoma not otherwise characterised and other disease subtypes not included in pixantrone's European marketing authorisation. Compared with the group that received treatment of physician's choice (n=62), complete or unconfirmed complete response rates at the end of the study in the pixantrone group (n=64) were statistically significantly higher (23.4% compared with 8.1%; p=0.027). Overall response rates were also statistically significantly higher in the pixantrone group (40.6% compared with 16.1%; p=0.003). Median progression-free survival was statistically significantly longer in patients who had received pixantrone than those who had received a comparator drug (5.7\xa0months compared with 2.5\xa0months, hazard ratio 0.56 [95% CI 0.38 to 0.81]; p=0.002). The manufacturer advised that median overall survival was not included because the aggressive B‑cell lymphoma analyses were exploratory.\n\nIn its original submission, the manufacturer presented a further analysis of patients with aggressive B‑cell lymphoma confirmed by onsite pathological review who received pixantrone (n=50) or a comparator (n=49) as third- or fourth-line treatment, which it stated was more closely aligned with pixantrone's marketing authorisation. It is not clear from the manufacturer's submission how this population differs from that in the base case of its cost-effectiveness analyses (see section\xa03.20 for details). The group receiving pixantrone had a statistically significantly higher complete response or unconfirmed complete response rate (28.0% compared with 4.0%; p=0.002) and overall response rate (48.0% compared with 12.2%; p<0.001), and statistically significantly longer progression-free survival (5.8\xa0months compared with 2.8\xa0months, hazard ratio not stated; p=0.002) than the comparator group receiving treatment of physician's choice. Median overall survival in this population was numerically higher in the pixantrone arm than the comparator arm but this difference was not statistically significant (13.9\xa0months compared with 7.8\xa0months, hazard ratio 0.76 [95% CI 0.47 to 1.24]; p=0.275). The manufacturer's submission did not state whether the results were for end of treatment or end of study.\n\nIn addition to the histologically defined subgroups of the PIX301 population in its original submission, the manufacturer also supplied subgroup analyses that showed the influence of previous rituximab treatment on pixantrone's efficacy in the subgroup of patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review. In this subgroup of patients who had previously received rituximab, there was no statistically significant difference between pixantrone (n=30) and the comparator arm (n=26) in the proportion of patients who had a complete or unconfirmed complete response at the end of treatment (16.7% compared with 7.7%; p=0.431). Median progression-free survival was longer in the pixantrone group than in the comparator group receiving treatment of physician's choice for this subgroup of patients but the difference did not reach statistical significance (3.5\xa0months compared with 2.3\xa0months, hazard ratio 0.66 [95% CI 0.38 to 1.14]). Similarly, median overall survival was longer in the pixantrone group than in the comparator group receiving treatment of physician's choice but the between-group difference was not statistically significant (6.0\xa0months compared with 4.6\xa0months, hazard ratio 0.85 [95% CI 0.48 to 1.50]).\n\nThe manufacturer's original submission described the adverse events in PIX301 for 68\xa0patients in the pixantrone group and 67\xa0patients in the comparator group who received treatment of physician's choice. One dose reduction was allowed for patients who had neutropenia during treatment, and reductions were similar in the pixantrone and comparator groups (18% compared with 15%). Dose delay was more frequent with pixantrone (40% compared with 22%).\n\nA similar number of patients had an adverse event of any grade but there was a higher incidence of grade\xa03 and\xa04 adverse events in the pixantrone group than in the comparator group (76.5% compared with 52.2%). Neutropenia occurred more frequently in the pixantrone group and was the most common adverse event of any grade (50.0% compared with 23.9%) and the most common grade\xa03\xa0or\xa04 adverse event (41.2% compared with 19.4%). Grade\xa03\xa0or\xa04 febrile neutropenia was also more common in the pixantrone group than in the comparator group (7.4% compared with 3.0%), and more patients in the pixantrone group than in the comparator group received an immunostimulant (51.5% compared with 26.9%). The manufacturer reported that severity of neutropenia did not increase with increasing cycle number and that the overall rates of grade\xa03\xa0and\xa04 infections were similar in the 2\xa0groups. It further stated that the common adverse events were similar to those expected in a heavily pretreated patient population, which reflected pixantrone's intended use in clinical practice in England and Wales (that is, third and subsequent lines of treatment).\n\nApproximately 40% of patients in both treatment arms presented with a history of cardiac disease at study enrolment, and cardiac risk factors were also similar in the 2\xa0groups. The manufacturer stated that pixantrone is an innovative treatment because it has been specifically designed to reduce cardiotoxicity associated with anthracyclines without compromising efficacy. More cardiac adverse events occurred in the pixantrone group (24\xa0patients [35.3%] than in the comparator group who received treatment of physician's choice (14\xa0patients [20.9%]). Thirteen (19.1%) patients in the pixantrone group experienced decreased left ventricular ejection fraction compared with 7\xa0patients in the comparator group. The manufacturer provided supporting cardiotoxicity data from the randomised open-label phase\xa0II PIX203 trial, which closed before enrolment completed. This trial compared the combination of cyclophosphamide, pixantrone, vincristine, prednisone and rituximab with the standard of care (that is, rituximab in combination with a regimen of cyclophosphamide, doxorubicin, vincristine and prednisone) as first-line treatment in patients with diffuse large B‑cell lymphoma. The cardiotoxicity results of PIX203 broadly supported those of PIX301.\n\n## Manufacturer's additional evidence in response to consultation on the first appraisal consultation document\n\nIn response to consultation on the first appraisal consultation document, the manufacturer requested and received permission from NICE to submit additional evidence. The additional evidence contained the results for 4\xa0subgroups and showed the effect of treatment in patients who had previously received rituximab. Two of the subgroups were patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review for all lines of therapy, and the other 2\xa0subgroups were patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment. During the second Committee meeting, the manufacturer clarified that the subgroups of all patients regardless of rituximab status (those patients who had previously received rituximab plus those who had not) were labelled as 'without rituximab' in its response to consultation.\n\nIn its additional evidence, the manufacturer presented amended results for the subgroup of patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review and had previously received rituximab (see section\xa03.11). Complete or unconfirmed complete response rates were higher in the pixantrone arm than in the comparator arm (20% compared with 11%) but this difference was not statistically significant. Results for progression-free survival and overall survival were as before, except for median progression-free survival in the comparator arm, which the manufacturer confirmed was an error. In its consultation response, the manufacturer also reiterated data for the subgroup of all patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review regardless of whether they had previously received rituximab or not (n=50 in the pixantrone group, n=47 in the comparator group). At the end of the study, there was no statistically significant difference in complete or unconfirmed complete response rates between the pixantrone and comparator groups (9\xa0patients compared with 4\xa0patients; p=0.236). However, the overall response rate was statistically significantly higher in the pixantrone group (18\xa0patients compared with 8\xa0patients; p=0.041). Median progression-free survival was statistically significantly longer in the pixantrone arm than in the comparator arm (5.6\xa0months compared with 2.5\xa0months, hazard ratio 0.51 [95% CI 0.33 to 0.78]; p\xa0value not stated) but there was no statistically significant difference in median overall survival between the 2\xa0groups (8.1\xa0months compared with 6.3\xa0months, hazard ratio 0.72 [95% CI 0.45 to 1.13]; p\xa0value not stated).\n\nIn its additional evidence, the manufacturer reiterated subgroup analyses for all patients (that is, patients who had previously received rituximab plus those who had not) with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment with pixantrone (n=39) or treatment of physician's choice (n=39). Compared with the group receiving treatment of physician's choice, the pixantrone group had a statistically significantly higher complete or unconfirmed complete response rate (23.1% compared with 5.1%; p=0.047) and overall response rate (43.6% compared with 12.8%; p=0.005). Median progression-free survival was statistically significantly longer with pixantrone than with treatment of physician's choice (5.7\xa0months compared with 2.8\xa0months, hazard ratio 0.44 [95% CI 0.27 to 0.71]) but there was no statistically significant difference in median overall survival between treatment groups (11.9\xa0months with pixantrone compared with 7.0\xa0months with treatment of physician's choice, hazard ratio 0.67 [95% CI 0.40 to 1.12]).\n\nIn its additional evidence, the manufacturer also provided results for a subgroup described as patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment who had previously received rituximab (n=25 in both study arms), but confirmed at the second Committee meeting that this population was in fact a subgroup of patients whose disease had been confirmed by onsite (not central) pathological review. The correct population (that is, with pathology confirmed by central independent review), whose results had previously been included as part of the manufacturer's clarification response, showed an increase in complete response or unconfirmed complete response in the pixantrone arm (n=20) compared with the comparator arm (n=18; 30% compared with 5.6%; p=0.093). There was no statistically significant difference between treatment arms in median progression-free survival (5.4\xa0months in the pixantrone group and 2.8\xa0months in the comparator group, hazard ratio 0.52 [95%\xa0CI 0.26 to 1.04]). Similarly, there was no statistically significant difference in median or mean overall survival between treatment arms (hazard ratio 0.76 [95%\xa0CI 0.38 to 1.55]). Median overall survival was 7.5\xa0months in the pixantrone group and 5.4\xa0months in the comparator group. Mean overall survival was 9.9\xa0months in the pixantrone arm and 7.9\xa0months in the comparator group (difference of 2.0\xa0months).\n\n# Cost effectiveness\n\nThe manufacturer did not identify any published economic evaluations or costing studies that were relevant to the decision problem. Consequently, it submitted a de novo economic analysis that assessed the cost effectiveness of pixantrone compared with treatment of physician's choice in treating multiply relapsed or refractory aggressive B‑cell lymphoma, which was later revised as part of the manufacturer's response to consultation (see section\xa03.31 for details of changes in the revised model). Further minor updates were made in the manufacturer's model that formed part of a patient access scheme submission which was submitted in July 2013. In November 2013, this was superseded by another patient access scheme submission, which applied a further simple discount to the model (see sections\xa03.34–3.38 for details).\n\n## Manufacturer's submission\n\nThe manufacturer advised that the base-case model considered patients who had received 2\xa0or\xa03 prior therapies and whose disease was sensitive to treatment with anthracyclines because this population was consistent with pixantrone's European marketing authorisation for treating multiply relapsed or refractory aggressive non-Hodgkin's lymphoma (the marketing authorisation notes that a treatment benefit has not been established 'when used as fifth line or greater chemotherapy in patients who are refractory to last therapy'). The clinical data for this population were derived from PIX301. The analysis was conducted from an NHS and personal and social services perspective and a lifetime horizon of 23\xa0years was used. Weekly cycles were chosen to capture the 4‑week treatment cycles of pixantrone and 3‑week treatment cycles of some of the comparator treatments and a half-cycle correction was applied. Costs and benefits were discounted at 3.5% per annum.\n\nThe manufacturer created a semi-Markov model that contained 3\xa0health states: stable or no progression, progressive or relapsed disease, and death. The stable or no progression health state had 2\xa0distinct subpopulations. The first of these was patients on initial third- or fourth-line treatment. The second was patients who had discontinued third- or fourth-line treatment (because of complete response, adverse event, completion of 6\xa0months' treatment or a non-clinical reason) but had not experienced progression. All patients entered the model in the on-treatment subpopulation within the stable or no progression health state. During each cycle, patients could remain in the on-treatment subpopulation of this health state, discontinue treatment and move into the other subpopulation in this health state, progress and move into the progressive disease health state, or die. Patients who discontinued treatment before progression remained at risk of progression or death. Following progression, patients were at risk of death and unable to return to the stable or no progression health state. It was assumed that the original treatment was stopped following disease progression and patients received further treatment or palliative care. Adverse events were captured as events within the model by applying a utility decrement (disutility).\n\nThe manufacturer outlined how the transition between health states was calculated from the clinical data for any given weekly cycle. It noted that semi-Markov models allow the use of a partition approach, which has been used extensively in oncology because it is particularly suited to progressive conditions that have ongoing risks that may vary over time. The distribution of the patient group between the different health states was estimated by calculating the area under the survival curves at each cycle. The progression-free survival curve defined the stable or no progression state, while the progressed state was defined by subtracting those patients who remained progression free from all surviving patients.\n\nClinical parameters for progression-free survival and overall survival were incorporated into the base case of the manufacturer's economic model by statistical analysis of patient-level data from the aggressive B‑cell population of PIX301. Predictive equations for progression-free survival and overall survival were derived by fitting the patient-level data and extrapolating beyond the data from PIX301 (around 2\xa0years). A log-normal distribution was used in the base case for both progression-free survival and overall survival.\n\nFurther clinical parameters were incorporated into the base case of the manufacturer's economic model. The cycle probability of treatment discontinuation distinguished between patients remaining on initial treatment and those who discontinued while stable. The frequency and duration of adverse events (grades\xa02–4) before progression while taking initial treatment were based on PIX301. Grade\xa03\xa0and\xa04 adverse events occurring in at least 5% of the total patient population were considered to have cost and utility consequences. Some grade\xa02, and rarer grade\xa03\xa0and\xa04, adverse events were included if considered important by clinical specialists in England. Other data from PIX301 that were used to inform the model were mean dose for the comparator treatments plus sex and body surface area.\n\nThere were no patient-reported outcomes in PIX301 and the manufacturer did not identify any utility data for any line of treatment in aggressive non-Hodgkin's lymphoma in its systematic literature review for studies on health-related quality of life. Utility data were identified from published sources for similar patient populations, and for disease areas with similar expected survival, disease progression, nature of the disease and quality of life. These were diffuse large B‑cell lymphoma, chronic myelogenous leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, renal cell carcinoma and melanoma. For its original model, the manufacturer considered the self-reported quality of life in older patients with aggressive diffuse large B‑cell lymphoma to give the estimation closest to the PIX301 trial population and used these values (pre-progression\xa00.81, post-progression\xa00.60) in its base-case analysis. The manufacturer did not provide a rationale for this decision. Utility values were assumed to depend only on the health state and any adverse events experienced, but not the treatment arm. Based on expert clinical opinion, the manufacturer assumed no difference in baseline health-related quality of life between the 2\xa0subpopulations in the stable or no progression health state. All stable/no progression patients were assumed to have similar quality of life (that is, there was no difference according to complete response, partial response or stable disease).\n\nThe manufacturer determined disutilities associated with each adverse event that was included in the original model from relevant literature from other oncology indications. If no utility decrements were available, the maximum value of the range identified was assumed by the manufacturer to keep the calculations conservative (that is, so that pixantrone was not favoured).\n\nAdverse events were modelled by the manufacturer as events rather than as health states and were assumed to be time independent because adverse events are likely to be experienced at different stages of treatment. Any grade\xa01–4 adverse event that occurred in less than 5% of the trial population was assumed to have no impact on quality of life. After consulting some clinical specialists in England, the manufacturer included some rarer grade\xa03 and 4 adverse events and some grade\xa02 adverse events that the clinical specialists considered to be important. Because no disutility values were available specifically for grade\xa02 and grade\xa03 or 4 adverse events, they were assumed to be the same for each grade. Within a health state, disutilities relating to an adverse event were applied to the proportion of patients assumed to experience the adverse event as weighted average disutilities. For each treatment, the manufacturer calculated a weighted average of grade-specific disutilities that were weighted by the number of effects of that particular grade. The disutility for each adverse event was then applied for the duration of that specific type of effect. The manufacturer's model limited the consideration of adverse events to patients on original treatment upon entering the model (pixantrone or treatment of physician's choice).\n\nCosts captured in the manufacturer's model included drugs and their administration, plus those associated with health state and disease management, including adverse events. Drug and administration costs in the original model were calculated based on average dose per administration from the PIX301 trial using the British national formulary (BNF) edition\xa062 (published in September 2011) and the NHS reference costs. No patient access scheme was incorporated in the original model. From the second attendance onwards, administration costs were £206 for each attendance for all drugs except etoposide 50\xa0mg (£163). At clarification, the manufacturer corrected an error in the vial price, which had been mistakenly quoted as £343.80 (based on the vial size given for pixantrone base) instead of £553.50 (equivalent to 50\xa0mg pixantrone dimaleate). It advised that this error had a minimal impact on the cost-effectiveness estimates (which increased by 0.3%) because the drug costs in the model had been calculated based on cost per administration. The total number of administrations varied according to the dosing schedule for each drug. Drug wastage was incorporated in the base case. Personal and social services costs were £476.42 per 28\xa0days for stable health state on treatment, £119.10 for stable health state on palliative care and £1993.89 for progressive health state. Disease management costs (comprising healthcare professional contact, disease follow-up and hospital-related costs) were different for active treatment and palliative care. For active treatment, health professional contact costs were £788.96 on treatment and £220.38 after treatment (per 28\xa0days), disease follow-up costs were £86.63 per 28\xa0days and annual hospital-related costs were £2357.28. For palliative care, health professional contact costs were £990.74 per 28\xa0days, disease follow-up costs were £18.44 per 28\xa0days and annual hospital-related costs were £1982.03. End-of-life care was excluded from the calculations because it affected only the last few weeks of life and estimates would be similar for pixantrone and its comparators. Within a health state, costs for managing an adverse event were applied to the proportion of patients assumed to experience the adverse event.\n\nThe manufacturer advised that the predicted median progression-free survival and predicted median overall survival were similar to the results reported in PIX301. Compared with the clinical trial results, the manufacturer noted that the original model slightly underestimated the median overall survival with pixantrone (13.1\xa0months compared with 13.8\xa0months) while overestimating it for the comparator (9.2\xa0months compared with 7.6\xa0months). It reported that, conversely, the original model overestimated the median progression-free survival for the pixantrone arm (7.8\xa0months compared with 6.4\xa0months) and slightly underestimated it for the comparator arm (3.2\xa0months compared with 3.5\xa0months).\n\nUsing the original model, the manufacturer's base-case analyses for pixantrone compared with treatment of physician's choice in patients with aggressive B‑cell lymphoma confirmed by onsite pathological review (third- or fourth-line treatment) produced a deterministic incremental cost-effectiveness ratio (ICER) of £28,423 per quality-adjusted life year (QALY) gained. Incremental costs were £17,638 and incremental QALYs were 0.62. Using the correct vial price supplied at clarification increased the ICER to £28,503 per QALY gained. No probabilistic base-case ICER was presented. All economic analysis results generated using the manufacturer's original model have been superseded by those using the model provided with the patient access scheme submission submitted in November 2013 (see sections\xa03.34–3.38).\n\n## Manufacturer's additional evidence in response to consultation on the first appraisal consultation document\n\nIn response to the first appraisal consultation document, the manufacturer provided a revised economic model, which contained these amendments:\n\nThe adverse-event disutilities used in the ERG's exploratory analyses were incorporated.\n\nDrug costs for comparator treatments were taken from the NHS Commercial Medicines Unit's Electronic Marketing Information Tool (eMIT) database instead of the BNF in line with NICE's Guide to the methods of technology appraisal (2013).\n\nUtility values were changed from self-reported quality of life in older patients with aggressive diffuse large B‑cell lymphoma (0.81 for the pre-progression health state, 0.60 for the post-progression health state) to those for second- and subsequent-line treatment of renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). This was in response to the Committee's conclusion in the first Committee meeting that the original utility values had overestimated quality of life for patients with multiply relapsed or refractory non-Hodgkin's lymphoma.The revised model did not incorporate a patient access scheme.\n\nUsing its revised model, the manufacturer provided cost-effectiveness estimates of pixantrone compared with treatment of physician's choice for several subgroups, including patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment and had previously had rituximab. The deterministic ICER for this subgroup was £45,282 per QALY gained (incremental costs £9170; incremental QALYs\xa00.20). No probabilistic ICER was provided. All economic analysis results generated using the manufacturer's revised model have been superseded by those using the model provided with the patient access scheme submission submitted in November 2013 (see sections\xa03.34–3.38).\n\n## Manufacturer's patient access scheme submissions\n\nThe manufacturer agreed a patient access scheme in July 2013, which was a confidential simple discount on the list price of pixantrone. It further updated its economic model so that costs for treating adverse events and the cost for methotrexate were in line with the Committee's preferred values decided at the second Committee meeting. All economic analysis results generated using the manufacturer's model provided with the patient access scheme submitted in July 2013 have been superseded by those using the model provided with the patient access scheme submission submitted in November 2013 (see sections\xa03.34–3.38).\n\nIn response to the second appraisal consultation document, the manufacturer submitted a patient access scheme in November 2013 that contained an additional discount to the patient access scheme proposed in July 2013. The November 2013 patient access scheme is a simple discount on the list price of pixantrone, and the economic model was further updated with this additional discount as part of this submission. The manufacturer advised that the patient access scheme would apply to patients with histologically confirmed aggressive non-Hodgkin's B‑cell lymphoma who had previously received rituximab and would be receiving pixantrone as a third- or fourth-line treatment. The manufacturer made no other revisions to the economic model.\n\nThe manufacturer provided cost-effectiveness estimates incorporating the patient access scheme submitted in November 2013 for pixantrone compared with treatment of physician's choice for patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment and had previously received rituximab. This additional discount reduced the deterministic ICER to £18,462 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.20).\n\nThe manufacturer tested the robustness of the model using one-way sensitivity analyses and reported that the key drivers of the cost-effectiveness estimates produced using its economic model were the parametric fitting methodology for progression-free survival and overall survival, and the utility estimate for the stable or no progression health state. The manufacturer noted that the ICER was sensitive to changes in the estimates for progression-free survival.\n\nIn its base-case patient access scheme submission provided in November 2013, the manufacturer used the same utility values as the revised version of the model, which were for patients receiving second- and subsequent-line treatment for renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). The manufacturer provided alternative utility scenarios using data from published sources for similar patient populations, and for disease areas with similar characteristics. These were second-line treatment in patients with chronic myelogenous leukaemia, third-line treatment in patients with chronic lymphocytic leukaemia, first-line maintenance treatment in patients with follicular lymphoma, first-line treatment in patients with metastatic renal cell carcinoma, self-reported quality of life during chemotherapy in elderly patients with aggressive non-Hodgkin's lymphoma and second-line treatment in patients with malignant melanoma. The ICERs ranged from £14,607 per QALY gained to £18,871 per QALY gained.\n\nTo explore uncertainty, the manufacturer undertook a probabilistic sensitivity analysis that incorporated the patient access scheme submitted in November 2013. The probabilistic mean ICER was £22,024 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs\xa00.18). However the manufacturer asserted that there was structural uncertainty inherent in the probabilistic sensitivity analysis that reduced the advantage of pixantrone and skewed the probabilistic results. It explained that the model assumed that overall survival and progression-free survival were independent, leading to the survival curves crossing (that is, more patients were in the progression-free survival state than alive) and the model artificially reduced progression-free survival to avoid this, and that this applied to around 30% of the simulations. In order to illustrate the structural uncertainty arising from the probabilistic ICER, the manufacturer provided additional analyses; for example, if it is assumed that overall survival and progression-free survival are not independent (by assuming the same random numbers for progression-free survival and overall survival using the Cholesky decomposition), the probabilistic mean ICER is £9938 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.21). The manufacturer also noted that the joint uncertainty of incremental QALYs and incremental costs did not follow a normal distribution, and reported that the median probabilistic ICER was £14,692 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.18). The manufacturer reported that pixantrone was more likely to be cost effective compared with treatment of physician's choice in patients with aggressive B‑cell lymphoma confirmed by central pathological review who were receiving third- or fourth-line treatment at a maximum acceptable ICER of £25,000 per QALY gained.\n\n# Evidence Review Group's comments\n\nThe ERG considered the evidence included by the manufacturer to be relevant to the decision problem in its analysis. No additional relevant trials were identified and the ERG found that the manufacturer's systematic review followed standard practices.\n\nThe ERG had concerns about the generalisability of the PIX301 population to clinical practice in England and Wales, particularly the potential effect of previous rituximab treatment on the response to pixantrone because rituximab is given as part of standard first-line treatment in the UK. The ERG noted that about 50% of patients in PIX301 had previously received treatment with a biological agent (for example, rituximab). The ERG considered the clinical benefit of pixantrone in patients who have previously been treated with rituximab to be a key area of uncertainty, given that there were no statistically significant differences between the pixantrone and comparator arms for complete or unconfirmed complete response, progression-free survival or overall survival in the subgroup of patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who had previously received rituximab.\n\nThe ERG considered whether the treatments of physician's choice in PIX301 represented clinical practice in England and Wales. Following input from its clinical specialists, the ERG noted that there is no consensus on which chemotherapy regimens should be used after second-line treatment fails and that there is a lack of comparative data on their clinical effectiveness. The ERG concluded that this meant the choice of treatment in the comparator arm of PIX301 was unlikely to be a key issue. It also concluded that the small number of patients receiving each treatment meant that the choice of treatment in the comparator group could not be reliably analysed.\n\nThe ERG was concerned about the statistical power of PIX301 to detect a difference between treatment groups. According to the manufacturer's revised power calculation, 81% power with 70\xa0patients per group (the intention-to-treat population) would be achieved if the true proportion of patients with complete or unconfirmed complete response was 22% in the pixantrone group and 5% in the comparator group. However, the observed proportions of patients with a complete or unconfirmed complete response in the intention-to-treat population were 20.0% in the pixantrone group and 5.7% in the comparator group. The ERG noted that the difference between groups did not always reach statistical significance, and that results of the analyses in the subgroups confirmed by central independent pathological review should be interpreted with caution because they are likely to be underpowered to detect a difference between treatment groups. For these reasons, the ERG had reservations about whether pixantrone had been shown to have superior efficacy in PIX301.\n\nThe ERG was concerned about the reliability of the diagnosis of aggressive non-Hodgkin's lymphoma at study entry. It noted that central independent pathological review by consensus was undertaken retrospectively (that is, after the trial), rather than at enrolment, and that aggressive disease was subsequently confirmed in only 104 of the 140\xa0patients who were randomised. Consequently, it felt that results from the full trial population might not reflect the benefit of pixantrone in patients with aggressive B‑cell lymphoma. The ERG acknowledged that the manufacturer said it had not been practical to confirm aggressive disease by central independent pathological review at enrolment, but considered it was important to evaluate data from the subgroup of patients with disease confirmed by central independent pathological review. The ERG noted that, as a subgroup analysis, the statistical power of PIX301 would be less than the intention-to-treat population.\n\nThe ERG considered the different patient populations in the subgroup analyses presented by the manufacturer. The ERG viewed the data from the post-hoc subgroup of patients with aggressive non-Hodgkin's B‑cell lymphoma that was histologically confirmed by central independent pathological review to be more relevant to the marketing authorisation and the decision problem in the NICE scope than the other 2\xa0subgroups categorised according to type of lymphoma determined by onsite pathological review (patients with aggressive non-Hodgkin's B‑cell lymphoma and patients with diffuse large B‑cell lymphoma). The ERG noted that retrospective central independent pathological review revealed 23% of patients receiving pixantrone and 29% of patients receiving a comparator in the intention-to-treat population had disease that was not subsequently confirmed as being aggressive. The ERG was aware that disease severity is an important factor in deciding treatment strategy because patients without aggressive disease are likely to have a more favourable response than those with aggressive disease.\n\nThe ERG considered the statistical robustness of the subgroup analyses. It observed that the comparative clinical-effectiveness results for most of the subgroups were based on post-hoc subgroup analyses. It also noted that the number of patients in the analysis was generally small, increasing uncertainty around the results. For subgroups based on retrospective histological confirmation of aggressive disease and previous rituximab treatment, the ERG noted the potential for unbalanced groups because randomisation had not been stratified by these factors. The ERG concluded that the results of the subgroup analyses should be interpreted with caution.\n\nThe ERG considered the adverse events reported to occur more often in the pixantrone group than the comparator group receiving treatment of physician's choice to be consistent with the common adverse events associated with pixantrone reported in the summary of product characteristics.\n\nOverall, the ERG considered the manufacturer's original model to be in line with current best practice recommendations, generally well constructed and largely transparent. The ERG considered that an important limitation of the manufacturer's original base-case analysis was that it used data from patients whose disease had not been histologically confirmed as aggressive. The ERG indicated that the subgroup of patients with aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review for all lines of treatment in PIX301 was the most informative to the decision problem because it excluded patients who were later found to have disease that was irrelevant to the decision problem (for example, indolent disease). However, the ERG noted that the manufacturer's estimate of cost effectiveness in this patient population was highly uncertain because it used post-hoc subgroup data and because the subgroups were not powered to detect a difference in efficacy between treatment with pixantrone and the comparators.\n\nThe ERG considered the utility weights used by the manufacturer in its original economic model to be potentially inappropriate. It noted that the utility values were from a population of patients receiving first-line treatment for aggressive non-Hodgkin's lymphoma and were derived from a study that had initially been rejected by the manufacturer in its systematic review. It further noted that the manufacturer's reported utility values were higher than those that have been derived for healthy older patients in the UK.\n\nThe ERG noted that the results of the manufacturer's original economic model may potentially be biased towards pixantrone because of an overestimation of pixantrone's relative progression-free survival benefit compared with treatment of physician's choice for the populations with aggressive B‑cell lymphoma (whether confirmed by onsite or central independent pathological review). Clinical specialist opinion received by the ERG expressed concern that the data used in the model may not be sufficient to reach reasonable conclusions about the clinical or cost effectiveness of pixantrone.\n\nThe ERG identified other areas of inaccuracy or uncertainty in the assumptions and parameter estimates used in the manufacturer's original model and indicated the most significant of these were structural assumptions made about treatment discontinuation, disutility, and the cost parameters used:\n\nThe potential double-counting of treatment discontinuation because of disease progression.\n\nExcluding adverse event disutilities for patients on further lines of treatment.\n\nDiscrepancies between the manufacturer's and ERG's interpretation of the literature on disutilities for adverse events.\n\nUsing weighted average adverse event rates to inform costs and disutilities associated with adverse events for patients on original treatment.\n\nMissing data from data used to inform average adverse event costs.\n\nExcluding costs associated with treating leukopenia and thrombocytopenia.\n\nUsing costs from BNF\xa062 (published September 2011) rather than BNF\xa064 (published September 2012).\n\nThe ERG critiqued the manufacturer's additional evidence submitted in response to the first consultation. Although there were some uncertainties in the definition and labelling of the manufacturer's subgroups, the ERG was able to validate the terminology used and check that the changes the manufacturer had made to its model were appropriate. The ERG indicated that, based on the European marketing authorisation and clinical practice in England and Wales, it was important to evaluate patients with aggressive B‑cell lymphoma confirmed by retrospective central independent pathological review who had previously received rituximab. However, it noted that it was also appropriate to evaluate a subgroup of these patients receiving third- or fourth-line treatment.\n\nThe ERG critiqued the manufacturer's patient access scheme submission. It validated the changes made to the economic model in the July 2013 and November 2013 submissions and agreed that the subgroup of patients covered by the patient access scheme was characteristic of patients in England and Wales who were likely to be eligible for treatment with pixantrone.\n\nThe ERG validated the manufacturer's deterministic and probabilistic sensitivity analyses on the updated base case in the patient access scheme submitted in November 2013, which were conducted in the same way as in the manufacturer's original submission. The ERG had commented in its critique of the manufacturer's original submission that the manufacturer's assessment of uncertainty was very detailed and that the probabilistic and one-way sensitivity analyses, including various scenario analyses, were satisfactorily reported.\n\nThe ERG commented that the absence of utility data in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma results in a great deal of uncertainty. The ERG stated that although the utility values derived from patients receiving second-line treatment for renal cell carcinoma were less favourable than those used in the manufacturer's original submission, they may still overestimate the utility of patients with aggressive non-Hodgkin's B‑cell lymphoma receiving third- or fourth-line treatment.\n\nThe ERG stated that the manufacturer's original base-case cost-effectiveness results (before inclusion of any patient access scheme) were generated deterministically rather than probabilistically (that is, mean values rather than distributions were used to inform the value of each parameter). However, the ERG noted that probabilistic cost-effectiveness results could be assessed using the manufacturer's original model. It noted a wide range in the 95% confidence interval for the mean probabilistic ICER. The ERG considered this showed substantial uncertainty in the manufacturer's cost-effectiveness results.\n\nUsing the manufacturer's original model (before inclusion of any patient access scheme), the ERG carried out exploratory sensitivity analyses to investigate the impact of alternative assumptions or parameters on the manufacturer's cost-effectiveness results. The ERG judged the population with aggressive B‑cell lymphoma confirmed by central independent pathological review for all lines of treatment in PIX301 to be the most relevant to the decision problem (because it excluded patients who were later found to have disease that was not relevant to the decision problem [for example, indolent disease]) and used it in all its exploratory analyses with the original model.\n\nBecause it had concluded that the utility values used by the manufacturer in its original model (before inclusion of any patient access scheme) may have been inappropriate, the ERG investigated how alternative utility values affected the manufacturer's original base case. The ERG presented a markedly increased ICER for pixantrone compared with treatment of physician's choice when it used utility data from chronic lymphocytic leukaemia patients receiving third- or later-line treatment to inform the utility of progression-free survival and progressive disease (0.428 for the pre-progression health state and 0.279 for the post-progression health state).\n\nThe ERG discussed the probabilistic cost-effectiveness results generated by the manufacturer using the patient access scheme submitted in November 2013, and validated the changes by the manufacturer to the economic model. The ERG commented that the manufacturer's probabilistic analysis showed that, after incorporating the patient access scheme, the probability of pixantrone being cost-effective compared with treatment of physician's choice was 49.3% at up to £20,000 per QALY gained and 55.7% at up to £30,000 per QALY gained. The ERG considered it important to note that, although 68% of probabilistic iterations showed a greater benefit for pixantrone than treatment of physician's choice, around 32% of probabilistic iterations indicated that patients treated with pixantrone fared worse than those who received treatment of physician's choice.\n\nFull details of all the evidence are in the evaluation report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pixantrone, having considered evidence on the nature of multiply relapsed or refractory non-Hodgkin's B‑cell lymphoma and the value placed on the benefits of pixantrone by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the treatment pathway for multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It heard from the clinical specialists that rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (also known as R‑CHOP) was the standard first-line treatment in England and Wales, and that most patients would also receive a rituximab-containing regimen second line. If their disease did not relapse within 6\xa0months of first-line treatment, patients would be treated with rituximab. The Committee also noted that the clinical specialists stated that people treated with rituximab were less likely to respond to any subsequent treatment. The Committee heard that a platinum-based regimen was offered as second-line treatment but that there was no consensus on third- or fourth-line treatment. The Committee heard from the clinical specialists and the patient expert that the aim of treatment at this disease stage was to reduce the impact of symptoms on quality of life, as well as extending life, and could include chemotherapy or participating in clinical trials. The clinical specialists highlighted that fifth-line options include palliative care or participating in clinical trials. The Committee also noted that the marketing authorisation states that the benefit of pixantrone treatment has not been established in patients when used as fifth-line or further chemotherapy in patients whose disease is refractory to last therapy.\n\nThe Committee heard from the patient expert about the impact of multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma on daily life and that the symptoms of the disease can reduce quality of life. It heard that patients are normally told at the start of their treatment that they are being treated with curative intent and that experiencing multiple relapses can be devastating; consequently, they would value any new treatment that could offer symptom relief, have a positive impact on quality of life and increase survival. The Committee acknowledged the demands that living with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma can place on patients and accepted that a treatment option for these patients is important.\n\n# Clinical effectiveness\n\nThe Committee reviewed the suitability of the clinical trial evidence submitted by the manufacturer and expressed several concerns about the PIX301 trial. It considered PIX301 to be underpowered because it had failed to recruit the planned number of patients. It also noted that European regulators prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response. The Committee heard from the clinical specialists that although this end point would have been acceptable when the trial began in 2004, positron emission tomography (PET) scans have made unconfirmed complete response obsolete in trials that have begun more recently. The Committee also heard from the clinical specialists that they considered studies that were powered to detect a difference in overall survival to be more useful for clinical decision-making. The Committee concluded that these fundamental concerns about the design of PIX301 meant that there was considerable uncertainty in the validity and robustness of its results.\n\nThe Committee discussed the relationship between the marketing authorisation, the PIX301 population and clinical practice in England and Wales. The Committee was aware that the intention-to-treat population included around 10% of patients who did not have aggressive B‑cell lymphoma, making them ineligible for treatment with pixantrone according to the terms of the marketing authorisation. The Committee further noted that the marketing authorisation is for multiply relapsed or refractory disease (that is, it is approved for patients who have received at least 2\xa0previous lines of treatment) and that this does not necessarily restrict its use to third- and fourth-line treatment. However, it also noted the comments received during consultation stating that patients receiving fifth-line or further treatment would likely have palliative treatment or participate in a clinical trial. The Committee was persuaded that pixantrone would most likely be used, within its marketing authorisation, as a third- or fourth-line treatment in clinical practice in England and Wales. The Committee concluded that, when assessing the PIX301 results, it would be more appropriate to consider the population with aggressive B‑cell lymphoma who had received third- or fourth-line treatment.\n\nThe Committee discussed how the tumour histologies were determined in the PIX301 population and whether this was generalisable to clinical practice in England and Wales. It was aware that tumour histology in the intention-to-treat population of PIX301 had been determined by onsite review by a single pathologist. The Committee heard from the clinical specialists that this was not representative of clinical practice in England and Wales, in which multidisciplinary team review is routine and specimens are examined by 2\xa0or 3\xa0pathologists. It noted that the Evidence Review Group (ERG) had also been advised by clinical specialists that a population with disease confirmed by central independent pathological review was more relevant to clinical practice in England and Wales. It also noted that a considerable proportion of patients were excluded after the central independent pathological review (for example, if indolent disease had been confirmed). The Committee concluded that it would be more appropriate to consider the PIX301 population with tumour histology confirmed by retrospective central independent pathological review by consensus than by onsite review by a single pathologist.\n\nThe Committee discussed whether the comparator arm (treatment of physician's choice) in PIX301 was relevant to clinical practice in England and Wales. It heard from clinical specialists that, apart from PIX301, there was no evidence base for selecting a third- or fourth-line treatment for multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma and that there was wide variation in the treatments used in clinical practice in England and Wales. The Committee concluded that all of the comparators used in the treatment of physician's choice arm in PIX301 were clinically relevant (although there was some uncertainty in the proportions in PIX301 compared with clinical practice in England and Wales), and the comparator arm was therefore acceptable for decision-making.\n\nThe Committee discussed the generalisability of previous treatments received by the PIX301 population to clinical practice in England and Wales. The Committee heard from the clinical specialists that rituximab is an integral part of standard first-line treatment in the NHS and is also often used as a second-line treatment. The Committee noted that the manufacturer's subgroup analyses showed a reduced benefit of pixantrone in patients who had previously received rituximab, and that many of the results showed no statistically significant difference between treatment arms (see sections\xa03.11 and 3.16–3.18). It also noted a clinical specialist's concern that statistical significance was not reached for the parameters complete or unconfirmed complete response, progression-free survival and overall survival for this subgroup. The Committee accepted the non statistically significant results because of the positive trend in all 3 outcomes for this subgroup. It was aware from comments received during consultation that this reduced benefit applied to other drugs in clinical development and was not specific to pixantrone. It was also aware of the obligation to the European Medicines Agency in pixantrone's European marketing authorisation requiring a trial to confirm the clinical benefit in patients who have previously received rituximab. However, the Committee acknowledged the comments received in response to consultation that the complete response rates with pixantrone in PIX301 were among the highest reported to date in trials for patients with diffuse large B‑cell lymphoma who had previously received rituximab. The Committee concluded that it was appropriate to evaluate the subgroup of patients in PIX301 who had previously received rituximab because this would apply to almost all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales.\n\nThe Committee considered the clinical-effectiveness results for the whole intention-to-treat trial population and all the post-hoc subgroups. It noted that in the intention-to-treat population, PIX301 was inadequately powered to detect a difference between treatment groups because it had accrued less than half of the planned 320\xa0patients. It noted that the difference in response rates, progression-free survival and overall survival between treatment groups did not always reach statistical significance in the intention-to-treat population (see section\xa03.17) and the post-hoc subgroups, and that there was no statistically significant difference in overall survival between treatment arms for any groups presented by the manufacturer. The Committee had reservations about whether superior efficacy of pixantrone had been shown for the intention-to-treat trial population.\n\nThe Committee then discussed the clinical effectiveness for the subgroup of patients it considered to be most appropriate for decision making (those receiving third- or fourth-line treatment and who had previously received rituximab [see section\xa03.18]). It concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice, and that the mean survival advantage of pixantrone compared with treatment of physician's choice was 2.0\xa0months. However, these results were not statistically significant (see section\xa03.18). The Committee also concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in the Committee's preferred subgroup.\n\nThe Committee discussed the adverse events associated with pixantrone. It noted the manufacturer's assertion that pixantrone was associated with less cardiotoxicity than anthracyclines. The Committee was aware that the final scope issued by NICE did not include any anthracyclines as comparators and that mitoxantrone was the only anthracenedione out of the 6\xa0comparators. It heard from clinical specialists that doxorubicin (an anthracycline) was used as first-line treatment, and that none of the comparators for third- or fourth-line treatment were associated with the similarly raised cardiovascular risk associated with anthracyclines. The Committee was aware that there were more cardiac adverse events in the pixantrone group than in the comparator group, who received treatment of physician's choice (35% compared with 21%). However, it heard from the clinical specialists that efficacy is considered key in this patient population and that, because of its cardiovascular safety profile compared with anthracyclines, pixantrone offered an opportunity for response in patients who had previously shown sensitivity to anthracyclines but who could not receive further lines of anthracycline treatment after relapse because they had reached the maximum lifetime dose. It concluded that pixantrone had an acceptable adverse-effect profile although it was associated with more cardiotoxicity than treatments such as oxaliplatin and gemcitabine that are routinely used in this population in clinical practice in England and Wales.\n\n# Cost effectiveness\n\nThe Committee discussed the manufacturer's general approach to developing the submitted pixantrone economic models. It noted that the ERG considered the manufacturer's approach to follow current best practice and was largely transparent. The Committee concluded that the outlined structure of the models adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pixantrone.\n\nThe Committee considered the manufacturer's cost-effectiveness analyses that included the patient access scheme for the Committee's preferred patient subgroup (that is, the subgroup with aggressive B‑cell lymphoma confirmed by central independent pathological review for third- or fourth-line treatment and who had previously received rituximab [see section\xa04.10]). In particular the Committee discussed how quality of life had been incorporated into the manufacturer's economic modelling. It was aware that the base-case analysis in the manufacturer's patient access scheme submitted in November 2013 used utility values for patients receiving second- and subsequent-line treatment for renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). It noted the absence of published utility values in the relevant patient population and that the manufacturer intends to fund additional research in this area. The Committee noted that the utility value for the pre-progression health state (0.76) was similar to that expected for a healthy older population in the UK, and it considered that the quality of life of patients receiving third- or fourth-line treatment for aggressive non-Hodgkin's B‑cell lymphoma could be lower than this. The Committee then reviewed the utility values selected by the ERG for its exploratory analyses using the manufacturer's original model and the revised model supplied with the patient access scheme submission, which were for patients receiving final-line treatment for chronic lymphocytic leukaemia (0.428 for the pre-progression health state and 0.279 for the post-progression health state). The Committee heard from the clinical specialists that there were differences between the 2\xa0conditions that could mean these utility values were too low, and decided that the ERG's utility values were likely to underestimate the quality of life for this population. Having excluded the ERG's low utility values, the Committee considered that the manufacturer's deterministic sensitivity analysis on the base case in the patient access scheme submission using various utility values (see section\xa03.37) showed that utility values were not a key driver of cost effectiveness. The Committee concluded that, although there was some uncertainty as to the true utility value, the utility values used in the manufacturer's revised model with the patient access scheme were acceptable for use in the Committee's decision-making.\n\nThe Committee considered the incremental cost-effectiveness ratios (ICERs) and considered those presented in the manufacturer's most recent cost-effectiveness analyses, which included the patient access scheme for the Committee's preferred patient subgroup. For the comparison of pixantrone with treatment of physician's choice, it noted that the manufacturer's deterministic and mean probabilistic ICERs incorporating the patient access scheme for this population were £18,500 and £22,000 per quality-adjusted life year (QALY) gained respectively. The Committee noted that the ERG had validated the changes made to the manufacturer's model as part of the patient access scheme submission in November 2013. The Committee concluded that the manufacturer's analysis was appropriate for its decision-making.\n\nThe Committee discussed the amount of uncertainty in the cost-effectiveness estimates for the Committee's preferred subgroup of patients, that is people with aggressive B‑cell lymphoma confirmed by central pathological review receiving third- or fourth-line treatment and who have previously received rituximab. The Committee was persuaded that the manufacturer's mean probabilistic ICER of £22,000 per QALY gained could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. It was aware that the median probabilistic ICER was £14,700 per QALY gained and that the probabilistic ICER reduced to £10,000 per QALY gained when assuming that progression-free survival and overall survival did not change independently of each other. The Committee noted that the manufacturer's exploratory probabilistic sensitivity analysis showed that the probability of pixantrone being cost effective compared with treatment of physician's choice was 56% at a maximum acceptable ICER of £30,000 per QALY gained, and approximately 50% at a maximum acceptable ICER of £20,000 per QALY gained. Additionally, although pixantrone was less clinically effective in 32% of simulations, it was less expensive than treatment of physician's choice in a high proportion of these at a maximum acceptable ICER of £20,000 per QALY gained. The Committee therefore agreed that the probability of pixantrone being cost-effective compared with treatment of physician's choice was acceptable. The Committee concluded that the most plausible ICER was likely to be less than £22,000 per QALY gained, and it concluded that pixantrone was recommended as a cost-effective use of NHS resources.\n\nThe Committee discussed whether pixantrone was innovative in its potential to make a significant and substantial impact on health-related benefits. It observed that pixantrone is the first drug that has been tested in a randomised phase\xa0III trial in patients with multiply relapsed or refractory aggressive non-Hodgkin's lymphoma. It examined whether pixantrone had the potential to make a significant and substantial impact on health-related benefits but heard from the clinical specialists that it was uncertain whether pixantrone could be considered a step change in treatment. On the basis of currently available evidence, the Committee did not consider pixantrone to be a step change in managing multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. The Committee observed that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The Committee concluded that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.\n\nThe Committee understood that pixantrone's conditional marketing authorisation is linked to results from the ongoing PIX306 study, which should be available in 2015. It noted that this larger randomised phase\xa0III study (n=350) will compare the effectiveness of pixantrone plus rituximab with gemcitabine plus rituximab in patients with relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma who have already received a rituximab-containing regimen. Given the relevance of the patient population (because virtually all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales will have previously received rituximab [see section\xa04.8]), the Committee recommended that the technology appraisal guidance on pixantrone for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma should be considered for review by NICE once the PIX306 results are available in 2015.\n\nThe Committee considered whether NICE's duties under the equality legislation required it to alter or to add to its recommendations. It noted that no equality issues had been raised during scoping, in any of the consultees' submissions, during consultation or during the Committee meetings. The Committee concluded that its decision on the use of pixantrone does not have a particular impact on any group with a protected characteristic in the equality legislation and that there was no need to alter or add to its recommendations.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA306\n\nAppraisal title: Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma\n\nSection\n\nKey conclusion\n\nPixantrone monotherapy is recommended as an option for treating adults with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma only if:\n\nthe person has previously been treated with rituximab and\n\nthe person is receiving third- or fourth-line treatment and\n\nthe manufacturer provides pixantrone with the discount agreed in the patient access scheme.\n\nThe Committee concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant.\n\nThe Committee noted that using the revised model that incorporated the patient access scheme, the manufacturer's deterministic ICER was £18,500 per quality-adjusted life year (QALY) gained and that the mean probabilistic ICER was £22,000 per QALY gained. The Committee agreed that the probability of pixantrone being cost effective compared with treatment of physician's choice was acceptable and that the most plausible ICER was likely to be less than £22,000 per QALY gained. It therefore concluded that pixantrone could be recommended as a cost-effective use of NHS resources.\n\n, 3.18, 4.8, 4.9, 4.10, 4.14, 4.15\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from the clinical specialists and the patient expert that the aim of treatment at this disease stage was to reduce the impact of symptoms on quality of life, as well as extending life, and could include chemotherapy and participating in clinical trials. The Committee heard from the patient expert that patients would value any new treatment that could offer symptom relief, have a positive impact on quality of life and increase survival. The Committee acknowledged the demands that living with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma can place on patients and accepted that a treatment option for these patients is important.\n\n, 4.3\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nPixantrone (Pixuvri, Cell Therapeutics) is an aza‑anthracenedione analogue and inhibitor of topoisomerase\xa0II. The Committee concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in clinical practice to treat multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant.\n\nThe Committee examined whether pixantrone had the potential to make a significant and substantial impact on health-related benefits. On the basis of currently available evidence, the Committee concluded that using pixantrone would not be a step change in managing multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma and that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.\n\n\n\n, 4.8, 4.9, 4.10, 4.18\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nPixantrone has a conditional marketing authorisation 'as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B‑cell lymphomas (NHL). The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy'.\n\nIn light of consultee and commentator responses to consultation, the Committee considered that it was appropriate to restrict its assessment of pixantrone to third- and fourth-line treatment. The Committee concluded that the subgroup in PIX301 with aggressive B‑cell lymphoma confirmed by central independent pathological review receiving third- or fourth-line treatment and who had previously received rituximab was the most appropriate for decision-making.\n\n, 4.5, 4.8, 4.9, 4.10\n\nAdverse reactions\n\nThe summary of product characteristics states that the most common toxicity with pixantrone is bone marrow suppression (particularly the neutrophil lineage) and that other toxicities such as nausea, vomiting and diarrhoea are generally infrequent, mild, reversible, manageable and as expected in patients treated with cytotoxic agents. Although the occurrence of cardiac toxicity indicated by congestive heart failure appears to be lower than that expected with related drugs like anthracyclines, the summary of product characteristics recommends monitoring left ventricular ejection fraction.\n\nThe Committee concluded that pixantrone had an acceptable adverse-event profile although it was associated with more cardiotoxicity than treatments such as oxaliplatin and gemcitabine that are routinely used in this population in clinical practice in England and Wales.\n\n, 4.11\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee considered that the PIX301 trial was underpowered because it had failed to recruit the planned number of patients. It also noted that European regulators prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response. The Committee considered that although the PIX301 study had included a high proportion of patients who would be eligible for treatment under the terms of the marketing authorisation, the intention-to-treat population was not appropriate for evaluation and decision-making. The Committee concluded that these fundamental concerns about the design of PIX301 meant that there was considerable uncertainty in the validity and robustness of its results.\n\n, 4.5\n\nRelevance to general clinical practice in the NHS\n\nBecause tumour specimens would be examined by 2\xa0or\xa03\xa0pathologists in clinical practice in England and Wales, the Committee concluded that it would be more appropriate to consider results from the PIX301 trial using a population with tumour histology confirmed by retrospective central independent pathological review by consensus than by onsite review by a single pathologist.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee was concerned that only just over half of patients in the PIX301 trial had previously received rituximab because it heard from the clinical specialists that rituximab is an integral part of standard first-line treatment in the NHS and also often used as a second-line treatment. It was aware of the obligation to the European Medicines Agency in pixantrone's marketing authorisation requiring a trial to confirm the clinical benefit in patients who have previously received rituximab. The Committee noted a reduced benefit of pixantrone in the subgroup of patients who had previously received rituximab, but concluded that it was appropriate to evaluate this subgroup because this would apply to almost all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales.\n\n, 4.19\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee was aware that the intention-to-treat population included patients whose tumour histology would make them ineligible for treatment with pixantrone according to the terms of the European marketing authorisation. The Committee concluded that the subgroup of patients in PIX301 with aggressive B‑cell lymphoma confirmed by central independent pathological review receiving third- or fourth-line treatment and who had previously received rituximab was the most appropriate for decision-making.\n\n, 4.9, 4.10\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that for the subgroup of patients it considered to be most appropriate for decision making (those receiving third- or fourth-line treatment and who had previously received rituximab) there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice, and that the mean survival advantage of pixantrone compared with treatment of physician's choice was 2.0\xa0months. However, these results were not statistically significant. The Committee concluded that there was limited and non-robust evidence to show pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma.\n\n, 4.10\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee concluded that the outlined structure of the models adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pixantrone.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee was persuaded that the manufacturer's mean probabilistic ICER of £22,000 per QALY gained could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant.\n\n, 4.10, 4.15\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee was aware that the utility value used by the manufacturer in its revised model incorporating the patient access scheme for the pre-progression health state was similar to that expected for an older population in the UK. The Committee considered that the quality of life of patients receiving third- or fourth-line treatment for aggressive non-Hodgkin's B‑cell lymphoma could be lower than this. The Committee concluded that, although there was some uncertainty as to the true utility value, the utility values used in the manufacturer's revised model that was part of the patient access scheme submission were appropriate for use in the Committee's decision-making. The Committee observed that there were no additional gains in health-related quality of life over those already included in the QALY calculations and concluded that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.\n\n, 4.18\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe patient access scheme applies to patients with histologically confirmed aggressive non-Hodgkin's B‑cell lymphoma who have previously received rituximab and are receiving pixantrone as a third- or fourth-line treatment.\n\n–3.38\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee concluded that there was limited and non-robust evidence to show pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant.\n\nThe patient access scheme reduced the mean probabilistic ICER to £22,000 per QALY gained. The Committee was persuaded that this ICER could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower.\n\n, 4.14, 4.15\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that, for the subgroup of patients with aggressive B‑cell lymphoma confirmed by central independent pathological review for third- or fourth-line treatment and who had previously received rituximab, the manufacturer's deterministic ICER incorporating the patient access scheme was £18,500 per QALY gained and the manufacturer's mean probabilistic ICER was £22,000 per QALY gained. The Committee noted that the exploratory analysis showed a high level of uncertainty around the ICER. However, the Committee was persuaded that this analysis could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. The Committee concluded that because the probabilistic ICER was likely to be less than £22,000 per QALY gained pixantrone was recommended as a cost-effective use of NHS resources.\n\n, 4.15\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer of pixantrone has agreed a patient access scheme with the Department of Health that makes pixantrone available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd-of-life considerations\n\nNot appropriate.\n\n, 4.17\n\nEqualities considerations and social value judgements\n\nThe Committee concluded that its decision on the use of pixantrone does not have a particular impact on any group with a protected characteristic in the equality legislation and that there was no need to alter or add to its recommendations.\n\n", 'Related NICE guidance': "Details are correct at the time of publication. Further information is available on the NICE website.\n\nRituximab for aggressive non-Hodgkin's lymphoma. NICE technology appraisal guidance 65 (2003).\n\nImproving outcomes in haematological cancers. NICE cancer service guidance (2003).", 'Review of guidance': 'The guidance on this technology will be considered for review when the PIX306 trial results are available and at the latest in November 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveFebruary 2014', 'Changes after publication': 'April 2014: Wording changes in sections 4.8 and 4.9.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt has been incorporated into the NICE pathway on blood and bone marrow cancers along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0448-8'}	https://www.nice.org.uk/guidance/ta306	Evidence-based recommendations on pixantrone (Pixuvri) for treating relapsed or refractory aggressive non-Hodgkin's B-cell lymphoma in adults.
5af586229f24358ce4a7256c977e197824764870	nice	Total hip replacement and resurfacing arthroplasty for end-stage arthritis of the hip	Total hip replacement and resurfacing arthroplasty for end-stage arthritis of the hip Evidence-based recommendations on artificial hips and hip resurfacing for treating end‑stage arthritis of the hip in adults. # Guidance This guidance replaces NICE technology appraisal guidance 2 issued in April 2000 and NICE technology appraisal guidance 44 in June 2002. Prostheses for total hip replacement and resurfacing arthroplasty are recommended as treatment options for people with end-stage arthritis of the hip only if the prostheses have rates (or projected rates) of revision of 5% or less at 10 years.# Clinical need and practice Arthritis refers to inflammation of a joint, and is a leading cause of pain and disability in the UK. Arthritis can have many causes, the most common of which is osteoarthritis (defined by a loss of cartilage within the joint and related changes in the associated bone). Estimates suggest that up to 8.5 million people in the UK are affected by joint pain that may be attributed to osteoarthritis. The second most common cause is rheumatoid arthritis (an autoimmune inflammatory disease that affects the synovial lining of joints). Around 400,000 people in the UK have rheumatoid arthritis. Symptoms of hip arthritis include pain and stiffness that limit daily activities such as walking, climbing stairs and performing household tasks. The diagnosis of arthritis of the hip is usually based on individual patient history and clinical examination assessing joint pain, deformity and reduced range of movement. Osteoarthritis: Care and management in adults (NICE clinical guideline 177) states that clinicians should first offer patients non-surgical treatments including exercise, physical therapy and analgesics, and should consider referring patients for joint replacement surgery if they have ongoing pain, joint stiffness, reduced function and a poor quality of life. People having elective primary surgery to relieve pain and disability caused by arthritis of the hip may receive either a total replacement of the damaged hip (total hip replacement) or a hip resurfacing arthroplasty. The National Joint Registry was set up by the Department of Health and Welsh Assembly Government for the mandatory collection of information on all hip, knee, ankle, elbow and shoulder replacement operations from NHS organisations and private practice, and to monitor the performance of joint replacement prostheses. Since 2009, all NHS patients who are having hip replacement surgery are invited to fill in Patient Reported Outcome Measures (PROMs) questionnaires about their health and quality of life before and after their surgery. Following publication of Guidance on the selection of prostheses for primary total hip replacement (NICE technology appraisal guidance 2), the National Health Purchasing and Supply Agency (PASA) was given the task of monitoring adherence to the technology appraisal recommendation. PASA set up a panel of experts known as the Orthopaedic Data Evaluation Panel (ODEP). PASA was subsequently replaced by NHS Supply Chain, which still manages and provides administrative support to ODEP. ODEP provides the NHS with an approved list of prostheses that meet the revision rate standard at 10 years set out in NICE guidance and which are suitable for use in primary hip replacement (see section 3.6). ODEP provides separate ratings for the 2 components of hip replacement prostheses (that is, stems and cups; see section 3.1). For hip prostheses with less than 10 years of clinical data, there are currently 3 entry standards expressed by ODEP as failure rate: 3% or less at 3 years; 5% or less at 5 years; and 7% or less at 7 years, which are considered to be consistent with the 10-year standard.# The technologies In total hip replacement (THR) surgery, the acetabulum (hip socket) is replaced with either a single-piece cup made from 1 material (polyethylene, ceramic or metal) or a 2-piece (modular) cup made from a metal outer shell and a polyethylene, ceramic or metal liner. The head of the femur (thigh bone) is replaced with either a single-piece metal stem and head, or a modular component consisting of a metal stem (which may consist of more than 1 piece) with a metal, ceramic or ceramicised metal head. THRs vary in what fixation method is used for each component of the prosthesis. In some THRs, all the components are fixed into position using cement (hereafter referred to as cemented THRs). Other types of THR are designed to be used without cement (hereafter referred to as cementless THRs); instead, they are inserted using press-fit fixation, and natural bone growth over time secures the prosthesis in place. Some prostheses are hybrid, in which the femoral component is cemented into place while the cup is fixed without cement, or reverse hybrid, in which the femoral component is fixed without cement while the cup is cemented into place. THRs may also vary by femoral head size, with a large head defined as being 36 mm or more in diameter. Hip resurfacing arthroplasty involves removing and replacing the surface of the femoral head with a hollow metal hemisphere, which fits into a metal cup fixed into the acetabulum. All resurfacing arthroplasty prostheses currently on the market are metal-on-metal (MoM), and can be hybrid or cementless. As with THR prostheses, resurfacing arthroplasty prostheses may also vary by femoral head size. Patient selection for THR or resurfacing arthroplasty depends on various factors, including but not limited to: patient characteristics (for example a patient's age, activity and underlying hip physiology); the surgeon's choice; and the surgeon's experience of using a particular class of prosthesis. Adverse events associated with hip replacement surgery (THR or resurfacing arthroplasty) may occur because of complications at the time of surgery, or may occur years afterwards. Complications that may lead to hip replacement revision surgery include prosthesis instability, dislocation, aseptic loosening, osteolysis (bone reabsorption), infection and prosthesis failure. Guidance on the selection of prostheses for primary total hip replacement (NICE technology appraisal guidance 2) recommends that the best prostheses should have a revision rate of 10% or less at 10 years or, as a minimum, a 3-year revision rate consistent with this. Guidance on the use of metal on metal hip resurfacing arthroplasty (NICE technology appraisal guidance 44) recommends MoM resurfacing arthroplasty as an option for people with advanced hip disease who would otherwise receive, and are likely to outlive, a conventional primary THR. The guidance recommends that the best prostheses should demonstrate the same revision rates as recommended in NICE technology appraisal guidance 2. The Medicines and Healthcare products Regulatory Agency (MHRA) monitors the safety of devices used in clinical practice. In June 2010, the MHRA issued an alert on all MoM hip replacement prostheses (both THR and resurfacing arthroplasty) after reports of soft tissue reactions that may be associated with pain. In June 2012, the MHRA released an updated alert noting that MoM prostheses (THR and resurfacing arthroplasty) may wear at an accelerated rate. The MHRA stated that people with MoM prostheses may develop soft tissue damage caused by wear debris from these prostheses. It advised annual monitoring of the hip using imaging and measurement of metal levels in the blood to determine whether a revision is needed in people with MoM hip replacement prostheses who have symptoms, or who have a certain type of MoM hip replacement, including stemmed MoM THRs with a larger femoral head (36 mm diameter or more) or the recalled DePuy ASR hip replacements (THR and resurfacing arthroplasty). Over 20 companies manufacture prostheses for hip replacement (THR and resurfacing arthroplasty), and some produce multiple brands of components. The NHS Supply Chain provided the average list price costs for 5 manufacturers of the 5 THR categories (varying by fixation method and bearing surface) identified by the Assessment Group and 3 manufacturers of resurfacing arthroplasty prostheses and associated accessories. The average list prices for THRs across the manufacturers were: £1557 for a cemented polyethylene cup plus a metal head; £3016 for a cementless metal cup with a polyethylene liner plus a metal head (cementless stem); £3869 for a cementless metal cup with a ceramic liner plus a ceramic head (cementless stem); £2650 for hybrid cementless metal cup with a polyethylene liner plus a metal head (cemented stem); and £1996 for cemented polyethylene cup with ceramic head (cemented stem). The average list price for resurfacing arthroplasty prostheses across the manufacturers was £2672. Typically, the price of hip replacement prostheses depends on the volume ordered and locally negotiated discounts, so the prices paid by the NHS are routinely lower than the list prices listed above.# Evidence and interpretation The Appraisal Committee (section 9) considered evidence from a number of sources (section 10). # Clinical effectiveness The Assessment Group conducted a systematic review of randomised controlled trials (RCTs), published systematic reviews and published registry studies of hip replacement procedures. In addition, the Assessment Group analysed individual patient data from the National Joint Registry (NJR). ## Systematic review of randomised controlled trials and published systematic reviews The Assessment Group identified 16 RCTs and 8 systematic reviews. It noted that there were a further 20 ongoing clinical trials. Three RCTs and 3 systematic reviews compared resurfacing arthroplasty with total hip replacement (THR); and 13 RCTs and 5 systematic reviews compared different types of THR with each other. The Assessment Group assessed the risk of bias and methodological quality of the studies (RCTs and systematic reviews), determining whether the evidence could be considered conclusive or non-conclusive based on the precision, consistency and clinical relevance of the effects. The Assessment Group recognised that studies included different measures of patient function and chose, based on previously published research, the following criteria for minimally clinically important differences (MCID): the Harris Hip Score (MCID range: 7–10); the Oxford Hip Score (MCID range: 5–7); the Western Ontario McMaster Osteoarthritis Index (MCID: 8); and the EQ‑5D measure of health‑related quality of life (MCID: 0.074). The Assessment Group considered the evidence from an RCT to be conclusive if it showed: a statistically significantly different effect between treatments for which the 95% confidence interval included the MCID or no effect if the MCID was outside the 95% confidence interval for any given outcome.The Assessment Group considered the evidence from an RCT to be inconclusive if: the confidence intervals were wide or there were missing data or the effects were inconsistent, if there were 2 separate trials that had assessed the same outcome.The Assessment Group further considered the evidence from a systematic review to be inconclusive if it: did not report pooled results of RCTs (that is, it reported the results narratively) or used inappropriate methods to pool data or reported inconsistent summary findings. Of the 3 RCTs comparing the effectiveness of resurfacing arthroplasty with THR, 1 RCT compared metal-on-metal (MoM) resurfacing arthroplasty with large-head MoM THR, 1 RCT compared MoM resurfacing arthroplasty with MoM THR, and 1 RCT compared MoM resurfacing arthroplasty with an unspecified bearing surface of THR. The 3 RCTs randomised a total of 422 patients (ranging from 104 to 192 per study) and the length of follow-up in the trials ranged from 1 to 6 years. The reported outcomes in the 3 RCTs comparing resurfacing arthroplasty with THR were function (assessed in 3 RCTs), risk of revision (assessed in 1 RCT), infection (assessed in 2 RCTs), aseptic loosening (assessed in 1 RCT), dislocation (assessed in 2 RCTs), deep vein thrombosis (assessed in 2 RCTs) and health-related quality of life (assessed in 2 RCTs; 1 used the EQ-5D and 1 used the SF-36 questionnaire). Five functional measures were used across the 3 RCTs. There was no difference between resurfacing arthroplasty and THR for the Oxford Hip Score, Western Ontario McMaster Osteoarthritis Index score, or the Merle D'Abigine and Postel score. The evidence was inconclusive for the Harris Hip Score and the University of California, Los Angeles activity score. The Assessment Group reported that infection rates differed between patients who had resurfacing arthroplasty and those who had THR. The Assessment Group's meta‑analysis of the 2 RCTs that assessed this outcome indicated that, 12–56 months after surgery, patients who had had THR developed more infections than patients who had had resurfacing arthroplasty (pooled odds ratio 7.94, 95% confidence interval 1.78 to 35.40). All data for the other outcomes (quality of life, revision dislocation, deep vein thrombosis, wound complication, aseptic loosening and mortality) reported in the 3 RCTs were inconclusive. Of the 3 systematic reviews comparing the effectiveness of resurfacing arthroplasty with THR, 2 synthesised data on function, 2 on risk of revision, 1 on infection, 2 on aseptic loosening, 2 on dislocation and 2 on mortality. The systematic reviews included data from both RCTs and observational studies, including single-arm studies of resurfacing arthroplasty or THR. Two of the systematic reviews assessed resurfacing arthroplasty compared with all types of THR and 1 systematic review compared resurfacing arthroplasty with cementless THR. Two of the systematic reviews included RCTs that the Assessment Group had critiqued separately. The Assessment Group considered the reported data on function to be inconclusive. The 2 systematic reviews that compared revision rates between resurfacing arthroplasty and THR showed that revision rates were higher after resurfacing arthroplasty (1 estimated a relative risk of 2.60 over a 10-year follow-up, 1 estimated an RR of 1.72 but did not report length of follow-up). Two systematic reviews found that resurfacing arthroplasty was associated with more component loosening than THR (RR 3.00, 95% CI 1.11 to 8.50 and RR 4.96, 95% CI 1.82 to 13.50 respectively). Both of these systematic reviews assessed dislocation rates and 1 found statistically significantly lower dislocation rates associated with resurfacing arthroplasty compared with THR (RR 0.20, 95% CI 0.10 to 0.5). The Assessment Group considered the reported data on all of the other outcomes (mortality, prosthesis failure and infection) to be inconclusive. The Assessment Group identified 13 RCTs comparing different types of THR with each other, including comparisons of different fixation methods, bearing surfaces, component materials, designs and component sizes. The number of people in each RCT ranged from 100 to 557. The length of follow-up ranged from 3 months to 20 years. Reported outcomes across the RCTs varied and included function, revision, osteolysis (bone reabsorption), aseptic loosening, infection, mortality, femoral fracture, dislocation, deep vein thrombosis, femoral head penetration (prosthesis movement) and quality of life (using SF-12). Four of the RCTs compared THRs with different fixation methods. Of these, 2 compared cemented with cementless cup fixation, 1 compared cemented with cementless femoral stem fixation and 1 compared cemented with cementless cup and femoral stem fixation. The Assessment Group reported that cemented cups had a lower risk of dislocation compared with cementless cups; its pooled estimate of the odds ratio for the 2 RCTs was 0.34 (95% CI 0.13 to 0.89). The Assessment Group found no other differences between the fixation methods. Six of the RCTs compared THR prostheses with different bearing surfaces, comparing: cross-linked polyethylene with non-cross-linked polyethylene cup liners (2 RCTs); oxinium with cobalt-chromium femoral heads (1 RCT); ceramic-on-ceramic with metal-on-polyethylene femoral head on cup liners (1 RCT); ceramic-on-ceramic with ceramic-on-polyethylene femoral head on cup liners (1 RCT); and steel-on-polyethylene with cobalt-chromium on cross-linked polyethylene and with cobalt-chromium-on-polyethylene femoral head on cup liners. One RCT with 10 years' follow-up, which assessed revision rates, found that THR prostheses with cross-linked polyethylene cup liners had lower revision rates than THRs with non-cross-linked polyethylene cup liners (RR 0.18, 95% CI 0.04 to 0.78). One RCT with 10 years' follow-up found that there was a lower risk of osteolysis with a ceramic-on-ceramic head on cup liner bearing surface than a metal-on-polyethylene femoral head on cup liner bearing surface (RR 0.10, 95% CI 0.02 to 0.32). One RCT with 2 years' follow-up found that steel-on-polyethylene and cobalt-chromium on cross-linked polyethylene femoral head on cup liner bearing surfaces both had a lower rate of femoral head penetration than cobalt-chromium-on-polyethylene or oxinium-on-polyethylene femoral head on cup liner bearing surfaces (p<0.001). There were no other differences reported in the RCTs that assessed THRs with different bearing surfaces. The Assessment Group reported results from 4 other RCTs that compared different types of THR. One RCT compared THRs with different cup shell designs (porous coated cups compared with arc-deposited hydroxyapatite coated cups). One RCT compared THRs with femoral stems made from cobalt-chromium or titanium. One RCT compared femoral stems with a short metaphyseal fitting with conventional metaphyseal and diaphyseal filling. One RCT compared THRs using a 36-mm femoral head with THRs using a 28-mm femoral head. The Assessment Group reported that the RCT comparing different femoral head sizes found a decreased risk of dislocation associated with 36-mm femoral heads compared with 28-mm femoral heads over a 1-year follow-up (RR 0.17, 95% CI 0.04 to 0.78). No other conclusive differences were reported in these 4 RCTs. The primary focus of the 5 systematic reviews evaluating different types of THR was the comparison of different cup fixation methods (cemented compared with cementless), and the materials used for prosthesis articulation with respect to the postoperative clinical function scores and revision rates. The Assessment Group considered most of the evidence to be inconclusive because the reviews had either reported only a narrative synthesis, or had used inappropriate pooling methods or had reported inconsistent summary findings. The only conclusive result identified by the Assessment Group was that there was no difference in the risk of revision between 2 different articulations: zirconia (a type of ceramic) head-on-polyethylene cup liner compared with a non-zirconia head-on-polyethylene cup liner (pooled difference in frequency of revisions over the studies' follow-up periods was 0.02, 95% CI −0.01 to 0.06). ## Systematic review of registry studies The Assessment Group reviewed studies based on registries of THR or resurfacing arthroplasty for people with end-stage arthritis of the hip. It identified 30 studies from a number of countries, which reported different outcomes, had different durations of follow-up, and made different comparisons. The Assessment Group identified 8 registry studies reporting on resurfacing arthroplasty. An analysis of the NJR in England and Wales showed that women had a 30% greater risk of revision with resurfacing than men (hazard ratio 1.30, 99% CI 1.01 to 1.76). Three of the 4 that compared revision rates between resurfacing arthroplasty and THR found that resurfacing arthroplasty had a higher revision rate than THR. A further analysis of the NJR showed that, although in women resurfacing always had higher revision rates than THR, in men resurfacing arthroplasty prostheses with a larger head size (54 mm) had similar predicted 5-year revision rates to THR prostheses. One study suggested that the risk of revision with resurfacing arthroplasty varied by country, and another study demonstrated lower revision rates in specialist compared with non-specialist centres. The Assessment Group identified 22 registry studies that reported only on THR and that presented analyses of either trends in revision rates or comparisons of revision rates across different types of THR. One study using NJR data from England and Wales (Smith et al. 2012) and 1 using combined data from registries from England, Wales, Australia and New Zealand assessed whether there was an association between femoral head size and revision rates for THR; the studies demonstrated that the relationship was dependent on bearing surface. Both studies showed that the revision rate for MoM THR increased as the femoral head size increased. Conversely, for bearing surfaces other than MoM, a large femoral head size was associated with a lower risk of revision compared with smaller femoral heads. One study (an analysis of the NJR by McMinn et al. 2012) showed, at a maximum of 8 years' follow-up, a higher mortality rate for patients having cemented compared with cementless THR (adjusted HR 1.11, 95% CI 1.07 to 1.16). The Assessment Group noted that, of the registries of joint replacement worldwide, the Swedish registry is the oldest. The Assessment Group presented data on revision rates using up to 19 years of follow-up from the Swedish registry for THR and resurfacing arthroplasty grouped together, but noted that these revision rates may include devices and practices no longer in use. The data suggested that revision rates depended on a patient's age at primary surgery. At a maximum of 19 years' follow-up, for people younger than 50 years at primary surgery, 39.8% of women and 37.4% of men had a revision; for people aged between 50 and 59 years, 26.3% of women and 32.8% of men had a revision; for people aged between 60 and 75 years, 12.8% of women and 19.5% of men had a revision; and for people over 75 years, 5.2% of women and 7.9% of men had a revision. ## Retrospective cohort analysis of individual patient data from the National Joint Registry The Assessment Group performed a retrospective cohort analysis of the NJR to estimate revision rates for the different types of prostheses for both populations in the final scope issued by NICE (that is, people for whom both resurfacing arthroplasty and THR were suitable and people for whom only THR was suitable). The Assessment Group obtained individual patient data from the NJR that included data from 2003 to September 2012 and for operations carried out in the NHS and in private practice. The final scope issued by NICE stipulated that different types of hip replacements should be considered separately, if evidence allows. The Assessment Group, advised by its clinical adviser, grouped the types of most commonly used THR into 7 categories. Of these, it selected the 4 most frequently used combinations and a further combination of a cemented stem with a ceramic head articulating with a cemented polyethylene cup. These 5 categories of THR prosthesis accounted for 62% of THRs in the NJR with available data. The categories were: category A: cemented polyethylene cup with a metal head (cemented stem) category B: cementless hydroxyapatite coated metal cup (with a polyethylene liner) with a metal head category C: cementless hydroxyapatite coated metal cup (with a polyethylene liner) with a ceramic head category D: cementless hydroxyapatite coated metal cup (with a polyethylene liner) with a metal head (cemented stem) category E: cemented polyethylene cup with a ceramic head (cemented stem). The Assessment Group addressed the population for whom either resurfacing arthroplasty or THR was suitable. It noted that NICE technology appraisal guidance 44 recommended resurfacing arthroplasty for people who would otherwise receive and outlive a conventional primary THR. This population primarily consisted of people younger than 65 years. The Assessment Group also stated that clinical opinion holds that clinicians offer resurfacing arthroplasty mainly to relatively active younger people, while THR is the usual option for less active older people. The Assessment Group noted that the NJR data did not include data on activity levels. In the absence of data on activity levels, the Assessment Group determined the suitability of resurfacing arthroplasty based on age and sex, and sampled people who had had THR who shared these characteristics. The mean age of this population was 55.8 years and 35% were women. The Assessment Group addressed the population for whom resurfacing arthroplasty was not suitable. The Assessment Group noted that most people who had THR documented in the NJR were older than 65 years but considered that, because there had been high revision rates after resurfacing arthroplasty, in the future fewer younger people may be considered as candidates for both procedures. As a result, the Assessment Group considered that the population for whom resurfacing arthroplasty was not suitable could be assumed to match the population who had THR documented in the NJR. The mean age of this population was 71.6 years and 64% were women. The Assessment Group analysed revision rates using the available data from the NJR (maximum follow-up of 9 years) using Kaplan–Meier estimates. For the population for whom both resurfacing arthroplasty and THR were suitable, the population was matched by age and sex. For the population for whom resurfacing was not suitable, the population was not matched by age and sex and the Kaplan–Meier estimates were not adjusted for these characteristics. The Assessment Group found that, consistent with previous published analyses of the NJR, the revision rate for resurfacing arthroplasty over 9 years of follow-up was about 3 times higher than for all the types of THR prostheses recorded in the NJR. The difference was even larger when comparing resurfacing arthroplasty with THR restricted to the 5 commonly used THR combinations (prosthesis categories A to E; see section 4.1.17). The Assessment Group presented data on revision rates for men and women separately. Revision rates for resurfacing arthroplasty unadjusted for age were higher for women (18% at 9 years) than for men (7% at 9 years). The Assessment Group performed additional analyses in which it excluded data from the 8.8% of people who had the now-recalled DePuy ASR resurfacing prosthesis. Although this lowered the revision rate for resurfacing arthroplasty slightly, the difference between the revision rates for resurfacing arthroplasty and THR remained large. The Assessment Group assessed the time to revision for the 5 categories of THR (A to E) separately. The Assessment Group noted that the revision rates for the cementless prostheses (category C) were higher than for the cemented prostheses (category E and category A). The Assessment Group noted that revision of each category of prosthesis appeared to occur more frequently for men who had any of the prostheses in these 5 categories than for women. To extrapolate revision rates beyond the up-to-9-year data in the NJR, the Assessment Group assessed the fit of various parametric models to the Kaplan–Meier analyses. The Assessment Group noted that, while the bathtub and log-normal models appear to fit the Kaplan–Meier values of revision, after extrapolation these models generated different revision rates. The Assessment Group noted an increasing risk of revision over time with the bathtub model and a decreasing risk of revision over time with the log-normal model. The Assessment Group considered that whether a person underwent revision surgery or not depended both on why the prosthesis had failed and on a person's suitability for revision surgery. The Assessment Group concluded that, for younger people, the risk of needing a revision would increase over time (because the risk of outliving the prosthesis would increase) and that, for older people, the risks of revision would decrease over time (because the risks of revision surgery might outweigh the benefits). The Assessment Group further concluded that, in active people, prostheses would be more likely to wear out and need revision. The Assessment Group used the bathtub model in its base case and the log-normal model in its sensitivity analyses of revision rates in people who were over 65 years when they had their THR. For the population for whom both resurfacing arthroplasty and THR were suitable, the bathtub model predicted revision rates at 10 years of 17.2% and 4.6% for resurfacing arthroplasty and THR respectively, and at 20 years of 48.3% and 12.9% respectively. For the population for whom resurfacing arthroplasty was not suitable, the bathtub model predicted revision rates (unadjusted for age and sex) at 10 years of 2.8% for category A prostheses, 3.9% for category B, 4.6% for category C, 3.0% for category D and 2.1% for category E. The model predicted revision rates at 20 years ranging from 5.2% for category E to 12.3% for category C. The Assessment Group repeated its analysis for the population for whom resurfacing was not suitable, adjusting the bathtub model for age and sex. It found that the relative revision rates across all 5 prosthesis categories were maintained after this adjustment. For the population for whom both resurfacing arthroplasty and THR were suitable, the Assessment Group predicted revision rates separately for women and men unadjusted for age. In people who had resurfacing arthroplasty, women had higher predicted revision rates at 10-, 20- and 30-year follow‑up than men. The estimated 10-year revision rates with resurfacing arthroplasty were 23.1% for women and 12.4% for men. In the population for whom resurfacing arthroplasty was not suitable, the Assessment Group explored a scenario in which the revision rate in people over 65 years who had THR decreased over time (see section 4.1.22). Using a log-normal distribution and stratifying by sex, the Assessment Group observed lower predicted revision rates compared with the bathtub model. The Assessment Group presented estimates of revision for the mean age in each category. For men over 65 years, the 10-year modelled revision rates for the 5 THR categories ranged from 1.9% (category E) to 3.9% (category C). For women aged over 65 years, the modelled 10-year revision rates for the 5 THR categories ranged from 1.4% (category E) to 2.8% (category B). The Assessment Group stated that a new rate, setting a standard revision rate for prostheses lower than that of the current standard of less than 10% at 10 years, is appropriate (see section 3.6). The Assessment Group noted that most THR prostheses currently meet this standard, but that most resurfacing arthroplasty prostheses do not. ## Manufacturer's clinical-effectiveness evidence NICE received submissions from 4 manufacturers (DePuy Synthes, JRI, Smith & Nephew and Stryker). The Assessment Group critiqued the submissions and noted that 1 of the 4 manufacturers had performed a systematic review of clinical effectiveness of resurfacing arthroplasty and THR, and that the other 3 manufacturers had provided a narrative review. The manufacturers commented on the difficulties with categorising different types of THR. In particular, 3 manufacturers noted variability in how well different prostheses perform within a category and that some individual manufacturer's brands may have lower revision rates than is typical of their category as a whole. One manufacturer commented that the 7-year revision rates for the 4 most commonly used cementless prostheses range from 2.6% to 4.1%. Another manufacturer noted that data from the NJR showed that its own resurfacing arthroplasty prosthesis, the Birmingham hip resurfacing system, had a revision rate at 7 years that was consistent with the NICE 10% at 10 years standard (it had a revision rate of 5.1%, 95% CI 4.6 to 5.6). Two manufacturers further stated that categorising by fixation method only may not capture the differences in revision rates that have been seen with different bearing surfaces. Several manufacturers highlighted that the NJR data may not be sufficiently mature to capture changes in risk with different hip prostheses over time. The manufacturers noted that the NJR, the Swedish registry and the Australian registry all showed lower revision rates with cemented prostheses than cementless prostheses in the shorter term after primary surgery, but suggested that this trend may not be maintained if people in the NJR are followed up for longer. The manufacturers highlighted that, after 8 years, the Swedish data showed the risk of revision was higher with cemented than cementless prostheses and, after 6 years, the Australian data showed that cemented THR had a higher revision rate than cementless THR. # Cost effectiveness ## Assessment Group's economic model The Assessment Group developed a Markov model based on the model described by Fitzpatrick et al. (1998), which it adapted to address the decision problem and updated with new data. The model had 4 health states and the cycle length was 1 year. Discounting of 3.5% was applied to both costs and outcomes. The analysis was from the perspective of the NHS and personal social services. The Assessment Group reported results for both a lifetime (80 years) and a 10-year time horizon. Two simulated cohorts entered the model, one of people for whom resurfacing was suitable, reflected by people in England and Wales who underwent resurfacing arthroplasty between 2003 and 2012 (age and sex matched with people who had THR categories A–E; see section 4.1.18); and the other of people for whom resurfacing arthroplasty was not suitable, represented by people in England and Wales who had THR categories A–E between 2003 and 2012 (see section 4.1.19). People entered the model at the point of their primary procedure (resurfacing arthroplasty or THR) and moved either to the 'successful primary' health state (that is, after successful initial primary surgery) or death. If primary hip replacement failed, people who needed revision moved to the 'revision total hip replacement state', received a THR (rather than resurfacing arthroplasty) and stayed in that state for 1 cycle (1 year). If revision was successful, people moved to the 'successful revision health state'. People in the model could have multiple revisions. The Assessment Group assumed that all sequelae of THR (surgical mortality after primary THR, revision THR or re-revision THR; risk of re-revision) occurred at the beginning of a cycle, and that mortality not related to hip replacement occurred at the end of a cycle. The transition probability between successful primary surgery and revision THR was based on the revision rates calculated and extrapolated from the NJR data. The Assessment Group based the transition probability between successful revision and further revision THR on the New Zealand Joint Registry (risk of re-revision per procedure 0.0326). The Assessment Group assumed that mortality associated with surgery was 0.5% per procedure (based on the NJR annual report 2012) and used data from the Office for National Statistics on death rates in England and Wales to determine all-cause mortality by age. To determine the utility associated with each health state, the Assessment Group used the NJR Patient Reported Outcomes Measures (PROMS) database, which reported EQ-5D-3L data post operation by age and sex for the year 2010/2011. The utility values applied in the 'successful primary' health state were 0.726 for people aged between 40 and 50 years; 0.753 for people aged between 50 and 60 years, 0.779 for people aged between 60 and 70 years, 0.764 for people aged between 70 and 80 years, and 0.721 for people aged between 80 and 90 years. The Assessment Group adjusted the utility values for the increasing age of the cohort after every 10 cycles of the model. The Assessment Group assumed that the utility values for people in the 'successful primary health state' were equivalent for people who had resurfacing arthroplasty or THR. The utility value in the 'revision THR health state' was 0.5624 and did not differ by type of THR, age or sex. The Assessment Group assumed that the utility value for a successful revision was the same as for successful primary surgery. Costs in the model included the costs of the surgery, prostheses, hospitalisation and follow-up. The Assessment Group assumed that the cost of surgery was the same for both THR and resurfacing arthroplasty, and included the cost of theatre overheads, theatre staff and X-rays. The costs were based on Vale et al. (2002), but were updated to 2011/2012 prices using the projected health service cost index. The overall cost of surgery per patient was £2805. The Assessment Group obtained the costs of prostheses from the NHS supply chain (see section 3.8). To compare resurfacing arthroplasty with THR for people for whom resurfacing arthroplasty is suitable, the Assessment Group combined the 5 categories of THR prostheses (see section 4.1.17) and generated a weighted average cost based on the frequency of use (from NJR data) of £2571 for THR categories A to E combined. Cemented prostheses needed an additional cost for cement and its preparation (£203.10 for prostheses in which both the stem and cup need cementing and £163.90 for prostheses in which only the stem needs cementing). The Assessment Group derived postoperative hospital costs from Edlin et al. (2012), an RCT that reported the costs of resurfacing arthroplasty and THR over 1 year. The Assessment Group estimated the average cost per day of a hospital stay at £296. People who had resurfacing arthroplasty stayed an average of 5.5 days and people who had a THR stayed an average of 5.7 days, resulting in an overall cost for hospital stays of £1628 for resurfacing arthroplasty and £1687 for THR. Edlin et al. also provided outpatient costs for follow-up after primary THR or resurfacing arthroplasty. The costs over the first 12 months of outpatient care, primary and community care, aids and adaptions provided by the NHS, pain relief and other medications, adjusted for inflation from 2009/2010 to 2011/2012 prices, totalled £501 for resurfacing arthroplasty and £394 for THR. The Assessment Group applied follow-up costs for all consecutive years for the lifetime of the model. The Assessment Group assumed that the costs of revision were the same for THR and resurfacing arthroplasty but depend on the reason for revision (Vanhegan et al. 2012). For example, surgery for infection and peri-prosthetic fracture resulted in longer operating times and lengths of stay than other reasons for revision. Vanhegan et al. reported costs of revision including the costs of the prostheses, materials, theatre, recovery room, inpatient physiotherapy, occupational therapy, pharmacy, radiology and laboratory, with costs based on the NHS 2007/2008 Payment by Results. The Assessment Group adjusted these costs for inflation to 2011/2012 prices by using the projected health service cost index. To derive the 'weighted average cost of revision' of £16,517, the Assessment Group weighted the mean cost of revision for aseptic loosening, deep infection, peri-prosthetic fracture and dislocation by the number of people who had experienced each of these problems in Vanhegan et al. The Assessment Group applied the follow-up costs from Edlin et al. (£394; see section 4.2.8) to the successful revision health state. For the population for whom resurfacing arthroplasty and THR were both suitable, the Assessment Group presented deterministic and probabilistic analyses for both a 10-year and a lifetime time horizon. In both the deterministic and probabilistic base case, THR dominated resurfacing arthroplasty (that is, it was less costly and more effective) over both the 10-year and the lifetime time horizons. For the population for whom resurfacing arthroplasty was not suitable, the Assessment Group presented deterministic and probabilistic analyses for both a 10-year and a lifetime time horizon. For a lifetime time horizon, the deterministic incremental analysis showed that THR category E dominated all of the other THR categories. The Assessment Group commented that the difference in quality-adjusted life years (QALYs) was negligible between THR categories A to E (a difference of 0.0064 between the most effective prosthesis category and the least effective prosthesis category in the lifetime deterministic analysis) and that the probabilistic analyses of costs and effectiveness showed that total costs and total QALYs of all categories overlapped. The Assessment Group performed 3 scenario analyses for the population for whom resurfacing arthroplasty and THR were suitable. One scenario analysis tested assumptions used to determine time to revision, and 2 scenarios tested assumptions on the costs of the prostheses. For both the 10-year and lifetime time horizons, all scenario analyses had a minimal effect on incremental costs and QALYs, and the results were consistent with the base case because THR continued to dominate resurfacing arthroplasty. The Assessment Group performed 7 sensitivity analyses for the population for whom resurfacing arthroplasty was not suitable. Three tested the assumptions used to extrapolate time to revision (including adjusting the analysis for age and sex), 3 tested assumptions on the costs of the prostheses, and 1 tested assumptions on the source of utility values for the successful primary and successful revision health states. The Assessment Group presented results for a 10-year and a lifetime time horizon. For a lifetime time horizon, THR category E continued to dominate all other categories in the following sensitivity analyses: time to revision (bathtub model controlled for age and sex); all 3 cost sensitivity analyses (unadjusted for age and sex with the highest and lowest costs of THR or a 20% discount applied to each prosthesis category); and postoperative utility values (taken from a Swedish cohort study rather than from NJR PROMS data). For the 2 scenarios in which the Assessment Group used the log-normal (rather than the bathtub) model to extrapolate long-term revision rates (1 in which the log‑normal model was adjusted for age and sex and 1 in which the model was unadjusted for these characteristics), THR category E was more costly and more effective than category A in the lifetime time horizon (deterministic incremental cost-effectiveness ratio £442,830 per QALY gained for the unadjusted model; deterministic ICER £227,031 per QALY gained for the log-normal model adjusted for age and gender). In these log-normal model scenario analyses, THR categories D, B and C continued to be dominated by category E in both the deterministic and probabilistic results. The Assessment Group performed subgroup analyses for men and women by age for whom resurfacing arthroplasty was suitable. The Assessment Group presented results for each sex stratified by 3 discrete ages, applying a weighting to the modelled revision rates for these subgroups for ages 40, 50 and 60 years. For all ages and in both men and women, THR dominated resurfacing arthroplasty over both the 10-year and lifetime time horizons. For people for whom resurfacing arthroplasty was not suitable, the Assessment Group presented results for 4 subgroups (men and women under 65 years, and men and women aged over 65 years). For men and women under 65 years, it presented the results for people aged 40, 50 and 60 years separately. For men and women over 65 years, it presented the results for people aged 70 and 80 years separately. For men and women under 65 years, the Assessment Group used the bathtub modelled revision rates and, for men and women over 65 years, the Assessment Group used the log-normal modelled revision rates. At a lifetime time horizon for men and women aged 70 and 80 years, THR category E was more costly and more effective (QALY difference ranged from 0.0001 and 0.0002) than category A, and dominated categories D, B and C. For women under 65 years, all other categories were dominated by category E. For men aged 40 years, all other categories were dominated by category A. In men aged 50 or 60 years, category E was more costly and more effective than category A and dominated categories D, C and B over the lifetime time horizon. ## Manufacturer's economic model Only 1 manufacturer (DePuy Synthes) that made a submission for the appraisal included an economic model. DePuy Synthes developed a transition-state Markov model that had 3 monthly cycles and a lifetime horizon (all patients were assumed to have died by age 100 years). Costs and outcomes were discounted at 3.5%. The health states in the model were the same as those in the Assessment Group's model (see section 4.2.3), but the model allowed each patient a maximum of 4 surgical revisions. In the DePuy Synthes model, the populations in the final scope issued by NICE were defined based on the patient characteristics of people in the NJR. The population for whom both resurfacing arthroplasty and THR were suitable was the population in the NJR who had resurfacing arthroplasty. The mean age in this population was 55.3 years and 70.9% were men. The population for whom resurfacing arthroplasty was not suitable was patients in the NJR who had THR. The mean age of this population was 70.4 years and 37.5% were men. For both populations, DePuy Synthes compared different types of THR prostheses based on methods of fixation comparing cemented, cementless, hybrid and reverse hybrid. It also assessed 2 of its own brands (1 cemented and 1 cementless). DePuy Synthes excluded MoM THR from its analyses, stating that THR using these bearing surfaces are no longer commercially available. DePuy Synthes used individual patient data from the NJR, including data for its own prosthesis brands grouped separately to estimate revision rates for up to 8 years' follow-up. It excluded incomplete entries and those in which osteoarthritis of the hip was not the indication for surgery. DePuy Synthes stated that previous models of revision had fitted different parametric distributions to the periods early and later after surgery, and separately categorised the causes of earlier or later revision. Reasons for early revision included dislocation, mismatch, infection, incorrect sizing and malalignment. Reasons for later revision included fracture of the prosthesis, lysis, pain, acetabular wear, dissociation of the liner, soft tissue reaction and 'other'. DePuy Synthes assessed models that would fit early revisions, late revisions and both combined. It used a Weibull model with a decreasing hazard over time, which it considered realistic for most prosthesis types with the possible exception of cemented prostheses because data from the Australian registry had shown that the risk of revision with cemented prostheses increases over time. DePuy Synthes based the rate of re-revision (revision subsequent to a first revision) on the New Zealand Joint Registry data (rate 0.0331 per year; 0.0083 per cycle). People stayed in the THR revision/re-revision health state for 1 cycle. The model allowed people to have up to 2 interventions in the same cycle. DePuy Synthes assumed that all people would receive the same type of prosthesis in revision surgery. DePuy Synthes assumed that mortality associated with surgery did not differ by type of prosthesis (0.5% per procedure), and applied an age- and sex-adjusted all-cause mortality rate. The model included the costs of both prostheses and surgery. DePuy Synthes obtained the costs of the prostheses from its own list prices and assumed equal costs for resurfacing arthroplasty and cemented THR. The total prosthesis costs were: cemented THR £1029.00; cementless £2550.50; hybrid £2011.50; and reverse hybrid £1568.00. For the group 'all THR', the manufacturer used a weighted cost (40% cemented, 40% cementless, 17% hybrid, 2% reverse hybrid). DePuy Synthes obtained surgical costs from a micro-costing study that included the costs of anaesthetics, surgical consumables, staff and theatre time. These costs differed across prosthesis type and are academic in confidence. The manufacturer based length of stay on NHS reference costs. DePuy Synthes did not model surgical and post-surgical complications, stating that the average cost and health-related quality of life reflected complications during surgery, and estimates of the risk of revision included complications that occurred after surgery. The manufacturer assumed that the cost of revision was £13,399.42 (which was double the mean cost of the primary procedure). However, unlike the Assessment Group, DePuy Synthes assumed that the cost of revision did not depend on the reason for revision. DePuy Synthes performed a systematic review to identify utility values. For its base case, DePuy Synthes used utility values from Rolfson et al. (2011, Swedish registry). The preoperative utility value was 0.41, and the postoperative utility value was 0.78. It applied a disutility of 0.145 (Briggs et al. 2003) to the postoperative utility value after revision to reflect the lower quality of life associated with a subsequent surgical intervention. In the DePuy Synthes base case for the population for whom both resurfacing arthroplasty and THR were suitable, THR (all types combined) dominated resurfacing arthroplasty. The total incremental cost of resurfacing arthroplasty was £2504.31 for 0.106 fewer QALYs. An incremental analysis calculated using the results for cemented, cementless, hybrid, reverse hybrid and resurfacing prosthesis categories, but excluding DePuy Synthes' own brands (because the costs and QALYs were marked as commercial in confidence and cannot be reported), showed that cemented prostheses dominated both cementless THR and resurfacing arthroplasty. Reverse hybrid prostheses were shown to be extendedly dominated (that is, were dominated by the combination of cemented and hybrid prostheses). The ICER for hybrid prostheses compared with cemented prostheses was £26,636 per QALY gained. For the population for whom resurfacing arthroplasty was not suitable, DePuy Synthes presented an incremental analysis of the results for cemented, reverse hybrid and cementless hybrid prostheses alongside the results for 2 of its own products and all THR prostheses combined. The results of the incremental analysis for the THR prosthesis categories only showed that cemented prostheses dominated reverse hybrid and cementless prostheses (the results for the manufacturer's own products cannot be reported here because the costs and QALYs are commercial in confidence) The ICER for hybrid prostheses compared with cemented prostheses was £259,667 per QALY gained. The manufacturer noted that the range of QALYs generated by the probabilistic analysis from 10,000 simulations overlapped substantially between the THR prosthesis categories, and concluded that all categories of THR are associated with a similar number of QALYs. DePuy Synthes conducted a number of one-way sensitivity analyses for the population for whom both resurfacing arthroplasty and THR were suitable. It presented the results in net monetary benefit, assuming a maximum acceptable ICER of £20,000 per QALY gained. There was a positive net monetary benefit associated with THR for all parameter values tested. This meant that THR is cost effective compared with resurfacing arthroplasty, given a maximum acceptable ICER of £20,000 per QALY gained. The most influential parameters were the cost of revision, the utility decrement associated with revision, and resource use items such as the cost of follow-up appointments, the overhead cost per theatre hour and the individual costs of prostheses components. DePuy Synthes also conducted sensitivity analyses for both the population for whom resurfacing arthroplasty and THR were suitable and for the population for whom resurfacing arthroplasty was not suitable, including: using NHS reference costs rather than costs from the micro-costing study; using EQ-5D from the NJR rather than the Swedish registry data; using an exponential rather than a Weibull model to extrapolate revision rate data; and stratifying the population to include people under 70 years or under 55 years. In all scenarios for both populations, the impact on total costs and total QALYs were minimal. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of THR and hip resurfacing arthroplasty for people with end-stage arthritis of the hip for whom non-surgical management has failed. It considered evidence on the nature of surgery for the treatment of pain and disability, and the value placed on the benefits of THR and resurfacing arthroplasty by people needing surgery. It also took into account the effective use of NHS resources. The Committee considered the care pathway for people with end-stage arthritis of the hip and the potential place of THR and resurfacing arthroplasty. The Committee discussed the factors that clinicians take into account when deciding whether to offer a THR or resurfacing arthroplasty to individual patients. The Committee heard from the Assessment Group's clinical adviser that the use of resurfacing prostheses has declined over the past few years, noting the Medicines and Healthcare products Regulatory Agency's alerts to recall some resurfacing prostheses and to monitor patients with MoM prostheses. The Committee heard that, after any type of hip replacement, some people need revision surgery to replace the primary prosthesis, and that being younger or more active can increase a person's risk of needing revision surgery. The Committee heard that clinicians take into account a person's risk of needing revision surgery when deciding whether to offer resurfacing arthroplasty or THR, and that clinicians in general consider resurfacing arthroplasty more suitable for younger and more active people. The Committee further heard that clinicians may be more likely to offer resurfacing arthroplasty to men than to women because higher revision rates have been observed in women, which may be associated with women tending to have smaller hips. The Assessment Group's clinical adviser also explained that, because older patients have shorter life expectancies than younger patients, they are less likely to need revision, and that clinicians tend to offer older patients THR. The Committee concluded that both THR and resurfacing arthroplasty are options for treatment of end-stage arthritis of the hip, and that clinicians consider together with patients the factors associated with the risk of revision when choosing the most appropriate procedure. Having considered which type of prosthesis would be appropriate (THR or resurfacing arthroplasty), the Committee then considered the choice of a given prosthesis, noting that prostheses vary in materials and fixation methods. The Committee heard that the operating surgeon generally chooses the type of prosthesis, taking into consideration those that achieve the recommended standard revision rate as provided by the Orthopaedic Data Evaluation Panel (ODEP). The Committee heard that surgeons need specific training for each class of prosthesis (for example, cemented or cementless THR), but that most orthopaedic surgeons in the UK are trained to use both cemented and cementless prostheses. The Committee further heard that an orthopaedic centre's experience and clinical data for individual prostheses further influence the choice of prosthesis. The Committee noted that the NJR contained data for hip replacements carried out in the NHS and in private practice, but heard that the prostheses used in the 2 healthcare sectors were not expected to differ because the same surgeons work in both the NHS and in private practice. The Committee considered whether surgeons offer cemented prostheses and cementless prostheses to different patients, and heard from the manufacturers and the Assessment Group's clinical adviser that there were no specific groups of patients for whom cemented or cementless prostheses would be specifically indicated. The Assessment Group's clinical adviser explained that a patient's age, sex and activity levels may influence a surgeon's choice of bearing surface for THR. The Committee understood that surgeons tend to choose not only the type but also the brand of hip prosthesis a patient receives, and that this is driven by factors including the surgeon's training, perception of which prostheses perform best, clinical data and experience using different prostheses, among other factors. The Committee heard from the Assessment Group's clinical adviser that revision surgery is more complex and associated with greater risks than primary THR or resurfacing arthroplasty. It heard from the clinical specialist that patients may need to be referred to a specialist centre for revision surgery. The Committee discussed whether any particular type of THR or resurfacing prosthesis reduced the complexity of subsequent revision surgery, and heard that resurfacing prostheses tended to be easier to replace than THR prostheses, but that the risks associated with surgery to the patients were similar. The Assessment Group's clinical adviser stated that a patient's operative and peri-operative risk depends on why the primary prosthesis failed (for example, infection or fracture) rather than the type of prosthesis, or whether it is cemented or cementless. The Committee recognised that revision surgery is more complicated than primary surgery and concluded that the complexity of the revision surgery is primarily determined by why the primary hip replacement failed. The Committee considered the clinical evidence available for this appraisal. It noted that the Assessment Group presented evidence from RCTs, systematic reviews, published registry studies and its analysis of data from the NJR, and discussed the relevance of each source to its decision making. The Committee noted the Assessment Group's concerns that the RCTs and systematic reviews it had identified involved small numbers of patients, had relatively short follow-up, reported different outcomes either incompletely or poorly, and were underpowered to detect differences in rates of revision. The Committee accepted that, because of these concerns, it was appropriate that the Assessment Group chose not to meta-analyse the RCTs. The Committee then considered data from registries. It noted that the Assessment Group's retrospective analysis of the NJR provided a record of the revision rates for all types of prostheses used in England and Wales since 2003, and as such provided long-term data generalisable to UK clinical practice. The Committee was aware that, although it is mandatory for NHS organisations to submit data to the NJR, when the registry first started clinicians provided data voluntarily, and that the registry may have missed some procedures that were carried out at the time. The Committee noted that the registry did not provide data on outcomes listed in the scope other than revision, and that it did not provide data on differences in the patient characteristics (for example, activity levels and comorbidities) that might affect both device choice and the risk for revision, causing confounding. The Committee noted the comments received on the appraisal consultation document, stating that there is a problem with an accurate link between the NJR data and Hospital Episode Statistics data, and that data on revision rates from the NJR had not been validated. The Committee concluded that it was appropriate to use both trial and observational data in its decision making, but that uncertainty resulting from the possibility of confounding should be taken into account. The Committee agreed that, although the NJR data had limitations, they are the most comprehensive data reflecting clinical practice in the NHS and therefore the most appropriate for decision making. The Committee considered the population for whom both procedures are suitable, and the population for whom resurfacing arthroplasty is not suitable. The Committee discussed the Assessment Group's analysis of revision rates of different types of hip replacement in both populations using the NJR data, and whether it had controlled for bias by confounding. The Committee noted that the Assessment Group had controlled for patient age and sex when comparing resurfacing arthroplasty with THR and when comparing different types of THR (in a sensitivity analysis ). The Committee also noted that the Assessment Group's analysis of the NJR in revision after resurfacing arthroplasty compared with THR was consistent with effect measures from RCTs and systematic reviews (see section 4.1.20). The Committee had heard that activity levels influence the choice of whether a person would be offered resurfacing arthroplasty, or which bearing surface of a THR is chosen, and would also affect the rate of wear of a prosthesis (see sections 4.3.2 and 4.3.3), but that the NJR did not contain data on activity. The Committee discussed whether having resurfacing arthroplasty rather than THR would allow people to be more active after their surgery. They heard from the Assessment Group's clinical specialist that observational studies had shown that people were more active after resurfacing arthroplasty than after THR, but were likely to have been more active before resurfacing arthroplasty compared with people who underwent THR, and that 1 RCT showed no difference in activity levels after surgery in people randomised to resurfacing arthroplasty or to THR. The Committee agreed that there was uncertainty around whether the difference in revision rates between THR and resurfacing arthroplasty could just be attributed to risk of failure of the prostheses because it is likely that people who have resurfacing are more active than people who have THR and higher activity may cause accelerated wear of a prosthesis. The Committee also heard that comorbidities may influence which type of prosthesis a patient receives and whether or not a patient is offered revision surgery. The Committee concluded that the Assessment Group's analysis of revision rates was consistent with published systematic reviews of trials, and controlled for some, but not all, potential confounders, notably activity level and comorbidities, and therefore uncertainty remained surrounding the relative revision rates between different types of prostheses. The Committee considered whether data on revision surgery in the Assessment Group's NJR data set could be considered a proxy for prosthesis failure. The Committee noted that the NJR captured revision rates, but not failure rates of the prostheses, and that some people need revision surgery for pain only (without the prosthesis failing). The Committee further noted that there are people who need a revision because their prosthesis has failed, but who are not fit enough to have surgery or who choose not to have surgery. The Committee appreciated that, in these people, the NJR data on revision rates may underestimate the true failure rate. After consultation on the appraisal consultation document, the Committee further considered revisions that result from prostheses failing and revisions that result from complications during surgery or errors in prosthesis insertion (early revision). The Committee heard from the manufacturers that they expected the proportions of revisions not directly related to device failures to be similar across classes of hip replacement prostheses. The Committee noted a comment received from a manufacturer during consultation stating that early failures associated with dislocation were the fault of the surgeon, but the Committee had no further evidence to support this conclusion. The Committee appreciated that the underlying reason for why a patient needed revision surgery may be difficult to identify and is not routinely recorded in the NJR. In addition, the Committee was told that there is no system that collects data about the prevalence of people living with a failed prosthesis who are unable to, or choose not to, have revision surgery, and no representative data on the proportion of revisions that are a result of failing prostheses. The Committee accepted that, while revision rates may not fully reflect prosthesis failure, revision was an important outcome both from the patient's perspective and in terms of costs and the resources needed. The Committee considered the approaches to modelling revision rates beyond the maximum 9 years of follow-up in the NJR. It discussed the bathtub model and the log-normal model used by the Assessment Group in its base case, and sensitivity analysis, and the Weibull model used by the manufacturer in its base case. The Committee noted that the bathtub model, which it understood was widely used in manufacturing to describe device failure, assumed that risk of revision would decrease initially and then increase over time, whereas the log-normal and Weibull models assumed an increasing risk of revision over time. The Committee compared the revision rates predicted by all 3 models with data from the Swedish registry, in which people aged between 60 and 75 years who had a hip replacement (resurfacing arthroplasty or THR) were followed up for 19 years. In the population for whom resurfacing was not suitable, the bathtub model predicted longer-term outcomes that fitted the data from the Swedish registry better than the log-normal model. The manufacturer's Weibull model did not fit the Swedish data as well as the Assessment Group's bathtub model did. The Committee noted that there was uncertainty surrounding the generalisability of the Swedish registry data to the UK population, in part because the Swedish registry was initiated earlier than the NJR. The Committee noted that the revision rates in the Swedish registry were higher than the revision rates predicted by the 3 models used to extrapolate data from the NJR. The Committee concluded that, of the 3 models presented to extrapolate revision rates beyond the 9-year follow-up of the NJR, the Assessment Group's bathtub extrapolation was the most plausible. The Committee examined the economic modelling that had been carried out for the appraisal. The Committee noted that the 2 economic models presented by the Assessment Group and by 1 manufacturer (DePuy Synthes) had similar structures and were based on a model structure that had been used in previous health economic evaluations of hip replacement prostheses. The Committee concluded that the outlined structure of the models adhered to the NICE reference case for economic analysis and was acceptable for the purpose outlined in the scope. The Committee considered the utility values and the source of the health-related quality-of-life data used by the Assessment Group and the manufacturer. The Committee observed that, in both models, the differences in QALYs gained between the types of hip replacement were very small (see section 4.2.11). The Committee discussed how different types of hip replacement surgery would affect a patient's quality of life. The Committee noted that the Assessment Group's utility values came from PROMs in the NJR and were collected postoperatively, but were not specific to individual types of prosthesis. The Committee noted that, in the manufacturer's model, different types of THR and resurfacing arthroplasty were also associated with the same utility value after surgery. The Committee noted that, in the manufacturer's model, a disutility of 0.145 had been applied after a successful revision. This was to reflect that a patient is unlikely to return to the level of health-related quality of life experienced after the primary surgery, whereas the Assessment Group had assumed that utility after a successful revision would be the same as utility after a successful primary hip replacement. The Committee heard from the Assessment Group's clinical specialist and the manufacturer that, although a successful primary hip replacement would be expected to relieve pain and disability associated with end-stage arthritis of the hip completely, revision surgery was associated with both greater risks and poorer functional outcomes than primary surgery and it was appropriate to apply a disutility value in the post-revision health state, as in the manufacturer's model. The Committee concluded that it was plausible that people who had revision surgery would have a lower quality of life than people who had a successful primary hip replacement. It further concluded that, given the available evidence, it was not possible to determine how use of different types of hip replacement prostheses would affect quality of life. The Committee discussed the costs of the prostheses. It understood that the Guide to the methods of technology appraisal 2008 recommends using public list prices in the reference-case analysis, but noted that the NHS routinely pays a lower price for hip replacement prostheses because of volume-dependent and locally negotiated discounts. The Committee was aware that the Assessment Group obtained an average of sample list prices from the NHS Supply Chain for multiple manufacturers, and that the manufacturer had presented list prices for its own brands. The Committee also noted that the Assessment Group's prices were higher than the manufacturer's (with some exceptions). The Committee concluded that there was considerable uncertainty surrounding the prices of prostheses. The Committee considered the base-case economic analyses presented by the Assessment Group and 1 manufacturer. It noted that they generated broadly similar results, that is, THR dominated resurfacing arthroplasty in both the Assessment Group's and manufacturer's base cases, and that resurfacing arthroplasty remained dominated in every sensitivity and subgroup analysis. The Committee also noted that, although the categories of THR differed in the Assessment Group's and manufacturer's analyses, cemented prostheses tended to be the least costly and most effective, but with small incremental differences in costs and QALYs compared with other types of THR. The Committee also noted that, in the analyses of cost effectiveness, the Assessment Group and manufacturer used the average revision rate across category, and that the revision rate was the most important key driver of costs and QALYs in the model. The Committee concluded that THR was more effective and less costly than resurfacing arthroplasty in all analyses, but that the small differences between cemented and cementless THR were associated with uncertainty. The Committee discussed the approach of comparing the cost effectiveness of categories of THR and resurfacing arthroplasty by category rather than by individual brands. The Committee was aware that devices can differ only slightly and that, within each category, there are multiple brands. The Committee further noted comments received on the appraisal consultation document that not all categories of THR had been investigated by the Assessment Group. The Committee was aware that the Assessment Group had assessed the 5 most frequently used combinations of bearing surface and fixation method in the NJR and considered this to be appropriate. The Committee considered that the Assessment Group and manufacturer had not taken into account the uncertainty related to revision rates of different brands of prostheses within a category. The Committee noted that the Assessment Group had modelled a revision rate of 17.2% for men and women at 10 years for resurfacing arthroplasty, and 12.4% for men only (in current practice resurfacing is predominantly used in men), and that these revision rates were higher than the current NICE standard of 10% or less at 10 years in NICE technology appraisal guidance 2 and NICE technology appraisal guidance 44. However, the Committee noted that 1 manufacturer of resurfacing arthroplasty products had provided evidence that its product had a revision rate lower than the NICE standard. In response to the appraisal consultation document, several consultees emphasised that revision rates vary between different brands of prosthesis within a category. The Committee noted again that making recommendations by revision rate allowed individual brands to be assessed separately. The Committee reiterated that it had considered making recommendations for prosthesis by category based on the average revision rate of multiple brands within a category. However, the Committee chose not to make recommendations by category, having concluded that this would disadvantage individual brands of prostheses with low revision rates, and would give an unfair advantage to individual brands with high revision rates within an overall well-performing category. The Committee considered whether it was still appropriate to recommend a revision rate for prostheses of 10% or less at 10 years, as recommended in NICE technology appraisal guidance 2 and NICE technology appraisal guidance 44. The Committee noted that the Assessment Group, having analysed and extrapolated data from the NJR for the population for whom both procedures were suitable, had estimated that the 10-year revision rate for resurfacing arthroplasty was worse (higher) than the standard, and that the 10-year revision rates for THR were much better (lower) than 10% at 10 years. Furthermore, the Committee noted that, in the population for whom resurfacing was not suitable, the highest estimate across the 5 categories of THR was less than 5% at 10 years. The Committee agreed that the current standard was too high for both populations, and was aware that prostheses become more cost effective the lower the revision rates. Therefore, it discussed how a new standard could be determined with the data available. The Committee considered that, because all of the categories of THR prostheses for both populations had a predicted revision rate of less than 5% at 10 years, the value reflecting the new standard for THRs should be no higher than 5%. Additionally, it considered that, because the predicted revision rate of THR was less than 5% at 10 years in the population for whom both THR and resurfacing arthroplasty were suitable, the revision rate standard for resurfacing arthroplasty should be the same as that for THRs. The Committee noted that, although the average revision rate was predicted to be 5% or less at 10 years, it was likely that within a category of THR some brands would perform poorly and would not meet this standard. The Committee discussed whether the proposed value should be reduced to even less than 5% to provide a more 'aspirational' standard. However, the Committee acknowledged that limitations in the data available (see section 4.3.6) did not allow it to determine the lowest revision rate that current practice could realistically achieve. The Committee concluded that it was appropriate to recommend that a prosthesis (for either resurfacing arthroplasty or THR) should meet a revision rate of 5% or less at 10 years. The Committee was aware that NICE technology appraisal guidance makes recommendations on the most cost-effective use of NHS resources but does not specify how to implement the guidance. It was also aware that the NICE Implementation Programme supports health and social care organisations to maximise the uptake and use of evidence and guidance. The Committee was further aware that ODEP, which is independent of NICE, currently provides the NHS with a list of prostheses that do or do not meet the standard for revision rates outlined in NICE technology appraisal guidance 2 and NICE technology appraisal guidance 44, and that there are initiatives to improve collecting and disseminating information on revision rates. The Committee discussed whether, given the current support for implementation available to the NHS, it would be possible to implement guidance in which recommendations depended on prostheses meeting a 5% or less revision rate at 10 years, particularly for brands with less than 10 years of data. The Committee was aware that NICE technology appraisal guidance 2 and NICE technology appraisal guidance 44 considered it reasonable to recommend prostheses with a minimum of 3 years of experience, provided the projected revision rate was consistent with the standard recommended at that time; the Committee considered that this remained appropriate. The Committee noted that the ODEP rating system includes 3 entry revision rate benchmarks assuming a linear relationship between the time since primary hip replacement and the proportion of people who would be expected to have a revision. The Committee agreed that, while other appropriate distributions may exist, the analysis of revision rates presented by the Assessment Group for this appraisal had shown it was reasonable to extrapolate using the bathtub function for prostheses with a follow-up of less than 10 years. Furthermore, the bathtub model accounted for a higher rate of early revisions, which may reflect surgical complications or other factors unrelated to the prosthesis (see sections 4.3.7 and 4.3.8). The Committee preferred the Assessment Group's method of extrapolating revision rates to a linear extrapolation, but was content that ODEP needs to determine the methods with which it estimates revision rates based on the quality of the data provided by the manufacturers and the timing of the reporting of revision rates in clinical practice. The Committee concluded that it would be reasonable to recommend prostheses with less than 10 years of data, provided that the revision rate was, in as much as the shorter term follow‑up data allow, consistent with 5% or less at 10 years and that the recommendation could be implemented within the current support framework provided by ODEP. It also concluded that prostheses currently with at least 3 years of data, which estimate a higher than 5% revision rate at 10 years when projected, should not continue to be offered to patients. The Committee considered other aspects of how prostheses are currently being rated and noted comments received from ODEP on the appraisal consultation document, in which ODEP clarified that it gave ratings for stem and cup components individually because of the large number of cup and stem components available and their many combinations. The Committee considered whether the revision rate standard of 5% or less at 10 years should apply to each cup and stem component separately. The Committee agreed that total hip replacement or resurfacing arthroplasty can be considered to meet the revision rate standard of 5% or less at 10 years if all components have an ODEP rating consistent with this standard. The Committee considered the cases in which there may be more than 1 prosthesis suitable for a patient that meets the revision rate standard of 5% or less at 10 years. It was aware that current arrangements of generating ODEP ratings do not provide the NHS with the absolute revision rate for an individual prosthesis but only information on whether or not the standard was achieved, and that this was because ODEP receives revision rates from several registries or published papers each with different volumes of implants making a scientifically robust aggregation difficult. The Committee considered that, if more than 1 prosthesis meets the 5% or less revision rate standard, it would prefer to recommend the most cost-effective prostheses (those with the lowest revision rates) but concluded that, without absolute revision rate data for each hip replacement system, this would not be feasible to implement. The Committee was aware that, because of uncertainties surrounding the costs of prostheses and the discounts available to the NHS, it was not possible to give an estimate of the mean price paid in the NHS for a given prosthesis. The Committee considered that its recommendations should promote maintaining (at least) the level of discount from prostheses' list prices currently offered to the NHS. The Committee discussed whether, if more than 1 prosthesis meets the 5% or less at 10 years revision rate standard, it should recommend the prosthesis with the lowest acquisition costs. The Committee considered comments received during consultation on the appraisal consultation document. It was aware that the cost of THR and resurfacing arthroplasty included both procedure costs and surgical costs. The Committee noted that the Assessment Group had used published literature to determine surgical costs and had assumed that these would be the same for resurfacing arthroplasty and THR. The Committee also noted that 1 manufacturer (DePuy Synthes) had carried out a costing study to estimate time in surgery and consumables, and that the manufacturer stated that procedure costs differed for resurfacing arthroplasty and for THR, and between various types of THR. The Committee heard from the manufacturers that the cost of a prosthesis may be a small proportion of the tariff paid by the NHS for a hip replacement. The Committee noted that the cost of a prosthesis is included in the fixed NHS tariff. The Committee considered the comments received from consultees on the appraisal consultation document, which stated that the benefits of manufacturer support packages had not been taken into account. However, the Committee concluded that tender costs included training in the use of a prosthesis. The Committee concluded that, although the NHS should be mindful of costs, in situations where multiple prostheses with a revision rate of 5% or less at 10 years are suitable for a patient, it could not currently recommend selecting a prosthesis with the lowest acquisition cost. The Committee further concluded that the recommended standards for revision rate would encourage manufacturers to maintain training programmes to ensure the lowest revision rates possible for their products. # Summary of Appraisal Committee's key conclusions TA304 Appraisal title: Total hip replacement and resurfacing arthroplasty for end-stage arthritis of the hip (review of technology appraisal guidance 2 and 44) Section Key conclusion Prostheses for total hip replacement and resurfacing arthroplasty are recommended as treatment options for people with end-stage arthritis of the hip only if the prostheses have rates (or projected rates) of revision of 5% or less at 10 years. Revision rate was the most important key driver of costs and quality-adjusted life years (QALYs) in the model. The Committee was aware that prostheses become more cost effective the lower the revision rates. The Committee considered that, because all of the categories of total hip replacement (THR) prostheses had a predicted revision rate of less than 5% at 10 years, the value reflecting the new standard should be no higher than 5%. It considered that, because the predicted revision rate of THR was less than 5% at 10 years in the population for whom both THR and resurfacing arthroplasty were suitable, the revision rate standard for resurfacing arthroplasty should be the same as that for THRs. Current practice Clinical need of patients, including the availability of alternative treatments Both THR and resurfacing arthroplasty are options for treating end-stage arthritis of the hip, and clinicians consider together with patients the factors associated with the risk of revision when choosing the most appropriate procedure. Clinicians may be more likely to offer resurfacing arthroplasty to men than to women because higher revision rates have been observed in women, which may be associated with women tending to have smaller hips. The operating surgeon generally chooses the prosthesis, taking into consideration those that achieve the recommended standard revision rate as provided by the Orthopaedic Data Evaluation Panel. The Committee heard that surgeons need specific training for each class of prosthesis (for example, cemented or cementless THR), but that most orthopaedic surgeons in the UK are trained to use both cemented and cementless prostheses. The Committee also heard that an orthopaedic centre's experience and clinical data for individual prostheses further influence choice of prosthesis. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? A successful primary hip replacement would be expected to completely relieve pain and disability associated with end-stage arthritis of the hip, and hip resurfacing prostheses tend to be easier to replace than THR prostheses, but the risks associated with surgery are similar. What is the position of the treatment in the pathway of care for the condition? The Committee reviewed the data available on the clinical and cost effectiveness of THR and hip resurfacing arthroplasty for people with end-stage arthritis of the hip for whom non-surgical management has failed. Adverse reactions Adverse events associated with hip replacement surgery (THR or resurfacing arthroplasty) may occur because of complications at the time of surgery or many years afterwards. Complications that may lead to hip replacement revision surgery include prosthesis instability, dislocation, aseptic loosening, osteolysis (bone reabsorption), infection and prosthesis failure. The Assessment Group's clinical adviser stated that a patient's operative and peri-operative risk after a revision is associated more with why the primary prosthesis failed (for example, infection or fracture) than with the type of prosthesis, or whether it is cemented or cementless. Evidence for clinical effectiveness Availability, nature and quality of evidence The Assessment Group presented evidence from RCTs, systematic reviews, published registry studies, and its analysis of data from the Natoinal Joint Registry (NJR). The RCTs and systematic reviews involved small numbers of patients, had relatively short follow-up, reported different outcomes either incompletely or poorly, and were underpowered to detect differences in rates of revision. The Assessment Group's retrospective analysis of the NJR provided a record of the revision rates for all types of prostheses used in England and Wales since 2003 and, as such, provided long-term data generalisable to UK clinical practice. The Committee noted comments received during consultation, stating that there is a problem with an accurate link with Hospital Episode Statistics data and that data on revision rates from the NJR have not been validated. The Committee noted that the registry did not provide data on outcomes listed in the scope other than revision, and that it did not provide data on differences in the patient characteristics (for example, activity level and comorbidities) that might affect both device choice and the risk for revision, and could therefore cause confounding. The Committee concluded that it was appropriate to use both trial and observational data in its decision making, but that uncertainty resulting from the possibility of confounding should be taken into account. The Committee agreed that, although the NJR data had limitations, they are the most comprehensive data reflecting clinical practice in the NHS and therefore the most appropriate for decision making. Relevance to general clinical practice in the NHS The Assessment Group's retrospective analysis of the NJR provided a record of the revision rates for all types of prostheses used in England and Wales since 2003 and, as such, provided long-term data generalisable to UK clinical practice. Uncertainties generated by the evidence The Committee heard that activity levels influence the choice of whether a person would be offered resurfacing arthroplasty, or which bearing surface of a THR is chosen, and would also affect the rate of wear of a prosthesis but that the NJR did not contain data on activity. It agreed that there was uncertainty around whether the difference in revision rates between THR and resurfacing arthroplasty could be attributed to failure of the prostheses because it is likely that people who have resurfacing are more active than people who have THR and higher activity may cause accelerated wear of a prosthesis. The Committee heard that comorbidities may be associated with which type of prosthesis a patient receives and whether or not a patient is offered revision surgery. The Committee concluded that the Assessment Group's analysis of revision rates controlled for some, but not all, potential confounders, notably activity and comorbidities, and that it was consistent with published systematic reviews of trials, but that there remained uncertainty surrounding the relative revision rates between different types of prostheses. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Clinicians may be more likely to offer resurfacing arthroplasty to men than to women because higher revision rates have been observed in women, which may be associated with women tending to have smaller hips. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that the Assessment Group had modelled a revision rate of 17.2% for men and women at 10 years for resurfacing arthroplasty, and 12.4% for men only (in current practice resurfacing is predominantly used in men), and that these revision rates were higher than the current NICE standard of 10% or less at 10 years in NICE technology appraisal guidance 2 and NICE technology appraisal guidance 44. All of the categories of THR prostheses for both populations had a predicted revision rate of less than 5% at 10 years. How has the new clinical evidence that has emerged since the original appraisal (TA2 and TA44) influenced the current recommendations? Since the original appraisals NICE technology appraisal guidance 2 and NICE technology appraisal guidance 44, data have become available for revision rates of prostheses used in the NHS and private practice in England and Wales and are documented in the NJR. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the base-case economic analyses presented by the Assessment Group and 1 of the manufacturers (DePuy Synthes). Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee understood that the Guide to the methods of technology appraisal 2008 recommends using publicly available list prices in the reference-case analysis, but noted that the NHS routinely pays a lower price for hip replacement prostheses because of volume-dependent and locally negotiated discounts. The Committee concluded that there was considerable uncertainty surrounding the prices of prostheses. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee concluded that it was plausible that people who had revision surgery would have a lower quality of life than people who had a successful primary hip replacement. It further concluded that, given the available evidence, it was not possible to determine how use of different types of hip replacement prostheses would affect quality of life. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable What are the key drivers of cost effectiveness? The Committee noted that, in the analyses of cost effectiveness, the Assessment Group and manufacturer used the average revision rate across category, and that the revision rate was the most important key driver of costs and QALYs in the model. Prostheses become more cost effective the lower the revision rates. Most likely cost-effectiveness estimate (given as an ICER) Incremental cost-effectiveness ratios (ICERs) were not the relevant parameter in determining the recommendations. This was because the ICERs were dependent on the predicted average revision rates of the analysed categories of prostheses, the differences in QALYs between categories were small, and individual brands may have different revision rates from the category average. How has the new cost-effectiveness evidence that has emerged since the original appraisal (TA2 and TA44) influenced the current recommendations? The Committee concluded that THR was more effective and less costly than resurfacing arthroplasty in all analyses, but that the small differences between cemented and cementless prostheses were associated with uncertainty. The Committee considered making recommendations for particular prostheses categories based on the point estimate reflecting the average revision rate of multiple brands of prostheses within a category. However, it concluded that this would disadvantage individual brands of prostheses with particularly low revision rates and would give an unfair advantage to individual brands with high revision rates within an overall well-performing category. The Committee concluded that it was appropriate to recommend that a prosthesis should meet a revision rate of 5% or less at 10 years. Additional factors taken into account Patient access schemes (PPRS) Not applicable End-of-life considerations Not applicable Equalities considerations and social value judgements During scoping, consultees said that the rates of total joint surgery in practice may vary in different groups of people. However, no changes were required to the scope because it did not define the population being considered by any of the protected equality characteristics. It was noted by the Committee that NICE technology appraisal guidance 2 and NICE technology appraisal guidance 44 were published before the current NICE equalities scheme was implemented. No equality issues were raised in the assessment report, the manufacturer's submissions or during the consultation on the assessment report or the Committee's discussions. n/a# Recommendations for further research The Committee recommended that research should be carried out to determine the relationship between activity and prosthesis failure. The Committee recommended the collection of data on prosthesis failure or on the prevalence of people living with a failed hip but for whom revision surgery is not suitable or who choose not to have revision surgery. The Committee further recommended that nomenclature for hip replacement failure needs to be established to allow demarcation of prosthesis-dependent and prosthesis-independent hip replacement failure. Furthermore, patient reported outcome measures collected as part of the National Joint Registry should allow for reporting of hip replacement failure in people who cannot or choose not to have revision surgery.# Related NICE guidance Details are correct at the time of publication. Further information is available on the NICE website. Osteoarthritis: care and management in adults. NICE clinical guideline 177 (2014). Arthroscopic femoro-acetabular surgery for hip impingement syndrome. NICE interventional procedure guidance 408 (2011). Minimally invasive total hip replacement. NICE interventional procedure guidance 363 (2010). Rheumatoid arthritis: the management of rheumatoid arthritis in adults. NICE clinical guideline 79 (2009). Guidance on the use of metal on metal hip resurfacing arthroplasty. NICE technology appraisal guidance 44 (2002). Guidance on the selection of prostheses for primary total hip replacement. NICE technology appraisal guidance 2 (2000).# Review of guidance The guidance on this technology will be considered for review in February 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew Dillon Chief ExecutiveFebruary 2014# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS. This guidance was developed using the NICE multiple technology appraisal process. It updates and replaces NICE technology appraisal guidance 2 (published April 2000) and NICE technology appraisal guidance 44 (published June 2002). It has been incorporated into the NICE pathway on rheumatoid arthritis and NICE pathway on osteoarthritis along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0444-0	{'Guidance': 'This guidance replaces NICE technology appraisal guidance 2 issued in April 2000 and NICE technology appraisal guidance 44 in June 2002.\n\nProstheses for total hip replacement and resurfacing arthroplasty are recommended as treatment options for people with end-stage arthritis of the hip only if the prostheses have rates (or projected rates) of revision of 5% or less at 10\xa0years.', 'Clinical need and practice': 'Arthritis refers to inflammation of a joint, and is a leading cause of pain and disability in the UK. Arthritis can have many causes, the most common of which is osteoarthritis (defined by a loss of cartilage within the joint and related changes in the associated bone). Estimates suggest that up to 8.5\xa0million people in the UK are affected by joint pain that may be attributed to osteoarthritis. The second most common cause is rheumatoid arthritis (an autoimmune inflammatory disease that affects the synovial lining of joints). Around 400,000\xa0people in the UK have rheumatoid arthritis.\n\nSymptoms of hip arthritis include pain and stiffness that limit daily activities such as walking, climbing stairs and performing household tasks. The diagnosis of arthritis of the hip is usually based on individual patient history and clinical examination assessing joint pain, deformity and reduced range of movement. Osteoarthritis: Care and management in adults (NICE clinical guideline\xa0177) states that clinicians should first offer patients non-surgical treatments including exercise, physical therapy and analgesics, and should consider referring patients for joint replacement surgery if they have ongoing pain, joint stiffness, reduced function and a poor quality of life. People having elective primary surgery to relieve pain and disability caused by arthritis of the hip may receive either a total replacement of the damaged hip (total hip replacement) or a hip resurfacing arthroplasty.\n\nThe National Joint Registry was set up by the Department of Health and Welsh Assembly Government for the mandatory collection of information on all hip, knee, ankle, elbow and shoulder replacement operations from NHS organisations and private practice, and to monitor the performance of joint replacement prostheses. Since 2009, all NHS patients who are having hip replacement surgery are invited to fill in Patient Reported Outcome Measures (PROMs) questionnaires about their health and quality of life before and after their surgery.\n\nFollowing publication of Guidance on the selection of prostheses for primary total hip replacement (NICE technology appraisal guidance 2), the National Health Purchasing and Supply Agency (PASA) was given the task of monitoring adherence to the technology appraisal recommendation. PASA set up a panel of experts known as the Orthopaedic Data Evaluation Panel (ODEP). PASA was subsequently replaced by NHS Supply Chain, which still manages and provides administrative support to ODEP. ODEP provides the NHS with an approved list of prostheses that meet the revision rate standard at 10\xa0years set out in NICE guidance and which are suitable for use in primary hip replacement (see section\xa03.6). ODEP provides separate ratings for the 2\xa0components of hip replacement prostheses (that is, stems and cups; see section\xa03.1). For hip prostheses with less than 10\xa0years of clinical data, there are currently 3\xa0entry standards expressed by ODEP as failure rate: 3% or less at 3\xa0years; 5% or less at 5\xa0years; and 7% or less at 7\xa0years, which are considered to be consistent with the 10-year standard.', 'The technologies': "In total hip replacement (THR) surgery, the acetabulum (hip socket) is replaced with either a single-piece cup made from 1\xa0material (polyethylene, ceramic or metal) or a 2-piece (modular) cup made from a metal outer shell and a polyethylene, ceramic or metal liner. The head of the femur (thigh bone) is replaced with either a single-piece metal stem and head, or a modular component consisting of a metal stem (which may consist of more than 1\xa0piece) with a metal, ceramic or ceramicised metal head.\n\nTHRs vary in what fixation method is used for each component of the prosthesis. In some THRs, all the components are fixed into position using cement (hereafter referred to as cemented THRs). Other types of THR are designed to be used without cement (hereafter referred to as cementless THRs); instead, they are inserted using press-fit fixation, and natural bone growth over time secures the prosthesis in place. Some prostheses are hybrid, in which the femoral component is cemented into place while the cup is fixed without cement, or reverse hybrid, in which the femoral component is fixed without cement while the cup is cemented into place. THRs may also vary by femoral head size, with a large head defined as being 36\xa0mm or more in diameter.\n\nHip resurfacing arthroplasty involves removing and replacing the surface of the femoral head with a hollow metal hemisphere, which fits into a metal cup fixed into the acetabulum. All resurfacing arthroplasty prostheses currently on the market are metal-on-metal (MoM), and can be hybrid or cementless. As with THR prostheses, resurfacing arthroplasty prostheses may also vary by femoral head size.\n\nPatient selection for THR or resurfacing arthroplasty depends on various factors, including but not limited to: patient characteristics (for example a patient's age, activity and underlying hip physiology); the surgeon's choice; and the surgeon's experience of using a particular class of prosthesis.\n\nAdverse events associated with hip replacement surgery (THR or resurfacing arthroplasty) may occur because of complications at the time of surgery, or may occur years afterwards. Complications that may lead to hip replacement revision surgery include prosthesis instability, dislocation, aseptic loosening, osteolysis (bone reabsorption), infection and prosthesis failure.\n\nGuidance on the selection of prostheses for primary total hip replacement (NICE technology appraisal guidance\xa02) recommends that the best prostheses should have a revision rate of 10% or less at 10\xa0years or, as a minimum, a 3-year revision rate consistent with this. Guidance on the use of metal on metal hip resurfacing arthroplasty (NICE technology appraisal guidance\xa044) recommends MoM resurfacing arthroplasty as an option for people with advanced hip disease who would otherwise receive, and are likely to outlive, a conventional primary THR. The guidance recommends that the best prostheses should demonstrate the same revision rates as recommended in NICE technology appraisal guidance\xa02.\n\nThe Medicines and Healthcare products Regulatory Agency (MHRA) monitors the safety of devices used in clinical practice. In June 2010, the MHRA issued an alert on all MoM hip replacement prostheses (both THR and resurfacing arthroplasty) after reports of soft tissue reactions that may be associated with pain. In June 2012, the MHRA released an updated alert noting that MoM prostheses (THR and resurfacing arthroplasty) may wear at an accelerated rate. The MHRA stated that people with MoM prostheses may develop soft tissue damage caused by wear debris from these prostheses. It advised annual monitoring of the hip using imaging and measurement of metal levels in the blood to determine whether a revision is needed in people with MoM hip replacement prostheses who have symptoms, or who have a certain type of MoM hip replacement, including stemmed MoM THRs with a larger femoral head (36\xa0mm diameter or more) or the recalled DePuy ASR hip replacements (THR and resurfacing arthroplasty).\n\nOver 20\xa0companies manufacture prostheses for hip replacement (THR and resurfacing arthroplasty), and some produce multiple brands of components. The NHS Supply Chain provided the average list price costs for 5\xa0manufacturers of the 5\xa0THR categories (varying by fixation method and bearing surface) identified by the Assessment Group and 3\xa0manufacturers of resurfacing arthroplasty prostheses and associated accessories. The average list prices for THRs across the manufacturers were: £1557 for a cemented polyethylene cup plus a metal head; £3016 for a cementless metal cup with a polyethylene liner plus a metal head (cementless stem); £3869 for a cementless metal cup with a ceramic liner plus a ceramic head (cementless stem); £2650 for hybrid cementless metal cup with a polyethylene liner plus a metal head (cemented stem); and £1996 for cemented polyethylene cup with ceramic head (cemented stem). The average list price for resurfacing arthroplasty prostheses across the manufacturers was £2672. Typically, the price of hip replacement prostheses depends on the volume ordered and locally negotiated discounts, so the prices paid by the NHS are routinely lower than the list prices listed above.", 'Evidence and interpretation': "The Appraisal Committee (section\xa09) considered evidence from a number of sources (section\xa010).\n\n# Clinical effectiveness\n\nThe Assessment Group conducted a systematic review of randomised controlled trials (RCTs), published systematic reviews and published registry studies of hip replacement procedures. In addition, the Assessment Group analysed individual patient data from the National Joint Registry (NJR).\n\n## Systematic review of randomised controlled trials and published systematic reviews\n\nThe Assessment Group identified 16\xa0RCTs and 8\xa0systematic reviews. It noted that there were a further 20\xa0ongoing clinical trials. Three RCTs and 3\xa0systematic reviews compared resurfacing arthroplasty with total hip replacement (THR); and 13\xa0RCTs and 5\xa0systematic reviews compared different types of THR with each other.\n\nThe Assessment Group assessed the risk of bias and methodological quality of the studies (RCTs and systematic reviews), determining whether the evidence could be considered conclusive or non-conclusive based on the precision, consistency and clinical relevance of the effects. The Assessment Group recognised that studies included different measures of patient function and chose, based on previously published research, the following criteria for minimally clinically important differences (MCID): the Harris Hip Score (MCID range: 7–10); the Oxford Hip Score (MCID range: 5–7); the Western Ontario McMaster Osteoarthritis Index (MCID: 8); and the EQ‑5D measure of health‑related quality of life (MCID: 0.074). The Assessment Group considered the evidence from an RCT to be conclusive if it showed:\n\na statistically significantly different effect between treatments for which the 95% confidence interval included the MCID or\n\nno effect if the MCID was outside the 95% confidence interval for any given outcome.The Assessment Group considered the evidence from an RCT to be inconclusive if:\n\nthe confidence intervals were wide or\n\nthere were missing data or\n\nthe effects were inconsistent, if there were 2\xa0separate trials that had assessed the same outcome.The Assessment Group further considered the evidence from a systematic review to be inconclusive if it:\n\ndid not report pooled results of RCTs (that is, it reported the results narratively) or\n\nused inappropriate methods to pool data or\n\nreported inconsistent summary findings.\n\nOf the 3\xa0RCTs comparing the effectiveness of resurfacing arthroplasty with THR, 1\xa0RCT compared metal-on-metal (MoM) resurfacing arthroplasty with large-head MoM THR, 1\xa0RCT compared MoM resurfacing arthroplasty with MoM THR, and 1\xa0RCT compared MoM resurfacing arthroplasty with an unspecified bearing surface of THR. The 3\xa0RCTs randomised a total of 422\xa0patients (ranging from 104 to 192 per study) and the length of follow-up in the trials ranged from 1\xa0to 6\xa0years.\n\nThe reported outcomes in the 3\xa0RCTs comparing resurfacing arthroplasty with THR were function (assessed in 3\xa0RCTs), risk of revision (assessed in 1\xa0RCT), infection (assessed in 2\xa0RCTs), aseptic loosening (assessed in 1\xa0RCT), dislocation (assessed in 2\xa0RCTs), deep vein thrombosis (assessed in 2\xa0RCTs) and health-related quality of life (assessed in 2\xa0RCTs; 1 used the EQ-5D and 1 used the SF-36 questionnaire). Five functional measures were used across the 3\xa0RCTs. There was no difference between resurfacing arthroplasty and THR for the Oxford Hip Score, Western Ontario McMaster Osteoarthritis Index score, or the Merle D'Abigine and Postel score. The evidence was inconclusive for the Harris Hip Score and the University of California, Los Angeles activity score. The Assessment Group reported that infection rates differed between patients who had resurfacing arthroplasty and those who had THR. The Assessment Group's meta‑analysis of the 2\xa0RCTs that assessed this outcome indicated that, 12–56\xa0months after surgery, patients who had had THR developed more infections than patients who had had resurfacing arthroplasty (pooled odds ratio 7.94, 95%\xa0confidence interval [CI] 1.78 to 35.40). All data for the other outcomes (quality of life, revision dislocation, deep vein thrombosis, wound complication, aseptic loosening and mortality) reported in the 3\xa0RCTs were inconclusive.\n\nOf the 3\xa0systematic reviews comparing the effectiveness of resurfacing arthroplasty with THR, 2 synthesised data on function, 2 on risk of revision, 1 on infection, 2 on aseptic loosening, 2 on dislocation and 2 on mortality. The systematic reviews included data from both RCTs and observational studies, including single-arm studies of resurfacing arthroplasty or THR. Two of the systematic reviews assessed resurfacing arthroplasty compared with all types of THR and 1\xa0systematic review compared resurfacing arthroplasty with cementless THR. Two of the systematic reviews included RCTs that the Assessment Group had critiqued separately. The Assessment Group considered the reported data on function to be inconclusive. The 2\xa0systematic reviews that compared revision rates between resurfacing arthroplasty and THR showed that revision rates were higher after resurfacing arthroplasty (1 estimated a relative risk [RR] of 2.60 [95%\xa0CI 1.31 to 5.15] over a 10-year follow-up, 1 estimated an RR of 1.72 [95%\xa0CI 1.20 to 2.45] but did not report length of follow-up). Two systematic reviews found that resurfacing arthroplasty was associated with more component loosening than THR (RR\xa03.00, 95%\xa0CI\xa01.11 to 8.50 and RR\xa04.96, 95%\xa0CI\xa01.82 to 13.50 respectively). Both of these systematic reviews assessed dislocation rates and 1 found statistically significantly lower dislocation rates associated with resurfacing arthroplasty compared with THR (RR\xa00.20, 95%\xa0CI 0.10 to 0.5). The Assessment Group considered the reported data on all of the other outcomes (mortality, prosthesis failure and infection) to be inconclusive.\n\nThe Assessment Group identified 13\xa0RCTs comparing different types of THR with each other, including comparisons of different fixation methods, bearing surfaces, component materials, designs and component sizes. The number of people in each RCT ranged from 100 to 557. The length of follow-up ranged from 3\xa0months to 20\xa0years. Reported outcomes across the RCTs varied and included function, revision, osteolysis (bone reabsorption), aseptic loosening, infection, mortality, femoral fracture, dislocation, deep vein thrombosis, femoral head penetration (prosthesis movement) and quality of life (using SF-12).\n\nFour of the RCTs compared THRs with different fixation methods. Of these, 2 compared cemented with cementless cup fixation, 1 compared cemented with cementless femoral stem fixation and 1 compared cemented with cementless cup and femoral stem fixation. The Assessment Group reported that cemented cups had a lower risk of dislocation compared with cementless cups; its pooled estimate of the odds ratio for the 2\xa0RCTs was 0.34 (95%\xa0CI 0.13 to 0.89). The Assessment Group found no other differences between the fixation methods.\n\nSix of the RCTs compared THR prostheses with different bearing surfaces, comparing: cross-linked polyethylene with non-cross-linked polyethylene cup liners (2\xa0RCTs); oxinium with cobalt-chromium femoral heads (1\xa0RCT); ceramic-on-ceramic with metal-on-polyethylene femoral head on cup liners (1\xa0RCT); ceramic-on-ceramic with ceramic-on-polyethylene femoral head on cup liners (1\xa0RCT); and steel-on-polyethylene with cobalt-chromium on cross-linked polyethylene and with cobalt-chromium-on-polyethylene femoral head on cup liners. One RCT with 10\xa0years' follow-up, which assessed revision rates, found that THR prostheses with cross-linked polyethylene cup liners had lower revision rates than THRs with non-cross-linked polyethylene cup liners (RR\xa00.18, 95%\xa0CI 0.04 to 0.78). One RCT with 10\xa0years' follow-up found that there was a lower risk of osteolysis with a ceramic-on-ceramic head on cup liner bearing surface than a metal-on-polyethylene femoral head on cup liner bearing surface (RR\xa00.10, 95%\xa0CI 0.02 to 0.32). One RCT with 2\xa0years' follow-up found that steel-on-polyethylene and cobalt-chromium on cross-linked polyethylene femoral head on cup liner bearing surfaces both had a lower rate of femoral head penetration than cobalt-chromium-on-polyethylene or oxinium-on-polyethylene femoral head on cup liner bearing surfaces (p<0.001). There were no other differences reported in the RCTs that assessed THRs with different bearing surfaces.\n\nThe Assessment Group reported results from 4\xa0other RCTs that compared different types of THR. One RCT compared THRs with different cup shell designs (porous coated cups compared with arc-deposited hydroxyapatite coated cups). One RCT compared THRs with femoral stems made from cobalt-chromium or titanium. One RCT compared femoral stems with a short metaphyseal fitting with conventional metaphyseal and diaphyseal filling. One RCT compared THRs using a 36-mm femoral head with THRs using a 28-mm femoral head. The Assessment Group reported that the RCT comparing different femoral head sizes found a decreased risk of dislocation associated with 36-mm femoral heads compared with 28-mm femoral heads over a 1-year follow-up (RR\xa00.17, 95%\xa0CI 0.04 to 0.78). No other conclusive differences were reported in these 4\xa0RCTs.\n\nThe primary focus of the 5\xa0systematic reviews evaluating different types of THR was the comparison of different cup fixation methods (cemented compared with cementless), and the materials used for prosthesis articulation with respect to the postoperative clinical function scores and revision rates. The Assessment Group considered most of the evidence to be inconclusive because the reviews had either reported only a narrative synthesis, or had used inappropriate pooling methods or had reported inconsistent summary findings. The only conclusive result identified by the Assessment Group was that there was no difference in the risk of revision between 2\xa0different articulations: zirconia (a type of ceramic) head-on-polyethylene cup liner compared with a non-zirconia head-on-polyethylene cup liner (pooled difference in frequency of revisions over the studies' follow-up periods was 0.02, 95%\xa0CI −0.01 to 0.06).\n\n## Systematic review of registry studies\n\nThe Assessment Group reviewed studies based on registries of THR or resurfacing arthroplasty for people with end-stage arthritis of the hip. It identified 30\xa0studies from a number of countries, which reported different outcomes, had different durations of follow-up, and made different comparisons.\n\nThe Assessment Group identified 8\xa0registry studies reporting on resurfacing arthroplasty. An analysis of the NJR in England and Wales showed that women had a 30% greater risk of revision with resurfacing than men (hazard ratio [HR] 1.30, 99%\xa0CI 1.01 to 1.76). Three of the 4 that compared revision rates between resurfacing arthroplasty and THR found that resurfacing arthroplasty had a higher revision rate than THR. A further analysis of the NJR showed that, although in women resurfacing always had higher revision rates than THR, in men resurfacing arthroplasty prostheses with a larger head size (54\xa0mm) had similar predicted 5-year revision rates to THR prostheses. One study suggested that the risk of revision with resurfacing arthroplasty varied by country, and another study demonstrated lower revision rates in specialist compared with non-specialist centres.\n\nThe Assessment Group identified 22\xa0registry studies that reported only on THR and that presented analyses of either trends in revision rates or comparisons of revision rates across different types of THR. One study using NJR data from England and Wales (Smith et al. 2012) and 1 using combined data from registries from England, Wales, Australia and New Zealand assessed whether there was an association between femoral head size and revision rates for THR; the studies demonstrated that the relationship was dependent on bearing surface. Both studies showed that the revision rate for MoM THR increased as the femoral head size increased. Conversely, for bearing surfaces other than MoM, a large femoral head size was associated with a lower risk of revision compared with smaller femoral heads. One study (an analysis of the NJR by McMinn et al. 2012) showed, at a maximum of 8\xa0years' follow-up, a higher mortality rate for patients having cemented compared with cementless THR (adjusted HR\xa01.11, 95%\xa0CI 1.07 to 1.16).\n\nThe Assessment Group noted that, of the registries of joint replacement worldwide, the Swedish registry is the oldest. The Assessment Group presented data on revision rates using up to 19\xa0years of follow-up from the Swedish registry for THR and resurfacing arthroplasty grouped together, but noted that these revision rates may include devices and practices no longer in use. The data suggested that revision rates depended on a patient's age at primary surgery. At a maximum of 19\xa0years' follow-up, for people younger than 50\xa0years at primary surgery, 39.8% of women and 37.4% of men had a revision; for people aged between 50 and 59\xa0years, 26.3% of women and 32.8% of men had a revision; for people aged between 60 and 75\xa0years, 12.8% of women and 19.5% of men had a revision; and for people over 75\xa0years, 5.2% of women and 7.9% of men had a revision.\n\n## Retrospective cohort analysis of individual patient data from the National Joint Registry\n\nThe Assessment Group performed a retrospective cohort analysis of the NJR to estimate revision rates for the different types of prostheses for both populations in the final scope issued by NICE (that is, people for whom both resurfacing arthroplasty and THR were suitable and people for whom only THR was suitable). The Assessment Group obtained individual patient data from the NJR that included data from 2003 to September 2012 and for operations carried out in the NHS and in private practice.\n\nThe final scope issued by NICE stipulated that different types of hip replacements should be considered separately, if evidence allows. The Assessment Group, advised by its clinical adviser, grouped the types of most commonly used THR into 7\xa0categories. Of these, it selected the 4 most frequently used combinations and a further combination of a cemented stem with a ceramic head articulating with a cemented polyethylene cup. These 5\xa0categories of THR prosthesis accounted for 62% of THRs in the NJR with available data. The categories were:\n\ncategory A: cemented polyethylene cup with a metal head (cemented stem)\n\ncategory B: cementless hydroxyapatite coated metal cup (with a polyethylene liner) with a metal head\n\ncategory C: cementless hydroxyapatite coated metal cup (with a polyethylene liner) with a ceramic head\n\ncategory D: cementless hydroxyapatite coated metal cup (with a polyethylene liner) with a metal head (cemented stem)\n\ncategory E: cemented polyethylene cup with a ceramic head (cemented stem).\n\nThe Assessment Group addressed the population for whom either resurfacing arthroplasty or THR was suitable. It noted that NICE technology appraisal guidance\xa044 recommended resurfacing arthroplasty for people who would otherwise receive and outlive a conventional primary THR. This population primarily consisted of people younger than 65\xa0years. The Assessment Group also stated that clinical opinion holds that clinicians offer resurfacing arthroplasty mainly to relatively active younger people, while THR is the usual option for less active older people. The Assessment Group noted that the NJR data did not include data on activity levels. In the absence of data on activity levels, the Assessment Group determined the suitability of resurfacing arthroplasty based on age and sex, and sampled people who had had THR who shared these characteristics. The mean age of this population was 55.8\xa0years and 35% were women.\n\nThe Assessment Group addressed the population for whom resurfacing arthroplasty was not suitable. The Assessment Group noted that most people who had THR documented in the NJR were older than 65\xa0years but considered that, because there had been high revision rates after resurfacing arthroplasty, in the future fewer younger people may be considered as candidates for both procedures. As a result, the Assessment Group considered that the population for whom resurfacing arthroplasty was not suitable could be assumed to match the population who had THR documented in the NJR. The mean age of this population was 71.6\xa0years and 64% were women.\n\nThe Assessment Group analysed revision rates using the available data from the NJR (maximum follow-up of 9\xa0years) using Kaplan–Meier estimates. For the population for whom both resurfacing arthroplasty and THR were suitable, the population was matched by age and sex. For the population for whom resurfacing was not suitable, the population was not matched by age and sex and the Kaplan–Meier estimates were not adjusted for these characteristics. The Assessment Group found that, consistent with previous published analyses of the NJR, the revision rate for resurfacing arthroplasty over 9\xa0years of follow-up was about 3\xa0times higher than for all the types of THR prostheses recorded in the NJR. The difference was even larger when comparing resurfacing arthroplasty with THR restricted to the 5\xa0commonly used THR combinations (prosthesis categories A to E; see section\xa04.1.17). The Assessment Group presented data on revision rates for men and women separately. Revision rates for resurfacing arthroplasty unadjusted for age were higher for women (18% at 9\xa0years) than for men (7% at 9\xa0years). The Assessment Group performed additional analyses in which it excluded data from the 8.8% of people who had the now-recalled DePuy ASR resurfacing prosthesis. Although this lowered the revision rate for resurfacing arthroplasty slightly, the difference between the revision rates for resurfacing arthroplasty and THR remained large.\n\nThe Assessment Group assessed the time to revision for the 5\xa0categories of THR (A to E) separately. The Assessment Group noted that the revision rates for the cementless prostheses (category\xa0C) were higher than for the cemented prostheses (category\xa0E and category\xa0A). The Assessment Group noted that revision of each category of prosthesis appeared to occur more frequently for men who had any of the prostheses in these 5\xa0categories than for women.\n\nTo extrapolate revision rates beyond the up-to-9-year data in the NJR, the Assessment Group assessed the fit of various parametric models to the Kaplan–Meier analyses. The Assessment Group noted that, while the bathtub and log-normal models appear to fit the Kaplan–Meier values of revision, after extrapolation these models generated different revision rates. The Assessment Group noted an increasing risk of revision over time with the bathtub model and a decreasing risk of revision over time with the log-normal model. The Assessment Group considered that whether a person underwent revision surgery or not depended both on why the prosthesis had failed and on a person's suitability for revision surgery. The Assessment Group concluded that, for younger people, the risk of needing a revision would increase over time (because the risk of outliving the prosthesis would increase) and that, for older people, the risks of revision would decrease over time (because the risks of revision surgery might outweigh the benefits). The Assessment Group further concluded that, in active people, prostheses would be more likely to wear out and need revision. The Assessment Group used the bathtub model in its base case and the log-normal model in its sensitivity analyses of revision rates in people who were over 65\xa0years when they had their THR.\n\nFor the population for whom both resurfacing arthroplasty and THR were suitable, the bathtub model predicted revision rates at 10\xa0years of 17.2% and 4.6% for resurfacing arthroplasty and THR respectively, and at 20\xa0years of 48.3% and 12.9% respectively. For the population for whom resurfacing arthroplasty was not suitable, the bathtub model predicted revision rates (unadjusted for age and sex) at 10\xa0years of 2.8% for category\xa0A prostheses, 3.9% for category\xa0B, 4.6% for category\xa0C, 3.0% for category\xa0D and 2.1% for category\xa0E. The model predicted revision rates at 20\xa0years ranging from 5.2% for category\xa0E to 12.3% for category\xa0C. The Assessment Group repeated its analysis for the population for whom resurfacing was not suitable, adjusting the bathtub model for age and sex. It found that the relative revision rates across all 5\xa0prosthesis categories were maintained after this adjustment.\n\nFor the population for whom both resurfacing arthroplasty and THR were suitable, the Assessment Group predicted revision rates separately for women and men unadjusted for age. In people who had resurfacing arthroplasty, women had higher predicted revision rates at 10-, 20- and 30-year follow‑up than men. The estimated 10-year revision rates with resurfacing arthroplasty were 23.1% for women and 12.4% for men.\n\nIn the population for whom resurfacing arthroplasty was not suitable, the Assessment Group explored a scenario in which the revision rate in people over 65\xa0years who had THR decreased over time (see section\xa04.1.22). Using a log-normal distribution and stratifying by sex, the Assessment Group observed lower predicted revision rates compared with the bathtub model. The Assessment Group presented estimates of revision for the mean age in each category. For men over 65\xa0years, the 10-year modelled revision rates for the 5\xa0THR categories ranged from 1.9% (category\xa0E) to 3.9% (category\xa0C). For women aged over 65\xa0years, the modelled 10-year revision rates for the 5\xa0THR categories ranged from 1.4% (category\xa0E) to 2.8% (category\xa0B).\n\nThe Assessment Group stated that a new rate, setting a standard revision rate for prostheses lower than that of the current standard of less than 10% at 10\xa0years, is appropriate (see section\xa03.6). The Assessment Group noted that most THR prostheses currently meet this standard, but that most resurfacing arthroplasty prostheses do not.\n\n## Manufacturer's clinical-effectiveness evidence\n\nNICE received submissions from 4\xa0manufacturers (DePuy Synthes, JRI, Smith & Nephew and Stryker). The Assessment Group critiqued the submissions and noted that 1 of the 4\xa0manufacturers had performed a systematic review of clinical effectiveness of resurfacing arthroplasty and THR, and that the other 3\xa0manufacturers had provided a narrative review.\n\nThe manufacturers commented on the difficulties with categorising different types of THR. In particular, 3\xa0manufacturers noted variability in how well different prostheses perform within a category and that some individual manufacturer's brands may have lower revision rates than is typical of their category as a whole. One manufacturer commented that the 7-year revision rates for the 4\xa0most commonly used cementless prostheses range from 2.6% to 4.1%. Another manufacturer noted that data from the NJR showed that its own resurfacing arthroplasty prosthesis, the Birmingham hip resurfacing system, had a revision rate at 7\xa0years that was consistent with the NICE 10% at 10\xa0years standard (it had a revision rate of 5.1%, 95%\xa0CI 4.6 to 5.6). Two manufacturers further stated that categorising by fixation method only may not capture the differences in revision rates that have been seen with different bearing surfaces.\n\nSeveral manufacturers highlighted that the NJR data may not be sufficiently mature to capture changes in risk with different hip prostheses over time. The manufacturers noted that the NJR, the Swedish registry and the Australian registry all showed lower revision rates with cemented prostheses than cementless prostheses in the shorter term after primary surgery, but suggested that this trend may not be maintained if people in the NJR are followed up for longer. The manufacturers highlighted that, after 8\xa0years, the Swedish data showed the risk of revision was higher with cemented than cementless prostheses and, after 6\xa0years, the Australian data showed that cemented THR had a higher revision rate than cementless THR.\n\n# Cost effectiveness\n\n## Assessment Group's economic model\n\nThe Assessment Group developed a Markov model based on the model described by Fitzpatrick et al. (1998), which it adapted to address the decision problem and updated with new data. The model had 4\xa0health states and the cycle length was 1\xa0year. Discounting of 3.5% was applied to both costs and outcomes. The analysis was from the perspective of the NHS and personal social services. The Assessment Group reported results for both a lifetime (80\xa0years) and a 10-year time horizon.\n\nTwo simulated cohorts entered the model, one of people for whom resurfacing was suitable, reflected by people in England and Wales who underwent resurfacing arthroplasty between 2003 and 2012 (age and sex matched with people who had THR categories A–E; see section\xa04.1.18); and the other of people for whom resurfacing arthroplasty was not suitable, represented by people in England and Wales who had THR categories A–E between 2003 and 2012 (see section\xa04.1.19).\n\nPeople entered the model at the point of their primary procedure (resurfacing arthroplasty or THR) and moved either to the 'successful primary' health state (that is, after successful initial primary surgery) or death. If primary hip replacement failed, people who needed revision moved to the 'revision total hip replacement state', received a THR (rather than resurfacing arthroplasty) and stayed in that state for 1\xa0cycle (1\xa0year). If revision was successful, people moved to the 'successful revision health state'. People in the model could have multiple revisions. The Assessment Group assumed that all sequelae of THR (surgical mortality after primary THR, revision THR or re-revision THR; risk of re-revision) occurred at the beginning of a cycle, and that mortality not related to hip replacement occurred at the end of a cycle.\n\nThe transition probability between successful primary surgery and revision THR was based on the revision rates calculated and extrapolated from the NJR data. The Assessment Group based the transition probability between successful revision and further revision THR on the New Zealand Joint Registry (risk of re-revision per procedure 0.0326). The Assessment Group assumed that mortality associated with surgery was 0.5% per procedure (based on the NJR annual report 2012) and used data from the Office for National Statistics on death rates in England and Wales to determine all-cause mortality by age.\n\nTo determine the utility associated with each health state, the Assessment Group used the NJR Patient Reported Outcomes Measures (PROMS) database, which reported EQ-5D-3L data post operation by age and sex for the year 2010/2011. The utility values applied in the 'successful primary' health state were 0.726 for people aged between 40 and 50\xa0years; 0.753 for people aged between 50 and 60\xa0years, 0.779 for people aged between 60 and 70\xa0years, 0.764 for people aged between 70 and 80\xa0years, and 0.721 for people aged between 80 and 90\xa0years. The Assessment Group adjusted the utility values for the increasing age of the cohort after every 10\xa0cycles of the model. The Assessment Group assumed that the utility values for people in the 'successful primary health state' were equivalent for people who had resurfacing arthroplasty or THR. The utility value in the 'revision THR health state' was 0.5624 and did not differ by type of THR, age or sex. The Assessment Group assumed that the utility value for a successful revision was the same as for successful primary surgery.\n\nCosts in the model included the costs of the surgery, prostheses, hospitalisation and follow-up. The Assessment Group assumed that the cost of surgery was the same for both THR and resurfacing arthroplasty, and included the cost of theatre overheads, theatre staff and X-rays. The costs were based on Vale et al. (2002), but were updated to 2011/2012 prices using the projected health service cost index. The overall cost of surgery per patient was £2805.\n\nThe Assessment Group obtained the costs of prostheses from the NHS supply chain (see section\xa03.8). To compare resurfacing arthroplasty with THR for people for whom resurfacing arthroplasty is suitable, the Assessment Group combined the 5\xa0categories of THR prostheses (see section\xa04.1.17) and generated a weighted average cost based on the frequency of use (from NJR data) of £2571 for THR categories A to E combined. Cemented prostheses needed an additional cost for cement and its preparation (£203.10 for prostheses in which both the stem and cup need cementing and £163.90 for prostheses in which only the stem needs cementing).\n\nThe Assessment Group derived postoperative hospital costs from Edlin et al. (2012), an RCT that reported the costs of resurfacing arthroplasty and THR over 1\xa0year. The Assessment Group estimated the average cost per day of a hospital stay at £296. People who had resurfacing arthroplasty stayed an average of 5.5\xa0days and people who had a THR stayed an average of 5.7\xa0days, resulting in an overall cost for hospital stays of £1628 for resurfacing arthroplasty and £1687 for THR. Edlin et al. also provided outpatient costs for follow-up after primary THR or resurfacing arthroplasty. The costs over the first 12\xa0months of outpatient care, primary and community care, aids and adaptions provided by the NHS, pain relief and other medications, adjusted for inflation from 2009/2010 to 2011/2012 prices, totalled £501 for resurfacing arthroplasty and £394 for THR. The Assessment Group applied follow-up costs for all consecutive years for the lifetime of the model.\n\nThe Assessment Group assumed that the costs of revision were the same for THR and resurfacing arthroplasty but depend on the reason for revision (Vanhegan et al. 2012). For example, surgery for infection and peri-prosthetic fracture resulted in longer operating times and lengths of stay than other reasons for revision. Vanhegan et al. reported costs of revision including the costs of the prostheses, materials, theatre, recovery room, inpatient physiotherapy, occupational therapy, pharmacy, radiology and laboratory, with costs based on the NHS 2007/2008 Payment by Results. The Assessment Group adjusted these costs for inflation to 2011/2012 prices by using the projected health service cost index. To derive the 'weighted average cost of revision' of £16,517, the Assessment Group weighted the mean cost of revision for aseptic loosening, deep infection, peri-prosthetic fracture and dislocation by the number of people who had experienced each of these problems in Vanhegan et al. The Assessment Group applied the follow-up costs from Edlin et al. (£394; see section\xa04.2.8) to the successful revision health state.\n\nFor the population for whom resurfacing arthroplasty and THR were both suitable, the Assessment Group presented deterministic and probabilistic analyses for both a 10-year and a lifetime time horizon. In both the deterministic and probabilistic base case, THR dominated resurfacing arthroplasty (that is, it was less costly and more effective) over both the 10-year and the lifetime time horizons.\n\nFor the population for whom resurfacing arthroplasty was not suitable, the Assessment Group presented deterministic and probabilistic analyses for both a 10-year and a lifetime time horizon. For a lifetime time horizon, the deterministic incremental analysis showed that THR category\xa0E dominated all of the other THR categories. The Assessment Group commented that the difference in quality-adjusted life years (QALYs) was negligible between THR categories A to E (a difference of 0.0064 between the most effective prosthesis category [E] and the least effective prosthesis category [C] in the lifetime deterministic analysis) and that the probabilistic analyses of costs and effectiveness showed that total costs and total QALYs of all categories overlapped.\n\nThe Assessment Group performed 3\xa0scenario analyses for the population for whom resurfacing arthroplasty and THR were suitable. One scenario analysis tested assumptions used to determine time to revision, and 2\xa0scenarios tested assumptions on the costs of the prostheses. For both the 10-year and lifetime time horizons, all scenario analyses had a minimal effect on incremental costs and QALYs, and the results were consistent with the base case because THR continued to dominate resurfacing arthroplasty.\n\nThe Assessment Group performed 7\xa0sensitivity analyses for the population for whom resurfacing arthroplasty was not suitable. Three tested the assumptions used to extrapolate time to revision (including adjusting the analysis for age and sex), 3\xa0tested assumptions on the costs of the prostheses, and 1\xa0tested assumptions on the source of utility values for the successful primary and successful revision health states. The Assessment Group presented results for a 10-year and a lifetime time horizon. For a lifetime time horizon, THR category\xa0E continued to dominate all other categories in the following sensitivity analyses: time to revision (bathtub model controlled for age and sex); all 3\xa0cost sensitivity analyses (unadjusted for age and sex with the highest and lowest costs of THR or a 20% discount applied to each prosthesis category); and postoperative utility values (taken from a Swedish cohort study rather than from NJR PROMS data). For the 2\xa0scenarios in which the Assessment Group used the log-normal (rather than the bathtub) model to extrapolate long-term revision rates (1 in which the log‑normal model was adjusted for age and sex and 1 in which the model was unadjusted for these characteristics), THR category\xa0E was more costly and more effective than category\xa0A in the lifetime time horizon (deterministic incremental cost-effectiveness ratio [ICER] £442,830 per QALY gained for the unadjusted model; deterministic ICER £227,031 per QALY gained for the log-normal model adjusted for age and gender). In these log-normal model scenario analyses, THR categories D, B and C continued to be dominated by category\xa0E in both the deterministic and probabilistic results.\n\nThe Assessment Group performed subgroup analyses for men and women by age for whom resurfacing arthroplasty was suitable. The Assessment Group presented results for each sex stratified by 3\xa0discrete ages, applying a weighting to the modelled revision rates for these subgroups for ages 40, 50 and 60\xa0years. For all ages and in both men and women, THR dominated resurfacing arthroplasty over both the 10-year and lifetime time horizons.\n\nFor people for whom resurfacing arthroplasty was not suitable, the Assessment Group presented results for 4\xa0subgroups (men and women under 65\xa0years, and men and women aged over 65\xa0years). For men and women under 65\xa0years, it presented the results for people aged 40, 50 and 60\xa0years separately. For men and women over 65\xa0years, it presented the results for people aged 70 and 80\xa0years separately. For men and women under 65\xa0years, the Assessment Group used the bathtub modelled revision rates and, for men and women over 65\xa0years, the Assessment Group used the log-normal modelled revision rates. At a lifetime time horizon for men and women aged 70 and 80\xa0years, THR category\xa0E was more costly and more effective (QALY difference ranged from 0.0001 and 0.0002) than category\xa0A, and dominated categories D, B and C. For women under 65\xa0years, all other categories were dominated by category\xa0E. For men aged 40\xa0years, all other categories were dominated by category\xa0A. In men aged 50 or 60\xa0years, category\xa0E was more costly and more effective than category\xa0A and dominated categories D, C and B over the lifetime time horizon.\n\n## Manufacturer's economic model\n\nOnly 1 manufacturer (DePuy Synthes) that made a submission for the appraisal included an economic model.\n\nDePuy Synthes developed a transition-state Markov model that had 3\xa0monthly cycles and a lifetime horizon (all patients were assumed to have died by age 100\xa0years). Costs and outcomes were discounted at 3.5%. The health states in the model were the same as those in the Assessment Group's model (see section\xa04.2.3), but the model allowed each patient a maximum of 4\xa0surgical revisions.\n\nIn the DePuy Synthes model, the populations in the final scope issued by NICE were defined based on the patient characteristics of people in the NJR. The population for whom both resurfacing arthroplasty and THR were suitable was the population in the NJR who had resurfacing arthroplasty. The mean age in this population was 55.3\xa0years and 70.9% were men. The population for whom resurfacing arthroplasty was not suitable was patients in the NJR who had THR. The mean age of this population was 70.4\xa0years and 37.5% were men.\n\nFor both populations, DePuy Synthes compared different types of THR prostheses based on methods of fixation comparing cemented, cementless, hybrid and reverse hybrid. It also assessed 2 of its own brands (1\xa0cemented and 1\xa0cementless). DePuy Synthes excluded MoM THR from its analyses, stating that THR using these bearing surfaces are no longer commercially available.\n\nDePuy Synthes used individual patient data from the NJR, including data for its own prosthesis brands grouped separately to estimate revision rates for up to 8\xa0years' follow-up. It excluded incomplete entries and those in which osteoarthritis of the hip was not the indication for surgery. DePuy Synthes stated that previous models of revision had fitted different parametric distributions to the periods early and later after surgery, and separately categorised the causes of earlier or later revision. Reasons for early revision included dislocation, mismatch, infection, incorrect sizing and malalignment. Reasons for later revision included fracture of the prosthesis, lysis, pain, acetabular wear, dissociation of the liner, soft tissue reaction and 'other'. DePuy Synthes assessed models that would fit early revisions, late revisions and both combined. It used a Weibull model with a decreasing hazard over time, which it considered realistic for most prosthesis types with the possible exception of cemented prostheses because data from the Australian registry had shown that the risk of revision with cemented prostheses increases over time.\n\nDePuy Synthes based the rate of re-revision (revision subsequent to a first revision) on the New Zealand Joint Registry data (rate 0.0331 per year; 0.0083 per cycle). People stayed in the THR revision/re-revision health state for 1\xa0cycle. The model allowed people to have up to 2\xa0interventions in the same cycle. DePuy Synthes assumed that all people would receive the same type of prosthesis in revision surgery. DePuy Synthes assumed that mortality associated with surgery did not differ by type of prosthesis (0.5% per procedure), and applied an age- and sex-adjusted all-cause mortality rate.\n\nThe model included the costs of both prostheses and surgery. DePuy Synthes obtained the costs of the prostheses from its own list prices and assumed equal costs for resurfacing arthroplasty and cemented THR. The total prosthesis costs were: cemented THR £1029.00; cementless £2550.50; hybrid £2011.50; and reverse hybrid £1568.00. For the group 'all THR', the manufacturer used a weighted cost (40% cemented, 40% cementless, 17% hybrid, 2% reverse hybrid). DePuy Synthes obtained surgical costs from a micro-costing study that included the costs of anaesthetics, surgical consumables, staff and theatre time. These costs differed across prosthesis type and are academic in confidence. The manufacturer based length of stay on NHS reference costs.\n\nDePuy Synthes did not model surgical and post-surgical complications, stating that the average cost and health-related quality of life reflected complications during surgery, and estimates of the risk of revision included complications that occurred after surgery.\n\nThe manufacturer assumed that the cost of revision was £13,399.42 (which was double the mean cost of the primary procedure). However, unlike the Assessment Group, DePuy Synthes assumed that the cost of revision did not depend on the reason for revision.\n\nDePuy Synthes performed a systematic review to identify utility values. For its base case, DePuy Synthes used utility values from Rolfson et al. (2011, Swedish registry). The preoperative utility value was 0.41, and the postoperative utility value was 0.78. It applied a disutility of 0.145 (Briggs et al. 2003) to the postoperative utility value after revision to reflect the lower quality of life associated with a subsequent surgical intervention.\n\nIn the DePuy Synthes base case for the population for whom both resurfacing arthroplasty and THR were suitable, THR (all types combined) dominated resurfacing arthroplasty. The total incremental cost of resurfacing arthroplasty was £2504.31 for 0.106 fewer QALYs. An incremental analysis calculated using the results for cemented, cementless, hybrid, reverse hybrid and resurfacing prosthesis categories, but excluding DePuy Synthes' own brands (because the costs and QALYs were marked as commercial in confidence and cannot be reported), showed that cemented prostheses dominated both cementless THR and resurfacing arthroplasty. Reverse hybrid prostheses were shown to be extendedly dominated (that is, were dominated by the combination of cemented and hybrid prostheses). The ICER for hybrid prostheses compared with cemented prostheses was £26,636 per QALY gained.\n\nFor the population for whom resurfacing arthroplasty was not suitable, DePuy Synthes presented an incremental analysis of the results for cemented, reverse hybrid and cementless hybrid prostheses alongside the results for 2 of its own products and all THR prostheses combined. The results of the incremental analysis for the THR prosthesis categories only showed that cemented prostheses dominated reverse hybrid and cementless prostheses (the results for the manufacturer's own products cannot be reported here because the costs and QALYs are commercial in confidence) The ICER for hybrid prostheses compared with cemented prostheses was £259,667 per QALY gained. The manufacturer noted that the range of QALYs generated by the probabilistic analysis from 10,000\xa0simulations overlapped substantially between the THR prosthesis categories, and concluded that all categories of THR are associated with a similar number of QALYs.\n\nDePuy Synthes conducted a number of one-way sensitivity analyses for the population for whom both resurfacing arthroplasty and THR were suitable. It presented the results in net monetary benefit, assuming a maximum acceptable ICER of £20,000 per QALY gained. There was a positive net monetary benefit associated with THR for all parameter values tested. This meant that THR is cost effective compared with resurfacing arthroplasty, given a maximum acceptable ICER of £20,000 per QALY gained. The most influential parameters were the cost of revision, the utility decrement associated with revision, and resource use items such as the cost of follow-up appointments, the overhead cost per theatre hour and the individual costs of prostheses components. DePuy Synthes also conducted sensitivity analyses for both the population for whom resurfacing arthroplasty and THR were suitable and for the population for whom resurfacing arthroplasty was not suitable, including: using NHS reference costs rather than costs from the micro-costing study; using EQ-5D from the NJR rather than the Swedish registry data; using an exponential rather than a Weibull model to extrapolate revision rate data; and stratifying the population to include people under 70\xa0years or under 55\xa0years. In all scenarios for both populations, the impact on total costs and total QALYs were minimal.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of THR and hip resurfacing arthroplasty for people with end-stage arthritis of the hip for whom non-surgical management has failed. It considered evidence on the nature of surgery for the treatment of pain and disability, and the value placed on the benefits of THR and resurfacing arthroplasty by people needing surgery. It also took into account the effective use of NHS resources.\n\nThe Committee considered the care pathway for people with end-stage arthritis of the hip and the potential place of THR and resurfacing arthroplasty. The Committee discussed the factors that clinicians take into account when deciding whether to offer a THR or resurfacing arthroplasty to individual patients. The Committee heard from the Assessment Group's clinical adviser that the use of resurfacing prostheses has declined over the past few years, noting the Medicines and Healthcare products Regulatory Agency's alerts to recall some resurfacing prostheses and to monitor patients with MoM prostheses. The Committee heard that, after any type of hip replacement, some people need revision surgery to replace the primary prosthesis, and that being younger or more active can increase a person's risk of needing revision surgery. The Committee heard that clinicians take into account a person's risk of needing revision surgery when deciding whether to offer resurfacing arthroplasty or THR, and that clinicians in general consider resurfacing arthroplasty more suitable for younger and more active people. The Committee further heard that clinicians may be more likely to offer resurfacing arthroplasty to men than to women because higher revision rates have been observed in women, which may be associated with women tending to have smaller hips. The Assessment Group's clinical adviser also explained that, because older patients have shorter life expectancies than younger patients, they are less likely to need revision, and that clinicians tend to offer older patients THR. The Committee concluded that both THR and resurfacing arthroplasty are options for treatment of end-stage arthritis of the hip, and that clinicians consider together with patients the factors associated with the risk of revision when choosing the most appropriate procedure.\n\nHaving considered which type of prosthesis would be appropriate (THR or resurfacing arthroplasty), the Committee then considered the choice of a given prosthesis, noting that prostheses vary in materials and fixation methods. The Committee heard that the operating surgeon generally chooses the type of prosthesis, taking into consideration those that achieve the recommended standard revision rate as provided by the Orthopaedic Data Evaluation Panel (ODEP). The Committee heard that surgeons need specific training for each class of prosthesis (for example, cemented or cementless THR), but that most orthopaedic surgeons in the UK are trained to use both cemented and cementless prostheses. The Committee further heard that an orthopaedic centre's experience and clinical data for individual prostheses further influence the choice of prosthesis. The Committee noted that the NJR contained data for hip replacements carried out in the NHS and in private practice, but heard that the prostheses used in the 2 healthcare sectors were not expected to differ because the same surgeons work in both the NHS and in private practice. The Committee considered whether surgeons offer cemented prostheses and cementless prostheses to different patients, and heard from the manufacturers and the Assessment Group's clinical adviser that there were no specific groups of patients for whom cemented or cementless prostheses would be specifically indicated. The Assessment Group's clinical adviser explained that a patient's age, sex and activity levels may influence a surgeon's choice of bearing surface for THR. The Committee understood that surgeons tend to choose not only the type but also the brand of hip prosthesis a patient receives, and that this is driven by factors including the surgeon's training, perception of which prostheses perform best, clinical data and experience using different prostheses, among other factors.\n\nThe Committee heard from the Assessment Group's clinical adviser that revision surgery is more complex and associated with greater risks than primary THR or resurfacing arthroplasty. It heard from the clinical specialist that patients may need to be referred to a specialist centre for revision surgery. The Committee discussed whether any particular type of THR or resurfacing prosthesis reduced the complexity of subsequent revision surgery, and heard that resurfacing prostheses tended to be easier to replace than THR prostheses, but that the risks associated with surgery to the patients were similar. The Assessment Group's clinical adviser stated that a patient's operative and peri-operative risk depends on why the primary prosthesis failed (for example, infection or fracture) rather than the type of prosthesis, or whether it is cemented or cementless. The Committee recognised that revision surgery is more complicated than primary surgery and concluded that the complexity of the revision surgery is primarily determined by why the primary hip replacement failed.\n\nThe Committee considered the clinical evidence available for this appraisal. It noted that the Assessment Group presented evidence from RCTs, systematic reviews, published registry studies and its analysis of data from the NJR, and discussed the relevance of each source to its decision making. The Committee noted the Assessment Group's concerns that the RCTs and systematic reviews it had identified involved small numbers of patients, had relatively short follow-up, reported different outcomes either incompletely or poorly, and were underpowered to detect differences in rates of revision. The Committee accepted that, because of these concerns, it was appropriate that the Assessment Group chose not to meta-analyse the RCTs. The Committee then considered data from registries. It noted that the Assessment Group's retrospective analysis of the NJR provided a record of the revision rates for all types of prostheses used in England and Wales since 2003, and as such provided long-term data generalisable to UK clinical practice. The Committee was aware that, although it is mandatory for NHS organisations to submit data to the NJR, when the registry first started clinicians provided data voluntarily, and that the registry may have missed some procedures that were carried out at the time. The Committee noted that the registry did not provide data on outcomes listed in the scope other than revision, and that it did not provide data on differences in the patient characteristics (for example, activity levels and comorbidities) that might affect both device choice and the risk for revision, causing confounding. The Committee noted the comments received on the appraisal consultation document, stating that there is a problem with an accurate link between the NJR data and Hospital Episode Statistics data, and that data on revision rates from the NJR had not been validated. The Committee concluded that it was appropriate to use both trial and observational data in its decision making, but that uncertainty resulting from the possibility of confounding should be taken into account. The Committee agreed that, although the NJR data had limitations, they are the most comprehensive data reflecting clinical practice in the NHS and therefore the most appropriate for decision making.\n\nThe Committee considered the population for whom both procedures are suitable, and the population for whom resurfacing arthroplasty is not suitable. The Committee discussed the Assessment Group's analysis of revision rates of different types of hip replacement in both populations using the NJR data, and whether it had controlled for bias by confounding. The Committee noted that the Assessment Group had controlled for patient age and sex when comparing resurfacing arthroplasty with THR and when comparing different types of THR (in a sensitivity analysis [see section\xa04.1.23]). The Committee also noted that the Assessment Group's analysis of the NJR in revision after resurfacing arthroplasty compared with THR was consistent with effect measures from RCTs and systematic reviews (see section\xa04.1.20). The Committee had heard that activity levels influence the choice of whether a person would be offered resurfacing arthroplasty, or which bearing surface of a THR is chosen, and would also affect the rate of wear of a prosthesis (see sections\xa04.3.2 and 4.3.3), but that the NJR did not contain data on activity. The Committee discussed whether having resurfacing arthroplasty rather than THR would allow people to be more active after their surgery. They heard from the Assessment Group's clinical specialist that observational studies had shown that people were more active after resurfacing arthroplasty than after THR, but were likely to have been more active before resurfacing arthroplasty compared with people who underwent THR, and that 1\xa0RCT showed no difference in activity levels after surgery in people randomised to resurfacing arthroplasty or to THR. The Committee agreed that there was uncertainty around whether the difference in revision rates between THR and resurfacing arthroplasty could just be attributed to risk of failure of the prostheses because it is likely that people who have resurfacing are more active than people who have THR and higher activity may cause accelerated wear of a prosthesis. The Committee also heard that comorbidities may influence which type of prosthesis a patient receives and whether or not a patient is offered revision surgery. The Committee concluded that the Assessment Group's analysis of revision rates was consistent with published systematic reviews of trials, and controlled for some, but not all, potential confounders, notably activity level and comorbidities, and therefore uncertainty remained surrounding the relative revision rates between different types of prostheses.\n\nThe Committee considered whether data on revision surgery in the Assessment Group's NJR data set could be considered a proxy for prosthesis failure. The Committee noted that the NJR captured revision rates, but not failure rates of the prostheses, and that some people need revision surgery for pain only (without the prosthesis failing). The Committee further noted that there are people who need a revision because their prosthesis has failed, but who are not fit enough to have surgery or who choose not to have surgery. The Committee appreciated that, in these people, the NJR data on revision rates may underestimate the true failure rate. After consultation on the appraisal consultation document, the Committee further considered revisions that result from prostheses failing and revisions that result from complications during surgery or errors in prosthesis insertion (early revision). The Committee heard from the manufacturers that they expected the proportions of revisions not directly related to device failures to be similar across classes of hip replacement prostheses. The Committee noted a comment received from a manufacturer during consultation stating that early failures associated with dislocation were the fault of the surgeon, but the Committee had no further evidence to support this conclusion. The Committee appreciated that the underlying reason for why a patient needed revision surgery may be difficult to identify and is not routinely recorded in the NJR. In addition, the Committee was told that there is no system that collects data about the prevalence of people living with a failed prosthesis who are unable to, or choose not to, have revision surgery, and no representative data on the proportion of revisions that are a result of failing prostheses. The Committee accepted that, while revision rates may not fully reflect prosthesis failure, revision was an important outcome both from the patient's perspective and in terms of costs and the resources needed.\n\nThe Committee considered the approaches to modelling revision rates beyond the maximum 9\xa0years of follow-up in the NJR. It discussed the bathtub model and the log-normal model used by the Assessment Group in its base case, and sensitivity analysis, and the Weibull model used by the manufacturer in its base case. The Committee noted that the bathtub model, which it understood was widely used in manufacturing to describe device failure, assumed that risk of revision would decrease initially and then increase over time, whereas the log-normal and Weibull models assumed an increasing risk of revision over time. The Committee compared the revision rates predicted by all 3\xa0models with data from the Swedish registry, in which people aged between 60 and 75\xa0years who had a hip replacement (resurfacing arthroplasty or THR) were followed up for 19\xa0years. In the population for whom resurfacing was not suitable, the bathtub model predicted longer-term outcomes that fitted the data from the Swedish registry better than the log-normal model. The manufacturer's Weibull model did not fit the Swedish data as well as the Assessment Group's bathtub model did. The Committee noted that there was uncertainty surrounding the generalisability of the Swedish registry data to the UK population, in part because the Swedish registry was initiated earlier than the NJR. The Committee noted that the revision rates in the Swedish registry were higher than the revision rates predicted by the 3\xa0models used to extrapolate data from the NJR. The Committee concluded that, of the 3\xa0models presented to extrapolate revision rates beyond the 9-year follow-up of the NJR, the Assessment Group's bathtub extrapolation was the most plausible.\n\nThe Committee examined the economic modelling that had been carried out for the appraisal. The Committee noted that the 2\xa0economic models presented by the Assessment Group and by 1\xa0manufacturer (DePuy Synthes) had similar structures and were based on a model structure that had been used in previous health economic evaluations of hip replacement prostheses. The Committee concluded that the outlined structure of the models adhered to the NICE reference case for economic analysis and was acceptable for the purpose outlined in the scope.\n\nThe Committee considered the utility values and the source of the health-related quality-of-life data used by the Assessment Group and the manufacturer. The Committee observed that, in both models, the differences in QALYs gained between the types of hip replacement were very small (see section\xa04.2.11). The Committee discussed how different types of hip replacement surgery would affect a patient's quality of life. The Committee noted that the Assessment Group's utility values came from PROMs in the NJR and were collected postoperatively, but were not specific to individual types of prosthesis. The Committee noted that, in the manufacturer's model, different types of THR and resurfacing arthroplasty were also associated with the same utility value after surgery. The Committee noted that, in the manufacturer's model, a disutility of 0.145 had been applied after a successful revision. This was to reflect that a patient is unlikely to return to the level of health-related quality of life experienced after the primary surgery, whereas the Assessment Group had assumed that utility after a successful revision would be the same as utility after a successful primary hip replacement. The Committee heard from the Assessment Group's clinical specialist and the manufacturer that, although a successful primary hip replacement would be expected to relieve pain and disability associated with end-stage arthritis of the hip completely, revision surgery was associated with both greater risks and poorer functional outcomes than primary surgery and it was appropriate to apply a disutility value in the post-revision health state, as in the manufacturer's model. The Committee concluded that it was plausible that people who had revision surgery would have a lower quality of life than people who had a successful primary hip replacement. It further concluded that, given the available evidence, it was not possible to determine how use of different types of hip replacement prostheses would affect quality of life.\n\nThe Committee discussed the costs of the prostheses. It understood that the Guide to the methods of technology appraisal 2008 recommends using public list prices in the reference-case analysis, but noted that the NHS routinely pays a lower price for hip replacement prostheses because of volume-dependent and locally negotiated discounts. The Committee was aware that the Assessment Group obtained an average of sample list prices from the NHS Supply Chain for multiple manufacturers, and that the manufacturer had presented list prices for its own brands. The Committee also noted that the Assessment Group's prices were higher than the manufacturer's (with some exceptions). The Committee concluded that there was considerable uncertainty surrounding the prices of prostheses.\n\nThe Committee considered the base-case economic analyses presented by the Assessment Group and 1\xa0manufacturer. It noted that they generated broadly similar results, that is, THR dominated resurfacing arthroplasty in both the Assessment Group's and manufacturer's base cases, and that resurfacing arthroplasty remained dominated in every sensitivity and subgroup analysis. The Committee also noted that, although the categories of THR differed in the Assessment Group's and manufacturer's analyses, cemented prostheses tended to be the least costly and most effective, but with small incremental differences in costs and QALYs compared with other types of THR. The Committee also noted that, in the analyses of cost effectiveness, the Assessment Group and manufacturer used the average revision rate across category, and that the revision rate was the most important key driver of costs and QALYs in the model. The Committee concluded that THR was more effective and less costly than resurfacing arthroplasty in all analyses, but that the small differences between cemented and cementless THR were associated with uncertainty.\n\nThe Committee discussed the approach of comparing the cost effectiveness of categories of THR and resurfacing arthroplasty by category rather than by individual brands. The Committee was aware that devices can differ only slightly and that, within each category, there are multiple brands. The Committee further noted comments received on the appraisal consultation document that not all categories of THR had been investigated by the Assessment Group. The Committee was aware that the Assessment Group had assessed the 5\xa0most frequently used combinations of bearing surface and fixation method in the NJR and considered this to be appropriate. The Committee considered that the Assessment Group and manufacturer had not taken into account the uncertainty related to revision rates of different brands of prostheses within a category. The Committee noted that the Assessment Group had modelled a revision rate of 17.2% for men and women at 10\xa0years for resurfacing arthroplasty, and 12.4% for men only (in current practice resurfacing is predominantly used in men), and that these revision rates were higher than the current NICE standard of 10% or less at 10\xa0years in NICE technology appraisal guidance\xa02 and NICE technology appraisal guidance\xa044. However, the Committee noted that 1\xa0manufacturer of resurfacing arthroplasty products had provided evidence that its product had a revision rate lower than the NICE standard. In response to the appraisal consultation document, several consultees emphasised that revision rates vary between different brands of prosthesis within a category. The Committee noted again that making recommendations by revision rate allowed individual brands to be assessed separately. The Committee reiterated that it had considered making recommendations for prosthesis by category based on the average revision rate of multiple brands within a category. However, the Committee chose not to make recommendations by category, having concluded that this would disadvantage individual brands of prostheses with low revision rates, and would give an unfair advantage to individual brands with high revision rates within an overall well-performing category.\n\nThe Committee considered whether it was still appropriate to recommend a revision rate for prostheses of 10% or less at 10\xa0years, as recommended in NICE technology appraisal guidance\xa02 and NICE technology appraisal guidance\xa044. The Committee noted that the Assessment Group, having analysed and extrapolated data from the NJR for the population for whom both procedures were suitable, had estimated that the 10-year revision rate for resurfacing arthroplasty was worse (higher) than the standard, and that the 10-year revision rates for THR were much better (lower) than 10% at 10\xa0years. Furthermore, the Committee noted that, in the population for whom resurfacing was not suitable, the highest estimate across the 5\xa0categories of THR was less than 5% at 10\xa0years. The Committee agreed that the current standard was too high for both populations, and was aware that prostheses become more cost effective the lower the revision rates. Therefore, it discussed how a new standard could be determined with the data available. The Committee considered that, because all of the categories of THR prostheses for both populations had a predicted revision rate of less than 5% at 10\xa0years, the value reflecting the new standard for THRs should be no higher than 5%. Additionally, it considered that, because the predicted revision rate of THR was less than 5% at 10\xa0years in the population for whom both THR and resurfacing arthroplasty were suitable, the revision rate standard for resurfacing arthroplasty should be the same as that for THRs. The Committee noted that, although the average revision rate was predicted to be 5% or less at 10\xa0years, it was likely that within a category of THR some brands would perform poorly and would not meet this standard. The Committee discussed whether the proposed value should be reduced to even less than 5% to provide a more 'aspirational' standard. However, the Committee acknowledged that limitations in the data available (see section\xa04.3.6) did not allow it to determine the lowest revision rate that current practice could realistically achieve. The Committee concluded that it was appropriate to recommend that a prosthesis (for either resurfacing arthroplasty or THR) should meet a revision rate of 5% or less at 10\xa0years.\n\nThe Committee was aware that NICE technology appraisal guidance makes recommendations on the most cost-effective use of NHS resources but does not specify how to implement the guidance. It was also aware that the NICE Implementation Programme supports health and social care organisations to maximise the uptake and use of evidence and guidance. The Committee was further aware that ODEP, which is independent of NICE, currently provides the NHS with a list of prostheses that do or do not meet the standard for revision rates outlined in NICE technology appraisal guidance\xa02 and NICE technology appraisal guidance\xa044, and that there are initiatives to improve collecting and disseminating information on revision rates. The Committee discussed whether, given the current support for implementation available to the NHS, it would be possible to implement guidance in which recommendations depended on prostheses meeting a 5% or less revision rate at 10\xa0years, particularly for brands with less than 10\xa0years of data. The Committee was aware that NICE technology appraisal guidance\xa02 and NICE technology appraisal guidance\xa044 considered it reasonable to recommend prostheses with a minimum of 3\xa0years of experience, provided the projected revision rate was consistent with the standard recommended at that time; the Committee considered that this remained appropriate. The Committee noted that the ODEP rating system includes 3\xa0entry revision rate benchmarks assuming a linear relationship between the time since primary hip replacement and the proportion of people who would be expected to have a revision. The Committee agreed that, while other appropriate distributions may exist, the analysis of revision rates presented by the Assessment Group for this appraisal had shown it was reasonable to extrapolate using the bathtub function for prostheses with a follow-up of less than 10\xa0years. Furthermore, the bathtub model accounted for a higher rate of early revisions, which may reflect surgical complications or other factors unrelated to the prosthesis (see sections\xa04.3.7 and 4.3.8). The Committee preferred the Assessment Group's method of extrapolating revision rates to a linear extrapolation, but was content that ODEP needs to determine the methods with which it estimates revision rates based on the quality of the data provided by the manufacturers and the timing of the reporting of revision rates in clinical practice. The Committee concluded that it would be reasonable to recommend prostheses with less than 10\xa0years of data, provided that the revision rate was, in as much as the shorter term follow‑up data allow, consistent with 5% or less at 10\xa0years and that the recommendation could be implemented within the current support framework provided by ODEP. It also concluded that prostheses currently with at least 3\xa0years of data, which estimate a higher than 5% revision rate at 10\xa0years when projected, should not continue to be offered to patients.\n\nThe Committee considered other aspects of how prostheses are currently being rated and noted comments received from ODEP on the appraisal consultation document, in which ODEP clarified that it gave ratings for stem and cup components individually because of the large number of cup and stem components available and their many combinations. The Committee considered whether the revision rate standard of 5% or less at 10\xa0years should apply to each cup and stem component separately. The Committee agreed that total hip replacement or resurfacing arthroplasty can be considered to meet the revision rate standard of 5% or less at 10\xa0years if all components have an ODEP rating consistent with this standard.\n\nThe Committee considered the cases in which there may be more than 1\xa0prosthesis suitable for a patient that meets the revision rate standard of 5% or less at 10\xa0years. It was aware that current arrangements of generating ODEP ratings do not provide the NHS with the absolute revision rate for an individual prosthesis but only information on whether or not the standard was achieved, and that this was because ODEP receives revision rates from several registries or published papers each with different volumes of implants making a scientifically robust aggregation difficult. The Committee considered that, if more than 1\xa0prosthesis meets the 5% or less revision rate standard, it would prefer to recommend the most cost-effective prostheses (those with the lowest revision rates) but concluded that, without absolute revision rate data for each hip replacement system, this would not be feasible to implement.\n\nThe Committee was aware that, because of uncertainties surrounding the costs of prostheses and the discounts available to the NHS, it was not possible to give an estimate of the mean price paid in the NHS for a given prosthesis. The Committee considered that its recommendations should promote maintaining (at least) the level of discount from prostheses' list prices currently offered to the NHS. The Committee discussed whether, if more than 1\xa0prosthesis meets the 5% or less at 10\xa0years revision rate standard, it should recommend the prosthesis with the lowest acquisition costs. The Committee considered comments received during consultation on the appraisal consultation document. It was aware that the cost of THR and resurfacing arthroplasty included both procedure costs and surgical costs. The Committee noted that the Assessment Group had used published literature to determine surgical costs and had assumed that these would be the same for resurfacing arthroplasty and THR. The Committee also noted that 1\xa0manufacturer (DePuy Synthes) had carried out a costing study to estimate time in surgery and consumables, and that the manufacturer stated that procedure costs differed for resurfacing arthroplasty and for THR, and between various types of THR. The Committee heard from the manufacturers that the cost of a prosthesis may be a small proportion of the tariff paid by the NHS for a hip replacement. The Committee noted that the cost of a prosthesis is included in the fixed NHS tariff. The Committee considered the comments received from consultees on the appraisal consultation document, which stated that the benefits of manufacturer support packages had not been taken into account. However, the Committee concluded that tender costs included training in the use of a prosthesis. The Committee concluded that, although the NHS should be mindful of costs, in situations where multiple prostheses with a revision rate of 5% or less at 10\xa0years are suitable for a patient, it could not currently recommend selecting a prosthesis with the lowest acquisition cost. The Committee further concluded that the recommended standards for revision rate would encourage manufacturers to maintain training programmes to ensure the lowest revision rates possible for their products.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA304\n\nAppraisal title: Total hip replacement and resurfacing arthroplasty for end-stage arthritis of the hip (review of technology appraisal guidance 2 and 44)\n\nSection\n\nKey conclusion\n\nProstheses for total hip replacement and resurfacing arthroplasty are recommended as treatment options for people with end-stage arthritis of the hip only if the prostheses have rates (or projected rates) of revision of 5% or less at 10\xa0years.\n\n\n\n\n\n\n\nRevision rate was the most important key driver of costs and quality-adjusted life years (QALYs) in the model. The Committee was aware that prostheses become more cost effective the lower the revision rates.\n\n\n\n\n\nThe Committee considered that, because all of the categories of total hip replacement (THR) prostheses had a predicted revision rate of less than 5% at 10\xa0years, the value reflecting the new standard should be no higher than 5%.\n\nIt considered that, because the predicted revision rate of THR was less than 5% at 10\xa0years in the population for whom both THR and resurfacing arthroplasty were suitable, the revision rate standard for resurfacing arthroplasty should be the same as that for THRs.\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nBoth THR and resurfacing arthroplasty are options for treating end-stage arthritis of the hip, and clinicians consider together with patients the factors associated with the risk of revision when choosing the most appropriate procedure.\n\n\n\n\n\n\n\n\n\nClinicians may be more likely to offer resurfacing arthroplasty to men than to women because higher revision rates have been observed in women, which may be associated with women tending to have smaller hips.\n\n\n\n\n\nThe operating surgeon generally chooses the prosthesis, taking into consideration those that achieve the recommended standard revision rate as provided by the Orthopaedic Data Evaluation Panel. The Committee heard that surgeons need specific training for each class of prosthesis (for example, cemented or cementless THR), but that most orthopaedic surgeons in the UK are trained to use both cemented and cementless prostheses. The Committee also heard that an orthopaedic centre's experience and clinical data for individual prostheses further influence choice of prosthesis.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nA successful primary hip replacement would be expected to completely relieve pain and disability associated with end-stage arthritis of the hip, and hip resurfacing prostheses tend to be easier to replace than THR prostheses, but the risks associated with surgery are similar.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee reviewed the data available on the clinical and cost effectiveness of THR and hip resurfacing arthroplasty for people with end-stage arthritis of the hip for whom non-surgical management has failed.\n\n\n\nAdverse reactions\n\nAdverse events associated with hip replacement surgery (THR or resurfacing arthroplasty) may occur because of complications at the time of surgery or many years afterwards. Complications that may lead to hip replacement revision surgery include prosthesis instability, dislocation, aseptic loosening, osteolysis (bone reabsorption), infection and prosthesis failure.\n\n\n\n\n\n\n\n\n\n\n\nThe Assessment Group's clinical adviser stated that a patient's operative and peri-operative risk after a revision is associated more with why the primary prosthesis failed (for example, infection or fracture) than with the type of prosthesis, or whether it is cemented or cementless.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Assessment Group presented evidence from RCTs, systematic reviews, published registry studies, and its analysis of data from the Natoinal Joint Registry (NJR). The RCTs and systematic reviews involved small numbers of patients, had relatively short follow-up, reported different outcomes either incompletely or poorly, and were underpowered to detect differences in rates of revision.\n\n\n\n\n\n\n\n\n\n\n\nThe Assessment Group's retrospective analysis of the NJR provided a record of the revision rates for all types of prostheses used in England and Wales since 2003 and, as such, provided long-term data generalisable to UK clinical practice.\n\n\n\n\n\nThe Committee noted comments received during consultation, stating that there is a problem with an accurate link with Hospital Episode Statistics data and that data on revision rates from the NJR have not been validated.\n\n\n\n\n\nThe Committee noted that the registry did not provide data on outcomes listed in the scope other than revision, and that it did not provide data on differences in the patient characteristics (for example, activity level and comorbidities) that might affect both device choice and the risk for revision, and could therefore cause confounding. The Committee concluded that it was appropriate to use both trial and observational data in its decision making, but that uncertainty resulting from the possibility of confounding should be taken into account. The Committee agreed that, although the NJR data had limitations, they are the most comprehensive data reflecting clinical practice in the NHS and therefore the most appropriate for decision making.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Assessment Group's retrospective analysis of the NJR provided a record of the revision rates for all types of prostheses used in England and Wales since 2003 and, as such, provided long-term data generalisable to UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee heard that activity levels influence the choice of whether a person would be offered resurfacing arthroplasty, or which bearing surface of a THR is chosen, and would also affect the rate of wear of a prosthesis but that the NJR did not contain data on activity. It agreed that there was uncertainty around whether the difference in revision rates between THR and resurfacing arthroplasty could be attributed to failure of the prostheses because it is likely that people who have resurfacing are more active than people who have THR and higher activity may cause accelerated wear of a prosthesis.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee heard that comorbidities may be associated with which type of prosthesis a patient receives and whether or not a patient is offered revision surgery.\n\n\n\n\n\nThe Committee concluded that the Assessment Group's analysis of revision rates controlled for some, but not all, potential confounders, notably activity and comorbidities, and that it was consistent with published systematic reviews of trials, but that there remained uncertainty surrounding the relative revision rates between different types of prostheses.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nClinicians may be more likely to offer resurfacing arthroplasty to men than to women because higher revision rates have been observed in women, which may be associated with women tending to have smaller hips.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that the Assessment Group had modelled a revision rate of 17.2% for men and women at 10\xa0years for resurfacing arthroplasty, and 12.4% for men only (in current practice resurfacing is predominantly used in men), and that these revision rates were higher than the current NICE standard of 10% or less at 10\xa0years in NICE technology appraisal guidance\xa02 and NICE technology appraisal guidance\xa044. All of the categories of THR prostheses for both populations had a predicted revision rate of less than 5% at 10\xa0years.\n\n, 4.3.14\n\nHow has the new clinical evidence that has emerged since the original appraisal (TA2 and TA44) influenced the current recommendations?\n\nSince the original appraisals NICE technology appraisal guidance\xa02 and NICE technology appraisal guidance\xa044, data have become available for revision rates of prostheses used in the NHS and private practice in England and Wales and are documented in the NJR.\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the base-case economic analyses presented by the Assessment Group and 1 of the manufacturers (DePuy Synthes).\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee understood that the Guide to the methods of technology appraisal 2008 recommends using publicly available list prices in the reference-case analysis, but noted that the NHS routinely pays a lower price for hip replacement prostheses because of volume-dependent and locally negotiated discounts. The Committee concluded that there was considerable uncertainty surrounding the prices of prostheses.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee concluded that it was plausible that people who had revision surgery would have a lower quality of life than people who had a successful primary hip replacement. It further concluded that, given the available evidence, it was not possible to determine how use of different types of hip replacement prostheses would affect quality of life.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted that, in the analyses of cost effectiveness, the Assessment Group and manufacturer used the average revision rate across category, and that the revision rate was the most important key driver of costs and QALYs in the model.\n\n\n\n\n\n\n\n\n\nProstheses become more cost effective the lower the revision rates.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nIncremental cost-effectiveness ratios (ICERs) were not the relevant parameter in determining the recommendations. This was because the ICERs were dependent on the predicted average revision rates of the analysed categories of prostheses, the differences in QALYs between categories were small, and individual brands may have different revision rates from the category average.\n\n, 4.3.13\n\nHow has the new cost-effectiveness evidence that has emerged since the original appraisal (TA2 and TA44) influenced the current recommendations?\n\nThe Committee concluded that THR was more effective and less costly than resurfacing arthroplasty in all analyses, but that the small differences between cemented and cementless prostheses were associated with uncertainty.\n\n\n\n\n\n\n\nThe Committee considered making recommendations for particular prostheses categories based on the point estimate reflecting the average revision rate of multiple brands of prostheses within a category. However, it concluded that this would disadvantage individual brands of prostheses with particularly low revision rates and would give an unfair advantage to individual brands with high revision rates within an overall well-performing category.\n\n\n\n\n\nThe Committee concluded that it was appropriate to recommend that a prosthesis should meet a revision rate of 5% or less at 10\xa0years.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable\n\n\n\nEnd-of-life considerations\n\nNot applicable\n\n\n\nEqualities considerations and social value judgements\n\nDuring scoping, consultees said that the rates of total joint surgery in practice may vary in different groups of people. However, no changes were required to the scope because it did not define the population being considered by any of the protected equality characteristics. It was noted by the Committee that NICE technology appraisal guidance 2 and NICE technology appraisal guidance 44 were published before the current NICE equalities scheme was implemented. No equality issues were raised in the assessment report, the manufacturer's submissions or during the consultation on the assessment report or the Committee's discussions.\n\nn/a", 'Recommendations for further research': 'The Committee recommended that research should be carried out to determine the relationship between activity and prosthesis failure.\n\nThe Committee recommended the collection of data on prosthesis failure or on the prevalence of people living with a failed hip but for whom revision surgery is not suitable or who choose not to have revision surgery. The Committee further recommended that nomenclature for hip replacement failure needs to be established to allow demarcation of prosthesis-dependent and prosthesis-independent hip replacement failure. Furthermore, patient reported outcome measures collected as part of the National Joint Registry should allow for reporting of hip replacement failure in people who cannot or choose not to have revision surgery.', 'Related NICE guidance': 'Details are correct at the time of publication. Further information is available on the NICE website.\n\nOsteoarthritis: care and management in adults. NICE clinical guideline 177 (2014).\n\nArthroscopic femoro-acetabular surgery for hip impingement syndrome. NICE interventional procedure guidance 408 (2011).\n\nMinimally invasive total hip replacement. NICE interventional procedure guidance 363 (2010).\n\nRheumatoid arthritis: the management of rheumatoid arthritis in adults. NICE clinical guideline 79 (2009).\n\nGuidance on the use of metal on metal hip resurfacing arthroplasty. NICE technology appraisal guidance 44 (2002).\n\nGuidance on the selection of prostheses for primary total hip replacement. NICE technology appraisal guidance 2 (2000).', 'Review of guidance': 'The guidance on this technology will be considered for review in February 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon Chief ExecutiveFebruary 2014', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt updates and replaces NICE technology appraisal guidance 2 (published April 2000) and NICE technology appraisal guidance 44 (published June 2002).\n\nIt has been incorporated into the NICE pathway on rheumatoid arthritis and NICE pathway on osteoarthritis along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0444-0'}	https://www.nice.org.uk/guidance/ta304	Evidence-based recommendations on artificial hips and hip resurfacing for treating end‑stage arthritis of the hip in adults.
36d9585abc06f3cad8b74861467de4ae7f0c0020	nice	Aflibercept for treating visual impairment caused by macular oedema secondary to central retinal vein occlusion	Aflibercept for treating visual impairment caused by macular oedema secondary to central retinal vein occlusion Evidence-based recommendations on aflibercept (Eylea) for treating sight problems caused by macular oedema from central retinal vein occlusion in adults. # Guidance Aflibercept solution for injection is recommended as an option for treating visual impairment caused by macular oedema secondary to central retinal vein occlusion only if the manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme.# The technology Aflibercept solution for injection (Eylea, Bayer) is a vascular endothelial growth factor (VEGF) inhibitor. It prevents the inappropriate growth of new blood vessels in the retina. Aflibercept solution for injection has a UK marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to central retinal vein occlusion (CRVO)'. Aflibercept is administered as a single 2 mg intravitreal injection. Each vial of aflibercept contains 4 mg in 0.1 ml, providing a usable amount to deliver a single dose of 0.05 ml containing 2 mg of aflibercept. After the initial injection, treatment is given monthly. The summary of product characteristics states that the interval between 2 doses should not be shorter than 1 month. If there is no improvement in visual and anatomic outcomes over the course of the first 3 injections, continued treatment is not recommended. Monthly treatment continues until visual and anatomical outcomes are stable for 3 monthly assessments. Thereafter the need for continued treatment should be reconsidered. The summary of product characteristics states that monitoring is recommended at the injection visits and that the monitoring schedule should be determined by the doctor responsible for the patient's care based on the response of the condition to treatment. For full details of posology, see the summary of product characteristics. Adverse reactions to treatment are mostly limited to the eye. The summary of product characteristics lists the following adverse reactions as common or very common for aflibercept solution for injection for macular oedema secondary to CRVO: conjunctival haemorrhage, increased intraocular pressure, eye pain, vitreous detachment, vitreous floaters, increased lacrimation, and ocular hyperaemia. Contraindications for aflibercept solution for injection include hypersensitivity to the active substance or any of its excipients, active or suspected ocular or periocular infection, and active severe intraocular inflammation. For full details of adverse reactions and contraindications, see the summary of product characteristics. The list price of aflibercept 40 mg/ml solution for injection is £816.00 per 0.1-ml vial (excluding VAT; 'British national formulary' edition 66). The manufacturer of aflibercept solution for injection has agreed a patient access scheme with the Department of Health which makes aflibercept solution for injection available with a discount applied to the list price. The level of discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of aflibercept solution for injection (from here onwards referred to as aflibercept) and a review of this submission by the Evidence Review Group (ERG; section 9). # Clinical effectiveness The manufacturer submitted evidence of clinical effectiveness for aflibercept compared with ranibizumab in people with macular oedema secondary to central retinal vein occlusion (CRVO). The main sources of evidence presented in the manufacturer's submission came from 2 randomised controlled trials that compared aflibercept with sham injection in people with macular oedema secondary to CRVO (COPERNICUS and GALILEO). In both trials the included patients had been diagnosed less than 9 months before the start of the trial and they had not received previous treatment for CRVO. COPERNICUS was a randomised, double-blind, multicentre trial conducted in 6 non-European countries. From week 0 to week 24, patients in the intervention group (n=114) received aflibercept every 4 weeks and patients in the comparator group (n=73) received a sham injection every 4 weeks. From week 24 to week 52 patients in both groups received aflibercept if they met protocol-specified retreatment criteria, and received a sham injection if retreatment was not indicated. After the first year, patients continued in a 1-year extension phase (up to 100 weeks) with aflibercept as needed (no sham injection). Patients were retreated with aflibercept if any of the following conditions were met: increase of 50 micrometres or more in central retinal thickness on optical coherence tomography (OCT) compared with lower previous measurement, new or persistent cystic retinal damages of sub-retinal fluid on OCT or persistent diffuse oedema of 250 micrometres or more in the central subfield on OCT, or a loss or gain of 5 letters or more between the current and most recent visit. All patients were eligible to receive pan retinal photocoagulation at any time if they developed neovascularisation. The average age of the patients was 66.3 years and most patients were male (57%). The mean best corrected visual acuity (BCVA) at baseline was 50.0 letters and 68% of patients had perfused retinal occlusion, which was defined as fewer than 10 disc areas of capillary non-perfusion on fluorescein angiography. The manufacturer did not report any statistically significant differences in the baseline characteristics between the 2 groups. GALILEO was a randomised, double-blind, multicentre trial conducted in 10 European and Asian-Pacific countries. None of the study centres was located in the UK. From week 0 to week 24, patients in the intervention group (n=103) received aflibercept every 4 weeks and patients in the comparator group (n=68) received a sham injection every 4 weeks. From week 24 to week 52, patients in the intervention group received aflibercept if they met protocol-specified retreatment criteria, or sham injection. Patients were assessed monthly using retreatment criteria as in COPERNICUS. Patients in the comparator group continued to receive sham injection from week 24 to week 52. From week 52 to week 76, all patients received aflibercept if they met the retreatment criteria, or sham injection, every 8 weeks. All patients were eligible to receive pan retinal photocoagulation at any time if they developed neovascularisation. The average age of the patients was 61.5 years and most patients were male (56%). The mean BCVA at baseline was 52.2 letters. Perfused retinal occlusion, defined as fewer than 10 disc areas of capillary non-perfusion on fluorescein angiography, was present in 86% of patients in the intervention group and 79% of patients in the comparator group. The manufacturer stated that there was a slight imbalance in mean central retinal thickness between the 2 groups (683.20 micrometres in aflibercept compared with 638.66 micrometres in sham). The manufacturer stated that these values are considered to be close to the baseline central retinal thickness values from other CRVO trials, including COPERNICUS. The manufacturer did not report any statistically significant differences in the other baseline characteristics between the 2 groups. The manufacturer used the same statistical analysis for the results from COPERNICUS and GALILEO and the intention-to-treat protocol was not used. In the primary efficacy analyses, data from all randomised patients who received any trial medication and had a baseline assessment and at least 1 efficacy assessment after baseline were included (full analysis set). Data were analysed according to the group to which patients were randomised. In the sensitivity analyses, data from all patients in the full analysis set who received at least 5 injections of trial medication and did not have any major protocol violations or deviations were included (per protocol population). Data were analysed according to which treatment patients received. In the safety analyses, data from all randomised patients who received any trial medication were included (safety population). Data were analysed according to which treatment patients received. The primary outcome of both COPERNICUS and GALILEO was the proportion of eyes with a gain of 15 or more letters in BCVA from baseline to week 24. Statistically significantly more patients gained 15 or more letters at 24 weeks with aflibercept than with sham in COPERNICUS (aflibercept 64/114 and sham 9/73 , p<0.001 adjusted by region and baseline BCVA ). There were also statistically significantly more patients in GALILEO who gained 15 or more letters at 24 weeks with aflibercept than with sham (aflibercept 62/103 and sham 15/68 , p<0.0001 adjusted by region and baseline BCVA ). The manufacturer performed a meta-analysis of the data from COPERNICUS and GALILEO at week 24 for the number of patients gaining 15 or more letters and the mean change in BCVA from baseline. The odds and relative risk of gaining 15 or more letters at 24 weeks was statistically significantly higher in the group receiving aflibercept compared with the group receiving sham injection (odds ratio 6.85 ; relative risk 3.28 ). Subgroup analysis showed that baseline perfusion status (presence or absence of ischaemia) did not appear to have any significant effect on response rates. From week 24 to week 52, patients in both groups in COPERNICUS received aflibercept treatment as needed and patients in GALILEO continued to receive treatment according to their group allocation at the start of the trial. At 52 weeks, there were statistically significantly more patients who had gained 15 or more letters in the group initially allocated to receive aflibercept than in the group initially allocated to receive sham injection in COPERNICUS (aflibercept 63/114 and sham 22/73 , p<0.001) and in GALILEO (aflibercept 62/103 and sham 22/68 , p=0.0004). From week 52 onwards, patients in both groups in COPERNICUS and GALILEO received aflibercept treatment as needed. At 76 weeks there were statistically significantly more patients who had gained 15 or more letters in the group initially allocated to receive aflibercept than in the group initially allocated to receive sham in GALILEO (aflibercept 59/103 and sham 20/68 , p<0.0004). At 100 weeks there were statistically significantly more patients who had gained 15 or more letters in the group initially allocated to receive aflibercept than in the group initially allocated to receive sham in COPERNICUS (aflibercept 56/114 and sham 17/73 , p=0.0003). Secondary outcomes in both trials included mean change at 24 weeks from baseline in BCVA, central retinal thickness, and the proportions of patients progressing to ocular neovascularisation. The mean change in BCVA and the mean change in central retinal thickness from baseline to 24 weeks were statistically significantly greater in the aflibercept group compared with the sham group in both COPERNICUS and GALILEO. The percentage of patients progressing to neovascularisation at week 24 was statistically significantly greater in the sham group compared with the aflibercept group in COPERNICUS, but there was no statistically significant difference between the groups in GALILEO. The manufacturer performed a network meta-analysis to compare aflibercept with ranibizumab and dexamethasone, because head-to-head comparison data were not available from randomised controlled trials. Six high-quality trials were included in the network meta-analysis. Two trials compared ranibizumab with sham injection (CRUISE and ROCC), 2 trials compared aflibercept with sham injection (COPERNICUS and GALILEO), and 2 trials compared dexamethasone intravitreal implant with sham injection (GENEVA 008 and GENEVA 009). Data for bevacizumab were not included in the analysis because the manufacturer did not consider treatment with bevacizumab to be the standard of care for people with CRVO and only 2 small studies of moderate-to-low quality were available (Epstein et al. 2012 and Wittstrom et al. 2012). Epstein compared bevacizumab with sham in 60 patients and Wittstrom compared bevacizumab with pan-retinal photocoagulation in 19 patients. The network meta-analysis was performed only on 6-month (24 weeks) trial data because of the switching of patients between treatment groups in some of the trials. For the comparison of ranibizumab with aflibercept, there was no statistically significant difference in the odds or relative risk of gaining 15 or more letters or of losing 15 or more letters. There was also no statistically significant difference in the mean change in BCVA from baseline to 24 weeks. For the comparison of dexamethasone with aflibercept, the odds and relative risk of gaining 15 or more letters from baseline to 24 weeks were statistically significantly smaller with dexamethasone and the mean change in BCVA was statistically significantly larger with aflibercept. The odds and relative risk of losing 15 or more letters were not reported. The results of the network meta-analysis were submitted as commercial in confidence and cannot be presented. Impact on health-related quality of life was measured by NEI VFQ-25 in COPERNICUS and by NEI VFQ-25 and EQ-5D in GALILEO. From baseline to 24 weeks, there was a statistically significant greater mean change in NEI VFQ-25 score in the aflibercept group of both COPERNICUS (aflibercept 7.2, standard deviation 12.1, and sham 0.8, SD 9.8; p=0.001) and GALILEO (aflibercept 7.5, SD not reported, and sham 3.5, SD not reported; p=0.001). From baseline to 52 weeks, there was a statistically significant greater mean change in NEI VFQ-25 score in the aflibercept group in GALILEO (aflibercept 7.8 and sham 4.5, p=0.0049) but there was no statistically significant difference in mean change in NEI VFQ-25 total score in COPERNICUS (aflibercept 7.5 and sham 5.1, p=0.216). The mean changes in NEI VFQ-25 total score at week 76 in GALILEO and week 100 in COPERNICUS were not statistically significantly different. EQ-5D values were reported for the European subset of the population in GALILEO and there were no significant differences in EQ-5D scores. The EQ-5D data were submitted as academic in confidence and therefore cannot be presented. The most common ocular treatment emergent adverse events in both trials and both groups were conjunctival haemorrhage, reduced visual acuity, eye pain, retinal haemorrhage, and increased intraocular pressure. There were deaths from arrhythmia, acute myocardial infarction, oesophageal adenocarcinoma, and pneumonia in the sham group of COPERNICUS. The exact number of deaths in this group was submitted as academic in confidence and cannot be presented. No deaths occurred in the aflibercept group of COPERNICUS or in either group in GALILEO. The manufacturer did not report whether the number of adverse events was statistically significantly different between the groups. The manufacturer stated that the number of patients who had adverse events in the trials included in the network meta-analysis was too low to conduct a robust network meta-analysis on safety end points. # Cost effectiveness The manufacturer developed a cost–utility Markov model that evaluated the cost effectiveness of aflibercept compared with ranibizumab in people with macular oedema secondary to CRVO. There were 25 health states in the model, defined by the BCVA in both the eye receiving treatment (the study eye) and the non-treated eye (the second eye), in addition to death. The health states were defined by a 15-letter range in BCVA. The model had 4-weekly cycles and a time horizon of 30 years, which was effectively a lifetime horizon given that the baseline age of the cohort was 64 years. Patients could move into an improved health state, remain in the same health state, or move into a worse health state. The BCVA for the patients' second eye was assumed to remain constant over time and so second eye involvement was not included in the model. The baseline distribution of the patient population between the 25 health states of the model was inferred from the pooled COPERNICUS and GALILEO baseline distributions of the study eye and second eye. The model assumes that the distributions are independent, resulting in an inferred 2-eyed patient distribution with the largest proportion of patients having BCVA of 64 to 50 in their study eye and BCVA of 80 or more in their second eye. The transition probabilities for aflibercept for the first 6 cycles (0 to 24 weeks) of the model were based on pooled data from COPERNICUS and GALILEO. To determine the transition probabilities for improvement in BCVA with ranibizumab for the first 6 cycles (0 to 24 weeks), the relative risk of gaining 15 or more letters with ranibizumab that was calculated in the network meta-analysis (see section 3.9) was applied to the aflibercept probabilities. The transition probabilities for moving to a worse BCVA with ranibizumab were assumed to be the same as with aflibercept. The transition probabilities for remaining in the same health state with ranibizumab were calculated by subtracting the transition probability for moving to a better health state and the transition probability for moving to a worse health state from 1. From cycle 6 to 13 (week 24 to week 52) it was not possible to use pooled data from COPERNICUS and GALILEO because patients in COPERNICUS were able to change treatments after week 24. Patients receiving ranibizumab in CRUISE were also able to change treatments after week 24. The manufacturer therefore chose to assume that, for both aflibercept and ranibizumab, patients' vision was maintained and patients remained in the same health state for cycles 6 to 13. From cycle 13 (week 52) onwards, it was assumed that for both aflibercept and ranibizumab, patients' BCVA deteriorated, following a natural disease history progression that remained constant over time (Klein et al. 1991). Because the second eye was assumed to have a constant BCVA, only the BCVA of the study eye was modelled. The manufacturer assumed an indefinite duration of treatment benefit, based on the treatment benefit seen at 24 weeks. The EQ-5D data collected in GALILEO were used for health-related quality-of-life data in the economic model. The utility values used in the base-case analysis were based on the EQ-5D value averaged across all 4 time points (0, 24, 52, and 76 weeks) for the European population in both the aflibercept and sham injection groups of GALILEO. The utility values obtained from these scores were then analysed based on the 'worse-seeing eye' of the patients, to reflect that patients enrolled to the 2 aflibercept trials were predominantly tested in their 'worse-seeing eye'. A total of 121 patients were included in the analyses, with 440 observations across all time points and across the 2 treatment groups. Each observation was assigned to 1 of the 5 health state BCVA ranges based on the BCVA achieved in the patient's 'worse-seeing eye'. The assignment was irrespective of whether the 'worse-seeing eye' was the study eye or the second eye. For each BCVA range, the average utility values were then estimated across these observations. The 'worse-seeing eye' utility values from the EQ-5D trial data for health states 1 to 5 were submitted as academic in confidence and cannot be presented. The 'worse-seeing eye' utility values were attributed to the 25 health states in the model based on the lower of the 2 BCVA scores represented in a health state. The manufacturer did not use the NEI VFQ-25 data collected in COPERNICUS and GALILEO because they stated that EQ-5D is the preferred measure in the NICE reference case. The manufacturer identified a relevant study by Czoski-Murray et al. (2009) that was used to obtain utility values used in the scenario analysis. Adverse events were not modelled in the base-case analysis because the manufacturer stated that antivascular endothelial growth factors (anti-VEGFs; including ranibizumab and aflibercept) have similar safety profiles to each other. Raised intraocular pressure, cataracts and retinal tears were modelled in the scenario analysis. Total costs for treatment were calculated from the unit costs for aflibercept or ranibizumab, administration, and a monitoring visit, multiplied by the number of treatment and monitoring visits needed. The direct drug costs in the model incorporated the confidential discount applied to the list price of aflibercept approved as part of the patient access scheme. The manufacturer assumed that 52.38% of administration visits for aflibercept and ranibizumab would take place in an outpatient setting and the remaining in a day-case setting. A weighted average was used to derive an administration cost of £257 for each drug. Monitoring visit costs were £197for each treatment. A one-stop model was applied, which assumed that administration visits can double as monitoring visits. It was assumed that aflibercept would need 5.75 administration and monitoring visits, and ranibizumab would need 5.50 administration and monitoring visits, from week 0 to week 24. From week 24 to week 52 it was assumed that aflibercept would need 2.55 administration visits and 3.50 monitoring visits, and that ranibizumab would need 3.30 administration visits and 4.40 monitoring visits. A cost associated with blindness was applied each month for the first and second year when the 'better-seeing eye' was declared blind (BCVA of 35 letters or fewer). The costs associated with blindness for year 1 and year 2 were submitted as commercial in confidence and cannot be presented. The manufacturer's base-case cost-effectiveness results (incorporating the patient access scheme for aflibercept but not for ranibizumab) showed that aflibercept dominated (that is, was less expensive and more effective than) ranibizumab because it resulted in more quality-adjusted life years (incremental quality adjusted life years 0.054) and lower costs (incremental costs −£2937). The manufacturer did not know the level of discount in the patient access scheme for ranibizumab because it is confidential so it applied a range of discounts to the list price of ranibizumab in its sensitivity analysis. When the manufacturer applied a discount to the list price of ranibizumab ranging from 0 to 50% in increments of 5%, aflibercept continued to dominate ranibizumab until the price of ranibizumab was discounted by 50%. When the price of ranibizumab was reduced by 50%, aflibercept had higher costs and more QALYs than ranibizumab, resulting in an incremental cost-effectiveness ratio (ICER) of £5871 per QALY gained. The ICERs resulting from the sensitivity analyses for the other key drivers of the model were not reported by the manufacturer. The manufacturer conducted one-way sensitivity analyses with and without the confidential discount applied to the list price of aflibercept. When using the discounted price of aflibercept, a net monetary benefit approach (calculated by multiplying the incremental QALYs by £20,000 and then subtracting the incremental costs) was used because aflibercept dominated ranibizumab in the base-case analysis. The results of the sensitivity analyses indicated that the model was sensitive to changes in the number of ranibizumab injections from 0 to 24 weeks and from 25 to 52 weeks, the relative risk of gaining 15 or more letters when comparing aflibercept with ranibizumab, the number of aflibercept injections from 25 to 52 weeks, and the number of monitoring treatments for ranibizumab from 0 to 52 weeks. The manufacturer conducted 3 scenario analyses. The first scenario analysis used treatment durations of 2 years and 4 years rather than 1 year. This showed that aflibercept continued to dominate ranibizumab with incremental QALYs of 0.054 with 2 or 4 years of treatment (incremental costs with discounted aflibercept price were not reported). The second scenario used utility values for the 'better-seeing eye' from Czoski-Murray et al. (2009), irrespective of whether the 'better-seeing eye' was the study eye or the second eye. In Czoski-Murray, a value of 0.828 is applied if either eye is in health state 1. If the highest BCVA in either eye was health state 2, a value of 0.735 was applied. If the highest BCVA in either eye was health state 3, a value of 0.627 was applied. If the highest BCVA in either eye was health state 4, a value of 0.519 was applied. If both eyes were in health state 5, a value of 0.469 was applied. Using Czoski-Murray utility values, aflibercept continued to dominate ranibizumab with incremental QALYs of 0.028 (incremental costs with discounted aflibercept price not reported). The third scenario modelled the inclusion of the costs of adverse events (cataracts, intraocular pressure, and retinal tear) that were not included in the base-case analysis. Aflibercept continued to dominate ranibizumab with incremental QALYs of 0.054 (incremental costs with discounted aflibercept price not reported). The manufacturer presented a fourth scenario analysis in which aflibercept was compared with dexamethasone. In the deterministic analysis, aflibercept was associated with more QALYs (incremental QALYs 0.189) and higher costs (incremental costs £612) which resulted in an ICER of £3236 per QALY gained. No subgroups were identified by the manufacturer for analysis. # Evidence review group critique of the manufacturer's submission The ERG commented that the manufacturer did not include bevacizumab or clinical observation as comparators even though they were listed as comparators in the final scope issued by NICE. The ERG noted that the manufacturer stated that it did not include bevacizumab or clinical observation as comparators because they are no longer considered routine or best practice since the publication of positive NICE guidance on Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 283) and Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229). The ERG noted that bevacizumab has been widely used in the NHS and that patients may be kept under observation if there are contraindications to anti-VEGF treatment (such as allergy and eye infections) or if they refuse intravitreal treatment. The ERG questioned whether bevacizumab and clinical observation should have been included as comparators. The ERG noted that it was not clear what proportion of patients in COPERNICUS and GALILEO had ischaemia or severe ischaemia, because different definitions of ischaemia and severe ischaemia exist. It suggested that the proportion of patients with ischaemia or severe ischaemia in the COPERNICUS and GALILEO trials may be lower than the proportion of patients with ischaemia or severe ischaemia and CRVO in England and Wales. The ERG questioned whether the results of COPERNICUS and GALILEO are applicable to patients with ischaemia or severe ischaemia. The ERG highlighted that stopping rules were not used in the manufacturer's model. The manufacturer highlighted that no additional stopping rules were recommended in NICE guidance on ranibizumab (NICE technology appraisal guidance 283). The ERG noted from the summary of product characteristics that stopping rules should be used for deterioration in visual acuity after 3 injections and if there is no fall in oedema fluid or central retinal thickness. The ERG was aware that the summary of product characteristics also states that continued treatment is not recommended if there is no improvement in visual and anatomic outcomes over the course of the first 3 injections. The ERG questioned whether a stopping rule should have been implemented in the model. The ERG considered that the manufacturer's model does not incorporate the relative risk of losing 15 or more letters. It highlighted that the relative risk of losing 15 or more letters is in favour of ranibizumab and detrimental to dexamethasone, and not including the relative risk of losing 15 or more letters could affect the model results for the efficacy of aflibercept. The ERG questioned whether the relative risk of losing 15 or more letters should have been included in the model. The ERG noted that, in the manufacturer's model, any net gain in visual acuity at 6 months broadly persists through the model lifetime. It highlighted that treatment was only received for 1 year. The ERG questioned whether it was reasonable to assume that the net gain at week 24 will remain for the lifetime of the patient. The ERG suggested that the implementation of the health-related quality-of-life data in the manufacturer's model may be conservative. It highlighted that, in the base-case analysis, it is assumed that the EQ-5D data are the health-related quality-of-life data for the 'worse-seeing eye'. The ERG noted that, as a consequence, this is only applied when the study eye is being modelled as the 'worse-seeing eye'. It also understood that it is assumed that the Czoski-Murray utility values are the health-related quality-of-life data for the 'better-seeing eye'. The ERG noted that, as a consequence, this is only applied when the study eye is being modelled as the 'better-seeing eye'. It questioned the appropriateness of this approach. The ERG considered that the utility values in the manufacturer's base-case analysis were obtained from the EQ-5D data from GALILEO and the utility values used in one of the manufacturer's scenario analyses were obtained from Czoski-Murray et al. (2009). It noted that utility values from Brown (1999) were used in NICE guidance on dexamethasone (NICE technology appraisal guidance 229) and ranibizumab (NICE technology appraisal guidance 283). The ERG questioned which utility values are the most appropriate to use in the cost-effectiveness analysis. The ERG argued that the costs of administration and monitoring for aflibercept and ranibizumab appeared to be overestimates. It stated that the outpatient administration costs could be reduced by costing them as 'Outpatient procedures: BZ23Z: Minor vitreous retinal procedures' and that the dedicated monitoring visit costs could be reduced by costing them as 'RA23Z: Ultrasound Scan, less than 20 minutes'. The ERG noted that the calculation used for the costs of raised intraocular pressure appears to be inappropriate. It stated that the costs of medication were unnecessarily divided by 13 and the costs of inpatient therapies were divided by 6. The ERG considered the application of the costs of blindness in the aflibercept and ranibizumab groups in the model appears to be inappropriate. It stated that the manufacturer's model only considers the incidence events of blindness for the aflibercept and ranibizumab groups, rather than considering the incident events and the prevalence of blindness as it does in the dexamethasone group. The ERG argued that the costs of blindness appear to have been underestimated. It stated that the manufacturer used Meads and Hyde (2003) as their source of the costs of depression. The ERG stated that McCrone et al. (2008) provides a more recent and more accurate estimate of the costs of depression. The ERG noted that the manufacturer assumed that 52.38% of administration visits for anti-VEGF therapy (ranibizumab and aflibercept) would take place in an outpatient setting and the remaining in a day-case setting. This results in an average weighted administration cost of £257. The ERG considered that all administration visits would take place in an outpatient setting, resulting in an administration cost of £181. In NICE's guidance on ranibizumab, the ranibizumab administration visit was costed as an office-based outpatient procedure. The ERG queried which administration cost was the most appropriate. The ERG conducted exploratory analyses, which involved the following modifications to the manufacturer's model: The number of dexamethasone administrations in year 1 was changed from 4.00 to 1.86. The cost per aflibercept or ranibizumab administration was changed from £257.45 to £180.73. The cost per dedicated monitoring visit for aflibercept or ranibizumab was changed from £197.00 to £130.01. The number of dedicated monitoring visits for aflibercept was changed from 2.43 to 0.95. The number of dedicated monitoring visits for ranibizumab was changed from 2.03 to 1.10. The cataract rate in the ranibizumab group was changed from 3.3% to 1.6%. The duration of quality of life impact of raised intraocular pressure was changed from 1 day per cycle to 1 cycle. The duration of quality of life impact of cataract was changed from 1 cycle to 3 cycles. The duration of quality of life impact of retinal tears was changed from 1 cycle to 4 cycles. The cost of raised intraocular pressure was changed from £33 to £4. The blindness mortality multipliers were changed from 1.54 to 0.00. The costs of blindness for aflibercept and ranibizumab were applied to both newly incident and prevalent cases of blindness instead of only the incident cases of blindness. The costs of blindness were increased. The costs were submitted as commercial in confidence and therefore cannot be presented. The ERG also corrected an error in the manufacturer's calculation of adverse event rates for aflibercept and dexamethasone from month 7 to 12. The ERG incorporated the confidential discount applied to the list price of aflibercept, but not the confidential discount for ranibizumab, in its exploratory analysis outlined in section 3.40. It showed that aflibercept dominated ranibizumab because it resulted in lower costs and higher QALYs (incremental costs −£3049, incremental QALYs 0.053). The ERG was aware that the discounts agreed in the patient access schemes for aflibercept and ranibizumab are confidential. Therefore, it applied a discount ranging from 0 to 50% to the list price of ranibizumab in its exploratory analysis as well as applying the discount to the list price of aflibercept. With the discounted price of aflibercept and a 0 to 45% reduction in the list price of ranibizumab, aflibercept dominated ranibizumab because it is less costly (incremental costs ranged from −£3049 to −£122) and has a greater QALY gain (incremental QALYs 0.053) than ranibizumab. With the discounted price of aflibercept and a 50% reduction in the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £3820 per QALY gained (incremental cost £203, incremental QALY 0.053). The ERG carried out sensitivity analyses around the relative risk of losing 15 or more letters at 6 months, the administration cost, duration of treatment, adverse events, and the source of utility values. The ERG used the discount to the list price of aflibercept and reduced the list price of ranibizumab by a value of either 0% or 10 to 50% in increments of 5%. When the relative risk of losing letters was included in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3005 to −£78, incremental QALYs 0.003). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £86,789 per QALY gained (incremental cost £247, incremental QALY 0.003). When the administration cost was reduced in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3083 to −£156, incremental QALYs 0.053). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £3176 per QALY gained (incremental cost £169, incremental QALY 0.053). When the duration of treatment was extended to 2 years and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£4422 to −£285, incremental QALYs 0.053). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £3274 per QALY gained (incremental cost £175, incremental QALY 0.053). When the duration of treatment was extended to 5 years and a discount of 0 to 50% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£6838 to −£31, incremental QALYs 0.053). When costs of adverse events were included in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3066 to −£139, incremental QALYs 0.053). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £3489 per QALY gained (incremental cost £187, incremental QALY 0.053). When Czoski-Murray utility values with the 'worse-seeing eye' were used in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3049 to −£122, incremental QALYs 0.053). When a 50% discount was applied to the list price of ranibizumab the ICER for aflibercept compared with ranibizumab was £3851 per QALY gained (incremental cost £203, incremental QALY 0.053). When Brown utility values with the 'worse-seeing eye' were used in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3049 to −£122, incremental QALYs 0.040). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £5076 per QALY gained (incremental cost £203, incremental QALY 0.040). The ERG also presented a deterministic ICER for aflibercept compared with dexamethasone. Incorporating the patient access scheme for aflibercept, the ICER for aflibercept compared with dexamethasone was £12,265 per QALY gained (incremental cost £2285, incremental QALY 0.186). The ERG also carried out exploratory analyses on the comparison of aflibercept with dexamethasone, incorporating the patient access scheme for aflibercept. Increasing the duration of treatment to 2 years resulted in an ICER for the comparison of aflibercept with dexamethasone of £14,034 per QALY gained and increasing it to 5 years resulted in an ICER of £18,699 per QALY gained. For the comparison of aflibercept with dexamethasone, using Czoski-Murray utility values with the 'worse-seeing eye' resulted in an ICER of £12,868 per QALY gained, and with the 'better-seeing eye' resulted in an ICER of £18,740 per QALY gained. Using Brown utility values with the 'worse-seeing eye' resulted in an ICER of £16,833 per QALY gained, and with the 'better-seeing eye' resulted in an ICER of £28,523 per QALY gained. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aflibercept, having considered evidence on the nature of macular oedema secondary to central retinal vein occlusion (CRVO) and the value placed on the benefits of aflibercept by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee heard from patient experts about the problems associated with visual impairment caused by macular oedema. It heard that the loss of vision has a significant effect on the independence of people with the condition. The patient experts also stated that the condition affects the ability to drive, and take part in hobbies such as reading and going to the cinema. The patient experts commented that the condition can affect people of working age, as they may be unable to work and support their family, and they may be unable to take time off work to attend regular follow-up or monitoring appointments. The patient experts acknowledged that although people may be worried about having an injection the eye, they are willing to receive injections to keep their sight. The Committee agreed that loss of vision caused by macular oedema secondary to CRVO seriously impairs health-related quality of life. The Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to CRVO is dexamethasone or antivascular endothelial growth factor (anti-VEGF) drugs, especially ranibizumab. The clinical specialists noted that the use of bevacizumab outside its marketing authorisation has decreased since NICE's guidance on Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 283) and Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229) recommended ranibizumab and dexamethasone as options for treating people with CRVO. The clinical specialists stated that they are more likely to use ranibizumab than dexamethasone even though it has a higher frequency of injections, because they believe that it has a decreased risk of side effects such as raised intraocular pressure and cataracts. The Committee concluded the current standard treatment for visual impairment caused by macular oedema secondary to CRVO is ranibizumab, although dexamethasone is also used. The Committee considered the comparators for the appraisal. It noted that the final scope issued by NICE included dexamethasone, ranibizumab, bevacizumab and clinical observation as comparators, but that the manufacturer only included dexamethasone and ranibizumab as comparators in its economic analysis. The Committee noted that the manufacturer did not include clinical observation as a comparator because it was of the opinion that patients would receive treatment with either ranibizumab or dexamethasone because NICE had recommended them as treatment options. The Committee was aware that the manufacturer did not include bevacizumab in its submission. The Committee acknowledged that the manufacturer's rationale for not including bevacizumab as a comparator was that its use in the NHS was not routine or best practice. The Committee heard from the clinical experts that the use of bevacizumab has decreased since the publication of NICE's guidance on ranibizumab (NICE technology appraisal guidance 283) and dexamethasone (NICE technology appraisal guidance 229). Most importantly, the Committee was concerned that there were only 2 small trials for bevacizumab compared with sham injections, and no direct comparisons of aflibercept with intravitreal bevacizumab are currently available. The Committee concluded that there is currently insufficient evidence for bevacizumab to make the robust comparisons with aflibercept needed for a cost-effectiveness analysis.The Committee further concluded that ranibizumab and dexamethasone were appropriate comparators in this appraisal. # Clinical effectiveness The Committee considered the populations in COPERNICUS and GALILEO. The Committee acknowledged that the trials did not exclude people with ischaemia or severe ischaemia. The Committee heard from the manufacturer that aflibercept was effective across the full trial populations of COPERNICUS and GALILEO. However, the Committee heard from the clinical specialists and the ERG that the proportions of patients with ischaemia or severe ischaemia in the trials were uncertain because different definitions of ischaemia and severe ischaemia exist. The Committee accepted that aflibercept could be considered effective for all of the population included in the trials. The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of aflibercept. It acknowledged that the main sources of evidence came from the COPERNICUS and GALILEO randomised controlled trials, which compared aflibercept with sham injection in people with CRVO. The Committee noted that in both COPERNICUS and GALILEO, aflibercept was associated with statistically significantly more eyes gaining 15 or more letters at 24 weeks compared with sham injection. The Committee was aware that people in the sham groups could receive aflibercept after 24 weeks in COPERNICUS and after 52 weeks in GALILEO. The Committee agreed that aflibercept resulted in greater visual gains when it was given to patients soon after diagnosis. The Committee concluded that aflibercept is a clinically effective treatment for visual impairment caused by macular oedema secondary to CRVO compared with sham injection. The Committee considered the evidence for the clinical effectiveness of aflibercept compared with ranibizumab and dexamethasone. It noted that evidence from direct comparisons was not available, and that a network meta-analysis was presented by the manufacturer. The Committee heard from the ERG that the methods used in the network meta-analysis were appropriate and that the analysis was well conducted. The Committee agreed that in the absence of a direct comparison, the results could be used to inform decisions about the clinical effectiveness of aflibercept compared with ranibizumab and dexamethasone. The Committee agreed that given the nature of the evidence, there was some uncertainty about the clinical effectiveness of aflibercept compared with ranibizumab and dexamethasone, but concluded that there was no evidence that aflibercept was not as clinically effective as ranibizumab or dexamethasone. The Committee considered the evidence for adverse effects associated with aflibercept. It noted that the overall frequency of adverse events in the COPERNICUS and GALILEO trials was low. The Committee heard from the clinical specialists that the safety profile of aflibercept is similar to that of ranibizumab, which is already licensed for use in this condition (see NICE guidance on ranibizumab ). The Committee concluded that treatment with aflibercept had a similar adverse event profile to ranibizumab. # Cost effectiveness The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. The Committee noted that the manufacturer had presented a comparison of aflibercept with ranibizumab for its base-case analysis and a comparison of aflibercept with dexamethasone as a scenario analysis. The Committee acknowledged that the ERG had concerns about some of the assumptions made by the manufacturer in the base-case analysis. In particular, the ERG queried why: any net gain in visual acuity at 24 weeks was assumed to persist through the lifetime of the model the relative risk of losing 15 or more letters at 24 weeks was not included in the model the duration of treatment was assumed to be 1 year EQ-5D data from GALILEO was used as a source of utility values the costs of adverse events were not included in the model a stopping rule was not included in the model the estimated administration costs of aflibercept and ranibizumab were high the estimated costs of blindness were low.The Committee considered each of these issues in turn, as detailed below. The Committee discussed the manufacturer's assumption that the benefits of treatment at 24 weeks would continue indefinitely throughout the lifetime of the model. The Committee heard from the ERG that the assumption may be optimistic and that it would exaggerate the quality-adjusted life year (QALY) gain of aflibercept over ranibizumab and dexamethasone. The Committee acknowledged that a sensitivity analysis around the duration of benefit of treatment was not undertaken by the manufacturer or the ERG. The Committee heard from the ERG that if the benefits of treatment at 24 weeks had not been assumed to continue indefinitely it was unlikely to change the overall results of the manufacturer's base-case analysis because aflibercept would still dominate (be less expensive and more effective than) ranibizumab. The Committee accepted that it was not appropriate to assume that the duration of treatment benefit at 24 weeks would continue indefinitely but concluded that it was likely to have little impact on the cost-effectiveness estimates. The Committee discussed how the manufacturer's model did not incorporate the relative risk of losing 15 or more letters. The Committee heard from the ERG that incorporating the relative risk of losing 15 or more letters into the model would ensure that the transition probabilities were correctly calculated. The ERG highlighted that including the relative risk of losing 15 or more letters in its exploratory analysis, which included the confidential discount applied to the list price for aflibercept, did not affect the dominance of aflibercept over ranibizumab except when a 50% reduction was applied to the list price of ranibizumab (see section 3.43). The Committee accepted that the relative risk of losing 15 or more letters should have been included in the manufacturer's model but concluded that including it was unlikely to change the dominance of aflibercept over ranibizumab. The Committee discussed the manufacturer's assumption that the duration of aflibercept treatment was 1 year. The Committee heard from the clinical specialists that most patients still receive treatment with anti-VEGF therapy in year 2 and around a third of patients receive treatment in year 3. The clinical specialists also noted that data on the difference in the length of treatment with ranibizumab or aflibercept for macular oedema secondary to CRVO are not yet available. The Committee considered the manufacturer's scenario analyses in which the treatment duration of aflibercept was extended to 2 years or 4 years (see section 3.25) and the ERG's exploratory sensitivity analyses in which treatment duration was extended to 2 or 5 years and which included the confidential discount applied to the list price for aflibercept and a range of discounts from 0 to 50% applied to the list price of ranibizumab (see section 3.43). The Committee noted that when treatment duration was extended to 5 years, aflibercept was dominant over ranibizumab regardless of the discount applied to the ranibizumab list price. The Committee concluded that the duration of aflibercept treatment was likely to be longer than 1 year, and that increasing the duration of treatment up to 5 years did not change the dominance of aflibercept over ranibizumab. The Committee considered the source of health-related quality-of-life data used in the manufacturer's model. The Committee acknowledged that EQ-5D data from the European subset of the GALILEO population were used as a source of utility values in the manufacturer's base-case analysis, which meets NICE's reference case. The Committee also considered the manufacturer's scenario analyses, which used Czoski-Murray utility values, and included the confidential discount applied to the list price for aflibercept, noting that this did not affect the dominance of aflibercept over ranibizumab. The Committee noted that the ERG also carried out an exploratory sensitivity analysis using utility values from Czoski-Murray and Brown, which included the confidential discount applied to the list price for aflibercept and a range of discounts from 0 to 50% applied to the list price of ranibizumab. The Committee noted that the use of these utility values did not affect the dominance of aflibercept over ranibizumab unless there was a 50% reduction in the list price of ranibizumab. The Committee concluded that the source of the utility values did not substantially affect the cost-effectiveness estimates of aflibercept compared with ranibizumab. The Committee considered how the cost of adverse events had not been included in the manufacturer' base-case analysis. It noted that the reason given in the manufacturer's submission was that anti-VEGFs have similar safety profiles to each other. The Committee also acknowledged that the manufacturer presented a scenario analysis that included adverse events and that adverse events were also included in the ERG's exploratory analyses (see sections 3.25 and 3.43). The Committee noted that aflibercept continued to dominate ranibizumab in the manufacturer's scenario analysis and in the ERG's exploratory analysis if adverse events were included and a discount of 0 to 45% in the list price of ranibizumab was applied. The Committee was aware that the incremental cost-effectiveness ratio (ICER) for aflibercept was less than £3500 per QALY gained when a 50% discount was applied to the list price of ranibizumab. The Committee concluded that even if adverse events had been included in the manufacturer's base-case analysis, it was likely that aflibercept would continue to dominate ranibizumab. The Committee discussed the fact that the manufacturer's model did not include a stopping rule. The Committee noted that the summary of product characteristics for aflibercept states that continued treatment is not recommended if there is no improvement in visual and anatomic outcomes over the course of the first 3 injections. It was also aware that the summary of product characteristics for ranibizumab for macular oedema secondary to retinal vein occlusion also states that continued treatment is not recommended if there is no improvement in visual acuity after 3 injections. The Committee heard from the clinical specialists that they would not continue treatment if there was no improvement in visual acuity after 3 injections. The Committee concluded that a stopping rule should have been included in the manufacturer's model. The Committee discussed the administration costs of aflibercept and ranibizumab included in the manufacturer's model. The Committee noted that the manufacturer used a weighted average cost, based on the assumption that 52.38% of patients would be treated in an outpatient setting and the remaining in a day-case setting. The Committee heard from the clinical specialists that most patients would be treated as outpatients; however, it also heard that not all units have the facilities to perform the treatment as an outpatient procedure. The Committee noted that the ERG presented lower costs of administration of aflibercept and ranibizumab in its report. The Committee concluded that the ERG's assumptions about the costs of administration were likely to be more realistic than those used by the manufacturer and therefore it was uncertain of the impact on the cost-effectiveness analyses. The Committee discussed the costs of blindness included in the manufacturer's model. The Committee was aware that the source of the estimated costs of depression associated with blindness used by the ERG was more recent than the source used by the manufacturer. The Committee also noted that the costs of blindness presented by the ERG in their report were higher than those in the base-case analysis. The Committee recognised that if the costs presented by the ERG had been used, aflibercept would continue to dominate ranibizumab. The Committee concluded that the ERG's assumption about the costs of blindness were likely to be more in line with clinical practice than those used by the manufacturer. The Committee considered the ICERs for aflibercept compared with ranibizumab estimated by the manufacturer and the ERG. It noted that these analyses incorporated the discount agreed in the patient access scheme for aflibercept and a range of discounts applied to the list price of ranibizumab. The Committee was aware of the actual discount agreed in the patient access scheme for ranibizumab (this was submitted as commercial in confidence and therefore cannot be presented). It agreed that the analyses undertaken by the manufacturer and the ERG captured the discount agreed in the patient access scheme for ranibizumab. The Committee noted that in the manufacturer's base-case analysis aflibercept dominated ranibizumab when the discounted price of aflibercept was used. The Committee considered the concerns raised by the ERG about the manufacturer's model and acknowledged the ERG's amendments to the manufacturer's model (see section 3.40). The Committee was aware that the ERG's exploratory analysis resulted in slightly more cost savings for aflibercept, and that aflibercept continued to dominate ranibizumab. The Committee also discussed the ERG's exploratory analysis around the list price of ranibizumab, incorporating the confidential discount on the list price for aflibercept. The Committee noted that a reduction of 0 to 45% in the list price of ranibizumab did not affect the dominance of aflibercept over ranibizumab. It also considered that when a 50% reduction was applied to the list price of ranibizumab, with the exception of the scenario of including the relative risk of losing 15 or more letters, the ICERs for aflibercept compared with ranibizumab ranged from £750 to £9300 per QALY gained. Taking into account the exact magnitude of the discounts agreed in the patient access schemes for aflibercept and ranibizumab, the Committee concluded that aflibercept was a cost-effective use of NHS resources compared with ranibizumab for treating people with visual impairment caused by macular oedema secondary to CRVO. The Committee discussed the manufacturer's scenario analysis comparing aflibercept with dexamethasone, and the ERG's exploratory analyses. The Committee noted that the ERG's exploratory analysis, which included the confidential discount applied to the list price for aflibercept, resulted in an ICER of £12,300 per QALY gained for aflibercept compared with dexamethasone. The Committee considered that using Czoski-Murray utility values resulted in an ICER of £12,900 per QALY gained and using Brown utility values resulted in an ICER of £16,800 per QALY gained when applied to the 'worse-seeing eye'. The Committee also acknowledged that even using the Brown utilities for the 'better-seeing eye', that is to say, the 'worst case scenario', the ICER was below the top end of the range that would normally be considered a cost-effective use of NHS resources (£20,000–30,000 per QALY gained). The Committee concluded that aflibercept was a cost-effective use of NHS resources compared with dexamethasone for treating people with visual impairment caused by macular oedema secondary to CRVO. The Committee discussed how innovative aflibercept is in its potential to make a significant and substantial impact on health-related benefits. It agreed that aflibercept as well as other anti-VEGF treatments were a substantial improvement over previous treatments, and considered that this improvement applied to the class of drugs. In addition there were no substantial benefits of aflibercept over its comparators that were not already captured in the QALY estimation in the modelling. # Summary of the Appraisal Committee's key conclusions TA305 Appraisal title: Aflibercept for treating visual impairment caused by macular oedema secondary to central retinal vein occlusion Section Key conclusion Aflibercept solution for injection is recommended as an option for treating visual impairment caused by macular oedema secondary to central retinal vein occlusion only if the manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme. The clinical evidence from the COPERNICUS and GALILEO trials, which compared aflibercept with sham injection, showed that aflibercept was associated with a greater proportion of eyes gaining 15 or more letters from baseline to 24 weeks than sham injection. The Committee accepted the results from the manufacturer's network meta-analysis. This showed that there is no statistically significant difference in the odds or relative risk of gaining 15 or more letters from baseline to 24 weeks for the comparison of aflibercept with ranibizumab, and that the odds and relative risk of gaining 15 or more letters from baseline to 24 weeks was statistically significantly smaller with dexamethasone compared with aflibercept. The key driver for the cost-effectiveness results for the comparison of aflibercept with ranibizumab is the discount applied to the list price of ranibizumab. For the comparison of aflibercept with dexamethasone, the key driver is the source of the health-related quality of life data and whether it was applied to the 'worse-seeing eye' or 'better-seeing eye'. Current practice Clinical need of patients, including the availability of alternative treatments The Committee heard that visual impairment caused by macular oedema secondary to central retinal vein occlusion seriously impairs health-related quality of life. The Committee heard that the current standard treatment for macular oedema secondary to central retinal vein occlusion is dexamethasone or antivascular endothelial growth factor (anti-VEGF) drugs, such as ranibizumab. However, clinicians are more likely to use ranibizumab than dexamethasone because it is believed to have fewer side effects. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee agreed that aflibercept as well as other anti-VEGF treatments were a substantial improvement over previous treatments, and considered that this improvement applied to the class of drugs. The Committee was not aware of any substantial benefits of aflibercept solution for injection over its comparators that were not already captured in the quality-adjusted life year (QALY) estimation in the modelling. What is the position of the treatment in the pathway of care for the condition? Aflibercept solution for injection has a UK marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to central retinal vein occlusion (CRVO)'. Adverse reactions The Committee agreed that the evidence suggested the overall frequency of adverse events in the trials was low with aflibercept solution for injection and concluded that aflibercept had a similar adverse event profile to ranibizumab. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee acknowledged that the evidence presented by the manufacturer was from 2 trials (COPERNICUS and GALILEO) and a network meta-analysis. The Committee was aware that the scope of the appraisal listed bevacizumab as a comparator. It noted that the manufacturer identified only 2 small trials of bevacizumab relevant to the network meta-analysis, and no trials that directly compared bevacizumab with aflibercept. The Committee concluded that there is currently not enough evidence to allow bevacizumab to be included with confidence in clinical and cost-effectiveness analyses. Relevance to general clinical practice in the NHS The Committee heard that the current standard treatment for visual impairment caused by macular oedema secondary to central retinal vein occlusion is dexamethasone or anti-VEGF drugs, such as ranibizumab. Uncertainties generated by the evidence The Committee heard from the clinical specialists and the Evidence Review Group (ERG) that different definitions of ischaemia and severe ischaemia exist. It concluded that it was unclear whether any evidence had been presented for people with ischaemia or severe ischaemia. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? None Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that aflibercept was associated with statistically significantly more eyes gaining 15 or more letters at 24 weeks compared with sham injection. The Committee concluded that aflibercept is a clinically effective treatment option for visual impairment caused by macular oedema secondary to central retinal vein occlusion. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. It accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee considered the following uncertainties in the model: the assumption that the benefits of treatment at 24 weeks would continue indefinitely not including the relative risk of losing 15 or more letters the assumption that the duration of aflibercept treatment was 1 year the use of EQ-5D data as a source of utility values not including the cost of adverse events not including a stopping rule -verestimated administration costs for aflibercept and ranibizumab underestimated costs of blindness.The Committee concluded that these uncertainties were unlikely to change the dominance of aflibercept over ranibizumab. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee noted that the utility values in the manufacturer's base-case analysis were obtained from the EQ-5D data from GALILEO. The Committee heard from the ERG that using utility values from Czoski-Murray or Brown did not substantially affect the cost-effectiveness estimates of aflibercept compared with ranibizumab. The Committee was not aware of any substantial benefits of aflibercept over its comparators that were not already captured in the QALY estimation in the modelling. Are there specific groups of people for whom the technology is particularly cost effective? None What are the key drivers of cost effectiveness? The manufacturer's sensitivity analyses showed that the cost effectiveness of aflibercept was sensitive to changes in the number of ranibizumab injections from 0 to 24 weeks and 25 to 52 weeks, the relative risk of gaining 15 or more letters when comparing aflibercept with ranibizumab, the number of aflibercept injections from 25 to 52 weeks, and the number of monitoring visits for ranibizumab from 0 to 52 weeks. Most likely cost-effectiveness estimate (given as an ICER) The Committee noted that the manufacturer's base-case analysis showed that aflibercept dominated ranibizumab (that is, it was more effective and less costly), resulting in more QALYs and lower costs. The Committee considered the uncertainties in the manufacturer's model and noted the ERG's exploratory analysis, which resulted in slightly more cost savings with aflibercept. It also noted that aflibercept continued to dominate ranibizumab despite the changes made by the ERG. The Committee noted that the ERG's exploratory analysis, which included the confidential discount applied to the list price for aflibercept, resulted in an incremental cost-effectiveness ratio (ICER) of £12,300 per QALY gained for aflibercept compared with dexamethasone. The Committee also noted that even using the Brown utilities for the 'better-seeing eye', that is to say, the 'worst case scenario', the ICER was below the top end of the range that would normally be considered a cost-effective use of NHS resources (£20,000–£30,000 per QALY gained). Additional factors taken into account Patient access schemes (PPRS) The Department of Health and the manufacturer have agreed that aflibercept will be available to the NHS with a patient access scheme which makes aflibercept available with a discount. The level of discount is commercial in confidence. End-of-life considerations Not applicable Equalities considerations and social value judgements No equality issues relevant to the Committee's recommendation were raised. # Related NICE guidance Details are correct at the time of publication. Further information is available on the NICE website. Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 283 (2013). Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229 (2011).# Review of guidance The guidance on this technology will be considered for review in February 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveFebruary 2014# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It has been incorporated into the NICE pathway on eye conditions along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0446-4	{'Guidance': 'Aflibercept solution for injection is recommended as an option for treating visual impairment caused by macular oedema secondary to central retinal vein occlusion only if the manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme.', 'The technology ': "Aflibercept solution for injection (Eylea, Bayer) is a vascular endothelial growth factor (VEGF) inhibitor. It prevents the inappropriate growth of new blood vessels in the retina. Aflibercept solution for injection has a UK marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to central retinal vein occlusion (CRVO)'.\n\nAflibercept is administered as a single 2\xa0mg intravitreal injection. Each vial of aflibercept contains 4\xa0mg in 0.1\xa0ml, providing a usable amount to deliver a single dose of 0.05\xa0ml containing 2\xa0mg of aflibercept. After the initial injection, treatment is given monthly. The summary of product characteristics states that the interval between 2\xa0doses should not be shorter than 1\xa0month. If there is no improvement in visual and anatomic outcomes over the course of the first 3\xa0injections, continued treatment is not recommended. Monthly treatment continues until visual and anatomical outcomes are stable for 3\xa0monthly assessments. Thereafter the need for continued treatment should be reconsidered. The summary of product characteristics states that monitoring is recommended at the injection visits and that the monitoring schedule should be determined by the doctor responsible for the patient's care based on the response of the condition to treatment. For full details of posology, see the summary of product characteristics.\n\nAdverse reactions to treatment are mostly limited to the eye. The summary of product characteristics lists the following adverse reactions as common or very common for aflibercept solution for injection for macular oedema secondary to CRVO: conjunctival haemorrhage, increased intraocular pressure, eye pain, vitreous detachment, vitreous floaters, increased lacrimation, and ocular hyperaemia. Contraindications for aflibercept solution for injection include hypersensitivity to the active substance or any of its excipients, active or suspected ocular or periocular infection, and active severe intraocular inflammation. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe list price of aflibercept 40\xa0mg/ml solution for injection is £816.00 per 0.1-ml vial (excluding VAT; 'British national formulary' [BNF] edition\xa066). The manufacturer of aflibercept solution for injection has agreed a patient access scheme with the Department of Health which makes aflibercept solution for injection available with a discount applied to the list price. The level of discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (section\xa08) considered evidence submitted by the manufacturer of aflibercept solution for injection (from here onwards referred to as aflibercept) and a review of this submission by the Evidence Review Group (ERG; section\xa09).\n\n# Clinical effectiveness\n\nThe manufacturer submitted evidence of clinical effectiveness for aflibercept compared with ranibizumab in people with macular oedema secondary to central retinal vein occlusion (CRVO). The main sources of evidence presented in the manufacturer's submission came from 2\xa0randomised controlled trials that compared aflibercept with sham injection in people with macular oedema secondary to CRVO (COPERNICUS and GALILEO). In both trials the included patients had been diagnosed less than 9\xa0months before the start of the trial and they had not received previous treatment for CRVO.\n\nCOPERNICUS was a randomised, double-blind, multicentre trial conducted in 6\xa0non-European countries. From week\xa00 to week\xa024, patients in the intervention group (n=114) received aflibercept every 4\xa0weeks and patients in the comparator group (n=73) received a sham injection every 4\xa0weeks. From week\xa024 to week\xa052 patients in both groups received aflibercept if they met protocol-specified retreatment criteria, and received a sham injection if retreatment was not indicated. After the first year, patients continued in a 1-year extension phase (up to 100\xa0weeks) with aflibercept as needed (no sham injection). Patients were retreated with aflibercept if any of the following conditions were met: increase of 50\xa0micrometres or more in central retinal thickness on optical coherence tomography (OCT) compared with lower previous measurement, new or persistent cystic retinal damages of sub-retinal fluid on OCT or persistent diffuse oedema of 250\xa0micrometres or more in the central subfield on OCT, or a loss or gain of 5\xa0letters or more between the current and most recent visit. All patients were eligible to receive pan retinal photocoagulation at any time if they developed neovascularisation. The average age of the patients was 66.3\xa0years and most patients were male (57%). The mean best corrected visual acuity (BCVA) at baseline was 50.0\xa0letters and 68% of patients had perfused retinal occlusion, which was defined as fewer than 10\xa0disc areas of capillary non-perfusion on fluorescein angiography. The manufacturer did not report any statistically significant differences in the baseline characteristics between the 2\xa0groups.\n\nGALILEO was a randomised, double-blind, multicentre trial conducted in 10\xa0European and Asian-Pacific countries. None of the study centres was located in the UK. From week\xa00 to week\xa024, patients in the intervention group (n=103) received aflibercept every 4\xa0weeks and patients in the comparator group (n=68) received a sham injection every 4\xa0weeks. From week\xa024 to week\xa052, patients in the intervention group received aflibercept if they met protocol-specified retreatment criteria, or sham injection. Patients were assessed monthly using retreatment criteria as in COPERNICUS. Patients in the comparator group continued to receive sham injection from week\xa024 to week\xa052. From week 52 to week 76, all patients received aflibercept if they met the retreatment criteria, or sham injection, every 8 weeks. All patients were eligible to receive pan retinal photocoagulation at any time if they developed neovascularisation. The average age of the patients was 61.5\xa0years and most patients were male (56%). The mean BCVA at baseline was 52.2\xa0letters. Perfused retinal occlusion, defined as fewer than 10\xa0disc areas of capillary non-perfusion on fluorescein angiography, was present in 86% of patients in the intervention group and 79% of patients in the comparator group. The manufacturer stated that there was a slight imbalance in mean central retinal thickness between the 2\xa0groups (683.20\xa0micrometres in aflibercept compared with 638.66\xa0micrometres in sham). The manufacturer stated that these values are considered to be close to the baseline central retinal thickness values from other CRVO trials, including COPERNICUS. The manufacturer did not report any statistically significant differences in the other baseline characteristics between the 2\xa0groups.\n\nThe manufacturer used the same statistical analysis for the results from COPERNICUS and GALILEO and the intention-to-treat protocol was not used. In the primary efficacy analyses, data from all randomised patients who received any trial medication and had a baseline assessment and at least 1\xa0efficacy assessment after baseline were included (full analysis set). Data were analysed according to the group to which patients were randomised. In the sensitivity analyses, data from all patients in the full analysis set who received at least 5\xa0injections of trial medication and did not have any major protocol violations or deviations were included (per protocol population). Data were analysed according to which treatment patients received. In the safety analyses, data from all randomised patients who received any trial medication were included (safety population). Data were analysed according to which treatment patients received.\n\nThe primary outcome of both COPERNICUS and GALILEO was the proportion of eyes with a gain of 15\xa0or more letters in BCVA from baseline to week\xa024. Statistically significantly more patients gained 15\xa0or more letters at 24\xa0weeks with aflibercept than with sham in COPERNICUS (aflibercept 64/114 [56%] and sham 9/73 [12%], p<0.001 adjusted by region [North America compared with rest of the world] and baseline BCVA [greater than 20/200 compared with 20/200 or lower]). There were also statistically significantly more patients in GALILEO who gained 15\xa0or more letters at 24\xa0weeks with aflibercept than with sham (aflibercept 62/103 [60%] and sham 15/68 [22%], p<0.0001 adjusted by region [Europe compared with Asia/Pacific] and baseline BCVA [greater than 20/200 compared with 20/200 or lower]). The manufacturer performed a meta-analysis of the data from COPERNICUS and GALILEO at week 24 for the number of patients gaining 15 or more letters and the mean change in BCVA from baseline. The odds and relative risk of gaining 15 or more letters at 24 weeks was statistically significantly higher in the group receiving aflibercept compared with the group receiving sham injection (odds ratio 6.85 [95% confidence interval 4.08 to 11.51]; relative risk 3.28 [95% confidence interval 2.25 to 4.79]). Subgroup analysis showed that baseline perfusion status (presence or absence of ischaemia) did not appear to have any significant effect on response rates.\n\nFrom week 24 to week 52, patients in both groups in COPERNICUS received aflibercept treatment as needed and patients in GALILEO continued to receive treatment according to their group allocation at the start of the trial. At 52 weeks, there were statistically significantly more patients who had gained 15 or more letters in the group initially allocated to receive aflibercept than in the group initially allocated to receive sham injection in COPERNICUS (aflibercept 63/114 [55%] and sham 22/73 [30%], p<0.001) and in GALILEO (aflibercept 62/103 [60%] and sham 22/68 [32%], p=0.0004).\n\nFrom week 52 onwards, patients in both groups in COPERNICUS and GALILEO received aflibercept treatment as needed. At 76 weeks there were statistically significantly more patients who had gained 15 or more letters in the group initially allocated to receive aflibercept than in the group initially allocated to receive sham in GALILEO (aflibercept 59/103 [57%] and sham 20/68 [29%], p<0.0004). At 100 weeks there were statistically significantly more patients who had gained 15 or more letters in the group initially allocated to receive aflibercept than in the group initially allocated to receive sham in COPERNICUS (aflibercept 56/114 [49%] and sham 17/73 [23%], p=0.0003).\n\nSecondary outcomes in both trials included mean change at 24\xa0weeks from baseline in BCVA, central retinal thickness, and the proportions of patients progressing to ocular neovascularisation. The mean change in BCVA and the mean change in central retinal thickness from baseline to 24 weeks were statistically significantly greater in the aflibercept group compared with the sham group in both COPERNICUS and GALILEO. The percentage of patients progressing to neovascularisation at week 24 was statistically significantly greater in the sham group compared with the aflibercept group in COPERNICUS, but there was no statistically significant difference between the groups in GALILEO.\n\nThe manufacturer performed a network meta-analysis to compare aflibercept with ranibizumab and dexamethasone, because head-to-head comparison data were not available from randomised controlled trials. Six high-quality trials were included in the network meta-analysis. Two trials compared ranibizumab with sham injection (CRUISE and ROCC), 2 trials compared aflibercept with sham injection (COPERNICUS and GALILEO), and 2 trials compared dexamethasone intravitreal implant with sham injection (GENEVA 008 and GENEVA 009). Data for bevacizumab were not included in the analysis because the manufacturer did not consider treatment with bevacizumab to be the standard of care for people with CRVO and only 2 small studies of moderate-to-low quality were available (Epstein et al. 2012 and Wittstrom et al. 2012). Epstein compared bevacizumab with sham in 60 patients and Wittstrom compared bevacizumab with pan-retinal photocoagulation in 19 patients.\n\nThe network meta-analysis was performed only on 6-month (24\xa0weeks) trial data because of the switching of patients between treatment groups in some of the trials. For the comparison of ranibizumab with aflibercept, there was no statistically significant difference in the odds or relative risk of gaining 15 or more letters or of losing 15 or more letters. There was also no statistically significant difference in the mean change in BCVA from baseline to 24 weeks. For the comparison of dexamethasone with aflibercept, the odds and relative risk of gaining 15 or more letters from baseline to 24 weeks were statistically significantly smaller with dexamethasone and the mean change in BCVA was statistically significantly larger with aflibercept. The odds and relative risk of losing 15 or more letters were not reported. The results of the network meta-analysis were submitted as commercial in confidence and cannot be presented.\n\nImpact on health-related quality of life was measured by NEI VFQ-25 in COPERNICUS and by NEI VFQ-25 and EQ-5D in GALILEO. From baseline to 24 weeks, there was a statistically significant greater mean change in NEI VFQ-25 score in the aflibercept group of both COPERNICUS (aflibercept 7.2, standard deviation [SD] 12.1, and sham 0.8, SD 9.8; p=0.001) and GALILEO (aflibercept 7.5, SD not reported, and sham 3.5, SD not reported; p=0.001). From baseline to 52\xa0weeks, there was a statistically significant greater mean change in NEI VFQ-25 score in the aflibercept group in GALILEO (aflibercept 7.8 and sham 4.5, p=0.0049) but there was no statistically significant difference in mean change in NEI VFQ-25 total score in COPERNICUS (aflibercept 7.5 and sham 5.1, p=0.216). The mean changes in NEI VFQ-25 total score at week 76 in GALILEO and week 100 in COPERNICUS were not statistically significantly different. EQ-5D values were reported for the European subset of the population in GALILEO and there were no significant differences in EQ-5D scores. The EQ-5D data were submitted as academic in confidence and therefore cannot be presented.\n\nThe most common ocular treatment emergent adverse events in both trials and both groups were conjunctival haemorrhage, reduced visual acuity, eye pain, retinal haemorrhage, and increased intraocular pressure. There were deaths from arrhythmia, acute myocardial infarction, oesophageal adenocarcinoma, and pneumonia in the sham group of COPERNICUS. The exact number of deaths in this group was submitted as academic in confidence and cannot be presented. No deaths occurred in the aflibercept group of COPERNICUS or in either group in GALILEO. The manufacturer did not report whether the number of adverse events was statistically significantly different between the groups.\n\nThe manufacturer stated that the number of patients who had adverse events in the trials included in the network meta-analysis was too low to conduct a robust network meta-analysis on safety end points.\n\n# Cost effectiveness\n\nThe manufacturer developed a cost–utility Markov model that evaluated the cost effectiveness of aflibercept compared with ranibizumab in people with macular oedema secondary to CRVO. There were 25 health states in the model, defined by the BCVA in both the eye receiving treatment (the study eye) and the non-treated eye (the second eye), in addition to death. The health states were defined by a 15-letter range in BCVA. The model had 4-weekly cycles and a time horizon of 30\xa0years, which was effectively a lifetime horizon given that the baseline age of the cohort was 64 years. Patients could move into an improved health state, remain in the same health state, or move into a worse health state. The BCVA for the patients' second eye was assumed to remain constant over time and so second eye involvement was not included in the model.\n\nThe baseline distribution of the patient population between the 25\xa0health states of the model was inferred from the pooled COPERNICUS and GALILEO baseline distributions of the study eye and second eye. The model assumes that the distributions are independent, resulting in an inferred 2-eyed patient distribution with the largest proportion of patients having BCVA of 64 to 50 in their study eye and BCVA of 80 or more in their second eye.\n\nThe transition probabilities for aflibercept for the first 6 cycles (0 to 24 weeks) of the model were based on pooled data from COPERNICUS and GALILEO. To determine the transition probabilities for improvement in BCVA with ranibizumab for the first 6 cycles (0 to 24 weeks), the relative risk of gaining 15 or more letters with ranibizumab that was calculated in the network meta-analysis (see section 3.9) was applied to the aflibercept probabilities. The transition probabilities for moving to a worse BCVA with ranibizumab were assumed to be the same as with aflibercept. The transition probabilities for remaining in the same health state with ranibizumab were calculated by subtracting the transition probability for moving to a better health state and the transition probability for moving to a worse health state from 1. From cycle 6 to 13 (week 24 to week 52) it was not possible to use pooled data from COPERNICUS and GALILEO because patients in COPERNICUS were able to change treatments after week 24. Patients receiving ranibizumab in CRUISE were also able to change treatments after week 24. The manufacturer therefore chose to assume that, for both aflibercept and ranibizumab, patients' vision was maintained and patients remained in the same health state for cycles 6 to 13. From cycle 13 (week\xa052) onwards, it was assumed that for both aflibercept and ranibizumab, patients' BCVA deteriorated, following a natural disease history progression that remained constant over time (Klein et al. 1991).\n\nBecause the second eye was assumed to have a constant BCVA, only the BCVA of the study eye was modelled. The manufacturer assumed an indefinite duration of treatment benefit, based on the treatment benefit seen at 24 weeks.\n\nThe EQ-5D data collected in GALILEO were used for health-related quality-of-life data in the economic model. The utility values used in the base-case analysis were based on the EQ-5D value averaged across all 4 time points (0, 24, 52, and 76 weeks) for the European population in both the aflibercept and sham injection groups of GALILEO. The utility values obtained from these scores were then analysed based on the 'worse-seeing eye' of the patients, to reflect that patients enrolled to the 2 aflibercept trials were predominantly tested in their 'worse-seeing eye'. A total of 121 patients were included in the analyses, with 440 observations across all time points and across the 2 treatment groups. Each observation was assigned to 1 of the 5 health state BCVA ranges based on the BCVA achieved in the patient's 'worse-seeing eye'. The assignment was irrespective of whether the 'worse-seeing eye' was the study eye or the second eye. For each BCVA range, the average utility values were then estimated across these observations. The 'worse-seeing eye' utility values from the EQ-5D trial data for health states 1 to 5 were submitted as academic in confidence and cannot be presented. The 'worse-seeing eye' utility values were attributed to the 25 health states in the model based on the lower of the 2\xa0BCVA scores represented in a health state. The manufacturer did not use the NEI VFQ-25 data collected in COPERNICUS and GALILEO because they stated that EQ-5D is the preferred measure in the NICE reference case. The manufacturer identified a relevant study by Czoski-Murray et al. (2009) that was used to obtain utility values used in the scenario analysis.\n\nAdverse events were not modelled in the base-case analysis because the manufacturer stated that antivascular endothelial growth factors (anti-VEGFs; including ranibizumab and aflibercept) have similar safety profiles to each other. Raised intraocular pressure, cataracts and retinal tears were modelled in the scenario analysis.\n\nTotal costs for treatment were calculated from the unit costs for aflibercept or ranibizumab, administration, and a monitoring visit, multiplied by the number of treatment and monitoring visits needed. The direct drug costs in the model incorporated the confidential discount applied to the list price of aflibercept approved as part of the patient access scheme. The manufacturer assumed that 52.38% of administration visits for aflibercept and ranibizumab would take place in an outpatient setting and the remaining in a day-case setting. A weighted average was used to derive an administration cost of £257 for each drug. Monitoring visit costs were £197for each treatment.\n\nA one-stop model was applied, which assumed that administration visits can double as monitoring visits. It was assumed that aflibercept would need 5.75 administration and monitoring visits, and ranibizumab would need 5.50 administration and monitoring visits, from week 0 to week 24. From week 24 to week 52 it was assumed that aflibercept would need 2.55 administration visits and 3.50 monitoring visits, and that ranibizumab would need 3.30 administration visits and 4.40 monitoring visits. A cost associated with blindness was applied each month for the first and second year when the 'better-seeing eye' was declared blind (BCVA of 35 letters or fewer). The costs associated with blindness for year 1 and year 2 were submitted as commercial in confidence and cannot be presented.\n\nThe manufacturer's base-case cost-effectiveness results (incorporating the patient access scheme for aflibercept but not for ranibizumab) showed that aflibercept dominated (that is, was less expensive and more effective than) ranibizumab because it resulted in more quality-adjusted life years (incremental quality adjusted life years [QALYs] 0.054) and lower costs (incremental costs −£2937).\n\nThe manufacturer did not know the level of discount in the patient access scheme for ranibizumab because it is confidential so it applied a range of discounts to the list price of ranibizumab in its sensitivity analysis. When the manufacturer applied a discount to the list price of ranibizumab ranging from 0 to 50% in increments of 5%, aflibercept continued to dominate ranibizumab until the price of ranibizumab was discounted by 50%. When the price of ranibizumab was reduced by 50%, aflibercept had higher costs and more QALYs than ranibizumab, resulting in an incremental cost-effectiveness ratio (ICER) of £5871 per QALY gained. The ICERs resulting from the sensitivity analyses for the other key drivers of the model were not reported by the manufacturer.\n\nThe manufacturer conducted one-way sensitivity analyses with and without the confidential discount applied to the list price of aflibercept. When using the discounted price of aflibercept, a net monetary benefit approach (calculated by multiplying the incremental QALYs by £20,000 and then subtracting the incremental costs) was used because aflibercept dominated ranibizumab in the base-case analysis. The results of the sensitivity analyses indicated that the model was sensitive to changes in the number of ranibizumab injections from 0 to 24 weeks and from 25 to 52 weeks, the relative risk of gaining 15 or more letters when comparing aflibercept with ranibizumab, the number of aflibercept injections from 25 to 52 weeks, and the number of monitoring treatments for ranibizumab from 0 to 52 weeks.\n\nThe manufacturer conducted 3\xa0scenario analyses. The first scenario analysis used treatment durations of 2\xa0years and 4\xa0years rather than 1\xa0year. This showed that aflibercept continued to dominate ranibizumab with incremental QALYs of 0.054 with 2 or 4\xa0years of treatment (incremental costs with discounted aflibercept price were not reported). The second scenario used utility values for the 'better-seeing eye' from Czoski-Murray et al. (2009), irrespective of whether the 'better-seeing eye' was the study eye or the second eye. In Czoski-Murray, a value of 0.828 is applied if either eye is in health state 1. If the highest BCVA in either eye was health state 2, a value of 0.735 was applied. If the highest BCVA in either eye was health state 3, a value of 0.627 was applied. If the highest BCVA in either eye was health state 4, a value of 0.519 was applied. If both eyes were in health state 5, a value of 0.469 was applied. Using Czoski-Murray utility values, aflibercept continued to dominate ranibizumab with incremental QALYs of 0.028 (incremental costs with discounted aflibercept price not reported). The third scenario modelled the inclusion of the costs of adverse events (cataracts, intraocular pressure, and retinal tear) that were not included in the base-case analysis. Aflibercept continued to dominate ranibizumab with incremental QALYs of 0.054 (incremental costs with discounted aflibercept price not reported).\n\nThe manufacturer presented a fourth scenario analysis in which aflibercept was compared with dexamethasone. In the deterministic analysis, aflibercept was associated with more QALYs (incremental QALYs 0.189) and higher costs (incremental costs £612) which resulted in an ICER of £3236 per QALY gained.\n\nNo subgroups were identified by the manufacturer for analysis.\n\n# Evidence review group critique of the manufacturer's submission\n\nThe ERG commented that the manufacturer did not include bevacizumab or clinical observation as comparators even though they were listed as comparators in the final scope issued by NICE. The ERG noted that the manufacturer stated that it did not include bevacizumab or clinical observation as comparators because they are no longer considered routine or best practice since the publication of positive NICE guidance on Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance\xa0283) and Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance\xa0229). The ERG noted that bevacizumab has been widely used in the NHS and that patients may be kept under observation if there are contraindications to anti-VEGF treatment (such as allergy and eye infections) or if they refuse intravitreal treatment. The ERG questioned whether bevacizumab and clinical observation should have been included as comparators.\n\nThe ERG noted that it was not clear what proportion of patients in COPERNICUS and GALILEO had ischaemia or severe ischaemia, because different definitions of ischaemia and severe ischaemia exist. It suggested that the proportion of patients with ischaemia or severe ischaemia in the COPERNICUS and GALILEO trials may be lower than the proportion of patients with ischaemia or severe ischaemia and CRVO in England and Wales. The ERG questioned whether the results of COPERNICUS and GALILEO are applicable to patients with ischaemia or severe ischaemia.\n\nThe ERG highlighted that stopping rules were not used in the manufacturer's model. The manufacturer highlighted that no additional stopping rules were recommended in NICE guidance on ranibizumab (NICE technology appraisal guidance\xa0283). The ERG noted from the summary of product characteristics that stopping rules should be used for deterioration in visual acuity after 3 injections and if there is no fall in oedema fluid or central retinal thickness. The ERG was aware that the summary of product characteristics also states that continued treatment is not recommended if there is no improvement in visual and anatomic outcomes over the course of the first 3 injections. The ERG questioned whether a stopping rule should have been implemented in the model.\n\nThe ERG considered that the manufacturer's model does not incorporate the relative risk of losing 15 or more letters. It highlighted that the relative risk of losing 15 or more letters is in favour of ranibizumab and detrimental to dexamethasone, and not including the relative risk of losing 15 or more letters could affect the model results for the efficacy of aflibercept. The ERG questioned whether the relative risk of losing 15 or more letters should have been included in the model.\n\nThe ERG noted that, in the manufacturer's model, any net gain in visual acuity at 6 months broadly persists through the model lifetime. It highlighted that treatment was only received for 1\xa0year. The ERG questioned whether it was reasonable to assume that the net gain at week 24 will remain for the lifetime of the patient.\n\nThe ERG suggested that the implementation of the health-related quality-of-life data in the manufacturer's model may be conservative. It highlighted that, in the base-case analysis, it is assumed that the EQ-5D data are the health-related quality-of-life data for the 'worse-seeing eye'. The ERG noted that, as a consequence, this is only applied when the study eye is being modelled as the 'worse-seeing eye'. It also understood that it is assumed that the Czoski-Murray utility values are the health-related quality-of-life data for the 'better-seeing eye'. The ERG noted that, as a consequence, this is only applied when the study eye is being modelled as the 'better-seeing eye'. It questioned the appropriateness of this approach.\n\nThe ERG considered that the utility values in the manufacturer's base-case analysis were obtained from the EQ-5D data from GALILEO and the utility values used in one of the manufacturer's scenario analyses were obtained from Czoski-Murray et al. (2009). It noted that utility values from Brown (1999) were used in NICE guidance on dexamethasone (NICE technology appraisal guidance\xa0229) and ranibizumab (NICE technology appraisal guidance\xa0283). The ERG questioned which utility values are the most appropriate to use in the cost-effectiveness analysis.\n\nThe ERG argued that the costs of administration and monitoring for aflibercept and ranibizumab appeared to be overestimates. It stated that the outpatient administration costs could be reduced by costing them as 'Outpatient procedures: BZ23Z: Minor vitreous retinal procedures' and that the dedicated monitoring visit costs could be reduced by costing them as 'RA23Z: Ultrasound Scan, less than 20\xa0minutes'.\n\nThe ERG noted that the calculation used for the costs of raised intraocular pressure appears to be inappropriate. It stated that the costs of medication were unnecessarily divided by 13 and the costs of inpatient therapies were divided by 6.\n\nThe ERG considered the application of the costs of blindness in the aflibercept and ranibizumab groups in the model appears to be inappropriate. It stated that the manufacturer's model only considers the incidence events of blindness for the aflibercept and ranibizumab groups, rather than considering the incident events and the prevalence of blindness as it does in the dexamethasone group.\n\nThe ERG argued that the costs of blindness appear to have been underestimated. It stated that the manufacturer used Meads and Hyde (2003) as their source of the costs of depression. The ERG stated that McCrone et al. (2008) provides a more recent and more accurate estimate of the costs of depression.\n\nThe ERG noted that the manufacturer assumed that 52.38% of administration visits for anti-VEGF therapy (ranibizumab and aflibercept) would take place in an outpatient setting and the remaining in a day-case setting. This results in an average weighted administration cost of £257. The ERG considered that all administration visits would take place in an outpatient setting, resulting in an administration cost of £181. In NICE's guidance on ranibizumab, the ranibizumab administration visit was costed as an office-based outpatient procedure. The ERG queried which administration cost was the most appropriate.\n\nThe ERG conducted exploratory analyses, which involved the following modifications to the manufacturer's model:\n\nThe number of dexamethasone administrations in year\xa01 was changed from 4.00 to 1.86.\n\nThe cost per aflibercept or ranibizumab administration was changed from £257.45 to £180.73.\n\nThe cost per dedicated monitoring visit for aflibercept or ranibizumab was changed from £197.00 to £130.01.\n\nThe number of dedicated monitoring visits for aflibercept was changed from 2.43 to 0.95.\n\nThe number of dedicated monitoring visits for ranibizumab was changed from 2.03 to 1.10.\n\nThe cataract rate in the ranibizumab group was changed from 3.3% to 1.6%.\n\nThe duration of quality of life impact of raised intraocular pressure was changed from 1 day per cycle to 1 cycle.\n\nThe duration of quality of life impact of cataract was changed from 1 cycle to 3 cycles.\n\nThe duration of quality of life impact of retinal tears was changed from 1 cycle to 4 cycles.\n\nThe cost of raised intraocular pressure was changed from £33 to £4.\n\nThe blindness mortality multipliers were changed from 1.54 to 0.00.\n\nThe costs of blindness for aflibercept and ranibizumab were applied to both newly incident and prevalent cases of blindness instead of only the incident cases of blindness.\n\nThe costs of blindness were increased. The costs were submitted as commercial in confidence and therefore cannot be presented. The ERG also corrected an error in the manufacturer's calculation of adverse event rates for aflibercept and dexamethasone from month 7 to 12.\n\nThe ERG incorporated the confidential discount applied to the list price of aflibercept, but not the confidential discount for ranibizumab, in its exploratory analysis outlined in section 3.40. It showed that aflibercept dominated ranibizumab because it resulted in lower costs and higher QALYs (incremental costs −£3049, incremental QALYs 0.053).\n\nThe ERG was aware that the discounts agreed in the patient access schemes for aflibercept and ranibizumab are confidential. Therefore, it applied a discount ranging from 0 to 50% to the list price of ranibizumab in its exploratory analysis as well as applying the discount to the list price of aflibercept. With the discounted price of aflibercept and a 0 to 45% reduction in the list price of ranibizumab, aflibercept dominated ranibizumab because it is less costly (incremental costs ranged from −£3049 to −£122) and has a greater QALY gain (incremental QALYs 0.053) than ranibizumab. With the discounted price of aflibercept and a 50% reduction in the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £3820 per QALY gained (incremental cost £203, incremental QALY 0.053).\n\nThe ERG carried out sensitivity analyses around the relative risk of losing 15 or more letters at 6 months, the administration cost, duration of treatment, adverse events, and the source of utility values. The ERG used the discount to the list price of aflibercept and reduced the list price of ranibizumab by a value of either 0% or 10 to 50% in increments of 5%.\n\nWhen the relative risk of losing letters was included in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3005 to −£78, incremental QALYs 0.003). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £86,789 per QALY gained (incremental cost £247, incremental QALY 0.003).\n\nWhen the administration cost was reduced in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3083 to −£156, incremental QALYs 0.053). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £3176 per QALY gained (incremental cost £169, incremental QALY 0.053).\n\nWhen the duration of treatment was extended to 2 years and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£4422 to −£285, incremental QALYs 0.053). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £3274 per QALY gained (incremental cost £175, incremental QALY 0.053).\n\nWhen the duration of treatment was extended to 5 years and a discount of 0 to 50% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£6838 to −£31, incremental QALYs 0.053).\n\nWhen costs of adverse events were included in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3066 to −£139, incremental QALYs 0.053). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £3489 per QALY gained (incremental cost £187, incremental QALY 0.053).\n\nWhen Czoski-Murray utility values with the 'worse-seeing eye' were used in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3049 to −£122, incremental QALYs 0.053). When a 50% discount was applied to the list price of ranibizumab the ICER for aflibercept compared with ranibizumab was £3851 per QALY gained (incremental cost £203, incremental QALY 0.053).\n\nWhen Brown utility values with the 'worse-seeing eye' were used in the model and a discount of 0 to 45% was applied to the list price of ranibizumab, aflibercept dominated ranibizumab (incremental costs ranged from −£3049 to −£122, incremental QALYs 0.040). When a 50% discount was applied to the list price of ranibizumab, the ICER for aflibercept compared with ranibizumab was £5076 per QALY gained (incremental cost £203, incremental QALY 0.040).\n\nThe ERG also presented a deterministic ICER for aflibercept compared with dexamethasone. Incorporating the patient access scheme for aflibercept, the ICER for aflibercept compared with dexamethasone was £12,265 per QALY gained (incremental cost £2285, incremental QALY 0.186).\n\nThe ERG also carried out exploratory analyses on the comparison of aflibercept with dexamethasone, incorporating the patient access scheme for aflibercept. Increasing the duration of treatment to 2 years resulted in an ICER for the comparison of aflibercept with dexamethasone of £14,034 per QALY gained and increasing it to 5 years resulted in an ICER of £18,699 per QALY gained. For the comparison of aflibercept with dexamethasone, using Czoski-Murray utility values with the 'worse-seeing eye' resulted in an ICER of £12,868 per QALY gained, and with the 'better-seeing eye' resulted in an ICER of £18,740 per QALY gained. Using Brown utility values with the 'worse-seeing eye' resulted in an ICER of £16,833 per QALY gained, and with the 'better-seeing eye' resulted in an ICER of £28,523 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aflibercept, having considered evidence on the nature of macular oedema secondary to central retinal vein occlusion (CRVO) and the value placed on the benefits of aflibercept by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from patient experts about the problems associated with visual impairment caused by macular oedema. It heard that the loss of vision has a significant effect on the independence of people with the condition. The patient experts also stated that the condition affects the ability to drive, and take part in hobbies such as reading and going to the cinema. The patient experts commented that the condition can affect people of working age, as they may be unable to work and support their family, and they may be unable to take time off work to attend regular follow-up or monitoring appointments. The patient experts acknowledged that although people may be worried about having an injection the eye, they are willing to receive injections to keep their sight. The Committee agreed that loss of vision caused by macular oedema secondary to CRVO seriously impairs health-related quality of life.\n\nThe Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to CRVO is dexamethasone or antivascular endothelial growth factor (anti-VEGF) drugs, especially ranibizumab. The clinical specialists noted that the use of bevacizumab outside its marketing authorisation has decreased since NICE's guidance on Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance\xa0283) and Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance\xa0229) recommended ranibizumab and dexamethasone as options for treating people with CRVO. The clinical specialists stated that they are more likely to use ranibizumab than dexamethasone even though it has a higher frequency of injections, because they believe that it has a decreased risk of side effects such as raised intraocular pressure and cataracts. The Committee concluded the current standard treatment for visual impairment caused by macular oedema secondary to CRVO is ranibizumab, although dexamethasone is also used.\n\nThe Committee considered the comparators for the appraisal. It noted that the final scope issued by NICE included dexamethasone, ranibizumab, bevacizumab and clinical observation as comparators, but that the manufacturer only included dexamethasone and ranibizumab as comparators in its economic analysis. The Committee noted that the manufacturer did not include clinical observation as a comparator because it was of the opinion that patients would receive treatment with either ranibizumab or dexamethasone because NICE had recommended them as treatment options. The Committee was aware that the manufacturer did not include bevacizumab in its submission. The Committee acknowledged that the manufacturer's rationale for not including bevacizumab as a comparator was that its use in the NHS was not routine or best practice. The Committee heard from the clinical experts that the use of bevacizumab has decreased since the publication of NICE's guidance on ranibizumab (NICE technology appraisal guidance\xa0283) and dexamethasone (NICE technology appraisal guidance\xa0229). Most importantly, the Committee was concerned that there were only 2 small trials for bevacizumab compared with sham injections, and no direct comparisons of aflibercept with intravitreal bevacizumab are currently available. The Committee concluded that there is currently insufficient evidence for bevacizumab to make the robust comparisons with aflibercept needed for a cost-effectiveness analysis.The Committee further concluded that ranibizumab and dexamethasone were appropriate comparators in this appraisal.\n\n# Clinical effectiveness\n\nThe Committee considered the populations in COPERNICUS and GALILEO. The Committee acknowledged that the trials did not exclude people with ischaemia or severe ischaemia. The Committee heard from the manufacturer that aflibercept was effective across the full trial populations of COPERNICUS and GALILEO. However, the Committee heard from the clinical specialists and the ERG\n\nthat the proportions of patients with ischaemia or severe ischaemia in the trials were uncertain because different definitions of ischaemia and severe ischaemia exist. The Committee accepted that aflibercept could be considered effective for all of the population included in the trials.\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of aflibercept. It acknowledged that the main sources of evidence came from the COPERNICUS and GALILEO randomised controlled trials, which compared aflibercept with sham injection in people with CRVO. The Committee noted that in both COPERNICUS and GALILEO, aflibercept was associated with statistically significantly more eyes gaining 15 or more letters at 24 weeks compared with sham injection. The Committee was aware that people in the sham groups could receive aflibercept after 24 weeks in COPERNICUS and after 52 weeks in GALILEO. The Committee agreed that aflibercept resulted in greater visual gains when it was given to patients soon after diagnosis. The Committee concluded that aflibercept is a clinically effective treatment for visual impairment caused by macular oedema secondary to CRVO compared with sham injection.\n\nThe Committee considered the evidence for the clinical effectiveness of aflibercept compared with ranibizumab and dexamethasone. It noted that evidence from direct comparisons was not available, and that a network meta-analysis was presented by the manufacturer. The Committee heard from the ERG that the methods used in the network meta-analysis were appropriate and that the analysis was well conducted. The Committee agreed that in the absence of a direct comparison, the results could be used to inform decisions about the clinical effectiveness of aflibercept compared with ranibizumab and dexamethasone. The Committee agreed that given the nature of the evidence, there was some uncertainty about the clinical effectiveness of aflibercept compared with ranibizumab and dexamethasone, but concluded that there was no evidence that aflibercept was not as clinically effective as ranibizumab or dexamethasone.\n\nThe Committee considered the evidence for adverse effects associated with aflibercept. It noted that the overall frequency of adverse events in the COPERNICUS and GALILEO trials was low. The Committee heard from the clinical specialists that the safety profile of aflibercept is similar to that of ranibizumab, which is already licensed for use in this condition (see NICE guidance on ranibizumab [NICE technology appraisal guidance\xa0283]). The Committee concluded that treatment with aflibercept had a similar adverse event profile to ranibizumab.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. The Committee noted that the manufacturer had presented a comparison of aflibercept with ranibizumab for its base-case analysis and a comparison of aflibercept with dexamethasone as a scenario analysis. The Committee acknowledged that the ERG had concerns about some of the assumptions made by the manufacturer in the base-case analysis. In particular, the ERG queried why:\n\nany net gain in visual acuity at 24 weeks was assumed to persist through the lifetime of the model\n\nthe relative risk of losing 15 or more letters at 24 weeks was not included in the model\n\nthe duration of treatment was assumed to be 1 year\n\nEQ-5D data from GALILEO was used as a source of utility values\n\nthe costs of adverse events were not included in the model\n\na stopping rule was not included in the model\n\nthe estimated administration costs of aflibercept and ranibizumab were high\n\nthe estimated costs of blindness were low.The Committee considered each of these issues in turn, as detailed below.\n\nThe Committee discussed the manufacturer's assumption that the benefits of treatment at 24 weeks would continue indefinitely throughout the lifetime of the model. The Committee heard from the ERG that the assumption may be optimistic and that it would exaggerate the quality-adjusted life year (QALY) gain of aflibercept over ranibizumab and dexamethasone. The Committee acknowledged that a sensitivity analysis around the duration of benefit of treatment was not undertaken by the manufacturer or the ERG. The Committee heard from the ERG that if the benefits of treatment at 24 weeks had not been assumed to continue indefinitely it was unlikely to change the overall results of the manufacturer's base-case analysis because aflibercept would still dominate (be less expensive and more effective than) ranibizumab. The Committee accepted that it was not appropriate to assume that the duration of treatment benefit at 24 weeks would continue indefinitely but concluded that it was likely to have little impact on the cost-effectiveness estimates.\n\nThe Committee discussed how the manufacturer's model did not incorporate the relative risk of losing 15 or more letters. The Committee heard from the ERG that incorporating the relative risk of losing 15 or more letters into the model would ensure that the transition probabilities were correctly calculated. The ERG highlighted that including the relative risk of losing 15 or more letters in its exploratory analysis, which included the confidential discount applied to the list price for aflibercept, did not affect the dominance of aflibercept over ranibizumab except when a 50% reduction was applied to the list price of ranibizumab (see section 3.43). The Committee accepted that the relative risk of losing 15 or more letters should have been included in the manufacturer's model but concluded that including it was unlikely to change the dominance of aflibercept over ranibizumab.\n\nThe Committee discussed the manufacturer's assumption that the duration of aflibercept treatment was 1 year. The Committee heard from the clinical specialists that most patients still receive treatment with anti-VEGF therapy in year 2 and around a third of patients receive treatment in year 3. The clinical specialists also noted that data on the difference in the length of treatment with ranibizumab or aflibercept for macular oedema secondary to CRVO are not yet available. The Committee considered the manufacturer's scenario analyses in which the treatment duration of aflibercept was extended to 2\xa0years or 4\xa0years (see section 3.25) and the ERG's exploratory sensitivity analyses in which treatment duration was extended to 2 or 5 years and which included the confidential discount applied to the list price for aflibercept and a range of discounts from 0 to 50% applied to the list price of ranibizumab (see section 3.43). The Committee noted that when treatment duration was extended to 5 years, aflibercept was dominant over ranibizumab regardless of the discount applied to the ranibizumab list price. The Committee concluded that the duration of aflibercept treatment was likely to be longer than 1 year, and that increasing the duration of treatment up to 5 years did not change the dominance of aflibercept over ranibizumab.\n\nThe Committee considered the source of health-related quality-of-life data used in the manufacturer's model. The Committee acknowledged that EQ-5D data from the European subset of the GALILEO population were used as a source of utility values in the manufacturer's base-case analysis, which meets NICE's reference case. The Committee also considered the manufacturer's scenario analyses, which used Czoski-Murray utility values, and included the confidential discount applied to the list price for aflibercept, noting that this did not affect the dominance of aflibercept over ranibizumab. The Committee noted that the ERG also carried out an exploratory sensitivity analysis using utility values from Czoski-Murray and Brown, which included the confidential discount applied to the list price for aflibercept and a range of discounts from 0 to 50% applied to the list price of ranibizumab. The Committee noted that the use of these utility values did not affect the dominance of aflibercept over ranibizumab unless there was a 50% reduction in the list price of ranibizumab. The Committee concluded that the source of the utility values did not substantially affect the cost-effectiveness estimates of aflibercept compared with ranibizumab.\n\nThe Committee considered how the cost of adverse events had not been included in the manufacturer' base-case analysis. It noted that the reason given in the manufacturer's submission was that anti-VEGFs have similar safety profiles to each other. The Committee also acknowledged that the manufacturer presented a scenario analysis that included adverse events and that adverse events were also included in the ERG's exploratory analyses (see sections 3.25 and 3.43). The Committee noted that aflibercept continued to dominate ranibizumab in the manufacturer's scenario analysis and in the ERG's exploratory analysis if adverse events were included and a discount of 0 to 45% in the list price of ranibizumab was applied. The Committee was aware that the incremental cost-effectiveness ratio (ICER) for aflibercept was less than £3500 per QALY gained when a 50% discount was applied to the list price of ranibizumab. The Committee concluded that even if adverse events had been included in the manufacturer's base-case analysis, it was likely that aflibercept would continue to dominate ranibizumab.\n\nThe Committee discussed the fact that the manufacturer's model did not include a stopping rule. The Committee noted that the summary of product characteristics for aflibercept states that continued treatment is not recommended if there is no improvement in visual and anatomic outcomes over the course of the first 3 injections. It was also aware that the summary of product characteristics for ranibizumab for macular oedema secondary to retinal vein occlusion also states that continued treatment is not recommended if there is no improvement in visual acuity after 3 injections. The Committee heard from the clinical specialists that they would not continue treatment if there was no improvement in visual acuity after 3 injections. The Committee concluded that a stopping rule should have been included in the manufacturer's model.\n\nThe Committee discussed the administration costs of aflibercept and ranibizumab included in the manufacturer's model. The Committee noted that the manufacturer used a weighted average cost, based on the assumption that 52.38% of patients would be treated in an outpatient setting and the remaining in a day-case setting. The Committee heard from the clinical specialists that most patients would be treated as outpatients; however, it also heard that not all units have the facilities to perform the treatment as an outpatient procedure. The Committee noted that the ERG presented lower costs of administration of aflibercept and ranibizumab in its report. The Committee concluded that the ERG's assumptions about the costs of administration were likely to be more realistic than those used by the manufacturer and therefore it was uncertain of the impact on the cost-effectiveness analyses.\n\nThe Committee discussed the costs of blindness included in the manufacturer's model. The Committee was aware that the source of the estimated costs of depression associated with blindness used by the ERG was more recent than the source used by the manufacturer. The Committee also noted that the costs of blindness presented by the ERG in their report were higher than those in the base-case analysis. The Committee recognised that if the costs presented by the ERG had been used, aflibercept would continue to dominate ranibizumab. The Committee concluded that the ERG's assumption about the costs of blindness were likely to be more in line with clinical practice than those used by the manufacturer.\n\nThe Committee considered the ICERs for aflibercept compared with ranibizumab estimated by the manufacturer and the ERG. It noted that these analyses incorporated the discount agreed in the patient access scheme for aflibercept and a range of discounts applied to the list price of ranibizumab. The Committee was aware of the actual discount agreed in the patient access scheme for ranibizumab (this was submitted as commercial in confidence and therefore cannot be presented). It agreed that the analyses undertaken by the manufacturer and the ERG captured the discount agreed in the patient access scheme for ranibizumab. The Committee noted that in the manufacturer's base-case analysis aflibercept dominated ranibizumab when the discounted price of aflibercept was used. The Committee considered the concerns raised by the ERG about the manufacturer's model and acknowledged the ERG's amendments to the manufacturer's model (see section 3.40). The Committee was aware that the ERG's exploratory analysis resulted in slightly more cost savings for aflibercept, and that aflibercept continued to dominate ranibizumab. The Committee also discussed the ERG's exploratory analysis around the list price of ranibizumab, incorporating the confidential discount on the list price for aflibercept. The Committee noted that a reduction of 0 to 45% in the list price of ranibizumab did not affect the dominance of aflibercept over ranibizumab. It also considered that when a 50% reduction was applied to the list price of ranibizumab, with the exception of the scenario of including the relative risk of losing 15 or more letters, the ICERs for aflibercept compared with ranibizumab ranged from £750 to £9300 per QALY gained. Taking into account the exact magnitude of the discounts agreed in the patient access schemes for aflibercept and ranibizumab, the Committee concluded that aflibercept was a cost-effective use of NHS resources compared with ranibizumab for treating people with visual impairment caused by macular oedema secondary to CRVO.\n\nThe Committee discussed the manufacturer's scenario analysis comparing aflibercept with dexamethasone, and the ERG's exploratory analyses. The Committee noted that the ERG's exploratory analysis, which included the confidential discount applied to the list price for aflibercept, resulted in an ICER of £12,300 per QALY gained for aflibercept compared with dexamethasone. The Committee considered that using Czoski-Murray utility values resulted in an ICER of £12,900 per QALY gained and using Brown utility values resulted in an ICER of £16,800 per QALY gained when applied to the 'worse-seeing eye'. The Committee also acknowledged that even using the Brown utilities for the 'better-seeing eye', that is to say, the 'worst case scenario', the ICER was below the top end of the range that would normally be considered a cost-effective use of NHS resources (£20,000–30,000 per QALY gained). The Committee concluded that aflibercept was a cost-effective use of NHS resources compared with dexamethasone for treating people with visual impairment caused by macular oedema secondary to CRVO.\n\nThe Committee discussed how innovative aflibercept is in its potential to make a significant and substantial impact on health-related benefits. It agreed that aflibercept as well as other anti-VEGF treatments were a substantial improvement over previous treatments, and considered that this improvement applied to the class of drugs. In addition there were no substantial benefits of aflibercept over its comparators that were not already captured in the QALY estimation in the modelling.\n\n# Summary of the Appraisal Committee's key conclusions\n\nTA305\n\nAppraisal title: Aflibercept for treating visual impairment caused by macular oedema secondary to central retinal vein occlusion\n\nSection\n\nKey conclusion\n\nAflibercept solution for injection is recommended as an option for treating visual impairment caused by macular oedema secondary to central retinal vein occlusion only if the manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme.\n\n\n\n\n\nThe clinical evidence from the COPERNICUS and GALILEO trials, which compared aflibercept with sham injection, showed that aflibercept was associated with a greater proportion of eyes gaining 15 or more letters from baseline to 24 weeks than sham injection.\n\n\n\n\n\nThe Committee accepted the results from the manufacturer's network meta-analysis. This showed that there is no statistically significant difference in the odds or relative risk of gaining 15 or more letters from baseline to 24 weeks for the comparison of aflibercept with ranibizumab, and that the odds and relative risk of gaining 15 or more letters from baseline to 24 weeks was statistically significantly smaller with dexamethasone compared with aflibercept.\n\n, 4.7\n\n\n\nThe key driver for the cost-effectiveness results for the comparison of aflibercept with ranibizumab is the discount applied to the list price of ranibizumab. For the comparison of aflibercept with dexamethasone, the key driver is the source of the health-related quality of life data and whether it was applied to the 'worse-seeing eye' or 'better-seeing eye'.\n\n, 4.19\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard that visual impairment caused by macular oedema secondary to central retinal vein occlusion seriously impairs health-related quality of life.\n\n\n\n\n\nThe Committee heard that the current standard treatment for macular oedema secondary to central retinal vein occlusion is dexamethasone or antivascular endothelial growth factor (anti-VEGF) drugs, such as ranibizumab. However, clinicians are more likely to use ranibizumab than dexamethasone because it is believed to have fewer side effects.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee agreed that aflibercept as well as other anti-VEGF treatments were a substantial improvement over previous treatments, and considered that this improvement applied to the class of drugs.\n\nThe Committee was not aware of any substantial benefits of aflibercept solution for injection over its comparators that were not already captured in the quality-adjusted life year (QALY) estimation in the modelling.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nAflibercept solution for injection has a UK marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to central retinal vein occlusion (CRVO)'.\n\n\n\nAdverse reactions\n\nThe Committee agreed that the evidence suggested the overall frequency of adverse events in the trials was low with aflibercept solution for injection and concluded that aflibercept had a similar adverse event profile to ranibizumab.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee acknowledged that the evidence presented by the manufacturer was from 2\xa0trials (COPERNICUS and GALILEO) and a network meta-analysis.\n\nThe Committee was aware that the scope of the appraisal listed bevacizumab as a comparator. It noted that the manufacturer identified only 2\xa0small trials of bevacizumab relevant to the network meta-analysis, and no trials that directly compared bevacizumab with aflibercept. The Committee concluded that there is currently not enough evidence to allow bevacizumab to be included with confidence in clinical and cost-effectiveness analyses.\n\n, 4.6, 4.7\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard that the current standard treatment for visual impairment caused by macular oedema secondary to central retinal vein occlusion is dexamethasone or anti-VEGF drugs, such as ranibizumab.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee heard from the clinical specialists and the Evidence Review Group (ERG) that different definitions of ischaemia and severe ischaemia exist. It concluded that it was unclear whether any evidence had been presented for people with ischaemia or severe ischaemia.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that aflibercept was associated with statistically significantly more eyes gaining 15 or more letters at 24\xa0weeks compared with sham injection. The Committee concluded that aflibercept is a clinically effective treatment option for visual impairment caused by macular oedema secondary to central retinal vein occlusion.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. It accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered the following uncertainties in the model:\n\nthe assumption that the benefits of treatment at 24\xa0weeks would continue indefinitely\n\nnot including the relative risk of losing 15 or more letters\n\nthe assumption that the duration of aflibercept treatment was 1\xa0year\n\nthe use of EQ-5D data as a source of utility values\n\nnot including the cost of adverse events\n\nnot including a stopping rule\n\noverestimated administration costs for aflibercept and ranibizumab\n\nunderestimated costs of blindness.The Committee concluded that these uncertainties were unlikely to change the dominance of aflibercept over ranibizumab.\n\n-4.17\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that the utility values in the manufacturer's base-case analysis were obtained from the EQ-5D data from GALILEO. The Committee heard from the ERG that using utility values from Czoski-Murray or Brown did not substantially affect the cost-effectiveness estimates of aflibercept compared with ranibizumab.\n\n\n\nThe Committee was not aware of any substantial benefits of aflibercept over its comparators that were not already captured in the QALY estimation in the modelling.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe manufacturer's sensitivity analyses showed that the cost effectiveness of aflibercept was sensitive to changes in the number of ranibizumab injections from 0 to 24\xa0weeks and 25 to 52\xa0weeks, the relative risk of gaining 15 or more letters when comparing aflibercept with ranibizumab, the number of aflibercept injections from 25 to 52\xa0weeks, and the number of monitoring visits for ranibizumab from 0 to 52\xa0weeks.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that the manufacturer's base-case analysis showed that aflibercept dominated ranibizumab (that is, it was more effective and less costly), resulting in more QALYs and lower costs. The Committee considered the uncertainties in the manufacturer's model and noted the ERG's exploratory analysis, which resulted in slightly more cost savings with aflibercept. It also noted that aflibercept continued to dominate ranibizumab despite the changes made by the ERG.\n\n\n\nThe Committee noted that the ERG's exploratory analysis, which included the confidential discount applied to the list price for aflibercept, resulted in an incremental cost-effectiveness ratio (ICER) of £12,300 per QALY gained for aflibercept compared with dexamethasone. The Committee also noted that even using the Brown utilities for the 'better-seeing eye', that is to say, the 'worst case scenario', the ICER was below the top end of the range that would normally be considered a cost-effective use of NHS resources (£20,000–£30,000 per QALY gained).\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe Department of Health and the manufacturer have agreed that aflibercept will be available to the NHS with a patient access scheme which makes aflibercept available with a discount. The level of discount is commercial in confidence.\n\n\n\n\n\nEnd-of-life considerations\n\nNot applicable\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues relevant to the Committee's recommendation were raised.\n\n", 'Related NICE guidance ': 'Details are correct at the time of publication. Further information is available on the NICE website.\n\nRanibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance\xa0283 (2013).\n\nDexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance\xa0229 (2011).', 'Review of guidance': 'The guidance on this technology will be considered for review in February 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveFebruary 2014', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt has been incorporated into the NICE pathway on eye conditions along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0446-4'}	https://www.nice.org.uk/guidance/ta305	Evidence-based recommendations on aflibercept (Eylea) for treating sight problems caused by macular oedema from central retinal vein occlusion in adults.
6c3ec3ec8a3acbfb7c7c65c0b5fc5b100b48777a	nice	Electrochemotherapy for primary basal cell carcinoma and primary squamous cell carcinoma	Electrochemotherapy for primary basal cell carcinoma and primary squamous cell carcinoma # Recommendations This document replaces previous guidance on electrochemotherapy for primary basal cell carcinoma and primary squamous cell carcinoma (interventional procedure guidance 447). Current evidence on the safety of electrochemotherapy for primary basal cell carcinoma (BCC) and primary squamous cell carcinoma (SCC) raises no major concerns. Evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and local audit, and with submission of data to a register (see 1.5). Clinicians wishing to undertake electrochemotherapy for treating primary BCC and primary SCC should take the following actions: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's efficacy and why it is being offered as an alternative to other established methods of treatment, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Patient selection should be carried out by a specialist skin cancer multidisciplinary team. Patient selection is particularly important because the cure rates for established treatments in accessible sites are very high. Careful consideration should be given to the reasons for offering electrochemotherapy, especially in the context of treating primary BCC and SCC with curative intent. This procedure should only be carried out by clinicians with specific training in the technique. Clinicians should submit data on all patients undergoing electrochemotherapy (including details of case selection, methods of follow-up and outcomes) to the InspECT register, an international register dedicated to electrochemotherapy, and review clinical outcomes locally. Entry into research trials should also be considered, with a view to providing data about cure and about recurrence rates, compared with other forms of treatment.# Indications and current treatments Basal cell carcinoma (BCC) is the most common type of skin cancer in the UK. It is generally a slow-growing, locally invasive epidermal skin tumour that rarely spreads to other parts of the body. Although it is not usually life-threatening, the tumour can cause extensive tissue destruction if it is not treated. Squamous cell carcinoma (SCC) is the second most common type of skin cancer in the UK. It may spread into local lymph nodes and metastasise to other parts of the body. Current treatments for BCC and SCC include surgical excision and radiotherapy, and less commonly curettage, cryotherapy and chemotherapy.# The procedure Electrochemotherapy is a local treatment that aims to enhance the effects of chemotherapy. The procedure is performed with the patient under general or local anaesthesia with or without sedation. Chemotherapy drugs are given first, either intravenously or directly into the tumour. Drug dose is individualised based on either body surface area or tumour volume. Shortly after drug administration, brief and intense electric pulses are delivered around or directly into the tumour using either surface plates or needle electrodes. This makes the cell membranes more permeable to the chemotherapy drugs so that their cytotoxic effect is increased. Different-shaped plates or electrodes are used depending on the tumour size, extent, shape and location. Treatment duration may vary depending on the number and size of tumours. Larger tumours may need several applications to cover the entire surface. Repeated treatments can be performed if necessary (within the lifetime dose limits of the chemotherapy drugs).# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A non-randomised comparative study of 113 patients (85 basal cell carcinoma and 28 squamous cell carcinoma ) compared 2 different electric pulse sequences for electrochemotherapy of stage I (T1N0M0) BCC and SCC tumours. The complete response rate was 83% at 12 months. A non-randomised comparative study of 34 patients comparing electrochemotherapy against either intratumoural bleomycin alone or electric pulse therapy included 21 patients with BCC or SCC (66 tumours). The study reported an objective response rate of 100% and a complete response of 94% (51/54) in BCC primary tumours treated with electrochemotherapy at 12 weeks. The 1 SCC tumour treated with electrochemotherapy had a partial response. There were no complete responses in the 11 BCC tumours treated with either intratumoural bleomycin alone (8 tumours) or electric pulse therapy alone (3 tumours). The study of 113 patients (85 BCC and 28 SCC tumours) with an initial 100% complete response reported that 14% (16/113) of tumours recurred between 2 and 6 months after treatment (no further details reported). A case series of 6 patients (3 BCC and 3 SCC tumours) reported no damage to nerve or ocular function after electrochemotherapy in 4 patients with tumours close to the facial nerve or eye muscles. The case series of 6 patients (3 BCC and 3 SCC tumours) reported a 'very satisfactory' cosmetic outcome at between 6 and 12 months after electrochemotherapy (no further details reported). The specialist advisers listed additional key efficacy outcomes as quality of life, control of bleeding and reduction of odour from fungating tumours.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Localised involuntary muscle contractions and a sensation of a jolt or shock associated with the electric pulses were reported in the study of 34 patients and 3 case series of 50, 24 and 15 patients. They stopped immediately when the electric pulses were discontinued. A septal cartilage perforation was reported in 1 patient receiving treatment in the right nasal vestibule in the case series of 6 patients. This occurred after a biopsy performed 8 weeks after treatment. No further details were reported. Slight burning of the skin was reported in 87% (7/8) of patients on whom the plate electrodes were used in the study of 34 patients. This healed within 6–8 weeks. No further details were reported. Erythema and oedema 72 hours after treatment were reported in the case series of 24 patients. No further details were reported. Increased tear production in the ipsilateral eye was reported in 2 patients who received treatment for tumours in the medial canthus in the case series of 6 patients. This caused no visual impairment and resolved within 2 months. No further details were reported. Post-treatment pain was described as 'moderate' and was managed with paracetamol and diclofenac for 5–7 days in the case series of 6 patients. Other side effects attributed to the chemotherapy agent such as slight nausea and allergic reactions were also reported. The specialist advisers listed additional key safety outcomes as increase in wound exudate after the procedure and chemotherapy toxicity, specifically pulmonary fibrosis as a result of chemotherapy (bleomycin).# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. Changes since first publication This guidance replaces interventional procedure guidance 447 (published March 2013). IPG447 was reconsidered by the Interventional Procedures Advisory Committee after an internal procedural error was identified. As a result of this changes were made to sections 1.1, 1.3 and 1.5 of the guidance and NICE consulted again on the revised document. The changes made to the recommendations were: : References to patient selection and special arrangements for research were removed and a recommendation to submit data to a register added. : The following text was added: 'Patient selection is particularly important because the cure rates for established treatments in accessible sites are very high.' : The following text was added: 'Entry into research trials should also be considered, with a view to providing data about cure and about recurrence rates, compared with other forms of treatment.' Some minor changes were also made to the rest of the document after consultation. We have produced a summary of this guidance for patients and carers. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0430-3	{'Recommendations': "This document replaces previous guidance on electrochemotherapy for primary basal cell carcinoma and primary squamous cell carcinoma (interventional procedure guidance 447).\n\nCurrent evidence on the safety of electrochemotherapy for primary basal cell carcinoma (BCC) and primary squamous cell carcinoma (SCC) raises no major concerns. Evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and local audit, and with submission of data to a register (see\xa01.5).\n\nClinicians wishing to undertake electrochemotherapy for treating primary BCC and primary SCC should take the following actions:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and why it is being offered as an alternative to other established methods of treatment, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nPatient selection should be carried out by a specialist skin cancer multidisciplinary team. Patient selection is particularly important because the cure rates for established treatments in accessible sites are very high. Careful consideration should be given to the reasons for offering electrochemotherapy, especially in the context of treating primary BCC and SCC with curative intent.\n\nThis procedure should only be carried out by clinicians with specific training in the technique.\n\nClinicians should submit data on all patients undergoing electrochemotherapy (including details of case selection, methods of follow-up and outcomes) to the InspECT register, an international register dedicated to electrochemotherapy, and review clinical outcomes locally. Entry into research trials should also be considered, with a view to providing data about cure and about recurrence rates, compared with other forms of treatment.", 'Indications and current treatments': 'Basal cell carcinoma (BCC) is the most common type of skin cancer in the UK. It is generally a slow-growing, locally invasive epidermal skin tumour that rarely spreads to other parts of the body. Although it is not usually life-threatening, the tumour can cause extensive tissue destruction if it is not treated. Squamous cell carcinoma (SCC) is the second most common type of skin cancer in the UK. It may spread into local lymph nodes and metastasise to other parts of the body.\n\nCurrent treatments for BCC and SCC include surgical excision and radiotherapy, and less commonly curettage, cryotherapy and chemotherapy.', 'The procedure': 'Electrochemotherapy is a local treatment that aims to enhance the effects of chemotherapy.\n\nThe procedure is performed with the patient under general or local anaesthesia with or without sedation. Chemotherapy drugs are given first, either intravenously or directly into the tumour. Drug dose is individualised based on either body surface area or tumour volume. Shortly after drug administration, brief and intense electric pulses are delivered around or directly into the tumour using either surface plates or needle electrodes. This makes the cell membranes more permeable to the chemotherapy drugs so that their cytotoxic effect is increased. Different-shaped plates or electrodes are used depending on the tumour size, extent, shape and location. Treatment duration may vary depending on the number and size of tumours. Larger tumours may need several applications to cover the entire surface. Repeated treatments can be performed if necessary (within the lifetime dose limits of the chemotherapy drugs).', 'Efficacy': "This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA non-randomised comparative study of 113\xa0patients (85\xa0basal cell carcinoma [BCC] and 28\xa0squamous cell carcinoma [SCC]) compared 2\xa0different electric pulse sequences for electrochemotherapy of stage I (T1N0M0) BCC and SCC tumours. The complete response rate was 83% at 12\xa0months.\n\nA non-randomised comparative study of 34\xa0patients comparing electrochemotherapy against either intratumoural bleomycin alone or electric pulse therapy included 21\xa0patients with BCC or SCC (66\xa0tumours). The study reported an objective response rate of 100% and a complete response of 94% (51/54) in BCC primary tumours treated with electrochemotherapy at 12\xa0weeks. The 1\xa0SCC tumour treated with electrochemotherapy had a partial response. There were no complete responses in the 11\xa0BCC tumours treated with either intratumoural bleomycin alone (8\xa0tumours) or electric pulse therapy alone (3\xa0tumours).\n\nThe study of 113\xa0patients (85\xa0BCC and 28\xa0SCC tumours) with an initial 100% complete response reported that 14% (16/113) of tumours recurred between 2 and 6\xa0months after treatment (no further details reported).\n\nA case series of 6\xa0patients (3 BCC and 3 SCC\xa0tumours) reported no damage to nerve or ocular function after electrochemotherapy in 4\xa0patients with tumours close to the facial nerve or eye muscles.\n\nThe case series of 6\xa0patients (3\xa0BCC and 3 SCC tumours) reported a 'very satisfactory' cosmetic outcome at between 6 and 12\xa0months after electrochemotherapy (no further details reported).\n\nThe specialist advisers listed additional key efficacy outcomes as quality of life, control of bleeding and reduction of odour from fungating tumours.", 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nLocalised involuntary muscle contractions and a sensation of a jolt or shock associated with the electric pulses were reported in the study of 34\xa0patients and 3\xa0case series of 50, 24 and 15\xa0patients. They stopped immediately when the electric pulses were discontinued.\n\nA septal cartilage perforation was reported in 1\xa0patient receiving treatment in the right nasal vestibule in the case series of 6\xa0patients. This occurred after a biopsy performed 8\xa0weeks after treatment. No further details were reported.\n\nSlight burning of the skin was reported in 87% (7/8) of\xa0patients on whom the plate electrodes were used in the study of 34\xa0patients. This healed within 6–8\xa0weeks. No further details were reported.\n\nErythema and oedema 72\xa0hours after treatment were reported in the case series of 24\xa0patients. No further details were reported.\n\nIncreased tear production in the ipsilateral eye was reported in 2\xa0patients who received treatment for tumours in the medial canthus in the case series of 6\xa0patients. This caused no visual impairment and resolved within 2\xa0months. No further details were reported.\n\nPost-treatment pain was described as 'moderate' and was managed with paracetamol and diclofenac for 5–7\xa0days in the case series of 6\xa0patients.\n\nOther side effects attributed to the chemotherapy agent such as slight nausea and allergic reactions were also reported.\n\nThe specialist advisers listed additional key safety outcomes as increase in wound exudate after the procedure and chemotherapy toxicity, specifically pulmonary fibrosis as a result of chemotherapy (bleomycin).", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': "NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nChanges since first publication\n\nThis guidance replaces interventional procedure guidance 447 (published March 2013). IPG447 was reconsidered by the Interventional Procedures Advisory Committee after an internal procedural error was identified. As a result of this changes were made to sections 1.1, 1.3 and 1.5 of the guidance and NICE consulted again on the revised document.\n\nThe changes made to the recommendations were:\n\n: References to patient selection and special arrangements for research were removed and a recommendation to submit data to a register added.\n\n: The following text was added: 'Patient selection is particularly important because the cure rates for established treatments in accessible sites are very high.'\n\n: The following text was added: 'Entry into research trials should also be considered, with a view to providing data about cure and about recurrence rates, compared with other forms of treatment.'\n\nSome minor changes were also made to the rest of the document after consultation.\n\nWe have produced a summary of this guidance for patients and carers.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0430-3"}	https://www.nice.org.uk/guidance/ipg478
ee7cffe7e208a6c0f859b6c571883c7f8707cffc	nice	Endoscopic thoracic sympathectomy for primary facial blushing	Endoscopic thoracic sympathectomy for primary facial blushing # Recommendations Current evidence on the efficacy and safety of endoscopic thoracic sympathectomy (ETS) for primary facial blushing is adequate to support the use of this procedure with normal arrangements for clinical governance, consent and audit. Clinicians wishing to undertake ETS for primary facial blushing should ensure that patients understand the risks of the procedure. In particular they should explain that: there is a risk of serious complications hyperhidrosis is usual after the procedure: this can be severe and distressing and some patients regret having had the procedure (especially because of subsequent and persistent hyperhidrosis) the procedure sometimes does not reduce facial blushing.Clinicians should also provide patients considering the procedure with clear written information. In view of the risk of side effects this procedure should only be considered in patients suffering from severe and debilitating primary facial blushing that has been refractory to other treatments. This procedure should only be undertaken by clinicians trained and experienced in thoracic endoscopy, and there should be the capacity to deal with intraoperative complications. Further research into ETS for primary facial blushing should include clear information on patient selection and should seek to identify which patient characteristics might predict severe side effects. All complications should be reported. Outcomes should include measurements of efficacy, including quality of life and social functioning both in the short and long term, and in particular the frequency and severity of compensatory hyperhidrosis.# Indications and current treatments Blushing or facial reddening is an involuntary reaction, usually as a result of a strong emotional response that stimulates the sympathetic nervous system to increase the flow of blood to the skin of the face. People with facial blushing may also have hyperhidrosis (excessive sweating). Conservative treatment for facial blushing includes oral medications such as beta-blockers or anticholinergics. When anxiety is the cause of blushing, psychological treatments such as cognitive behavioural therapy may be used. If blushing fails to respond to conservative medical treatment or behavioural therapy, then surgical sympathectomy is an option: this can be done either by open or endoscopic approaches. Endoscopic sympathectomy is now usually the preferred technique because it is associated with less pain, improved cosmesis and more rapid recovery than open sympathectomy.# The procedure The aim of endoscopic thoracic sympathectomy (ETS) for primary facial blushing is to reduce the frequency and duration of blushing by dividing the sympathetic nerves that lie along the sympathetic chain beside the vertebral column. ETS is usually done with the patient under general anaesthesia. Small incisions are made in the axilla and an endoscope is inserted. The lung is partially collapsed. The sympathetic chain is visualised and the chosen part of the chain is divided by electrocautery or endoscopic scissors, or surgical clips may be applied. The extent of division varies but usually involves the part of the sympathetic chain over the second or third ribs, or both. Gas is removed from the pleural space, allowing the lung to re-expand, and the wounds are closed. The procedure is then usually repeated on the other side.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a case series of 831 patients with facial blushing who had endoscopic thoracic sympathectomy (ETS), mean symptom improvement score (assessed on a visual analogue scale; scores from 0 to 10, with 10 indicating worst possible symptoms) decreased from 9 before the procedure to 3 after the procedure in patients with facial blushing at a mean follow-up of 29 months; this difference was significant (p<0.0001). A case series of 80 patients (12 patients with isolated facial blushing) reported complete resolution in 33% (4/12) of patients with isolated facial blushing at a mean follow-up of 20 months. A case series of 180 patients with isolated facial blushing reported symptom recurrence (1 month to 1 year after the procedure) in 2% (4/173) of patients; all patients subsequently underwent reoperation with 'good results'. In the case series of 80 patients (59 patients with facial blushing, isolated or in association with hyperhidrosis) quality of life (assessed on a 5-point Likert scale) was reported to be 'much better' in 63% (37/59) of patients, and there was 'some improvement' in 15% (9/59) of patients and 'no change' in 8% (5/59) of patients. A case series of 1700 patients (648 patients with blushing or blushing with hyperhidrosis) reported satisfaction rates of 74% in patients with facial blushing (n=536) at a mean follow-up of 15 years (absolute number not reported). In a case series of 1152 patients, 85% of the 244 patients with facial blushing reported being 'totally satisfied' at a mean follow-up of 8 months (absolute number not reported). The specialist advisers stated that key efficacy outcomes were symptom improvement, absence of symptoms and the patient's perception of improvement of symptoms.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A non-systematic review article reported that 5 patients died because of major intrathoracic bleeding after endoscopic thoracic sympathectomy (ETS) but the total number of patients treated by the procedure was not documented: in 2 patients a trocar lacerated the subclavian artery; in 1 patient an intercostal vein was damaged; the causes in the other 2 patients were not described. An additional 4 deaths after ETS were reported in the non-systematic review article: 3 were due to problems related to anaesthetic technique, and 1 patient had an unexplained cerebral event 'some hours' after ETS. The total number of patients treated by the procedure was not documented. Compensatory hyperhidrosis occurring mainly at the axillae, trunk and groin (assessed using Hyperhidrosis Disease Severity Scale; scores range from 1 to 4, with higher score indicating intolerable sweating interfering with daily activities) was reported to be 'intolerable' in 4% (n=1) of patients, 'hardly tolerable' in 21% (n=5) of patients, and 'tolerable' in 54% (n=13) of patients with facial blushing in a case series of 73 patients (denominator unclear). Half of the patients had compensatory hyperhidrosis within 1 month of the procedure. Severe compensatory hyperhidrosis on the trunk and regret associated with having had the procedure was reported in 6% of patients in the case series of 831 patients at a mean follow-up of 29 months (absolute number not reported). Compensatory hyperhidrosis that was considered 'incapacitating' and regret associated with having had the procedure was reported in 11% (190/1700) of patients with facial blushing or hyperhidrosis at a mean follow-up of 15 years. Horner's syndrome on one side of the face was reported in 10% (2/21) of patients with facial blushing in a case series of 202 patients (1 patient underwent blepharoplasty; no further details) and in 1 patient in the case series of 180 patients with isolated facial blushing: this resolved after 2 days. Pneumothorax (needing a chest tube) was reported in 1 patient in the case series of 180 patients with isolated facial blushing. A chest drain was needed postoperatively (no further details provided) in 9% (5/59) of patients with facial blushing in the case series of 80 patients. Worsening of symptoms was reported in 1 patient and worsening of quality of life was reported in 14% (8/59) of patients with isolated facial blushing or blushing with hyperhidrosis (n=59) in the case series of 80 patients. In the case series of 1152 patients (244 patients with facial blushing), 13% of patients were 'dissatisfied to some extent' and 2% regretted the operation at a mean follow-up of 8 months (absolute numbers not reported). A randomised controlled trial (comparing sympathectomy of the second versus the second and third thoracic ganglia) of 100 patients with isolated facial blushing reported that overall 13% (12/93) of patients regretted the operation (reasons not reported) at a mean follow-up of 12 months; there was no significant difference between the groups treated by different extents of sympathectomy. Additional safety events reported in a series of endoscopic thoracic sympathectomies done for a variety of indications were bleeding, haemothorax, chylothorax, pulmonary embolus and brachial plexus damage; it is unclear if these events were in patients with facial blushing. The specialist advisers listed harlequin face, post-thoracoscopy chronic pain, and wound infection as adverse events reported in the literature. They listed anecdotal adverse events as air embolism and arm ischaemia. Theoretical adverse events were reported as death, dry hands and visceral injury.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. # Changes after publication November 2014: Minor maintenance Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0436-5	{'Recommendations': 'Current evidence on the efficacy and safety of endoscopic thoracic sympathectomy (ETS) for primary facial blushing is adequate to support the use of this procedure with normal arrangements for clinical governance, consent and audit.\n\nClinicians wishing to undertake ETS for primary facial blushing should ensure that patients understand the risks of the procedure. In particular they should explain that:\n\nthere is a risk of serious complications\n\nhyperhidrosis is usual after the procedure: this can be severe and distressing and some patients regret having had the procedure (especially because of subsequent and persistent hyperhidrosis)\n\nthe procedure sometimes does not reduce facial blushing.Clinicians should also provide patients considering the procedure with clear written information.\n\nIn view of the risk of side effects this procedure should only be considered in patients suffering from severe and debilitating primary facial blushing that has been refractory to other treatments.\n\nThis procedure should only be undertaken by clinicians trained and experienced in thoracic endoscopy, and there should be the capacity to deal with intraoperative complications.\n\nFurther research into ETS for primary facial blushing should include clear information on patient selection and should seek to identify which patient characteristics might predict severe side effects. All complications should be reported. Outcomes should include measurements of efficacy, including quality of life and social functioning both in the short and long term, and in particular the frequency and severity of compensatory hyperhidrosis.', 'Indications and current treatments': 'Blushing or facial reddening is an involuntary reaction, usually as a result of a strong emotional response that stimulates the sympathetic nervous system to increase the flow of blood to the skin of the face. People with facial blushing may also have hyperhidrosis (excessive sweating).\n\nConservative treatment for facial blushing includes oral medications such as beta-blockers or anticholinergics. When anxiety is the cause of blushing, psychological treatments such as cognitive behavioural therapy may be used.\n\nIf blushing fails to respond to conservative medical treatment or behavioural therapy, then surgical sympathectomy is an option: this can be done either by open or endoscopic approaches. Endoscopic sympathectomy is now usually the preferred technique because it is associated with less pain, improved cosmesis and more rapid recovery than open sympathectomy.', 'The procedure': 'The aim of endoscopic thoracic sympathectomy (ETS) for primary facial blushing is to reduce the frequency and duration of blushing by dividing the sympathetic nerves that lie along the sympathetic chain beside the vertebral column.\n\nETS is usually done with the patient under general anaesthesia. Small incisions are made in the axilla and an endoscope is inserted. The lung is partially collapsed. The sympathetic chain is visualised and the chosen part of the chain is divided by electrocautery or endoscopic scissors, or surgical clips may be applied. The extent of division varies but usually involves the part of the sympathetic chain over the second or third ribs, or both. Gas is removed from the pleural space, allowing the lung to re-expand, and the wounds are closed. The procedure is then usually repeated on the other side.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a case series of 831\xa0patients with facial blushing who had endoscopic thoracic sympathectomy (ETS), mean symptom improvement score (assessed on a visual analogue scale; scores from 0\xa0to 10, with 10 indicating worst possible symptoms) decreased from 9\xa0before the procedure to 3\xa0after the procedure in patients with facial blushing at a mean follow-up of 29\xa0months; this difference was significant (p<0.0001).\n\nA case series of 80\xa0patients (12\xa0patients with isolated facial blushing) reported complete resolution in 33%\xa0(4/12) of patients with isolated facial blushing at a mean follow-up of 20\xa0months.\n\nA case series of 180\xa0patients with isolated facial blushing reported symptom recurrence (1\xa0month to 1\xa0year after the procedure) in 2%\xa0(4/173) of patients; all patients subsequently underwent reoperation with 'good results'.\n\nIn the case series of 80 patients (59\xa0patients with facial blushing, isolated or in association with hyperhidrosis) quality of life (assessed on a 5-point Likert scale) was reported to be 'much better' in 63%\xa0(37/59) of patients, and there was 'some improvement' in 15%\xa0(9/59) of patients and 'no change' in 8%\xa0(5/59) of patients.\n\nA case series of 1700 patients (648\xa0patients with blushing or blushing with hyperhidrosis) reported satisfaction rates of 74% in patients with facial blushing (n=536) at a mean follow-up of 15\xa0years (absolute number not reported). In a case series of 1152\xa0patients, 85% of the 244\xa0patients with facial blushing reported being 'totally satisfied' at a mean follow-up of 8\xa0months (absolute number not reported).\n\nThe specialist advisers stated that key efficacy outcomes were symptom improvement, absence of symptoms and the patient's perception of improvement of symptoms.", 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA non-systematic review article reported that 5\xa0patients died because of major intrathoracic bleeding after endoscopic thoracic sympathectomy (ETS) but the total number of patients treated by the procedure was not documented: in 2\xa0patients a trocar lacerated the subclavian artery; in 1\xa0patient an intercostal vein was damaged; the causes in the other 2\xa0patients were not described.\n\nAn additional 4\xa0deaths after ETS were reported in the non-systematic review article: 3\xa0were due to problems related to anaesthetic technique, and 1\xa0patient had an unexplained cerebral event 'some hours' after ETS. The total number of patients treated by the procedure was not documented.\n\nCompensatory hyperhidrosis occurring mainly at the axillae, trunk and groin (assessed using Hyperhidrosis Disease Severity Scale; scores range from 1\xa0to 4, with higher score indicating intolerable sweating interfering with daily activities) was reported to be 'intolerable' in 4%\xa0(n=1) of patients, 'hardly tolerable' in 21%\xa0(n=5) of patients, and 'tolerable' in 54%\xa0(n=13) of patients with facial blushing in a case series of 73\xa0patients (denominator unclear). Half of the patients had compensatory hyperhidrosis within 1\xa0month of the procedure. Severe compensatory hyperhidrosis on the trunk and regret associated with having had the procedure was reported in 6% of patients in the case series of 831\xa0patients at a mean follow-up of 29\xa0months (absolute number not reported). Compensatory hyperhidrosis that was considered 'incapacitating' and regret associated with having had the procedure was reported in 11%\xa0(190/1700) of patients with facial blushing or hyperhidrosis at a mean follow-up of 15\xa0years.\n\nHorner's syndrome on one side of the face was reported in 10%\xa0(2/21) of patients with facial blushing in a case series of 202\xa0patients (1\xa0patient underwent blepharoplasty; no further details) and in 1\xa0patient in the case series of 180\xa0patients with isolated facial blushing: this resolved after 2\xa0days.\n\nPneumothorax (needing a chest tube) was reported in 1\xa0patient in the case series of 180\xa0patients with isolated facial blushing. A chest drain was needed postoperatively (no further details provided) in 9%\xa0(5/59) of patients with facial blushing in the case series of 80\xa0patients.\n\nWorsening of symptoms was reported in 1\xa0patient and worsening of quality of life was reported in 14%\xa0(8/59) of patients with isolated facial blushing or blushing with hyperhidrosis (n=59) in the case series of 80\xa0patients.\n\nIn the case series of 1152\xa0patients (244\xa0patients with facial blushing), 13% of patients were 'dissatisfied to some extent' and 2% regretted the operation at a mean follow-up of 8\xa0months (absolute numbers not reported). A randomised controlled trial (comparing sympathectomy of the second versus the second and third thoracic ganglia) of 100\xa0patients with isolated facial blushing reported that overall 13%\xa0(12/93) of patients regretted the operation (reasons not reported) at a mean follow-up of 12\xa0months; there was no significant difference between the groups treated by different extents of sympathectomy.\n\nAdditional safety events reported in a series of endoscopic thoracic sympathectomies done for a variety of indications were bleeding, haemothorax, chylothorax, pulmonary embolus and brachial plexus damage; it is unclear if these events were in patients with facial blushing.\n\nThe specialist advisers listed harlequin face, post-thoracoscopy chronic pain, and wound infection as adverse events reported in the literature. They listed anecdotal adverse events as air embolism and arm ischaemia. Theoretical adverse events were reported as death, dry hands and visceral injury.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\n# Changes after publication\n\nNovember 2014: Minor maintenance\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0436-5'}	https://www.nice.org.uk/guidance/ipg480
40c04b7697c0b1cb0fb3102f6cd66e8e5f621039	nice	Optical coherence tomography to guide percutaneous coronary intervention	Optical coherence tomography to guide percutaneous coronary intervention # Recommendations The evidence on the safety of optical coherence tomography (OCT) to guide percutaneous coronary intervention (PCI) shows no major concerns. The evidence on efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake OCT to guide PCI should take the following actions. Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Enter details about all patients undergoing OCT to guide PCI onto the UK Central Cardiac Audit Database and review local clinical outcomes. NICE encourages further research into OCT to guide PCI compared against PCI with no intravascular imaging or PCI with intravascular ultrasound. Research outcomes should include data on medium- and long-term clinical outcomes, including the need for revascularisation.# Indications and current treatments Optical coherence tomography (OCT) uses a catheter emitting near-infrared light to produce high-resolution images of blood vessel walls. It may be used to assess stenotic lesions in the coronary arteries and to image the result of stent deployment during percutaneous coronary interventions. Coronary angiography is used to image coronary arteries immediately before angioplasty. Intravascular ultrasound or OCT may be used to provide additional and complementary information to coronary angiography.# The procedure Optical coherence tomography (OCT) is usually performed using local anaesthesia. A guide wire and delivery sheath are introduced percutaneously into either the femoral or radial artery and passed into the target coronary artery using fluoroscopic image guidance. OCT imaging needs a blood-free field. This was first achieved by an occlusive technique, using an occlusion balloon with first-generation time-domain OCT (TD OCT), but this technique is no longer used in clinical practice. A non-occlusive technique is now used, involving continuous flushing of contrast with frequency-domain OCT (FD OCT). For non-occlusive OCT, a guide wire through which contrast can be injected is used. The imaging catheter is delivered over this wire. Injection of contrast and imaging take place concurrently. Second-generation FD OCT devices aim to improve image quality and, more importantly, increase the speed of image acquisition by a factor of 10. FD OCT has superseded TD OCT in the UK. The resolution of coronary OCT is reported to be 10 times higher than that of intravascular ultrasound, and has rapid 3-dimensional reconstruction capability. The aim of providing more detailed images is to improve clinical outcome.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A retrospective case series compared 335 matched pairs of patients undergoing percutaneous coronary intervention (PCI) with either angiographic guidance alone or a combination of angiographic and frequency-domain optical coherence tomography (FD OCT) guidance. Cardiac death or myocardial infarction (MI) were less frequent in patients treated by PCI with a combination of angiographic and FD OCT guidance than in those treated by PCI with angiographic guidance alone over a follow-up period of 1 year. There were 15 cardiac deaths and 29 MIs in the angiography-only group, and 4 cardiac deaths and 18 MIs in the combined angiography and FD-OCT group; odds ratio 0.49; 95% confidence interval 0.25 to 0.96, p=0.037. A randomised controlled trial comparing FD OCT against intravascular ultrasound for PCI optimisation in 70 patients reported that there was inferior stent expansion, both focal (65% versus 80%, p=0.002) and diffuse (84% versus 99%, p=0.003), when FD OCT had been used for guidance. PCI guided by FD OCT also showed a significant increase in residual stent-edge plaque burden (51% versus 42%, p<0.001). There were no significant differences in stent apposition. In the retrospective case series comparing 335 matched pairs of patients undergoing PCI with either angiographic guidance or a combination of angiographic and FD OCT guidance, FD OCT led to additional interventions (further stenting and additional balloon dilation) in 116 patients (35%). In a case series of 40 patients in whom OCT was performed to evaluate ambiguous or intermediate lesions, 60% (24/40) were treated by PCI and 40% (16/40) had PCI deferred. None of the patients for whom PCI was deferred had a coronary event within an average follow-up of 4.6 months. The specialist advisers listed a key efficacy outcome as a change in diagnosis or management due to OCT imaging results. They cited as examples identifying culprit or non-culprit plaques in acute coronary syndromes, identifying intracoronary or intra-stent thrombus, identifying dissections and complications after stenting, examining stent deformation and conformation, identifying modes of stent failure including neoatherogenesis, and documenting stent tissue coverage.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A large coronary perforation occurred (no further details of cause available) during optical coherence tomography (OCT) imaging in 1 patient presented in a case report, leading to reduced blood pressure and loss of consciousness. Surgical repair was done but the patient died of cardiac arrest after 7 days. A minor type A coronary dissection occurred in 1 patient in the case series of 468 patients during time-domain OCT (TD OCT) imaging. Coronary blood flow was not impaired and further treatment was not needed. Ventricular fibrillation occurred in 5 patients in a case series of 468 patients during TD OCT imaging, in 3 out of 256 during occlusive imaging and 2 out of 212 during non-occlusive imaging. In all cases, sinus rhythm was promptly restored after stopping OCT imaging and external defibrillation. Ventricular ectopic beats were noted in 3 patients in a case series of 90 patients undergoing 114 OCT image acquisitions. Air embolism occurred in 3 patients in the case series of 468 patients during TD OCT imaging. All responded promptly to air aspiration, treatment with nitrates and, in 1 patient, nitroprusside administration. Mechanical device failure occurred in 1 patient in the case series of 468 patients. The imaging wire became trapped within the struts of a stent and the tip fractured and remained within the stent. At 4 month follow-up there had been no clinical consequences and angiography showed no flow abnormalities. Multiple thrombi were reported during OCT imaging in 3 patients presented in case reports. These formed during OCT imaging in the left anterior descending artery causing total occlusion in 1 patient and subtotal occlusion in 2 others. All resolved with appropriate management and all patients recovered uneventfully. Vessel spasm during withdrawal of the OCT wire was reported in a single case report. This caused chest pain and ST elevation but resolved with an intracoronary injection of nitrate. Self-limiting chest pain was reported by 48% of patients (225/468) during TD OCT imaging in the case series of 468 patients. This was significantly more common when the occlusive rather than the non-occlusive technique was used (70% versus 21% , p<0.001). Self-limiting QRS widening or ST depression and ST elevation occurred in 192 (46%) of 468 patients treated by occlusive or non-occlusive TD OCT. These were significantly more common when the occlusive rather than the non-occlusive technique was used (61% versus 27% , p<0.001). The specialist advisers described the possibility that emergency revascularisation might be needed as a result of some of the complications of OCT which were reported in the literature.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0442-6	{'Recommendations': "The evidence on the safety of optical coherence tomography (OCT) to guide percutaneous coronary intervention (PCI) shows no major concerns. The evidence on efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake OCT to guide PCI should take the following actions.\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nEnter details about all patients undergoing OCT to guide PCI onto the UK Central Cardiac Audit Database and review local clinical outcomes.\n\nNICE encourages further research into OCT to guide PCI compared against PCI with no intravascular imaging or PCI with intravascular ultrasound. Research outcomes should include data on medium- and long-term clinical outcomes, including the need for revascularisation.", 'Indications and current treatments': 'Optical coherence tomography (OCT) uses a catheter emitting near-infrared light to produce high-resolution images of blood vessel walls. It may be used to assess stenotic lesions in the coronary arteries and to image the result of stent deployment during percutaneous coronary interventions.\n\nCoronary angiography is used to image coronary arteries immediately before angioplasty. Intravascular ultrasound or OCT may be used to provide additional and complementary information to coronary angiography.', 'The procedure': 'Optical coherence tomography (OCT) is usually performed using local anaesthesia. A guide wire and delivery sheath are introduced percutaneously into either the femoral or radial artery and passed into the target coronary artery using fluoroscopic image guidance. OCT imaging needs a blood-free field. This was first achieved by an occlusive technique, using an occlusion balloon with first-generation time-domain OCT (TD OCT), but this technique is no longer used in clinical practice. A non-occlusive technique is now used, involving continuous flushing of contrast with frequency-domain OCT (FD OCT). For non-occlusive OCT, a guide wire through which contrast can be injected is used. The imaging catheter is delivered over this wire. Injection of contrast and imaging take place concurrently.\n\nSecond-generation FD OCT devices aim to improve image quality and, more importantly, increase the speed of image acquisition by a factor of 10. FD OCT has superseded TD OCT in the UK.\n\nThe resolution of coronary OCT is reported to be 10 times higher than that of intravascular ultrasound, and has rapid 3-dimensional reconstruction capability. The aim of providing more detailed images is to improve clinical outcome.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA retrospective case series compared 335 matched pairs of patients undergoing percutaneous coronary intervention (PCI) with either angiographic guidance alone or a combination of angiographic and frequency-domain optical coherence tomography (FD OCT) guidance. Cardiac death or myocardial infarction (MI) were less frequent in patients treated by PCI with a combination of angiographic and FD OCT guidance than in those treated by PCI with angiographic guidance alone over a follow-up period of 1 year. There were 15 cardiac deaths and 29 MIs in the angiography-only group, and 4 cardiac deaths and 18 MIs in the combined angiography and FD-OCT group; odds ratio 0.49; 95% confidence interval 0.25 to 0.96, p=0.037.\n\nA randomised controlled trial comparing FD OCT against intravascular ultrasound for PCI optimisation in 70 patients reported that there was inferior stent expansion, both focal (65% versus 80%, p=0.002) and diffuse (84% versus 99%, p=0.003), when FD OCT had been used for guidance. PCI guided by FD OCT also showed a significant increase in residual stent-edge plaque burden (51% versus 42%, p<0.001). There were no significant differences in stent apposition.\n\nIn the retrospective case series comparing 335 matched pairs of patients undergoing PCI with either angiographic guidance or a combination of angiographic and FD OCT guidance, FD OCT led to additional interventions (further stenting and additional balloon dilation) in 116 patients (35%).\n\nIn a case series of 40 patients in whom OCT was performed to evaluate ambiguous or intermediate lesions, 60% (24/40) were treated by PCI and 40% (16/40) had PCI deferred. None of the patients for whom PCI was deferred had a coronary event within an average follow-up of 4.6 months.\n\nThe specialist advisers listed a key efficacy outcome as a change in diagnosis or management due to OCT imaging results. They cited as examples identifying culprit or non-culprit plaques in acute coronary syndromes, identifying intracoronary or intra-stent thrombus, identifying dissections and complications after stenting, examining stent deformation and conformation, identifying modes of stent failure including neoatherogenesis, and documenting stent tissue coverage.', 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA large coronary perforation occurred (no further details of cause available) during optical coherence tomography (OCT) imaging in 1 patient presented in a case report, leading to reduced blood pressure and loss of consciousness. Surgical repair was done but the patient died of cardiac arrest after 7 days.\n\nA minor type A coronary dissection occurred in 1 patient in the case series of 468 patients during time-domain OCT (TD OCT) imaging. Coronary blood flow was not impaired and further treatment was not needed.\n\nVentricular fibrillation occurred in 5 patients in a case series of 468 patients during TD OCT imaging, in 3 out of 256 during occlusive imaging and 2 out of 212 during non-occlusive imaging. In all cases, sinus rhythm was promptly restored after stopping OCT imaging and external defibrillation. Ventricular ectopic beats were noted in 3 patients in a case series of 90 patients undergoing 114 OCT image acquisitions.\n\nAir embolism occurred in 3 patients in the case series of 468 patients during TD OCT imaging. All responded promptly to air aspiration, treatment with nitrates and, in 1 patient, nitroprusside administration.\n\nMechanical device failure occurred in 1 patient in the case series of 468 patients. The imaging wire became trapped within the struts of a stent and the tip fractured and remained within the stent. At 4 month follow-up there had been no clinical consequences and angiography showed no flow abnormalities.\n\nMultiple thrombi were reported during OCT imaging in 3 patients presented in case reports. These formed during OCT imaging in the left anterior descending artery causing total occlusion in 1 patient and subtotal occlusion in 2 others. All resolved with appropriate management and all patients recovered uneventfully.\n\nVessel spasm during withdrawal of the OCT wire was reported in a single case report. This caused chest pain and ST elevation but resolved with an intracoronary injection of nitrate.\n\nSelf-limiting chest pain was reported by 48% of patients (225/468) during TD OCT imaging in the case series of 468 patients. This was significantly more common when the occlusive rather than the non-occlusive technique was used (70% [180/256] versus 21% [45/212], p<0.001).\n\nSelf-limiting QRS widening or ST depression and ST elevation occurred in 192 (46%) of 468 patients treated by occlusive or non-occlusive TD OCT. These were significantly more common when the occlusive rather than the non-occlusive technique was used (61% [139/256] versus 27% [53/212], p<0.001).\n\nThe specialist advisers described the possibility that emergency revascularisation might be needed as a result of some of the complications of OCT which were reported in the literature.', 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0442-6'}	https://www.nice.org.uk/guidance/ipg481
3f56ec517df5ffb2500c8cfd45ebc9027c12a3bb	nice	Arthroscopic trochleoplasty for patellar instability	Arthroscopic trochleoplasty for patellar instability # Recommendations Current evidence on the safety and efficacy of arthroscopic trochleoplasty for patellar instability is inadequate in quantity and quality. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake arthroscopic trochleoplasty for patellar instability should take the following actions: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having arthroscopic trochleoplasties (see section 7.1). Patient selection should be done by surgeons with expertise in managing patellar instability. The procedure should be undertaken by surgeons with experience in open trochleoplasty and in arthroscopic procedures on the knee. NICE encourages further research into arthroscopic trochleoplasty for patellar instability, including publication of consecutive patient series. Patient selection should be described in detail. Reported outcomes should include functional and quality‑of‑life measures, as well as reoperation rates.# Indications and current treatments Patellar instability occurs when the patella fails to engage securely in the trochlea at the start of flexion; it slips laterally and either dislocates completely or slips back medially to its correct position as flexion continues. In some patients this happens because the trochlear groove is too shallow or uneven (trochlear dysplasia). Conservative treatment includes physiotherapy and exercises to strengthen the quadriceps. Surgical approaches include direct reconstruction of the dysplastic trochlea or correction of associated factors by procedures such as medial patellofemoral ligament reconstruction. Trochleoplasty aims to reshape the bony anatomy of the trochlea: it may involve deepening the groove or elevating the lateral wall of the trochlea (which should be higher than the medial wall). Trochleoplasty is usually done as an open procedure, which is associated with risks such as arthrofibrosis and, rarely, infection.# The procedure Arthroscopic trochleoplasty aims to deepen the trochlea in the same way as open trochleoplasty but with less soft tissue trauma, which should reduce postoperative pain and allow more rapid recovery. Arthroscopic trochleoplasty is done with the patient under general or regional anaesthesia. Using an arthroscopic approach, the articular cartilage of the trochlea is raised as a flap. A round burr shaver is then used to deepen the trochlear groove. The articular cartilage is then returned to the deepened groove and fixed in place. The procedure is often done in combination with medial patellofemoral ligament reconstruction.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. The only available literature on efficacy was 1 case series of 31 patients with recurrent patellar dislocation and trochlear dysplasia type B to D. A case series of 31 patients reported outcomes for 29 knees with a median follow‑up of 29 months. The median Kujala score (scores range from 0 to 100 with higher scores indicating less severe symptoms) improved from 64 before the procedure to 95 at follow‑up. The median Tegner score (scores range from 0 to 10 with higher scores indicating higher activity levels) improved from 4 before the procedure to 6 at follow‑up. The median knee injury and osteoarthritis outcome scores for pain, symptoms, activities of daily living, sport and quality of life improved from 86, 82, 91, 40 and 25 before the procedure to 94, 86, 99, 85 and 75 respectively at follow‑up (all p values <0.001). The case series of 31 patients reported that patients were satisfied with the outcome of the operation for 93% (27/29) of knees. The case series of 31 patients reported that 17% (5/29) of knees needed further surgery. Two patients developed symptomatic subluxations 28 months after the procedure and were both treated by medialisation of the tibial tubercle. Three patients had pronounced postoperative anterior knee pain at flexion and had tightness of the lateral retinaculum, indicating lateral hyper‑pressure syndromes; all were subsequently treated by lateral releases. The case series of 31 patients reported that there were no redislocations over a median follow‑up of 29 months. The specialist advisers listed additional efficacy outcomes as including International Knee Documentation Committee scores, and radiological outcomes such as patellar tilt and sulcus angle.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. No infections, cartilage flake breakage or necrosis were reported in the case series of 31 patients. Suspected infection from the superolateral portal was reported, within 3 months of arthroscopic trochleoplasty, in 1 patient in a case series of 8 patients. This was resolved with oral antibiotic treatment. The specialist advisers listed theoretical adverse events as pain, stiffness, persistent instability, chondrolysis, non‑union, the inability to correctly visualise the amount of correction needed, and the inability to securely fix down the flaps to the deepened groove.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0409-9	{'Recommendations': "Current evidence on the safety and efficacy of arthroscopic trochleoplasty for patellar instability is inadequate in quantity and quality. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake arthroscopic trochleoplasty for patellar instability should take the following actions:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having arthroscopic trochleoplasties (see section\xa07.1).\n\nPatient selection should be done by surgeons with expertise in managing patellar instability.\n\nThe procedure should be undertaken by surgeons with experience in open trochleoplasty and in arthroscopic procedures on the knee.\n\nNICE encourages further research into arthroscopic trochleoplasty for patellar instability, including publication of consecutive patient series. Patient selection should be described in detail. Reported outcomes should include functional and quality‑of‑life measures, as well as reoperation rates.", 'Indications and current treatments': 'Patellar instability occurs when the patella fails to engage securely in the trochlea at the start of flexion; it slips laterally and either dislocates completely or slips back medially to its correct position as flexion continues. In some patients this happens because the trochlear groove is too shallow or uneven (trochlear dysplasia).\n\nConservative treatment includes physiotherapy and exercises to strengthen the quadriceps. Surgical approaches include direct reconstruction of the dysplastic trochlea or correction of associated factors by procedures such as medial patellofemoral ligament reconstruction. Trochleoplasty aims to reshape the bony anatomy of the trochlea: it may involve deepening the groove or elevating the lateral wall of the trochlea (which should be higher than the medial wall). Trochleoplasty is usually done as an open procedure, which is associated with risks such as arthrofibrosis and, rarely, infection.', 'The procedure': 'Arthroscopic trochleoplasty aims to deepen the trochlea in the same way as open trochleoplasty but with less soft tissue trauma, which should reduce postoperative pain and allow more rapid recovery.\n\nArthroscopic trochleoplasty is done with the patient under general or regional anaesthesia. Using an arthroscopic approach, the articular cartilage of the trochlea is raised as a flap. A round burr shaver is then used to deepen the trochlear groove. The articular cartilage is then returned to the deepened groove and fixed in place. The procedure is often done in combination with medial patellofemoral ligament reconstruction.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. The only available literature on efficacy was 1\xa0case series of 31\xa0patients with recurrent patellar dislocation and trochlear dysplasia type\xa0B to D.\n\nA case series of 31\xa0patients reported outcomes for 29\xa0knees with a median follow‑up of 29\xa0months. The median Kujala score (scores range from 0 to 100 with higher scores indicating less severe symptoms) improved from\xa064 before the procedure to\xa095 at follow‑up. The median Tegner score (scores range from\xa00 to\xa010 with higher scores indicating higher activity levels) improved from\xa04 before the procedure to\xa06 at follow‑up. The median knee injury and osteoarthritis outcome scores for pain, symptoms, activities of daily living, sport and quality of life improved from 86, 82, 91, 40 and\xa025 before the procedure to 94, 86, 99, 85 and\xa075 respectively at follow‑up (all p values <0.001).\n\nThe case series of 31\xa0patients reported that patients were satisfied with the outcome of the operation for 93% (27/29) of knees.\n\nThe case series of 31\xa0patients reported that 17% (5/29) of knees needed further surgery. Two patients developed symptomatic subluxations 28\xa0months after the procedure and were both treated by medialisation of the tibial tubercle. Three patients had pronounced postoperative anterior knee pain at flexion and had tightness of the lateral retinaculum, indicating lateral hyper‑pressure syndromes; all were subsequently treated by lateral releases.\n\nThe case series of 31\xa0patients reported that there were no redislocations over a median follow‑up of 29\xa0months.\n\nThe specialist advisers listed additional efficacy outcomes as including International Knee Documentation Committee scores, and radiological outcomes such as patellar tilt and sulcus angle.', 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nNo infections, cartilage flake breakage or necrosis were reported in the case series of 31\xa0patients.\n\nSuspected infection from the superolateral portal was reported, within 3\xa0months of arthroscopic trochleoplasty, in 1\xa0patient in a case series of 8\xa0patients. This was resolved with oral antibiotic treatment.\n\nThe specialist advisers listed theoretical adverse events as pain, stiffness, persistent instability, chondrolysis, non‑union, the inability to correctly visualise the amount of correction needed, and the inability to securely fix down the flaps to the deepened groove.', 'Further information': 'This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n \n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0409-9'}	https://www.nice.org.uk/guidance/ipg474
71c7f252976bf3b8be0504afd2dc67ff9d65969d	nice	Insertion of prostatic urethral lift implants to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia	Insertion of prostatic urethral lift implants to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia # Recommendations Current evidence on the efficacy and safety of insertion of prostatic urethral lift implants to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. During the consent process clinicians should, in particular, advise patients about the range of possible treatment options and the possible need for further procedures if symptoms recur. The procedure should only be carried out by clinicians with specific training in the insertion of prostatic urethral lift implants. NICE encourages further research and publication of results from consecutive case series of patients having this procedure. Details of patient selection should be clearly documented. Reported outcomes should include the effects of the procedure on symptoms and quality of life, the duration of benefits, and the need for further procedures. All complications should be reported. NICE may review this procedure in the light of longer-term outcomes.# Indications and current treatments Benign prostatic hyperplasia is a common condition that affects older men. It is characterised by an increase in the size of the prostate, which is caused by an increased number of stromal and epithelial cells. Benign prostatic hyperplasia can cause lower urinary tract symptoms including hesitancy during micturition, interrupted or decreased urine stream, nocturia, incomplete voiding and urinary retention. Mild symptoms are usually managed conservatively. Drugs such as alpha blockers and 5‑alpha-reductase inhibitors can be used. If symptoms are more severe, then surgical treatments may be used including transurethral resection of the prostate (TURP), transurethral vaporisation of the prostate, or holmium laser enucleation of the prostate (see The management of lower urinary tract symptoms in men ).# The procedure The aim of insertion of prostatic urethral lift implants for lower urinary tract symptoms secondary to benign prostatic hyperplasia is to secure the prostatic lobes in retracted positions such that the lumen of the urethra is increased. The procedure is designed to cause less tissue injury than surgical resection or thermal ablation, and it is claimed to reduce the risk of complications such as sexual dysfunction and incontinence. The procedure is undertaken transurethrally with the patient under local or general anaesthesia. A pre-loaded delivery device is passed through a rigid sheath under cystoscopic visualisation. The delivery device is used to compress one lateral lobe of the prostate in an anterolateral direction towards the prostatic capsule. A needle is then advanced through the lobe and capsule, and a monofilament implant with 2 end pieces is deployed. One end of the implant is anchored in the urethra and the other on the outer surface of the prostatic capsule, retracting the prostatic lobe away from the urethral lumen. Multiple implants are usually inserted during the same procedure.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a randomised controlled trial (RCT) of 206 patients comparing 140 patients treated by prostatic urethral lift against 66 patients treated by a sham procedure there was a significant difference in mean change in American Urological Association Symptom Index (AUASI) score (scores range from 0 to 35; higher score indicating greater severity) at 3‑month follow-up. The mean score decreased by 11 points at follow-up from a baseline score of 22 in patients treated by prostatic urethral lift and by 6 points at follow-up from a baseline score of 24 in patients treated by the sham procedure (p=0.003 difference between the groups). A case series of 64 patients reported a significant improvement in International Prostate Symptom Score (scale 0 to 35; higher score indicating more severe symptoms) at follow-up intervals from 2 weeks to 24 months. The mean score improved from 22 at baseline to 13 at 2‑year follow‑up (n=33; p<0.001). The RCT of 206 patients reported a significant difference in change in AUASI quality-of-life scores (scale 0 to 5; higher score indicating lower quality of life) at 3 months. The mean quality-of-life score decreased from 5 to 2 in patients treated by prostatic urethral lift and from 5 to 4 in patients treated by the sham procedure (p<0.001 difference between the groups). The case series of 64 patients reported Sexual Health Inventory for Men scores (scale assesses erectile dysfunction, with scores ranging from 1 to 25, with 1 being the most severe and 25 being healthy). There was a statistically significant improvement in score in 26 patients (for whom results were reported), from 18 at baseline to 20 at 1‑year follow‑up (p=0.01). The RCT of 206 patients reported a significant improvement in mean urinary flow rate at 3 months. The mean improvement in urinary flow was 4 ml/s in patients treated by prostatic urethral lift and 2 ml/s in patients treated by the sham procedure (from 8 ml/s at baseline for both groups; p=0.005 difference between the groups). A case series of 19 patients reported a significant reduction in mean post-voiding residual volume, from 147 ml at baseline to 46 ml at 3‑month follow‑up (n=11; p=0.01). The RCT of 206 patients reported retreatment at 1 year in 5% (7/140) of patients treated by prostatic urethral lift. Five patients underwent further prostatic urethral lift treatment because of insufficient response and 2 patients were treated by transurethral prostate resection (TURP) or laser vaporisation (reasons for retreatment not reported). The case series of 64 patients reported that 20% (13/64) of patients had further procedures. Four patients had TURP or photoselective vaporisation of the prostate within 7 months. Nine patients with symptomatic improvement after the initial procedure had TURP (n=4), photoselective vaporisation (n=4) or prostatic urethral lift (n=1) (at a mean of 13 months after the procedure) because of recurrent lower urinary tract symptoms. The specialist advisers listed key efficacy outcomes as symptom improvement, improvement in quality of life, reducing or stopping medical therapy, flow improvement, reduction in post-void residual volume and maintenance of sexual and ejaculatory function.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Urinary tract infections (within 3 months of the procedure) were reported in 3% (4/140) of patients treated by prostatic urethral lift and 2% (1/66) of patients treated by a sham procedure in the randomised controlled trial of 206 patients (level of significance not reported). Orchitis was reported in 3% (3/102) of patients in a case series of 102 patients (duration and timing not reported). Symptoms of prostatitis (penile and perineal discomfort, pain on erection and ejaculation) were reported in 1 patient in the case series of 64 patients (treated with antibiotics). Urinary retention (within 30 days of the procedure) was reported in 16% (3/19) of patients in the case series of 19 patients (reported as lasting median 3.5 days; no further details given). Transient urge incontinence was reported in 8% (5/64) of patients in the case series of 64 patients (resolved within 8 days). Incomplete voiding (within 30 days of the procedure) was reported in 1 patient in the case series of 19 patients (lasting 42 days). Erectile dysfunction was reported within 30 days of the procedure in 11% (2/19) of patients in the case series of 19 patients. This spontaneously resolved after 23 days in 1 patient and 127 days in the other patient. The specialist advisers listed bleeding, prostatic swelling and retention (needing catheterisation) as anecdotal adverse events. The specialist advisers considered vascular and rectal injury to be theoretical adverse events.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0412-9	{'Recommendations': 'Current evidence on the efficacy and safety of insertion of prostatic urethral lift implants to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nDuring the consent process clinicians should, in particular, advise patients about the range of possible treatment options and the possible need for further procedures if symptoms recur.\n\nThe procedure should only be carried out by clinicians with specific training in the insertion of prostatic urethral lift implants.\n\nNICE encourages further research and publication of results from consecutive case series of patients having this procedure. Details of patient selection should be clearly documented. Reported outcomes should include the effects of the procedure on symptoms and quality of life, the duration of benefits, and the need for further procedures. All complications should be reported. NICE may review this procedure in the light of longer-term outcomes.', 'Indications and current treatments': 'Benign prostatic hyperplasia is a common condition that affects older men. It is characterised by an increase in the size of the prostate, which is caused by an increased number of stromal and epithelial cells. Benign prostatic hyperplasia can cause lower urinary tract symptoms including hesitancy during micturition, interrupted or decreased urine stream, nocturia, incomplete voiding and urinary retention.\n\nMild symptoms are usually managed conservatively. Drugs such as alpha blockers and 5‑alpha-reductase inhibitors can be used. If symptoms are more severe, then surgical treatments may be used including transurethral resection of the prostate (TURP), transurethral vaporisation of the prostate, or holmium laser enucleation of the prostate (see The management of lower urinary tract symptoms in men [NICE clinical guideline\xa097]).', 'The procedure': 'The aim of insertion of prostatic urethral lift implants for lower urinary tract symptoms secondary to benign prostatic hyperplasia is to secure the prostatic lobes in retracted positions such that the lumen of the urethra is increased. The procedure is designed to cause less tissue injury than surgical resection or thermal ablation, and it is claimed to reduce the risk of complications such as sexual dysfunction and incontinence.\n\nThe procedure is undertaken transurethrally with the patient under local or general anaesthesia. A pre-loaded delivery device is passed through a rigid sheath under cystoscopic visualisation. The delivery device is used to compress one lateral lobe of the prostate in an anterolateral direction towards the prostatic capsule. A needle is then advanced through the lobe and capsule, and a monofilament implant with 2\xa0end pieces is deployed. One end of the implant is anchored in the urethra and the other on the outer surface of the prostatic capsule, retracting the prostatic lobe away from the urethral lumen. Multiple implants are usually inserted during the same procedure.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a randomised controlled trial (RCT) of 206\xa0patients comparing 140\xa0patients treated by prostatic urethral lift against 66\xa0patients treated by a sham procedure there was a significant difference in mean change in American Urological Association Symptom Index (AUASI) score (scores range from 0 to 35; higher score indicating greater severity) at 3‑month follow-up. The mean score decreased by 11\xa0points at follow-up from a baseline score of 22 in patients treated by prostatic urethral lift and by 6 points at follow-up from a baseline score of 24 in patients treated by the sham procedure (p=0.003 difference between the groups).\n\nA case series of 64\xa0patients reported a significant improvement in International Prostate Symptom Score (scale 0 to 35; higher score indicating more severe symptoms) at follow-up intervals from 2\xa0weeks to 24\xa0months. The mean score improved from 22 at baseline to 13 at 2‑year follow‑up (n=33; p<0.001).\n\nThe RCT of 206\xa0patients reported a significant difference in change in AUASI quality-of-life scores (scale 0 to 5; higher score indicating lower quality of life) at 3\xa0months. The mean quality-of-life score decreased from 5 to 2 in patients treated by prostatic urethral lift and from 5 to 4 in patients treated by the sham procedure (p<0.001 difference between the groups).\n\nThe case series of 64\xa0patients reported Sexual Health Inventory for Men scores (scale assesses erectile dysfunction, with scores ranging from 1 to 25, with 1 being the most severe and 25 being healthy). There was a statistically significant improvement in score in 26\xa0patients (for whom results were reported), from 18 at baseline to 20 at 1‑year follow‑up (p=0.01).\n\nThe RCT of 206\xa0patients reported a significant improvement in mean urinary flow rate at 3\xa0months. The mean improvement in urinary flow was 4\xa0ml/s in patients treated by prostatic urethral lift and 2\xa0ml/s in patients treated by the sham procedure (from 8\xa0ml/s at baseline for both groups; p=0.005 difference between the groups).\n\nA case series of 19\xa0patients reported a significant reduction in mean post-voiding residual volume, from 147\xa0ml at baseline to 46\xa0ml at 3‑month follow‑up (n=11; p=0.01).\n\nThe RCT of 206\xa0patients reported retreatment at 1\xa0year in 5% (7/140) of patients treated by prostatic urethral lift. Five patients underwent further prostatic urethral lift treatment because of insufficient response and 2\xa0patients were treated by transurethral prostate resection (TURP) or laser vaporisation (reasons for retreatment not reported). The case series of 64\xa0patients reported that 20% (13/64) of patients had further procedures. Four patients had TURP or photoselective vaporisation of the prostate within 7\xa0months. Nine patients with symptomatic improvement after the initial procedure had TURP (n=4), photoselective vaporisation (n=4) or prostatic urethral lift (n=1) (at a mean of 13\xa0months after the procedure) because of recurrent lower urinary tract symptoms.\n\nThe specialist advisers listed key efficacy outcomes as symptom improvement, improvement in quality of life, reducing or stopping medical therapy, flow improvement, reduction in post-void residual volume and maintenance of sexual and ejaculatory function.', 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nUrinary tract infections (within 3\xa0months of the procedure) were reported in 3% (4/140) of patients treated by prostatic urethral lift and 2% (1/66) of patients treated by a sham procedure in the randomised controlled trial of 206\xa0patients (level of significance not reported).\n\nOrchitis was reported in 3% (3/102) of patients in a case series of 102\xa0patients (duration and timing not reported).\n\nSymptoms of prostatitis (penile and perineal discomfort, pain on erection and ejaculation) were reported in 1\xa0patient in the case series of 64\xa0patients (treated with antibiotics).\n\nUrinary retention (within 30\xa0days of the procedure) was reported in 16% (3/19) of patients in the case series of 19\xa0patients (reported as lasting median 3.5\xa0days; no further details given).\n\nTransient urge incontinence was reported in 8% (5/64) of patients in the case series of 64\xa0patients (resolved within 8\xa0days).\n\nIncomplete voiding (within 30\xa0days of the procedure) was reported in 1\xa0patient in the case series of 19\xa0patients (lasting 42\xa0days).\n\nErectile dysfunction was reported within 30\xa0days of the procedure in 11% (2/19) of patients in the case series of 19\xa0patients. This spontaneously resolved after 23\xa0days in 1\xa0patient and 127\xa0days in the other patient.\n\nThe specialist advisers listed bleeding, prostatic swelling and retention (needing catheterisation) as anecdotal adverse events. The specialist advisers considered vascular and rectal injury to be theoretical adverse events.', 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence the guidance is based on is also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0412-9'}	https://www.nice.org.uk/guidance/ipg475
f87f016f21d86cfe494a610e4ba356f07cf2c5a6	nice	Transcranial magnetic stimulation for treating and preventing migraine	Transcranial magnetic stimulation for treating and preventing migraine # Recommendations Transcranial magnetic stimulation (TMS) has been evaluated for use during the aura before a migraine episode or at the start of a migraine episode, with the intention of stopping or reducing the severity of the episode ('treatment'); or at planned intervals, with the intention of reducing the frequency and/or severity of migraine episodes ('prevention'). Evidence on the efficacy of TMS for the treatment of migraine is limited in quantity and for the prevention of migraine is limited in both quality and quantity. Evidence on its safety in the short and medium term is adequate but there is uncertainty about the safety of long-term or frequent use of TMS. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Patient selection should normally be done in specialist headache clinics and the procedure should only be used under the direction of clinicians specialising in the management of headache. Patients should be informed that TMS is not intended to provide a cure for migraine and that reduction in symptoms may be modest. Clinicians wishing to undertake TMS for treating and preventing migraine should take the following actions. Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having TMS for the treatment and prevention of migraine (see section 7.1). NICE encourages further research on TMS for treating and preventing migraine. Data should be collected for all patients not entered into controlled trials. Studies should describe clearly whether its use is for treatment or prevention. They should report details of patient selection and the dose and frequency of use. Outcome measures should include the number and severity of migraine episodes, and quality of life in both the short and long term. The development of any neurological disorders (such as epilepsy) in the short or longer term after starting treatment should be documented.# Indications and current treatments Migraine is a common condition characterised by recurrent, pulsatile, unilateral or bilateral headaches that may last from hours to days and are often accompanied by nausea and sensitivity to light and sound. Migraine headache may be preceded by an aura, which can include visual or olfactory disturbances, or difficulties with speech (dysphasia). The second edition of International Classification of Headache Disorders (International Headache Society 2004) provides a classification of migraine types. Current treatment for migraine aims to prevent or stop episodes and manage symptoms with drugs such as triptans, analgesics and anti-emetics (as recommended in Headaches: diagnosis and management of headaches in young people and adults ). Other treatments include nerve blocks, botulinum toxin type A injections (as recommended in Botulinum toxin type A for the prevention of headaches in adults with chronic migraine ) or acupuncture.# The procedure Transcranial magnetic stimulation (TMS) is a non-invasive procedure that aims to treat or prevent migraine episodes in people with acute or chronic migraine (with or without aura). TMS is given using a tabletop or handheld device that delivers a predetermined level of magnetic pulse or pulses to the head. The device is placed on the scalp and either single (sTMS) or repeated (rTMS) magnetic pulses are delivered. The frequency, intensity, duration and interval times of pulses can be varied. Treatments can be automatically recorded by the device in an integrated headache diary, which can be used to identify headache patterns and trigger factors. Patients may continue to use regular medications, including drugs to prevent migraines.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A multicentre randomised controlled trial of 164 patients treated for at least 1 attack of migraine with aura with a handheld single transcranial magnetic stimulation (sTMS) device (n=82) or with sham stimulation (n=82) reported that pain-free rates 2 hours after stimulation were significantly better with sTMS (39% ) than with sham stimulation (22% ; p=0.018). Sustained pain-free response rates (with no recurrence and no rescue drug use) significantly favoured sTMS at 24 hours (29% versus 16% ; p=0.0405) and 48 hours (27% versus 13% ; p=0.0327) after treatment. There were no significant differences in secondary outcomes (headache response at 2 hours, use of rescue drugs, Migraine Disability Assessment score and consistency of pain relief response) between groups. A case series of 51 patients with 'medically resistant migraine' using repeated transcranial magnetic stimulation( rTMS) for prevention reported that 98% (50/51) of patients had a greater than 50% reduction in headache frequency at the end of 1 week and the improvement persisted at follow-up of 4 weeks in 80.4% (41/51) of patients. Headache frequency and severity, functional disability and use of rescue drugs were significantly reduced at all time points (1, 2, 3 and 4 weeks, p<0.0001) but the maximum benefit was observed in the first 2 weeks. A case series of 27 patients with migraine comparing low-frequency rTMS (n=14) against sham stimulation (n=13) for prevention reported no significant difference between groups for any reported outcome (including number and duration of migraine attacks, mean pain intensity and use of analgesics). The 'within-group' findings showed a significant decrease in the number of migraine attacks during 8 weeks within the rTMS group from 9.36±2.82 attacks to 6.79±4.28 attacks (p=0.007), and a non-significant decrease within the sham group (numbers not reported; p=0.216). There was a significant reduction in migraine days during 8 weeks in both rTMS and sham groups (from 17.69±11.63 days to 13.15±9.27 days and from 14.36±5.07 days to 9.50±6.80 days respectively). The rTMS group showed a significant reduction in migraine hours during 8 weeks from 125.93±80.31 hours to 85.36±72.27 hours (p=0.035); the difference was not significant in the sham group (numbers not reported; p=0.080). The specialist advisers listed additional efficacy outcomes as complete resolution of a migraine attack, reduction in headache severity, and improvement in associated symptoms, disability and quality of life.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. No device-related serious adverse events were reported in the randomised controlled trial of 164 patients. Slight 'unsustained' dizziness (n=1), drowsiness (n=1) and tiredness (n=2) were reported in a case series of 42 patients after treatment with low- or high-intensity transcranial magnetic stimulation (TMS). None of these events recurred or needed medical attention. Amyostasia (muscle tremor causing difficulty in standing, n=1), irritability (n=1), 'vigorous dreams' (n=1) and phonophobia (n=1) were reported after repeated TMS (rTMS) treatment in the case series of 27 patients. The specialist advisers listed transient muscle contraction, pain at the stimulation site and hearing impairment during rTMS as additional anecdotal adverse events. The specialist advisers considered theoretical adverse events to include local scalp irritation, mood disorders, cognitive impairment, triggering of epilepsy during treatment and 'kindling' leading to seizures. One adviser raised the theoretical possibility of 'permanent neural changes' with prolonged use of rTMS.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and is developing an audit tool (which is for use at local discretion). # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0416-7	{'Recommendations': "Transcranial magnetic stimulation (TMS) has been evaluated for use during the aura before a migraine episode or at the start of a migraine episode, with the intention of stopping or reducing the severity of the episode ('treatment'); or at planned intervals, with the intention of reducing the frequency and/or severity of migraine episodes ('prevention').\n\nEvidence on the efficacy of TMS for the treatment of migraine is limited in quantity and for the prevention of migraine is limited in both quality and quantity. Evidence on its safety in the short and medium term is adequate but there is uncertainty about the safety of long-term or frequent use of TMS. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nPatient selection should normally be done in specialist headache clinics and the procedure should only be used under the direction of clinicians specialising in the management of headache.\n\nPatients should be informed that TMS is not intended to provide a cure for migraine and that reduction in symptoms may be modest.\n\nClinicians wishing to undertake TMS for treating and preventing migraine should take the following actions.\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having TMS for the treatment and prevention of migraine (see section 7.1).\n\nNICE encourages further research on TMS for treating and preventing migraine. Data should be collected for all patients not entered into controlled trials. Studies should describe clearly whether its use is for treatment or prevention. They should report details of patient selection and the dose and frequency of use. Outcome measures should include the number and severity of migraine episodes, and quality of life in both the short and long term. The development of any neurological disorders (such as epilepsy) in the short or longer term after starting treatment should be documented.", 'Indications and current treatments': 'Migraine is a common condition characterised by recurrent, pulsatile, unilateral or bilateral headaches that may last from hours to days and are often accompanied by nausea and sensitivity to light and sound. Migraine headache may be preceded by an aura, which can include visual or olfactory disturbances, or difficulties with speech (dysphasia). The second edition of International Classification of Headache Disorders (International Headache Society 2004) provides a classification of migraine types.\n\nCurrent treatment for migraine aims to prevent or stop episodes and manage symptoms with drugs such as triptans, analgesics and anti-emetics (as recommended in Headaches: diagnosis and management of headaches in young people and adults [NICE clinical guideline 150]). Other treatments include nerve blocks, botulinum toxin type A injections (as recommended in Botulinum toxin type A for the prevention of headaches in adults with chronic migraine [NICE technology appraisal guidance 260]) or acupuncture.', 'The procedure': 'Transcranial magnetic stimulation (TMS) is a non-invasive procedure that aims to treat or prevent migraine episodes in people with acute or chronic migraine (with or without aura). TMS is given using a tabletop or handheld device that delivers a predetermined level of magnetic pulse or pulses to the head.\n\nThe device is placed on the scalp and either single (sTMS) or repeated (rTMS) magnetic pulses are delivered. The frequency, intensity, duration and interval times of pulses can be varied. Treatments can be automatically recorded by the device in an integrated headache diary, which can be used to identify headache patterns and trigger factors. Patients may continue to use regular medications, including drugs to prevent migraines.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA multicentre randomised controlled trial of 164\xa0patients treated for at least 1\xa0attack of migraine with aura with a handheld single transcranial magnetic stimulation (sTMS) device (n=82) or with sham stimulation (n=82) reported that pain-free rates 2\xa0hours after stimulation were significantly better with sTMS (39% [32/82]) than with sham stimulation (22% [18/82]; p=0.018). Sustained pain-free response rates (with no recurrence and no rescue drug use) significantly favoured sTMS at 24\xa0hours (29% [24/82] versus 16% [13/82]; p=0.0405) and 48\xa0hours (27% [22/82] versus 13% [11/82]; p=0.0327) after treatment. There were no significant differences in secondary outcomes (headache response at 2\xa0hours, use of rescue drugs, Migraine Disability Assessment [MIDAS] score and consistency of pain relief response) between groups.\n\nA case series of 51\xa0patients with 'medically resistant migraine' using repeated transcranial magnetic stimulation( rTMS) for prevention reported that 98% (50/51) of patients had a greater than 50% reduction in headache frequency at the end of 1\xa0week and the improvement persisted at follow-up of 4\xa0weeks in 80.4% (41/51) of patients. Headache frequency and severity, functional disability and use of rescue drugs were significantly reduced at all time points (1, 2, 3 and 4\xa0weeks, p<0.0001) but the maximum benefit was observed in the first 2\xa0weeks.\n\nA case series of 27\xa0patients with migraine comparing low-frequency rTMS (n=14) against sham stimulation (n=13) for prevention reported no significant difference between groups for any reported outcome (including number and duration of migraine attacks, mean pain intensity and use of analgesics). The 'within-group' findings showed a significant decrease in the number of migraine attacks during 8\xa0weeks within the rTMS group from 9.36±2.82\xa0attacks to 6.79±4.28\xa0attacks (p=0.007), and a non-significant decrease within the sham group (numbers not reported; p=0.216). There was a significant reduction in migraine days during 8\xa0weeks in both rTMS and sham groups (from 17.69±11.63\xa0days to 13.15±9.27\xa0days [p=0.012] and from 14.36±5.07\xa0days to 9.50±6.80\xa0days [p=0.006] respectively). The rTMS group showed a significant reduction in migraine hours during 8\xa0weeks from 125.93±80.31\xa0hours to 85.36±72.27\xa0hours (p=0.035); the difference was not significant in the sham group (numbers not reported; p=0.080).\n\nThe specialist advisers listed additional efficacy outcomes as complete resolution of a migraine attack, reduction in headache severity, and improvement in associated symptoms, disability and quality of life.", 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nNo device-related serious adverse events were reported in the randomised controlled trial of 164\xa0patients.\n\nSlight 'unsustained' dizziness (n=1), drowsiness (n=1) and tiredness (n=2) were reported in a case series of 42\xa0patients after treatment with low- or high-intensity transcranial magnetic stimulation (TMS). None of these events recurred or needed medical attention.\n\nAmyostasia (muscle tremor causing difficulty in standing, n=1), irritability (n=1), 'vigorous dreams' (n=1) and phonophobia (n=1) were reported after repeated TMS (rTMS) treatment in the case series of 27\xa0patients.\n\nThe specialist advisers listed transient muscle contraction, pain at the stimulation site and hearing impairment during rTMS as additional anecdotal adverse events. The specialist advisers considered theoretical adverse events to include local scalp irritation, mood disorders, cognitive impairment, triggering of epilepsy during treatment and 'kindling' leading to seizures. One adviser raised the theoretical possibility of 'permanent neural changes' with prolonged use of rTMS.", 'Further information': 'This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and is developing an audit tool (which is for use at local discretion).\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0416-7'}	https://www.nice.org.uk/guidance/ipg477
4517ca0fb6989a065a93a621d9c06e9c26abe232	nice	Radiofrequency ablation of the soft palate for snoring	Radiofrequency ablation of the soft palate for snoring # Recommendations This document replaces previous guidance on radiofrequency ablation of the soft palate for snoring (NICE interventional procedure guidance 124). Current evidence suggests that there are no major safety concerns associated with radiofrequency ablation of the soft palate for snoring. The evidence on the short-term efficacy of the procedure is adequate, although uncertainties remain about its efficacy in the longer term. Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit. During the consent process clinicians should, in particular, inform patients of the uncertainty about the procedure's long-term efficacy and of the possible need for further procedures if symptoms recur. Patient selection is important: the sound of snoring can arise from several different levels in the upper airway and this procedure should only be used for patients whose snoring has been shown to be caused by abnormal movement of the soft palate and in whom sleep apnoea has been excluded. NICE encourages further research into radiofrequency ablation of the soft palate for snoring. This could take the form of data collection, with the specific aim of documenting long-term outcomes and the need for further treatment.# Indications and current treatments Snoring is a noisy inspiratory sound produced by vibration and partial airway obstruction in the pharynx. One cause is vibration of the soft palate. It can lead to disrupted sleep, daytime tiredness and poor concentration – both for the person who snores and anyone sleeping close by. Conservative treatments involve lifestyle changes, including weight loss, avoiding alcohol and sedatives, stopping smoking and sleep position training. Physical appliances (such as dental or oral devices) have also been used to maintain normal airflow dynamics during sleep. Procedures available for pharyngeal airway obstruction include laser-assisted uvulopalatoplasty (LAUP) and uvulopalatopharyngoplasty (UPPP).# The procedure Radiofrequency ablation aims to stiffen the soft palate. It may be combined with other techniques (such as removal of the uvula or tonsillectomy) to reduce airflow obstruction and vibration in the airway. The procedure is usually done using local anaesthesia in outpatients. An electrode delivery device is introduced into the mouth and directed upwards towards the soft palate. A needle tip makes a series of very shallow punctures in the underlying muscle. Radiofrequency energy is delivered at each puncture site, commonly in the mid-portion of the palate from the uvular base to the posterior nasal spine. Alternatively, 2 lateral applications can be given at a lower energy setting and to several areas on either side. The intention is to scar and tighten the soft palate. If necessary the procedure can be repeated several weeks later: it is often carried out 2 or 3 times.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A randomised controlled trial of 23 patients comparing radiofrequency ablation (n=12) against a sham procedure (n=11) showed a significant improvement in snoring scores (assessed by bed partner using a 10‑point visual analogue scale; 0: no snoring, 10: excessive snoring prompting bed partner to leave the room) for the radiofrequency ablation group at 6 to 8‑week follow-up, compared against the sham group. The mean score decreased from 8 to 5 in the radiofrequency ablation group and from 8.4 to 8.0 in the sham group (p<0.05 for difference between groups). However, only 2 out of 12 patients in the radiofrequency ablation group had a score below 3 (defined as the criterion for success). In the randomised controlled trial of 23 patients, daytime sleepiness (assessed using the Epworth Sleepiness Scale; lower scores indicating a better outcome) at 6 to 8‑week follow-up decreased from 5 before the procedure to 4 after the procedure in the radiofrequency ablation group, and from 5 to 4 in the sham group. The difference between the 2 groups was not statistically significant (p=0.77). A case series of 52 patients measured quality of life using a questionnaire. Thirty-nine per cent (20/52) of patients reported a 'great' improvement, 19% (10/52) reported a 'moderate' improvement, 25% (13/52) reported a 'mild' improvement and 17% (9/52) reported 'no improvement'. The mean quality-of-life score improved from 4 to 9 (p<0.05) at a mean follow-up of 7 months (details on the scale not reported). In a case series of 29 patients, 25% of patients (number not reported) reported satisfaction with the outcome 3 to 4 years after the procedure. Further treatment was carried out in 28% (8/29) of patients (4 had mandibular advancement devices, 1 had continuous positive airway pressure and 3 had radiofrequency-assisted uvulopalatoplasty). The specialist advisers listed the following key efficacy outcomes: improvement in snoring and upper airway obstruction leading to resolution of daytime sleepiness and improved quality of life for patient and partner.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Bleeding was reported in 2 patients in a case series of 218 patients. One patient developed a submucosal haematoma of the soft palate (timing unclear) associated with haemorrhage that needed haemostasis (no further details). Another patient had bleeding after their third radiofrequency ablation treatment (19 days after the procedure), which was treated by bipolar coagulation. Airway oedema (timing unclear) needing treatment with corticosteroids was reported in 5% (2/40) of patients after radiofrequency ablation in a non-randomised comparative study of 70 patients comparing radiofrequency ablation against injection snoreplasty. Swelling of the uvula (1 day after the procedure) needing hospital admission (no further details) was reported in 1 patient in the case series of 218 patients. Mild to moderate mucosal erosion (timing unclear) was reported in 48% (10/23) of patients in a case series of 23 patients. Infection of the soft palate was reported in 6 patients after the procedure in the case series of 218 patients (timing unclear; treated by oral antibiotics). One patient went on to develop a peritonsillar abscess that needed surgical drainage. Ulceration at the site of radiofrequency ablation probe insertion was reported in 5 patients in the case series of 29 patients. All ulcers healed within 'a couple of weeks'. The specialist advisers listed perforation of palate and palatal fistula as anecdotal adverse events. They also said that a theoretical adverse event was regurgitation due to palatal insufficiency.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. This guidance was developed using the NICE interventional procedures guidance process. It updates and replaces NICE interventional procedure guidance 124. We have produced a summary of this guidance for patients and carers. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0414-3	{'Recommendations': "This document replaces previous guidance on radiofrequency ablation of the soft palate for snoring (NICE interventional procedure guidance 124).\n\nCurrent evidence suggests that there are no major safety concerns associated with radiofrequency ablation of the soft palate for snoring. The evidence on the short-term efficacy of the procedure is adequate, although uncertainties remain about its efficacy in the longer term. Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit.\n\nDuring the consent process clinicians should, in particular, inform patients of the uncertainty about the procedure's long-term efficacy and of the possible need for further procedures if symptoms recur.\n\nPatient selection is important: the sound of snoring can arise from several different levels in the upper airway and this procedure should only be used for patients whose snoring has been shown to be caused by abnormal movement of the soft palate and in whom sleep apnoea has been excluded.\n\nNICE encourages further research into radiofrequency ablation of the soft palate for snoring. This could take the form of data collection, with the specific aim of documenting long-term outcomes and the need for further treatment.", 'Indications and current treatments': 'Snoring is a noisy inspiratory sound produced by vibration and partial airway obstruction in the pharynx. One cause is vibration of the soft palate. It can lead to disrupted sleep, daytime tiredness and poor concentration – both for the person who snores and anyone sleeping close by.\n\nConservative treatments involve lifestyle changes, including weight loss, avoiding alcohol and sedatives, stopping smoking and sleep position training. Physical appliances (such as dental or oral devices) have also been used to maintain normal airflow dynamics during sleep. Procedures available for pharyngeal airway obstruction include laser-assisted uvulopalatoplasty (LAUP) and uvulopalatopharyngoplasty (UPPP).', 'The procedure': 'Radiofrequency ablation aims to stiffen the soft palate. It may be combined with other techniques (such as removal of the uvula or tonsillectomy) to reduce airflow obstruction and vibration in the airway.\n\nThe procedure is usually done using local anaesthesia in outpatients. An electrode delivery device is introduced into the mouth and directed upwards towards the soft palate. A needle tip makes a series of very shallow punctures in the underlying muscle. Radiofrequency energy is delivered at each puncture site, commonly in the mid-portion of the palate from the uvular base to the posterior nasal spine. Alternatively, 2 lateral applications can be given at a lower energy setting and to several areas on either side. The intention is to scar and tighten the soft palate. If necessary the procedure can be repeated several weeks later: it is often carried out 2 or 3 times.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA randomised controlled trial of 23\xa0patients comparing radiofrequency ablation (n=12) against a sham procedure (n=11) showed a significant improvement in snoring scores (assessed by bed partner using a 10‑point visual analogue scale; 0: no snoring, 10: excessive snoring prompting bed partner to leave the room) for the radiofrequency ablation group at 6 to 8‑week follow-up, compared against the sham group. The mean score decreased from 8 to 5 in the radiofrequency ablation group and from 8.4 to 8.0 in the sham group (p<0.05 for difference between groups). However, only 2 out of 12\xa0patients in the radiofrequency ablation group had a score below\xa03 (defined as the criterion for success).\n\nIn the randomised controlled trial of 23\xa0patients, daytime sleepiness (assessed using the Epworth Sleepiness Scale; lower scores indicating a better outcome) at 6 to 8‑week follow-up decreased from 5 before the procedure to\xa04 after the procedure in the radiofrequency ablation group, and from 5 to 4 in the sham group. The difference between the 2\xa0groups was not statistically significant (p=0.77).\n\nA case series of 52\xa0patients measured quality of life using a questionnaire. Thirty-nine per cent (20/52) of patients reported a 'great' improvement, 19% (10/52) reported a 'moderate' improvement, 25% (13/52) reported a 'mild' improvement and 17% (9/52) reported 'no improvement'. The mean quality-of-life score improved from 4 to 9 (p<0.05) at a mean follow-up of 7 months (details on the scale not reported).\n\nIn a case series of 29\xa0patients, 25% of patients (number not reported) reported satisfaction with the outcome 3 to 4\xa0years after the procedure. Further treatment was carried out in 28% (8/29) of patients (4\xa0had mandibular advancement devices, 1\xa0had continuous positive airway pressure and 3\xa0had radiofrequency-assisted uvulopalatoplasty).\n\nThe specialist advisers listed the following key efficacy outcomes: improvement in snoring and upper airway obstruction leading to resolution of daytime sleepiness and improved quality of life for patient and partner.", 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nBleeding was reported in 2\xa0patients in a case series of 218\xa0patients. One patient developed a submucosal haematoma of the soft palate (timing unclear) associated with haemorrhage that needed haemostasis (no further details). Another patient had bleeding after their third radiofrequency ablation treatment (19\xa0days after the procedure), which was treated by bipolar coagulation.\n\nAirway oedema (timing unclear) needing treatment with corticosteroids was reported in 5% (2/40) of patients after radiofrequency ablation in a non-randomised comparative study of 70\xa0patients comparing radiofrequency ablation against injection snoreplasty.\n\nSwelling of the uvula (1\xa0day after the procedure) needing hospital admission (no further details) was reported in 1\xa0patient in the case series of 218\xa0patients.\n\nMild to moderate mucosal erosion (timing unclear) was reported in 48% (10/23) of patients in a case series of 23\xa0patients.\n\nInfection of the soft palate was reported in 6\xa0patients after the procedure in the case series of 218\xa0patients (timing unclear; treated by oral antibiotics). One patient went on to develop a peritonsillar abscess that needed surgical drainage.\n\nUlceration at the site of radiofrequency ablation probe insertion was reported in 5\xa0patients in the case series of 29\xa0patients. All ulcers healed within 'a couple of weeks'.\n\nThe specialist advisers listed perforation of palate and palatal fistula as anecdotal adverse events. They also said that a theoretical adverse event was regurgitation due to palatal insufficiency.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 124.\n\nWe have produced a summary of this guidance for patients and carers.\n\nNICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0414-3'}	https://www.nice.org.uk/guidance/ipg476
071ac95cdc9685fc53082e56c8fa36557eec3d9e	nice	Behaviour change: individual approaches	Behaviour change: individual approaches This guideline covers changing health-damaging behaviours among people aged 16 and over using interventions such as goals and planning, feedback and monitoring, and social support. It aims to help tackle a range of behaviours including alcohol misuse, poor eating patterns, lack of physical activity, unsafe sexual behaviour and smoking. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Recommendation 1 Develop a local behaviour change policy and strategy National and local policy makers and commissioners of behaviour change services and their partners (see who should take action?) should: Ensure policies and strategies aim to improve everyone's health and wellbeing. Use health equity audit to ensure health inequalities will not increase, and if possible will decrease as a result of the local behaviour change strategy and related programmes and interventions. Develop a commissioning strategy, linked to relevant policies, for an evidence-based behaviour change programme of population, community, organisational and individual-level behaviour change interventions. For example, see NICE's guidelines on alcohol-use disorders: prevention and obesity prevention. Also note that the NICE guideline on behaviour change: general approaches recommends delivering individual interventions in tandem with complementary activities at the population, community and organisational levels. Work with the local community to develop the strategy (see the NICE guideline on community engagement). Ensure the strategy, and any related policies, are sustainable and meet local needs, identified through joint strategic needs assessments (JSNAs) and other local data. Identify the behaviours the strategy will address, and the outcomes it aims to achieve. Bear in mind that some interventions and programmes can address more than 1 behaviour (for example, sexual behaviour and alcohol consumption). Ensure the content, scale and intensity of each intervention is proportionate to the level of social, economic or environmental disadvantage someone faces and the support they need (proportionate universalism). Identify a leader within each local authority area, for example, the director of public health or an elected member of cabinet, to address specific behaviours (such as smoking and physical activity). # Recommendation 2 Ensure organisation policies, strategies, resources and training all support behaviour change Directors in national and local organisations whose employees deliver behaviour change interventions should ensure policies, strategies and resources are in place to provide behaviour change support for staff, as well as service users. This support could take the form of behaviour change services for staff. Or it could involve creating environments that support health-promoting behaviour (for examples, see the NICE guidelines on tobacco and physical activity in the workplace). National and local organisations whose employees deliver behaviour change interventions should review job descriptions and person specifications to check that they include behaviour change knowledge and skills (or competencies), if they are a specific part of someone's job (see recommendation 9). Managers of health, wellbeing and social care services should determine which staff in contact with the public are best placed to deliver different levels of a behaviour change intervention (see recommendation 9). They should ensure those staff have the knowledge and skills (or competencies) needed to assess behaviours and individual needs (see recommendation 8) and to deliver the intervention. Employers should ensure staff are aware of the importance of being supportive, motivating people and showing them empathy (see recommendation 12). Directors and managers should ensure staff receive behaviour change training and supervision related to their roles and responsibilities (see recommendation 9). They should also be offered ongoing professional development on behaviour change theories, methods and skills (see recommendation 12). Mentors and supervisors with relevant training and experience (see recommendation 11 and recommendation 12) should support staff who are delivering behaviour change interventions. This includes helping them to set their own goals, providing constructive feedback on their practice and encouraging them to be aware of their duty of care. It also involves making them aware of the likely perceptions and expectations of those taking part in behaviour change interventions and programmes. # Recommendation 3 Commission interventions from services willing to share intervention details and data Commissioners of behaviour change services and their partners (see who should take action?) should: Only commission behaviour change interventions and programmes that meet the recommendations in this guidance and in the NICE guideline on behaviour change: general approaches. Ensure behaviour change interventions aim to both initiate and maintain change. Interventions should include techniques to address relapse and recognise that it is common. Commission interventions that are proven to be effective at changing and maintaining behaviour change. (See recommendation 4; also see the NICE topic pages on alcohol, diet, nutrition and obesity, physical activity, sexual health and smoking and tobacco.) Specify in service specifications that providers: make a detailed description of the intervention publicly available (see recommendation 6) collate accurate, standardised and comparable routine data on behaviours that affect health and wellbeing. (For example, behaviours covered by the Public Health Outcomes Framework.) Commission interventions from providers who agree to make their evaluation and monitoring data available to commissioners and local and national organisations. (The aim is to aid the design, delivery and monitoring of service processes and outcomes.) For example, data could be collected on: process assessment and quality assurance health outcomes. # Recommendation 4 Commission high quality, effective behaviour change interventions National and local policy makers, commissioners of behaviour change services and their partners (see who should take action?) should: Find out whether behaviour change interventions and programmes that are already in place are effective, cost effective and apply evidence-based principles. (See the NICE guideline on behaviour change: general approaches). Ensure that, when commissioning behaviour change interventions and programmes: Evaluation plans tailored for the intervention and target behaviours are built in from the outset. Resources (staff, time and funds) are allocated for independent evaluation of the short-, medium- and long-term outcomes. A quality assurance process is in place to assess whether the intervention was delivered as planned (intervention fidelity), achieves the target behaviour change and health and wellbeing outcomes, and reduces health inequalities. (The frequency of quality assurance checks should be specified.) There are quality assurance checks if an intervention has already been shown to be effective. All information on intervention processes and outcomes is recorded in a form that can be made available if needed (for example, on a secure database). Commission and evaluate a pilot if it is not clear whether an intervention shown to be effective for a specific behaviour, population or setting can be applied to other behaviours, settings or populations (see recommendation 16). Commission an intervention for which there is no evidence of effectiveness only if it is accompanied by an adequately powered and controlled evaluation that measures relevant outcomes (see recommendation 16). Stop running interventions or programmes if there is good evidence to suggest they are not effective or are harmful. # Recommendation 5 Plan behaviour change interventions and programmes taking local needs into account Commissioners and providers of behaviour change services, and intervention designers (see who should take action?) should: Work together and with other key stakeholders (for example, people who use services, communities and researchers) to select priority areas for interventions, based on local need. They should also identify suitable interventions that are acceptable to the target audiences. Take into account the local social and cultural contexts to ensure equitable access for everyone who needs help and make best use of existing resources and skills. Base behaviour change interventions and programmes on evidence of effectiveness (see recommendations 6 and recommendation 7). Take into account: the objectives of the intervention or programme evaluation plans (see recommendation 4 and recommendation 16) the target population (including characteristics such as socioeconomic status) whether there is a need to offer tailored interventions for specific subgroups (for example, see the NICE guideline on type 2 diabetes: prevention in people at high risk) intervention characteristics: content, assessment of participants, mode of delivery, intensity and duration of the intervention, who will deliver it, where and when the training needs of those delivering the intervention or programme the quality of the behavioural support provided by those delivering the intervention or programme availability of, and access to, services once the intervention has finished follow up and support to maintain the new behaviour plans to monitor and measure intervention fidelity. # Recommendation 6 Develop acceptable, practical and sustainable behaviour change interventions and programmes Commissioners of behaviour change services and intervention designers (see who should take action?) should: Work together and with other key stakeholders (for example, people who use services, communities and researchers) to develop (co-produce) behaviour change interventions and programmes that are acceptable, practical and sustainable. This should also reduce duplication between services. Develop interventions that: are evidence-based have clear objectives that have been developed and agreed with stakeholders identify the core skills, knowledge and experience (competencies) needed to deliver the intervention (including for the specific behaviour change techniques used) provide details of the training needed (including learning outcomes) for practitioners include a monitoring and evaluation plan developed according to agreed objectives. Before implementing a behaviour-change intervention, describe in detail the principles it is based on. Put these details in a manual. This should include: clearly stated objectives on what the intervention will deliver the evidence base used (such as from NICE guidance on a specific topic) an explanation of how the intervention works (mechanism of action), for example, by targeting capability, opportunity and motivation. Ensure manuals also include a detailed description of the intervention including: resources, setting or context, activities, processes and outcomes (including a pictorial description of the relationship between these variables, such as a conceptual map or logic model) intervention characteristics (see recommendation 5) a clear definition of the behaviour change techniques used so that each component can be replicated (for example, by using a taxonomy) details of how to tailor the intervention to meet individual needs (see recommendation 8) plans to address long-term maintenance of behaviour change and relapse implementation details: who will deliver what, to whom, when and how. Make the manual publicly available, for example, on a website (provide copyright details and 'training before use' requirements). If there are changes to an intervention during delivery, or after evaluation, ensure the manual is updated accordingly. # Recommendation 7 Use proven behaviour change techniques when designing interventions Providers of behaviour change interventions and programmes and intervention designers should: Design behaviour change interventions to include techniques that have been shown to be effective at changing behaviour. These techniques are described in principle 4 of the NICE guideline on behaviour change: general approaches and include: Goals and planning. Work with the client to: agree goals for behaviour and the resulting outcomes develop action plans and prioritise actions develop coping plans to prevent and manage relapses consider achievement of outcomes and further goals and plans. Feedback and monitoring (for example, regular weight assessment for weight management interventions): encourage and support self-monitoring of behaviour and its outcomes and provide feedback on behaviour and its outcomes. Social support. If appropriate advise on, and arrange for, friends, relatives, colleagues or 'buddies' to provide practical help, emotional support, praise or reward. Ensure the techniques used match the service user's needs (see recommendation 8). Consider using other evidence-based behaviour change techniques that may also be effective. See the NICE topic pages on alcohol, diet, nutrition and obesity, physical activity, sexual health and smoking and tobacco for details of specific techniques. Clearly define and provide a rationale for all behaviour change techniques that have been included. Ensure novel techniques – or those for which the evidence base is limited – are evaluated (see recommendation 16). Consider delivering an intervention remotely (or providing remote follow-up) if there is evidence that this is an effective way of changing behaviour. For example, use the telephone, text messaging, apps or the internet. # Recommendation 8 Ensure interventions meet individual needs Providers of behaviour change programmes and interventions and trained behaviour change practitioners should: Ensure service users are given clear information on the behaviour change interventions and services available and how to use them. If necessary, they should help people to access the services. Ensure services are acceptable to, and meet, service users' needs. This includes any needs in relation to a disability or another 'protected characteristic' in relation to equity. Recognise the times when people may be more open to change, such as when recovering from a behaviour-related condition (for example, following diagnosis of cardiovascular disease) or when becoming a parent. Also recognise when offering a behaviour change intervention may not be appropriate due to personal circumstances. Trained behaviour change practitioners (see recommendation 12 and recommendation 13) should: Before starting an intervention: Assess participants' health in relation to the behaviour and the type of actions needed. For example, they should ensure the level and type of physical activity recommended is appropriate, bearing in mind the person's physical health. (As an example, see the NICE guideline on weight management before, during and after pregnancy.) Ensure the intensity of the intervention matches the person's need for support to change their behaviour. Discuss what the likely impact will be if the participant makes changes to their behaviour (in terms of their health and wellbeing and the health and wellbeing of those they are in contact with). Plan at what point before, during and after a behaviour change intervention a review will be undertaken to assess progress towards goals and then tailor the intervention and follow-up support accordingly. Tailor interventions to meet participants' needs by assessing and then addressing: People's behaviour: if available, use a validated assessment tool appropriate for the specific population or setting. For example, alcohol screening tools used in prisons are different from those used in accident and emergency departments. Participants' physical and psychological capability to make change. The context in which they live and work (that is, their physical, economic and social environment). How motivated they are to change: if many behaviours need to be changed, assess which one – or ones – the person is most motivated to tackle (see capability, opportunity and motivation). Any specific needs with regards to sexual orientation, gender identity, gender, culture, faith or any type of disability. # Recommendation 9 Deliver very brief, brief, extended brief and high intensity behaviour change interventions and programmes Commissioners and providers of behaviour change services should: Encourage health, wellbeing and social care staff (see who should take action?) in direct contact with the general public to use a very brief intervention to motivate people to change behaviours that may damage their health. The interventions should also be used to inform people about services or interventions that can help them improve their general health and wellbeing. Encourage staff who regularly come into contact with people whose health and wellbeing could be at risk to provide them with a brief intervention. (The risk could be due to current behaviours, sociodemographic characteristics or family history.) Encourage behaviour change service providers and other health and social care staff dealing with the general public to provide an extended brief intervention to people they regularly see for 30 minutes or more who: are involved in risky behaviours (for example harmful drinking - the latest definitions on alcohol limits are described in the glossary of the NICE guideline on alcohol use disorders: prevention) have a number of health problems have been assessed as being at increased or higher risk of harm have been successfully making changes to their behaviour but need more support to maintain that change have found it difficult to change or have not benefited from a very brief or brief intervention. Encourage behaviour change service providers and practitioners to provide high intensity interventions (typically these last more than 30 minutes and are delivered over a number of sessions) for people they regularly work with who: have been assessed as being at high risk of causing harm to their health and wellbeing (for example, adults with a BMI more than 40 – see the NICE guideline on obesity prevention) and/or have a serious medical condition that needs specialist advice and monitoring (for example, people with type 2 diabetes or cardiovascular disease) and/or have not benefited from lower-intensity interventions (for example, an extended brief intervention). # Recommendation 10 Ensure behaviour change is maintained for at least a year Providers and practitioners involved with behaviour change programmes and interventions should help people maintain their behaviour change in the long term (more than 1 year) by ensuring they: receive feedback and monitoring at regular intervals for a minimum of 1 year after they complete the intervention (the aim is to make sure they can get help if they show any sign of relapse) have well-rehearsed action plans (such as 'if–then' plans) that they can easily put into practice if they relapse have thought about how they can make changes to their own immediate physical environment to prevent a relapse have the social support they need to maintain changes are helped to develop routines that support the new behaviour (note that small, manageable changes to daily routine are most likely to be maintained). # Recommendation 11 Commission training for all staff involved in helping to change people's behaviour Commissioners, local education and training boards, and managers and supervisors (see who should take action?) should: Commission training for relevant staff to meet the service specification for any behaviour change intervention or programme. This should: cover all the various activities, from a very brief intervention offered when the opportunity arises to extended brief interventions include assessment of people's behaviours and needs address equity issues provide the latest available evidence of effectiveness and describe how an intervention works (mechanism of action). Ensure training programmes on behaviour change provide: evidence-based content (see recommendation 7) evidence-based training methods trainers with proven skills, knowledge and experience (competencies) in the particular area (see recommendation 12) monitoring using relevant behaviour change competency frameworks or assessment. Commissioners and local education and training boards should: Ensure training programmes consider: where programmes and interventions will be delivered training participants' characteristics (such as background) whether behaviour change is part of participants' main role, integral to their role but not the main focus, or an additional task (see recommendation 9). Ensure training includes ongoing professional development on how to encourage behaviour change. This could include regular refresher training to maintain the quality of delivery of behaviour change interventions. Ensure training is evaluated in terms of outcomes (see recommendation 14) and process (for example, via participant feedback). # Recommendation 12 Provide training for behaviour change practitioners Providers of behaviour change training should: Ensure training objectives include the range of knowledge and skills (competences) needed to deliver specific interventions. Ensure practitioners are trained to adopt a person-centred approach when assessing people's needs and planning and developing an intervention for them. Ensure behaviour change practitioners: understand the factors that may affect behaviour change, including the psychological, social, cultural and economic factors (see recommendation 8) are aware of behaviours that adversely affect people's health and wellbeing, and the benefits of prevention and management can address health inequalities by tailoring interventions to people's specific needs, including their cultural, social and economic needs and other 'protected characteristics' are able to assess people's needs and can help select appropriate evidence-based interventions know how an intervention works (mechanism of action) recognise the specific behaviour change techniques used in the intervention they will be delivering understand how to access, and how to direct and refer people to, specialist support services (for example, they should know how people can get help to change their behaviour after hospitalisation, a routine GP appointment or an intervention) understand local policy and demographics. Ensure behaviour change practitioners have the skills to: assess people's behaviour using validated assessment tools and measures communicate effectively, for example, by giving people health, wellbeing and other information, by using reflective listening and knowing how to show empathy develop rapport and relationships with service users develop a person's motivation to change by encouraging and enabling them to manage their own behaviour (see recommendation 7) deliver the relevant behaviour change techniques help prevent and manage relapses (see recommendation 10). Ensure behaviour change practitioners who provide interventions to groups can: elicit group discussions provide group tasks that promote interaction or bonding encourage mutual support within the group. Give practitioners the opportunity to learn how to tailor interventions to meet the needs and preferences of different groups and to test this ability (both during and after training). Ensure trainers have adequate time and resources to assess participants' motivation, skills, confidence and knowledge when they are delivering interventions to particular groups. # Recommendation 13 Provide training for health and social care practitioners All those who train or accredit health and social care professionals (see who should take action?) should: Ensure behaviour change knowledge, skills and delivery techniques comprise a formal element of initial training, work placements and ongoing continuous professional development for all those who deliver health and social care services. (See recommendation 12 for details of training content.) Ensure all health and social care professionals can, as a minimum, deliver a very brief intervention. (Training modules can be found online, for example, see the National Centre for Smoking Cessation and Training's very brief advice training module.) # Recommendation 14 Assess behaviour change practitioners and provide feedback Providers of behaviour change training should: Assess the ability of trainees to deliver behaviour change techniques and tailor interventions to meet people's needs. Employers (this includes workplace managers, supervisors and mentors of trainees) should: Ensure behaviour change practitioners who have received training are regularly assessed on their ability to deliver behaviour change interventions. This ranges from a very brief intervention to a high intensity intervention (the latter typically lasts longer than 30 minutes and is delivered over multiple sessions). Assessment should reflect the intervention content. It should also include practitioners' ability to provide participants with behaviour change techniques and to tailor interventions to participants' needs. In addition, it should include service user feedback. Providers of behaviour change training and employers should: Ideally, record behaviour change sessions as part of the assessment. Intervention components, such as behaviour change techniques, should be identified in transcripts. Audio or video recording equipment could be used. If this is not possible then, as a minimum, a reliable observation tool should be used to record the intervention. An example of the latter would be a checklist of key intervention components. Obtain the consent of the practitioner and service user for all assessments. They should also ensure the organisation's confidentiality requirements are met. Provide behaviour change practitioners with feedback on their performance, both orally and in writing, starting with feedback on good performance. If necessary, negotiate and set jointly agreed goals and an action plan. Provide them with the option of refresher training. # Recommendation 15 Monitor behaviour change interventions Commissioners, providers and researchers (see who should take action?) should ensure all interventions are monitored in terms of: process measures (for example, uptake and reach of the intervention) impact on health inequalities behavioural outcomes in the short, medium and long-term how closely they follow the intervention manual (intervention fidelity) (see recommendation 6). If possible, providers should adapt existing electronic systems to collect data on the behaviour of participants. For an example of what could be collected on smoking, see the National Centre for Smoking Cessation and Training stop smoking service client record form. # Recommendation 16 Evaluate behaviour change interventions Before introducing a new intervention, commissioners and providers of behaviour change interventions and researchers should be clear about the objectives and how these will be measured and evaluated. (Researchers could include practitioners and others; for more details see who should take action?) See Medical Research Council guidance on the development, evaluation and implementation of complex interventions to improve health. Commissioners and providers should ensure evaluation is carried out by a team of researchers or an organisation that has not been involved in delivering the intervention. Researchers should work with commissioners and providers to plan evaluation before the intervention takes place. This may entail getting specialist input (for example, from the National Institute for Health Research's research design service). Researchers should use objective, validated measures of outcome and process if they are available. They should ensure the design makes it possible to provide new evidence of effectiveness and, ideally, cost effectiveness – and details on why it is effective (mechanism of action). See principles 7 and 8 in the NICE guideline on behaviour change: general approaches. Commissioners, providers and researchers should ensure evaluation includes: a description of the evaluation design assessment of intervention fidelity consistent use of valid, reliable measures (using the same tools to assess behaviours) before, during and following an intervention (that is, ensuring baseline and outcome measures match) rigorous qualitative assessments to evaluate how well interventions will work in practice and how acceptable they are to services users and practitioners assessment of processes and outcomes using both objective and self-reported measures establishing and ensuring routine data collection adequate sample sizes assessment of long-term outcomes (more than 1 year). Providers of existing interventions should work with researchers to ensure they are rigorously evaluated. # Recommendation 17 National support for behaviour change interventions and programmes National organisations that support the monitoring, collection and surveillance of routine data should work together to: determine what routine data health, social care and voluntary organisations should record on health-related behaviours (such as smoking and alcohol) collect these data to monitor the outcomes of activities to improve the public's health (include: behaviour change interventions; national, regional and local policies and initiatives; and communication campaigns) track the prevalence of these behaviours over time, region and social group and report on findings support local implementation of behaviour change interventions based on evidence of effectiveness. National organisations responsible for behaviour change training and curricula (see who should take action?) should work together to: provide a central repository for behaviour change training curricula assess whether behaviour change competency frameworks and training curricula promote an evidence-based approach to behaviour change provide guidance on the suitability of these frameworks and curricula in terms of who they are aimed at and whether their content is evidence based. National organisations responsible for research funding should ensure research related to behaviour change includes, as a minimum, details of: intervention content and how it was delivered who delivered the intervention format (methods by which the intervention was administered) where and when the intervention was delivered recipients intervention intensity and duration intervention fidelity. # Terms used in this guideline ## Behaviour change competency frameworks Behaviour change competency frameworks describe the knowledge and skills required to deliver interventions to people to help them change their behaviour (Dixon and Johnston 2010). ## Behaviour change interventions Behaviour change interventions involve sets of techniques, used together, which aim to change the health behaviours of individuals, communities or whole populations. ## Behaviour change practitioner Anyone who delivers behaviour change techniques and interventions can be a behaviour change practitioner, regardless of their professional background, as long as they have received specific training in these techniques. However, not all practitioners can deliver all interventions or techniques. ## Behaviour change programme Behaviour change programmes are a coordinated set of more than one intervention that share common aims and objectives. ## Behaviour change techniques The term 'behaviour change technique' is used in this guidance to mean the component of an intervention that has been designed to change behaviour, such as social support. The technique must meet specified criteria so that it can be identified, delivered and reliably replicated. It should also be observable and irreducible (behaviour change techniques are the smallest 'active' component of an intervention.) They can be used alone or in combination with other behaviour change techniques. ## Brief intervention A brief intervention involves oral discussion, negotiation or encouragement, with or without written or other support or follow-up. It may also involve a referral for further interventions, directing people to other options, or more intensive support. Brief interventions can be delivered by anyone who is trained in the necessary skills and knowledge. These interventions are often carried out when the opportunity arises, typically taking no more than a few minutes for basic advice. ## Capability, opportunity and motivation For any change in behaviour to occur, a person must: Be physically and psychologically capable of performing the necessary actions. Have the physical and social opportunity. People may face barriers to change because of their income, ethnicity, social position or other factors. For example, it is more difficult to have a healthy diet in an area with many fast food outlets, no shops selling fresh food and with poor public transport links if you do not have a car. Be more motivated to adopt the new, rather than the old behaviour, whenever necessary. This is known as the COM-B model (Michie et al. 2011d). ## Choice architecture interventions In this guidance, 'choice architecture intervention' is used to mean changing the context in which someone will make a decision in order to influence how they act. For example, placing healthier snacks closer to a shop checkout and putting sugary and high-fat options out of reach may influence people to make a healthier choice because it is more accessible. Behaviour change approaches based on choice architecture are also referred to as 'nudge' or 'nudging' interventions (Thaler and Sunstein 2008). ## Community-level interventions A community-level intervention targets a particular community in a specific geographic area, or with a shared identity or interest. For example, it could involve addressing local infrastructure and planning issues that discourage people in a specific geographical area from cycling. This could include ensuring local facilities and services are easily accessible by bicycle and changing the layout of roads to improve safety and reduce traffic speeds. ## Co-produce Co-production means ensuring public services are developed and delivered by professionals, people using the services, their families and their neighbours working together in an equal and reciprocal way to agree what is needed, where and how. ## Extended brief intervention An extended brief intervention is similar in content to a brief intervention but usually lasts more than 30 minutes and consists of an individually-focused discussion. It can involve a single session or multiple brief sessions. ## Feedback and monitoring In 'feedback and monitoring' a specific behaviour (for example, alcoholic drinks consumed) or outcome (for example, changes in weight following changes to diet) is recorded. The person trying to change their behaviour is given feedback on the recorded behaviour or outcomes (for example, measurement of weight) or comment on progress towards a set goal. Monitoring can be done by a third party, or by the person themselves ('self-monitoring'). ## Goals and planning 'Goals and planning' refers to a group of behaviour change techniques that help people to set goals for their behaviour or for an outcome of the behaviour (such as weight loss) and plan how these goals will be met. Action plans include a description of what will happen in what situation or at what time: how often it will happen, for how long, and where it will take place. Behaviour goals are reviewed regularly in the light of experience and further plans are made according to past progress towards goals. ## Independent evaluation Independent evaluations are conducted by someone who is not involved in commissioning or delivering an intervention and does not have a vested interest in the outcome. Evaluations can look at process or outcome and answer such questions as: Was an intervention delivered according to the plan or service specification? What changes were there in the behaviour of, or health outcomes for, service users? Why did the planned intervention lead (or not lead) to changes in behaviour or health outcomes? ## Individual-level behaviour change interventions In this guidance, 'individual-level behaviour change intervention' is used to mean action that aims to help someone with a specific health condition, or a behaviour that may affect their health. It can be delivered on a one-to-one, group or remote basis, but the focus is on creating measurable change in a specific person. A nutritional intervention offered to anyone with a specific biomarker (for example, a specific body mass index) or health status (for example, obesity) is an example. However, a nutritional intervention offered to everyone in the country, or a particular city, is not. Although delivered to an individual, the intervention may affect a whole group or population. The interventions referred to throughout the guidance include one or more behaviour change technique. ## Intervention fidelity Intervention fidelity is the degree to which the planned components of an intervention have been delivered as intended. ## Logic model Logic models are narrative or visual depictions of real-life processes leading to a desired result. Using a logic model as a planning tool allows precise communication about the purposes of a project or intervention, its components and the sequence of activities needed to achieve a given goal. It also helps to set out the evaluation priorities right from the beginning of the process. ## Motivation Motivation is the process that starts, guides and maintains goal-related behaviour, for example making changes to diet and exercise to lose weight. It involves biological, emotional, social and cognitive forces. ## Outcomes Outcomes are the impact that a test, treatment, policy, programme or other intervention has on a person, group or population. Outcomes from interventions to improve the public's health could include changes in their knowledge and behaviour leading to a change in their health and wellbeing. ## Person-centred approach Using a 'person-centred' approach, services work in collaboration with service users as equal partners to decide on the design and delivery of services. This approach takes into account people's needs and builds relationships with family members. It also takes into account their social, cultural and economic context, motivation and skills, including any potential barriers they face to achieving and maintaining behaviour change. Person-centred care involves compassion, dignity and respect. ## Population-level interventions Population-level interventions are national policies or campaigns that address the underlying social, economic and environmental conditions of a population to improve everyone's health. This type of intervention could include, for example, distributing leaflets to the whole population highlighting the importance of being physically active, adopting a healthy diet and being a healthy weight. ## Proportionate universalism In a proportionate universalist approach, interventions are delivered to the whole population, with the intensity adjusted according to the needs of specific groups (for example, some groups may need more frequent help and advice). This type of approach can help to reduce the social gradient and benefit everybody. ## Social support Social support involves friends, relatives, or colleagues providing support for people who want to change their behaviour (for example, to quit smoking). It can take the form of: Practical help (for example, helping someone to free up the time they need to get to a service or use a facility, or helping them to get there). Emotional support (for example, a partner or friend could go walking or cycling with the person on a regular basis if they want to get physically fit). Praise or reward for trying to change, whatever the result. (For example, a partner or friend could make sure they congratulate the person for attempting to lose weight or stop smoking.) ## Taxonomy A taxonomy is a system of naming, describing and classifying techniques, items or objects. For example, a website taxonomy includes all the elements of a website and divides them into mutually exclusive groups and subgroups. An example of a behaviour-change technique taxonomy that can be applied across behaviours is described in Michie et al. 2013. ## Very brief intervention A very brief intervention can take from 30 seconds to a couple of minutes. It is mainly about giving people information, or directing them where to go for further help. It may also include other activities such as raising awareness of risks, or providing encouragement and support for change. It follows an 'ask, advise, assist' structure. For example, very brief advice on smoking would involve recording the person's smoking status and advising them that stop smoking services offer effective help to quit. Then, depending on the person's response, they may be directed to these services for additional support.# Who should take action? # Introduction The guidance is for: commissioners, managers, training and education organisations, service providers and practitioners with public health as part of their remit working within local authorities, the NHS, and the wider public, private, voluntary and community sectors. It is particularly aimed at those who commission, design, investigate and deliver interventions to help people change their behaviour – or who encourage or support behaviour change as part of their role. This includes those who provide training on behaviour change. The guidance may also be of interest to policy makers, researchers, individuals, groups or organisations wishing to work in partnership with health and social care and other service providers. In addition, it may be of interest to people who want to change their behaviour (for example, to stop smoking), their families and other members of the public. # Who should do what at a glance Who should take action? Recommendation National policy makers Local policy makers Commissioners Health and wellbeing boards Individuals, groups or organisations wishing to work with health and social care service providers Directors and employers Providers of behaviour change interventions and programmes Intervention designers Trained behaviour change practitioners; trained staff working in health, wellbeing and social care services who have contact with the general public Local education and training boards Managers, supervisors and mentors of staff delivering interventions Providers of training Royal colleges, faculties, schools, voluntary sector and sector skills councils that train or accredit health and social care professionals Researchers Academics Research funders National organisations with a remit for improving or assessing health, providing services and training National organisations with a remit for supporting data monitoring, collection and surveillance # Who should take action in detail ## Recommendation 1 Local strategy developers (such as health and wellbeing boards); national and local policy makers and commissioners of behaviour change services and their partners in health, local authority and voluntary sector organisations; individuals, groups or organisations wishing to work in partnership with health and social care service providers. ## Recommendation 2 Directors, managers and employers in national and local organisations whose employees deliver behaviour change interventions. ## Recommendation 3 Local policy makers and commissioners of behaviour change services and their partners in health, local authority and voluntary sector organisations; individuals, groups or organisations wishing to work in partnership with health and social care service providers. ## Recommendation 4 National and local policy makers and commissioners of behaviour change services and their partners in health, local authority and voluntary sector organisations; individuals, groups or organisations wishing to work in partnership with health and social care service providers. ## Recommendation 5 Commissioners of behaviour change services in health, local authorities and voluntary sector organisations; providers of behaviour change interventions and programmes; intervention designers (including researchers, academics and practitioners). ## Recommendation 6 Commissioners of behaviour change services in health, local authorities and voluntary sector organisations; intervention designers (including researchers, academics and practitioners). ## Recommendation 7 Providers of behaviour change interventions and programmes; intervention designers (including researchers, academics and practitioners). ## Recommendation 8 Providers of behaviour change programmes and interventions, trained behaviour change practitioners. ## Recommendation 9 Commissioners and providers of behaviour change services in health, local authority and voluntary sector organisations; trained behaviour change practitioners; staff working in health, wellbeing and social care services who have contact with the general public. ## Recommendation 10 Providers and practitioners involved with behaviour change programmes and interventions. ## Recommendation 11 Commissioners of behaviour change services in health, local authority and voluntary sector organisations; local education and training boards; managers and supervisors of staff delivering behaviour change interventions. ## Recommendation 12 Providers of behaviour change training. ## Recommendation 13 Royal colleges, faculties, schools, voluntary sector and sector skills councils that train or accredit health and social care professionals. ## Recommendation 14 Providers of behaviour change training; workplace managers, supervisors and mentors of trainees. ## Recommendation 15 Commissioners and providers of behaviour change interventions in health, local authority and voluntary sector organisations; researchers (including academics, practitioners and individuals) developing, delivering and evaluating behaviour change interventions. ## Recommendation 16 Commissioners and providers of behaviour change interventions in health, local authority and voluntary sector organisations; commissioners and funders of research; researchers (including academics, practitioners and others capable of developing, delivering and evaluating behaviour change interventions). ## Recommendation 17 National organisations that support the monitoring, collection and surveillance of routine data; national organisations responsible for behaviour change training and curricula (including, Health Education England, Public Health England, Local Government Association, NHS England, the Department of Health and Office of National statistics); national organisations responsible for research funding.# Context Practitioners use a range of interventions when working with someone to improve their health. Each intervention will usually involve one or more behaviour change techniques. However, there is a lack of practical advice on which techniques should be used to tackle specific behaviours (for example, in relation to diet, smoking and alcohol) and with people from specific populations or with particular risk factors. For an individual to improve their health in the medium and long term, behaviour change must be sustained. Maintaining changes to behaviour can involve both helping people to deal with relapses, and ensuring that new behaviours become habitual. Sustained behaviour change is most likely to occur when a combination of individual, community and population-level interventions are used. In addition, there is a reasonable evidence base relating to motivation to change (Lai et al. 2010; Ruger et al. 2008). In 2011, the House of Lords Science and Technology Select Committee reviewed a range of factors that impact on behaviour change. In its final report, the Committee recommended that NICE should update its guidance on the topic; in particular it wanted, 'more explicit advice on how behaviour change techniques could be applied to reduce obesity, alcohol abuse and smoking' (House of Lords 2011). Considerable research has been undertaken to specify behaviour change interventions in terms of their component parts. This has led to a definition of behaviour change techniques relevant for a range of health behaviours (Michie et al. 2013) and for specific behaviours: to improve their diet or encourage physical activity (Abraham and Michie 2008; Conn et al. 2002; Inoue et al. 2003; Michie et al. 2011a) to prevent weight gain (Hardeman et al. 2000) to stop smoking (Michie et al. 2011b) to reduce alcohol intake (Michie et al. 2012) to prevent HIV (Albarracin et al. 2005). Work is currently underway to explore the extent to which techniques may be applicable across different behaviours. The classification system has been shown to be reliable. Its validity is now being assessed (Michie et al. 2013). The importance of having a theoretical basis for the design and evaluation of interventions is well established (Medical Research Council 2008; Craig et al. 2008). For example, it can help ensure better outcomes (Albarracin et al. 2005) as well as providing a means of understanding why an intervention is effective or not. Work has been done to establish theoretical frameworks for behaviour change (Abraham and Michie 2008; Michie et al. 2011a; West 2009) and evidence continues to emerge about these theories (Tuah et al. 2011; Williams and French 2011). This section describes the factors and issues the Programme Development Group (PDG) considered when developing the recommendations. Please note: this section does not contain the recommendations. There is a wealth of information and recommendations in existing NICE guidance on interventions related to the behaviours covered in this guidance: alcohol use, eating patterns, physical activity, sexual behaviour and smoking. The PDG did not aim to update or critique these recommendations. Rather, it considered new evidence to add value to the recommendations already made. The PDG agreed that the principles in the NICE guideline on behaviour change: general approaches relevant to the remit of this guidance were still applicable. These were: principles 1 (planning), 3 (education and training), 4 (individual-level behaviour change interventions and programmes), 7 (effectiveness) and 8 (cost-effectiveness). This guidance focuses mainly on individual-level behaviour change interventions. However, the PDG agreed that these need to be viewed in the context of a range of other interventions. This includes those delivered at population and community level and those related to the environments in which choices about behaviours take place (see the NICE guideline on behaviour change: general approaches). The PDG noted that tackling behaviour change among people younger than 16, in particular in relation to issues such as alcohol use and sexual risk-taking, is important. However, this was not part of the remit for this guidance. The PDG used various terms to describe the target group of an intervention. It did not feel that any term was preferable and used 'participants' and 'service users' interchangeably. The PDG discussed the role of commercial companies in contributing to behaviour change and the potential contribution they could make to behaviour change interventions. Suppliers and manufacturers could, for example, provide (free of charge) useful data to aid understanding about behaviours such as alcohol use or eating patterns. The PDG agreed that some of the recommendations were ambitious and may prove difficult to resource at local level. However, it was keen to set a 'gold standard' for service delivery as an aspirational target. The PDG did not think it was useful to look at specific behaviour change techniques in isolation. The Group agreed that single technique interventions may be effective for some people (or with some behaviours). However, it also noted that behaviour change often comes about because of a range of techniques working together (as well as other factors, such as context). The question is, which behaviour change techniques work most effectively together? The Group noted that theories of behaviour change may help determine which techniques should work synergistically. The PDG noted that there was evidence of effectiveness for the behaviour change techniques recommended in relation to specific behaviours. However, the Group also noted, that the effectiveness of techniques across behaviours and populations was not always clear or necessarily supported by the evidence. The behaviour change techniques taxonomy used in the evidence reviews (Michie et al. 2013) helped in discussions and in informing the evidence synthesis. However, the PDG had some concerns about the findings reported in review 2. This was due to the quality of reporting in intervention studies and the associated difficulty of coding behaviour change techniques on the basis of limited information. First, variations in reporting behaviour change techniques in the published data posed challenges when trying to provide consistent coding across interventions. Second, many tests were undertaken in the analysis in which behaviour change technique data were pooled across interventions for different behaviours and populations. This, combined with coding issues, could lead to the wrong conclusion concerning whether or not a technique is associated with behaviour change. Third, the potential moderating effect of other variables (such as mode of delivery and intervention intensity) was not addressed in the review analysis. The authors of review 2 coded the behaviour change techniques used for 'usual care' and the 'control arm' in each study. This was to ensure all the behaviour change techniques used (in both the intervention and comparator) in any study were included in the meta-regression analysis. The accuracy of this coding was, however, dependent on the level of detail provided in published studies about the control arm. The PDG noted that, as with the reporting of interventions in published research, detail about control arms was often poor or missing. Generally there was not enough specific detail. The PDG did not think recommendations could be based solely on the findings of the meta-regression analysis in evidence review 2. It noted that this review provided evidence of the effect sizes of behaviour change interventions and details of the behaviour change techniques used. The PDG agreed that triangulation – looking for consistent effects across the different evidence considered by the group – would be appropriate. Consequently, if specific behaviour change techniques were evident in effective interventions in the evidence reviews and expert testimony, these findings were used as the basis for recommendations. The PDG only made recommendations about behaviour change techniques that were identified using the triangulation process. Hence, a particular technique may not be recommended because of a lack of supporting evidence from more than one source, rather than due to evidence that it is not effective. The evidence reviews that informed this guidance were structured around the specific taxonomy developed by Michie et al. (2013). While two-thirds of the possible behaviour change techniques defined in the taxonomy were identified in the included evidence, relatively few were identified often. This does not necessarily mean that techniques not mentioned were not used in the interventions. It may be that they are not reported or described in enough detail to be identified in published articles. The lack of evidence on sexual behaviour in the commissioned reviews made it difficult for the PDG to make recommendations on these interventions. The PDG noted that interventions aimed at changing people's alcohol use, eating patterns, physical activity, sexual behaviour and smoking are generally cost effective. The same is true for a number of other health behaviours that have been subjected to research. The Group also noted that there was little or no consistent association between the presence of any one behaviour change technique (or cluster of techniques) and an intervention being cost effective. The PDG ensured the first recommendation highlights the need for an integrated programme of population, community, organisational and individual-level behaviour change interventions. It noted that interventions that target many levels simultaneously tend to be the most effective. The PDG noted that it was important for all policy and strategy to be in line with the principles of proportionate universalism. This involves providing universal services and additional tailored support to meet the particular needs and choices of those who may find it difficult to use the services. The PDG discussed whether practitioners and services should aim to change one behaviour at a time or multiple behaviours at once. It also discussed the best strategy to deal with multiple behaviours. Given the lack of evidence on the best approach, the Group made a recommendation for further research. The PDG was concerned that if private companies were commissioned to provide a behaviour change service they may not share data because of commercial interests. It noted the importance of data-sharing for the purposes of monitoring processes and outcomes. The PDG noted the importance of ensuring all behaviour change interventions and programmes are conducted in an ethical manner. For example, this might involve ensuring participants in an intervention are fully informed of its content and how their data may be used. It might also involve ensuring national data protection and confidentiality policies are met. The PDG considered that sustained changes in behaviour (that is, the maintenance of behaviour change) are vital to improve public health outcomes. It noted the need to plan for this at the start. The Group also noted that measurable changes in health at a population level may happen over the medium to long term, whereas changes in behaviour of individuals could be detected over shorter time periods. The PDG noted the importance of long-term evaluation of behaviour change interventions and programmes. It also noted that, in reality, effectiveness is often not assessed beyond 6–12 weeks following an intervention. The PDG noted that details of various study designs, their internal validity, and how to assess the quality of a study can be found in appendix D of Methods for the development of NICE public health guidance (third edition). The PDG noted that the majority of published journal articles on behaviour change interventions do not provide enough detail to determine the techniques used in intervention and control groups. Where detail is provided, it may reflect the topic covered. For example, scientific studies on alcohol are based on a more standardised way of reporting than, say, scientific studies within the sexual health field. The Group discussed the need for manuals providing practical detail of the intervention techniques used, and for these to be made publicly available. The PDG noted that a lack of detail in published journal articles on studies claiming to use motivational interviewing had affected the Group's ability to determine the behaviour techniques used. The PDG recognised that motivational interviewing is based on a clear set of principles and components. But as the articles did not specify which principles and components were used, the Group could not assume that motivational interviewing was used. This made it impossible to recommend this approach. It also added further support to the Group's recommendation that manuals should provide details of all the intervention components used. The PDG acknowledged stakeholder concerns about intellectual property, copyright issues and the potentially inappropriate use of the information kept in manuals on behaviour change interventions. (For example, someone may use the information to set up their own commercial behaviour change intervention without having had the appropriate training needed to deliver it.) However, it was generally agreed that it was important to make manuals for all interventions publicly available, for example, as a condition of funding for projects in receipt of public monies. As most journals now have web supplements, the PDG noted that it is possible to provide detailed reports of intervention designs, whatever the word limit of the main paper. The PDG discussed the fact that some journals only publish evaluations of interventions that come with publicly available manuals detailing the full protocols used. It welcomed this practice. The recommendations contained in this guidance reflect the PDG's conclusions about intervention planning, based on the evidence considered. However, the PDG recognised that a number of other planning tools and resources – for example, 'intervention mapping' (Bartholomew et al. 2011) – could be systematically employed to enhance intervention design and effectiveness (see 4.31 below). Intervention mapping aids collaborative planning by people from different professional backgrounds during intervention development. The approach proposes 6 intervention design stages: Stage 1: A needs assessment determines what (if anything) needs to be changed for whom. Stage 2: Primary and secondary intervention objectives are defined. This involves specifying the precise behaviour changes participants will be expected to make. Stage 3: Designers identify the underlying evidence-based techniques that maintain current (unwanted) behaviour patterns and may generate the specified changes. Stage 4: Practical ways of delivering these techniques are developed and integrated into the intervention. Stage 5: How the intervention will be used or delivered in everyday contexts is considered. Stage 6: Evaluation to assess whether the intervention changed specified behaviours in context. These stages are iterative in that, for example, anticipation of how the intervention will be used or delivered may lead to a change in design and a return to stage 4. Similarly, when the exact behaviour changes are defined in stage 2, these may need to be evaluated. The result is an intervention 'map' of matrices and plans that guide the design, implementation and evaluation of an intervention. The PDG noted the importance of not just the content of an intervention, but who is delivering it (and their core competencies), to whom, how and where. The PDG discussed the importance of making sure all key components of a given intervention are adopted so that they have high intervention fidelity and are sustainable. The PDG agreed that a behaviour change taxonomy for designing interventions was a useful tool. However, the Group was clear that the inclusion of a behaviour change technique in a taxonomy did not necessarily mean there was a strong evidence base for that technique. Evidence showed that behaviour change interventions by GPs and other medical staff can be effective. However, the PDG felt that a focus solely on such interventions may lead to a widening in health inequalities, because people from the most vulnerable groups often do not use primary care services. The Group did not want to exclude such interventions, rather it raised the need to find alternative ways of reaching vulnerable groups. Members agreed that understanding how people come into contact with, and access, services was key to the design of behaviour change interventions. The PDG noted that details of validated tools and measures for assessing behaviour can be found in academic publications. The Group also noted that specific assessment tools have been recommended by NICE. For example, tools for assessing alcohol use are recommended in the NICE guideline on alcohol-use disorders: prevention. The PDG agreed that although information is usually a necessary precursor to behaviour change, information alone is not always sufficient to influence behaviour. The PDG noted that social, economic and cultural contexts can have an impact on behaviour. Although a sense of connection and belonging at school, within the family or community promotes resilience, unhealthy behaviour can also be embedded in social processes and patterns. The Group also noted that diverse health outcomes can be established early in life. Recommendations were made to include goals and planning and feedback and monitoring techniques in behaviour change interventions. This was based on a cross-examination of behaviour change techniques identified in expert paper 14, the evidence reviews and the NICE guideline on behaviour change: general approaches. (Triangulation techniques were used.) The process indicated that the techniques would be effective as part of interventions on alcohol, diet, physical activity and smoking. These behaviour change techniques are described in detail in Michie et al. (2013). Time constraints meant it was not possible to review additional evidence on sexual health interventions and behaviour change techniques. However, the PDG noted that in existing NICE guidance, social support was frequently used in effective interventions for all behaviours (alcohol, diet, physical activity, sexual behaviour and smoking). The PDG noted that social support provided by friends, family and associates could help to create an environment in which people felt able to make changes. However, members also noted that, if not managed effectively, social support provided by non-professionals (such as family members) could sometimes lead to an unhealthy co‑dependency, bullying, manipulation or other negative behaviour. The PDG noted that principle 4 (on individuals) in the NICE guideline on behaviour change: general approaches recommended specific behaviour change techniques. The Group agreed that, for consistency of approach, these would be 'coded' using the taxonomy applied in the commissioned evidence reviews for this guidance (Michie et al. 2013). This taxonomy identified the following groups of behaviour change techniques: goals and planning, feedback and monitoring, social support, natural consequences, comparison of behaviour, repetition and substitution and antecedents. The PDG noted that interventions are unlikely to be effective if providers are not properly trained or the setting is not appropriate. The Group also noted that some behaviour change techniques, such as self-monitoring, might be difficult for some people. The PDG was aware of a growing interest in the use of new technology, including phone and tablet apps, to deliver behaviour change interventions. The Group noted that the evidence is mixed and there have not been many formal evaluations of its effectiveness. But it also noted that evidence to support the use of technology is encouraging (see recommendation 7). The PDG noted the importance of training. For example, the Group discussed the fact that if one person successfully trained 100 practitioners they, in turn, could help 10,000 people, and the knock-on effects would be huge. The PDG discussed the importance of communication skills when providing behaviour change interventions. In particular, it noted the importance of knowing how to initiate a conversation, develop rapport and communicate information effectively. Communication skills include reflective listening, the use of open ended questions and affirmation skills. The PDG did not discuss the accreditation of training. This may be an area where future guidance is needed. The PDG was concerned that training programmes still describe the stages of change model (also known as the transtheoretical model) as a theoretical basis for behaviour change interventions. The PDG wanted to highlight that, although it may help practitioners and service users to understand the experience of behaviour change, it is not a theory that is able to accurately explain and predict such change. It was noted that interventions based on this model alone have not, according to the evidence reviewed here, demonstrated effectiveness. The PDG was clear that being trained to deliver one behaviour change intervention does not necessarily mean that a practitioner is then competent to deliver other behaviour change interventions. The Group was aware of the danger that practitioners and service users may assume their competency extends further than it actually does. The PDG noted that behaviour change training is a behaviour change intervention in its own right. The PDG noted that this guidance is not intended to make recommendations on how to undertake research in this area. The PDG noted that well-conducted evaluation studies and randomised controlled trials – with minimal bias – give the best quality evidence. Anecdotal evidence and smaller or poorly conducted studies are much less reliable and the Group agreed that it was best not to use these as a basis for investment decisions. The Group also noted that NICE, NHS Evidence and the Cochrane Collaboration provide guidance to help identify behaviour change interventions or programmes to invest in for a particular topic, population or setting. The PDG noted that qualitative, as well as quantitative, measures are important when trying to understand why something does or does not work – and under what circumstances. They can also help to identify any improvements or changes that need to be made. The PDG noted that the setting where an intervention is delivered and the person delivering it may be the two main factors that make an intervention effective (or ineffective). The PDG discussed the meaning of independent evaluation. The Group was clear that this was not synonymous with external evaluation. Rather, it could be carried out inside an organisation as long as it was not conducted by those actually involved in designing or delivering the intervention. The PDG noted that local organisations may need support to help them decide on the most appropriate behaviour change interventions and training to commission or provide in their area. Members discussed how a unified national approach might achieve this, with organisations and research funders working together to ensure appropriate data collection, evaluation and dissemination of evidence. The PDG also noted that some organisations, for example Public Health England and NICE (through NICE evidence services) are already working towards this goal. On the basis of current evidence, the PDG felt that it would be premature to make any recommendations on the use of choice architecture interventions (see expert paper 8). As a result, only research recommendations were made on this. A scoping review of the evidence base for choice architecture interventions targeting healthy behaviour indicated that the majority of evidence involved diet (see expert paper 8). However, in the absence of a full systematic review, the PDG questioned whether such interventions did lead to a healthy diet. The PDG noted that, in the context of choice architecture, 'doing nothing' is not a neutral approach, because this simply maintains the status quo. And the status quo may, for example, be an 'obesogenic environment' constructed by commercial interests. The PDG recognised that choice architecture interventions may appeal to people working in a local authority setting. The reasons are twofold. First, this type of behaviour change intervention may be perceived to be relatively low cost. Second, it has the potential to reach a relatively large number of people. However, there is only limited evidence on how effective these interventions are at changing health-related behaviour. The PDG agreed that anyone wishing to commission or provide such an intervention as part of a behaviour change service should be aware of this lack of evidence. The Group agreed that choice architecture interventions, if used, needed to be subject to independent evaluation. Although the PDG was not able to make recommendations on choice architecture interventions, members noted that a further evidence synthesis on this approach is due to be published soon. The PDG advised that if this synthesis is published prior to the routine update of this guidance, the update should be bought forward.# Recommendations for research The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects. All the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity. . Which choice architecture interventions help to reduce increased-risk and higher-risk drinking of alcohol, improve sexual health behaviours, help stop or reduce smoking, or increase the physical activity levels of the general UK population? How is this related to sociodemographic variables? . What evidence of effectiveness is there on the use of choice architecture interventions in commercial settings to influence health-related behaviours? How can findings from commercial settings support non-commercial choice architecture approaches to support behaviour change to improve health? . Which combinations of behaviour change techniques and modes of delivery are effective and cost effective in initiating particular behaviour changes, and in maintaining those changes? How does this vary among people from different socio-demographic groups or with different levels of motivation, access to information or skills? Include research that builds the evidence base on the effectiveness of each behaviour change technique. For example, experimental and meta-analytic work could clarify which behaviour change techniques work when, and for whom. . Which behaviour change interventions and programmes are effective and cost effective at changing multiple behaviours and maintaining behaviour change? How does this vary among people from different sociodemographic groups? . What characteristics of behaviour change training influence the effectiveness of behaviour change practitioners? . How effective and cost effective are behaviour change interventions delivered remotely (that is, by telephone, text message, phone and tablet apps or the internet)? How does this vary among behaviours and among people from different sociodemographic groups? . How do behaviour change techniques lead to change? What are the best methods of testing the relationship between the theories that describe change processes and the effectiveness of interventions in practice? More detail identified during development of this guidance is provided in gaps in the evidence.# References Abraham C, Michie S (2008) A taxonomy of behaviour change techniques used in interventions. Health Psychology 27: 379–87 Albarracin D, Gillette JC, Earl AN et al. (2005) A test of major assumptions about behaviour change: A comprehensive look at the effects of passive and active HIV-prevention interventions since the beginning of the epidemic. Psychological Bulletin 131: 856−97 Bartholomew LK, Parcel GS, Kok G et al. (2011) Planning health promotion programs: an intervention mapping approach 3rd edition. San Francisco: Jossey-Bass Conn VS, Valentine JC, Cooper HM (2002) Interventions to increase physical activity among aging adults: A meta-analysis. Annals of Behavioral Medicine 24: 190–200 Craig P, Dieppe P, Macintyre S et al. (2008) Developing and evaluating complex interventions: the new Medical Research Council guidance. BMJ 337: a1655 Dixon D, Johnston M (2010) Health behaviours change competency framework: competencies to deliver interventions to change lifestyle behaviours that affect health. Edinburgh: The Scottish Government Gellman MD, Turner JR (2013) Encyclopaedia of Behavioral Medicine. New York: Springer. Hardeman W, Griffin S, Johnston M et al. (2000) Interventions to prevent weight gain: a systematic review of psychological models and behaviour change methods. International Journal of Obesity 24: 131−43 House of Lords (2011) Inquiry: behaviour change Inoue S, Odagiri Y, Wakui S et al. (2003) Randomized controlled trial to evaluate the effect of a physical activity intervention program based on behavioural medicine. Journal of Tokyo Medical University 61: 154−65 Lai DTC, Cahill K, Qin Y et al. (2010) Motivational interviewing for smoking cessation. Cochrane Database of Systematic Reviews issue 1 Marteau T, Ogilvie D, Roland M et al. (2011) Judging nudging: can nudging improve population health? British Medical Journal 342: d228 Medical Research Council (2008) Complex interventions guidance Michie S, Richardson M, Johnston M et al (2013) The behaviour change technique taxonomy (v1) of 93 hierarchically clustered techniques: building an international consensus for the reporting of behaviour change interventions. Annals of behavioural medicine March 20 Michie S, Whittington C, Hamoudi Z et al. (2012) Identification of behaviour change techniques to reduce excessive alcohol consumption. Addiction 107: 1431–40 Michie S, Ashford S, Falko F et al. (2011a) Refined taxonomy of behaviour change techniques to help people change their physical activity and healthy eating behaviours: The CALO-RE taxonomy. Psychology and Health 28: 1–20 Michie S, Hyder N, Walia A et al. (2011b) Development of a taxonomy of behaviour change techniques used in individual behavioural support for smoking cessation. Addictive Behaviours 36: 315–19 Michie S, Abraham C, Eccles MP et al. (2011c) Strengthening evaluation and implementation by specifying components of behaviour change interventions: a study protocol. Implementation Science 6: 10 Michie S, van Stralen MM, West R (2011d) The behaviour change wheel: a new method for characterising and designing behaviour change interventions, Implementation Science 6: 42 Ruger JP, Weinstein MC, Hammond SK et al. (2008) Cost-effectiveness of motivational interviewing for smoking cessation and relapse prevention among low-income pregnant women: a randomized controlled trial. Value Health 11: 191–8 Thaler R, Sunstein C (2008) Nudge: improving decisions about health, wealth, and happiness. Connecticut: Yale University Press Tuah NAA, Amiel C, Qureshi S et al. (2011) Transtheoretical model for dietary and physical exercise modification in weight loss management for overweight and obese adults. Cochrane Database of Systematic Reviews issue 10 West R (2009) The multiple facets of cigarette addiction and what they mean for encouraging and helping smokers to stop. Journal of Chronic Obstructive Pulmonary Disease 6: 277−83 Williams SL, French DP (2011) What are the most effective intervention techniques for changing physical activity self-efficacy and physical activity behaviour – and are they the same? Health Education Research 26: 308–22# The evidence # Introduction The evidence statements from 3 reviews are provided by external contractors (see supporting evidence). This section lists how the evidence statements and the expert papers link to the relevant recommendations. It also sets out a brief summary of findings from the economic analysis and the fieldwork. # How the evidence and expert papers link to the recommendations The evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document. Evidence statement number 1.1 indicates that the linked statement is numbered 1 in review 1. Evidence statement number 2.1.3 indicates that the linked statement is numbered 1.3 in review 2. Evidence statement number 3.3.4 indicates that the linked statement is numbered 3.4 in review 3. EP1 indicates that expert paper 1 is linked to a recommendation. The reviews, expert papers and economic analysis are available. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: EP3, EP4, EP6–9, EP13 Recommendation 2: evidence statements 3.1.1, 3.1.2, 3.1.3 EP 10, EP11 Recommendation 3: EP4–6, EP9, EP13 Recommendation 4: EP1, EP3–5, EP14 Recommendation 5: EP1–3, EP5, EP14 Recommendation 6: EP1–3 Recommendation 7: evidence statements 1.2, 1.4, 1.6, 1.7, 1.9, 1.10–1.19, 1.20, 1.21, 2.1.8, 2.3.7, 2.3.11, 2.3.13, 2.3.17, 2.4.4, 2.4.5, 2.4.8, 2.5.5, 2.5.6, 2.5.7, 2.5.9, 2.5.11, 2.5.15, 3.3.3, 3.3.4, 3.3.6, 3.3.7, EP14 Recommendation 8: EP1–3, EP5, EP6, EP9 Recommendation 9: EP10–12 Recommendation 10: evidence statements 1.2, 1.4, 1.6, 1.7, 1.9, 1.10–1.19, 1.20, 1.21, 2.4.4, 2.4.5, 2.5.5, 2.5.6, 3.3.3, 3.3.4, 3.3.6, 3.3.7, EP14 Recommendation 11: EP5, EP10–12 Recommendation 12: evidence statements: 3.3.1–3, 3.2.1, 3.2.2, 3.3.1–9, EP5, EP10–12 Recommendation 13: EP5, EP10–12 Recommendation 14: EP5, EP10–12 Recommendation 15: EP1–3 Recommendation 16: EP1–3, EP14 Recommendation 17: IDE # Economic analysis Review 1 identified 79 interventions dealing with 6 behaviours: smoking, diet, physical activity, alcohol, sexual health and multiple health targets. All interventions fall well below the accepted £20,000–£30,000 costs per quality-adjusted life year (QALY) threshold. However, sensitivity analyses suggest that some may have incremental cost-effectiveness ratios (ICERs) above this threshold. In this review, sexual health interventions were least cost effective but no other characteristics or behaviour change techniques were related to cost-effectiveness estimates. Review 2 identified 251 interventions across the 6 behaviours, of which 102 provided cost–utility estimates (£/QALY). Using the upper estimate and lower threshold (the most cautious approach), 85% of interventions were identified as cost effective. Using the lower estimates, smoking cessation interventions were significantly more cost effective than interventions targeting multiple behaviours. Across all interventions, those targeting the general population had better cost–utility results and were more likely to be cost effective than those aimed at vulnerable populations. Regression analyses across, as well as within, behaviours suggests there is little or no consistent association between the presence of an individual behaviour change technique (or cluster of behaviour change techniques) and an intervention being cost effective. The authors of the reviews state that the findings need to be interpreted cautiously given: the different search strategies for reviews 1 (based on interventions already assessed by NICE as cost effective) and 2 (based on the search strategy used for evidence review 2) reliance on incomplete information in published papers heterogeneity in economic analyses lack of consensus for a definition of 'choice architecture' bias in reporting of study findings. # Fieldwork findings Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. Fieldwork participants who are involved in, or support, behaviour change activities were fairly positive about the recommendations and their potential to help change an individual's behaviour. This included practitioners, commissioners, service providers, health and wellbeing board members, national bodies (from both the public and private sectors), royal colleges and academics. Many participants welcomed the emphasis on evidence-based investment, but were keen to ensure this should not stifle innovation or narrow the options available to commissioners. They described the commissioning recommendations as bold and ambitious. While recognising that they may be difficult to implement in the current climate, participants did not believe the approach should be diluted. There were some concerns that independent evaluation may be viewed as unaffordable. It was suggested that evaluation should be built into the original design or service specification to ensure it does take place. Fieldwork participants did not think the recommendations offered a new approach, but they agreed that the measures had not been implemented universally. They believed wider, more systematic implementation would be achieved if there was a clearer definition of the techniques and training requirements for staff and commissioners.# Gaps in the evidence The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below. . There is a lack of evidence on the effectiveness or cost-effectiveness of using choice architecture interventions to change alcohol, sexual health behaviours, smoking and physical activity-related behaviours (with the exception of choice architecture interventions to promote stair use). In particular, there is a lack of UK-based primary research exploring the differential impacts of such interventions. (Source: Expert paper 8) . There is a lack of evaluation, using appropriate research designs, of choice architecture interventions used in commercial settings to determine their effectiveness, cost-effectiveness or usability in non-commercial settings. (Source: Expert paper 14) . There is a lack of review-level work and primary research examining the effectiveness of individual behaviour change techniques. (Source: Expert paper 14) . There is a lack of evidence addressing what the most effective approach is to dealing with multiple behaviours (for example, if someone smokes, consumes alcohol above recommended weekly limits and is physically inactive). Specifically: a) Should behaviours be approached in sequence or in combination? b) If multiple behaviours are addressed in combination, how is this decided? For example, is it based on the types of behaviour? How dependent is it on the person's capability, opportunity and motivation? (Source: Expert paper 14) . There is a lack of evidence prospectively investigating the relationship between practitioner training, subsequent competencies and behaviour change interventions. In particular, studies have not looked at the effect size of competencies or training. (Source: Evidence review 3) . There is limited research on the training needed to address barriers to delivering behaviour change interventions. (Source: Evidence review 3) . There is a lack of published research that provides details of the theoretical basis of an intervention (beyond the naming of a theory). There is a lack of evidence on how theoretical accounts of behaviour change can be used to guide evidence synthesis (combining multiple sources of quantitative evidence, such as meta-regression, meta-analysis) of behaviour change interventions. (Source: Evidence review 2) . There is a lack of recent evidence (post-2003) on behaviour change techniques used to influence sexual behaviour. In particular, there is a lack of UK randomised control trials with populations aged 16 and over. (Source: Evidence review 2) The Committee made 7 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in recommendations for research.	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Recommendation 1 Develop a local behaviour change policy and strategy\n\nNational and local policy makers and commissioners of behaviour change services and their partners (see who should take action?) should:\n\nEnsure policies and strategies aim to improve everyone's health and wellbeing.\n\nUse health equity audit to ensure health inequalities will not increase, and if possible will decrease as a result of the local behaviour change strategy and related programmes and interventions.\n\nDevelop a commissioning strategy, linked to relevant policies, for an evidence-based behaviour change programme of population, community, organisational and individual-level behaviour change interventions. For example, see NICE's guidelines on alcohol-use disorders: prevention and obesity prevention. Also note that the NICE guideline on behaviour change: general approaches recommends delivering individual interventions in tandem with complementary activities at the population, community and organisational levels.\n\nWork with the local community to develop the strategy (see the NICE guideline on community engagement).\n\nEnsure the strategy, and any related policies, are sustainable and meet local needs, identified through joint strategic needs assessments (JSNAs) and other local data.\n\nIdentify the behaviours the strategy will address, and the outcomes it aims to achieve. Bear in mind that some interventions and programmes can address more than 1 behaviour (for example, sexual behaviour and alcohol consumption).\n\nEnsure the content, scale and intensity of each intervention is proportionate to the level of social, economic or environmental disadvantage someone faces and the support they need (proportionate universalism).\n\nIdentify a leader within each local authority area, for example, the director of public health or an elected member of cabinet, to address specific behaviours (such as smoking and physical activity).\n\n# Recommendation 2 Ensure organisation policies, strategies, resources and training all support behaviour change\n\nDirectors in national and local organisations whose employees deliver behaviour change interventions should ensure policies, strategies and resources are in place to provide behaviour change support for staff, as well as service users. This support could take the form of behaviour change services for staff. Or it could involve creating environments that support health-promoting behaviour (for examples, see the NICE guidelines on tobacco and physical activity in the workplace).\n\nNational and local organisations whose employees deliver behaviour change interventions should review job descriptions and person specifications to check that they include behaviour change knowledge and skills (or competencies), if they are a specific part of someone's job (see recommendation 9).\n\nManagers of health, wellbeing and social care services should determine which staff in contact with the public are best placed to deliver different levels of a behaviour change intervention (see recommendation 9). They should ensure those staff have the knowledge and skills (or competencies) needed to assess behaviours and individual needs (see recommendation 8) and to deliver the intervention.\n\nEmployers should ensure staff are aware of the importance of being supportive, motivating people and showing them empathy (see recommendation 12).\n\nDirectors and managers should ensure staff receive behaviour change training and supervision related to their roles and responsibilities (see recommendation 9). They should also be offered ongoing professional development on behaviour change theories, methods and skills (see recommendation 12).\n\nMentors and supervisors with relevant training and experience (see recommendation 11 and recommendation 12) should support staff who are delivering behaviour change interventions. This includes helping them to set their own goals, providing constructive feedback on their practice and encouraging them to be aware of their duty of care. It also involves making them aware of the likely perceptions and expectations of those taking part in behaviour change interventions and programmes.\n\n# Recommendation 3 Commission interventions from services willing to share intervention details and data\n\nCommissioners of behaviour change services and their partners (see who should take action?) should:\n\nOnly commission behaviour change interventions and programmes that meet the recommendations in this guidance and in the NICE guideline on behaviour change: general approaches.\n\nEnsure behaviour change interventions aim to both initiate and maintain change. Interventions should include techniques to address relapse and recognise that it is common.\n\nCommission interventions that are proven to be effective at changing and maintaining behaviour change. (See recommendation 4; also see the NICE topic pages on alcohol, diet, nutrition and obesity, physical activity, sexual health and smoking and tobacco.)\n\nSpecify in service specifications that providers:\n\n\n\nmake a detailed description of the intervention publicly available (see recommendation 6)\n\ncollate accurate, standardised and comparable routine data on behaviours that affect health and wellbeing. (For example, behaviours covered by the Public Health Outcomes Framework.)\n\n\n\nCommission interventions from providers who agree to make their evaluation and monitoring data available to commissioners and local and national organisations. (The aim is to aid the design, delivery and monitoring of service processes and outcomes.) For example, data could be collected on:\n\n\n\nprocess assessment and quality assurance\n\nhealth outcomes.\n\n\n\n# Recommendation 4 Commission high quality, effective behaviour change interventions\n\nNational and local policy makers, commissioners of behaviour change services and their partners (see who should take action?) should:\n\nFind out whether behaviour change interventions and programmes that are already in place are effective, cost effective and apply evidence-based principles. (See the NICE guideline on behaviour change: general approaches).\n\nEnsure that, when commissioning behaviour change interventions and programmes:\n\n\n\nEvaluation plans tailored for the intervention and target behaviours are built in from the outset.\n\nResources (staff, time and funds) are allocated for independent evaluation of the short-, medium- and long-term outcomes.\n\nA quality assurance process is in place to assess whether the intervention was delivered as planned (intervention fidelity), achieves the target behaviour change and health and wellbeing outcomes, and reduces health inequalities. (The frequency of quality assurance checks should be specified.)\n\nThere are quality assurance checks if an intervention has already been shown to be effective.\n\nAll information on intervention processes and outcomes is recorded in a form that can be made available if needed (for example, on a secure database).\n\n\n\nCommission and evaluate a pilot if it is not clear whether an intervention shown to be effective for a specific behaviour, population or setting can be applied to other behaviours, settings or populations (see recommendation 16).\n\nCommission an intervention for which there is no evidence of effectiveness only if it is accompanied by an adequately powered and controlled evaluation that measures relevant outcomes (see recommendation 16).\n\nStop running interventions or programmes if there is good evidence to suggest they are not effective or are harmful.\n\n# Recommendation 5 Plan behaviour change interventions and programmes taking local needs into account\n\nCommissioners and providers of behaviour change services, and intervention designers (see who should take action?) should:\n\nWork together and with other key stakeholders (for example, people who use services, communities and researchers) to select priority areas for interventions, based on local need. They should also identify suitable interventions that are acceptable to the target audiences.\n\nTake into account the local social and cultural contexts to ensure equitable access for everyone who needs help and make best use of existing resources and skills.\n\nBase behaviour change interventions and programmes on evidence of effectiveness (see recommendations 6 and recommendation 7).\n\nTake into account:\n\n\n\nthe objectives of the intervention or programme\n\nevaluation plans (see recommendation 4 and recommendation 16)\n\nthe target population (including characteristics such as socioeconomic status)\n\nwhether there is a need to offer tailored interventions for specific subgroups (for example, see the NICE guideline on type 2 diabetes: prevention in people at high risk)\n\nintervention characteristics: content, assessment of participants, mode of delivery, intensity and duration of the intervention, who will deliver it, where and when\n\nthe training needs of those delivering the intervention or programme\n\nthe quality of the behavioural support provided by those delivering the intervention or programme\n\navailability of, and access to, services once the intervention has finished\n\nfollow up and support to maintain the new behaviour\n\nplans to monitor and measure intervention fidelity.\n\n\n\n# Recommendation 6 Develop acceptable, practical and sustainable behaviour change interventions and programmes\n\nCommissioners of behaviour change services and intervention designers (see who should take action?) should:\n\nWork together and with other key stakeholders (for example, people who use services, communities and researchers) to develop (co-produce) behaviour change interventions and programmes that are acceptable, practical and sustainable. This should also reduce duplication between services.\n\nDevelop interventions that:\n\n\n\nare evidence-based\n\nhave clear objectives that have been developed and agreed with stakeholders\n\nidentify the core skills, knowledge and experience (competencies) needed to deliver the intervention (including for the specific behaviour change techniques used)\n\nprovide details of the training needed (including learning outcomes) for practitioners\n\ninclude a monitoring and evaluation plan developed according to agreed objectives.\n\n\n\nBefore implementing a behaviour-change intervention, describe in detail the principles it is based on. Put these details in a manual. This should include:\n\n\n\nclearly stated objectives on what the intervention will deliver\n\nthe evidence base used (such as from NICE guidance on a specific topic)\n\nan explanation of how the intervention works (mechanism of action), for example, by targeting capability, opportunity and motivation.\n\n\n\nEnsure manuals also include a detailed description of the intervention including:\n\n\n\nresources, setting or context, activities, processes and outcomes (including a pictorial description of the relationship between these variables, such as a conceptual map or logic model)\n\nintervention characteristics (see recommendation 5)\n\na clear definition of the behaviour change techniques used so that each component can be replicated (for example, by using a taxonomy)\n\ndetails of how to tailor the intervention to meet individual needs (see recommendation 8)\n\nplans to address long-term maintenance of behaviour change and relapse\n\nimplementation details: who will deliver what, to whom, when and how.\n\n\n\nMake the manual publicly available, for example, on a website (provide copyright details and 'training before use' requirements). If there are changes to an intervention during delivery, or after evaluation, ensure the manual is updated accordingly.\n\n# Recommendation 7 Use proven behaviour change techniques when designing interventions\n\nProviders of behaviour change interventions and programmes and intervention designers should:\n\nDesign behaviour change interventions to include techniques that have been shown to be effective at changing behaviour. These techniques are described in principle 4 of the NICE guideline on behaviour change: general approaches and include:\n\n\n\nGoals and planning. Work with the client to:\n\n\n\nagree goals for behaviour and the resulting outcomes\n\ndevelop action plans and prioritise actions\n\ndevelop coping plans to prevent and manage relapses\n\nconsider achievement of outcomes and further goals and plans.\n\n\n\nFeedback and monitoring (for example, regular weight assessment for weight management interventions):\n\n\n\nencourage and support self-monitoring of behaviour and its outcomes and\n\nprovide feedback on behaviour and its outcomes.\n\n\n\nSocial support. If appropriate advise on, and arrange for, friends, relatives, colleagues or 'buddies' to provide practical help, emotional support, praise or reward.\n\n\n\nEnsure the techniques used match the service user's needs (see recommendation 8).\n\nConsider using other evidence-based behaviour change techniques that may also be effective. See the NICE topic pages on alcohol, diet, nutrition and obesity, physical activity, sexual health and smoking and tobacco for details of specific techniques.\n\nClearly define and provide a rationale for all behaviour change techniques that have been included.\n\nEnsure novel techniques – or those for which the evidence base is limited – are evaluated (see recommendation 16).\n\nConsider delivering an intervention remotely (or providing remote follow-up) if there is evidence that this is an effective way of changing behaviour. For example, use the telephone, text messaging, apps or the internet.\n\n# Recommendation 8 Ensure interventions meet individual needs\n\nProviders of behaviour change programmes and interventions and trained behaviour change practitioners should:\n\nEnsure service users are given clear information on the behaviour change interventions and services available and how to use them. If necessary, they should help people to access the services.\n\nEnsure services are acceptable to, and meet, service users' needs. This includes any needs in relation to a disability or another 'protected characteristic' in relation to equity.\n\nRecognise the times when people may be more open to change, such as when recovering from a behaviour-related condition (for example, following diagnosis of cardiovascular disease) or when becoming a parent. Also recognise when offering a behaviour change intervention may not be appropriate due to personal circumstances.\n\nTrained behaviour change practitioners (see recommendation 12 and recommendation 13) should:\n\nBefore starting an intervention:\n\n\n\nAssess participants' health in relation to the behaviour and the type of actions needed. For example, they should ensure the level and type of physical activity recommended is appropriate, bearing in mind the person's physical health. (As an example, see the NICE guideline on weight management before, during and after pregnancy.)\n\nEnsure the intensity of the intervention matches the person's need for support to change their behaviour.\n\nDiscuss what the likely impact will be if the participant makes changes to their behaviour (in terms of their health and wellbeing and the health and wellbeing of those they are in contact with).\n\n\n\nPlan at what point before, during and after a behaviour change intervention a review will be undertaken to assess progress towards goals and then tailor the intervention and follow-up support accordingly.\n\nTailor interventions to meet participants' needs by assessing and then addressing:\n\n\n\nPeople's behaviour: if available, use a validated assessment tool appropriate for the specific population or setting. For example, alcohol screening tools used in prisons are different from those used in accident and emergency departments.\n\nParticipants' physical and psychological capability to make change.\n\nThe context in which they live and work (that is, their physical, economic and social environment).\n\nHow motivated they are to change: if many behaviours need to be changed, assess which one – or ones – the person is most motivated to tackle (see capability, opportunity and motivation).\n\nAny specific needs with regards to sexual orientation, gender identity, gender, culture, faith or any type of disability.\n\n\n\n# Recommendation 9 Deliver very brief, brief, extended brief and high intensity behaviour change interventions and programmes\n\nCommissioners and providers of behaviour change services should:\n\nEncourage health, wellbeing and social care staff (see who should take action?) in direct contact with the general public to use a very brief intervention to motivate people to change behaviours that may damage their health. The interventions should also be used to inform people about services or interventions that can help them improve their general health and wellbeing.\n\nEncourage staff who regularly come into contact with people whose health and wellbeing could be at risk to provide them with a brief intervention. (The risk could be due to current behaviours, sociodemographic characteristics or family history.)\n\nEncourage behaviour change service providers and other health and social care staff dealing with the general public to provide an extended brief intervention to people they regularly see for 30\xa0minutes or more who:\n\n\n\nare involved in risky behaviours (for example harmful drinking [high-risk drinking]- the latest definitions on alcohol limits are described in the glossary of the NICE guideline on alcohol use disorders: prevention)\n\nhave a number of health problems\n\nhave been assessed as being at increased or higher risk of harm\n\nhave been successfully making changes to their behaviour but need more support to maintain that change\n\nhave found it difficult to change or have not benefited from a very brief or brief intervention.\n\n\n\nEncourage behaviour change service providers and practitioners to provide high intensity interventions (typically these last more than 30 minutes and are delivered over a number of sessions) for people they regularly work with who:\n\n\n\nhave been assessed as being at high risk of causing harm to their health and wellbeing (for example, adults with a BMI more than 40 – see the NICE guideline on obesity prevention) and/or\n\nhave a serious medical condition that needs specialist advice and monitoring (for example, people with type\xa02 diabetes or cardiovascular disease) and/or\n\nhave not benefited from lower-intensity interventions (for example, an extended brief intervention).\n\n\n\n# Recommendation 10 Ensure behaviour change is maintained for at least a year\n\nProviders and practitioners involved with behaviour change programmes and interventions should help people maintain their behaviour change in the long term (more than 1\xa0year) by ensuring they:\n\nreceive feedback and monitoring at regular intervals for a minimum of 1\xa0year after they complete the intervention (the aim is to make sure they can get help if they show any sign of relapse)\n\nhave well-rehearsed action plans (such as 'if–then' plans) that they can easily put into practice if they relapse\n\nhave thought about how they can make changes to their own immediate physical environment to prevent a relapse\n\nhave the social support they need to maintain changes\n\nare helped to develop routines that support the new behaviour (note that small, manageable changes to daily routine are most likely to be maintained).\n\n# Recommendation 11 Commission training for all staff involved in helping to change people's behaviour\n\nCommissioners, local education and training boards, and managers and supervisors (see who should take action?) should:\n\nCommission training for relevant staff to meet the service specification for any behaviour change intervention or programme. This should:\n\n\n\ncover all the various activities, from a very brief intervention offered when the opportunity arises to extended brief interventions\n\ninclude assessment of people's behaviours and needs\n\naddress equity issues\n\nprovide the latest available evidence of effectiveness and describe how an intervention works (mechanism of action).\n\n\n\nEnsure training programmes on behaviour change provide:\n\n\n\nevidence-based content (see recommendation 7)\n\nevidence-based training methods\n\ntrainers with proven skills, knowledge and experience (competencies) in the particular area (see recommendation 12)\n\nmonitoring using relevant behaviour change competency frameworks or assessment.\n\n\n\nCommissioners and local education and training boards should:\n\nEnsure training programmes consider:\n\n\n\nwhere programmes and interventions will be delivered\n\ntraining participants' characteristics (such as background)\n\nwhether behaviour change is part of participants' main role, integral to their role but not the main focus, or an additional task (see recommendation 9).\n\n\n\nEnsure training includes ongoing professional development on how to encourage behaviour change. This could include regular refresher training to maintain the quality of delivery of behaviour change interventions.\n\nEnsure training is evaluated in terms of outcomes (see recommendation 14) and process (for example, via participant feedback).\n\n# Recommendation 12 Provide training for behaviour change practitioners\n\nProviders of behaviour change training should:\n\nEnsure training objectives include the range of knowledge and skills (competences) needed to deliver specific interventions.\n\nEnsure practitioners are trained to adopt a person-centred approach when assessing people's needs and planning and developing an intervention for them.\n\nEnsure behaviour change practitioners:\n\n\n\nunderstand the factors that may affect behaviour change, including the psychological, social, cultural and economic factors (see recommendation 8)\n\nare aware of behaviours that adversely affect people's health and wellbeing, and the benefits of prevention and management\n\ncan address health inequalities by tailoring interventions to people's specific needs, including their cultural, social and economic needs and other 'protected characteristics'\n\nare able to assess people's needs and can help select appropriate evidence-based interventions\n\nknow how an intervention works (mechanism of action)\n\nrecognise the specific behaviour change techniques used in the intervention they will be delivering\n\nunderstand how to access, and how to direct and refer people to, specialist support services (for example, they should know how people can get help to change their behaviour after hospitalisation, a routine GP appointment or an intervention)\n\nunderstand local policy and demographics.\n\n\n\nEnsure behaviour change practitioners have the skills to:\n\n\n\nassess people's behaviour using validated assessment tools and measures\n\ncommunicate effectively, for example, by giving people health, wellbeing and other information, by using reflective listening and knowing how to show empathy\n\ndevelop rapport and relationships with service users\n\ndevelop a person's motivation to change by encouraging and enabling them to manage their own behaviour (see recommendation 7)\n\ndeliver the relevant behaviour change techniques\n\nhelp prevent and manage relapses (see recommendation 10).\n\n\n\nEnsure behaviour change practitioners who provide interventions to groups can:\n\n\n\nelicit group discussions\n\nprovide group tasks that promote interaction or bonding\n\nencourage mutual support within the group.\n\n\n\nGive practitioners the opportunity to learn how to tailor interventions to meet the needs and preferences of different groups and to test this ability (both during and after training).\n\nEnsure trainers have adequate time and resources to assess participants' motivation, skills, confidence and knowledge when they are delivering interventions to particular groups.\n\n# Recommendation 13 Provide training for health and social care practitioners\n\nAll those who train or accredit health and social care professionals (see who should take action?) should:\n\nEnsure behaviour change knowledge, skills and delivery techniques comprise a formal element of initial training, work placements and ongoing continuous professional development for all those who deliver health and social care services. (See recommendation 12 for details of training content.)\n\nEnsure all health and social care professionals can, as a minimum, deliver a very brief intervention. (Training modules can be found online, for example, see the National Centre for Smoking Cessation and Training's very brief advice training module.)\n\n# Recommendation 14 Assess behaviour change practitioners and provide feedback\n\nProviders of behaviour change training should:\n\nAssess the ability of trainees to deliver behaviour change techniques and tailor interventions to meet people's needs.\n\nEmployers (this includes workplace managers, supervisors and mentors of trainees) should:\n\nEnsure behaviour change practitioners who have received training are regularly assessed on their ability to deliver behaviour change interventions. This ranges from a very brief intervention to a high intensity intervention (the latter typically lasts longer than 30\xa0minutes and is delivered over multiple sessions). Assessment should reflect the intervention content. It should also include practitioners' ability to provide participants with behaviour change techniques and to tailor interventions to participants' needs. In addition, it should include service user feedback.\n\nProviders of behaviour change training and employers should:\n\nIdeally, record behaviour change sessions as part of the assessment. Intervention components, such as behaviour change techniques, should be identified in transcripts. Audio or video recording equipment could be used. If this is not possible then, as a minimum, a reliable observation tool should be used to record the intervention. An example of the latter would be a checklist of key intervention components.\n\nObtain the consent of the practitioner and service user for all assessments. They should also ensure the organisation's confidentiality requirements are met.\n\nProvide behaviour change practitioners with feedback on their performance, both orally and in writing, starting with feedback on good performance. If necessary, negotiate and set jointly agreed goals and an action plan. Provide them with the option of refresher training.\n\n# Recommendation 15 Monitor behaviour change interventions\n\nCommissioners, providers and researchers (see who should take action?) should ensure all interventions are monitored in terms of:\n\n\n\nprocess measures (for example, uptake and reach of the intervention)\n\nimpact on health inequalities\n\nbehavioural outcomes in the short, medium and long-term\n\nhow closely they follow the intervention manual (intervention fidelity) (see recommendation 6).\n\n\n\nIf possible, providers should adapt existing electronic systems to collect data on the behaviour of participants. For an example of what could be collected on smoking, see the National Centre for Smoking Cessation and Training stop smoking service client record form.\n\n# Recommendation 16 Evaluate behaviour change interventions\n\nBefore introducing a new intervention, commissioners and providers of behaviour change interventions and researchers should be clear about the objectives and how these will be measured and evaluated. (Researchers could include practitioners and others; for more details see who should take action?) See Medical Research Council guidance on the development, evaluation and implementation of complex interventions to improve health.\n\nCommissioners and providers should ensure evaluation is carried out by a team of researchers or an organisation that has not been involved in delivering the intervention.\n\nResearchers should work with commissioners and providers to plan evaluation before the intervention takes place. This may entail getting specialist input (for example, from the National Institute for Health Research's research design service).\n\nResearchers should use objective, validated measures of outcome and process if they are available. They should ensure the design makes it possible to provide new evidence of effectiveness and, ideally, cost effectiveness – and details on why it is effective (mechanism of action). See principles 7 and 8 in the NICE guideline on behaviour change: general approaches.\n\nCommissioners, providers and researchers should ensure evaluation includes:\n\n\n\na description of the evaluation design\n\nassessment of intervention fidelity\n\nconsistent use of valid, reliable measures (using the same tools to assess behaviours) before, during and following an intervention (that is, ensuring baseline and outcome measures match)\n\nrigorous qualitative assessments to evaluate how well interventions will work in practice and how acceptable they are to services users and practitioners\n\nassessment of processes and outcomes using both objective and self-reported measures\n\nestablishing and ensuring routine data collection\n\nadequate sample sizes\n\nassessment of long-term outcomes (more than 1\xa0year).\n\n\n\nProviders of existing interventions should work with researchers to ensure they are rigorously evaluated.\n\n# Recommendation 17 National support for behaviour change interventions and programmes\n\nNational organisations that support the monitoring, collection and surveillance of routine data should work together to:\n\n\n\ndetermine what routine data health, social care and voluntary organisations should record on health-related behaviours (such as smoking and alcohol)\n\ncollect these data to monitor the outcomes of activities to improve the public's health (include: behaviour change interventions; national, regional and local policies and initiatives; and communication campaigns)\n\ntrack the prevalence of these behaviours over time, region and social group and report on findings\n\nsupport local implementation of behaviour change interventions based on evidence of effectiveness.\n\n\n\nNational organisations responsible for behaviour change training and curricula (see who should take action?) should work together to:\n\n\n\nprovide a central repository for behaviour change training curricula\n\nassess whether behaviour change competency frameworks and training curricula promote an evidence-based approach to behaviour change\n\nprovide guidance on the suitability of these frameworks and curricula in terms of who they are aimed at and whether their content is evidence based.\n\n\n\nNational organisations responsible for research funding should ensure research related to behaviour change includes, as a minimum, details of:\n\n\n\nintervention content and how it was delivered\n\nwho delivered the intervention\n\nformat (methods by which the intervention was administered)\n\nwhere and when the intervention was delivered\n\nrecipients\n\nintervention intensity and duration\n\nintervention fidelity.\n\n\n\n# Terms used in this guideline\n\n## Behaviour change competency frameworks\n\nBehaviour change competency frameworks describe the knowledge and skills required to deliver interventions to people to help them change their behaviour (Dixon and Johnston 2010).\n\n## Behaviour change interventions\n\nBehaviour change interventions involve sets of techniques, used together, which aim to change the health behaviours of individuals, communities or whole populations.\n\n## Behaviour change practitioner\n\nAnyone who delivers behaviour change techniques and interventions can be a behaviour change practitioner, regardless of their professional background, as long as they have received specific training in these techniques. However, not all practitioners can deliver all interventions or techniques.\n\n## Behaviour change programme\n\nBehaviour change programmes are a coordinated set of more than one intervention that share common aims and objectives.\n\n## Behaviour change techniques\n\nThe term 'behaviour change technique' is used in this guidance to mean the component of an intervention that has been designed to change behaviour, such as social support. The technique must meet specified criteria so that it can be identified, delivered and reliably replicated. It should also be observable and irreducible (behaviour change techniques are the smallest 'active' component of an intervention.) They can be used alone or in combination with other behaviour change techniques.\n\n## Brief intervention\n\nA brief intervention involves oral discussion, negotiation or encouragement, with or without written or other support or follow-up. It may also involve a referral for further interventions, directing people to other options, or more intensive support. Brief interventions can be delivered by anyone who is trained in the necessary skills and knowledge. These interventions are often carried out when the opportunity arises, typically taking no more than a few minutes for basic advice.\n\n## Capability, opportunity and motivation\n\nFor any change in behaviour to occur, a person must:\n\nBe physically and psychologically capable of performing the necessary actions.\n\nHave the physical and social opportunity. People may face barriers to change because of their income, ethnicity, social position or other factors. For example, it is more difficult to have a healthy diet in an area with many fast food outlets, no shops selling fresh food and with poor public transport links if you do not have a car.\n\nBe more motivated to adopt the new, rather than the old behaviour, whenever necessary.\n\nThis is known as the COM-B model (Michie et al. 2011d).\n\n## Choice architecture interventions\n\nIn this guidance, 'choice architecture intervention' is used to mean changing the context in which someone will make a decision in order to influence how they act. For example, placing healthier snacks closer to a shop checkout and putting sugary and high-fat options out of reach may influence people to make a healthier choice because it is more accessible. Behaviour change approaches based on choice architecture are also referred to as 'nudge' or 'nudging' interventions (Thaler and Sunstein 2008).\n\n## Community-level interventions\n\nA community-level intervention targets a particular community in a specific geographic area, or with a shared identity or interest. For example, it could involve addressing local infrastructure and planning issues that discourage people in a specific geographical area from cycling. This could include ensuring local facilities and services are easily accessible by bicycle and changing the layout of roads to improve safety and reduce traffic speeds.\n\n## Co-produce\n\nCo-production means ensuring public services are developed and delivered by professionals, people using the services, their families and their neighbours working together in an equal and reciprocal way to agree what is needed, where and how.\n\n## Extended brief intervention\n\nAn extended brief intervention is similar in content to a brief intervention but usually lasts more than 30\xa0minutes and consists of an individually-focused discussion. It can involve a single session or multiple brief sessions.\n\n## Feedback and monitoring\n\nIn 'feedback and monitoring' a specific behaviour (for example, alcoholic drinks consumed) or outcome (for example, changes in weight following changes to diet) is recorded. The person trying to change their behaviour is given feedback on the recorded behaviour or outcomes (for example, measurement of weight) or comment on progress towards a set goal. Monitoring can be done by a third party, or by the person themselves ('self-monitoring').\n\n## Goals and planning\n\n'Goals and planning' refers to a group of behaviour change techniques that help people to set goals for their behaviour or for an outcome of the behaviour (such as weight loss) and plan how these goals will be met. Action plans include a description of what will happen in what situation or at what time: how often it will happen, for how long, and where it will take place. Behaviour goals are reviewed regularly in the light of experience and further plans are made according to past progress towards goals.\n\n## Independent evaluation\n\nIndependent evaluations are conducted by someone who is not involved in commissioning or delivering an intervention and does not have a vested interest in the outcome. Evaluations can look at process or outcome and answer such questions as:\n\nWas an intervention delivered according to the plan or service specification?\n\nWhat changes were there in the behaviour of, or health outcomes for, service users?\n\nWhy did the planned intervention lead (or not lead) to changes in behaviour or health outcomes?\n\n## Individual-level behaviour change interventions\n\nIn this guidance, 'individual-level behaviour change intervention' is used to mean action that aims to help someone with a specific health condition, or a behaviour that may affect their health. It can be delivered on a one-to-one, group or remote basis, but the focus is on creating measurable change in a specific person. A nutritional intervention offered to anyone with a specific biomarker (for example, a specific body mass index) or health status (for example, obesity) is an example. However, a nutritional intervention offered to everyone in the country, or a particular city, is not. Although delivered to an individual, the intervention may affect a whole group or population.\n\nThe interventions referred to throughout the guidance include one or more behaviour change technique.\n\n## Intervention fidelity\n\nIntervention fidelity is the degree to which the planned components of an intervention have been delivered as intended.\n\n## Logic model\n\nLogic models are narrative or visual depictions of real-life processes leading to a desired result. Using a logic model as a planning tool allows precise communication about the purposes of a project or intervention, its components and the sequence of activities needed to achieve a given goal. It also helps to set out the evaluation priorities right from the beginning of the process.\n\n## Motivation\n\nMotivation is the process that starts, guides and maintains goal-related behaviour, for example making changes to diet and exercise to lose weight. It involves biological, emotional, social and cognitive forces.\n\n## Outcomes\n\nOutcomes are the impact that a test, treatment, policy, programme or other intervention has on a person, group or population. Outcomes from interventions to improve the public's health could include changes in their knowledge and behaviour leading to a change in their health and wellbeing.\n\n## Person-centred approach\n\nUsing a 'person-centred' approach, services work in collaboration with service users as equal partners to decide on the design and delivery of services. This approach takes into account people's needs and builds relationships with family members. It also takes into account their social, cultural and economic context, motivation and skills, including any potential barriers they face to achieving and maintaining behaviour change. Person-centred care involves compassion, dignity and respect.\n\n## Population-level interventions\n\nPopulation-level interventions are national policies or campaigns that address the underlying social, economic and environmental conditions of a population to improve everyone's health. This type of intervention could include, for example, distributing leaflets to the whole population highlighting the importance of being physically active, adopting a healthy diet and being a healthy weight.\n\n## Proportionate universalism\n\nIn a proportionate universalist approach, interventions are delivered to the whole population, with the intensity adjusted according to the needs of specific groups (for example, some groups may need more frequent help and advice). This type of approach can help to reduce the social gradient and benefit everybody.\n\n## Social support\n\nSocial support involves friends, relatives, or colleagues providing support for people who want to change their behaviour (for example, to quit smoking). It can take the form of:\n\nPractical help (for example, helping someone to free up the time they need to get to a service or use a facility, or helping them to get there).\n\nEmotional support (for example, a partner or friend could go walking or cycling with the person on a regular basis if they want to get physically fit).\n\nPraise or reward for trying to change, whatever the result. (For example, a partner or friend could make sure they congratulate the person for attempting to lose weight or stop smoking.)\n\n## Taxonomy\n\nA taxonomy is a system of naming, describing and classifying techniques, items or objects. For example, a website taxonomy includes all the elements of a website and divides them into mutually exclusive groups and subgroups. An example of a behaviour-change technique taxonomy that can be applied across behaviours is described in Michie et al. 2013.\n\n## Very brief intervention\n\nA very brief intervention can take from 30\xa0seconds to a couple of minutes. It is mainly about giving people information, or directing them where to go for further help. It may also include other activities such as raising awareness of risks, or providing encouragement and support for change. It follows an 'ask, advise, assist' structure. For example, very brief advice on smoking would involve recording the person's smoking status and advising them that stop smoking services offer effective help to quit. Then, depending on the person's response, they may be directed to these services for additional support.", 'Who should take action?': '# Introduction\n\nThe guidance is for: commissioners, managers, training and education organisations, service providers and practitioners with public health as part of their remit working within local authorities, the NHS, and the wider public, private, voluntary and community sectors.\n\nIt is particularly aimed at those who commission, design, investigate and deliver interventions to help people change their behaviour – or who encourage or support behaviour change as part of their role. This includes those who provide training on behaviour change.\n\nThe guidance may also be of interest to policy makers, researchers, individuals, groups or organisations wishing to work in partnership with health and social care and other service providers. In addition, it may be of interest to people who want to change their behaviour (for example, to stop smoking), their families and other members of the public.\n\n# Who should do what at a glance\n\nWho should take action?\n\nRecommendation\n\nNational policy makers\n\n, 4\n\nLocal policy makers\n\n, 3, 4\n\nCommissioners\n\n, 5, 6, 9, 11, 15, 16\n\nHealth and wellbeing boards\n\n\n\nIndividuals, groups or organisations wishing to work with health and social care service providers\n\n, 3, 4\n\nDirectors and employers\n\n, 11\n\nProviders of behaviour change interventions and programmes\n\n, 7, 8, 9, 10, 15, 16\n\nIntervention designers\n\n, 6, 7\n\nTrained behaviour change practitioners; trained staff working in health, wellbeing and social care services who have contact with the general public\n\n, 9, 10\n\nLocal education and training boards\n\n\n\nManagers, supervisors and mentors of staff delivering interventions\n\n, 11, 14\n\nProviders of training\n\n, 14, 17\n\nRoyal colleges, faculties, schools, voluntary sector and sector skills councils that train or accredit health and social care professionals\n\n, 17\n\nResearchers\n\n, 6 ,7, 15, 16\n\nAcademics\n\n, 6 ,7, 15, 16\n\nResearch funders\n\n, 17\n\nNational organisations with a remit for improving or assessing health, providing services and training\n\n, 17\n\nNational organisations with a remit for supporting data monitoring, collection and surveillance\n\n\n\n# Who should take action in detail\n\n## Recommendation 1\n\nLocal strategy developers (such as health and wellbeing boards); national and local policy makers and commissioners of behaviour change services and their partners in health, local authority and voluntary sector organisations; individuals, groups or organisations wishing to work in partnership with health and social care service providers.\n\n## Recommendation 2\n\nDirectors, managers and employers in national and local organisations whose employees deliver behaviour change interventions.\n\n## Recommendation 3\n\nLocal policy makers and commissioners of behaviour change services and their partners in health, local authority and voluntary sector organisations; individuals, groups or organisations wishing to work in partnership with health and social care service providers.\n\n## Recommendation 4\n\nNational and local policy makers and commissioners of behaviour change services and their partners in health, local authority and voluntary sector organisations; individuals, groups or organisations wishing to work in partnership with health and social care service providers.\n\n## Recommendation 5\n\nCommissioners of behaviour change services in health, local authorities and voluntary sector organisations; providers of behaviour change interventions and programmes; intervention designers (including researchers, academics and practitioners).\n\n## Recommendation 6\n\nCommissioners of behaviour change services in health, local authorities and voluntary sector organisations; intervention designers (including researchers, academics and practitioners).\n\n## Recommendation 7\n\nProviders of behaviour change interventions and programmes; intervention designers (including researchers, academics and practitioners).\n\n## Recommendation 8\n\nProviders of behaviour change programmes and interventions, trained behaviour change practitioners.\n\n## Recommendation 9\n\nCommissioners and providers of behaviour change services in health, local authority and voluntary sector organisations; trained behaviour change practitioners; staff working in health, wellbeing and social care services who have contact with the general public.\n\n## Recommendation 10\n\nProviders and practitioners involved with behaviour change programmes and interventions.\n\n## Recommendation 11\n\nCommissioners of behaviour change services in health, local authority and voluntary sector organisations; local education and training boards; managers and supervisors of staff delivering behaviour change interventions.\n\n## Recommendation 12\n\nProviders of behaviour change training.\n\n## Recommendation 13\n\nRoyal colleges, faculties, schools, voluntary sector and sector skills councils that train or accredit health and social care professionals.\n\n## Recommendation 14\n\nProviders of behaviour change training; workplace managers, supervisors and mentors of trainees.\n\n## Recommendation 15\n\nCommissioners and providers of behaviour change interventions in health, local authority and voluntary sector organisations; researchers (including academics, practitioners and individuals) developing, delivering and evaluating behaviour change interventions.\n\n## Recommendation 16\n\nCommissioners and providers of behaviour change interventions in health, local authority and voluntary sector organisations; commissioners and funders of research; researchers (including academics, practitioners and others capable of developing, delivering and evaluating behaviour change interventions).\n\n## Recommendation 17\n\nNational organisations that support the monitoring, collection and surveillance of routine data; national organisations responsible for behaviour change training and curricula (including, Health Education England, Public Health England, Local Government Association, NHS England, the Department of Health and Office of National statistics); national organisations responsible for research funding.', 'Context': "Practitioners use a range of interventions when working with someone to improve their health. Each intervention will usually involve one or more behaviour change techniques. However, there is a lack of practical advice on which techniques should be used to tackle specific behaviours (for example, in relation to diet, smoking and alcohol) and with people from specific populations or with particular risk factors.\n\nFor an individual to improve their health in the medium and long term, behaviour change must be sustained. Maintaining changes to behaviour can involve both helping people to deal with relapses, and ensuring that new behaviours become habitual.\n\nSustained behaviour change is most likely to occur when a combination of individual, community and population-level interventions are used. In addition, there is a reasonable evidence base relating to motivation to change (Lai et al. 2010; Ruger et al. 2008).\n\nIn 2011, the House of Lords Science and Technology Select Committee reviewed a range of factors that impact on behaviour change. In its final report, the Committee recommended that NICE should update its guidance on the topic; in particular it wanted, 'more explicit advice on how behaviour change techniques could be applied to reduce obesity, alcohol abuse and smoking' (House of Lords 2011).\n\nConsiderable research has been undertaken to specify behaviour change interventions in terms of their component parts. This has led to a definition of behaviour change techniques relevant for a range of health behaviours (Michie et al. 2013) and for specific behaviours:\n\nto improve their diet or encourage physical activity (Abraham and Michie 2008; Conn et al. 2002; Inoue et al. 2003; Michie et al. 2011a)\n\nto prevent weight gain (Hardeman et al. 2000)\n\nto stop smoking (Michie et al. 2011b)\n\nto reduce alcohol intake (Michie et al. 2012)\n\nto prevent HIV (Albarracin et al. 2005).\n\nWork is currently underway to explore the extent to which techniques may be applicable across different behaviours. The classification system has been shown to be reliable. Its validity is now being assessed (Michie et al. 2013).\n\nThe importance of having a theoretical basis for the design and evaluation of interventions is well established (Medical Research Council 2008; Craig et al. 2008). For example, it can help ensure better outcomes (Albarracin et al. 2005) as well as providing a means of understanding why an intervention is effective or not.\n\nWork has been done to establish theoretical frameworks for behaviour change (Abraham and Michie 2008; Michie et al. 2011a; West 2009) and evidence continues to emerge about these theories (Tuah et al. 2011; Williams and French 2011).\n\nThis section describes the factors and issues the Programme Development Group (PDG) considered when developing the recommendations. Please note: this section does not contain the recommendations.\n\nThere is a wealth of information and recommendations in existing NICE guidance on interventions related to the behaviours covered in this guidance: alcohol use, eating patterns, physical activity, sexual behaviour and smoking. The PDG did not aim to update or critique these recommendations. Rather, it considered new evidence to add value to the recommendations already made.\n\nThe PDG agreed that the principles in the NICE guideline on behaviour change: general approaches relevant to the remit of this guidance were still applicable. These were: principles 1 (planning), 3 (education and training), 4 (individual-level behaviour change interventions and programmes), 7 (effectiveness) and 8 (cost-effectiveness).\n\nThis guidance focuses mainly on individual-level behaviour change interventions. However, the PDG agreed that these need to be viewed in the context of a range of other interventions. This includes those delivered at population and community level and those related to the environments in which choices about behaviours take place (see the NICE guideline on behaviour change: general approaches).\n\nThe PDG noted that tackling behaviour change among people younger than 16, in particular in relation to issues such as alcohol use and sexual risk-taking, is important. However, this was not part of the remit for this guidance.\n\nThe PDG used various terms to describe the target group of an intervention. It did not feel that any term was preferable and used 'participants' and 'service users' interchangeably.\n\nThe PDG discussed the role of commercial companies in contributing to behaviour change and the potential contribution they could make to behaviour change interventions. Suppliers and manufacturers could, for example, provide (free of charge) useful data to aid understanding about behaviours such as alcohol use or eating patterns.\n\nThe PDG agreed that some of the recommendations were ambitious and may prove difficult to resource at local level. However, it was keen to set a 'gold standard' for service delivery as an aspirational target.\n\nThe PDG did not think it was useful to look at specific behaviour change techniques in isolation. The Group agreed that single technique interventions may be effective for some people (or with some behaviours). However, it also noted that behaviour change often comes about because of a range of techniques working together (as well as other factors, such as context). The question is, which behaviour change techniques work most effectively together? The Group noted that theories of behaviour change may help determine which techniques should work synergistically.\n\nThe PDG noted that there was evidence of effectiveness for the behaviour change techniques recommended in relation to specific behaviours. However, the Group also noted, that the effectiveness of techniques across behaviours and populations was not always clear or necessarily supported by the evidence.\n\nThe behaviour change techniques taxonomy used in the evidence reviews (Michie et al. 2013) helped in discussions and in informing the evidence synthesis. However, the PDG had some concerns about the findings reported in review 2. This was due to the quality of reporting in intervention studies and the associated difficulty of coding behaviour change techniques on the basis of limited information. First, variations in reporting behaviour change techniques in the published data posed challenges when trying to provide consistent coding across interventions. Second, many tests were undertaken in the analysis in which behaviour change technique data were pooled across interventions for different behaviours and populations. This, combined with coding issues, could lead to the wrong conclusion concerning whether or not a technique is associated with behaviour change. Third, the potential moderating effect of other variables (such as mode of delivery and intervention intensity) was not addressed in the review analysis.\n\nThe authors of review 2 coded the behaviour change techniques used for 'usual care' and the 'control arm' in each study. This was to ensure all the behaviour change techniques used (in both the intervention and comparator) in any study were included in the meta-regression analysis. The accuracy of this coding was, however, dependent on the level of detail provided in published studies about the control arm. The PDG noted that, as with the reporting of interventions in published research, detail about control arms was often poor or missing. Generally there was not enough specific detail.\n\nThe PDG did not think recommendations could be based solely on the findings of the meta-regression analysis in evidence review 2. It noted that this review provided evidence of the effect sizes of behaviour change interventions and details of the behaviour change techniques used.\n\nThe PDG agreed that triangulation – looking for consistent effects across the different evidence considered by the group – would be appropriate. Consequently, if specific behaviour change techniques were evident in effective interventions in the evidence reviews and expert testimony, these findings were used as the basis for recommendations.\n\nThe PDG only made recommendations about behaviour change techniques that were identified using the triangulation process. Hence, a particular technique may not be recommended because of a lack of supporting evidence from more than one source, rather than due to evidence that it is not effective.\n\nThe evidence reviews that informed this guidance were structured around the specific taxonomy developed by Michie et al. (2013). While two-thirds of the possible behaviour change techniques defined in the taxonomy were identified in the included evidence, relatively few were identified often. This does not necessarily mean that techniques not mentioned were not used in the interventions. It may be that they are not reported or described in enough detail to be identified in published articles.\n\nThe lack of evidence on sexual behaviour in the commissioned reviews made it difficult for the PDG to make recommendations on these interventions.\n\nThe PDG noted that interventions aimed at changing people's alcohol use, eating patterns, physical activity, sexual behaviour and smoking are generally cost effective. The same is true for a number of other health behaviours that have been subjected to research. The Group also noted that there was little or no consistent association between the presence of any one behaviour change technique (or cluster of techniques) and an intervention being cost effective.\n\nThe PDG ensured the first recommendation highlights the need for an integrated programme of population, community, organisational and individual-level behaviour change interventions. It noted that interventions that target many levels simultaneously tend to be the most effective.\n\nThe PDG noted that it was important for all policy and strategy to be in line with the principles of proportionate universalism. This involves providing universal services and additional tailored support to meet the particular needs and choices of those who may find it difficult to use the services.\n\nThe PDG discussed whether practitioners and services should aim to change one behaviour at a time or multiple behaviours at once. It also discussed the best strategy to deal with multiple behaviours. Given the lack of evidence on the best approach, the Group made a recommendation for further research.\n\nThe PDG was concerned that if private companies were commissioned to provide a behaviour change service they may not share data because of commercial interests. It noted the importance of data-sharing for the purposes of monitoring processes and outcomes.\n\nThe PDG noted the importance of ensuring all behaviour change interventions and programmes are conducted in an ethical manner. For example, this might involve ensuring participants in an intervention are fully informed of its content and how their data may be used. It might also involve ensuring national data protection and confidentiality policies are met.\n\nThe PDG considered that sustained changes in behaviour (that is, the maintenance of behaviour change) are vital to improve public health outcomes. It noted the need to plan for this at the start. The Group also noted that measurable changes in health at a population level may happen over the medium to long term, whereas changes in behaviour of individuals could be detected over shorter time periods.\n\nThe PDG noted the importance of long-term evaluation of behaviour change interventions and programmes. It also noted that, in reality, effectiveness is often not assessed beyond 6–12\xa0weeks following an intervention.\n\nThe PDG noted that details of various study designs, their internal validity, and how to assess the quality of a study can be found in appendix D of Methods for the development of NICE public health guidance (third edition).\n\nThe PDG noted that the majority of published journal articles on behaviour change interventions do not provide enough detail to determine the techniques used in intervention and control groups. Where detail is provided, it may reflect the topic covered. For example, scientific studies on alcohol are based on a more standardised way of reporting than, say, scientific studies within the sexual health field. The Group discussed the need for manuals providing practical detail of the intervention techniques used, and for these to be made publicly available.\n\nThe PDG noted that a lack of detail in published journal articles on studies claiming to use motivational interviewing had affected the Group's ability to determine the behaviour techniques used. The PDG recognised that motivational interviewing is based on a clear set of principles and components. But as the articles did not specify which principles and components were used, the Group could not assume that motivational interviewing was used. This made it impossible to recommend this approach. It also added further support to the Group's recommendation that manuals should provide details of all the intervention components used.\n\nThe PDG acknowledged stakeholder concerns about intellectual property, copyright issues and the potentially inappropriate use of the information kept in manuals on behaviour change interventions. (For example, someone may use the information to set up their own commercial behaviour change intervention without having had the appropriate training needed to deliver it.) However, it was generally agreed that it was important to make manuals for all interventions publicly available, for example, as a condition of funding for projects in receipt of public monies.\n\nAs most journals now have web supplements, the PDG noted that it is possible to provide detailed reports of intervention designs, whatever the word limit of the main paper. The PDG discussed the fact that some journals only publish evaluations of interventions that come with publicly available manuals detailing the full protocols used. It welcomed this practice.\n\nThe recommendations contained in this guidance reflect the PDG's conclusions about intervention planning, based on the evidence considered. However, the PDG recognised that a number of other planning tools and resources – for example, 'intervention mapping' (Bartholomew et al. 2011) – could be systematically employed to enhance intervention design and effectiveness (see 4.31 below).\n\nIntervention mapping aids collaborative planning by people from different professional backgrounds during intervention development. The approach proposes 6 intervention design stages:\n\nStage 1: A needs assessment determines what (if anything) needs to be changed for whom.\n\nStage 2: Primary and secondary intervention objectives are defined. This involves specifying the precise behaviour changes participants will be expected to make.\n\nStage 3: Designers identify the underlying evidence-based techniques that maintain current (unwanted) behaviour patterns and may generate the specified changes.\n\nStage 4: Practical ways of delivering these techniques are developed and integrated into the intervention.\n\nStage 5: How the intervention will be used or delivered in everyday contexts is considered.\n\nStage 6: Evaluation to assess whether the intervention changed specified behaviours in context. These stages are iterative in that, for example, anticipation of how the intervention will be used or delivered may lead to a change in design and a return to stage 4. Similarly, when the exact behaviour changes are defined in stage 2, these may need to be evaluated. The result is an intervention 'map' of matrices and plans that guide the design, implementation and evaluation of an intervention.\n\nThe PDG noted the importance of not just the content of an intervention, but who is delivering it (and their core competencies), to whom, how and where.\n\nThe PDG discussed the importance of making sure all key components of a given intervention are adopted so that they have high intervention fidelity and are sustainable.\n\nThe PDG agreed that a behaviour change taxonomy for designing interventions was a useful tool. However, the Group was clear that the inclusion of a behaviour change technique in a taxonomy did not necessarily mean there was a strong evidence base for that technique.\n\nEvidence showed that behaviour change interventions by GPs and other medical staff can be effective. However, the PDG felt that a focus solely on such interventions may lead to a widening in health inequalities, because people from the most vulnerable groups often do not use primary care services. The Group did not want to exclude such interventions, rather it raised the need to find alternative ways of reaching vulnerable groups. Members agreed that understanding how people come into contact with, and access, services was key to the design of behaviour change interventions.\n\nThe PDG noted that details of validated tools and measures for assessing behaviour can be found in academic publications. The Group also noted that specific assessment tools have been recommended by NICE. For example, tools for assessing alcohol use are recommended in the NICE guideline on alcohol-use disorders: prevention.\n\nThe PDG agreed that although information is usually a necessary precursor to behaviour change, information alone is not always sufficient to influence behaviour.\n\nThe PDG noted that social, economic and cultural contexts can have an impact on behaviour. Although a sense of connection and belonging at school, within the family or community promotes resilience, unhealthy behaviour can also be embedded in social processes and patterns. The Group also noted that diverse health outcomes can be established early in life.\n\nRecommendations were made to include goals and planning and feedback and monitoring techniques in behaviour change interventions. This was based on a cross-examination of behaviour change techniques identified in expert paper 14, the evidence reviews and the NICE guideline on behaviour change: general approaches. (Triangulation techniques were used.) The process indicated that the techniques would be effective as part of interventions on alcohol, diet, physical activity and smoking. These behaviour change techniques are described in detail in Michie et al. (2013).\n\nTime constraints meant it was not possible to review additional evidence on sexual health interventions and behaviour change techniques. However, the PDG noted that in existing NICE guidance, social support was frequently used in effective interventions for all behaviours (alcohol, diet, physical activity, sexual behaviour and smoking).\n\nThe PDG noted that social support provided by friends, family and associates could help to create an environment in which people felt able to make changes. However, members also noted that, if not managed effectively, social support provided by non-professionals (such as family members) could sometimes lead to an unhealthy co‑dependency, bullying, manipulation or other negative behaviour.\n\nThe PDG noted that principle 4 (on individuals) in the NICE guideline on behaviour change: general approaches recommended specific behaviour change techniques. The Group agreed that, for consistency of approach, these would be 'coded' using the taxonomy applied in the commissioned evidence reviews for this guidance (Michie et al. 2013). This taxonomy identified the following groups of behaviour change techniques: goals and planning, feedback and monitoring, social support, natural consequences, comparison of behaviour, repetition and substitution and antecedents.\n\nThe PDG noted that interventions are unlikely to be effective if providers are not properly trained or the setting is not appropriate. The Group also noted that some behaviour change techniques, such as self-monitoring, might be difficult for some people.\n\nThe PDG was aware of a growing interest in the use of new technology, including phone and tablet apps, to deliver behaviour change interventions. The Group noted that the evidence is mixed and there have not been many formal evaluations of its effectiveness. But it also noted that evidence to support the use of technology is encouraging (see recommendation 7).\n\nThe PDG noted the importance of training. For example, the Group discussed the fact that if one person successfully trained 100 practitioners they, in turn, could help 10,000 people, and the knock-on effects would be huge.\n\nThe PDG discussed the importance of communication skills when providing behaviour change interventions. In particular, it noted the importance of knowing how to initiate a conversation, develop rapport and communicate information effectively. Communication skills include reflective listening, the use of open ended questions and affirmation skills.\n\nThe PDG did not discuss the accreditation of training. This may be an area where future guidance is needed.\n\nThe PDG was concerned that training programmes still describe the stages of change model (also known as the transtheoretical model) as a theoretical basis for behaviour change interventions. The PDG wanted to highlight that, although it may help practitioners and service users to understand the experience of behaviour change, it is not a theory that is able to accurately explain and predict such change. It was noted that interventions based on this model alone have not, according to the evidence reviewed here, demonstrated effectiveness.\n\nThe PDG was clear that being trained to deliver one behaviour change intervention does not necessarily mean that a practitioner is then competent to deliver other behaviour change interventions. The Group was aware of the danger that practitioners and service users may assume their competency extends further than it actually does.\n\nThe PDG noted that behaviour change training is a behaviour change intervention in its own right.\n\nThe PDG noted that this guidance is not intended to make recommendations on how to undertake research in this area.\n\nThe PDG noted that well-conducted evaluation studies and randomised controlled trials – with minimal bias – give the best quality evidence. Anecdotal evidence and smaller or poorly conducted studies are much less reliable and the Group agreed that it was best not to use these as a basis for investment decisions. The Group also noted that NICE, NHS Evidence and the Cochrane Collaboration provide guidance to help identify behaviour change interventions or programmes to invest in for a particular topic, population or setting.\n\nThe PDG noted that qualitative, as well as quantitative, measures are important when trying to understand why something does or does not work – and under what circumstances. They can also help to identify any improvements or changes that need to be made.\n\nThe PDG noted that the setting where an intervention is delivered and the person delivering it may be the two main factors that make an intervention effective (or ineffective).\n\nThe PDG discussed the meaning of independent evaluation. The Group was clear that this was not synonymous with external evaluation. Rather, it could be carried out inside an organisation as long as it was not conducted by those actually involved in designing or delivering the intervention.\n\nThe PDG noted that local organisations may need support to help them decide on the most appropriate behaviour change interventions and training to commission or provide in their area. Members discussed how a unified national approach might achieve this, with organisations and research funders working together to ensure appropriate data collection, evaluation and dissemination of evidence. The PDG also noted that some organisations, for example Public Health England and NICE (through NICE evidence services) are already working towards this goal.\n\nOn the basis of current evidence, the PDG felt that it would be premature to make any recommendations on the use of choice architecture interventions (see expert paper 8). As a result, only research recommendations were made on this.\n\nA scoping review of the evidence base for choice architecture interventions targeting healthy behaviour indicated that the majority of evidence involved diet (see expert paper 8). However, in the absence of a full systematic review, the PDG questioned whether such interventions did lead to a healthy diet.\n\nThe PDG noted that, in the context of choice architecture, 'doing nothing' is not a neutral approach, because this simply maintains the status quo. And the status quo may, for example, be an 'obesogenic environment' constructed by commercial interests.\n\nThe PDG recognised that choice architecture interventions may appeal to people working in a local authority setting. The reasons are twofold. First, this type of behaviour change intervention may be perceived to be relatively low cost. Second, it has the potential to reach a relatively large number of people. However, there is only limited evidence on how effective these interventions are at changing health-related behaviour. The PDG agreed that anyone wishing to commission or provide such an intervention as part of a behaviour change service should be aware of this lack of evidence. The Group agreed that choice architecture interventions, if used, needed to be subject to independent evaluation.\n\nAlthough the PDG was not able to make recommendations on choice architecture interventions, members noted that a further evidence synthesis on this approach is due to be published soon. The PDG advised that if this synthesis is published prior to the routine update of this guidance, the update should be bought forward.", 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.\n\nAll the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity.\n\n. Which choice architecture interventions help to reduce increased-risk and higher-risk drinking of alcohol, improve sexual health behaviours, help stop or reduce smoking, or increase the physical activity levels of the general UK population? How is this related to sociodemographic variables?\n\n. What evidence of effectiveness is there on the use of choice architecture interventions in commercial settings to influence health-related behaviours? How can findings from commercial settings support non-commercial choice architecture approaches to support behaviour change to improve health?\n\n. Which combinations of behaviour change techniques and modes of delivery are effective and cost effective in initiating particular behaviour changes, and in maintaining those changes? How does this vary among people from different socio-demographic groups or with different levels of motivation, access to information or skills? Include research that builds the evidence base on the effectiveness of each behaviour change technique. For example, experimental and meta-analytic work could clarify which behaviour change techniques work when, and for whom.\n\n. Which behaviour change interventions and programmes are effective and cost effective at changing multiple behaviours and maintaining behaviour change? How does this vary among people from different sociodemographic groups?\n\n. What characteristics of behaviour change training influence the effectiveness of behaviour change practitioners?\n\n. How effective and cost effective are behaviour change interventions delivered remotely (that is, by telephone, text message, phone and tablet apps or the internet)? How does this vary among behaviours and among people from different sociodemographic groups?\n\n. How do behaviour change techniques lead to change? What are the best methods of testing the relationship between the theories that describe change processes and the effectiveness of interventions in practice?\n\nMore detail identified during development of this guidance is provided in gaps in the evidence.", 'References': 'Abraham C, Michie S (2008) A taxonomy of behaviour change techniques used in interventions. Health Psychology 27: 379–87\n\nAlbarracin D, Gillette JC, Earl AN et al. (2005) A test of major assumptions about behaviour change: A comprehensive look at the effects of passive and active HIV-prevention interventions since the beginning of the epidemic. Psychological Bulletin 131: 856−97\n\nBartholomew LK, Parcel GS, Kok G et al. (2011) Planning health promotion programs: an intervention mapping approach 3rd edition. San Francisco: Jossey-Bass\n\nConn VS, Valentine JC, Cooper HM (2002) Interventions to increase physical activity among aging adults: A meta-analysis. Annals of Behavioral Medicine 24: 190–200\n\nCraig P, Dieppe P, Macintyre S et al. (2008) Developing and evaluating complex interventions: the new Medical Research Council guidance. BMJ 337: a1655\n\nDixon D, Johnston M (2010) Health behaviours change competency framework: competencies to deliver interventions to change lifestyle behaviours that affect health. Edinburgh: The Scottish Government\n\nGellman MD, Turner JR (2013) Encyclopaedia of Behavioral Medicine. New York: Springer.\n\nHardeman W, Griffin S, Johnston M et al. (2000) Interventions to prevent weight gain: a systematic review of psychological models and behaviour change methods. International Journal of Obesity 24: 131−43\n\nHouse of Lords (2011) Inquiry: behaviour change [online]\n\nInoue S, Odagiri Y, Wakui S et al. (2003) Randomized controlled trial to evaluate the effect of a physical activity intervention program based on behavioural medicine. Journal of Tokyo Medical University 61: 154−65\n\nLai DTC, Cahill K, Qin Y et al. (2010) Motivational interviewing for smoking cessation. Cochrane Database of Systematic Reviews issue 1\n\nMarteau T, Ogilvie D, Roland M et al. (2011) Judging nudging: can nudging improve population health? British Medical Journal 342: d228\n\nMedical Research Council (2008) Complex interventions guidance [online]\n\nMichie S, Richardson M, Johnston M et al (2013) The behaviour change technique taxonomy (v1) of 93 hierarchically clustered techniques: building an international consensus for the reporting of behaviour change interventions. Annals of behavioural medicine March 20 [Epub ahead of print]\n\nMichie S, Whittington C, Hamoudi Z et al. (2012) Identification of behaviour change techniques to reduce excessive alcohol consumption. Addiction 107: 1431–40\n\nMichie S, Ashford S, Falko F et al. (2011a) Refined taxonomy of behaviour change techniques to help people change their physical activity and healthy eating behaviours: The CALO-RE taxonomy. Psychology and Health 28: 1–20\n\nMichie S, Hyder N, Walia A et al. (2011b) Development of a taxonomy of behaviour change techniques used in individual behavioural support for smoking cessation. Addictive Behaviours 36: 315–19\n\nMichie S, Abraham C, Eccles MP et al. (2011c) Strengthening evaluation and implementation by specifying components of behaviour change interventions: a study protocol. Implementation Science 6: 10\n\nMichie S, van Stralen MM, West R (2011d) The behaviour change wheel: a new method for characterising and designing behaviour change interventions, Implementation Science 6: 42\n\nRuger JP, Weinstein MC, Hammond SK et al. (2008) Cost-effectiveness of motivational interviewing for smoking cessation and relapse prevention among low-income pregnant women: a randomized controlled trial. Value Health 11: 191–8\n\nThaler R, Sunstein C (2008) Nudge: improving decisions about health, wealth, and happiness. Connecticut: Yale University Press\n\nTuah NAA, Amiel C, Qureshi S et al. (2011) Transtheoretical model for dietary and physical exercise modification in weight loss management for overweight and obese adults. Cochrane Database of Systematic Reviews issue 10\n\nWest R (2009) The multiple facets of cigarette addiction and what they mean for encouraging and helping smokers to stop. Journal of Chronic Obstructive Pulmonary Disease 6: 277−83\n\nWilliams SL, French DP (2011) What are the most effective intervention techniques for changing physical activity self-efficacy and physical activity behaviour – and are they the same? Health Education Research 26: 308–22', 'The evidence': "# Introduction\n\nThe evidence statements from 3 reviews are provided by external contractors (see supporting evidence).\n\nThis section lists how the evidence statements and the expert papers link to the relevant recommendations. It also sets out a brief summary of findings from the economic analysis and the fieldwork.\n\n# How the evidence and expert papers link to the recommendations\n\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document.\n\nEvidence statement number 1.1 indicates that the linked statement is numbered 1 in review 1. Evidence statement number 2.1.3 indicates that the linked statement is numbered 1.3 in review 2. Evidence statement number 3.3.4 indicates that the linked statement is numbered 3.4 in review 3. EP1 indicates that expert paper 1 is linked to a recommendation.\n\nThe reviews, expert papers and economic analysis are available. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: EP3, EP4, EP6–9, EP13\n\nRecommendation 2: evidence statements 3.1.1, 3.1.2, 3.1.3 EP 10, EP11\n\nRecommendation 3: EP4–6, EP9, EP13\n\nRecommendation 4: EP1, EP3–5, EP14\n\nRecommendation 5: EP1–3, EP5, EP14\n\nRecommendation 6: EP1–3\n\nRecommendation 7: evidence statements 1.2, 1.4, 1.6, 1.7, 1.9, 1.10–1.19, 1.20, 1.21, 2.1.8, 2.3.7, 2.3.11, 2.3.13, 2.3.17, 2.4.4, 2.4.5, 2.4.8, 2.5.5, 2.5.6, 2.5.7, 2.5.9, 2.5.11, 2.5.15, 3.3.3, 3.3.4, 3.3.6, 3.3.7, EP14\n\nRecommendation 8: EP1–3, EP5, EP6, EP9\n\nRecommendation 9: EP10–12\n\nRecommendation 10: evidence statements 1.2, 1.4, 1.6, 1.7, 1.9, 1.10–1.19, 1.20, 1.21, 2.4.4, 2.4.5, 2.5.5, 2.5.6, 3.3.3, 3.3.4, 3.3.6, 3.3.7, EP14\n\nRecommendation 11: EP5, EP10–12\n\nRecommendation 12: evidence statements: 3.3.1–3, 3.2.1, 3.2.2, 3.3.1–9, EP5, EP10–12\n\nRecommendation 13: EP5, EP10–12\n\nRecommendation 14: EP5, EP10–12\n\nRecommendation 15: EP1–3\n\nRecommendation 16: EP1–3, EP14\n\nRecommendation 17: IDE\n\n# Economic analysis\n\nReview 1 identified 79 interventions dealing with 6 behaviours: smoking, diet, physical activity, alcohol, sexual health and multiple health targets. All interventions fall well below the accepted £20,000–£30,000 costs per quality-adjusted life year (QALY) threshold. However, sensitivity analyses suggest that some may have incremental cost-effectiveness ratios (ICERs) above this threshold. In this review, sexual health interventions were least cost effective but no other characteristics or behaviour change techniques were related to cost-effectiveness estimates.\n\nReview 2 identified 251 interventions across the 6 behaviours, of which 102 provided cost–utility estimates (£/QALY). Using the upper estimate and lower threshold (the most cautious approach), 85% of interventions were identified as cost effective. Using the lower estimates, smoking cessation interventions were significantly more cost effective than interventions targeting multiple behaviours.\n\nAcross all interventions, those targeting the general population had better cost–utility results and were more likely to be cost effective than those aimed at vulnerable populations. Regression analyses across, as well as within, behaviours suggests there is little or no consistent association between the presence of an individual behaviour change technique (or cluster of behaviour change techniques) and an intervention being cost effective.\n\nThe authors of the reviews state that the findings need to be interpreted cautiously given:\n\nthe different search strategies for reviews 1 (based on interventions already assessed by NICE as cost effective) and 2 (based on the search strategy used for evidence review 2)\n\nreliance on incomplete information in published papers\n\nheterogeneity in economic analyses\n\nlack of consensus for a definition of 'choice architecture'\n\nbias in reporting of study findings.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations.\n\nFieldwork participants who are involved in, or support, behaviour change activities were fairly positive about the recommendations and their potential to help change an individual's behaviour. This included practitioners, commissioners, service providers, health and wellbeing board members, national bodies (from both the public and private sectors), royal colleges and academics.\n\nMany participants welcomed the emphasis on evidence-based investment, but were keen to ensure this should not stifle innovation or narrow the options available to commissioners.\n\nThey described the commissioning recommendations as bold and ambitious. While recognising that they may be difficult to implement in the current climate, participants did not believe the approach should be diluted.\n\nThere were some concerns that independent evaluation may be viewed as unaffordable. It was suggested that evaluation should be built into the original design or service specification to ensure it does take place.\n\nFieldwork participants did not think the recommendations offered a new approach, but they agreed that the measures had not been implemented universally. They believed wider, more systematic implementation would be achieved if there was a clearer definition of the techniques and training requirements for staff and commissioners.", 'Gaps in the evidence': "The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below.\n\n. There is a lack of evidence on the effectiveness or cost-effectiveness of using choice architecture interventions to change alcohol, sexual health behaviours, smoking and physical activity-related behaviours (with the exception of choice architecture interventions to promote stair use). In particular, there is a lack of UK-based primary research exploring the differential impacts of such interventions. (Source: Expert paper 8)\n\n. There is a lack of evaluation, using appropriate research designs, of choice architecture interventions used in commercial settings to determine their effectiveness, cost-effectiveness or usability in non-commercial settings. (Source: Expert paper 14)\n\n. There is a lack of review-level work and primary research examining the effectiveness of individual behaviour change techniques. (Source: Expert paper 14)\n\n. There is a lack of evidence addressing what the most effective approach is to dealing with multiple behaviours (for example, if someone smokes, consumes alcohol above recommended weekly limits and is physically inactive). Specifically:\n\na) Should behaviours be approached in sequence or in combination?\n\nb) If multiple behaviours are addressed in combination, how is this decided? For example, is it based on the types of behaviour? How dependent is it on the person's capability, opportunity and motivation?\n\n(Source: Expert paper 14)\n\n. There is a lack of evidence prospectively investigating the relationship between practitioner training, subsequent competencies and behaviour change interventions. In particular, studies have not looked at the effect size of competencies or training. (Source: Evidence review 3)\n\n. There is limited research on the training needed to address barriers to delivering behaviour change interventions. (Source: Evidence review 3)\n\n. There is a lack of published research that provides details of the theoretical basis of an intervention (beyond the naming of a theory). There is a lack of evidence on how theoretical accounts of behaviour change can be used to guide evidence synthesis (combining multiple sources of quantitative evidence, such as meta-regression, meta-analysis) of behaviour change interventions. (Source: Evidence review 2)\n\n. There is a lack of recent evidence (post-2003) on behaviour change techniques used to influence sexual behaviour. In particular, there is a lack of UK randomised control trials with populations aged 16 and over. (Source: Evidence review 2)\n\nThe Committee made 7 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in recommendations for research."}	https://www.nice.org.uk/guidance/ph49	This guideline covers changing health-damaging behaviours among people aged 16 and over using interventions such as goals and planning, feedback and monitoring, and social support. It aims to help tackle a range of behaviours including alcohol misuse, poor eating patterns, lack of physical activity, unsafe sexual behaviour and smoking.
8866952a8d4823ae17fcee201e18dbd999f67cfa	nice	Percutaneous closure of patent foramen ovale to prevent recurrent cerebral embolic events	Percutaneous closure of patent foramen ovale to prevent recurrent cerebral embolic events # Recommendations This document replaces previous guidance on percutaneous closure of patent foramen ovale for the prevention of cerebral embolic stroke (interventional procedure guidance 109). Evidence on the safety of percutaneous closure of patent foramen ovale to prevent recurrent cerebral embolic events shows serious but infrequent complications. Evidence on its efficacy is adequate. Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit. The procedure should only be performed in units with appropriate arrangements for urgent cardiac surgical support in the event of complications. Clinicians should enter details about all patients undergoing percutaneous closure of patent foramen ovale to prevent recurrent cerebral embolic events onto the UK Central Cardiac Audit Database.# Indications and current treatments Before birth, the fetal heart has an opening called the foramen ovale between the right and left atria. This allows blood to bypass the lungs and be directed straight to the left side of the circulation, supplying blood to the brain and body before it returns to the placenta. The foramen ovale usually closes spontaneously after birth; however, in approximately 1 in 4 people the foramen ovale remains fully or partially open into adulthood. This is then known as patent foramen ovale. Most people with patent foramen ovale have no ill effects. However, patent foramen ovale increases the risk of blood clots (for example from deep vein thrombosis in the legs) crossing from the right side into the left side of the heart, and from there into the arterial system where they may block blood vessels. If arteries in the brain become blocked then a stroke or a transient ischaemic attack occurs. This passage of material from the right of the circulation to the left is called paradoxical embolism. The optimal treatment for patent foramen ovale in patients who have had a thromboembolic event remains undefined. Medical management with anticoagulation (usually warfarin) or antiplatelet therapy (for example aspirin) is commonly used to reduce the risk of further paradoxical thrombus emboli. Surgical closure of patent foramen ovale is sometimes performed as an adjunct to other open-heart surgery, but is rarely done on its own because of associated morbidity.# The procedure Percutaneous closure of patent foramen ovale has been introduced as an option for patients who have had a cerebral embolic event (such as stroke or transient ischaemic attack) and in whom paradoxical embolism through patent foramen ovale is considered to be the cause. It provides an alternative to surgical closure, which is typically considered for patients in whom medical management has failed or for patients in whom anticoagulant or antiplatelet therapy are contraindicated. Percutaneous closure is performed using local anaesthesia and intravenous sedation, or with the patient under general anaesthesia. A closure device is introduced using a guide wire and delivery sheath through a small incision in the groin into the femoral vein. It is then passed into the heart and across the patent foramen ovale. The closure device is released to close the defect using image guidance such as echocardiography. Devices of differing design and mechanism are available.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. A randomised controlled trial (RCT) of 980 patients treated by percutaneous patent foramen ovale closure or medical therapy reported rates of stroke of 0.7 and 1.4 per 100 patient-years respectively in the intention-to-treat population (p=0.08). An RCT of 909 patients reported that the cumulative incidence of a composite end point of stroke or transient ischaemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurological causes between 31 days and 2 years, was 6% in the percutaneous patent foramen ovale closure group and 7% in the medical therapy group (p=0.37). An RCT of 414 patients reported a composite end point of death, non-fatal stroke, transient ischaemic attack or peripheral embolism in 3% (7/204) of patients treated by percutaneous patent foramen ovale closure and 5% (11/210) of patients treated by medical therapy, with a mean follow-up of 4 years (p=0.34). A meta-analysis of 58 observational studies (8185 patients treated by percutaneous patent foramen ovale closure and 2142 patients treated by medical therapy) reported a pooled incidence of recurrent neurological events of 0.8 (95% confidence interval 0.5 to 1.1) per 100 person-years for percutaneous patent foramen ovale closure and 4.4 (95% CI 3.2 to 5.6) per 100 person-years for medical therapy. The RCT of 909 patients treated by percutaneous patent foramen ovale closure or medical therapy reported successful closure at 2‑year follow-up in 87% (320/369) of patients who had the procedure. The meta-analysis of 58 observational studies reported a residual shunt immediately after the procedure in 25% (95% CI 17 to 34) of patients; 6% (95% CI 0 to 18) of patients had a residual shunt for more than 12 months. A UK register reported that 98% (4133/4202) of patients treated by percutaneous patent foramen ovale closure were alive and 2% (69/4202) of patients were dead at a median follow-up of 3.8 years. Actuarial 5‑year and 10‑year survival were 98% and 97% respectively. The specialist advisers listed key efficacy outcomes as reduction in the rate of stroke and systemic emboli, and complete functional closure of the patent foramen ovale.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. The occurrence of any serious adverse event was reported in 23% (numbers not stated), 17% (68/402), and 21% (43/204) of patients treated by percutaneous closure and 22% (numbers not stated), 17% (76/458), and 18% (37/210) of patients treated by medical therapy in the randomised controlled trials (RCTs) of 980, 909, and 414 patients respectively (p=0.7, 0.9 and 0.4 respectively). Death related to the procedure (not further defined) was reported in 0.1% (95% confidence interval 0 to 0.3) of patients in the meta‑analysis of 58 studies (8185 patients treated by percutaneous patent foramen ovale closure and 2142 patients treated by medical therapy). Pericardial effusion or tamponade was reported in 0.3% (95% CI 0 to 0.6) of patients in the meta-analysis of 58 studies. Details of treatment and outcome were not provided. Perforation of the left atrium and cardiac perforation (not further described) were each reported in 1 patient treated by percutaneous closure in the RCTs of 909 and 980 patients respectively. Vascular surgical repair (not further defined) was reported in 1 patient in the RCT of 909 patients. Device embolisation or malposition (not further described) was reported in 0.4% (95% CI 0.2 to 0.7) of patients in the meta-analysis of 58 studies. Bleeding (described as serious or major) was reported in 3% (10/378) and 0.5% (1/204) of patients treated by percutaneous closure and 1% (4/374 and 3/210) of patients treated by medical therapy in the RCTs of 909 and 414patients respectively. Major bleeding that was considered to be device- or procedure-related was reported in 0.4% (2/499) of patients treated by percutaneous closure in the RCT of 980 patients. Air embolism was reported in 0.6% (95% CI 0.2 to 1.0) of patients in the meta-analysis of 58 observation studies (not further described). Infective or bacterial endocarditis that was considered to be device- or procedure-related was reported in 1 patient in the RCT of 980 patients (no further information was given). Cardiac thrombus, together with deep vein thrombosis and pulmonary embolism, was detected 4 months after the closure procedure in 1 patient in the RCT of 980 patients. A fistula between the aortic root and right atrium was described in 1 patient in a case report. There was incomplete patent foramen ovale obliteration with residual shunting in both directions 6 months after the closure procedure. The device was removed through a mini-thoracotomy and the fistula was closed. Atrial fibrillation was reported in 6% (23/402) of patients treated by percutaneous patent foramen ovale closure and 0.7% (3/458) of patients treated by medical therapy in the RCT of 909 patients (p<0.001). In the closure group, 61% (14/23) of the patients with atrial fibrillation developed it within 30 days of the procedure; atrial fibrillation was transient in 17 patients and persistent in 6 patients. Serious atrial fibrillation (not further defined) was reported in 1% (2/204 and 2/210) of patients in each group in the RCT of 414 patients. The specialist advisers listed additional adverse events reported in the literature as embolism of clots attached to the device, device erosion, and transient worsening of migraine.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0377-1	{'Recommendations': 'This document replaces previous guidance on percutaneous closure of patent foramen ovale for the prevention of cerebral embolic stroke (interventional procedure guidance 109).\n\nEvidence on the safety of percutaneous closure of patent foramen ovale to prevent recurrent cerebral embolic events shows serious but infrequent complications. Evidence on its efficacy is adequate. Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit.\n\nThe procedure should only be performed in units with appropriate arrangements for urgent cardiac surgical support in the event of complications.\n\nClinicians should enter details about all patients undergoing percutaneous closure of patent foramen ovale to prevent recurrent cerebral embolic events onto the UK Central Cardiac Audit Database.', 'Indications and current treatments': 'Before birth, the fetal heart has an opening called the foramen ovale between the right and left atria. This allows blood to bypass the lungs and be directed straight to the left side of the circulation, supplying blood to the brain and body before it returns to the placenta. The foramen ovale usually closes spontaneously after birth; however, in approximately 1 in 4 people the foramen ovale remains fully or partially open into adulthood. This is then known as patent foramen ovale.\n\nMost people with patent foramen ovale have no ill effects. However, patent foramen ovale increases the risk of blood clots (for example from deep vein thrombosis in the legs) crossing from the right side into the left side of the heart, and from there into the arterial system where they may block blood vessels. If arteries in the brain become blocked then a stroke or a transient ischaemic attack occurs. This passage of material from the right of the circulation to the left is called paradoxical embolism.\n\nThe optimal treatment for patent foramen ovale in patients who have had a thromboembolic event remains undefined. Medical management with anticoagulation (usually warfarin) or antiplatelet therapy (for example aspirin) is commonly used to reduce the risk of further paradoxical thrombus emboli. Surgical closure of patent foramen ovale is sometimes performed as an adjunct to other open-heart surgery, but is rarely done on its own because of associated morbidity.', 'The procedure': 'Percutaneous closure of patent foramen ovale has been introduced as an option for patients who have had a cerebral embolic event (such as stroke or transient ischaemic attack) and in whom paradoxical embolism through patent foramen ovale is considered to be the cause. It provides an alternative to surgical closure, which is typically considered for patients in whom medical management has failed or for patients in whom anticoagulant or antiplatelet therapy are contraindicated.\n\nPercutaneous closure is performed using local anaesthesia and intravenous sedation, or with the patient under general anaesthesia. A closure device is introduced using a guide wire and delivery sheath through a small incision in the groin into the femoral vein. It is then passed into the heart and across the patent foramen ovale. The closure device is released to close the defect using image guidance such as echocardiography. Devices of differing design and mechanism are available.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nA randomised controlled trial (RCT) of 980 patients treated by percutaneous patent foramen ovale closure or medical therapy reported rates of stroke of 0.7 and 1.4 per 100\xa0patient-years respectively in the intention-to-treat population (p=0.08). An RCT of 909\xa0patients reported that the cumulative incidence of a composite end point of stroke or transient ischaemic attack during 2\xa0years of follow-up, death from any cause during the first 30\xa0days, or death from neurological causes between 31\xa0days and 2\xa0years, was 6% in the percutaneous patent foramen ovale closure group and 7% in the medical therapy group (p=0.37). An RCT of 414 patients reported a composite end point of death, non-fatal stroke, transient ischaemic attack or peripheral embolism in 3% (7/204) of patients treated by percutaneous patent foramen ovale closure and 5% (11/210) of patients treated by medical therapy, with a mean follow-up of 4\xa0years (p=0.34). A meta-analysis of 58 observational studies (8185\xa0patients treated by percutaneous patent foramen ovale closure and 2142 patients treated by medical therapy) reported a pooled incidence of recurrent neurological events of 0.8 (95% confidence interval [CI] 0.5 to 1.1) per 100\xa0person-years for percutaneous patent foramen ovale closure and 4.4 (95%\xa0CI 3.2 to 5.6) per 100\xa0person-years for medical therapy.\n\nThe RCT of 909\xa0patients treated by percutaneous patent foramen ovale closure or medical therapy reported successful closure at 2‑year follow-up in 87% (320/369) of patients who had the procedure. The meta-analysis of 58 observational studies reported a residual shunt immediately after the procedure in 25% (95%\xa0CI 17 to 34) of patients; 6% (95%\xa0CI 0 to 18) of patients had a residual shunt for more than 12\xa0months.\n\nA UK register reported that 98% (4133/4202) of patients treated by percutaneous patent foramen ovale closure were alive and 2% (69/4202) of patients were dead at a median follow-up of 3.8\xa0years. Actuarial 5‑year and 10‑year survival were 98% and 97% respectively.\n\nThe specialist advisers listed key efficacy outcomes as reduction in the rate of stroke and systemic emboli, and complete functional closure of the patent foramen ovale.', 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nThe occurrence of any serious adverse event was reported in 23% (numbers not stated), 17% (68/402), and 21% (43/204) of patients treated by percutaneous closure and 22% (numbers not stated), 17% (76/458), and 18% (37/210) of patients treated by medical therapy in the randomised controlled trials (RCTs) of 980, 909, and 414 patients respectively (p=0.7, 0.9 and 0.4 respectively).\n\nDeath related to the procedure (not further defined) was reported in 0.1% (95% confidence interval [CI] 0 to 0.3) of patients in the meta‑analysis of 58 studies (8185 patients treated by percutaneous patent foramen ovale closure and 2142 patients treated by medical therapy).\n\nPericardial effusion or tamponade was reported in 0.3% (95%\xa0CI 0 to 0.6) of patients in the meta-analysis of 58 studies. Details of treatment and outcome were not provided.\n\nPerforation of the left atrium and cardiac perforation (not further described) were each reported in 1 patient treated by percutaneous closure in the RCTs of 909 and 980 patients respectively. Vascular surgical repair (not further defined) was reported in 1 patient in the RCT of 909 patients.\n\nDevice embolisation or malposition (not further described) was reported in 0.4% (95%\xa0CI 0.2 to 0.7) of patients in the meta-analysis of 58 studies.\n\nBleeding (described as serious or major) was reported in 3% (10/378) and 0.5% (1/204) of patients treated by percutaneous closure and 1% (4/374 and 3/210) of patients treated by medical therapy in the RCTs of 909 and 414patients respectively. Major bleeding that was considered to be device- or procedure-related was reported in 0.4% (2/499) of patients treated by percutaneous closure in the RCT of 980 patients.\n\nAir embolism was reported in 0.6% (95%\xa0CI 0.2 to 1.0) of patients in the meta-analysis of 58 observation studies (not further described).\n\nInfective or bacterial endocarditis that was considered to be device- or procedure-related was reported in 1 patient in the RCT of 980 patients (no further information was given).\n\nCardiac thrombus, together with deep vein thrombosis and pulmonary embolism, was detected 4\xa0months after the closure procedure in 1 patient in the RCT of 980 patients.\n\nA fistula between the aortic root and right atrium was described in 1 patient in a case report. There was incomplete patent foramen ovale obliteration with residual shunting in both directions 6\xa0months after the closure procedure. The device was removed through a mini-thoracotomy and the fistula was closed.\n\nAtrial fibrillation was reported in 6% (23/402) of patients treated by percutaneous patent foramen ovale closure and 0.7% (3/458) of patients treated by medical therapy in the RCT of 909 patients (p<0.001). In the closure group, 61% (14/23) of the patients with atrial fibrillation developed it within 30\xa0days of the procedure; atrial fibrillation was transient in 17 patients and persistent in 6 patients. Serious atrial fibrillation (not further defined) was reported in 1% (2/204 and 2/210) of patients in each group in the RCT of 414 patients.\n\nThe specialist advisers listed additional adverse events reported in the literature as embolism of clots attached to the device, device erosion, and transient worsening of migraine.', 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0377-1'}	https://www.nice.org.uk/guidance/ipg472
02a363673d702c759c2b08501a54fa7f2340e538	nice	Uterine artery embolisation for treating adenomyosis	Uterine artery embolisation for treating adenomyosis # Recommendations Current evidence on uterine artery embolisation for treating adenomyosis shows that the procedure is efficacious for symptom relief in the short and medium term for a substantial proportion of patients. There are no major safety concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit. During the consent process patients should be informed, in particular, that symptoms may not be relieved, that symptoms may return and that further procedures may be needed. Patients contemplating pregnancy should be informed that the effects of the procedure on fertility are uncertain. Patient selection should be carried out by a multidisciplinary team, including a gynaecologist and an interventional radiologist. NICE encourages further research into the effects of uterine artery embolisation compared with other procedures to treat adenomyosis, particularly for patients wishing to maintain or improve their fertility.# Indications and current treatments Adenomyosis is a benign condition characterised by the presence of ectopic endometrial glands and stroma within the myometrium. It frequently occurs coincidentally with fibroids. Adenomyosis may cause no symptoms but some women with adenomyosis experience heavy, prolonged menstrual bleeding with severe cramps, pelvic pain and discomfort. Treatment for symptomatic adenomyosis includes anti-inflammatory medications, hormone therapy and endometrial ablation. For severe symptoms that do not respond adequately, hysterectomy has been the conventional surgical treatment. Uterine artery embolisation may be an alternative option for patients who do not wish to have hysterectomy and/or who wish to preserve their fertility.# The procedure The aim of uterine artery embolisation for treating adenomyosis is to block the blood supply to the adenomyosis, causing it to shrink. The intended benefits of the procedure are that it offers a less invasive alternative to hysterectomy, and fertility may be preserved. With the patient under sedation and local anaesthesia, a catheter is inserted into the femoral artery (bilateral catheters are sometimes used). Fluoroscopic guidance is used to manipulate the catheter into the uterine artery. Small embolisation particles are injected through the catheter into both uterine arteries. Various embolisation agents can be used for this procedure.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. In a case series of 54 patients with adenomyosis, 78% (42/54) of whom presented with menorrhagia, resolution of menorrhagia was reported in 26% (10/39) of patients at a mean follow-up of 5 years. In a case series of 40 patients (90% presenting with menorrhagia), symptoms had resolved in 78% (28/36) of patients at a median follow-up of 40 months. In a case series of 27 patients, complete resolution of dysmenorrhoea was reported in 38% (7/18), 57% (9/16), 36% (4/11) and 64% (7/11) of patients at 6, 12, 24 and 36 months respectively. In the case series of 54 patients with adenomyosis, 43% (23/54) presented with bulk-related symptoms. Complete resolution of these symptoms was reported in 35% (8/23) of patients at a mean follow-up of 5 years. In the case series of 27 patients, complete resolution of bulk-related symptoms was reported in 38% (7/18), 31% (5/16), 46% (5/11) and 55% (6/11) of patients at 6, 12, 24 and 36 months respectively. In a case series of 15 patients, a significant improvement in quality of life was reported at a mean follow-up of 8 months in the following domains: ability to perform activities of daily life, ability to socialise outside the home, overall energy level, pain or cramping during menstruation (p<0.001), and pain during sexual intercourse (p=0.02). In the case series of 54 patients with adenomyosis, 5 patients became pregnant (3 delivered successfully and 2 opted for abortion). In a case series of 18 patients with adenomyosis, 44% (8/18) of patients had subsequent treatments because of treatment failure or recurrent symptoms. Twenty-eight per cent (5/18) of patients underwent hysterectomy (4 months after the procedure in 1 patient because of treatment failure, and between 9 and 27 months after the procedure in 4 patients because of recurrent symptoms). Eleven per cent (2/18) of patients needed additional treatments and 6% (1/18) of patients needed endometrial balloon thermocoagulation because of recurrent symptoms (timing unclear). The specialist advisers listed key efficacy outcomes to be quality of life, symptom resolution and need for further treatment.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. Severe cramping pain (4 days after the procedure; treated successfully by analgesia) was reported in 1 patient in the case series of 18 patients. Worsening of symptoms was reported in 82% (9/11) of patients in the case series of 27 patients at 3 years follow-up. Three patients opted for hormonal therapy to help with symptom relief and none chose hysterectomy. Amenorrhoea was reported in 4% (2/54) of patients (aged 41 and 44 years) immediately after the procedure in the case series of 54 patients (no further details available). Transient increased vaginal discharge was reported in 8% (3/40) of patients in a case series of 40 patients (timing unclear). The specialist advisers noted that adverse events from uterine artery embolisation used for adenomyosis are unlikely to differ significantly from those occurring when the procedure is used for fibroids. They include post-embolisation syndrome and non-target embolisation.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0379-5	{'Recommendations': 'Current evidence on uterine artery embolisation for treating adenomyosis shows that the procedure is efficacious for symptom relief in the short and medium term for a substantial proportion of patients. There are no major safety concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nDuring the consent process patients should be informed, in particular, that symptoms may not be relieved, that symptoms may return and that further procedures may be needed. Patients contemplating pregnancy should be informed that the effects of the procedure on fertility are uncertain.\n\nPatient selection should be carried out by a multidisciplinary team, including a gynaecologist and an interventional radiologist.\n\nNICE encourages further research into the effects of uterine artery embolisation compared with other procedures to treat adenomyosis, particularly for patients wishing to maintain or improve their fertility.', 'Indications and current treatments': 'Adenomyosis is a benign condition characterised by the presence of ectopic endometrial glands and stroma within the myometrium. It frequently occurs coincidentally with fibroids. Adenomyosis may cause no symptoms but some women with adenomyosis experience heavy, prolonged menstrual bleeding with severe cramps, pelvic pain and discomfort.\n\nTreatment for symptomatic adenomyosis includes anti-inflammatory medications, hormone therapy and endometrial ablation. For severe symptoms that do not respond adequately, hysterectomy has been the conventional surgical treatment. Uterine artery embolisation may be an alternative option for patients who do not wish to have hysterectomy and/or who wish to preserve their fertility.', 'The procedure': 'The aim of uterine artery embolisation for treating adenomyosis is to block the blood supply to the adenomyosis, causing it to shrink. The intended benefits of the procedure are that it offers a less invasive alternative to hysterectomy, and fertility may be preserved.\n\nWith the patient under sedation and local anaesthesia, a catheter is inserted into the femoral artery (bilateral catheters are sometimes used). Fluoroscopic guidance is used to manipulate the catheter into the uterine artery. Small embolisation particles are injected through the catheter into both uterine arteries.\n\nVarious embolisation agents can be used for this procedure.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nIn a case series of 54 patients with adenomyosis, 78% (42/54) of whom presented with menorrhagia, resolution of menorrhagia was reported in 26% (10/39) of patients at a mean follow-up of 5\xa0years. In a case series of 40 patients (90% [36/40] presenting with menorrhagia), symptoms had resolved in 78% (28/36) of patients at a median follow-up of 40\xa0months.\n\nIn a case series of 27 patients, complete resolution of dysmenorrhoea was reported in 38% (7/18), 57% (9/16), 36% (4/11) and 64% (7/11) of patients at 6, 12, 24 and 36\xa0months respectively.\n\nIn the case series of 54 patients with adenomyosis, 43% (23/54) presented with bulk-related symptoms. Complete resolution of these symptoms was reported in 35% (8/23) of patients at a mean follow-up of 5\xa0years. In the case series of 27 patients, complete resolution of bulk-related symptoms was reported in 38% (7/18), 31% (5/16), 46% (5/11) and 55% (6/11) of patients at 6, 12, 24 and 36\xa0months respectively.\n\nIn a case series of 15 patients, a significant improvement in quality of life was reported at a mean follow-up of 8\xa0months in the following domains: ability to perform activities of daily life, ability to socialise outside the home, overall energy level, pain or cramping during menstruation (p<0.001), and pain during sexual intercourse (p=0.02).\n\nIn the case series of 54 patients with adenomyosis, 5 patients became pregnant (3 delivered successfully and 2 opted for abortion).\n\nIn a case series of 18 patients with adenomyosis, 44% (8/18) of patients had subsequent treatments because of treatment failure or recurrent symptoms. Twenty-eight per cent (5/18) of patients underwent hysterectomy (4 months after the procedure in 1 patient because of treatment failure, and between 9 and 27\xa0months after the procedure in 4 patients because of recurrent symptoms). Eleven per cent (2/18) of patients needed additional treatments and 6% (1/18) of patients needed endometrial balloon thermocoagulation because of recurrent symptoms (timing unclear).\n\nThe specialist advisers listed key efficacy outcomes to be quality of life, symptom resolution and need for further treatment.', 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nSevere cramping pain (4\xa0days after the procedure; treated successfully by analgesia) was reported in 1 patient in the case series of 18 patients.\n\nWorsening of symptoms was reported in 82% (9/11) of patients in the case series of 27 patients at 3\xa0years follow-up. Three patients opted for hormonal therapy to help with symptom relief and none chose hysterectomy.\n\nAmenorrhoea was reported in 4% (2/54) of patients (aged 41 and 44\xa0years) immediately after the procedure in the case series of 54 patients (no further details available).\n\nTransient increased vaginal discharge was reported in 8% (3/40) of patients in a case series of 40 patients (timing unclear).\n\nThe specialist advisers noted that adverse events from uterine artery embolisation used for adenomyosis are unlikely to differ significantly from those occurring when the procedure is used for fibroids. They include post-embolisation syndrome and non-target embolisation.', 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0379-5'}	https://www.nice.org.uk/guidance/ipg473
1a48cba7d52bceb934daa59253a82f395b742881	nice	Ranibizumab for treating choroidal neovascularisation associated with pathological myopia	Ranibizumab for treating choroidal neovascularisation associated with pathological myopia Evidence-based recommendations on ranibizumab (Lucentis) for treating choroidal neovascularisation associated with pathological myopia in adults. # Guidance Ranibizumab is recommended as an option for treating visual impairment due to choroidal neovascularisation secondary to pathological myopia when the manufacturer provides ranibizumab with the discount agreed in the patient access scheme.# The technology Ranibizumab (Lucentis, Novartis) belongs to a class of drugs that blocks the action of vascular endothelial growth factor (VEGF)‑A. By blocking the action of VEGF‑A, ranibizumab prevents abnormal blood vessels developing, thereby limiting visual loss and improving vision. Ranibizumab has a marketing authorisation for 'the treatment of visual impairment due to choroidal neovascularisation secondary to pathologic myopia'. Ranibizumab is administered as a single 0.5 mg intravitreal injection. Each vial of ranibizumab contains 2.3 mg in 0.23 ml; overfilling is considered necessary to achieve an injectable dose of 0.5 mg. The summary of product characteristics states that monitoring is recommended monthly for the first 2 months and at least every 3 months thereafter during the first year. If monitoring reveals signs of disease activity, for example, reduced visual acuity and/or signs of lesion activity, further treatment is recommended. Adverse reactions to treatment are mostly limited to the eye. Those commonly reported in clinical trials include vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, sensation of a foreign body in the eye, increased production of tears, blepharitis, dry eye, ocular hyperaemia, itching of the eye and increased intraocular pressure. Nasopharyngitis, arthralgia and headaches are also commonly reported. Contraindications to ranibizumab include known hypersensitivity to the active substance or to any of its excipients, active or suspected ocular or periocular infections, and active severe intraocular inflammation. For full details of adverse reactions and contraindications, see the summary of product characteristics. The list price of ranibizumab 10 mg/ml is £742.17 per 0.23‑ml vial (excluding VAT; 'British national formulary' edition 66). The manufacturer of ranibizumab (Novartis) has agreed a patient access scheme with the Department of Health, revised in the context of Ranibizumab for treating diabetic macular oedema (NICE technology appraisal guidance 274), which makes ranibizumab available with a discount applied to all invoices. The level of the discount is commercial‑in‑confidence (see section 5.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of ranibizumab and a review of this submission by the Evidence Review Group (ERG; section 9). # Clinical effectiveness The manufacturer submitted evidence of clinical and cost effectiveness for ranibizumab compared with verteporfin photodynamic therapy (vPDT) in people with choroidal neovascularisation associated with pathological myopia. Pathological myopia is a chronic condition characterised by excessive lengthening of the eye and degenerative changes at the back of the eye. These changes to the eye can cause blood vessels to leak or bleed into the retina in a process known as choroidal neovascularisation. This can result in visual impairment, in particular a loss of central vision. The manufacturer did not provide a comparison with bevacizumab, which is listed as a comparator in the scope for this appraisal. It did not consider bevacizumab to be a valid comparator because it is unlicensed for this condition and not routinely used. The main sources of evidence presented in the manufacturer's submission came from a Novartis phase III trial (RADIANCE) and 2 other randomised trials (Gharbiya 2010; Iacono 2012). Gharbiya (2010) and Iacono (2012) compared ranibizumab with bevacizumab. However, the manufacturer did not present data from the bevacizumab arm of these trials. RADIANCE compared ranibizumab with vPDT in people with visual impairment caused by choroidal neovascularisation secondary to pathological myopia. The trial was a randomised, double‑blind, multicentre study conducted in 20 countries, which compared 2 groups of patients using ranibizumab (n=222) with 1 group using vPDT (n=55). On day 1 of treatment, patients in the ranibizumab groups received 0.5 mg of ranibizumab and patients in the vPDT group were given 6 mg/m2 of verteporfin intravenously, followed by a light dose of 50 J/cm2 at an intensity of 600 mW/cm2 for 83 seconds. In the ranibizumab disease activity group (n=116) and the vPDT group, patients were re‑treated if visual impairment caused by intra or subretinal fluid, or active leakage secondary to pathological myopia, was seen. Treatment was continued until these effects were no longer seen. In the ranibizumab disease stabilisation group (n=106), patients were re‑treated if there was a loss of best corrected visual acuity (BCVA) because of disease activity. Treatment was continued until BCVA was stable for 3 consecutive monthly assessments. The primary end point of RADIANCE was the mean average change in BCVA between baseline and months 1–3, measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, in which a score of 85 letters corresponds to normal visual acuity. Gains in BCVA (reported as mean±standard deviation ) were statistically significantly greater in both ranibizumab groups (disease activity group; 10.6±7.3 letters, p<0.0001 compared with vPDT, disease stabilisation group; 10.5±8.2 letters, p<0.0001 compared with vPDT) than in the vPDT group (2.2±9.5 letters). The secondary end points included the proportion of patients gaining 10 or more or 15 or more letters, mean change in BCVA, and changes in central retinal thickness from baseline. Both of the ranibizumab groups had statistically significantly more patients gaining 10 or more letters or 15 or more letters than the vPDT group. There was no statistically significant difference between either of the ranibizumab groups compared with the vPDT group in mean change in BCVA or in mean change in central retinal thickness. The length of follow‑up was 12 months for the 2 ranibizumab groups. After 3 months, 72% of the patients in the vPDT group received ranibizumab. Therefore, the manufacturer did not compare the results of the vPDT group with the results of the ranibizumab groups after the initial 3‑month period. The 2 other randomised trials (Gharbiya 2010; Iacono 2012) were single‑centre trials conducted in Italy comparing ranibizumab with bevacizumab. The manufacturer did not present the data for the bevacizumab arm for either trial. The Iacono (2012) study was a double‑blind clinical trial in people with subfoveal choroidal neovascularisation secondary to pathological myopia (55 eyes; ranibizumab=27, bevacizumab=28) with a follow‑up period of 18 months. Gharbiya (2010) was an interventional study in people with subfoveal or juxtafoveal choroidal neovascularisation secondary to pathological myopia and evidence of leakage from the choroidal neovascularisation lesion (32 eyes; ranibizumab=16, bevacizumab=16) with a follow‑up period of 6 months. The mean (±SD) change in BCVA was 9±NR (not reported) letters in the ranibizumab arm of the Iacono (2012) study and 17.3±11.1 letters in the ranibizumab arm of the Gharbiya (2010) study. It was not reported how many patients gained 10 or more letters in the Iacono study, although 7 (30%) gained 15 or more letters in the ranibizumab arm. In the ranibizumab arm of the Gharbiya (2010) study, 12 (75%) patients gained 10 letters or more and 9 (56%) gained 15 letters or more. The mean change in retinal thickness was not reported in the Iacono (2012) study. In the ranibizumab arm of the Gharbiya (2010) study, the mean change in retinal thickness was −45±NR micrometers. The manufacturer identified 6 non‑randomised studies relevant to the decision problem. All 6 studies investigated the use of ranibizumab in patients with choroidal neovascularisation secondary to pathological myopia, with follow‑up times ranging from a mean of 8 months to a median of 17 months. One study was a multicentre phase II study (the REPAIR study) and the other 5 studies were prospective case‑series (Calvo‑Gonzalez 2011; Lalloum 2010; Ouhadj 2010; Silva 2010; Vadala 2011). A statistically significant change in BCVA from baseline to time of assessment was shown in 4 of the 6 studies. The number of patients who gained 15 or more letters at follow‑up ranged from 24–47%. Adverse effects of ranibizumab were reported in RADIANCE. Ocular adverse events in the ranibizumab disease activity group were 16 (14%, 0 severe), 31 (26%, 1 severe), and 44 (37%, 1 severe) and in the ranibizumab disease stabilisation group were 29 (27%, 0 severe), 38 (36%, 0 severe), and 46 (43%, 1 severe) by 3, 6, and 12 months respectively. There were 5 (9%) ocular adverse events in the vPDT group by 3 months, of which none were severe. Non‑ocular adverse events in the ranibizumab disease activity group were 30 (25%, 1 severe), 42 (36%, 3 severe), and 51 (43%, 6 severe) and in the ranibizumab disease stabilisation group were 27 (26%, 0 severe), 38 (36%, 1 severe), and 48 (45%, 3 severe) by 3, 6, and 12 months respectively. There were 6 (11%) non‑ocular adverse events in the vPDT group by 3 months, of which none were severe. There were no systemic or significant ocular adverse events in the Iacono (2012) or Gharbiya (2010) trials. REPAIR reported adverse events that occurred in 2 or more patients. Ocular adverse events occurred in 29 (45%) patients and non‑ocular adverse events in 39 (60%) patients over 12 months. Calvo‑Gonzalez (2011) reported that 2 eyes developed anterior uveitis over a mean follow‑up of 16 months. The other 4 non‑randomised studies (Lalloum 2010; Ouhadj 2010; Silva 2010; Vadala 2011) reported that no systemic or ocular adverse events were observed, with the mean follow‑up ranging from 8 to 17 months. Impact on health‑related quality of life was measured in RADIANCE. The change in National Eye Institute Visual Functioning Questionnaire 25 item (NEI VFQ‑25) composite score from baseline to 3 months (reported as mean±SD) was statistically significantly higher for the 2 ranibizumab groups (disease activity group; 4.3±10.1, p<0.05 compared with vPDT, disease stabilisation group; 5.3±14.0, p<0.05 compared with vPDT) compared with the vPDT group (0.3±12.6). The mean (±SD) change in the EQ‑5D questionnaire from baseline to 3 months was 2.3±55.0, 4.2±NR, and 2.1±NR for the ranibizumab disease activity, ranibizumab disease stabilisation, and vPDT groups respectively. The mean (±SD) reduction in Work Productivity and Activity Impairment Questionnaire: General Health (WPAI‑GH) score from baseline to 3 months was 22.0±55.0, 21.9±75.2, and 10.2±59.9 for the ranibizumab disease activity, ranibizumab disease stabilisation, and vPDT groups respectively. The statistical significance of the differences between the groups for the EQ‑5D and WPAI‑GH scores were not reported. # Cost effectiveness The manufacturer developed a cost–utility Markov model that evaluated the cost effectiveness of ranibizumab compared with vPDT in people with choroidal neovascularisation associated with pathological myopia. There were 8 health states in the model, defined by the BCVA in the treated eye in addition to the absorbing health state of death. The health states were defined by a 10‑letter range in BCVA. The model had 3‑monthly cycles and a lifetime time horizon. The transition probabilities for the first cycle of the model (baseline to month 3) for both ranibizumab and vPDT were based on RADIANCE. For the next 3 cycles (months 4 to 12), the transition probabilities between health states were derived from RADIANCE for ranibizumab and from the Verteporfin in Photodynamic Therapy (VIP) trial for vPDT. VIP compared vPDT with photodynamic therapy in 120 patients with subfoveal choroidal neovascularisation secondary to pathological myopia. For cycles 5 onwards (1 year onwards), a slow worsening of visual acuity was assumed, based on natural disease progression reported in Yoshida (2002) for the base case and an additional 6 natural history studies for the other transition probabilities. The model included crossover from the better‑seeing eye to the worse‑seeing eye and vice versa as patients changed health states. A baseline rate of bilateral involvement (that is, both eyes affected by choroidal neovascularisation) of 15% was derived from 2 published studies (Cohen 1996; Hampton 1983) and the model assumed no incidence of choroidal neovascularisation secondary to pathological myopia after baseline measurement. Based on expert opinion, the manufacturer estimated a recurrence of choroidal neovascularisation in 6% of patients each year after the first 2 years of modelling. The manufacturer assumed an indefinite duration of treatment benefit, based on the treatment benefit seen at year 1. Base‑case utility values for the better‑seeing eye were taken from a published study of the UK general population in which BCVA health states were simulated with contact lenses that created the effects of age‑related macular degeneration (Czoski‑Murray et al. 2009). They ranged from 0.850 in patients with a BCVA of 86 to 100 letters to 0.353 for those with a BCVA of less than 25 letters. Base‑case utility values for the worse‑seeing eye were calculated from the values for the better‑seeing eye, with the assumption that the maximum utility gain in the worse‑seeing eye was 0.1. These utilities therefore ranged from 0.850 for a BCVA of 86 to 100 letters, to 0.750 for a BCVA of less than 25 letters. Disutilities were defined as adverse events that occurred in more than 5 patients and were suspected to be related to the study drug or ocular injection in RADIANCE (for ranibizumab) or VIP (for vPDT). Disutilities were conjunctival haemorrhage (ranibizumab; 8.5%, vPDT; 0%), increased intraocular pressure (ranibizumab; 4.2%, vPDT; 0%), visual disturbance (ranibizumab; 0%, vPDT; 14.8%), and injection site adverse events (ranibizumab; 0%, vPDT; 9.9%). Total costs for treatment were calculated from the unit costs, administration costs, and the cost of a monitoring visit multiplied by the total number of treatment visits and monitoring visits needed. The cost of blindness was calculated as £17,326 in the first year and £17,245 in each year after. The manufacturer's base‑case deterministic cost‑effectiveness analysis results showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more QALYs (13.18 compared with 12.75) and lower costs (£9694 compared with £12,455). The manufacturer similarly presented base‑case probabilistic results which showed that ranibizumab dominated vPDT. The manufacturer conducted one‑way sensitivity analyses using a net monetary benefit approach (calculated by multiplying the incremental QALYs by £20,000 and then subtracting the incremental costs) because ranibizumab dominated vPDT in the base‑case analysis. The sensitivity analysis showed that the model was sensitive to changes in the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits and the maximum utility gain in the worse‑seeing eye. The results of the manufacturer's sensitivity analysis showed that ranibizumab remained dominant up to a unit cost of £783 (range £0–3750) and when up to 12 injections were needed in either year 1 or year 2 (range 0–12, with vPDT given 3.4 times per year). Scenario analyses showed that ranibizumab remained dominant when other methods for calculating transition probabilities, such as keeping transition probabilities constant across all visual acuity levels, and other sources of natural history data (Bottoni et al. 2001; Hampton et al. 1983; Hotchkiss et al. 1981; Kojima et al. 2006; Secretan et al. 1997; Tabandeh et al. 1999; Yoshida et al. 2002), were used, and when the maximum gain in utility for the worse‑seeing eye is 0.2 or 0.3. The sensitivity analysis showed that there was a 100% probability of ranibizumab being cost effective if the maximum acceptable ICER was £20,000 or £30,000 per QALY gained. The manufacturer conducted 3 scenario analyses. The first scenario analysis involved calculating the transition probabilities from patient‑level data using 3 different methods. The base‑case method used probabilities that were dependent on the current BCVA level and assumed the patient could move from any health state to any other health state in each cycle. The second method used probabilities that were dependent on the patients' current BCVA level for the top 2 health states only, so that a patient could only gain or lose up to 2 health states in each cycle. The third method used a constant probability across all BCVA levels, regardless of the patient's current BCVA level, and assumed that patients could only gain or lose up to 2 health states each cycle. The second scenario analysis involved using different sources for calculating transition probabilities beyond year 1. The third scenario analysis involved using different values for the maximum utility gains for the worse‑seeing eye. Ranibizumab continued to dominate vPDT in all of the scenario analyses. # ERG critique of the manufacturer's submission The ERG commented that the manufacturer did not include bevacizumab as a comparator even though it was included in the NICE appraisal scope. The ERG noted that the manufacturer stated that bevacizumab is unlicensed for use in the UK for choroidal neovascularisation associated with pathological myopia and that use of bevacizumab is not established practice in the UK for this indication. The ERG stated that although vPDT has a UK marketing authorisation for treatment of choroidal neovascularisation, it is rarely used in clinical practice. The ERG found 2 head‑to‑head trials of bevacizumab and ranibizumab. The ERG noted that the manufacturer had included these 2 trials in their submission, but had only presented data from the ranibizumab arms. The ERG stated that neither of these studies showed statistically significant differences between the ranibizumab and bevacizumab arms in mean change from baseline in BCVA, mean change in central retinal thickness, or in the number of patients gaining 10 or more or 15 or more letters. The ERG noted that in RADIANCE the primary end point was at 3 months, and the ERG's clinical specialist thought that 12 months should be the minimum to assess longer term efficacy of treatment. The ERG stated that in VIP, the statistically significant difference between the vPDT and photodynamic therapy groups in the primary end point at 3 months was no longer seen at 24 months, and that this could also be true for ranibizumab. The ERG believed that it was unlikely that a 3‑month follow‑up period would provide adequate information about potential adverse effects of the anti‑VEGF treatment. The ERG noted that geographic atrophy, which is an advanced form of dry age‑related macular degeneration in which the rods and cones of the retina degenerate, is a common feature in patients with pathological myopia. It stated that the development of geographic atrophy or extension of pre‑existing geographic atrophy has been recognised as a potential side effect in patients with age‑related macular degeneration having anti‑VEGF treatment. The ERG was concerned that geographic atrophy was not assessed in RADIANCE because it can affect long‑term visual outcomes. The ERG noted that there was a difference between the patient populations in the RADIANCE and VIP trials. It was concerned that RADIANCE included a greater proportion of patients with non‑subfoveal involvement. The ERG stated that this may affect the comparability of the trials, because patients with subfoveal involvement tend to have a worse prognosis. The ERG suggested that the difference in the number of patients with subfoveal involvement in the 2 trials may overestimate the benefit of ranibizumab. The ERG noted that the model accounted for the possibility of the better‑seeing eye becoming the worse‑seeing eye, and vice versa, as patients change health states. The ERG stated that the method used by the manufacturer may underestimate the net quality‑adjusted life year (QALY) gains and costs of blindness that may arise from the more effective treatment. The ERG questioned whether an appropriate source had been used for the health‑related quality of life data in the model. The ERG identified the Brown et al. (1999) study, which measured health‑related quality of life directly from patients with impaired vision in at least 1 eye, producing a narrower range of utility values than the study by Czoski‑Murray et al. (2009). The ERG noted that the number of ranibizumab injections needed in years 2 and 3 may have been underestimated. It described a study by Franqueira et al. (2012) that reported results of a 3‑year retrospective study of 40 eyes with choroidal neovascularisation associated with pathological myopia. The mean number of injections in the study was 2.4 in year 2. The ERG suggested that 1.7 injections in year 2 would be a more reasonable assumption than the 1 injection in year 2 assumed in the manufacturer's model. The ERG commented that the costs of blindness may have been overestimated. This was driven by the different costs of residential care calculated by the ERG and the manufacturer. The ERG suggested that a cost of blindness of £7510 in the first year and £7429 in each subsequent year, based on 2011 Personal and Social Services Research Unit costs and 30% of people being privately funded, was a more reasonable assumption. The ERG noted that there were health state probabilities included in the manufacturer's model that were populated by relatively few patients. It was unsure whether the trials provided sufficient patient‑level data to be able to sensibly populate a model with 8 health states and a 64 cell transition probability matrix. Therefore the ERG was concerned about the reliability of the manufacturer's probability modelling. The ERG noted some uncertainty about the use of mortality multipliers in the manufacturer's model. It stated that the definition of visual impairment in Christ et al. (2008), which was used by the manufacturer as a source of the multipliers, was ambiguous. The ERG noted that EQ‑5D data were collected in RADIANCE but were not included in the manufacturer's submission. The ERG requested the EQ‑5D data during the clarification process and these were provided by the manufacturer. The ERG commented that the data indicated that changes in the BCVA of the worse‑seeing eye had no impact on patients' health‑related quality of life. The ERG stated that the manufacturer's assumption that treatment benefit would continue indefinitely was optimistic. The ERG performed exploratory analyses that incorporated alternative durations of treatment benefit of 1, 5, 10 and 20 years. This caused the net savings, QALYs and health benefits to decrease compared with those in the manufacturer's model. Ranibizumab remained dominant compared with vPDT even for a 1 year duration of treatment benefit. The ERG highlighted minor errors in the manufacturer's model, in the calculation of the quarterly proportion of patients worsening, derived from natural history data. These errors were acknowledged in the manufacturer's clarification responses. The ERG corrected the errors in their exploratory analysis of the manufacturer's model. The ERG conducted an exploratory analysis which involved the following modifications to the manufacturer's model: Brown et al. (1999) as a source of utility values in addition to Czoski‑Murray et al. (2009) changed the dose of ranibizumab in year 2 from 1 to 1.7 changed the costs of blindness from £17,326 in year 1 and £17,245 in each subsequent year to £7510 and £7429 respectively changed the mortality multiplier for blindness (BCVA of 35 letters or less) from 1.54 to 1.48 corrected the calculation of the quarterly proportion of patients worsening. In the ERG's exploratory analysis, ranibizumab dominated vPDT. The total cost of ranibizumab was £10,055 and of vPDT was £12,529 (incremental cost −£2474). Using utility values from Brown et al. (1999), the total QALYs were 14.514 for ranibizumab and 14.170 for vPDT (incremental QALYs 0.344). Using utility values from Czoski‑Murray et al. (2009), the total QALYs were 13.105 for ranibizumab and 12.838 for vPDT (incremental QALYs 0.266). Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of choroidal neovascularisation associated with pathological myopia and the value placed on the benefits of ranibizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee considered the current management of visual impairment caused by choroidal neovascularisation associated with pathological myopia. The clinical specialist stated that verteporfin photodynamic therapy (vPDT) has been used since 2005, and before this, no treatment was available. It heard from the clinical specialist that vPDT is not effective in most patients. The Committee discussed the use of vPDT and noted that its use is now diminishing because of the anti‑vascular endothelial growth factor (anti‑VEGF) treatments, such as ranibizumab and bevacizumab. It noted that bevacizumab is used outside of its marketing authorisation and has to be formulated under a 'specials' licence. It concluded that a licensed alternative treatment to vPDT for visual impairment caused by choroidal neovascularisation with pathological myopia would be welcomed by clinicians and patients. The Committee considered the impact of visual impairment caused by choroidal neovascularisation with pathological myopia on the everyday life of patients. The Committee understood from the patient expert that the condition affects a younger group of patients compared with other eye conditions and so affects the ability to work, drive, and care for children or other dependents. It heard from the patient expert that loss of vision has a significant effect on the independence of people with the condition and can lead to depression. The Committee agreed that loss of vision caused by choroidal neovascularisation seriously impairs quality of life. The Committee considered the comparators for this appraisal. The Committee expressed concern that the manufacturer had not included bevacizumab as a comparator. It noted that the scope listed vPDT and bevacizumab as comparators, although it was aware that bevacizumab does not have a marketing authorisation for treating visual impairment caused by choroidal neovascularisation associated with pathological myopia. The Committee noted that appropriate comparators should be established practice in England. This is not intended to be restrictive, but to emphasise the need for comparison with all relevant comparators; any drug in routine use or considered to be best practice should be considered a potential comparator. The Committee heard from the manufacturer that it considered that bevacizumab was not an appropriate comparator because its use in the NHS is not routine or best practice. The Committee heard from the patient expert and clinical specialist that bevacizumab is used in some patients, but only after some delay to agreement for funding. The Committee noted that the written statements submitted by the Royal College of Ophthalmologists, the Royal College of Pathologists, and the Macular Society suggested considerable use of bevacizumab in the NHS for this indication. The Committee also noted that there are 2 trials (see section 4.7) that compared ranibizumab with bevacizumab in choroidal neovascularisation associated with pathological myopia. However, both of these had a small number of patients. The Committee heard from the clinical specialist that there are some residual safety concerns with the use of bevacizumab, but considered these to be minor. It was aware of the conclusions of the Decision Support Unit report (Bevacizumab in eye conditions: Issues related to quality, use, efficacy and safety), which stated that adverse event rates were low in all bevacizumab and comparator groups. However, the Committee also noted that the use of bevacizumab in the eye had not been assessed by the regulatory agencies. It agreed that bevacizumab was a legitimate potential comparator with respect to its use in the NHS. The Committee concluded that because the available evidence for bevacizumab in this indication was limited to 2 small trials, there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and cost‑effectiveness analysis, but it did not rule out the possibility of future evidence providing that confidence. # Clinical effectiveness The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. The Committee acknowledged that the evidence was primarily from RADIANCE, which compared ranibizumab with vPDT, and was complemented by evidence from 2 other randomised trials that compared ranibizumab with bevacizumab, even though the manufacturer did not present the data for the bevacizumab arms of these trials in its submission. The Committee noted that ranibizumab was associated with a greater improvement than vPDT in best corrected visual acuity (BCVA) between baseline and months 1–3. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia. The Committee discussed the primary end point of RADIANCE, which was the mean average change in BCVA between baseline and months 1–3. The Committee heard from the clinical specialist that 3 months was not a long time period to assess the longer term benefits of ranibizumab. However, the other studies of ranibizumab and the long‑term follow‑up of its use in other eye conditions suggest a sustained effect. The Committee concluded that, because the clinical effectiveness of ranibizumab was not compared with vPDT after 3 months in RADIANCE, there is uncertainty about the long‑term efficacy of ranibizumab for visual impairment caused by choroidal neovascularisation associated with pathological myopia. The Committee considered the 2 trials presented in the manufacturer's submission that compared the use of ranibizumab and bevacizumab in choroidal neovascularisation associated with pathological myopia. The Committee noted that this was in line with the scope, in which bevacizumab was included as a comparator. The Committee heard from the clinical specialist that the 2 trials, although small, showed ranibizumab and bevacizumab to be equally effective. It was aware that the manufacturer presented only the results from the ranibizumab arms of these trials in their submission and that the Evidence Review Group (ERG) had presented the results from the bevacizumab arms in their report (see section 3.19). The Committee concluded that ranibizumab is likely to be as clinically effective as bevacizumab in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia. The Committee considered the trial evidence for adverse events associated with ranibizumab. The Committee discussed whether geographic atrophy was under‑reported because markers of this effect were not measured in RADIANCE. The clinical specialist argued that there was no particular reason to expect geographic atrophy as a side effect of ranibizumab treatment. The Committee was aware that the main adverse events listed in the summary of product characteristics were eye pain, ocular hyperaemia, increased intraocular pressure, vitritis, and vitreous detachment. The Committee agreed that the evidence suggested manageable adverse events with ranibizumab, and concluded that ranibizumab was safe and well tolerated in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia. # Cost effectiveness The Committee considered the cost‑effectiveness evidence presented in the manufacturer's submission, including the base‑case results, the sensitivity and scenario analyses and the ERG's critique of the manufacturer's evidence. It noted that the manufacturer had not included bevacizumab as a comparator in its economic model. The Committee understood that the manufacturer's base‑case analysis showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more quality‑adjusted life years (QALYs; 13.18 compared with 12.75) and lower costs (£9694 compared with £12,455). The Committee accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer. In particular, the Committee queried: the larger proportion of patients with subfoveal involvement at baseline in the VIP trial than in the RADIANCE trial the assumption of an indefinite duration of benefit of ranibizumab treatment the low number of ranibizumab injections needed in year 2 of treatment the high estimated costs of blindness the low estimated costs of ranibizumab and vPDT administration the lack of clarity about the source of the mortality multipliers used in the model the underestimated changes in net QALY gains and the cost of blindness resulting from the method used to account for the possibility of the treated eye changing from being the better‑seeing eye to being the worse‑seeing eye the use of Czoski‑Murray et al. (2009) as a source of utility values, rather than the EQ‑5D data collected in RADIANCE.The Committee considered each of these issues in turn, as detailed below. The Committee considered the clinical‑effectiveness data that were used in the manufacturer's economic model. It recognised that the clinical‑effectiveness data for ranibizumab were derived from RADIANCE and the data for vPDT after 3 months were derived from the VIP trial. The Committee noted that there was a larger proportion of patients at baseline with subfoveal involvement in VIP compared with RADIANCE and it was concerned that this might have had an impact on the model. The Committee heard from the clinical specialist that an imbalance would only be clinically relevant if it was in the number of patients with extra‑foveal involvement, and that this did not appear to be the case. The Committee concluded that the imbalance in the number of patients with subfoveal involvement in RADIANCE and VIP was unlikely to have a large impact on the manufacturer's model. The Committee discussed the manufacturer's assumption that the average BCVA gain at the end of year 1 would continue indefinitely. The Committee heard from the clinical specialist that data collected at the 3 time points in RADIANCE showed that the benefit of ranibizumab was maintained for at least 12 months. The Committee noted that the ERG's sensitivity analyses included different durations of treatment benefit, and that ranibizumab dominated vPDT even when the duration of treatment benefit was reduced to 1 year. The Committee concluded that the duration of treatment benefit was likely to be less than the manufacturer's assumption of an indefinite duration, and that ranibizumab dominated vPDT when the duration of effect was reduced. The Committee discussed the manufacturer's assumption about the number of ranibizumab injections that people would receive in clinical practice. The Committee heard from the clinical specialist that, on average, patients only need ranibizumab injections in the first 3 months of their first year of treatment. The clinical specialist also stated that patients in the REPAIR trial had well preserved eyesight after 18 months and did not need further treatment. The Committee noted that the ERG had increased the number of ranibizumab injections in the second year of ranibizumab treatment from 1.0 to 1.7 in its exploratory analysis. Based on experience with patients using ranibizumab, the clinical specialist felt that this number could be too high. The Committee concluded that the number of injections included in the manufacturer's base case could be an underestimate and that even if the number of injections was increased, ranibizumab would continue to dominate vPDT. The Committee considered the costs of blindness used in the manufacturer's economic model. It noted that the ERG presented lower costs of blindness in their report. The Committee heard from the ERG that the difference in the costs of blindness was mainly related to the way the costs for private residential care were calculated. The Committee noted that the manufacturer's sensitivity analysis showed that the model was not sensitive to changes in the costs of blindness. The Committee concluded that the ERG's assumptions about the costs of blindness were likely to be more realistic than those used by the manufacturer, and that if the ERG's assumptions had been used, ranibizumab would continue to dominate vPDT. The Committee discussed the administration costs of ranibizumab used in the manufacturer's economic model. It noted that these costs were likely to be an underestimate of the true costs incurred in the NHS. The Committee recognised that the manufacturer's sensitivity analysis showed that the model was not sensitive to changes in the administration costs. The Committee concluded that although some uncertainty remained about the NHS costs involved in the administration of ranibizumab, the uncertainty was not great enough to affect the dominance of ranibizumab over vPDT. The Committee discussed the mortality multipliers that the manufacturer had used in its economic model. It heard from the ERG that the source of some of the mortality multipliers was unclear. The ERG also stated that changing the mortality multipliers to alternative values had little impact on the cost savings or QALYs for ranibizumab. The Committee concluded that the manufacturer's rationale for some of the mortality multipliers used in their model was unclear, and that any changes to them were unlikely to change the dominance of ranibizumab over vPDT. The Committee considered the method used in the manufacturer's economic model to account for the possibility of the treated eye changing from being the better‑seeing eye to being the worse‑seeing eye as patients changed health states. The Committee understood that the way the manufacturer had modelled this seemed to underestimate the changes in net QALY gains and costs of blindness that may arise from the more effective treatment. The Committee noted that it was not possible to quantify the size of the effect on the base‑case analysis. The Committee concluded that the modelling of the treated eye changing from being the better‑seeing eye to being the worse‑seeing eye as patients changed health states may have had an impact on the base‑case analysis, which showed that ranibizumab dominated vPDT, although the level of impact remained unclear. The Committee discussed the utility values used in the manufacturer's economic model. The Committee noted that the source of utility data used in the base‑case analysis (Czoski‑Murray et al. 2009) was used in Ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance 274), Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 283), and Aflibercept solution for injection for treating wet age-related macular degeneration (NICE technology appraisal guidance 294). It was aware that EQ‑5D data were also collected in RADIANCE, but these data were not used in the model. The Committee heard from the manufacturer that the EQ‑5D data from RADIANCE were not included because the EQ‑5D is widely recognised as not being sensitive in studies of eye conditions. The Committee heard from the ERG that using the EQ‑5D data collected in RADIANCE did not have a large effect on the model, although the effect for the worse‑seeing eye was not clear. The Committee concluded that using the EQ‑5D data from RADIANCE was unlikely to change the overall results of the base‑case analysis and that ranibizumab would continue to dominate vPDT. The Committee noted that the manufacturer's model had not included bevacizumab as a comparator and so the base‑case analysis was limited to a comparison of ranibizumab with vPDT. However, because the available evidence for bevacizumab in this indication was limited to 2 small trials (see section 4.4), there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and cost‑effectiveness analysis. The Committee considered the uncertainties in the manufacturer's model and noted that they did not have an effect on the overall results of the base‑case analysis, which showed that ranibizumab dominated vPDT. The Committee concluded that ranibizumab was a cost‑effective use of NHS resources for treating people with visual impairment caused by choroidal neovascularisation associated with pathological myopia when vPDT was the comparator. The Committee discussed how innovative ranibizumab is in its potential to make a significant and substantial impact on health‑related benefits. It agreed that anti‑VEGF treatments, such as ranibizumab, were a substantial improvement over previous treatments, and considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was a step forward in providing health‑related patient benefits, not the act of licensing. In addition there were no substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling. The Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. No equality issues were raised during the appraisal process or at the Committee meeting. Therefore the Committee concluded that no alterations or additions to its recommendations were needed. # Summary of Appraisal Committee's key conclusions TA298 Appraisal title: Ranibizumab for treating choroidal neovascularisation associated with pathological myopia Section Key conclusion Ranibizumab is recommended as an option for treating choroidal neovascularisation associated with pathological myopia when the manufacturer provides ranibizumab with the discount agreed in the patient access scheme. The clinical evidence from RADIANCE, which compared ranibizumab with vPDT, showed that ranibizumab was associated with a greater improvement than vPDT in best corrected visual acuity between baseline and months 1–3, although there is uncertainty about the efficacy after 3 months. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia. The key drivers of the cost‑effectiveness analysis included the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits and the maximum utility gain in the worse‑seeing eye. The manufacturer's base‑case cost‑effectiveness analysis showed that ranibizumab dominated vPDT, resulting in more QALYs and lower costs. The Committee concluded that the uncertainties associated with the key drivers in the model were unlikely to have an effect on the overall cost‑effectiveness results. The Committee therefore recommended ranibizumab as a cost‑effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments The Committee heard that visual impairment caused by choroidal neovascularisation seriously impairs quality of life. The Committee heard that the current standard treatment for choroidal neovascularisation secondary to pathological myopia is vPDT. However, it is not effective in most patients and its use is diminishing because of anti‑VEGF treatments. The Committee heard from a clinical specialist that the non‑licensed use of bevacizumab in the NHS is not routine or best practice. However, written statements from the Royal College of Ophthalmologists, the Royal College of Pathologists, and the Macular Society suggested considerable use of bevacizumab in the NHS for this indication. The Committee heard from the patient expert and the clinical specialist that there are often delays in agreements to fund ranibizumab or bevacizumab. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits? The Committee agreed that anti‑VEGF treatments (such as ranibizumab) were a substantial improvement over previous treatments. It was not aware of any substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling. What is the position of the treatment in the pathway of care for the condition? The Committee assessed the clinical effectiveness of ranibizumab compared with vPDT for treating visual impairment caused by choroidal neovascularisation associated with pathological myopia. Adverse reactions The Committee was aware that the main adverse events listed in the summary of product characteristics were eye pain, ocular hyperaemia, increased intraocular pressure, vitritis, and vitreous detachment. The Committee agreed that the evidence suggested manageable adverse events with ranibizumab, and concluded that ranibizumab was safe and well tolerated in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee acknowledged that the evidence presented by the manufacturer was primarily from RADIANCE, which compared ranibizumab with vPDT. This evidence was complemented by data from the ranibizumab arm of 2 other randomised trials. The Committee was aware that the scope of the appraisal listed bevacizumab as a comparator. It noted that the ERG identified only 2 small trials that compared ranibizumab and bevacizumab. The Committee concluded that there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and cost‑effectiveness analysis. Relevance to general clinical practice in the NHS The Committee heard that the current standard treatment for visual impairment caused by choroidal neovascularisation secondary to pathological myopia is vPDT. However, it is not effective in most patients and its use is diminishing because of anti‑VEGF treatments, such as ranibizumab and bevacizumab. Uncertainties generated by the evidence The Committee noted that the primary end point of RADIANCE was the mean average change in BCVA between baseline and months 1–3. The Committee heard from a clinical specialist that 3 months was not a long time period to assess the longer term benefits of ranibizumab. The Committee concluded that, because the clinical effectiveness of ranibizumab was not compared with vPDT after 3 months, there is uncertainty about the long‑term efficacy of ranibizumab for choroidal neovascularisation associated with pathological myopia. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? None Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that ranibizumab was associated with a greater improvement than vPDT in BCVA between baseline and months 1–3. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. It accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer. The Committee noted that the manufacturer had not included bevacizumab as a comparator in its economic model. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee considered the larger proportion of patients with subfoveal involvement in the VIP trial, which provided the vPDT data after 3 months. However, it concluded that the imbalance between RADIANCE and VIP was unlikely to have a large impact on the manufacturer's model. The Committee considered the manufacturer's assumption that the average BCVA gain at the end of year 1 would continue indefinitely. It concluded that the duration of treatment benefit was likely to be less than the manufacturer's assumption of an indefinite duration, but that ranibizumab dominated vPDT when the duration of effect was reduced. The Committee discussed whether the manufacturer's assumption about the number of ranibizumab injections that people would receive in clinical practice was too low. It concluded that the number of injections included in the manufacturer's base case could be an underestimate, and that even if the number of injections was increased, the base‑case analysis would not be affected. The Committee discussed whether the costs of blindness used in the manufacturer's model were too high. The Committee noted that the ERG presented lower costs of blindness in their report. The Committee concluded that the ERG's assumptions about the costs of blindness were likely to be more realistic than those used by the manufacturer, and that any changes were unlikely to have a large impact on the base‑case analysis. The Committee discussed whether the administration costs of ranibizumab used in the manufacturer's model were an underestimate. It concluded that the NHS costs were uncertain, but the uncertainty was not great enough to affect the base‑case analysis. The Committee discussed whether the mortality multipliers used in the manufacturer's economic model were appropriate. It concluded that the manufacturer's rationale for some of the mortality multipliers in the model was unclear, and that any changes to them were unlikely to change the base‑case analysis. The Committee discussed whether the method used in the manufacturer's model to account for the possibility of the treated eye changing from being the better‑seeing eye to the worse‑seeing eye as patients change health states was appropriate. It concluded that the modelling may have had an impact on the base‑case analysis, but the level of impact was unclear. The Committee considered that EQ‑5D data were collected in RADIANCE, but were not used in the manufacturer's economic model. It concluded that using the EQ‑5D data from RADIANCE was unlikely to change the overall results of the base‑case analysis. Incorporation of health‑related quality‑of‑life benefits and utility values Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered? The Committee noted that the EQ‑5D data collected in RADIANCE was not used in the model and the manufacturer used utility values from Czoski‑Murray et al. (2009), in line with previous appraisals of drugs for eye conditions. The Committee heard from the ERG that using the EQ‑5D data from RADIANCE did not have had a large effect on the model, although the effect for the worse‑seeing eye was not clear. The Committee concluded that using the EQ‑5D data from RADIANCE was unlikely to change the overall results of the base‑case analysis. The Committee was not aware of any substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling. Are there specific groups of people for whom the technology is particularly cost effective? None What are the key drivers of cost effectiveness? The manufacturer's sensitivity analyses showed that the cost effectiveness of ranibizumab was sensitive to changes in the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits, and the maximum utility gain in the worse‑seeing eye. Most likely cost‑effectiveness estimate (given as an ICER) The Committee noted that manufacturer's base‑case analysis showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more QALYs (13.18 compared with 12.75) and lower costs (£9694 compared with £12,455). The Committee considered the uncertainties in the manufacturer's model and noted that they were unlikely to have an effect on the overall results of the base‑case analysis, which showed that ranibizumab dominated vPDT. Additional factors taken into account Patient access schemes (PPRS) The Department of Health and the manufacturer have agreed that ranibizumab will be available to the NHS with a patient access scheme which makes ranibizumab available with a discount. The level of discount is commercial in confidence. End‑of‑life considerations Not applicable Equalities considerations and social value judgements No equality issues were raised during the appraisal process or at the Committee meeting. Therefore the Committee concluded that no alterations or additions to its recommendations were needed. # Related NICE guidance Details are correct at the time of publication. Further information is available on the NICE website. Aflibercept solution for injection for treating wet age-related macular degeneration. NICE technology appraisal guidance 294 (2013). Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 283 (2013). Ranibizumab for the treatment of diabetic macular oedema (rapid review of TA237). NICE technology appraisal guidance 274 (2013). Fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema after an inadequate response to prior therapy. NICE technology appraisal guidance 271 (2013). Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229 (2011). Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. NICE technology appraisal guidance 155 (2008). Guidance on the use of photodynamic therapy for age-related macular degeneration. NICE technology appraisal guidance 68 (2003).# Review of guidance The guidance on this technology will be considered for review in March 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveNovember 2013# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It has been incorporated into the NICE pathway on eye conditions along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0362-7	{'Guidance': 'Ranibizumab is recommended as an option for treating visual impairment due to choroidal neovascularisation secondary to pathological myopia when the manufacturer provides ranibizumab with the discount agreed in the patient access scheme.', 'The technology ': "Ranibizumab (Lucentis, Novartis) belongs to a class of drugs that blocks the action of vascular endothelial growth factor (VEGF)‑A. By blocking the action of VEGF‑A, ranibizumab prevents abnormal blood vessels developing, thereby limiting visual loss and improving vision. Ranibizumab has a marketing authorisation for 'the treatment of visual impairment due to choroidal neovascularisation secondary to pathologic myopia'.\n\nRanibizumab is administered as a single 0.5\xa0mg intravitreal injection. Each vial of ranibizumab contains 2.3\xa0mg in 0.23\xa0ml; overfilling is considered necessary to achieve an injectable dose of 0.5\xa0mg. The summary of product characteristics states that monitoring is recommended monthly for the first 2\xa0months and at least every 3\xa0months thereafter during the first year. If monitoring reveals signs of disease activity, for example, reduced visual acuity and/or signs of lesion activity, further treatment is recommended.\n\nAdverse reactions to treatment are mostly limited to the eye. Those commonly reported in clinical trials include vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, sensation of a foreign body in the eye, increased production of tears, blepharitis, dry eye, ocular hyperaemia, itching of the eye and increased intraocular pressure. Nasopharyngitis, arthralgia and headaches are also commonly reported. Contraindications to ranibizumab include known hypersensitivity to the active substance or to any of its excipients, active or suspected ocular or periocular infections, and active severe intraocular inflammation. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe list price of ranibizumab 10\xa0mg/ml is £742.17 per 0.23‑ml vial (excluding VAT; 'British national formulary' [BNF] edition 66). The manufacturer of ranibizumab (Novartis) has agreed a patient access scheme with the Department of Health, revised in the context of Ranibizumab for treating diabetic macular oedema (NICE technology appraisal guidance 274), which makes ranibizumab available with a discount applied to all invoices. The level of the discount is commercial‑in‑confidence (see section 5.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of ranibizumab and a review of this submission by the Evidence Review Group (ERG; section 9).\n\n# Clinical effectiveness\n\nThe manufacturer submitted evidence of clinical and cost effectiveness for ranibizumab compared with verteporfin photodynamic therapy (vPDT) in people with choroidal neovascularisation associated with pathological myopia. Pathological myopia is a chronic condition characterised by excessive lengthening of the eye and degenerative changes at the back of the eye. These changes to the eye can cause blood vessels to leak or bleed into the retina in a process known as choroidal neovascularisation. This can result in visual impairment, in particular a loss of central vision. The manufacturer did not provide a comparison with bevacizumab, which is listed as a comparator in the scope for this appraisal. It did not consider bevacizumab to be a valid comparator because it is unlicensed for this condition and not routinely used.\n\nThe main sources of evidence presented in the manufacturer's submission came from a Novartis phase III trial (RADIANCE) and 2\xa0other randomised trials (Gharbiya 2010; Iacono 2012). Gharbiya (2010) and Iacono (2012) compared ranibizumab with bevacizumab. However, the manufacturer did not present data from the bevacizumab arm of these trials.\n\nRADIANCE compared ranibizumab with vPDT in people with visual impairment caused by choroidal neovascularisation secondary to pathological myopia. The trial was a randomised, double‑blind, multicentre study conducted in 20\xa0countries, which compared 2\xa0groups of patients using ranibizumab (n=222) with 1\xa0group using vPDT (n=55). On day\xa01 of treatment, patients in the ranibizumab groups received 0.5\xa0mg of ranibizumab and patients in the vPDT group were given 6\xa0mg/m2 of verteporfin intravenously, followed by a light dose of 50\xa0J/cm2 at an intensity of 600\xa0mW/cm2 for 83\xa0seconds. In the ranibizumab disease activity group (n=116) and the vPDT group, patients were re‑treated if visual impairment caused by intra or subretinal fluid, or active leakage secondary to pathological myopia, was seen. Treatment was continued until these effects were no longer seen. In the ranibizumab disease stabilisation group (n=106), patients were re‑treated if there was a loss of best corrected visual acuity (BCVA) because of disease activity. Treatment was continued until BCVA was stable for 3\xa0consecutive monthly assessments.\n\nThe primary end point of RADIANCE was the mean average change in BCVA between baseline and months\xa01–3, measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, in which a score of 85 letters corresponds to normal visual acuity. Gains in BCVA (reported as mean±standard deviation [SD]) were statistically significantly greater in both ranibizumab groups (disease activity group; 10.6±7.3\xa0letters, p<0.0001 compared with vPDT, disease stabilisation group; 10.5±8.2\xa0letters, p<0.0001 compared with vPDT) than in the vPDT group (2.2±9.5\xa0letters). The secondary end points included the proportion of patients gaining 10\xa0or more or 15\xa0or more letters, mean change in BCVA, and changes in central retinal thickness from baseline. Both of the ranibizumab groups had statistically significantly more patients gaining 10\xa0or more letters or 15\xa0or more letters than the vPDT group. There was no statistically significant difference between either of the ranibizumab groups compared with the vPDT group in mean change in BCVA or in mean change in central retinal thickness. The length of follow‑up was 12\xa0months for the 2\xa0ranibizumab groups. After 3\xa0months, 72% of the patients in the vPDT group received ranibizumab. Therefore, the manufacturer did not compare the results of the vPDT group with the results of the ranibizumab groups after the initial 3‑month period.\n\nThe 2\xa0other randomised trials (Gharbiya 2010; Iacono 2012) were single‑centre trials conducted in Italy comparing ranibizumab with bevacizumab. The manufacturer did not present the data for the bevacizumab arm for either trial. The Iacono (2012) study was a double‑blind clinical trial in people with subfoveal choroidal neovascularisation secondary to pathological myopia (55\xa0eyes; ranibizumab=27, bevacizumab=28) with a follow‑up period of 18\xa0months. Gharbiya (2010) was an interventional study in people with subfoveal or juxtafoveal choroidal neovascularisation secondary to pathological myopia and evidence of leakage from the choroidal neovascularisation lesion (32\xa0eyes; ranibizumab=16, bevacizumab=16) with a follow‑up period of 6\xa0months. The mean (±SD) change in BCVA was 9±NR (not reported) letters in the ranibizumab arm of the Iacono (2012) study and 17.3±11.1\xa0letters in the ranibizumab arm of the Gharbiya (2010) study. It was not reported how many patients gained 10\xa0or more letters in the Iacono study, although 7 (30%) gained 15\xa0or more letters in the ranibizumab arm. In the ranibizumab arm of the Gharbiya (2010) study, 12 (75%) patients gained 10\xa0letters or more and 9 (56%) gained 15\xa0letters or more. The mean change in retinal thickness was not reported in the Iacono (2012) study. In the ranibizumab arm of the Gharbiya (2010) study, the mean change in retinal thickness was −45±NR micrometers.\n\nThe manufacturer identified 6\xa0non‑randomised studies relevant to the decision problem. All 6\xa0studies investigated the use of ranibizumab in patients with choroidal neovascularisation secondary to pathological myopia, with follow‑up times ranging from a mean of 8\xa0months to a median of 17\xa0months. One study was a multicentre phase II study (the REPAIR study) and the other 5\xa0studies were prospective case‑series (Calvo‑Gonzalez 2011; Lalloum 2010; Ouhadj 2010; Silva 2010; Vadala 2011). A statistically significant change in BCVA from baseline to time of assessment was shown in 4 of the 6\xa0studies. The number of patients who gained 15\xa0or more letters at follow‑up ranged from 24–47%.\n\nAdverse effects of ranibizumab were reported in RADIANCE. Ocular adverse events in the ranibizumab disease activity group were 16\xa0(14%, 0 severe), 31\xa0(26%, 1 severe), and 44\xa0(37%, 1 severe) and in the ranibizumab disease stabilisation group were 29\xa0(27%, 0 severe), 38\xa0(36%, 0 severe), and 46\xa0(43%, 1 severe) by 3, 6, and 12\xa0months respectively. There were 5\xa0(9%) ocular adverse events in the vPDT group by 3\xa0months, of which none were severe. Non‑ocular adverse events in the ranibizumab disease activity group were 30\xa0(25%, 1 severe), 42\xa0(36%, 3 severe), and 51\xa0(43%, 6 severe) and in the ranibizumab disease stabilisation group were 27\xa0(26%, 0 severe), 38\xa0(36%, 1 severe), and 48\xa0(45%, 3 severe) by 3, 6, and 12\xa0months respectively. There were 6\xa0(11%) non‑ocular adverse events in the vPDT group by 3\xa0months, of which none were severe. There were no systemic or significant ocular adverse events in the Iacono (2012) or Gharbiya (2010) trials. REPAIR reported adverse events that occurred in 2\xa0or more patients. Ocular adverse events occurred in 29 (45%) patients and non‑ocular adverse events in 39 (60%) patients over 12\xa0months. Calvo‑Gonzalez (2011) reported that 2\xa0eyes developed anterior uveitis over a mean follow‑up of 16\xa0months. The other 4\xa0non‑randomised studies (Lalloum 2010; Ouhadj 2010; Silva 2010; Vadala 2011) reported that no systemic or ocular adverse events were observed, with the mean follow‑up ranging from 8 to 17\xa0months.\n\nImpact on health‑related quality of life was measured in RADIANCE. The change in National Eye Institute Visual Functioning Questionnaire 25 item (NEI VFQ‑25) composite score from baseline to 3\xa0months (reported as mean±SD) was statistically significantly higher for the 2\xa0ranibizumab groups (disease activity group; 4.3±10.1, p<0.05 compared with vPDT, disease stabilisation group; 5.3±14.0, p<0.05 compared with vPDT) compared with the vPDT group (0.3±12.6). The mean (±SD) change in the EQ‑5D questionnaire from baseline to 3\xa0months was 2.3±55.0, 4.2±NR, and 2.1±NR for the ranibizumab disease activity, ranibizumab disease stabilisation, and vPDT groups respectively. The mean (±SD) reduction in Work Productivity and Activity Impairment Questionnaire: General Health (WPAI‑GH) score from baseline to 3\xa0months was 22.0±55.0, 21.9±75.2, and 10.2±59.9 for the ranibizumab disease activity, ranibizumab disease stabilisation, and vPDT groups respectively. The statistical significance of the differences between the groups for the EQ‑5D and WPAI‑GH scores were not reported.\n\n# Cost effectiveness\n\nThe manufacturer developed a cost–utility Markov model that evaluated the cost effectiveness of ranibizumab compared with vPDT in people with choroidal neovascularisation associated with pathological myopia. There were 8\xa0health states in the model, defined by the BCVA in the treated eye in addition to the absorbing health state of death. The health states were defined by a 10‑letter range in BCVA. The model had 3‑monthly cycles and a lifetime time horizon.\n\nThe transition probabilities for the first cycle of the model (baseline to month\xa03) for both ranibizumab and vPDT were based on RADIANCE. For the next 3\xa0cycles (months\xa04 to 12), the transition probabilities between health states were derived from RADIANCE for ranibizumab and from the Verteporfin in Photodynamic Therapy (VIP) trial for vPDT. VIP compared vPDT with photodynamic therapy in 120\xa0patients with subfoveal choroidal neovascularisation secondary to pathological myopia. For cycles\xa05 onwards (1\xa0year onwards), a slow worsening of visual acuity was assumed, based on natural disease progression reported in Yoshida (2002) for the base case and an additional 6\xa0natural history studies for the other transition probabilities. The model included crossover from the better‑seeing eye to the worse‑seeing eye and vice versa as patients changed health states.\n\nA baseline rate of bilateral involvement (that is, both eyes affected by choroidal neovascularisation) of 15% was derived from 2\xa0published studies (Cohen 1996; Hampton 1983) and the model assumed no incidence of choroidal neovascularisation secondary to pathological myopia after baseline measurement. Based on expert opinion, the manufacturer estimated a recurrence of choroidal neovascularisation in 6% of patients each year after the first 2\xa0years of modelling. The manufacturer assumed an indefinite duration of treatment benefit, based on the treatment benefit seen at year\xa01.\n\nBase‑case utility values for the better‑seeing eye were taken from a published study of the UK general population in which BCVA health states were simulated with contact lenses that created the effects of age‑related macular degeneration (Czoski‑Murray et al. 2009). They ranged from 0.850 in patients with a BCVA of 86 to 100\xa0letters to 0.353 for those with a BCVA of less than 25\xa0letters. Base‑case utility values for the worse‑seeing eye were calculated from the values for the better‑seeing eye, with the assumption that the maximum utility gain in the worse‑seeing eye was 0.1. These utilities therefore ranged from 0.850 for a BCVA of 86 to 100\xa0letters, to 0.750 for a BCVA of less than 25\xa0letters.\n\nDisutilities were defined as adverse events that occurred in more than 5\xa0patients and were suspected to be related to the study drug or ocular injection in RADIANCE (for ranibizumab) or VIP (for vPDT). Disutilities were conjunctival haemorrhage (ranibizumab; 8.5%, vPDT; 0%), increased intraocular pressure (ranibizumab; 4.2%, vPDT; 0%), visual disturbance (ranibizumab; 0%, vPDT; 14.8%), and injection site adverse events (ranibizumab; 0%, vPDT; 9.9%).\n\nTotal costs for treatment were calculated from the unit costs, administration costs, and the cost of a monitoring visit multiplied by the total number of treatment visits and monitoring visits needed. The cost of blindness was calculated as £17,326 in the first year and £17,245 in each year after.\n\nThe manufacturer's base‑case deterministic cost‑effectiveness analysis results showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more QALYs (13.18 compared with 12.75) and lower costs (£9694 compared with £12,455). The manufacturer similarly presented base‑case probabilistic results which showed that ranibizumab dominated vPDT.\n\nThe manufacturer conducted one‑way sensitivity analyses using a net monetary benefit approach (calculated by multiplying the incremental QALYs by £20,000 and then subtracting the incremental costs) because ranibizumab dominated vPDT in the base‑case analysis. The sensitivity analysis showed that the model was sensitive to changes in the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits and the maximum utility gain in the worse‑seeing eye. The results of the manufacturer's sensitivity analysis showed that ranibizumab remained dominant up to a unit cost of £783 (range £0–3750) and when up to 12\xa0injections were needed in either year\xa01 or year\xa02 (range 0–12, with vPDT given 3.4\xa0times per year). Scenario analyses showed that ranibizumab remained dominant when other methods for calculating transition probabilities, such as keeping transition probabilities constant across all visual acuity levels, and other sources of natural history data (Bottoni et al. 2001; Hampton et al. 1983; Hotchkiss et al. 1981; Kojima et al. 2006; Secretan et al. 1997; Tabandeh et al. 1999; Yoshida et al. 2002), were used, and when the maximum gain in utility for the worse‑seeing eye is 0.2 or 0.3. The sensitivity analysis showed that there was a 100% probability of ranibizumab being cost effective if the maximum acceptable ICER was £20,000 or £30,000 per QALY gained.\n\nThe manufacturer conducted 3\xa0scenario analyses. The first scenario analysis involved calculating the transition probabilities from patient‑level data using 3\xa0different methods. The base‑case method used probabilities that were dependent on the current BCVA level and assumed the patient could move from any health state to any other health state in each cycle. The second method used probabilities that were dependent on the patients' current BCVA level for the top 2\xa0health states only, so that a patient could only gain or lose up to 2\xa0health states in each cycle. The third method used a constant probability across all BCVA levels, regardless of the patient's current BCVA level, and assumed that patients could only gain or lose up to 2\xa0health states each cycle. The second scenario analysis involved using different sources for calculating transition probabilities beyond year\xa01. The third scenario analysis involved using different values for the maximum utility gains for the worse‑seeing eye. Ranibizumab continued to dominate vPDT in all of the scenario analyses.\n\n# ERG critique of the manufacturer's submission\n\nThe ERG commented that the manufacturer did not include bevacizumab as a comparator even though it was included in the NICE appraisal scope. The ERG noted that the manufacturer stated that bevacizumab is unlicensed for use in the UK for choroidal neovascularisation associated with pathological myopia and that use of bevacizumab is not established practice in the UK for this indication. The ERG stated that although vPDT has a UK marketing authorisation for treatment of choroidal neovascularisation, it is rarely used in clinical practice.\n\nThe ERG found 2\xa0head‑to‑head trials of bevacizumab and ranibizumab. The ERG noted that the manufacturer had included these 2\xa0trials in their submission, but had only presented data from the ranibizumab arms. The ERG stated that neither of these studies showed statistically significant differences between the ranibizumab and bevacizumab arms in mean change from baseline in BCVA, mean change in central retinal thickness, or in the number of patients gaining 10\xa0or more or 15\xa0or more letters.\n\nThe ERG noted that in RADIANCE the primary end point was at 3\xa0months, and the ERG's clinical specialist thought that 12\xa0months should be the minimum to assess longer term efficacy of treatment. The ERG stated that in VIP, the statistically significant difference between the vPDT and photodynamic therapy groups in the primary end point at 3\xa0months was no longer seen at 24\xa0months, and that this could also be true for ranibizumab. The ERG believed that it was unlikely that a 3‑month follow‑up period would provide adequate information about potential adverse effects of the anti‑VEGF treatment.\n\nThe ERG noted that geographic atrophy, which is an advanced form of dry age‑related macular degeneration in which the rods and cones of the retina degenerate, is a common feature in patients with pathological myopia. It stated that the development of geographic atrophy or extension of pre‑existing geographic atrophy has been recognised as a potential side effect in patients with age‑related macular degeneration having anti‑VEGF treatment. The ERG was concerned that geographic atrophy was not assessed in RADIANCE because it can affect long‑term visual outcomes.\n\nThe ERG noted that there was a difference between the patient populations in the RADIANCE and VIP trials. It was concerned that RADIANCE included a greater proportion of patients with non‑subfoveal involvement. The ERG stated that this may affect the comparability of the trials, because patients with subfoveal involvement tend to have a worse prognosis. The ERG suggested that the difference in the number of patients with subfoveal involvement in the 2\xa0trials may overestimate the benefit of ranibizumab.\n\nThe ERG noted that the model accounted for the possibility of the better‑seeing eye becoming the worse‑seeing eye, and vice versa, as patients change health states. The ERG stated that the method used by the manufacturer may underestimate the net quality‑adjusted life year (QALY) gains and costs of blindness that may arise from the more effective treatment.\n\nThe ERG questioned whether an appropriate source had been used for the health‑related quality of life data in the model. The ERG identified the Brown et al. (1999) study, which measured health‑related quality of life directly from patients with impaired vision in at least 1\xa0eye, producing a narrower range of utility values than the study by Czoski‑Murray et al. (2009).\n\nThe ERG noted that the number of ranibizumab injections needed in years\xa02 and 3 may have been underestimated. It described a study by Franqueira et al. (2012) that reported results of a 3‑year retrospective study of 40\xa0eyes with choroidal neovascularisation associated with pathological myopia. The mean number of injections in the study was 2.4 in year\xa02. The ERG suggested that 1.7\xa0injections in year\xa02 would be a more reasonable assumption than the 1\xa0injection in year\xa02 assumed in the manufacturer's model.\n\nThe ERG commented that the costs of blindness may have been overestimated. This was driven by the different costs of residential care calculated by the ERG and the manufacturer. The ERG suggested that a cost of blindness of £7510 in the first year and £7429 in each subsequent year, based on 2011 Personal and Social Services Research Unit costs and 30% of people being privately funded, was a more reasonable assumption.\n\nThe ERG noted that there were health state probabilities included in the manufacturer's model that were populated by relatively few patients. It was unsure whether the trials provided sufficient patient‑level data to be able to sensibly populate a model with 8\xa0health states and a 64\xa0cell transition probability matrix. Therefore the ERG was concerned about the reliability of the manufacturer's probability modelling.\n\nThe ERG noted some uncertainty about the use of mortality multipliers in the manufacturer's model. It stated that the definition of visual impairment in Christ et al. (2008), which was used by the manufacturer as a source of the multipliers, was ambiguous.\n\nThe ERG noted that EQ‑5D data were collected in RADIANCE but were not included in the manufacturer's submission. The ERG requested the EQ‑5D data during the clarification process and these were provided by the manufacturer. The ERG commented that the data indicated that changes in the BCVA of the worse‑seeing eye had no impact on patients' health‑related quality of life.\n\nThe ERG stated that the manufacturer's assumption that treatment benefit would continue indefinitely was optimistic. The ERG performed exploratory analyses that incorporated alternative durations of treatment benefit of 1, 5, 10 and 20\xa0years. This caused the net savings, QALYs and health benefits to decrease compared with those in the manufacturer's model. Ranibizumab remained dominant compared with vPDT even for a 1\xa0year duration of treatment benefit.\n\nThe ERG highlighted minor errors in the manufacturer's model, in the calculation of the quarterly proportion of patients worsening, derived from natural history data. These errors were acknowledged in the manufacturer's clarification responses. The ERG corrected the errors in their exploratory analysis of the manufacturer's model.\n\nThe ERG conducted an exploratory analysis which involved the following modifications to the manufacturer's model:\n\nBrown et al. (1999) as a source of utility values in addition to Czoski‑Murray et al. (2009)\n\nchanged the dose of ranibizumab in year\xa02 from 1 to 1.7\n\nchanged the costs of blindness from £17,326 in year\xa01 and £17,245 in each subsequent year to £7510 and £7429 respectively\n\nchanged the mortality multiplier for blindness (BCVA of 35\xa0letters or less) from 1.54 to 1.48\n\ncorrected the calculation of the quarterly proportion of patients worsening.\n\nIn the ERG's exploratory analysis, ranibizumab dominated vPDT. The total cost of ranibizumab was £10,055 and of vPDT was £12,529 (incremental cost −£2474). Using utility values from Brown et al. (1999), the total QALYs were 14.514 for ranibizumab and 14.170 for vPDT (incremental QALYs 0.344). Using utility values from Czoski‑Murray et al. (2009), the total QALYs were 13.105 for ranibizumab and 12.838 for vPDT (incremental QALYs 0.266).\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of choroidal neovascularisation associated with pathological myopia and the value placed on the benefits of ranibizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the current management of visual impairment caused by choroidal neovascularisation associated with pathological myopia. The clinical specialist stated that verteporfin photodynamic therapy (vPDT) has been used since 2005, and before this, no treatment was available. It heard from the clinical specialist that vPDT is not effective in most patients. The Committee discussed the use of vPDT and noted that its use is now diminishing because of the anti‑vascular endothelial growth factor (anti‑VEGF) treatments, such as ranibizumab and bevacizumab. It noted that bevacizumab is used outside of its marketing authorisation and has to be formulated under a 'specials' licence. It concluded that a licensed alternative treatment to vPDT for visual impairment caused by choroidal neovascularisation with pathological myopia would be welcomed by clinicians and patients.\n\nThe Committee considered the impact of visual impairment caused by choroidal neovascularisation with pathological myopia on the everyday life of patients. The Committee understood from the patient expert that the condition affects a younger group of patients compared with other eye conditions and so affects the ability to work, drive, and care for children or other dependents. It heard from the patient expert that loss of vision has a significant effect on the independence of people with the condition and can lead to depression. The Committee agreed that loss of vision caused by choroidal neovascularisation seriously impairs quality of life.\n\nThe Committee considered the comparators for this appraisal. The Committee expressed concern that the manufacturer had not included bevacizumab as a comparator. It noted that the scope listed vPDT and bevacizumab as comparators, although it was aware that bevacizumab does not have a marketing authorisation for treating visual impairment caused by choroidal neovascularisation associated with pathological myopia. The Committee noted that appropriate comparators should be established practice in England. This is not intended to be restrictive, but to emphasise the need for comparison with all relevant comparators; any drug in routine use or considered to be best practice should be considered a potential comparator. The Committee heard from the manufacturer that it considered that bevacizumab was not an appropriate comparator because its use in the NHS is not routine or best practice. The Committee heard from the patient expert and clinical specialist that bevacizumab is used in some patients, but only after some delay to agreement for funding. The Committee noted that the written statements submitted by the Royal College of Ophthalmologists, the Royal College of Pathologists, and the Macular Society suggested considerable use of bevacizumab in the NHS for this indication. The Committee also noted that there are 2\xa0trials (see section 4.7) that compared ranibizumab with bevacizumab in choroidal neovascularisation associated with pathological myopia. However, both of these had a small number of patients. The Committee heard from the clinical specialist that there are some residual safety concerns with the use of bevacizumab, but considered these to be minor. It was aware of the conclusions of the Decision Support Unit report (Bevacizumab in eye conditions: Issues related to quality, use, efficacy and safety), which stated that adverse event rates were low in all bevacizumab and comparator groups. However, the Committee also noted that the use of bevacizumab in the eye had not been assessed by the regulatory agencies. It agreed that bevacizumab was a legitimate potential comparator with respect to its use in the NHS. The Committee concluded that because the available evidence for bevacizumab in this indication was limited to 2\xa0small trials, there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and cost‑effectiveness analysis, but it did not rule out the possibility of future evidence providing that confidence.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. The Committee acknowledged that the evidence was primarily from RADIANCE, which compared ranibizumab with vPDT, and was complemented by evidence from 2\xa0other randomised trials that compared ranibizumab with bevacizumab, even though the manufacturer did not present the data for the bevacizumab arms of these trials in its submission. The Committee noted that ranibizumab was associated with a greater improvement than vPDT in best corrected visual acuity (BCVA) between baseline and months\xa01–3. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia.\n\nThe Committee discussed the primary end point of RADIANCE, which was the mean average change in BCVA between baseline and months\xa01–3. The Committee heard from the clinical specialist that 3\xa0months was not a long time period to assess the longer term benefits of ranibizumab. However, the other studies of ranibizumab and the long‑term follow‑up of its use in other eye conditions suggest a sustained effect. The Committee concluded that, because the clinical effectiveness of ranibizumab was not compared with vPDT after 3 months in RADIANCE, there is uncertainty about the long‑term efficacy of ranibizumab for visual impairment caused by choroidal neovascularisation associated with pathological myopia.\n\nThe Committee considered the 2\xa0trials presented in the manufacturer's submission that compared the use of ranibizumab and bevacizumab in choroidal neovascularisation associated with pathological myopia. The Committee noted that this was in line with the scope, in which bevacizumab was included as a comparator. The Committee heard from the clinical specialist that the 2\xa0trials, although small, showed ranibizumab and bevacizumab to be equally effective. It was aware that the manufacturer presented only the results from the ranibizumab arms of these trials in their submission and that the Evidence Review Group (ERG) had presented the results from the bevacizumab arms in their report (see section 3.19). The Committee concluded that ranibizumab is likely to be as clinically effective as bevacizumab in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia.\n\nThe Committee considered the trial evidence for adverse events associated with ranibizumab. The Committee discussed whether geographic atrophy was under‑reported because markers of this effect were not measured in RADIANCE. The clinical specialist argued that there was no particular reason to expect geographic atrophy as a side effect of ranibizumab treatment. The Committee was aware that the main adverse events listed in the summary of product characteristics were eye pain, ocular hyperaemia, increased intraocular pressure, vitritis, and vitreous detachment. The Committee agreed that the evidence suggested manageable adverse events with ranibizumab, and concluded that ranibizumab was safe and well tolerated in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia.\n\n# Cost effectiveness\n\nThe Committee considered the cost‑effectiveness evidence presented in the manufacturer's submission, including the base‑case results, the sensitivity and scenario analyses and the ERG's critique of the manufacturer's evidence. It noted that the manufacturer had not included bevacizumab as a comparator in its economic model. The Committee understood that the manufacturer's base‑case analysis showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more quality‑adjusted life years (QALYs; 13.18 compared with 12.75) and lower costs (£9694 compared with £12,455).\n\nThe Committee accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer. In particular, the Committee queried:\n\nthe larger proportion of patients with subfoveal involvement at baseline in the VIP trial than in the RADIANCE trial\n\nthe assumption of an indefinite duration of benefit of ranibizumab treatment\n\nthe low number of ranibizumab injections needed in year\xa02 of treatment\n\nthe high estimated costs of blindness\n\nthe low estimated costs of ranibizumab and vPDT administration\n\nthe lack of clarity about the source of the mortality multipliers used in the model\n\nthe underestimated changes in net QALY gains and the cost of blindness resulting from the method used to account for the possibility of the treated eye changing from being the better‑seeing eye to being the worse‑seeing eye\n\nthe use of Czoski‑Murray et al. (2009) as a source of utility values, rather than the EQ‑5D data collected in RADIANCE.The Committee considered each of these issues in turn, as detailed below.\n\nThe Committee considered the clinical‑effectiveness data that were used in the manufacturer's economic model. It recognised that the clinical‑effectiveness data for ranibizumab were derived from RADIANCE and the data for vPDT after 3\xa0months were derived from the VIP trial. The Committee noted that there was a larger proportion of patients at baseline with subfoveal involvement in VIP compared with RADIANCE and it was concerned that this might have had an impact on the model. The Committee heard from the clinical specialist that an imbalance would only be clinically relevant if it was in the number of patients with extra‑foveal involvement, and that this did not appear to be the case. The Committee concluded that the imbalance in the number of patients with subfoveal involvement in RADIANCE and VIP was unlikely to have a large impact on the manufacturer's model.\n\nThe Committee discussed the manufacturer's assumption that the average BCVA gain at the end of year\xa01 would continue indefinitely. The Committee heard from the clinical specialist that data collected at the 3\xa0time points in RADIANCE showed that the benefit of ranibizumab was maintained for at least 12\xa0months. The Committee noted that the ERG's sensitivity analyses included different durations of treatment benefit, and that ranibizumab dominated vPDT even when the duration of treatment benefit was reduced to 1\xa0year. The Committee concluded that the duration of treatment benefit was likely to be less than the manufacturer's assumption of an indefinite duration, and that ranibizumab dominated vPDT when the duration of effect was reduced.\n\nThe Committee discussed the manufacturer's assumption about the number of ranibizumab injections that people would receive in clinical practice. The Committee heard from the clinical specialist that, on average, patients only need ranibizumab injections in the first 3\xa0months of their first year of treatment. The clinical specialist also stated that patients in the REPAIR trial had well preserved eyesight after 18\xa0months and did not need further treatment. The Committee noted that the ERG had increased the number of ranibizumab injections in the second year of ranibizumab treatment from 1.0 to 1.7 in its exploratory analysis. Based on experience with patients using ranibizumab, the clinical specialist felt that this number could be too high. The Committee concluded that the number of injections included in the manufacturer's base case could be an underestimate and that even if the number of injections was increased, ranibizumab would continue to dominate vPDT.\n\nThe Committee considered the costs of blindness used in the manufacturer's economic model. It noted that the ERG presented lower costs of blindness in their report. The Committee heard from the ERG that the difference in the costs of blindness was mainly related to the way the costs for private residential care were calculated. The Committee noted that the manufacturer's sensitivity analysis showed that the model was not sensitive to changes in the costs of blindness. The Committee concluded that the ERG's assumptions about the costs of blindness were likely to be more realistic than those used by the manufacturer, and that if the ERG's assumptions had been used, ranibizumab would continue to dominate vPDT.\n\nThe Committee discussed the administration costs of ranibizumab used in the manufacturer's economic model. It noted that these costs were likely to be an underestimate of the true costs incurred in the NHS. The Committee recognised that the manufacturer's sensitivity analysis showed that the model was not sensitive to changes in the administration costs. The Committee concluded that although some uncertainty remained about the NHS costs involved in the administration of ranibizumab, the uncertainty was not great enough to affect the dominance of ranibizumab over vPDT.\n\nThe Committee discussed the mortality multipliers that the manufacturer had used in its economic model. It heard from the ERG that the source of some of the mortality multipliers was unclear. The ERG also stated that changing the mortality multipliers to alternative values had little impact on the cost savings or QALYs for ranibizumab. The Committee concluded that the manufacturer's rationale for some of the mortality multipliers used in their model was unclear, and that any changes to them were unlikely to change the dominance of ranibizumab over vPDT.\n\nThe Committee considered the method used in the manufacturer's economic model to account for the possibility of the treated eye changing from being the better‑seeing eye to being the worse‑seeing eye as patients changed health states. The Committee understood that the way the manufacturer had modelled this seemed to underestimate the changes in net QALY gains and costs of blindness that may arise from the more effective treatment. The Committee noted that it was not possible to quantify the size of the effect on the base‑case analysis. The Committee concluded that the modelling of the treated eye changing from being the better‑seeing eye to being the worse‑seeing eye as patients changed health states may have had an impact on the base‑case analysis, which showed that ranibizumab dominated vPDT, although the level of impact remained unclear.\n\nThe Committee discussed the utility values used in the manufacturer's economic model. The Committee noted that the source of utility data used in the base‑case analysis (Czoski‑Murray et al. 2009) was used in Ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance\xa0274), Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance\xa0283), and Aflibercept solution for injection for treating wet age-related macular degeneration (NICE technology appraisal guidance 294). It was aware that EQ‑5D data were also collected in RADIANCE, but these data were not used in the model. The Committee heard from the manufacturer that the EQ‑5D data from RADIANCE were not included because the EQ‑5D is widely recognised as not being sensitive in studies of eye conditions. The Committee heard from the ERG that using the EQ‑5D data collected in RADIANCE did not have a large effect on the model, although the effect for the worse‑seeing eye was not clear. The Committee concluded that using the EQ‑5D data from RADIANCE was unlikely to change the overall results of the base‑case analysis and that ranibizumab would continue to dominate vPDT.\n\nThe Committee noted that the manufacturer's model had not included bevacizumab as a comparator and so the base‑case analysis was limited to a comparison of ranibizumab with vPDT. However, because the available evidence for bevacizumab in this indication was limited to 2\xa0small trials (see section 4.4), there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and cost‑effectiveness analysis. The Committee considered the uncertainties in the manufacturer's model and noted that they did not have an effect on the overall results of the base‑case analysis, which showed that ranibizumab dominated vPDT. The Committee concluded that ranibizumab was a cost‑effective use of NHS resources for treating people with visual impairment caused by choroidal neovascularisation associated with pathological myopia when vPDT was the comparator.\n\nThe Committee discussed how innovative ranibizumab is in its potential to make a significant and substantial impact on health‑related benefits. It agreed that anti‑VEGF treatments, such as ranibizumab, were a substantial improvement over previous treatments, and considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was a step forward in providing health‑related patient benefits, not the act of licensing. In addition there were no substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling.\n\nThe Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. No equality issues were raised during the appraisal process or at the Committee meeting. Therefore the Committee concluded that no alterations or additions to its recommendations were needed.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA298\n\nAppraisal title: Ranibizumab for treating choroidal neovascularisation associated with pathological myopia\n\nSection\n\nKey conclusion\n\nRanibizumab is recommended as an option for treating choroidal neovascularisation associated with pathological myopia when the manufacturer provides ranibizumab with the discount agreed in the patient access scheme.\n\nThe clinical evidence from RADIANCE, which compared ranibizumab with vPDT, showed that ranibizumab was associated with a greater improvement than vPDT in best corrected visual acuity between baseline and months 1–3, although there is uncertainty about the efficacy after 3 months. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia.\n\nThe key drivers of the cost‑effectiveness analysis included the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits and the maximum utility gain in the worse‑seeing eye. The manufacturer's base‑case cost‑effectiveness analysis showed that ranibizumab dominated vPDT, resulting in more QALYs and lower costs. The Committee concluded that the uncertainties associated with the key drivers in the model were unlikely to have an effect on the overall cost‑effectiveness results. The Committee therefore recommended ranibizumab as a cost‑effective use of NHS resources.\n\n, 3.4, 3.15–3.16, 4.5–4.6, 4.9, 4.19\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard that visual impairment caused by choroidal neovascularisation seriously impairs quality of life.\n\nThe Committee heard that the current standard treatment for choroidal neovascularisation secondary to pathological myopia is vPDT. However, it is not effective in most patients and its use is diminishing because of anti‑VEGF treatments.\n\nThe Committee heard from a clinical specialist that the non‑licensed use of bevacizumab in the NHS is not routine or best practice. However, written statements from the Royal College of Ophthalmologists, the Royal College of Pathologists, and the Macular Society suggested considerable use of bevacizumab in the NHS for this indication.\n\nThe Committee heard from the patient expert and the clinical specialist that there are often delays in agreements to fund ranibizumab or bevacizumab.\n\n–4.4\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee agreed that anti‑VEGF treatments (such as ranibizumab) were a substantial improvement over previous treatments.\n\nIt was not aware of any substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee assessed the clinical effectiveness of ranibizumab compared with vPDT for treating visual impairment caused by choroidal neovascularisation associated with pathological myopia.\n\n\n\nAdverse reactions\n\nThe Committee was aware that the main adverse events listed in the summary of product characteristics were eye pain, ocular hyperaemia, increased intraocular pressure, vitritis, and vitreous detachment. The Committee agreed that the evidence suggested manageable adverse events with ranibizumab, and concluded that ranibizumab was safe and well tolerated in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee acknowledged that the evidence presented by the manufacturer was primarily from RADIANCE, which compared ranibizumab with vPDT. This evidence was complemented by data from the ranibizumab arm of 2 other randomised trials.\n\nThe Committee was aware that the scope of the appraisal listed bevacizumab as a comparator. It noted that the ERG identified only 2 small trials that compared ranibizumab and bevacizumab. The Committee concluded that there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and cost‑effectiveness analysis.\n\n–4.5\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard that the current standard treatment for visual impairment caused by choroidal neovascularisation secondary to pathological myopia is vPDT. However, it is not effective in most patients and its use is diminishing because of anti‑VEGF treatments, such as ranibizumab and bevacizumab.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted that the primary end point of RADIANCE was the mean average change in BCVA between baseline and months 1–3. The Committee heard from a clinical specialist that 3 months was not a long time period to assess the longer term benefits of ranibizumab. The Committee concluded that, because the clinical effectiveness of ranibizumab was not compared with vPDT after 3 months, there is uncertainty about the long‑term efficacy of ranibizumab for choroidal neovascularisation associated with pathological myopia.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that ranibizumab was associated with a greater improvement than vPDT in BCVA between baseline and months 1–3. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. It accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer.\n\nThe Committee noted that the manufacturer had not included bevacizumab as a comparator in its economic model.\n\n–4.10\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered the larger proportion of patients with subfoveal involvement in the VIP trial, which provided the vPDT data after 3 months. However, it concluded that the imbalance between RADIANCE and VIP was unlikely to have a large impact on the manufacturer's model.\n\nThe Committee considered the manufacturer's assumption that the average BCVA gain at the end of year 1 would continue indefinitely. It concluded that the duration of treatment benefit was likely to be less than the manufacturer's assumption of an indefinite duration, but that ranibizumab dominated vPDT when the duration of effect was reduced.\n\nThe Committee discussed whether the manufacturer's assumption about the number of ranibizumab injections that people would receive in clinical practice was too low. It concluded that the number of injections included in the manufacturer's base case could be an underestimate, and that even if the number of injections was increased, the base‑case analysis would not be affected.\n\nThe Committee discussed whether the costs of blindness used in the manufacturer's model were too high. The Committee noted that the ERG presented lower costs of blindness in their report. The Committee concluded that the ERG's assumptions about the costs of blindness were likely to be more realistic than those used by the manufacturer, and that any changes were unlikely to have a large impact on the base‑case analysis.\n\nThe Committee discussed whether the administration costs of ranibizumab used in the manufacturer's model were an underestimate. It concluded that the NHS costs were uncertain, but the uncertainty was not great enough to affect the base‑case analysis.\n\nThe Committee discussed whether the mortality multipliers used in the manufacturer's economic model were appropriate. It concluded that the manufacturer's rationale for some of the mortality multipliers in the model was unclear, and that any changes to them were unlikely to change the base‑case analysis.\n\nThe Committee discussed whether the method used in the manufacturer's model to account for the possibility of the treated eye changing from being the better‑seeing eye to the worse‑seeing eye as patients change health states was appropriate. It concluded that the modelling may have had an impact on the base‑case analysis, but the level of impact was unclear.\n\nThe Committee considered that EQ‑5D data were collected in RADIANCE, but were not used in the manufacturer's economic model. It concluded that using the EQ‑5D data from RADIANCE was unlikely to change the overall results of the base‑case analysis.\n\n–4.18\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that the EQ‑5D data collected in RADIANCE was not used in the model and the manufacturer used utility values from Czoski‑Murray et al. (2009), in line with previous appraisals of drugs for eye conditions. The Committee heard from the ERG that using the EQ‑5D data from RADIANCE did not have had a large effect on the model, although the effect for the worse‑seeing eye was not clear. The Committee concluded that using the EQ‑5D data from RADIANCE was unlikely to change the overall results of the base‑case analysis.\n\nThe Committee was not aware of any substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling.\n\n, 4.20\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe manufacturer's sensitivity analyses showed that the cost effectiveness of ranibizumab was sensitive to changes in the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits, and the maximum utility gain in the worse‑seeing eye.\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe Committee noted that manufacturer's base‑case analysis showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more QALYs (13.18 compared with 12.75) and lower costs (£9694 compared with £12,455). The Committee considered the uncertainties in the manufacturer's model and noted that they were unlikely to have an effect on the overall results of the base‑case analysis, which showed that ranibizumab dominated vPDT.\n\n, 4.11–4.18, 4.19\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe Department of Health and the manufacturer have agreed that ranibizumab will be available to the NHS with a patient access scheme which makes ranibizumab available with a discount. The level of discount is commercial in confidence.\n\n\n\nEnd‑of‑life considerations\n\nNot applicable\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were raised during the appraisal process or at the Committee meeting. Therefore the Committee concluded that no alterations or additions to its recommendations were needed.\n\n", 'Related NICE guidance ': 'Details are correct at the time of publication. Further information is available on the NICE website.\n\nAflibercept solution for injection for treating wet age-related macular degeneration. NICE technology appraisal guidance 294 (2013).\n\nRanibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 283 (2013).\n\nRanibizumab for the treatment of diabetic macular oedema (rapid review of TA237). NICE technology appraisal guidance 274 (2013).\n\nFluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema after an inadequate response to prior therapy. NICE technology appraisal guidance 271 (2013).\n\nDexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion.\xa0NICE technology appraisal guidance 229 (2011).\n\nRanibizumab and pegaptanib for the treatment of age-related macular degeneration.\xa0NICE technology appraisal guidance 155 (2008).\n\nGuidance on the use of photodynamic therapy for age-related macular degeneration.\xa0NICE technology appraisal guidance 68 (2003).', 'Review of guidance': 'The guidance on this technology will be considered for review in March 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveNovember 2013', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt has been incorporated into the NICE pathway on eye conditions along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0362-7'}	https://www.nice.org.uk/guidance/ta298	Evidence-based recommendations on ranibizumab (Lucentis) for treating choroidal neovascularisation associated with pathological myopia in adults.
807f5b8d406014c918b33d1410c9135e8c02d719	nice	Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people	Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people Evidence-based recommendations on peginterferon alfa (Pegasys; ViraferonPeg) and ribavirin (Copegus) for treating chronic hepatitis C in children and young people. # Guidance This guidance updates and replaces: section 1.7, bullet 2 only, of NICE technology appraisal guidance 75 (TA75) 'Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C' part of section 1.6 of NICE technology appraisal guidance 106 (TA106) 'Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C'. Peginterferon alfa in combination with ribavirin is recommended, within its marketing authorisation, as an option for treating chronic hepatitis C in children and young people.# Clinical need and practice Hepatitis C is a disease of the liver caused by the hepatitis C virus (HCV). The presence of HCV RNA (ribonucleic acid) in serum indicates infection. There are 2 main phases of infection: acute and chronic. Acute hepatitis C refers to the period immediately after infection, whereas chronic hepatitis C is defined as infection that lasts for more than 6 months. In the UK, there are 2 major routes of HCV transmission: sharing needles in intravenous drug misuse and receiving transfusions of infected blood or blood products. However, children acquire the virus primarily from their mothers at birth. Breast feeding does not appear to increase the risk of HCV transmission. Six main genetic types of HCV, known as genotypes 1 to 6, with further subtyping (a–j) have been found. In England and Wales genotypes 1 and 3 account for more than 90% of all diagnosed infections. The effectiveness of antiviral treatment depends on the viral genotype; the response is generally better in people infected with genotypes 2 or 3 than in those infected with genotypes 1, 4, 5 or 6. Infection with HCV can lead to complications, including hepatic dysfunction, hepatic cirrhosis, hepatocellular carcinoma and death. Progression to severe hepatitis or cirrhosis during childhood is rare (less than 5%) and the mean time to development of cirrhosis in people infected as infants is estimated to be 28 years. Estimates from the Health Protection Agency in 2011 show that HCV was newly diagnosed in 26 people aged 1 year or younger and 21 people aged 1–14 years in England in 2010. Estimates for chronic infection in children and young people in the UK are not available. The aim of treatment is to clear the virus from the blood. Sustained virological response, defined as undetectable serum HCV RNA 6 months after the end of treatment, usually indicates resolved infection, although relapse occurs in approximately 5% of people after 5 years.# The technologies Peginterferon alfa‑2a (Pegasys, Roche Products) in combination with ribavirin has a UK marketing authorisation for the treatment of children and adolescents 5 years of age and older with chronic hepatitis C, who test positive for serum hepatitis C virus (HCV) ribonucleic acid (RNA) and who have not previously received any treatment. Peginterferon alfa‑2a is administered subcutaneously once weekly. The dose depends on body surface area, and it should not be used in children with a body surface area of less than 0.71 m2 (for whom there are no data). The recommended treatment duration is 24 weeks (genotypes 2 or 3) or 48 weeks (all other genotypes) depending on baseline viral load and whether or not a child has a virological response (defined as a 100‑fold decrease in, or undetectable levels of, serum HCV RNA) at week 24. Virological response by week 24 is predictive of sustained virological response. If adverse reactions occur, the dose can be reduced. Peginterferon alfa‑2b (ViraferonPeg, Merck Sharp and Dohme ) in combination with ribavirin has a UK marketing authorisation for the treatment of children aged 3 years and older and adolescents who have chronic hepatitis C without hepatic decompensation, who test positive for serum HCV RNA and who have not previously received any treatment. Dosing of peginterferon alfa‑2b for children and adolescents is determined by body surface area and the recommended dose is 60 micrograms/m2 per week subcutaneously in combination with ribavirin. The recommended treatment duration is 48 weeks for children and adolescents with genotype 1 or 4. Treatment should be stopped after 12 weeks if serum HCV RNA decreases less than 100‑fold compared with pre-treatment levels or if serum HCV RNA is detectable at week 24. For children and adolescents with genotype 2 or 3, treatment is 24 weeks. If adverse reactions occur, the dose can be reduced. Ribavirin (manufactured as Copegus by Roche Products) has a marketing authorisation in combination with peginterferon alfa‑2a or interferon alfa‑2a for treating chronic hepatitis C; the marketing authorisation for Copegus does not include specific recommendations for use in children and young people. Copegus is available as 200‑mg or 400‑mg tablets. Ribavirin manufactured by MSD (as Rebetol) has a marketing authorisation in combination with peginterferon alfa‑2b or interferon alfa‑2b for treating chronic hepatitis C in children and young people aged 3 years and older. Rebetol is available as an oral solution and 200‑mg hard capsules. The recommended dose of either ribavirin in combination with peginterferon alfa‑2a or ‑2b is based on body weight; the average daily dose is 15 mg/kg, given in 2 doses. The most common adverse reactions to ribavirin include anaemia, dry cough and rash. Peginterferon alfa‑2a and ‑2b are contraindicated for treating chronic hepatitis C in children and young people with a history of severe psychiatric conditions. The summaries of product characteristics for peginterferon alfa‑2a and ‑2b mention the following adverse reactions in children and young people: severe psychiatric and central nervous system effects (particularly depression, suicidal ideation and attempted suicide), weight loss and growth inhibition. The summaries of product characteristics state that, when deciding not to defer treatment until adulthood, it is important for clinicians to consider that combination therapy may inhibit growth and that it is uncertain whether this effect is reversible. Therefore the summaries of product characteristics suggest that a child or young person is treated before or after the pubertal growth spurt whenever possible. For full details of adverse reactions and contraindications, see the summaries of product characteristics. The price of peginterferon alfa‑2a is £107.76 for a 135‑microgram prefilled syringe or pen and £124.40 for a 180‑microgram prefilled syringe or pen (excluding VAT; 'British national formulary' edition 65). The price of peginterferon alfa‑2b is £1.33 per microgram and it is available in 50-, 80-, 100-, 120- and 150‑microgram pens costing £66.46, £106.34, £132.92, £159.51 and £199.38 respectively (BNF edition 65). The Assessment Group calculated that, based on an average age of 11 years, a body weight of 35.5 kg and a body surface area of 1.19 m2, a 24‑week course of peginterferon alfa‑2a plus ribavirin costs approximately £3700 and a 48‑week course of treatment costs approximately £7400; a 24‑week course of peginterferon alfa‑2b plus ribavirin oral solution costs approximately £4000 and a 48‑week course of treatment costs approximately £8100. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (section 8) considered evidence from several sources (section 9). # Clinical effectiveness The Assessment Group focused on 5 specific questions to determine the following: sustained virological response to treatment biochemical response to treatment histological response to treatment change in quality of life adverse reactions to treatment, including effects on growth. The Assessment Group identified 1 randomised controlled trial and 1 single‑arm trial evaluating peginterferon alfa‑2a and ribavirin. The randomised controlled trial (Schwarz et al. 2011) was the pivotal regulatory trial for treatment in people aged 5–18 years with chronic hepatitis C. Because the comparator arm was peginterferon monotherapy (that is, without ribavirin), it did not meet the inclusion criteria for the appraisal. Therefore, the Assessment Group used data from the intervention arm (n=55), treating it as an uncontrolled observational study. The single-arm trial (Sokal et al. 2010, n=65) included children and young people aged 6–17 years. For peginterferon alfa‑2b and ribavirin, the Assessment Group identified 5 single‑arm studies. A single‑arm clinical trial evaluating peginterferon alfa‑2b and ribavirin (Wirth et al. 2010, n=107) included children and young people aged 3–17 years. The other 4 studies included populations with narrower age ranges than those specified in the UK marketing authorisation (Al Ali et al. 2010, single-arm trial ; Ghaffar et al. 2009 ; Jara et al. 2008 ; Pawlowska et al. 2010 ). The duration of the trials in the Assessment Group's efficacy review ranged from 24–52 weeks. The Assessment Group found no studies in children or young people co‑infected with HIV. The Assessment Group considered that the quality of the included studies was generally poor because they lacked control groups, except for the study by Schwarz et al., in which the comparison arm was not relevant to this appraisal. The Assessment Group showed that, among other uncertainties, conducting an accurate assessment of the generalisability of the studies was difficult because of substantial variation in the patient inclusion criteria and the countries represented. The primary outcome of the 7 studies was sustained virological response defined as undetectable serum hepatitis C virus (HCV) ribonucleic acid (RNA) at 24 weeks after the end of treatment (in both peginterferon alfa‑2a studies and 4 peginterferon alfa‑2b studies) or 12 months after the end of the treatment (Ghaffar et al. study of peginterferon alfa‑2b). Concentrations of serum HCV RNA at baseline varied across the 7 included studies. For the 2 peginterferon alfa‑2a studies, the sustained virological responses were 53% and 66% in Schwarz et al. and Sokal et al. respectively. For the 5 peginterferon alfa‑2b studies, sustained virological response to treatment ranged from 29 to 75%, and proportions in 3 of the studies were comparable to responses seen in the peginterferon alfa‑2a studies (Pawlowska et al., 49% ; Wirth et al., 65% ; Jara et al., 50% ). The 2 studies (Schwarz et al., Sokal et al.) evaluating peginterferon alfa‑2a showed that patients with genotype 2 or 3 were more likely to have a sustained virological response than patients with other genotypes (80 to 89% compared with 47 to 57%). In studies evaluating peginterferon alfa‑2b, the proportions with a sustained virological response were similar for genotype 1, ranging from 46 to 53%, whereas the proportions achieved for genotype 2 or 3 and genotype 4 varied (50 to 100% and 0 to 80% respectively). Both peginterferon alfa‑2a studies (Schwarz et al., Sokal et al.) and 1 peginterferon alfa‑2b study (Wirth et al.) reported sustained virological responses according to baseline viral load. The results suggest that children and young people with a low baseline viral load (less than 500,000 IU/ml, or 600,000 IU/ml or less) appear to have higher proportions of sustained virological responses (range 70–79%) than those with a higher viral load (more than 500,000 IU/ml, or 600,000 IU/ml or more, range 49–55%). Sokal et al. and Wirth et al. reported that a higher proportion of children and young people with genotype 2 or 3 had a sustained virological response compared with those with genotype 1, 4, 5 or 6, regardless of viral load. Wirth et al. reported that, in people with genotype 1, the proportion having a sustained virological response was higher in those with low baseline viral load than in those with high baseline viral load (72% compared with 29%, p=0.0006). The proportions of sustained virological responses in 2 of the studies presented were higher in children and young people who had not been previously treated (55–62%) compared with those who had been previously treated (17–33%). The Pawlowska et al. study presented sustained virological response by genotype subgroup, but the numerators in each subgroup did not add up correctly to the total number of treatment-naive and previously treated patients in the trial (because study participants with genotype 3 HCV were excluded), and the numbers in these subgroups were small. Three studies reported the proportion of sustained virological responses according to activities of alanine aminotransferase in serum at baseline. In the 2 peginterferon alfa‑2a studies (Schwarz et al.; Sokal et al.), the proportion of sustained virological responses was higher in those with lower alanine aminotransferase activities at baseline (range 70–80%) compared with those who had higher baseline serum alanine aminotransferase activities (range 41–58%). Sokal et al. showed that, in children and young people with lower baseline alanine aminotransferase activities, sustained virological response did not differ by genotype. However, for children and young people with elevated baseline alanine aminotransferase activities, those with genotype 2 or 3 had a higher proportion of sustained virological responses than those with other genotypes. In the peginterferon alfa‑2b study (Wirth et al.), sustained virological response was similar in children and young people with lower and elevated alanine aminotransferase activities at baseline (67% and 64% respectively). Both the peginterferon alfa‑2a studies reported sustained virological response according to baseline liver histology. Of children and young people without hepatic fibrosis at baseline, 43% (Schwarz et al. study) and 76% (Sokal et al. study) had a sustained virological response, although the Assessment Group noted the limited numbers in the Schwarz et al. subgroup (n=7). The proportion of children and young people with some degree of fibrosis having a sustained virological response in the 2 studies was 53% and 60% (Schwarz et al. and Sokal et al. respectively). The proportion of children and young people whose hepatitis C relapsed was reported by Schwarz et al. (17%) and in 4 peginterferon alfa‑2b studies (8% in Al Ali et al.; 17% in Pawlowska et al.; 8% in Wirth et al. ; 3% in Jara et al.). Two of the peginterferon alfa-2b studies (Al Ali et al.; Jara et al.) did not specifically define relapse, but reported data that the Assessment Group inferred to be relapse of hepatitis C. Problems with growth and weight are listed as adverse reactions to treatment in the summary of product characteristics. One study of peginterferon alfa‑2a (Sokal et al.) and 3 studies of peginterferon alfa‑2b (Pawlowska et al.; Wirth et al.; Jara et al.) reported changes in height and weight during treatment. Sokal et al. reported that, at baseline and follow-up for height and weight, little influence on growth was seen. Pawlowska et al. reported that treatment with peginterferon alfa‑2b and ribavirin had no influence on height at 24 weeks after treatment or 2 years after follow-up. In the remaining 2 peginterferon alfa‑2b studies, growth rates decreased during treatment but subsequently recovered. Jara et al. observed that growth during the 48‑week treatment period was reduced in 85% of children and young people (22/26) by 1.6 cm compared with the growth velocity fiftieth percentile for age and sex. Growth velocity was described as normal in the 6‑month period after the end of treatment; however, patients did not regain their height percentile. Wirth et al. observed that 70% (75/107) of children and young people had an inhibited growth velocity to less than the third percentile for age and sex during treatment. Mean growth velocity was 2.47 cm per year during treatment and 5.73 cm per year in the follow-up period. The decrease in mean height percentile during treatment was greater in children and young people whose treatment duration was longer than in those whose treatment duration was shorter. The 3 studies of peginterferon alfa‑2b each reported that patients lost weight during treatment. Jara et al. observed that 67% (20/30) of children and young people lost weight, with 23% (7/30) losing more than 5% of their baseline weight. Weight gain occurred when treatment stopped. Pawlowska et al. observed that 43% (23/53) of patients lost more than 10% of their baseline weight. Wirth et al. reported that 19% (20/107) of children and young people lost weight, with a mean loss in the weight percentile of −15.5 during treatment and a mean gain of 12.3 during follow-up. The Schwarz et al. trial reported changes in quality of life after treatment with peginterferon alfa‑2a, assessed using the Child Health Questionnaire – Parent Form 50, and in child and adolescent behavioural and emotional functioning (using the Child Behaviour Checklist), depression (using the Children's Depression Inventory) and cognitive functioning (using the Behaviour Rating Inventory of Executive Function). The Child Health Questionnaire, Child Behaviour Checklist and Behaviour Rating Inventory of Executive Function instruments were all completed by the child's parent or guardian, whereas the child completed the Children's Depression Inventory. Most children and young people (86–95%) showed no changes in any of the measures of quality of life, behaviour, depression or executive function after 24 weeks of treatment. The exception was mean Child Health Questionnaire physical summary scores, which declined from baseline, indicating worse physical aspects of quality of life; 15% experienced a clinically significant decline and no patients experienced a clinically significant improvement (p=0.013 for changes in mean scores). However, after 1 or 2 years of follow-up, none of the children and young people who completed 48 weeks of treatment showed differences from baseline (p>0.05) for any of the quality-of-life outcome measures. None of the 5 studies of peginterferon alfa‑2b reported health-related quality-of-life outcomes. ## Assessment Group's critique of Roche's clinical-effectiveness submission According to the Assessment Group, Roche did not conduct a systematic review of clinical effectiveness. The bibliographic databases and search strategies provided by the manufacturer were not sufficiently detailed to permit the Assessment Group to reproduce the evidence. Roche provided clinical-effectiveness results primarily from Schwarz et al., Sokal et al. and 2 other uncontrolled trials, which did not meet the inclusion criteria for the decision problem because 1 study had a population older than that specified in the scope and the other study was retrospective and did not provide details of peginterferon dose or treatment duration. The Assessment Group commented that Roche did not report the methods it used to screen, extract or quality assess the literature. The Assessment Group noted that Roche reported comparative data for both arms of the study by Schwarz et al., even though peginterferon alfa‑2a monotherapy is outside the marketing authorisation and scope. The Assessment Group noted that the proportion of patients with a sustained virological response in Roche's submission were comparable with those seen in the assessment report. Roche did not report virological outcomes during treatment or health-related quality of life. Effects of treatment on weight, height and growth were reported only from the studies excluded from the Assessment Group's evaluation. Roche concluded that the evidence demonstrated that peginterferon alfa‑2a plus ribavirin was effective compared with best supportive care for all genotypes. The Assessment Group commented that, although Roche stated in its submission that there was no safety concern with regard to adverse reactions to peginterferon alfa‑2a, it reached this conclusion using data only from the Schwarz et al. study, in which both treatment arms received peginterferon alfa‑2a. ## Assessment Group's critique of Merck Sharp and Dohme's clinical-effectiveness submission MSD's submission reported a systematic review of clinical effectiveness that included 8 studies, but only presented study characteristics for 5. Of the 8 studies, 6 were among the Assessment Group's 7 studies: 4 for peginterferon alfa‑2b (Al Ali et al.; Jara et al.; Pawlowska et al.; Wirth et al.) and 2 for peginterferon alfa‑2a (Schwarz et al.; Sokal et al.). Of the studies included in the manufacturer's submission but excluded from the assessment report, 1 had included patients older than the age range specified in the scope and the other included patients who had previously received non-pegylated interferon. The MSD submission did not include the Ghaffar et al. study included in the assessment report. MSD's submission included data on growth inhibition and adverse events, and a meta-analysis that pooled data for sustained virological response, virological response at 24 weeks, relapse, discontinuation of treatment and selected adverse events. The Assessment Group commented that the sustained virological response rates included in MSD's submission were comparable with those in the assessment report, and that there was moderate to substantial heterogeneity in the meta-analyses (and therefore the interpretation of the results was unclear). MSD concluded that both peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin were effective compared with best supportive care, and that there were no clear differences between treatments. # Cost effectiveness The Assessment Group systematically reviewed existing economic evaluations of peginterferon alfa‑2a and peginterferon alfa‑2b treatment in children and young people with chronic hepatitis C. It identified a conference abstract and a paper, but neither met its criteria for inclusion. The Assessment Group also systematically reviewed the literature on health-related quality of life of people with chronic hepatitis C to populate the economic model with health-state utility values and calculate quality-adjusted life years (QALYs). It restricted searches to studies using EQ‑5D. The Assessment Group identified 2 published studies (Bjornsson et al. 2009, Chong et al. 2003) performed in adults with chronic hepatitis C in Sweden and Canada, but found no studies in children. The Assessment Group concluded that the estimates were sufficiently robust to use in its economic evaluation. ## Roche's economic model for peginterferon alfa‑2a plus ribavirin Roche submitted an economic evaluation using a Markov model with a structure similar to other models used to evaluate treatments for chronic hepatitis C in adults. Roche compared the costs and health outcomes of treatment with peginterferon alfa‑2a plus ribavirin with best supportive care (no drug treatment). Roche's model extrapolated the health effects of peginterferon alfa‑2a plus ribavirin in children and young people with hepatitis C reflecting the population characteristics of the clinical trials over a 30‑year time horizon. Children enter the model at an average age of 11 years in a model state of mild or moderate hepatitis C-related fibrosis (88% and 12% respectively), based on the weighted average of children and young people participating in the peginterferon alfa‑2a studies. Children and young people with HCV genotype 1, 4 or 5 whose disease has responded to treatment with peginterferon alfa‑2a plus ribavirin at 24 weeks receive treatment for 48 weeks. Children and young people with HCV genotype 2 or 3 are split into 2 groups to compare 24 weeks of treatment with 48 weeks of treatment. One group receives treatment for 24 weeks only and the other for 48 weeks (if their hepatitis C responds to treatment at 24 weeks). If treatment does not result in a sustained virological response, children and young people remain in their current health state or 'progress' to mild hepatic fibrosis, moderate hepatic fibrosis, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (liver cancer), liver transplantation or death. For transitions to decompensated cirrhosis, hepatocellular carcinoma and liver transplantation, Roche used transition probabilities from adults used in previous appraisals for chronic hepatitis C. Roche assumed that the mortality risks for those in the sustained virological response, mild hepatic fibrosis, moderate hepatic fibrosis and compensated cirrhosis states were the same as in the general population. Roche assumed that the mortality risks for people in the decompensated cirrhosis, hepatocellular carcinoma and liver transplantation states were similar to those of people with chronic liver disease. Roche's model also included a probability of spontaneous sustained virological response in untreated children: an annual probability of 2.37% for children with maternally transmitted HCV within the first 5 years and an annual probability of 1.65% for children with HCV acquired by other means. Based on the studies identified by Roche, 70% of children have maternally transmitted HCV and 30% have non-maternally transmitted HCV. Roche assumed that the most common adverse reactions seen in the studies, such as flu-like illness, chest infections, headache, and gastrointestinal and skin disorders, would impact on health-related quality of life, but not on costs. Roche did not include depression related to peginterferon alfa‑2a as an adverse reaction in the economic model. It assumed that the disutility from treatment with peginterferon alfa‑2a was equal to treatment with non-pegylated interferon, as seen in the Wright et al. (2006) study in adults. Roche's base-case analysis considered treatment-naive children and young people, as reflected in the peginterferon alfa‑2a studies and in accordance with the UK marketing authorisation. Roche also presented an analysis for a subgroup of patients whose disease does not respond to treatment and who are re-treated. The model evaluated costs from the perspective of the NHS and personal social services. Costs and health outcomes were discounted at a rate of 3.5% per annum, in accordance with the NICE reference case. Roche estimated the clinical effectiveness of treatment in the base case according to the weighted average percentages of patients who had a sustained virological response in the Schwarz et al. study and 3 uncontrolled studies: 59% for genotypes 1, 4, 5 and 6 with 48 weeks of treatment and 89% for genotypes 2 and 3 with 24 weeks of treatment. Roche included the cost of peginterferon alfa‑2a and ribavirin, as well as the cost of evaluating and monitoring patients. Administration costs were not included. The drug doses depended on age, body surface area and weight, and the base-case model assumed an average dose corresponding to the dosing regimen of the population in the Schwarz et al. trial using an age-related mean height and weight from the Health Survey for England 2010. In the base case, the estimated costs for 48 weeks of combination therapy were £8307. Roche assumed that patients do not share vials. Roche assumed that children and young people who have a sustained virological response would not incur any further costs related to chronic hepatitis C. Roche performed sensitivity analyses using assumptions from previous appraisals in which sustained virological response costs were £335 and follow-up surveillance costs for children and young people whose hepatitis C has responded in the first year were £165. For children and young people younger than 17 years, Roche applied a baseline utility of 0.95 in line with a study by Saigal et al. (1994). For the healthy population aged 17 years and older, the model applied utility values for adults, derived using an algorithm developed by Ara and Brazier (2009), in line with the EQ‑5D derived utility weights used in previous health technology assessments for adults with chronic hepatitis C. The mean utility value for sustained virological response after mild disease was 0.83, whereas the utility weight for having mild disease was 0.77 and for receiving peginterferon treatment for mild disease was 0.66. The mean utility value for moderate liver disease was 0.66 and for receiving treatment for moderate disease was 0.55, compared with 0.55 for compensated cirrhosis, 0.45 for either decompensated cirrhosis or hepatocellular carcinoma and 0.67 after liver transplantation. ## Results of Roche's economic model The cost-effectiveness result for Roche's base-case population for peginterferon alfa‑2a plus ribavirin compared with best supportive care was £3914 per QALY gained for children and young people with HCV genotype 1, 4 or 5. Peginterferon alfa‑2a plus ribavirin dominated (that is, was less costly and more effective than) best supportive care for children and young people with HCV genotype 2 or 3. The results from Roche's cost-effectiveness acceptability curves for its base-case populations showed that the probability that peginterferon alfa‑2a plus ribavirin treatment was cost effective compared with best supportive care at £20,000 per QALY gained for children and young people with HCV genotype 1, 4 or 5 treated for 48 weeks was 91.6%, and for children and young people with HCV genotype 2 or 3 treated for 24 weeks was 97.2%. Roche performed one-way and two-way deterministic analyses and found that the results were most sensitive to the time horizon, rate of disease progression, probability that a patient had a sustained virological response with treatment, liver disease at baseline, the value of the health-state utilities and annual cost of achieving sustained virological response. The cost effectiveness of peginterferon alfa‑2a compared with best supportive care remained below £13,000 per QALY gained for all analyses. ## Merck Sharp and Dohme's economic model for peginterferon alfa‑2b plus ribavirin MSD submitted a de novo economic evaluation based on previously published economic evaluations of the treatment of chronic hepatitis C in adults. It compared the costs and health outcomes of peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin for treating children and young people aged 3–17 years compared with best supportive care. The base‑case economic analysis included previously untreated children and young people aged 5–17 years without HIV co‑infection. Because peginterferon alfa‑2b has a marketing authorisation that also includes children aged 3–4 years, MSD conducted an additional subgroup analysis in this age group. It used a Markov model that follows a hypothetical cohort over a lifetime time horizon (up to age 100 years). People enter the model in the mild hepatitis C, moderate hepatitis C or compensated cirrhosis states and receive treatment in cycle 1 for 12, 24 or 48 weeks depending on stopping rules (whether a patient's disease responds during treatment) and genotype. The modelled health states are: mild liver fibrosis, moderate liver fibrosis, compensated cirrhosis of the liver, decompensated cirrhosis of the liver, hepatocellular carcinoma (liver cancer), liver transplantation or death. MSD used child-specific probabilities for transitions between the mild and moderate fibrosis states, and the moderate fibrosis and compensated cirrhosis states. Transition probabilities from studies in adults were used for more advanced hepatitis C health states. MSD assumed that the mortality risks for people in the sustained virological response, mild liver fibrosis, moderate liver fibrosis and compensated cirrhosis states were the same as for the general population. MSD assumed that children and young people in the decompensated cirrhosis, hepatocellular carcinoma and liver transplantation states have a higher mortality risk than the general population. MSD's base-case analysis considered treatment-naive children and young people using data from peginterferon alfa‑2b studies and in accordance with the UK marketing authorisation for peginterferon alfa‑2b. The model evaluated costs from the perspective of the NHS and personal social services. Costs and health outcomes were discounted at a rate of 3.5% per annum, in accordance with the NICE reference case. MSD modelled parameters reflecting the clinical effectiveness of peginterferon alfa‑2a and ‑2b plus ribavirin in the base case, using calculated weighted averages of the percentage of patients who had a sustained virological response from 8 trials (section 4.1.19). MSD included the costs of peginterferon alfa‑2a and ‑2b plus ribavirin, of investigations, and of monitoring during and after treatment. MSD did not include costs associated with treating adverse events, noting the precedent of Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (part review of NICE technology appraisal guidance 75 and 106) (NICE technology appraisal 200). Dosing depended on age, body surface area and weight. The average ages at model entry were 7 years (age 5–8 years; 30.8%), 11 years (age 9–13 years; 38.5%) and 16 years (age 14–17 years; 30.8%) and there was an equal distribution of males and females. For body weight and height, MSD derived its estimates from mean values from the UK World Health Organisation growth charts for 2009 and UK 1990 standard centile charts presented in BNF 63. MSD assumed that patients do not share vials. MSD used health-state costs presented in previous appraisals of adults because it did not identify any published evidence on costs associated with chronic hepatitis C in children and young people. The costs associated with having a sustained virological response for children and young people starting with mild to moderate hepatitis C were applied for 5 years in the model, while the costs associated with having a sustained virological response for children and young people starting with cirrhosis were applied over the person's lifetime. The costs associated with each health state were inflated to 2010/11 values using the Hospital and Community Health Services Pay and Price Index used in the economic model. Child-specific costs for resource use and monitoring while on treatment, including follow‑up visits after the completion of treatment, were also included in the model. Because there is no published evidence on health-related quality of life for children and young people with chronic hepatitis C, MSD used values for its economic analysis from previous NICE technology appraisals of adults with chronic hepatitis C. The utility values for patients with mild hepatitis C were elicited using the standard EQ‑5D time trade-off tariff from people with hepatitis C (Wright et al). The disutility value for treatment-emergent adverse reactions was also derived from this trial. People receiving peginterferon alfa‑2b plus ribavirin had a utility value of 0.77 at baseline and 0.66 when assessed at 12 and 24 weeks after starting treatment. MSD applied the resulting reduction in utility of 0.11 to all patients receiving peginterferon alfa‑2b in the model regardless of disease severity. MSD obtained utility values for patients with moderate and compensated cirrhosis from a multicentre observational study involving 302 patients with severe liver disease associated with chronic hepatitis (reported in Wright et al.). For the remaining health states, MSD used utility values from a prospective multicentre study by Longworth et al. (2004) assessing health-related quality of life before and after liver transplant in the UK. ## Results of Merck Sharp and Dohme's economic model The cost-effectiveness results for MSD's base-case population (age 5–17 years) suggested that both types of peginterferon alfa (2a and 2b) plus ribavirin dominated best supportive care, that is, were more effective and cost less. MSD obtained a similar result for children aged 3–4 years. Both types of peginterferon alfa (2a and 2b) plus ribavirin dominated best supportive care for all genotypes. Peginterferon alfa‑2b dominated peginterferon alfa‑2a in the base-case analysis (all ages, −£3397 per QALY gained) and in all subgroup analyses, except in children and young people aged 9–13 years, and in children and young people with HCV genotypes 1 or 4. MSD conducted deterministic sensitivity analyses around structural assumptions (time horizon, discount rates) and the modelled parameter values. The deterministic sensitivity analyses showed that peginterferon alfa‑2b dominated best supportive care in most scenarios, except in those in which MSD varied the time horizon, assumed efficacy and discount rates. ## Assessment Group's critique of the cost-effectiveness analyses by Roche and Merck Sharp and Dohme The Assessment Group critiqued the Roche and MSD submissions and considered that the economic models met all of the requirements for methodological quality and generalisability, except that neither manufacturer provided evidence that its model had been validated. Roche and MSD used the state-transition model applied in previous health technology assessments of peginterferon alfa treatments in adult populations, which the Assessment Group considered appropriate, commenting that most of the time spent in the model would be after treatment as an adult, rather than as a child. Because most children and young people start treatment (and enter the model) with mild chronic hepatitis C, few will progress to more severe health states before they become adults. Therefore, the Assessment Group considered that health-state transition values from adults used in the manufacturers' models were appropriate. Both Roche and MSD conducted literature reviews to estimate the transition probabilities from mild-to-moderate and moderate-to-compensated cirrhosis health states. The transition probability for mild-to-moderate hepatitis C was 0.014 per cycle in both manufacturers' submissions, whereas the transition probabilities for moderate hepatitis C to compensated cirrhosis differed for Roche (0.021) and MSD (0.0038) and for the Assessment Group (see section 4.2.29). The manufacturers' models used different time horizons: Roche used a time horizon of 30 years and MSD used a lifetime horizon. Another difference between the manufacturers' models was that Roche assumed that some patients have a spontaneous sustained virological response (that is, without treatment) in its base-case, whereas MSD only tested this assumption in a sensitivity analysis. The Assessment Group commented on the small (less than 3%) probability of spontaneous sustained virological response assumed by Roche, noting it was unlikely to affect the cost-effectiveness results. Both manufacturers applied the same health-state utility values used in previous adult chronic hepatitis C models except for the values for sustained virological response in the mild disease state, which were almost identical in both submissions (0.83 and 0.82 Roche and MSD respectively). Roche did not provide utility values for having a sustained virological response in the moderate disease or compensated cirrhosis health states. Most health-state costs used in the manufacturers' submissions were similar or the same. ## Assessment Group's economic model The Assessment Group developed an economic model estimating the cost effectiveness of peginterferon alfa‑2a and peginterferon alfa‑2b (both plus ribavirin) for treating chronic hepatitis C in children and young people compared with each other and with best supportive care. The model converted the probability of sustained virological response (the definition of treatment effectiveness) to long-term survival outcomes from the systematic review. The perspective of the analysis was that of the NHS and personal social services. The model time horizon was 70 years and the cycle length was 1 year. The costs and benefits were discounted at 3.5% per year, in accordance with the NICE reference case. Costs were taken from the most recently available data (2011/12). The Assessment Group confirmed the functionality of its model by checking the structure, calculations and data inputs. The Assessment Group adapted models used in Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C (extension of technology appraisal guidance 75) (NICE technology appraisal 106) and Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (part review of NICE technology appraisal guidance 75 and 106) (NICE technology appraisal 200), which assessed chronic hepatitis C in adults. The Assessment Group modified the structure of the model to include health states for the different levels of fibrosis (F0–F4, METAVIR scoring system), instead of the health states of mild hepatitis C, moderate hepatitis C and compensated cirrhosis. It did this based on evidence from Thein et al. (2008), which reviewed published rates of progression specific to stages of fibrosis progression rates based on 111 studies of people with chronic hepatitis C (n=33, 121). In the model, people with chronic hepatitis C with a METAVIR score between F0 and F3 or compensated cirrhosis (F4) can have a sustained virological response; remain in their current health state; or progress to more severe stages of liver disease. The Assessment Group assumed that a person who has a sustained virological response does not experience a relapse. It also assumed that people who have a sustained virological response or chronic hepatitis C with a METAVIR score between F0 and F4 have the same mortality risk as the general population, whereas people with decompensated liver disease, hepatocellular carcinoma and those who undergo liver transplantation have higher mortality risks. The Assessment Group incorporated most of the assumptions made in the models used in previous technology appraisals for chronic hepatitis C in adults, including: that a person's disease state before treatment influences the subsequent risk of progressive liver disease and health-related quality of life; that a person who does not have a sustained virological response has the same risk of disease progression as a person who does not receive treatment; that a person with mild or moderate hepatitis C and compensated cirrhosis has the same probability of having a sustained virological response; that the model excludes the rare possibility of having to stop treatment because of adverse reactions; and that the model excludes costs associated with managing adverse reactions because they are unlikely to be substantial. After discussion with experts, the Assessment Group further assumed that no patient would have a sustained virological response spontaneously (that is, without treatment); that a patient with genotype 1 or 4 HCV stops treatment at 24 weeks if there is no virological response by week 12; and that it would be acceptable to include transition probabilities, utility weights and health-state costs from adults in the model. Although the Assessment Group noted that a child's hepatitis C can affect parents' or carers' quality of life, it did not find sufficient evidence to include it in the model. The Assessment Group commented that stigma associated with hepatitis C may lower the quality of life of children and young people; however, the data were sparse. The Assessment Group used the baseline characteristics of the populations from the clinical trials in its model including the distribution across METAVIR stages of chronic hepatitis C of 24.6% at stage F0 (no fibrosis), 66.2% at stage F1 (portal fibrosis with no septa), 7.1% at stage F2 (portal fibrosis with few septa), 2.1% at stage F3 (septal fibrosis with no cirrhosis) and 0 at stage F4 (compensated cirrhosis). For utility values and health-state costs, the Assessment Group used values from previous technology appraisals so that F0 and F1 corresponded to the mild, and F2 and F3 to the moderate, hepatitis C health states. The Assessment Group searched for new evidence related to the natural history of hepatitis C in children or young people, but found none. ## Results of Assessment Group's economic model The Assessment Group's probabilistic cost-effectiveness results for the base-case population suggested that both peginterferon alfa‑2a and peginterferon alfa‑2b dominated best supportive care because they were less expensive and more effective. Treatment was more effective for genotype 2 or 3 than for genotype 1 or 4. The Assessment Group's base-case results for peginterferon alfa‑2a compared with peginterferon alfa‑2b showed that peginterferon alfa‑2a cost less (£19,055 compared with £20,371) and was more effective than peginterferon alfa‑2b (22.25 QALYs compared with 22.19 QALYs). For people with genotype 1 or 4, peginterferon alfa‑2a was also less costly and more effective than peginterferon alfa‑2b (£21,278 compared with £22,316; 22.00 QALYs compared with 21.97 QALYs). However, for people with genotype 2 or 3, peginterferon alfa‑2a cost more and was less effective than peginterferon alfa‑2b (£11,831 compared with £11,202; 23.05 QALYs compared with 23.21 QALYs). The Assessment Group stated that the estimates of clinical effectiveness were key drivers of the differences in costs and outcomes between peginterferon alfa‑2a and peginterferon alfa‑2b within the model. The Assessment Group performed one-way deterministic sensitivity analyses investigating the effect of uncertainty on the cost-effectiveness results varying the time horizon (30 years and 90 years); discount rate (0% discount for both costs and outcomes, 6% discount for costs with 1.5% discount for outcomes, 1.5% discount for both cost and outcomes, and 6% for both cost and outcomes); the proportions of people who had a sustained virological response with peginterferon alfa‑2a (69% and 51%) and with peginterferon alfa‑2b (65% and 52%); degree of liver fibrosis (100% F0, 100% F2, 100% F3 and 20% F4); starting age (5 years and 16 years); transition probabilities (lower confidence interval and upper CI); utility values (lower CI, upper CI and from previous appraisal); and health-state costs (lower CI and upper CI). In all analyses, both peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin dominated best supportive care. The analyses showed that the model was most sensitive to changes in the discount rate chosen and the time horizon. In most cases, peginterferon alfa‑2b was dominated by peginterferon alfa‑2a for all changes to the model parameters except for changes to the value reflecting the proportion of people who have a sustained virological response (peginterferon alfa‑2a ‑ 51%; or peginterferon alfa‑2b ‑ 65%) and the starting age of the cohort (age 5 years). However, the Assessment Group commented that the deterministic sensitivity analysis for peginterferon alfa‑2b compared with peginterferon alfa‑2a should be treated with caution because of uncertainty around the relative treatment effect. The Assessment Group also conducted scenario analyses. In 1 scenario analysis, it varied the transition probabilities between the chronic hepatitis C health states (F0–F3) to the decompensated cirrhosis health state (F4), varying the transition probabilities from 0.1 (used in the base case) to between 0.05 and 0.3, with the same probability applied for transitions between each of the states from F0 to F4. Peginterferon alfa‑2a dominated best supportive care for all transition probabilities used in the scenario analysis to a lesser or greater extent depending on the amount of time spent in the chronic hepatitis C state. Another scenario analysis assessed the impact of delaying peginterferon alfa‑2a treatment until age 18–30 years instead of starting it during childhood. This 'watchful waiting' strategy was associated with slightly higher costs (between £21,959 and £26,668) and slightly reduced QALYs (between 22.22 and 21.79 QALYs) compared with treatment during childhood (£19,055 and 22.25 QALYs for the base case). The Assessment Group commented that the conclusions made in scenarios 2 and 3 would also apply to peginterferon alfa‑2b compared with best supportive care. The Assessment Group conducted probabilistic sensitivity analyses for the following parameters: the proportion of children and young people with a given genotype, transition probabilities, health-state utilities and costs associated with monitoring, health states and treatment. The results of the probabilistic sensitivity analysis closely reflect the results of the deterministic base case. The probabilities that peginterferon alfa‑2a and ‑2b are cost effective at £20,000 and £30,000 per QALY gained were 68% and 66% for peginterferon alfa‑2a, and 32% and 34% for peginterferon alfa‑2b, respectively. ## Comparison of the Assessment Group and manufacturers' models The Assessment Group compared its results with those of the manufacturers. It commented that all 3 models found that peginterferon alfa‑2a and peginterferon alfa‑2b (each plus ribavirin) dominated best supportive care. MSD and the Assessment Group also compared peginterferon alfa‑2a with peginterferon alfa‑2b. The Assessment Group's results, which suggested that peginterferon alfa‑2a dominated peginterferon alfa‑2b, differed from those of MSD, which suggested that peginterferon alfa‑2b dominated peginterferon alfa‑2a. The Assessment Group suggested caution when interpreting these results because the differences were marginal. The costs and QALY estimates used in each evaluation varied. The differences in costs were based on the use of a shorter time horizon (Roche) or the length of time spent in chronic hepatitis C health states (shorter in the Assessment Group's analysis compared with MSD's). The differences in QALY estimates were based on the use of a shorter time horizon (Roche) and the lower utility values used (MSD) compared with the Assessment Group's model. ## Innovation Roche commented that pegylated interferons have existed for over 15 years, so it does not consider pegylated interferon to be an innovative medicine, but instead is an option available to physicians, patients and carers when considering treatments for chronic hepatitis C. By contrast, MSD considered that peginterferon alfa (2a and 2b) plus ribavirin were innovative therapies for treating chronic hepatitis C in adults when first launched and that extending the marketing authorisation to children and young people means that this innovation now applies to younger patients. In addition, peginterferon alfa‑2a and peginterferon alfa‑2b are dosed once weekly, compared with the 3‑times weekly dosing of interferon alfa, therefore reducing the burden of the treatment. MSD believes that successfully treating chronic hepatitis C in children and young people will affect parents and carers, and this would not be captured in calculating the QALY. MSD cited a study reporting that hepatitis C among children and young people is associated with increased carer stress, and a study conducted in Australia indicating substantial quality-of-life benefits for parents and carers when the child has a sustained virological response. MSD also commented that children and young people with chronic hepatitis C who have a sustained virological response do not infect others with the virus, and this reduces the risk of onward transmission of HCV in the UK. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin, having considered evidence on the nature of chronic hepatitis C in children and young people and the value placed on the benefits of technologies by people with the condition, their families and carers, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. ## Clinical effectiveness The Committee heard from the clinical specialists that both peginterferon alfa‑2a and peginterferon alfa‑2b (each plus ribavirin) are currently used to treat some children and young people with chronic hepatitis C in the UK. The clinical specialists confirmed that the 2 peginterferons are considered equivalent in their mechanism of action and clinical efficacy; however, peginterferon alfa‑2b is prescribed more frequently because it can also be given to children who are aged 3–4 years. The Committee heard from the clinical specialists that the decision to treat children, instead of delaying treatment until a child is symptomatic ('watchful waiting') or reaches adulthood, depends on the age of the child and how the infection is contracted and therefore how likely a spontaneous sustained virological response is without treatment. The Committee heard that children aged 3 years or younger, or those who contract HCV infection through a blood transfusion, are more likely to have a spontaneous sustained virological response during the acute infection phase than those who are aged 4 years and older or who have contracted the infection from their mother at birth and are in the chronic phase. The Committee recognised that the decision to treat with either regimen would largely be determined by clinical judgement and the specifics of the marketing authorisation. The Committee considered the impact that difficult family circumstances, such as parents who misuse drugs, may have on the ability of children and young people to adhere to treatment. It heard that clinical specialists do not recommend treating children and young people and their mothers (if they also have hepatitis C) at the same time because the adverse reactions of treatment for each might affect adherence. The clinical specialists indicated that support for children and young people and their families is not routinely available from adult hepatology centres and, to adhere to treatment, children and young people need specialised support, which is only available in some specialist hepatology centres in England and Wales. The Committee noted that families living away from a specialist centre would have the burden of travelling for treatment and monitoring. The Committee concluded that, although the timing of treatment is important, and better health outcomes are more likely if support is provided to ensure adherence to treatment, how to manage the disease is ultimately the decision of parents or carers, and the child or young person, together with clinicians,. The Committee considered the evidence presented on the proportion of children and young people with chronic hepatitis C who have a sustained virological response after treatment with peginterferon alfa plus ribavirin. It acknowledged the paucity of relevant studies in children and young people identified by the manufacturers and the Assessment Group, and noted that these studies had enrolled few patients and were generally of poor quality. In addition, because the evidence base largely comprised single-arm studies that did not have any control groups which did not receive therapy, the Committee would have expected the manufacturers' and Assessment Group's submissions to have provided supporting data from adult trials to establish the efficacy of peginterferon alfa (2a and 2b) plus ribavirin. The Committee was aware that having a lower viral load or milder degree of liver damage at the start of treatment increases the likelihood of a sustained virological response. Despite the limitations of the clinical evidence and the lack of comparative evidence, the Committee concluded that peginterferon alfa (2a and 2b) plus ribavirin is an effective therapy in children and young people with chronic hepatitis C across all genotypes. The Committee discussed the generalisability of the trial results to the UK population and heard from the clinical specialists that the average age of entry into the trials (age 11 years) reflects the average age of children and young people currently treated in the UK, although it was noted that, in the future, patients will be treated at a younger age once newer therapies become available. The Committee also heard from the clinical specialists that some children clear the virus spontaneously without treatment, but that the proportion that do is considerably lower than the proportion that cleared the virus when treated in the single-arm studies. The Committee was satisfied that the trial results were largely generalisable to the UK population. The Committee queried whether there were any subgroups in which treatment with peginterferon alfa plus ribavirin would be most clinically effective, whether there were groups in which clinicians chose to 'watch and wait' rather than to treat, and if there was a general acceptance in the clinical community about the 'best' time to treat chronic hepatitis C. The clinical specialists stated that children and young people with interleukin‑28 (IL‑28) gene polymorphism were more likely to clear HCV with or without treatment, but that testing for IL‑28 is not routinely performed in UK clinical practice. The Committee heard from the clinical specialists that obesity is an increasing problem in children and young people and although it has been linked with a lower probability of having a sustained virological response, it is not currently a factor that precludes patients from having treatment. With respect to the timing of treatment, the Committee heard from the clinical specialists that, because younger children have lower baseline viral loads and less liver damage, both of which improve the response to treatment, treating early was better than treating later in adolescence or adulthood. The Committee also heard that before the age of 10 years a child's immune system mounts less of an inflammatory response to HCV, and that this period precedes the pubertal growth spurt; therefore, treatment given at this time reduces the possible negative impact on a child's growth rate. Additionally, because young children have fewer comorbidities and generally do not consume alcohol, they have fewer complications associated with liver disease and therefore are more likely to have favourable outcomes following treatment. The Committee heard from the clinical specialists that another benefit of treating a child early is that he or she may not remember the treatment itself or even ever having had hepatitis C. The Committee concluded that clinical experience supported early treatment, but that the decision about whether and when to treat should be made by parents or carers together with the child's or young person's clinician. The Committee considered how likely it is that children and young people with a sustained virological response will remain free from HCV; that is, how likely it is that they will be 'cured'. It understood that 95% of children and young people treated before the onset of significant liver disease and who have a sustained virological response remain free from HCV for the rest of their lives. The Committee heard from the clinical specialists that people do not generally undergo repeat liver biopsies after treatment has been completed, but studies showed that children and young people with sustained virological responses remained healthy in the following 5 years. It noted however that these studies were small and not necessarily representative of the UK population; therefore the Committee would have expected to have been presented with data from trials in adults with HCV to augment the evidence related to the likelihood of a long-term response in children and young people after treatment with peginterferon alfa plus ribavirin. Nevertheless, the Committee concluded that it was plausible that a sustained virological response achieved in childhood or adolescence could last throughout a person's lifetime. The Committee was aware that the population identified in the scope specified children and young people who have not previously been treated for HCV. It heard that clinicians do not offer re-treatment to children and young people previously treated with peginterferon plus ribavirin. Instead, when treatment has not resulted in a sustained virological response, these children and young people might be enrolled in a clinical trial of a newer technology or offered further treatment options (such as boceprevir or telaprevir) from 18 years of age, in line with guidelines for the treatment of adults with chronic hepatitis C. The Committee was reassured by the clinical specialists that children and young people would be treated only once with peginterferon alfa plus ribavirin, if it was recommended for routine use in UK clinical practice. The Committee considered the adverse reactions of treatment with peginterferon alfa plus ribavirin. It heard that the main adverse reactions are: severe psychiatric and central nervous system effects, particularly depression, suicidal ideation and attempted suicide, weight loss and growth inhibition. The Committee heard from the patient expert that the patient community had documented aggressive behaviour possibly attributable to ribavirin. However, such aggressive behaviour was attributed by the manufacturers to peginterferon alfa, not ribavirin. The manufacturers and the clinical specialists explained that, without studies that compare treatment with peginterferon alfa with and without ribavirin, it was sometimes difficult to separate the adverse reactions of peginterferon alfa from those of ribavirin. The Committee was aware that the Schwarz et al. study made this comparison, but these data were not presented to the Committee. The Committee also heard that other important adverse reactions associated with treatment are slowed growth and weight loss, both of which are of particular concern during the pubertal growth period. The clinical specialists explained that 48 weeks of treatment with peginterferon alfa plus ribavirin during this period can result in a small reduction in expected height and, while some studies have shown that growth resumes after treatment, some children and young people do not return to their pre-treatment growth percentile. The Committee acknowledged advice from the clinical specialists that, if a decision is made to delay treatment beyond puberty, clinicians would monitor the patient's condition and, if it worsens, treatment options would be re-evaluated. The Committee concluded that, although treatment with peginterferon alfa plus ribavirin may impair growth, the possibility of progressive liver disease without treatment outweighs the problems associated with being slightly shorter. The Committee considered whether there is a stigma associated with hepatitis C in children and young people. The clinical specialists and patient experts expressed the opinion that a stigma associated with hepatitis C does exist, in part related to its association with intravenous drug misuse. The Committee heard that children and young people with hepatitis C have more difficultly being placed with foster parents because of largely unfounded fears that the virus will be transmitted to other family members and also because of possible psychological effects associated with treatment. The Committee concluded that hepatitis C was associated with a stigma, and early successful treatment would lessen the stigma later in life. The Committee considered whether peginterferon alfa (2a and 2b) plus ribavirin were innovative technologies for treating hepatitis C in children and young people. It was aware that, when first introduced for adults, both peginterferons were likely to have been innovative treatments. However, the Committee concluded that, although peginterferon alfa plus ribavirin represented a useful treatment option for children and young people with chronic hepatitis C, the technologies themselves could no longer be considered innovative for the purpose of this evaluation, since they had already been used successfully in adults. ## Cost effectiveness The Committee considered the Assessment Group's and the 2 manufacturers' economic models. It noted that: The Assessment Group's and MSD's cost-effectiveness results for their respective base cases showed that peginterferon alfa plus ribavirin was more effective and less costly than best supportive care across all genotypes. Roche's cost-effectiveness modelling resulted in an incremental cost-effectiveness ratio (ICER) for peginterferon alfa plus ribavirin of £3900 per QALY gained compared with best supportive care in children and young people with HCV genotype 1, 4 or 5. Peginterferon alfa plus ribavirin dominated best supportive care in children and young people with genotype 2 or 3. When comparing the 2 peginterferons, the Assessment Group's base case showed that peginterferon alfa‑2a dominated peginterferon alfa‑2b, whereas MSD found that peginterferon alfa‑2b mainly dominated peginterferon alfa‑2a. The Committee noted that the stopping rules differed between both the manufacturers' submissions and the Assessment Report (section 4.2.3 , 4.2.11 , and 4.2.23 ). It was aware that, according to the summary of product characteristics for peginterferon alfa‑2a, patients infected with HCV genotype 2 or 3 should receive 24 weeks of treatment, whereas patients infected with any other genotype should receive 48 weeks of therapy unless they have detectable levels of HCV RNA despite an initial 24 weeks of therapy, at which point they should stop therapy because it is unlikely they will have a sustained virological response with continued therapy. The Committee heard from the clinical specialists that, in practice, children and young people with genotype 2 or 3 are evaluated for an early virological response at 12 weeks, although they generally continue to receive treatment for 24 weeks. Children and young people with genotype 1 or 4 are encouraged to stop treatment at 24 weeks if there has not been a virological response, although some parents prefer their children to continue treatment for the full 48 weeks regardless of initial response. The Committee would have expected the stopping rules to be consistent with clinical practice and the marketing authorisation of both products but concluded that, although the stopping rules varied across the models, the uncertainty associated with this was unlikely to alter the conclusions about the cost effectiveness of either of the peginterferons compared with best supportive care. The Committee discussed whether, for patients who do not have a sustained virological response to peginterferon alfa plus ribavirin, subsequent treatment in adulthood with the second-generation technologies boceprevir (see Boceprevir for the treatment of genotype 1 chronic hepatitis C, NICE technology appraisal 253) and telaprevir (see Telaprevir for the treatment of genotype 1 chronic hepatitis C, NICE technology appraisal 252) should have been included in the economic models. It was concerned that none of the economic evaluations included re-treatment options for young people reaching 18 years of age, and noted that the impact of the future costs of these technologies in the model is uncertain. The Committee acknowledged that, despite this limitation, the results were largely robust to changes in variables within the model and therefore it was satisfied that the omission of the costs of future technologies in the model would not greatly affect conclusions about the cost effectiveness of peginterferon alfa plus ribavirin. The Committee, however, stated that it would expect future economic evaluations of treatments for children and young people with HCV to take into account the use of technologies currently licensed for adults and recommended as an option by NICE when re-treatment is required in adulthood. The Committee noted that the utility values used in the models were based on previous technology appraisals in adults with chronic hepatitis C, and that they had not been updated, or revalidated to assess their appropriateness for an appraisal of treatments in a younger population. The Committee stated that it would have expected more detailed information about the source and validation of utility values relied on in the manufacturers' submissions. The Committee heard that the Assessment Group related the health states used in previous technology appraisals in adults with chronic hepatitis C to the METAVIR system and conducted searches to identify new evidence related to the natural history of hepatitis C in children or young people, but found no new data. It also noted that the Assessment Group relied on published utility values derived from the health-related quality of life of adults with chronic hepatitis C in Sweden and Canada to populate its economic model. The Assessment Group told the Committee that it chose these data because they were more recent than values used in previous hepatitis C technology appraisals and were based on larger sample sizes. The Committee questioned the manufacturers' and Assessment Group's choice of utility values and stated their preference for utility values derived from UK population studies. Although the Committee remained uncertain about what effect alternative utility values would have on the cost-effectiveness results, it agreed that an exploration of alternative utility values would not affect conclusions about the cost effectiveness in this appraisal. The Committee considered the conflicting opinions in the manufacturers' submissions and the Assessment Report on whether some people can have a spontaneous sustained virological response without treatment. The Committee considered it appropriate that Roche assumed that a spontaneous 'cure' could occur in a small number of patients in its base case, but noted that this assumption was omitted from the base-case analyses of MSD and the Assessment Group, although both considered the impact of assuming a spontaneous sustained virological response in sensitivity analyses. The Committee heard from the clinical specialists that a spontaneous sustained virological response would probably only occur before the age of 4 years or during the acute phase of HCV infection. The Committee concluded that addressing the impact of a spontaneous sustained virological response on the ICERs would not greatly affect the conclusions about the cost effectiveness of peginterferon alfa plus ribavirin in this appraisal, but stated that analyses in future appraisals of treatments for hepatitis C should include sensitivity analyses accounting for the possibility of a spontaneous cure without treatment. The Committee was aware that the Roche model did not take into account costs associated with hepatitis C after treatment. It heard from the clinical specialists that this was a realistic assumption and that paediatric patients, once successfully treated, were not referred to adult hepatology clinics unless liver damage was present. The Committee considered the disutilities associated with adverse reactions of treatment with peginterferon alfa plus ribavirin. It noted that none of the models included disutility associated with growth impairment. The Committee pointed out that such disutilities were included in the Assessment Group's economic model for Human growth hormone (somatropin) for the treatment of growth failure in children (review) (NICE technology appraisal 188), but that the children in that appraisal were considerably shorter than the average child with chronic hepatitis C. Nonetheless, the Committee would have expected the model to have included a utility decrement for growth impairment, considering that it is a significant adverse effect of peginterferon alfa plus ribavirin treatment. The Committee concluded, however, that, other than for extremely short children, this was unlikely to outweigh the benefits of treatment. The Committee considered the use of peginterferon alfa plus ribavirin in children and young people with chronic hepatitis C who are co‑infected with HIV. It concluded that, although these patients were not represented in the pivotal clinical trials, based on the current evidence available, there was no reason to make any different provision for them. It did, however, note that there might be occasions when ribavirin might interact with drugs for HIV, necessitating a review of the patient's optimal treatment strategy. The Committee considered whether there were any benefits that were not adequately captured in the QALY calculation. It acknowledged that there were some health benefits gained by parents or carers as a result of children or young people receiving peginterferon alfa plus ribavirin treatment for chronic hepatitis C. For these benefits to be given special consideration, the Committee acknowledged that they must provide more health benefits than treatments for other conditions. In this case, the clinical specialists and patient experts suggested that successful treatment might, in part, alleviate a mother's burden of psychological guilt of mother-to-child transmission of hepatitis C. Additionally, although the risk of non-maternal transmission is minimal, foster parents may be reluctant to foster children with hepatitis C and may be concerned about transmission to other children in the household, a concern that would be removed if a sustained virological response was achieved through treatment. Furthermore, the Committee acknowledged the significant public health impact of successful treatment on reducing HCV transmission rates to uninfected people in the UK population and considered that, if this benefit was included in the model, the results were likely to be even more favourable. The Committee agreed that there were health benefits that had not been adequately captured in the QALY calculation but that, because of the favourable cost-effectiveness results, this did not need any further action. The Committee noted that the estimates of clinical effectiveness were key drivers of the differences in costs and outcomes in the cost-effectiveness analysis of peginterferon alfa‑2a compared with peginterferon alfa‑2b. However, because the clinical effectiveness estimates were very similar for both peginterferon alfa‑2a and peginterferon alfa‑2b (see section 4.3.2), the Committee was not convinced that there was sufficient evidence to recommend 1 treatment over the other. The Committee agreed that peginterferon alfa (2a and 2b) plus ribavirin were more effective and less costly than best supportive care across all genotypes, and it was certain that addressing the shortcomings identified in the economic evaluations presented would not alter its conclusion. Therefore, the Committee concluded that peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin, when used in line with their marketing authorisations, were a cost-effective use of NHS resources as an option for treating chronic hepatitis C in children and young people across all genotypes. # Summary of Appraisal Committee's key conclusions TA300 Appraisal title: Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people Section Key conclusion Peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin are recommended as treatment options, within their licensed indications, for children and young people with chronic hepatitis C. Reasons for key conclusion: The Committee agreed that peginterferon alfa (2a and 2b) plus ribavirin were more effective and less costly than best supportive care across all genotypes, and it was certain that addressing the shortcomings identified in the economic evaluations presented would not alter its conclusion. The Committee was not convinced that there was sufficient evidence to recommend 1 treatment over the other. Current practice Clinical need of patients, including the availability of alternative treatments Currently, there is no other treatment for chronic hepatitis C licensed for children and young people in the UK. The technology Proposed benefits of the technology Treatment with peginterferon alfa could provide a sustained virological response that could potentially last for the lifetime of the child or young person, effectively providing a cure. Treatment with peginterferon alfa could provide benefits to parents and carers, including reducing the guilt burden associated with maternal transmission of hepatitis C. Treatment with peginterferon alfa in young children could help avoid the social stigma associated with hepatitis C infection. How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee concluded that, although peginterferon alfa plus ribavirin represented a useful treatment option for children with hepatitis C, the technologies themselves were not innovative for the purpose of this evaluation. What is the position of the treatment in the pathway of care for the condition? Peginterferon alfa‑2a and peginterferon alfa‑2b are clinically equivalent and the decision to treat with either will largely be determined by clinical judgement and the specifics of the marketing authorisation. Children and young people are only treated once with peginterferon alfa plus ribavirin in UK clinical practice. Adverse reactions The main adverse reactions are: severe psychiatric and central nervous system effects, particularly depression, suicidal ideation and attempted suicide, weight loss and growth inhibition. The Committee concluded that peginterferon alfa has an impact on children's growth, but the problem of progressive liver disease outweighs the problems associated with being shorter than a child would otherwise have been without treatment. Evidence for clinical effectiveness Availability, nature and quality of evidence The systematic reviews conducted by the manufacturers and the Assessment Group identified few relevant studies in children and young people and these studies were small and of generally poor quality. Relevance to general clinical practice in the NHS The Committee heard that the average age of entry into the trials reflected the average age of children and young people currently treated in the UK and therefore was satisfied that the trial results were largely generalisable to the UK population. Uncertainties generated by the evidence Because the evidence base largely comprised single-arm studies that did not have any control groups receiving no therapy, the Committee would have expected the manufacturers' and Assessment Group's submissions to have provided supporting data from adult trials to establish the efficacy of peginterferon alfa (2a and 2b) plus ribavirin. Studies were presented to support the contention that children are 'cured' following peginterferon alfa plus ribavirin treatment. The studies that followed children with sustained virological responses 5 years on showed that the children remained healthy, but these studies were small and not necessarily representative of the UK population. The Committee would have expected data from trials in adults to be presented in order to augment the evidence of the likelihood of an enduring response from peginterferon alfa plus ribavirin in children. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Experience suggests that early treatment with peginterferon alfa plus ribavirin is better than later treatment, but the decision about whether and when to treat should be made by parents or carers together with the child or young person's clinician. Estimate of the size of the clinical effectiveness including strength of supporting evidence Peginterferon alfa (2a and 2b) plus ribavirin is an effective therapy in children and young people with chronic hepatitis C across all genotypes. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the Assessment Group's and the 2 manufacturer's economic models. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee questioned the manufacturers' decision to rely on previous utility values without validating them and the Assessment Group's decision for using Swedish and Canadian health-related quality-of-life data, considering the Committee's preference for utility values derived from UK population studies. The Committee noted that none of the models included disutility associated with growth impairment. Although each of the models presented incorporated different stopping rules, the Committee would have expected the stopping rules to be consistent with clinical practice and the marketing authorisation of both products. Spontaneous sustained virological response without treatment was not included in MSD's or the Assessment Group's base-case, although they considered it in sensitivity analyses. Nevertheless, the Committee was certain that addressing the shortcomings identified in the economic evaluations would not alter its conclusion. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? Utility values used in the manufacturers' models were based on previous technology appraisals in adults and the values had not been updated, revalidated or presented to the Committee. Successful treatment could reduce HCV transmission rates to uninfected people in the UK population and if this benefit was included in the model, the results would likely be even more favourable. Treatment with peginterferon alfa plus ribavirin might, in part, alleviate a mother's burden of psychological guilt of mother-to-child transmission of hepatitis C and remove concerns about horizontal transmission. Are there specific groups of people for whom the technology is particularly cost effective? N/A What are the key drivers of cost effectiveness? For the comparison of peginterferon alfa‑2a with peginterferon alfa‑2b, the key drivers of cost effectiveness were the estimates of clinical effectiveness. Most likely cost-effectiveness estimate (given as an ICER) The manufacturer's and Assessment Group's base-case results showed that peginterferon alfa‑2a and peginterferon alfa‑2b (both plus ribavirin) dominated best supportive care in all genotypes, except Roche's cost-effectiveness results for children and young people with HCV genotype 1, 4 or 5, which resulted in an ICER of £3900 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) N/A End-of-life considerations N/A Equalities considerations and social value judgements During the scoping consultation, it was suggested that young people who misuse drugs, recent immigrants and asylum seekers who are children should be considered in this appraisal. However, because NICE does not exclude any specific groups of children and young people in this appraisal, this suggestion did not need further action. -# Related NICE guidance Details are correct at the time of publication. Further information is available on the NICE website. # Published Hepatitis B and C: ways to promote and offer testing to people at increased risk of infection. NICE public health guidance 43 (2012). Boceprevir for the treatment of genotype 1 chronic hepatitis C. NICE technology appraisal guidance 253 (2012). Telaprevir for the treatment of genotype 1 chronic hepatitis C. NICE technology appraisal guidance 252 (2012). Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (part review of NICE technology appraisal guidance 75 and 106). NICE technology appraisal guidance 200 (2010). Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C (extension of technology appraisal guidance 75). NICE technology appraisal guidance 106 (2006). Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C (review and extension of technology appraisal guidance 14). NICE technology appraisal guidance 75 (2004). # Under development NICE is developing the following guidance: Hepatitis C. NICE clinical guideline. Publication date to be confirmed. # NICE Pathways Hepatitis B and C testing. NICE Pathway (2012).# Review of guidance The guidance on this technology will be considered for review by the Guidance Executive in September 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew Dillon Chief ExecutiveNovember 2013# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. This guidance updates and replaces: section 1.7, bullet 2 only, of NICE technology appraisal guidance 75 (TA75) 'Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C' part of section 1.6 of NICE technology appraisal guidance 106 (TA106) 'Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C' It has been incorporated into the NICE pathway on hepatitis B and C testing along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0366-5	{'Guidance': "This guidance updates and replaces:\n\nsection 1.7, bullet 2 only, of NICE technology appraisal guidance 75 (TA75)\xa0'Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C'\n\npart of section 1.6 of NICE technology appraisal guidance 106 (TA106)\xa0'Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C'.\n\nPeginterferon alfa in combination with ribavirin is recommended, within its marketing authorisation, as an option for treating chronic hepatitis\xa0C in children and young people.", 'Clinical need and practice': 'Hepatitis\xa0C is a disease of the liver caused by the hepatitis\xa0C virus (HCV). The presence of HCV\xa0RNA (ribonucleic acid) in serum indicates infection. There are 2 main phases of infection: acute and chronic. Acute hepatitis\xa0C refers to the period immediately after infection, whereas chronic hepatitis\xa0C is defined as infection that lasts for more than 6\xa0months. In the UK, there are 2 major routes of HCV transmission: sharing needles in intravenous drug misuse and receiving transfusions of infected blood or blood products. However, children acquire the virus primarily from their mothers at birth. Breast feeding does not appear to increase the risk of HCV transmission.\n\nSix main genetic types of HCV, known as genotypes 1 to 6, with further subtyping (a–j) have been found. In England and Wales genotypes 1 and 3 account for more than 90% of all diagnosed infections. The effectiveness of antiviral treatment depends on the viral genotype; the response is generally better in people infected with genotypes 2 or 3 than in those infected with genotypes 1, 4, 5 or 6.\n\nInfection with HCV can lead to complications, including hepatic dysfunction, hepatic cirrhosis, hepatocellular carcinoma and death. Progression to severe hepatitis or cirrhosis during childhood is rare (less than 5%) and the mean time to development of cirrhosis in people infected as infants is estimated to be 28\xa0years.\n\nEstimates from the Health Protection Agency in 2011 show that HCV was newly diagnosed in 26 people aged 1\xa0year or younger and 21 people aged 1–14\xa0years in England in 2010. Estimates for chronic infection in children and young people in the UK are not available.\n\nThe aim of treatment is to clear the virus from the blood. Sustained virological response, defined as undetectable serum HCV\xa0RNA 6\xa0months after the end of treatment, usually indicates resolved infection, although relapse occurs in approximately 5% of people after 5\xa0years.', 'The technologies': "Peginterferon alfa‑2a (Pegasys, Roche Products) in combination with ribavirin has a UK marketing authorisation for the treatment of children and adolescents 5\xa0years of age and older with chronic hepatitis\xa0C, who test positive for serum hepatitis\xa0C virus (HCV) ribonucleic acid (RNA) and who have not previously received any treatment. Peginterferon alfa‑2a is administered subcutaneously once weekly. The dose depends on body surface area, and it should not be used in children with a body surface area of less than 0.71\xa0m2 (for whom there are no data). The recommended treatment duration is 24\xa0weeks (genotypes 2 or 3) or 48\xa0weeks (all other genotypes) depending on baseline viral load and whether or not a child has a virological response (defined as a 100‑fold decrease in, or undetectable levels of, serum HCV\xa0RNA) at week\xa024. Virological response by week\xa024 is predictive of sustained virological response. If adverse reactions occur, the dose can be reduced.\n\nPeginterferon alfa‑2b (ViraferonPeg, Merck Sharp and Dohme [MSD]) in combination with ribavirin has a UK marketing authorisation for the treatment of children aged 3\xa0years and older and adolescents who have chronic hepatitis\xa0C without hepatic decompensation, who test positive for serum HCV\xa0RNA and who have not previously received any treatment. Dosing of peginterferon alfa‑2b for children and adolescents is determined by body surface area and the recommended dose is 60\xa0micrograms/m2 per week subcutaneously in combination with ribavirin. The recommended treatment duration is 48\xa0weeks for children and adolescents with genotype 1 or 4. Treatment should be stopped after 12\xa0weeks if serum HCV\xa0RNA decreases less than 100‑fold compared with pre-treatment levels or if serum HCV\xa0RNA is detectable at week\xa024. For children and adolescents with genotype 2 or 3, treatment is 24\xa0weeks. If adverse reactions occur, the dose can be reduced.\n\nRibavirin (manufactured as Copegus by Roche Products) has a marketing authorisation in combination with peginterferon alfa‑2a or interferon alfa‑2a for treating chronic hepatitis\xa0C; the marketing authorisation for Copegus does not include specific recommendations for use in children and young people. Copegus is available as 200‑mg or 400‑mg tablets. Ribavirin manufactured by MSD (as Rebetol) has a marketing authorisation in combination with peginterferon alfa‑2b or interferon alfa‑2b for treating chronic hepatitis\xa0C in children and young people aged 3\xa0years and older. Rebetol is available as an oral solution and 200‑mg hard capsules. The recommended dose of either ribavirin in combination with peginterferon alfa‑2a or ‑2b is based on body weight; the average daily dose is 15\xa0mg/kg, given in 2\xa0doses. The most common adverse reactions to ribavirin include anaemia, dry cough and rash.\n\nPeginterferon alfa‑2a and ‑2b are contraindicated for treating chronic hepatitis\xa0C in children and young people with a history of severe psychiatric conditions. The summaries of product characteristics for peginterferon alfa‑2a and ‑2b mention the following adverse reactions in children and young people: severe psychiatric and central nervous system effects (particularly depression, suicidal ideation and attempted suicide), weight loss and growth inhibition. The summaries of product characteristics state that, when deciding not to defer treatment until adulthood, it is important for clinicians to consider that combination therapy may inhibit growth and that it is uncertain whether this effect is reversible. Therefore the summaries of product characteristics suggest that a child or young person is treated before or after the pubertal growth spurt whenever possible. For full details of adverse reactions and contraindications, see the summaries of product characteristics.\n\nThe price of peginterferon alfa‑2a is £107.76 for a 135‑microgram prefilled syringe or pen and £124.40 for a 180‑microgram prefilled syringe or pen (excluding VAT; 'British national formulary' [BNF] edition\xa065). The price of peginterferon alfa‑2b is £1.33 per microgram and it is available in 50-, 80-, 100-, 120- and 150‑microgram pens costing £66.46, £106.34, £132.92, £159.51 and £199.38 respectively (BNF edition\xa065). The Assessment Group calculated that, based on an average age of 11\xa0years, a body weight of 35.5\xa0kg and a body surface area of 1.19\xa0m2, a 24‑week course of peginterferon alfa‑2a plus ribavirin costs approximately £3700 and a 48‑week course of treatment costs approximately £7400; a 24‑week course of peginterferon alfa‑2b plus ribavirin oral solution costs approximately £4000 and a 48‑week course of treatment costs approximately £8100. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (section\xa08) considered evidence from several sources (section\xa09).\n\n# Clinical effectiveness\n\nThe Assessment Group focused on 5 specific questions to determine the following:\n\nsustained virological response to treatment\n\nbiochemical response to treatment\n\nhistological response to treatment\n\nchange in quality of life\n\nadverse reactions to treatment, including effects on growth.\n\nThe Assessment Group identified 1 randomised controlled trial and 1 single‑arm trial evaluating peginterferon alfa‑2a and ribavirin. The randomised controlled trial (Schwarz et al. 2011) was the pivotal regulatory trial for treatment in people aged 5–18\xa0years with chronic hepatitis\xa0C. Because the comparator arm was peginterferon monotherapy (that is, without ribavirin), it did not meet the inclusion criteria for the appraisal. Therefore, the Assessment Group used data from the intervention arm (n=55), treating it as an uncontrolled observational study. The single-arm trial (Sokal et al. 2010, n=65) included children and young people aged 6–17\xa0years.\n\nFor peginterferon alfa‑2b and ribavirin, the Assessment Group identified 5 single‑arm studies. A single‑arm clinical trial evaluating peginterferon alfa‑2b and ribavirin (Wirth et al. 2010, n=107) included children and young people aged 3–17\xa0years. The other 4 studies included populations with narrower age ranges than those specified in the UK marketing authorisation (Al Ali et al. 2010, single-arm trial [n=12, children and young people aged 14–17\xa0years]; Ghaffar et al. 2009 [n=7, children and young people aged 8–16\xa0years]; Jara et al. 2008 [n=30, children and young people aged 3–16\xa0years]; Pawlowska et al. 2010 [n=53, children and young people aged 8–17\xa0years]). The duration of the trials in the Assessment Group's efficacy review ranged from 24–52\xa0weeks. The Assessment Group found no studies in children or young people co‑infected with HIV.\n\nThe Assessment Group considered that the quality of the included studies was generally poor because they lacked control groups, except for the study by Schwarz et al., in which the comparison arm was not relevant to this appraisal. The Assessment Group showed that, among other uncertainties, conducting an accurate assessment of the generalisability of the studies was difficult because of substantial variation in the patient inclusion criteria and the countries represented.\n\nThe primary outcome of the 7 studies was sustained virological response defined as undetectable serum hepatitis\xa0C virus (HCV) ribonucleic acid (RNA) at 24\xa0weeks after the end of treatment (in both peginterferon alfa‑2a studies and 4 peginterferon alfa‑2b studies) or 12\xa0months after the end of the treatment (Ghaffar et al. study of peginterferon alfa‑2b). Concentrations of serum HCV\xa0RNA at baseline varied across the 7 included studies. For the 2 peginterferon alfa‑2a studies, the sustained virological responses were 53% and 66% in Schwarz et al. and Sokal et al. respectively. For the 5 peginterferon alfa‑2b studies, sustained virological response to treatment ranged from 29 to 75%, and proportions in 3 of the studies were comparable to responses seen in the peginterferon alfa‑2a studies (Pawlowska et al., 49% [26/53]; Wirth et al., 65% [70/107]; Jara et al., 50% [15/30]).\n\nThe 2 studies (Schwarz et al., Sokal et al.) evaluating peginterferon alfa‑2a showed that patients with genotype 2 or 3 were more likely to have a sustained virological response than patients with other genotypes (80 to 89% compared with 47 to 57%). In studies evaluating peginterferon alfa‑2b, the proportions with a sustained virological response were similar for genotype\xa01, ranging from 46 to 53%, whereas the proportions achieved for genotype 2 or 3 and genotype 4 varied (50 to 100% and 0 to 80% respectively).\n\nBoth peginterferon alfa‑2a studies (Schwarz et al., Sokal et al.) and 1 peginterferon alfa‑2b study (Wirth et al.) reported sustained virological responses according to baseline viral load. The results suggest that children and young people with a low baseline viral load (less than 500,000\xa0IU/ml, or 600,000\xa0IU/ml or less) appear to have higher proportions of sustained virological responses (range 70–79%) than those with a higher viral load (more than 500,000\xa0IU/ml, or 600,000\xa0IU/ml or more, range 49–55%). Sokal et al. and Wirth et al. reported that a higher proportion of children and young people with genotype 2 or 3 had a sustained virological response compared with those with genotype 1, 4, 5 or 6, regardless of viral load. Wirth et al. reported that, in people with genotype\xa01, the proportion having a sustained virological response was higher in those with low baseline viral load than in those with high baseline viral load (72% compared with 29%, p=0.0006).\n\nThe proportions of sustained virological responses in 2 of the studies presented were higher in children and young people who had not been previously treated (55–62%) compared with those who had been previously treated (17–33%). The Pawlowska et al. study presented sustained virological response by genotype subgroup, but the numerators in each subgroup did not add up correctly to the total number of treatment-naive and previously treated patients in the trial (because study participants with genotype\xa03 HCV were excluded), and the numbers in these subgroups were small.\n\nThree studies reported the proportion of sustained virological responses according to activities of alanine aminotransferase in serum at baseline. In the 2 peginterferon alfa‑2a studies (Schwarz et al.; Sokal et al.), the proportion of sustained virological responses was higher in those with lower alanine aminotransferase activities at baseline (range 70–80%) compared with those who had higher baseline serum alanine aminotransferase activities (range 41–58%). Sokal et al. showed that, in children and young people with lower baseline alanine aminotransferase activities, sustained virological response did not differ by genotype. However, for children and young people with elevated baseline alanine aminotransferase activities, those with genotype 2 or 3 had a higher proportion of sustained virological responses than those with other genotypes. In the peginterferon alfa‑2b study (Wirth et al.), sustained virological response was similar in children and young people with lower and elevated alanine aminotransferase activities at baseline (67% and 64% respectively).\n\nBoth the peginterferon alfa‑2a studies reported sustained virological response according to baseline liver histology. Of children and young people without hepatic fibrosis at baseline, 43% (Schwarz et al. study) and 76% (Sokal et al. study) had a sustained virological response, although the Assessment Group noted the limited numbers in the Schwarz et al. subgroup (n=7). The proportion of children and young people with some degree of fibrosis having a sustained virological response in the 2 studies was 53% and 60% (Schwarz et al. and Sokal et al. respectively).\n\nThe proportion of children and young people whose hepatitis\xa0C relapsed was reported by Schwarz et al. (17%) and in 4 peginterferon alfa‑2b studies (8% in Al Ali et al.; 17% in Pawlowska et al.; 8% in Wirth et al. [12% for genotype\xa01]; 3% in Jara et al.). Two of the peginterferon alfa-2b studies (Al Ali et al.; Jara et al.) did not specifically define relapse, but reported data that the Assessment Group inferred to be relapse of hepatitis\xa0C.\n\nProblems with growth and weight are listed as adverse reactions to treatment in the summary of product characteristics. One study of peginterferon alfa‑2a (Sokal et al.) and 3 studies of peginterferon alfa‑2b (Pawlowska et al.; Wirth et al.; Jara et al.) reported changes in height and weight during treatment. Sokal et al. reported that, at baseline and follow-up for height and weight, little influence on growth was seen. Pawlowska et al. reported that treatment with peginterferon alfa‑2b and ribavirin had no influence on height at 24\xa0weeks after treatment or 2\xa0years after follow-up. In the remaining 2 peginterferon alfa‑2b studies, growth rates decreased during treatment but subsequently recovered. Jara et al. observed that growth during the 48‑week treatment period was reduced in 85% of children and young people (22/26) by 1.6\xa0cm compared with the growth velocity fiftieth percentile for age and sex. Growth velocity was described as normal in the 6‑month period after the end of treatment; however, patients did not regain their height percentile. Wirth et al. observed that 70% (75/107) of children and young people had an inhibited growth velocity to less than the third percentile for age and sex during treatment. Mean growth velocity was 2.47\xa0cm per year during treatment and 5.73\xa0cm per year in the follow-up period. The decrease in mean height percentile during treatment was greater in children and young people whose treatment duration was longer than in those whose treatment duration was shorter.\n\nThe 3 studies of peginterferon alfa‑2b each reported that patients lost weight during treatment. Jara et al. observed that 67% (20/30) of children and young people lost weight, with 23% (7/30) losing more than 5% of their baseline weight. Weight gain occurred when treatment stopped. Pawlowska et al. observed that 43% (23/53) of patients lost more than 10% of their baseline weight. Wirth et al. reported that 19% (20/107) of children and young people lost weight, with a mean loss in the weight percentile of −15.5 during treatment and a mean gain of 12.3 during follow-up.\n\nThe Schwarz et al. trial reported changes in quality of life after treatment with peginterferon alfa‑2a, assessed using the Child Health Questionnaire – Parent Form 50, and in child and adolescent behavioural and emotional functioning (using the Child Behaviour Checklist), depression (using the Children's Depression Inventory) and cognitive functioning (using the Behaviour Rating Inventory of Executive Function). The Child Health Questionnaire, Child Behaviour Checklist and Behaviour Rating Inventory of Executive Function instruments were all completed by the child's parent or guardian, whereas the child completed the Children's Depression Inventory. Most children and young people (86–95%) showed no changes in any of the measures of quality of life, behaviour, depression or executive function after 24\xa0weeks of treatment. The exception was mean Child Health Questionnaire physical summary scores, which declined from baseline, indicating worse physical aspects of quality of life; 15% experienced a clinically significant decline and no patients experienced a clinically significant improvement (p=0.013 for changes in mean scores). However, after 1 or 2\xa0years of follow-up, none of the children and young people who completed 48\xa0weeks of treatment showed differences from baseline (p>0.05) for any of the quality-of-life outcome measures.\n\nNone of the 5 studies of peginterferon alfa‑2b reported health-related quality-of-life outcomes.\n\n## Assessment Group's critique of Roche's clinical-effectiveness submission\n\nAccording to the Assessment Group, Roche did not conduct a systematic review of clinical effectiveness. The bibliographic databases and search strategies provided by the manufacturer were not sufficiently detailed to permit the Assessment Group to reproduce the evidence. Roche provided clinical-effectiveness results primarily from Schwarz et al., Sokal et al. and 2 other uncontrolled trials, which did not meet the inclusion criteria for the decision problem because 1 study had a population older than that specified in the scope and the other study was retrospective and did not provide details of peginterferon dose or treatment duration. The Assessment Group commented that Roche did not report the methods it used to screen, extract or quality assess the literature.\n\nThe Assessment Group noted that Roche reported comparative data for both arms of the study by Schwarz et al., even though peginterferon alfa‑2a monotherapy is outside the marketing authorisation and scope. The Assessment Group noted that the proportion of patients with a sustained virological response in Roche's submission were comparable with those seen in the assessment report. Roche did not report virological outcomes during treatment or health-related quality of life. Effects of treatment on weight, height and growth were reported only from the studies excluded from the Assessment Group's evaluation. Roche concluded that the evidence demonstrated that peginterferon alfa‑2a plus ribavirin was effective compared with best supportive care for all genotypes.\n\nThe Assessment Group commented that, although Roche stated in its submission that there was no safety concern with regard to adverse reactions to peginterferon alfa‑2a, it reached this conclusion using data only from the Schwarz et al. study, in which both treatment arms received peginterferon alfa‑2a.\n\n## Assessment Group's critique of Merck Sharp and Dohme's clinical-effectiveness submission\n\nMSD's submission reported a systematic review of clinical effectiveness that included 8 studies, but only presented study characteristics for 5. Of the 8 studies, 6 were among the Assessment Group's 7 studies: 4 for peginterferon alfa‑2b (Al Ali et al.; Jara et al.; Pawlowska et al.; Wirth et al.) and 2 for peginterferon alfa‑2a (Schwarz et al.; Sokal et al.). Of the studies included in the manufacturer's submission but excluded from the assessment report, 1 had included patients older than the age range specified in the scope and the other included patients who had previously received non-pegylated interferon. The MSD submission did not include the Ghaffar et al. study included in the assessment report.\n\nMSD's submission included data on growth inhibition and adverse events, and a meta-analysis that pooled data for sustained virological response, virological response at 24\xa0weeks, relapse, discontinuation of treatment and selected adverse events. The Assessment Group commented that the sustained virological response rates included in MSD's submission were comparable with those in the assessment report, and that there was moderate to substantial heterogeneity in the meta-analyses (and therefore the interpretation of the results was unclear). MSD concluded that both peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin were effective compared with best supportive care, and that there were no clear differences between treatments.\n\n# Cost effectiveness\n\nThe Assessment Group systematically reviewed existing economic evaluations of peginterferon alfa‑2a and peginterferon alfa‑2b treatment in children and young people with chronic hepatitis\xa0C. It identified a conference abstract and a paper, but neither met its criteria for inclusion.\n\nThe Assessment Group also systematically reviewed the literature on health-related quality of life of people with chronic hepatitis\xa0C to populate the economic model with health-state utility values and calculate quality-adjusted life years (QALYs). It restricted searches to studies using EQ‑5D. The Assessment Group identified 2 published studies (Bjornsson et al. 2009, Chong et al. 2003) performed in adults with chronic hepatitis\xa0C in Sweden and Canada, but found no studies in children. The Assessment Group concluded that the estimates were sufficiently robust to use in its economic evaluation.\n\n## Roche's economic model for peginterferon alfa‑2a plus ribavirin\n\nRoche submitted an economic evaluation using a Markov model with a structure similar to other models used to evaluate treatments for chronic hepatitis\xa0C in adults. Roche compared the costs and health outcomes of treatment with peginterferon alfa‑2a plus ribavirin with best supportive care (no drug treatment). Roche's model extrapolated the health effects of peginterferon alfa‑2a plus ribavirin in children and young people with hepatitis\xa0C reflecting the population characteristics of the clinical trials over a 30‑year time horizon. Children enter the model at an average age of 11\xa0years in a model state of mild or moderate hepatitis\xa0C-related fibrosis (88% and 12% respectively), based on the weighted average of children and young people participating in the peginterferon alfa‑2a studies. Children and young people with HCV genotype 1, 4 or 5 whose disease has responded to treatment with peginterferon alfa‑2a plus ribavirin at 24\xa0weeks receive treatment for 48\xa0weeks. Children and young people with HCV genotype 2 or 3 are split into 2 groups to compare 24\xa0weeks of treatment with 48\xa0weeks of treatment. One group receives treatment for 24\xa0weeks only and the other for 48\xa0weeks (if their hepatitis\xa0C responds to treatment at 24\xa0weeks). If treatment does not result in a sustained virological response, children and young people remain in their current health state or 'progress' to mild hepatic fibrosis, moderate hepatic fibrosis, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (liver cancer), liver transplantation or death. For transitions to decompensated cirrhosis, hepatocellular carcinoma and liver transplantation, Roche used transition probabilities from adults used in previous appraisals for chronic hepatitis\xa0C. Roche assumed that the mortality risks for those in the sustained virological response, mild hepatic fibrosis, moderate hepatic fibrosis and compensated cirrhosis states were the same as in the general population. Roche assumed that the mortality risks for people in the decompensated cirrhosis, hepatocellular carcinoma and liver transplantation states were similar to those of people with chronic liver disease.\n\nRoche's model also included a probability of spontaneous sustained virological response in untreated children: an annual probability of 2.37% for children with maternally transmitted HCV within the first 5\xa0years and an annual probability of 1.65% for children with HCV acquired by other means. Based on the studies identified by Roche, 70% of children have maternally transmitted HCV and 30% have non-maternally transmitted HCV. Roche assumed that the most common adverse reactions seen in the studies, such as flu-like illness, chest infections, headache, and gastrointestinal and skin disorders, would impact on health-related quality of life, but not on costs. Roche did not include depression related to peginterferon alfa‑2a as an adverse reaction in the economic model. It assumed that the disutility from treatment with peginterferon alfa‑2a was equal to treatment with non-pegylated interferon, as seen in the Wright et al. (2006) study in adults.\n\nRoche's base-case analysis considered treatment-naive children and young people, as reflected in the peginterferon alfa‑2a studies and in accordance with the UK marketing authorisation. Roche also presented an analysis for a subgroup of patients whose disease does not respond to treatment and who are re-treated. The model evaluated costs from the perspective of the NHS and personal social services. Costs and health outcomes were discounted at a rate of 3.5% per annum, in accordance with the NICE reference case.\n\nRoche estimated the clinical effectiveness of treatment in the base case according to the weighted average percentages of patients who had a sustained virological response in the Schwarz et al. study and 3 uncontrolled studies: 59% for genotypes 1, 4, 5 and 6 with 48\xa0weeks of treatment and 89% for genotypes 2 and 3 with 24\xa0weeks of treatment. Roche included the cost of peginterferon alfa‑2a and ribavirin, as well as the cost of evaluating and monitoring patients. Administration costs were not included. The drug doses depended on age, body surface area and weight, and the base-case model assumed an average dose corresponding to the dosing regimen of the population in the Schwarz et al. trial using an age-related mean height and weight from the Health Survey for England 2010. In the base case, the estimated costs for 48\xa0weeks of combination therapy were £8307. Roche assumed that patients do not share vials.\n\nRoche assumed that children and young people who have a sustained virological response would not incur any further costs related to chronic hepatitis\xa0C. Roche performed sensitivity analyses using assumptions from previous appraisals in which sustained virological response costs were £335 and follow-up surveillance costs for children and young people whose hepatitis\xa0C has responded in the first year were £165.\n\nFor children and young people younger than 17\xa0years, Roche applied a baseline utility of 0.95 in line with a study by Saigal et al. (1994). For the healthy population aged 17\xa0years and older, the model applied utility values for adults, derived using an algorithm developed by Ara and Brazier (2009), in line with the EQ‑5D derived utility weights used in previous health technology assessments for adults with chronic hepatitis\xa0C. The mean utility value for sustained virological response after mild disease was 0.83, whereas the utility weight for having mild disease was 0.77 and for receiving peginterferon treatment for mild disease was 0.66. The mean utility value for moderate liver disease was 0.66 and for receiving treatment for moderate disease was 0.55, compared with 0.55 for compensated cirrhosis, 0.45 for either decompensated cirrhosis or hepatocellular carcinoma and 0.67 after liver transplantation.\n\n## Results of Roche's economic model\n\nThe cost-effectiveness result for Roche's base-case population for peginterferon alfa‑2a plus ribavirin compared with best supportive care was £3914 per QALY gained for children and young people with HCV genotype 1, 4 or 5. Peginterferon alfa‑2a plus ribavirin dominated (that is, was less costly and more effective than) best supportive care for children and young people with HCV genotype 2 or 3. The results from Roche's cost-effectiveness acceptability curves for its base-case populations showed that the probability that peginterferon alfa‑2a plus ribavirin treatment was cost effective compared with best supportive care at £20,000 per QALY gained for children and young people with HCV genotype 1, 4 or 5 treated for 48\xa0weeks was 91.6%, and for children and young people with HCV genotype 2 or 3 treated for 24\xa0weeks was 97.2%.\n\nRoche performed one-way and two-way deterministic analyses and found that the results were most sensitive to the time horizon, rate of disease progression, probability that a patient had a sustained virological response with treatment, liver disease at baseline, the value of the health-state utilities and annual cost of achieving sustained virological response. The cost effectiveness of peginterferon alfa‑2a compared with best supportive care remained below £13,000 per QALY gained for all analyses.\n\n## Merck Sharp and Dohme's economic model for peginterferon alfa‑2b plus ribavirin\n\nMSD submitted a de novo economic evaluation based on previously published economic evaluations of the treatment of chronic hepatitis\xa0C in adults. It compared the costs and health outcomes of peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin for treating children and young people aged 3–17\xa0years compared with best supportive care. The base‑case economic analysis included previously untreated children and young people aged 5–17\xa0years without HIV co‑infection. Because peginterferon alfa‑2b has a marketing authorisation that also includes children aged 3–4\xa0years, MSD conducted an additional subgroup analysis in this age group. It used a Markov model that follows a hypothetical cohort over a lifetime time horizon (up to age 100\xa0years). People enter the model in the mild hepatitis\xa0C, moderate hepatitis\xa0C or compensated cirrhosis states and receive treatment in cycle 1 for 12, 24 or 48\xa0weeks depending on stopping rules (whether a patient's disease responds during treatment) and genotype. The modelled health states are: mild liver fibrosis, moderate liver fibrosis, compensated cirrhosis of the liver, decompensated cirrhosis of the liver, hepatocellular carcinoma (liver cancer), liver transplantation or death. MSD used child-specific probabilities for transitions between the mild and moderate fibrosis states, and the moderate fibrosis and compensated cirrhosis states. Transition probabilities from studies in adults were used for more advanced hepatitis\xa0C health states. MSD assumed that the mortality risks for people in the sustained virological response, mild liver fibrosis, moderate liver fibrosis and compensated cirrhosis states were the same as for the general population. MSD assumed that children and young people in the decompensated cirrhosis, hepatocellular carcinoma and liver transplantation states have a higher mortality risk than the general population.\n\nMSD's base-case analysis considered treatment-naive children and young people using data from peginterferon alfa‑2b studies and in accordance with the UK marketing authorisation for peginterferon alfa‑2b. The model evaluated costs from the perspective of the NHS and personal social services. Costs and health outcomes were discounted at a rate of 3.5% per annum, in accordance with the NICE reference case.\n\nMSD modelled parameters reflecting the clinical effectiveness of peginterferon alfa‑2a and ‑2b plus ribavirin in the base case, using calculated weighted averages of the percentage of patients who had a sustained virological response from 8 trials (section 4.1.19). MSD included the costs of peginterferon alfa‑2a and ‑2b plus ribavirin, of investigations, and of monitoring during and after treatment. MSD did not include costs associated with treating adverse events, noting the precedent of Peginterferon alfa and ribavirin for the treatment of chronic hepatitis\xa0C (part review of NICE technology appraisal guidance 75 and 106) (NICE technology appraisal 200). Dosing depended on age, body surface area and weight. The average ages at model entry were 7\xa0years (age 5–8\xa0years; 30.8%), 11\xa0years (age 9–13\xa0years; 38.5%) and 16\xa0years (age 14–17\xa0years; 30.8%) and there was an equal distribution of males and females. For body weight and height, MSD derived its estimates from mean values from the UK World Health Organisation growth charts for 2009 and UK 1990 standard centile charts presented in BNF\xa063. MSD assumed that patients do not share vials.\n\nMSD used health-state costs presented in previous appraisals of adults because it did not identify any published evidence on costs associated with chronic hepatitis\xa0C in children and young people. The costs associated with having a sustained virological response for children and young people starting with mild to moderate hepatitis\xa0C were applied for 5\xa0years in the model, while the costs associated with having a sustained virological response for children and young people starting with cirrhosis were applied over the person's lifetime. The costs associated with each health state were inflated to 2010/11 values using the Hospital and Community Health Services Pay and Price Index used in the economic model. Child-specific costs for resource use and monitoring while on treatment, including follow‑up visits after the completion of treatment, were also included in the model.\n\nBecause there is no published evidence on health-related quality of life for children and young people with chronic hepatitis\xa0C, MSD used values for its economic analysis from previous NICE technology appraisals of adults with chronic hepatitis\xa0C. The utility values for patients with mild hepatitis\xa0C were elicited using the standard EQ‑5D time trade-off tariff from people with hepatitis\xa0C (Wright et al). The disutility value for treatment-emergent adverse reactions was also derived from this trial. People receiving peginterferon alfa‑2b plus ribavirin had a utility value of 0.77 at baseline and 0.66 when assessed at 12 and 24\xa0weeks after starting treatment. MSD applied the resulting reduction in utility of 0.11 to all patients receiving peginterferon alfa‑2b in the model regardless of disease severity. MSD obtained utility values for patients with moderate and compensated cirrhosis from a multicentre observational study involving 302 patients with severe liver disease associated with chronic hepatitis (reported in Wright et al.). For the remaining health states, MSD used utility values from a prospective multicentre study by Longworth et al. (2004) assessing health-related quality of life before and after liver transplant in the UK.\n\n## Results of Merck Sharp and Dohme's economic model\n\nThe cost-effectiveness results for MSD's base-case population (age 5–17\xa0years) suggested that both types of peginterferon alfa (2a and 2b) plus ribavirin dominated best supportive care, that is, were more effective and cost less. MSD obtained a similar result for children aged 3–4\xa0years. Both types of peginterferon alfa (2a and 2b) plus ribavirin dominated best supportive care for all genotypes. Peginterferon alfa‑2b dominated peginterferon alfa‑2a in the base-case analysis (all ages, −£3397 per QALY gained) and in all subgroup analyses, except in children and young people aged 9–13\xa0years, and in children and young people with HCV genotypes 1 or 4. MSD conducted deterministic sensitivity analyses around structural assumptions (time horizon, discount rates) and the modelled parameter values. The deterministic sensitivity analyses showed that peginterferon alfa‑2b dominated best supportive care in most scenarios, except in those in which MSD varied the time horizon, assumed efficacy and discount rates.\n\n## Assessment Group's critique of the cost-effectiveness analyses by Roche and Merck Sharp and Dohme\n\nThe Assessment Group critiqued the Roche and MSD submissions and considered that the economic models met all of the requirements for methodological quality and generalisability, except that neither manufacturer provided evidence that its model had been validated.\n\nRoche and MSD used the state-transition model applied in previous health technology assessments of peginterferon alfa treatments in adult populations, which the Assessment Group considered appropriate, commenting that most of the time spent in the model would be after treatment as an adult, rather than as a child. Because most children and young people start treatment (and enter the model) with mild chronic hepatitis\xa0C, few will progress to more severe health states before they become adults. Therefore, the Assessment Group considered that health-state transition values from adults used in the manufacturers' models were appropriate.\n\nBoth Roche and MSD conducted literature reviews to estimate the transition probabilities from mild-to-moderate and moderate-to-compensated cirrhosis health states. The transition probability for mild-to-moderate hepatitis\xa0C was 0.014 per cycle in both manufacturers' submissions, whereas the transition probabilities for moderate hepatitis\xa0C to compensated cirrhosis differed for Roche (0.021) and MSD (0.0038) and for the Assessment Group (see section 4.2.29).\n\nThe manufacturers' models used different time horizons: Roche used a time horizon of 30\xa0years and MSD used a lifetime horizon. Another difference between the manufacturers' models was that Roche assumed that some patients have a spontaneous sustained virological response (that is, without treatment) in its base-case, whereas MSD only tested this assumption in a sensitivity analysis. The Assessment Group commented on the small (less than 3%) probability of spontaneous sustained virological response assumed by Roche, noting it was unlikely to affect the cost-effectiveness results. Both manufacturers applied the same health-state utility values used in previous adult chronic hepatitis\xa0C models except for the values for sustained virological response in the mild disease state, which were almost identical in both submissions (0.83 and 0.82 Roche and MSD respectively). Roche did not provide utility values for having a sustained virological response in the moderate disease or compensated cirrhosis health states. Most health-state costs used in the manufacturers' submissions were similar or the same.\n\n## Assessment Group's economic model\n\nThe Assessment Group developed an economic model estimating the cost effectiveness of peginterferon alfa‑2a and peginterferon alfa‑2b (both plus ribavirin) for treating chronic hepatitis\xa0C in children and young people compared with each other and with best supportive care. The model converted the probability of sustained virological response (the definition of treatment effectiveness) to long-term survival outcomes from the systematic review. The perspective of the analysis was that of the NHS and personal social services. The model time horizon was 70\xa0years and the cycle length was 1\xa0year. The costs and benefits were discounted at 3.5% per year, in accordance with the NICE reference case. Costs were taken from the most recently available data (2011/12). The Assessment Group confirmed the functionality of its model by checking the structure, calculations and data inputs.\n\nThe Assessment Group adapted models used in Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis\xa0C (extension of technology appraisal guidance 75) (NICE technology appraisal 106) and Peginterferon alfa and ribavirin for the treatment of chronic hepatitis\xa0C (part review of NICE technology appraisal guidance 75 and 106) (NICE technology appraisal 200), which assessed chronic hepatitis\xa0C in adults. The Assessment Group modified the structure of the model to include health states for the different levels of fibrosis (F0–F4, METAVIR scoring system), instead of the health states of mild hepatitis\xa0C, moderate hepatitis\xa0C and compensated cirrhosis. It did this based on evidence from Thein et al. (2008), which reviewed published rates of progression specific to stages of fibrosis progression rates based on 111 studies of people with chronic hepatitis\xa0C (n=33, 121). In the model, people with chronic hepatitis\xa0C with a METAVIR score between F0 and F3 or compensated cirrhosis (F4) can have a sustained virological response; remain in their current health state; or progress to more severe stages of liver disease. The Assessment Group assumed that a person who has a sustained virological response does not experience a relapse. It also assumed that people who have a sustained virological response or chronic hepatitis\xa0C with a METAVIR score between F0 and F4 have the same mortality risk as the general population, whereas people with decompensated liver disease, hepatocellular carcinoma and those who undergo liver transplantation have higher mortality risks.\n\nThe Assessment Group incorporated most of the assumptions made in the models used in previous technology appraisals for chronic hepatitis\xa0C in adults, including: that a person's disease state before treatment influences the subsequent risk of progressive liver disease and health-related quality of life; that a person who does not have a sustained virological response has the same risk of disease progression as a person who does not receive treatment; that a person with mild or moderate hepatitis\xa0C and compensated cirrhosis has the same probability of having a sustained virological response; that the model excludes the rare possibility of having to stop treatment because of adverse reactions; and that the model excludes costs associated with managing adverse reactions because they are unlikely to be substantial. After discussion with experts, the Assessment Group further assumed that no patient would have a sustained virological response spontaneously (that is, without treatment); that a patient with genotype 1 or 4 HCV stops treatment at 24\xa0weeks if there is no virological response by week\xa012; and that it would be acceptable to include transition probabilities, utility weights and health-state costs from adults in the model. Although the Assessment Group noted that a child's hepatitis\xa0C can affect parents' or carers' quality of life, it did not find sufficient evidence to include it in the model. The Assessment Group commented that stigma associated with hepatitis\xa0C may lower the quality of life of children and young people; however, the data were sparse.\n\nThe Assessment Group used the baseline characteristics of the populations from the clinical trials in its model including the distribution across METAVIR stages of chronic hepatitis\xa0C of 24.6% at stage F0 (no fibrosis), 66.2% at stage F1 (portal fibrosis with no septa), 7.1% at stage F2 (portal fibrosis with few septa), 2.1% at stage F3 (septal fibrosis with no cirrhosis) and 0 at stage F4 (compensated cirrhosis).\n\nFor utility values and health-state costs, the Assessment Group used values from previous technology appraisals so that F0 and F1 corresponded to the mild, and F2 and F3 to the moderate, hepatitis\xa0C health states. The Assessment Group searched for new evidence related to the natural history of hepatitis\xa0C in children or young people, but found none.\n\n## Results of Assessment Group's economic model\n\nThe Assessment Group's probabilistic cost-effectiveness results for the base-case population suggested that both peginterferon alfa‑2a and peginterferon alfa‑2b dominated best supportive care because they were less expensive and more effective. Treatment was more effective for genotype 2 or 3 than for genotype 1 or 4.\n\nThe Assessment Group's base-case results for peginterferon alfa‑2a compared with peginterferon alfa‑2b showed that peginterferon alfa‑2a cost less (£19,055 compared with £20,371) and was more effective than peginterferon alfa‑2b (22.25 QALYs compared with 22.19 QALYs). For people with genotype 1 or 4, peginterferon alfa‑2a was also less costly and more effective than peginterferon alfa‑2b (£21,278 compared with £22,316; 22.00 QALYs compared with 21.97 QALYs). However, for people with genotype 2 or 3, peginterferon alfa‑2a cost more and was less effective than peginterferon alfa‑2b (£11,831 compared with £11,202; 23.05 QALYs compared with 23.21 QALYs). The Assessment Group stated that the estimates of clinical effectiveness were key drivers of the differences in costs and outcomes between peginterferon alfa‑2a and peginterferon alfa‑2b within the model.\n\nThe Assessment Group performed one-way deterministic sensitivity analyses investigating the effect of uncertainty on the cost-effectiveness results varying the time horizon (30\xa0years and 90\xa0years); discount rate (0% discount for both costs and outcomes, 6% discount for costs with 1.5% discount for outcomes, 1.5% discount for both cost and outcomes, and 6% for both cost and outcomes); the proportions of people who had a sustained virological response with peginterferon alfa‑2a (69% and 51%) and with peginterferon alfa‑2b (65% and 52%); degree of liver fibrosis (100% F0, 100% F2, 100% F3 and 20% F4); starting age (5\xa0years and 16\xa0years); transition probabilities (lower confidence interval [CI] and upper CI); utility values (lower CI, upper CI and from previous appraisal); and health-state costs (lower CI and upper CI). In all analyses, both peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin dominated best supportive care. The analyses showed that the model was most sensitive to changes in the discount rate chosen and the time horizon. In most cases, peginterferon alfa‑2b was dominated by peginterferon alfa‑2a for all changes to the model parameters except for changes to the value reflecting the proportion of people who have a sustained virological response (peginterferon alfa‑2a ‑ 51%; or peginterferon alfa‑2b ‑ 65%) and the starting age of the cohort (age 5\xa0years). However, the Assessment Group commented that the deterministic sensitivity analysis for peginterferon alfa‑2b compared with peginterferon alfa‑2a should be treated with caution because of uncertainty around the relative treatment effect.\n\nThe Assessment Group also conducted scenario analyses. In 1 scenario analysis, it varied the transition probabilities between the chronic hepatitis\xa0C health states (F0–F3) to the decompensated cirrhosis health state (F4), varying the transition probabilities from 0.1 (used in the base case) to between 0.05 and 0.3, with the same probability applied for transitions between each of the states from F0 to F4. Peginterferon alfa‑2a dominated best supportive care for all transition probabilities used in the scenario analysis to a lesser or greater extent depending on the amount of time spent in the chronic hepatitis\xa0C state. Another scenario analysis assessed the impact of delaying peginterferon alfa‑2a treatment until age 18–30\xa0years instead of starting it during childhood. This 'watchful waiting' strategy was associated with slightly higher costs (between £21,959 and £26,668) and slightly reduced QALYs (between 22.22 and 21.79 QALYs) compared with treatment during childhood (£19,055 and 22.25 QALYs for the base case). The Assessment Group commented that the conclusions made in scenarios 2 and 3 would also apply to peginterferon alfa‑2b compared with best supportive care.\n\nThe Assessment Group conducted probabilistic sensitivity analyses for the following parameters: the proportion of children and young people with a given genotype, transition probabilities, health-state utilities and costs associated with monitoring, health states and treatment. The results of the probabilistic sensitivity analysis closely reflect the results of the deterministic base case. The probabilities that peginterferon alfa‑2a and ‑2b are cost effective at £20,000 and £30,000 per QALY gained were 68% and 66% for peginterferon alfa‑2a, and 32% and 34% for peginterferon alfa‑2b, respectively.\n\n## Comparison of the Assessment Group and manufacturers' models\n\nThe Assessment Group compared its results with those of the manufacturers. It commented that all 3 models found that peginterferon alfa‑2a and peginterferon alfa‑2b (each plus ribavirin) dominated best supportive care. MSD and the Assessment Group also compared peginterferon alfa‑2a with peginterferon alfa‑2b. The Assessment Group's results, which suggested that peginterferon alfa‑2a dominated peginterferon alfa‑2b, differed from those of MSD, which suggested that peginterferon alfa‑2b dominated peginterferon alfa‑2a. The Assessment Group suggested caution when interpreting these results because the differences were marginal. The costs and QALY estimates used in each evaluation varied. The differences in costs were based on the use of a shorter time horizon (Roche) or the length of time spent in chronic hepatitis\xa0C health states (shorter in the Assessment Group's analysis compared with MSD's). The differences in QALY estimates were based on the use of a shorter time horizon (Roche) and the lower utility values used (MSD) compared with the Assessment Group's model.\n\n## Innovation\n\nRoche commented that pegylated interferons have existed for over 15\xa0years, so it does not consider pegylated interferon to be an innovative medicine, but instead is an option available to physicians, patients and carers when considering treatments for chronic hepatitis\xa0C. By contrast, MSD considered that peginterferon alfa (2a and 2b) plus ribavirin were innovative therapies for treating chronic hepatitis\xa0C in adults when first launched and that extending the marketing authorisation to children and young people means that this innovation now applies to younger patients. In addition, peginterferon alfa‑2a and peginterferon alfa‑2b are dosed once weekly, compared with the 3‑times weekly dosing of interferon alfa, therefore reducing the burden of the treatment.\n\nMSD believes that successfully treating chronic hepatitis\xa0C in children and young people will affect parents and carers, and this would not be captured in calculating the QALY. MSD cited a study reporting that hepatitis\xa0C among children and young people is associated with increased carer stress, and a study conducted in Australia indicating substantial quality-of-life benefits for parents and carers when the child has a sustained virological response.\n\nMSD also commented that children and young people with chronic hepatitis\xa0C who have a sustained virological response do not infect others with the virus, and this reduces the risk of onward transmission of HCV in the UK.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin, having considered evidence on the nature of chronic hepatitis\xa0C in children and young people and the value placed on the benefits of technologies by people with the condition, their families and carers, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n## Clinical effectiveness\n\nThe Committee heard from the clinical specialists that both peginterferon alfa‑2a and peginterferon alfa‑2b (each plus ribavirin) are currently used to treat some children and young people with chronic hepatitis\xa0C in the UK. The clinical specialists confirmed that the 2 peginterferons are considered equivalent in their mechanism of action and clinical efficacy; however, peginterferon alfa‑2b is prescribed more frequently because it can also be given to children who are aged 3–4\xa0years. The Committee heard from the clinical specialists that the decision to treat children, instead of delaying treatment until a child is symptomatic ('watchful waiting') or reaches adulthood, depends on the age of the child and how the infection is contracted and therefore how likely a spontaneous sustained virological response is without treatment. The Committee heard that children aged 3\xa0years or younger, or those who contract HCV infection through a blood transfusion, are more likely to have a spontaneous sustained virological response during the acute infection phase than those who are aged 4\xa0years and older or who have contracted the infection from their mother at birth and are in the chronic phase. The Committee recognised that the decision to treat with either regimen would largely be determined by clinical judgement and the specifics of the marketing authorisation.\n\nThe Committee considered the impact that difficult family circumstances, such as parents who misuse drugs, may have on the ability of children and young people to adhere to treatment. It heard that clinical specialists do not recommend treating children and young people and their mothers (if they also have hepatitis\xa0C) at the same time because the adverse reactions of treatment for each might affect adherence. The clinical specialists indicated that support for children and young people and their families is not routinely available from adult hepatology centres and, to adhere to treatment, children and young people need specialised support, which is only available in some specialist hepatology centres in England and Wales. The Committee noted that families living away from a specialist centre would have the burden of travelling for treatment and monitoring. The Committee concluded that, although the timing of treatment is important, and better health outcomes are more likely if support is provided to ensure adherence to treatment, how to manage the disease is ultimately the decision of parents or carers, and the child or young person, together with clinicians,.\n\nThe Committee considered the evidence presented on the proportion of children and young people with chronic hepatitis\xa0C who have a sustained virological response after treatment with peginterferon alfa plus ribavirin. It acknowledged the paucity of relevant studies in children and young people identified by the manufacturers and the Assessment Group, and noted that these studies had enrolled few patients and were generally of poor quality. In addition, because the evidence base largely comprised single-arm studies that did not have any control groups which did not receive therapy, the Committee would have expected the manufacturers' and Assessment Group's submissions to have provided supporting data from adult trials to establish the efficacy of peginterferon alfa (2a and 2b) plus ribavirin. The Committee was aware that having a lower viral load or milder degree of liver damage at the start of treatment increases the likelihood of a sustained virological response. Despite the limitations of the clinical evidence and the lack of comparative evidence, the Committee concluded that peginterferon alfa (2a and 2b) plus ribavirin is an effective therapy in children and young people with chronic hepatitis\xa0C across all genotypes.\n\nThe Committee discussed the generalisability of the trial results to the UK population and heard from the clinical specialists that the average age of entry into the trials (age 11\xa0years) reflects the average age of children and young people currently treated in the UK, although it was noted that, in the future, patients will be treated at a younger age once newer therapies become available. The Committee also heard from the clinical specialists that some children clear the virus spontaneously without treatment, but that the proportion that do is considerably lower than the proportion that cleared the virus when treated in the single-arm studies. The Committee was satisfied that the trial results were largely generalisable to the UK population.\n\nThe Committee queried whether there were any subgroups in which treatment with peginterferon alfa plus ribavirin would be most clinically effective, whether there were groups in which clinicians chose to 'watch and wait' rather than to treat, and if there was a general acceptance in the clinical community about the 'best' time to treat chronic hepatitis\xa0C. The clinical specialists stated that children and young people with interleukin‑28 (IL‑28) gene polymorphism were more likely to clear HCV with or without treatment, but that testing for IL‑28 is not routinely performed in UK clinical practice. The Committee heard from the clinical specialists that obesity is an increasing problem in children and young people and although it has been linked with a lower probability of having a sustained virological response, it is not currently a factor that precludes patients from having treatment. With respect to the timing of treatment, the Committee heard from the clinical specialists that, because younger children have lower baseline viral loads and less liver damage, both of which improve the response to treatment, treating early was better than treating later in adolescence or adulthood. The Committee also heard that before the age of 10\xa0years a child's immune system mounts less of an inflammatory response to HCV, and that this period precedes the pubertal growth spurt; therefore, treatment given at this time reduces the possible negative impact on a child's growth rate. Additionally, because young children have fewer comorbidities and generally do not consume alcohol, they have fewer complications associated with liver disease and therefore are more likely to have favourable outcomes following treatment. The Committee heard from the clinical specialists that another benefit of treating a child early is that he or she may not remember the treatment itself or even ever having had hepatitis\xa0C. The Committee concluded that clinical experience supported early treatment, but that the decision about whether and when to treat should be made by parents or carers together with the child's or young person's clinician.\n\nThe Committee considered how likely it is that children and young people with a sustained virological response will remain free from HCV; that is, how likely it is that they will be 'cured'. It understood that 95% of children and young people treated before the onset of significant liver disease and who have a sustained virological response remain free from HCV for the rest of their lives. The Committee heard from the clinical specialists that people do not generally undergo repeat liver biopsies after treatment has been completed, but studies showed that children and young people with sustained virological responses remained healthy in the following 5\xa0years. It noted however that these studies were small and not necessarily representative of the UK population; therefore the Committee would have expected to have been presented with data from trials in adults with HCV to augment the evidence related to the likelihood of a long-term response in children and young people after treatment with peginterferon alfa plus ribavirin. Nevertheless, the Committee concluded that it was plausible that a sustained virological response achieved in childhood or adolescence could last throughout a person's lifetime.\n\nThe Committee was aware that the population identified in the scope specified children and young people who have not previously been treated for HCV. It heard that clinicians do not offer re-treatment to children and young people previously treated with peginterferon plus ribavirin. Instead, when treatment has not resulted in a sustained virological response, these children and young people might be enrolled in a clinical trial of a newer technology or offered further treatment options (such as boceprevir or telaprevir) from 18\xa0years of age, in line with guidelines for the treatment of adults with chronic hepatitis\xa0C. The Committee was reassured by the clinical specialists that children and young people would be treated only once with peginterferon alfa plus ribavirin, if it was recommended for routine use in UK clinical practice.\n\nThe Committee considered the adverse reactions of treatment with peginterferon alfa plus ribavirin. It heard that the main adverse reactions are: severe psychiatric and central nervous system effects, particularly depression, suicidal ideation and attempted suicide, weight loss and growth inhibition. The Committee heard from the patient expert that the patient community had documented aggressive behaviour possibly attributable to ribavirin. However, such aggressive behaviour was attributed by the manufacturers to peginterferon alfa, not ribavirin. The manufacturers and the clinical specialists explained that, without studies that compare treatment with peginterferon alfa with and without ribavirin, it was sometimes difficult to separate the adverse reactions of peginterferon alfa from those of ribavirin. The Committee was aware that the Schwarz et al. study made this comparison, but these data were not presented to the Committee. The Committee also heard that other important adverse reactions associated with treatment are slowed growth and weight loss, both of which are of particular concern during the pubertal growth period. The clinical specialists explained that 48\xa0weeks of treatment with peginterferon alfa plus ribavirin during this period can result in a small reduction in expected height and, while some studies have shown that growth resumes after treatment, some children and young people do not return to their pre-treatment growth percentile. The Committee acknowledged advice from the clinical specialists that, if a decision is made to delay treatment beyond puberty, clinicians would monitor the patient's condition and, if it worsens, treatment options would be re-evaluated. The Committee concluded that, although treatment with peginterferon alfa plus ribavirin may impair growth, the possibility of progressive liver disease without treatment outweighs the problems associated with being slightly shorter.\n\nThe Committee considered whether there is a stigma associated with hepatitis\xa0C in children and young people. The clinical specialists and patient experts expressed the opinion that a stigma associated with hepatitis\xa0C does exist, in part related to its association with intravenous drug misuse. The Committee heard that children and young people with hepatitis\xa0C have more difficultly being placed with foster parents because of largely unfounded fears that the virus will be transmitted to other family members and also because of possible psychological effects associated with treatment. The Committee concluded that hepatitis\xa0C was associated with a stigma, and early successful treatment would lessen the stigma later in life.\n\nThe Committee considered whether peginterferon alfa (2a and 2b) plus ribavirin were innovative technologies for treating hepatitis\xa0C in children and young people. It was aware that, when first introduced for adults, both peginterferons were likely to have been innovative treatments. However, the Committee concluded that, although peginterferon alfa plus ribavirin represented a useful treatment option for children and young people with chronic hepatitis\xa0C, the technologies themselves could no longer be considered innovative for the purpose of this evaluation, since they had already been used successfully in adults.\n\n## Cost effectiveness\n\nThe Committee considered the Assessment Group's and the 2 manufacturers' economic models. It noted that:\n\nThe Assessment Group's and MSD's cost-effectiveness results for their respective base cases showed that peginterferon alfa plus ribavirin was more effective and less costly than best supportive care across all genotypes.\n\nRoche's cost-effectiveness modelling resulted in an incremental cost-effectiveness ratio (ICER) for peginterferon alfa plus ribavirin of £3900 per QALY gained compared with best supportive care in children and young people with HCV genotype 1, 4 or 5. Peginterferon alfa plus ribavirin dominated best supportive care in children and young people with genotype 2 or 3.\n\nWhen comparing the 2 peginterferons, the Assessment Group's base case showed that peginterferon alfa‑2a dominated peginterferon alfa‑2b, whereas MSD found that peginterferon alfa‑2b mainly dominated peginterferon alfa‑2a.\n\nThe Committee noted that the stopping rules differed between both the manufacturers' submissions and the Assessment Report (section 4.2.3 [Roche], 4.2.11 [MSD], and 4.2.23 [Assessment Group]). It was aware that, according to the summary of product characteristics for peginterferon alfa‑2a, patients infected with HCV genotype 2 or 3 should receive 24\xa0weeks of treatment, whereas patients infected with any other genotype should receive 48\xa0weeks of therapy unless they have detectable levels of HCV\xa0RNA despite an initial 24\xa0weeks of therapy, at which point they should stop therapy because it is unlikely they will have a sustained virological response with continued therapy. The Committee heard from the clinical specialists that, in practice, children and young people with genotype 2 or 3 are evaluated for an early virological response at 12\xa0weeks, although they generally continue to receive treatment for 24\xa0weeks. Children and young people with genotype 1 or 4 are encouraged to stop treatment at 24\xa0weeks if there has not been a virological response, although some parents prefer their children to continue treatment for the full 48\xa0weeks regardless of initial response. The Committee would have expected the stopping rules to be consistent with clinical practice and the marketing authorisation of both products but concluded that, although the stopping rules varied across the models, the uncertainty associated with this was unlikely to alter the conclusions about the cost effectiveness of either of the peginterferons compared with best supportive care.\n\nThe Committee discussed whether, for patients who do not have a sustained virological response to peginterferon alfa plus ribavirin, subsequent treatment in adulthood with the second-generation technologies boceprevir (see Boceprevir for the treatment of genotype 1 chronic hepatitis\xa0C, NICE technology appraisal 253) and telaprevir (see Telaprevir for the treatment of genotype 1 chronic hepatitis\xa0C, NICE technology appraisal 252) should have been included in the economic models. It was concerned that none of the economic evaluations included re-treatment options for young people reaching 18\xa0years of age, and noted that the impact of the future costs of these technologies in the model is uncertain. The Committee acknowledged that, despite this limitation, the results were largely robust to changes in variables within the model and therefore it was satisfied that the omission of the costs of future technologies in the model would not greatly affect conclusions about the cost effectiveness of peginterferon alfa plus ribavirin. The Committee, however, stated that it would expect future economic evaluations of treatments for children and young people with HCV to take into account the use of technologies currently licensed for adults and recommended as an option by NICE when re-treatment is required in adulthood.\n\nThe Committee noted that the utility values used in the models were based on previous technology appraisals in adults with chronic hepatitis\xa0C, and that they had not been updated, or revalidated to assess their appropriateness for an appraisal of treatments in a younger population. The Committee stated that it would have expected more detailed information about the source and validation of utility values relied on in the manufacturers' submissions. The Committee heard that the Assessment Group related the health states used in previous technology appraisals in adults with chronic hepatitis\xa0C to the METAVIR system and conducted searches to identify new evidence related to the natural history of hepatitis\xa0C in children or young people, but found no new data. It also noted that the Assessment Group relied on published utility values derived from the health-related quality of life of adults with chronic hepatitis\xa0C in Sweden and Canada to populate its economic model. The Assessment Group told the Committee that it chose these data because they were more recent than values used in previous hepatitis\xa0C technology appraisals and were based on larger sample sizes. The Committee questioned the manufacturers' and Assessment Group's choice of utility values and stated their preference for utility values derived from UK population studies. Although the Committee remained uncertain about what effect alternative utility values would have on the cost-effectiveness results, it agreed that an exploration of alternative utility values would not affect conclusions about the cost effectiveness in this appraisal.\n\nThe Committee considered the conflicting opinions in the manufacturers' submissions and the Assessment Report on whether some people can have a spontaneous sustained virological response without treatment. The Committee considered it appropriate that Roche assumed that a spontaneous 'cure' could occur in a small number of patients in its base case, but noted that this assumption was omitted from the base-case analyses of MSD and the Assessment Group, although both considered the impact of assuming a spontaneous sustained virological response in sensitivity analyses. The Committee heard from the clinical specialists that a spontaneous sustained virological response would probably only occur before the age of 4\xa0years or during the acute phase of HCV infection. The Committee concluded that addressing the impact of a spontaneous sustained virological response on the ICERs would not greatly affect the conclusions about the cost effectiveness of peginterferon alfa plus ribavirin in this appraisal, but stated that analyses in future appraisals of treatments for hepatitis\xa0C should include sensitivity analyses accounting for the possibility of a spontaneous cure without treatment.\n\nThe Committee was aware that the Roche model did not take into account costs associated with hepatitis\xa0C after treatment. It heard from the clinical specialists that this was a realistic assumption and that paediatric patients, once successfully treated, were not referred to adult hepatology clinics unless liver damage was present.\n\nThe Committee considered the disutilities associated with adverse reactions of treatment with peginterferon alfa plus ribavirin. It noted that none of the models included disutility associated with growth impairment. The Committee pointed out that such disutilities were included in the Assessment Group's economic model for Human growth hormone (somatropin) for the treatment of growth failure in children (review) (NICE technology appraisal 188), but that the children in that appraisal were considerably shorter than the average child with chronic hepatitis\xa0C. Nonetheless, the Committee would have expected the model to have included a utility decrement for growth impairment, considering that it is a significant adverse effect of peginterferon alfa plus ribavirin treatment. The Committee concluded, however, that, other than for extremely short children, this was unlikely to outweigh the benefits of treatment.\n\nThe Committee considered the use of peginterferon alfa plus ribavirin in children and young people with chronic hepatitis\xa0C who are co‑infected with HIV. It concluded that, although these patients were not represented in the pivotal clinical trials, based on the current evidence available, there was no reason to make any different provision for them. It did, however, note that there might be occasions when ribavirin might interact with drugs for HIV, necessitating a review of the patient's optimal treatment strategy.\n\nThe Committee considered whether there were any benefits that were not adequately captured in the QALY calculation. It acknowledged that there were some health benefits gained by parents or carers as a result of children or young people receiving peginterferon alfa plus ribavirin treatment for chronic hepatitis\xa0C. For these benefits to be given special consideration, the Committee acknowledged that they must provide more health benefits than treatments for other conditions. In this case, the clinical specialists and patient experts suggested that successful treatment might, in part, alleviate a mother's burden of psychological guilt of mother-to-child transmission of hepatitis\xa0C. Additionally, although the risk of non-maternal transmission is minimal, foster parents may be reluctant to foster children with hepatitis\xa0C and may be concerned about transmission to other children in the household, a concern that would be removed if a sustained virological response was achieved through treatment. Furthermore, the Committee acknowledged the significant public health impact of successful treatment on reducing HCV transmission rates to uninfected people in the UK population and considered that, if this benefit was included in the model, the results were likely to be even more favourable. The Committee agreed that there were health benefits that had not been adequately captured in the QALY calculation but that, because of the favourable cost-effectiveness results, this did not need any further action.\n\nThe Committee noted that the estimates of clinical effectiveness were key drivers of the differences in costs and outcomes in the cost-effectiveness analysis of peginterferon alfa‑2a compared with peginterferon alfa‑2b. However, because the clinical effectiveness estimates were very similar for both peginterferon alfa‑2a and peginterferon alfa‑2b (see section 4.3.2), the Committee was not convinced that there was sufficient evidence to recommend 1\xa0treatment over the other. The Committee agreed that peginterferon alfa (2a and 2b) plus ribavirin were more effective and less costly than best supportive care across all genotypes, and it was certain that addressing the shortcomings identified in the economic evaluations presented would not alter its conclusion. Therefore, the Committee concluded that peginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin, when used in line with their marketing authorisations, were a cost-effective use of NHS resources as an option for treating chronic hepatitis\xa0C in children and young people across all genotypes.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA300\n\nAppraisal title: Peginterferon alfa and ribavirin for treating chronic hepatitis\xa0C in children and young people\n\nSection\n\nKey conclusion\n\nPeginterferon alfa‑2a plus ribavirin and peginterferon alfa‑2b plus ribavirin are recommended as treatment options, within their licensed indications, for children and young people with chronic hepatitis\xa0C.\n\n\n\nReasons for key conclusion:\n\nThe Committee agreed that peginterferon alfa (2a and 2b) plus ribavirin were more effective and less costly than best supportive care across all genotypes, and it was certain that addressing the shortcomings identified in the economic evaluations presented would not alter its conclusion.\n\nThe Committee was not convinced that there was sufficient evidence to recommend 1 treatment over the other.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nCurrently, there is no other treatment for chronic hepatitis\xa0C licensed for children and young people in the UK.\n\n-\n\nThe technology\n\nProposed benefits of the technology\n\nTreatment with peginterferon alfa could provide a sustained virological response that could potentially last for the lifetime of the child or young person, effectively providing a cure.\n\n\n\nTreatment with peginterferon alfa could provide benefits to parents and carers, including reducing the guilt burden associated with maternal transmission of hepatitis\xa0C.\n\n\n\nTreatment with peginterferon alfa in young children could help avoid the social stigma associated with hepatitis\xa0C infection.\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee concluded that, although peginterferon alfa plus ribavirin represented a useful treatment option for children with hepatitis\xa0C, the technologies themselves were not innovative for the purpose of this evaluation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nPeginterferon alfa‑2a and peginterferon alfa‑2b are clinically equivalent and the decision to treat with either will largely be determined by clinical judgement and the specifics of the marketing authorisation.\n\n\n\nChildren and young people are only treated once with peginterferon alfa plus ribavirin in UK clinical practice.\n\n\n\nAdverse reactions\n\nThe main adverse reactions are: severe psychiatric and central nervous system effects, particularly depression, suicidal ideation and attempted suicide, weight loss and growth inhibition. The Committee concluded that peginterferon alfa has an impact on children's growth, but the problem of progressive liver disease outweighs the problems associated with being shorter than a child would otherwise have been without treatment.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe systematic reviews conducted by the manufacturers and the Assessment Group identified few relevant studies in children and young people and these studies were small and of generally poor quality.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard that the average age of entry into the trials reflected the average age of children and young people currently treated in the UK and therefore was satisfied that the trial results were largely generalisable to the UK population.\n\n\n\nUncertainties generated by the evidence\n\nBecause the evidence base largely comprised single-arm studies that did not have any control groups receiving no therapy, the Committee would have expected the manufacturers' and Assessment Group's submissions to have provided supporting data from adult trials to establish the efficacy of peginterferon alfa (2a and 2b) plus ribavirin.\n\n\n\nStudies were presented to support the contention that children are 'cured' following peginterferon alfa plus ribavirin treatment. The studies that followed children with sustained virological responses 5\xa0years on showed that the children remained healthy, but these studies were small and not necessarily representative of the UK population. The Committee would have expected data from trials in adults to be presented in order to augment the evidence of the likelihood of an enduring response from peginterferon alfa plus ribavirin in children.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nExperience suggests that early treatment with peginterferon alfa plus ribavirin is better than later treatment, but the decision about whether and when to treat should be made by parents or carers together with the child or young person's clinician.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nPeginterferon alfa (2a and 2b) plus ribavirin is an effective therapy in children and young people with chronic hepatitis\xa0C across all genotypes.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the Assessment Group's and the 2 manufacturer's economic models.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee questioned the manufacturers' decision to rely on previous utility values without validating them and the Assessment Group's decision for using Swedish and Canadian health-related quality-of-life data, considering the Committee's preference for utility values derived from UK population studies.\n\n\n\nThe Committee noted that none of the models included disutility associated with growth impairment.\n\n\n\nAlthough each of the models presented incorporated different stopping rules, the Committee would have expected the stopping rules to be consistent with clinical practice and the marketing authorisation of both products.\n\n\n\nSpontaneous sustained virological response without treatment was not included in MSD's or the Assessment Group's base-case, although they considered it in sensitivity analyses.\n\n\n\nNevertheless, the Committee was certain that addressing the shortcomings identified in the economic evaluations would not alter its conclusion.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nUtility values used in the manufacturers' models were based on previous technology appraisals in adults and the values had not been updated, revalidated or presented to the Committee.\n\n\n\nSuccessful treatment could reduce HCV transmission rates to uninfected people in the UK population and if this benefit was included in the model, the results would likely be even more favourable.\n\n\n\nTreatment with peginterferon alfa plus ribavirin might, in part, alleviate a mother's burden of psychological guilt of mother-to-child transmission of hepatitis\xa0C and remove concerns about horizontal transmission.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nN/A\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nFor the comparison of peginterferon alfa‑2a with peginterferon alfa‑2b, the key drivers of cost effectiveness were the estimates of clinical effectiveness.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe manufacturer's and Assessment Group's base-case results showed that peginterferon alfa‑2a and peginterferon alfa‑2b (both plus ribavirin) dominated best supportive care in all genotypes, except Roche's cost-effectiveness results for children and young people with HCV genotype 1, 4 or 5, which resulted in an ICER of £3900 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nN/A\n\n-\n\nEnd-of-life considerations\n\nN/A\n\n-\n\nEqualities considerations and social value judgements\n\nDuring the scoping consultation, it was suggested that young people who misuse drugs, recent immigrants and asylum seekers who are children should be considered in this appraisal. However, because NICE does not exclude any specific groups of children and young people in this appraisal, this suggestion did not need further action.\n\n-", 'Related NICE guidance': 'Details are correct at the time of publication. Further information is available on the NICE website.\n\n# Published\n\nHepatitis B and C: ways to promote and offer testing to people at increased risk of infection. NICE public health guidance 43 (2012).\n\nBoceprevir for the treatment of genotype 1 chronic hepatitis\xa0C. NICE technology appraisal guidance 253 (2012).\n\nTelaprevir for the treatment of genotype 1 chronic hepatitis\xa0C. NICE technology appraisal guidance 252 (2012).\n\nPeginterferon alfa and ribavirin for the treatment of chronic hepatitis\xa0C (part review of NICE technology appraisal guidance 75 and 106). NICE technology appraisal guidance 200 (2010).\n\nPeginterferon alfa and ribavirin for the treatment of mild chronic hepatitis\xa0C (extension of technology appraisal guidance 75). NICE technology appraisal guidance 106 (2006).\n\nInterferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis\xa0C (review and extension of technology appraisal guidance 14). NICE technology appraisal guidance 75 (2004).\n\n# Under development\n\nNICE is developing the following guidance:\n\nHepatitis\xa0C. NICE clinical guideline. Publication date to be confirmed.\n\n# NICE Pathways\n\nHepatitis B and C testing. NICE Pathway (2012).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in September 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon Chief ExecutiveNovember 2013', 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nThis guidance updates and replaces:\n\nsection 1.7, bullet 2 only, of NICE technology appraisal guidance 75 (TA75)\xa0'Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C'\n\npart of section 1.6 of NICE technology appraisal guidance 106 (TA106)\xa0'Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C'\n\nIt has been incorporated into the NICE pathway on hepatitis B and C testing along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0366-5"}	https://www.nice.org.uk/guidance/ta300	Evidence-based recommendations on peginterferon alfa (Pegasys; ViraferonPeg) and ribavirin (Copegus) for treating chronic hepatitis C in children and young people.
3d72aeadcaee37a7aa34ad393eae76eb0bc7ed69	nice	Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy	Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy Evidence-based recommendations on fluocinolone acetonide intravitreal implant (Iluvien) for treating chronic diabetic macular oedema in adults. # Guidance This guidance replaces NICE technology appraisal guidance 271 issued in January 2013. The review of fluocinolone acetonide intravitreal implant for treatment of chronic diabetic macular oedema after an inadequate response to prior therapy has resulted in a change in the guidance. See About this guidance for more information. Fluocinolone acetonide intravitreal implant is recommended as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if: the implant is to be used in an eye with an intraocular (pseudophakic) lens and the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme.# The technology Fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) contains a corticosteroid that has anti‑inflammatory and anti‑vascular endothelial growth factor (anti‑VEGF) properties. It is administered by intravitreal injection. Each implant contains 190 micrograms of fluocinolone acetonide, releasing 0.2 micrograms/day for approximately 36 months. Fluocinolone acetonide intravitreal implant has a marketing authorisation for 'the treatment of vision impairment associated with chronic diabetic macular oedema considered insufficiently responsive to available therapies'. The summary of product characteristics states that administration in both eyes concurrently is not recommended (see summary of product characteristics sections 4.2 and 4.4). The summary of product characteristics lists the following adverse reactions for fluocinolone acetonide intravitreal implant: cataract, increased intraocular pressure, floaters (myodesopsia), retinal detachments, vitreous haemorrhages or detachments, glaucoma and endophthalmitis. For full details of adverse reactions and contraindications, see the summary of product characteristics. Fluocinolone acetonide intravitreal implant is available in a 190‑microgram implant at a price of £5500 (excluding VAT; 'British National Formulary' 65th edition). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of fluocinolone acetonide intravitreal implant has agreed a patient access scheme with the Department of Health in which fluocinolone acetonide intravitreal implant will be available with a discount (see section 5.3). The details of the scheme were provided as commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission The Appraisal Committee (section 9) considered evidence submitted by the manufacturer of fluocinolone acetonide intravitreal implant and a review of this submission by the Evidence Review Group (ERG; section 10). The manufacturer submitted evidence on the clinical and cost effectiveness of fluocinolone acetonide intravitreal implant compared with optimised standard of care and laser photocoagulation monotherapy. The manufacturer did not provide any specific analyses comparing fluocinolone acetonide intravitreal implant with triamcinolone alone or the anti‑vascular endothelial growth factor (anti‑VEGF) treatments bevacizumab and ranibizumab alone. The main source of evidence in the manufacturer's submission was a preplanned analysis of data from the FAME A and B randomised controlled trials that evaluated the safety and efficacy of fluocinolone acetonide intravitreal implant for treating diabetic macular oedema. The preplanned analysis focused on duration of diabetic macular oedema, analysing patients who had had the condition for durations above and below the median separately. When the trial was unblinded the median duration was determined to be 3 years. The subgroup in the submission was patients with duration of diabetic macular oedema over 3 years (the manufacturer calculated the duration of diabetic macular oedema as the year of randomisation to treatment minus the year of diagnosis of the disease plus 1). FAME A and B were 2 identical, randomised, double‑blinded, sham injection‑controlled multicentre trials conducted over 36 months. The results of the trials were combined and presented in the submission as a single analysis. Patients were randomised 1:2:2 to sham injection, 0.2 micrograms/day (low‑dose) or 0.5 micrograms/day (high‑dose) fluocinolone acetonide intravitreal implant. Participants in the trials were adults with diabetic macular oedema who were aged between 18 and 85, who had received at least 1 previous laser treatment, whose best corrected visual acuity (BCVA) was ≥19 to ≤68 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, and whose central retinal thickness was 250 microns or more at baseline. Exclusion criteria were intraocular pressure over 21 mmHg, and systolic blood pressure over 180 mmHg or diastolic blood pressure over 105 mmHg. In both groups (sham injection and low‑ or high‑dose implant) additional treatment with laser photocoagulation was given as needed after week 6. Approximately 61% of the sham injection group and 41% of the fluocinolone acetonide intravitreal implant group received treatment with laser photocoagulation during the study. The mean number of laser treatments was 1.4 and 0.8 in the sham injection and fluocinolone acetonide intravitreal implant groups respectively. Re‑treatment with fluocinolone acetonide intravitreal implant was offered at any time after the month 12 assessments if patients experienced vision loss (5 letters or more) or retinal thickening of 50 microns or more compared with their best status in the previous 12 months. Patients in both groups also received a range of therapies not allowed in the study protocol. These included intravitreal steroids (triamcinolone and dexamethasone), anti‑VEGF therapy, vitrectomies and posterior sub‑Tenon steroids. The number of off‑protocol treatments was higher in the sham injection group than in the fluocinolone acetonide intravitreal implant group (117 compared with 48); approximately 35% of patients in the sham injection group and 13% of patients in the fluocinolone acetonide intravitreal implant group received at least 1 off‑protocol treatment. Data from these patients were included in the analysis population. The primary outcome reported in the FAME trials was the proportion of people with an improvement of 15 or more letters from baseline BCVA at month 24. Secondary outcomes included: mean change in BCVA mean change in excess retinal thickness percentage with 3‑step (15 letters or more) worsening of ETDRS percentage needing laser photocoagulation. There were 956 patients enrolled in the FAME trials. Of these, 536 formed the subgroup of patients with chronic diabetic macular oedema for longer than 3 years. Of this subgroup of patients comprehensive data were presented by the manufacturer for the 0.2 micrograms/day implant group only, because only the low dose has been licensed. The resulting number of patients with chronic diabetic macular oedema in the subgroup that formed the basis of the manufacturer's submission was 321 (209 in the 0.2 micrograms/day implant group and 112 in the sham injection group). The mean age of the patients was 62.9 years in the sham injection group (n=112) and 63.7 years in the 0.2 micrograms/day implant group (n=209). In the trials, the majority of patients had chronic diabetic macular oedema in both eyes at baseline, but only 1 eye was treated. In most cases, the worse‑seeing eye was treated. At month 24, the proportions of patients with chronic diabetic macular oedema who had a ≥15 letter increase from baseline BCVA were 13.4% and 34.4% in the sham injection and 0.2 micrograms/day implant groups respectively (p<0.001). The proportions of patients who had a ≥15 letter improvement in BCVA at month 36 (13.4% and 34.0% respectively ) were comparable to those observed in month 24. There were numerical increases in mean change in BCVA from baseline in the 0.2 micrograms/day implant group compared with the sham injection group at all evaluations (12 through to 36 months); this was statistically significant at months 30 and 36. At month 36, there was a mean improvement of 7.6 letters in the 0.2 micrograms/day implant treatment group compared with 1.8 letters in the sham injection group (p<0.004). The FAME trials included an assessment of health‑related quality of life using the Visual Function Questionnaire‑25 (VFQ‑25) at baseline and months 24 and 36. These data were provided in the clinical study reports of the FAME trials. The manufacturer stated that the VFQ‑25 was not used in the economic model because it measures overall visual function which is driven by vision in the better‑seeing eye, whereas in the FAME trials, the majority of patients had their worse‑seeing eye treated. The VFQ‑25 values are marked by the manufacturer as academic in confidence and therefore not presented here. The manufacturer also included laser photocoagulation monotherapy as a relevant comparator for fluocinolone acetonide intravitreal implant. The manufacturer conducted a literature search and identified 1 relevant study: DRCR Protocol B (2008). This study was a phase 3, multicentre, randomised clinical trial conducted in the USA to compare intravitreal triamcinolone with focal/grid laser photocoagulation in patients with diabetic macular oedema. The manufacturer noted that the severity of diabetic macular oedema in the DRCR study was not as great as in the FAME trials. Of the DRCR population, approximately 40% of people had not had their disease treated with laser and there was no stipulation on duration of diabetic macular oedema at randomisation. A comparison of outcomes data as reported in the DRCR and FAME clinical trials was presented. The manufacturer did not use any statistical methods to compare the data indirectly. The manufacturer noted that the proportion of people with a ≥15 letter improvement in BCVA in the FAME trials at month 36 demonstrated a numerical difference in favour of fluocinolone acetonide intravitreal implant (34.0% compared with 18% for laser photocoagulation at 24 months in the DRCR Protocol B study). The manufacturer's submission included data from the FAME trials for ocular adverse events in people with chronic diabetic macular oedema (duration of 3 years or longer). The data suggested that fluocinolone acetonide intravitreal implant is associated with the formation or progression of cataract and increased intraocular pressure. In the FAME trials, 34.4% (72/209) of patients in the fluocinolone acetonide intravitreal implant group experienced increased intraocular pressure or ocular hypertension compared with 14.3% (16/112) in the sham injection group. At baseline, 58.9% (66/112) of people in the sham injection group and 54.5% (114/209) in the fluocinolone intravitreal implant group were phakic (still had their natural lens). Of those who were phakic at baseline, 77.9% of the fluocinolone acetonide intravitreal implant group and 77.0% of the sham injection group had a pre‑existing cataract. Cataract surgery was needed by 85.1% (97/114) of the fluocinolone acetonide intravitreal implant group and 36.4% (24/66) of the sham injection group who were phakic at baseline. The manufacturer provided a subgroup analysis of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens (that is, they had already had an operation for cataract removal and had been fitted with an intraocular lens to replace the natural crystalline lens) at entry into the FAME trials. The manufacturer considered the overall treatment effect in this subgroup to be similar to that for the phakic population; however, increased benefits arose through the removal of a known adverse event (advancement of cataract development) and removal of the costs associated with cataract surgery. Of the people with chronic diabetic macular oedema, there were 46 (41.1%) who had a pseudophakic lens in the sham injection group and 95 (45.5%) in the 0.2 micrograms/day fluocinolone‑treated group. For this subgroup, at 36 months, 31.6% in the fluocinolone‑treated group and 17.4% in the sham injection group had a greater than 15‑letter increase from baseline BCVA, giving a difference of 14.2% (95% CI 28.6% to −0.2%). The economic evidence provided by the manufacturer in its submission comprised a literature review (which identified no relevant published cost‑effectiveness studies) and a de‑novo cost–utility analysis. The manufacturer's economic evaluation compared fluocinolone acetonide intravitreal implant with the comparator ('optimised standard of care') in the FAME trials for a cohort of patients with chronic diabetic macular oedema. The model also included a comparison of fluocinolone acetonide intravitreal implant with laser photocoagulation using data for laser photocoagulation from the DRCR Protocol B study. The manufacturer's model included 14 health states (13 BCVA health states and death) which were defined by bands of 5 ETDRS letters in the treated eye. Utility values associated with the 13 BCVA‑related health states captured the effect of varying degrees of visual gain or loss on patients' quality of life. The model structure made no distinction between treatment of the better‑seeing eye and the worse‑seeing eye. The model had a 15‑year time horizon and a quarterly cycle length, with costs and benefits both being discounted at 3.5%. For the first 3 years, the distribution of patients across health states was drawn directly from the FAME trials data. Beyond 3 years, a Markov model structure was adopted with transition probabilities being applied. The base‑case analysis assumed that 1 fluocinolone acetonide intravitreal implant is needed every 3 years. Patients needed to have gained 5 or more ETDRS letters of visual acuity between baseline and month 36 to receive a further implant at month 36. In addition, using data from the FAME trials the manufacturer applied a drop‑out rate (for those who withdrew consent, were lost to follow‑up or died) to the patients receiving fluocinolone acetonide intravitreal implant who were re‑treated at the end of the first 36 months (these details are marked by the manufacturer as commercial in confidence and therefore not presented here). This adjusted re‑treatment rate was applied equally to each health state. Patients in both the fluocinolone group and the optimised standard of care group also received laser treatments based on rates from the FAME trials, and in the first 3 years could receive other therapies including triamcinolone, ranibizumab, bevacizumab and dexamethasone, again based on rates in the FAME trials. In the base‑case analysis, it was assumed that 35% of patients would receive bilateral treatment in the optimised standard of care group. The manufacturer assumed that bilateral treatment would be contraindicated for patients treated in the first eye with fluocinolone acetonide intravitreal implant who had a subsequent rise in intraocular pressure greater than 30 mmHg. Therefore the bilateral treatment rate in the fluocinolone group was reduced based on the proportion of patients with raised intraocular pressure observed in the FAME trials. The clinical efficacy data from the FAME trials were used directly to calculate the number of patients in each of the model health states in each quarter for the first 3 years. Changes after 3 years were extrapolated from the FAME trials data. The FAME data were divided into patients whose disease had responded to and not responded to treatment based on the ETDRS 5‑letter criteria. Data were then analysed to determine the numbers of patients whose vision improved or worsened by at least 5 letters each quarter. The average net changes in the last 4 quarters of the FAME trials were used in the model to extrapolate improvements in vision beyond 3 years. For patients receiving another implant at 36 months, the model assumed that 5% of patients in each health state would improve by 5 letters every quarter. For patients not receiving a further implant at 36 months, the model assumed that 3% of patients in each health state would experience a transition to a lower health state every quarter. In the optimised standard of care group and laser group, the model assumed that 3% of patients in each health state would have a worsening in vision of 5 letters and therefore move to a worse health state every quarter. The manufacturer did not consider it appropriate to include the VFQ‑25 values in the economic model because VFQ‑25 is driven by vision in the better‑seeing eye, whereas in the FAME trials, the majority of patients had their worse‑seeing eye treated (these values are marked by the manufacturer as academic in confidence and are therefore not presented here). Furthermore, the manufacturer stated that a mapping exercise was not considered because there was not a universally accepted mapping process to convert VFQ‑25 data to utility scores. The manufacturer conducted a systematic review to identify utility values reported in the literature for populations with visual impairment. The review of the articles included diabetic macular oedema and other disorders affecting visual acuity (such as age‑related macular degeneration). Based on the data available, the manufacturer chose to use time trade‑off data from Brown et al. (2000) as the source of utility values for its submission. Brown et al. (2000) was a US study that measured utility values in 5 groups according to visual acuity in the better‑seeing eye in a population of patients with age‑related macular degeneration. The values estimated by Brown et al. (2000) and the values used within the model ranged from 0.40 in the lowest health state (<20 ETDRS letters) to 0.89 in the highest health state (≥75 ETDRS letters). The Brown et al. (2000) study did not report utility weights in patients with BCVAs between 35 and 50, and therefore the unweighted averages of the utility weights above and below this range were assumed. For patients who received treatment in both eyes, a 25% bilateral treatment quality‑adjusted life year (QALY) uplift was also applied to the aggregate QALYs. The model did not consider utility decrements due to adverse events, or procedures and interventions for the adverse events. The manufacturer stated that because the utility was calculated for BCVA values, and the BCVA values were based on the trial data, the impact on patient vision of adverse events such as cataract formation was reflected in the BCVA of the treated eye. The model included the costs of fluocinolone acetonide intravitreal implant as well as laser and other therapies at the rates observed in the FAME trials. Adverse event costs were also included. The manufacturer applied an annual cost of blindness of £6298 to the proportion of patients whose treated‑eye BCVA fell below 35 letters. In its deterministic base case, based on an incremental cost of £11,330 and an incremental QALY value of 0.500, the manufacturer estimated an incremental cost‑effectiveness ratio (ICER) without the patient access scheme of £22,655 per QALY gained for fluocinolone acetonide intravitreal implant compared with optimised standard of care. Following a request for clarification from the ERG the manufacturer provided a revised analysis. The manufacturer acknowledged that the health‑related quality of life values from Brown et al. (2000) may not apply to patients having their worse‑seeing eye treated. The manufacturer therefore used revised health‑related quality of life values to reflect a weighted average of values for people having their worse‑ and better‑seeing eyes treated, taken from a study by Heintz et al. (2012). As well as changing health‑related quality of life values, the manufacturer's revised analysis also amended: male and female mortality rates to revise the pooled annual all‑cause mortality risk, the proportion of patients needing bilateral treatment, the percentage of patients needing bilateral treatment and for whom a second fluocinolone acetonide intravitreal implant treatment was not contraindicated, the quality of life uplift from bilateral treatment to 10%, and the unadjusted response rate in the fluocinolone group to a rate based upon a 10‑letter re‑treatment criterion. The manufacturer's amendments reduced the estimate of cost effectiveness for fluocinolone acetonide intravitreal implant compared with optimised standard of care from £22,655 to £19,268 per QALY gained without the patient access scheme, based on an incremental cost of £11,927 and an incremental QALY value of 0.619. # ERG comments on the manufacturer's submission The ERG commented that the 3‑year data used to inform the first 3 years of the economic model were robust, although the more usual modelling approach would have been to use transition probability matrices. The structure of the model means it cannot be manipulated during this 3‑year period to explore different scenarios. The ERG commented that it would have been more appropriate for the manufacturer to use a model structure that modelled patients as having 2 eyes, rather than undertaking an ad hoc adjustment to the output of a model in which patients only had 1 eye. The ERG noted that the FAME trials had a reasonable proportion of patients who had their better‑seeing eye treated, and that the rate of chronic diabetic macular oedema in the other eye was high. The ERG also noted that the distribution between health states for patients whose disease had responded to and not responded to fluocinolone acetonide intravitreal implant at 36 months was modelled as being a constant percentage of the overall patient distribution at 36 months. The ERG commented that this approach was not justified, and could lead to bias in the estimates of cost effectiveness for fluocinolone acetonide intravitreal implant. The ERG noted that the manufacturer's base‑case model applied a re‑treatment criterion of a minimum 5‑letter improvement between baseline and 36 months. The ERG commented that a more realistic criterion might be a minimum 10‑letter improvement between baseline and 36 months, which the manufacturer applied in response to the clarification request from the ERG. However, the ERG commented that this only changed the number of patients not receiving another fluocinolone acetonide intravitreal implant at 36 months and did not affect their distribution across health states. In the manufacturer's submission clinical effectiveness beyond 3 years was extrapolated from the FAME trials data. The ERG commented that rather than including the proportions of patients whose disease improved or worsened each quarter of a year, the proportions were netted. The ERG considered that the reasons for analysing the data in this way were unclear. The ERG commented that because in the FAME trials patients had only 1 eye treated, assumptions were needed about rates of bilateral treatment. In the base‑case analysis, it was assumed that 35% of patients would need bilateral treatment; this percentage was increased in the revised analysis (these details are marked by the manufacturer as academic in confidence and therefore not presented here). The ERG considered that the manufacturer's revision was too high because a proportion of patients would not have visual impairment in both eyes because of diabetic macular oedema, and a proportion would not be able to have both eyes treated because of raised intraocular pressure or other reasons. The ERG commented that there was considerable uncertainty about the appropriateness of the utility values used in the model. The original submission used utility values that related to sight in the better‑seeing eye. The ERG considered there were limitations in the data (based on Heintz et al. 2012) used in the revised analysis because these provided only 3 quality of life values over 13 health states, were based on small patient numbers, and were non‑monotonic. # Exploratory analyses by the ERG Initially, the ERG made a series of revisions to address what it considered to be possible errors in the model. These were: a change to the formulae for averaging mortality between male and female rates a change to the formulae for applying the yearly natural discontinuation rate (the detail of which is commercial in confidence) in the cohort flow cells a change to the formula for the percentage of patients remaining on fluocinolone acetonide intravitreal implant after year 9.The cumulative impact of correcting the 3 errors was to increase the ICER without the patient access scheme from £22,655 to £26,526 per QALY gained for fluocinolone acetonide intravitreal implant compared with optimised standard of care. The ERG also conducted additional exploratory analyses changing: how the cost of fluorescein angiography needed before each laser administration was applied in the model the number of laser administrations per patient the unit costs for adverse event procedures how the proportions of people whose disease improved and worsened each quarter year after 36 months was calculated the rate of bilateral treatment the cost of blindness the cost and quality of life uplift applied for bilateral treatment for patients in the fluocinolone group whose condition needed bilateral treatment but for whom a second implant was contraindicated.The cumulative impact of these changes resulted in ICERs of £37,740 for the 5‑letter response criterion (with an incremental cost of £14,569 and an incremental QALY of 0.386) and £35,940 for the 10‑letter response criterion (with an incremental cost of £12,736 and an incremental QALY of 0.354) without the patient access scheme. The ERG also conducted further exploratory sensitivity analyses with a particular focus on the source of utility values. These additional analyses modelled the impact of changes in the BCVA of the better‑seeing eye using Brown et al. (1999). This US study of 325 patients measured utility values in 12 groups according to visual acuity in the better‑seeing eye in a population of patients with impaired vision in at least 1 eye. The values estimated by Brown et al. (1999) used within the model vary from 0.54 in the lowest health state (<20 ETDRS letters) to 0.89 in the highest health state (≥75 ETDRS letters), giving a range of 0.350 across the health states of the model. The ERG commented that if its cost‑effectiveness estimates without the patient access scheme for fluocinolone acetonide intravitreal implant compared with optimised standard of care were used as a starting point (£37,740 per QALY gained for the 5‑letter response criterion and £35,940 per QALY gained for the 10‑letter response criterion), applying the health‑related quality of life values taken from Brown et al. (1999) would suggest cost‑effectiveness estimates of £66,744 per QALY gained (5‑letter response criterion) and £64,249 per QALY gained (10‑letter response criterion). The ERG explored the effect of using health‑related quality of life values from a regression analysis in the manufacturer's submission for Ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance 237, replaced by technology appraisal guidance 274), and from Brown et al. (1999) and Brown et al. (2000). The ERG noted that there was uncertainty around the health‑related quality of life impact resulting from changes in the BCVA of the worse‑seeing eye, and presented 6 scenario analyses to take this into account in conjunction with the 3 different sources of utility values: Scenario analysis 1: A flat health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have no impact. Scenario analysis 2: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 15% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 15% of 0.350 which equals 0.053. Scenario analysis 3: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 30% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 30% of 0.350 which equals 0.105. Scenario analysis 4: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 50% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 50% of 0.350 which equals 0.175. Scenario analysis 5: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 70% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 70% of 0.350 which equals 0.245. Scenario analysis 6: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 100% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 0.350. The ERG also assumed that 20% and 40% of people received unilateral treatment in their better‑seeing eye and worse‑seeing eye respectively. For the fluocinolone group it was further assumed that 34% of people received bilateral treatment with fluocinolone acetonide intravitreal implant (that is, in both eyes), whereas 6% received treatment with fluocinolone acetonide intravitreal implant in the first eye but not in the second eye. In the optimised standard of care group, the ERG similarly assumed that 20% and 40% of people received unilateral treatment in their better‑seeing and worse‑seeing eye respectively; whereas 40% of people were assumed to receive treatment in both eyes. The ERG completed sensitivity analyses without the patient access scheme. Using Brown et al. (1999), the ICERs (based on a 10‑letter response criterion and including a bilateral benefit) ranged from £48,533 per QALY gained (scenario analysis 6, where changes in the BCVA of the worse‑seeing eye have 100% of the range of changes in the BCVA of the better‑seeing eye, that is, a range of 0.350) to £110,730 per QALY gained (scenario analysis 1, where changes in the BCVA of the worse‑seeing eye are assumed to have no impact). Using Brown et al. (2000), the equivalent ICERs ranged between £30,910 and £61,942 per QALY gained for fluocinolone acetonide intravitreal implant compared with optimised standard of care. Using the utility values derived from the manufacturer's submission for NICE technology appraisal guidance 237, based upon the 10‑letter response criterion and including a bilateral benefit, the ICERs ranged from £69,802 (scenario analysis 6) to £251,686 per QALY gained (scenario analysis 1). Using a 10‑letter response criterion, including a bilateral benefit and assuming scenario analysis 3 the ICER values were £47,604 per QALY gained using Brown et al. (2000) utilities and £80,037 per QALY gained using Brown et al. (1999) utilities. Full details of all the evidence are in the manufacturer's submission and the ERG report for NICE technology appraisal guidance 271. # Rapid review of NICE technology appraisal guidance 271: patient access scheme In NICE technology appraisal guidance 271, fluocinolone acetonide intravitreal implant was not recommended for treating chronic diabetic macular oedema. After publication, the manufacturer agreed a patient access scheme with the Department of Health and submitted revised analyses to be considered in a rapid review of the original guidance. The manufacturer presented analyses for the full population of people with chronic diabetic macular oedema and for the subgroup of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens. In the revised economic model the manufacturer included: BCVA patient distributions in the extrapolation from month 36 onwards that were specific to a patient's response status BCVA patient distributions in the extrapolation for the pseudophakic subgroup that were based on the final 30 months of observations from the FAME trials, and BCVA patient distributions for the full chronic diabetic macular oedema population that were based on the final 12 months of observations analyses using utility values from Brown et al. (1999) and Brown et al. (2000), as well as an analysis using utilities from Czoski‑Murray et al. (2009) (used in NICE technology appraisal guidance 237, replaced by technology appraisal guidance 274) an assumption that changes in vision for people treated in their worse‑seeing eye had 30% of the health‑related quality of life impact of the same change in vision from treating their best‑seeing eye an assumption that 20% of patients are unilaterally treated in the best‑seeing eye, 40% of patients are unilaterally treated in the worst‑seeing eye, and the remaining 40% of patients receive bilateral treatment. The manufacturer also clarified some characteristics of the people enrolled in the FAME trials. It stated that people in the trials were as severely affected as patients who would receive fluocinolone acetonide intravitreal implant in routine clinical practice. It stated that in clinical practice, a BCVA of 20/80 is generally considered poor and insufficiently responsive to treatment. It noted that in the FAME trials 59% of the patients with chronic diabetic macular oedema had vision of 20/80 or worse at baseline. Of these, 42.7% and 12.7% of patients had a 15‑letter gain in the fluocinolone acetonide intravitreal implant and optimised standard of care groups respectively (p<0.001). The manufacturer also stated that in the FAME trials all patients had at least 1 prior macular laser treatment before randomisation. It noted that in the optimised standard of care group, people with diabetic macular oedema for more than 3 years showed lower levels of response (13.4% of patients) than people with diabetic macular oedema for less than 3 years (27.8% of patients); whereas in the fluocinolone acetonide intravitreal implant group, people with diabetic macular oedema for more than 3 years showed higher levels of response (34% of patients) than people with diabetic macular oedema for less than 3 years (22.3% of patients). The manufacturer considered that fluocinolone acetonide intravitreal implant provided significant additive benefit for people with chronic diabetic macular oedema whose disease was responding insufficiently to other therapies. The manufacturer presented the results for the comparison between fluocinolone acetonide intravitreal implant and optimised standard of care with the patient access scheme for the whole population with chronic diabetic macular oedema and for the subgroup of people with a pseudophakic lens. The ICERs for the whole population with the patient access scheme were £37,630 using the utilities from Brown et al. (2000) and £63,472 using the utilities from Brown et al. (1999) per QALY gained. The ICER using the utilities from Czoski‑Murray et al. (2009) was £42,663 per QALY gained. In the pseudophakic subgroup the ICERs were £17,639 using the utilities from Brown et al. (2000) and £30,296 using the utilities from Brown et al. (1999) per QALY gained. Using the utilities form Czosky‑Murray et al. (2009) the ICER was £19,884 per QALY gained. The manufacturer carried out a sensitivity analysis assuming that patients would not be re‑treated with fluocinolone acetonide intravitreal implant automatically at month 36. Re‑treatment would only take place if there was a response to treatment and a BCVA less than 20/32 at month 36. These analyses resulted in small reductions in the ICERs. With the patient access scheme, the ICERs for the chronic diabetic macular oedema population were £34,668 using utilities from Brown et al. (2000) and £57,476 using utilities from Brown et al. (1999) per QALY gained. In the pseudophakic subgroup, the ICERs were £16,642 using the utilities from Brown et al. (2000) and £28,584 using the utilities from Brown et al. (1999) per QALY gained. # Comments on the manufacturer's rapid review submission by the Evidence Review Group The ERG stated that there continued to be uncertainty about the best source of utilities to be used in the model. It noted that utilities from Brown et al. (1999) represented a more diverse group of patients with different eye conditions, all of whom were visually impaired with vision of at best 20/40 in at least 1 eye. The ERG considered that utilities from Brown et al. (1999) may be preferable to those from Brown et al. (2000) because Brown et al. (1999) included more patients, which allows a finer gradation of utility estimates for a given BCVA. The number of patients for a given BCVA band was also higher in Brown et al. (1999). The ERG also noted that one‑third of patients in Brown et al. (1999) had diabetes compared with none in Brown et al. (2000). The ERG commented that it was unable to source the utility values from Czoski‑Murray et al. (2009) used by the manufacturer. The ERG applied the Czoski‑Murray utility function adjusted for an average age of 63 and found similar ranges to those used by the manufacturer. The ERG noted that patients included in Czoski‑Murray et al. (2009) used contact lenses to simulate different degrees of visual loss. It also noted that the duration of the simulated visual impairment was short, and so the utility values may not apply to patients with longer duration of visual loss. The ERG commented that the differences between the ICERs for the whole chronic diabetic macular oedema population and the pseudophakic subgroup were in part driven by differences in the distribution of patients across health states. The ERG noted that there were uncertainties around these distributions because for the pseudophakic subgroup, the difference in the baseline distributions between the fluocinolone group and the optimised standard of care group may indicate a breakdown in randomisation. It also noted that there were differences in the 36‑month patient distributions within the optimised standard of care group, between the full chronic diabetic macular oedema population and the pseudophakic subgroup. The ERG commented on the importance of these patient distributions because they are the basis for the extrapolations in the model. The ERG checked the manufacturer's ICERs and found minor differences in the values. The ERG commented that there were some small changes made to response rates and drop‑out rates that had not been previously applied in the model. The ERG also commented that there were some errors in the adverse effect cost calculations, but correcting for these had little impact on the ICERs. The deterministic ICERs from the ERG check with the patient access scheme for the chronic diabetic macular oedema population were £64,549 and £37,996 per QALY gained using Brown et al. (1999) and Brown et al. (2000) utilities respectively. For the pseudophakic subgroup, the ICERs with the patient access scheme were £30,025 (using Brown et al. utilities), £21,027 (using Czoski‑Murray utilities) and £17,487 (using Brown et al. utilities) per QALY gained. The ERG noted that the manufacturer presented a sensitivity analysis that assumed that patients would be re‑treated at month 36 only if their disease responded to fluocinolone and they had a BCVA <20/32. The ERG commented that this change only affected costs in the fluocinolone acetonide intravitreal implant group without any clinical impact of these patients stopping treatment. It also stated that the impact on costs may be underestimated as the re‑treatment adjustment was only applied to the second re‑treatment with fluocinolone acetonide intravitreal implant (at month 36) but not to subsequent re‑treatments.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of fluocinolone acetonide intravitreal implant, having considered evidence on the nature of chronic diabetic macular oedema after an inadequate response to prior therapy and the value placed on the benefits of fluocinolone acetonide intravitreal implant by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee discussed the causes of diabetic macular oedema, and recognised the importance of good control of blood glucose, blood pressure and blood lipids in reducing the risk of diabetic macular oedema, the progression of diabetic macular oedema and other complications. The Committee discussed the impact of visual impairment on people with diabetic macular oedema. It was aware of comments from patient experts describing the significant negative impact that visual impairment has on the physical and emotional wellbeing of people with diabetic macular oedema. The Committee noted that people with diabetes manage some aspects of their own condition and that visual impairment can affect their ability to do this. This in turn can increase the risk of long‑term disease complications such as kidney disease, cardiovascular disease and amputations. The Committee also heard from clinical specialists that chronic diabetic macular oedema tends to be a bilateral condition (that is, affecting both eyes) with the potential risk of losing sight in both eyes. The clinical specialists stated that chronic diabetic macular oedema therefore affects the quality of life of people with the condition by causing visual impairment and also that of their carers because of loss of independence. The Committee noted comments from clinical specialists which highlighted that several studies have reported depression in people with chronic diabetic macular oedema. The Committee recognised the impact of visual impairment on people with diabetic macular oedema, particularly those with chronic diabetic macular oedema that is not responsive to available therapies. The Committee discussed the current management of diabetic macular oedema. The Committee was aware that Ranibizumab for treating diabetic macular oedema (NICE technology appraisal guidance 274) is the only NICE guidance relating specifically to treating diabetic macular oedema. It noted that the marketing authorisation for fluocinolone acetonide intravitreal implant specified its use only when diabetic macular oedema was insufficiently responsive to available therapies and that this population was not covered by NICE technology appraisal guidance 274. The Committee heard from the clinical specialists that when anti‑vascular endothelial growth factor (anti‑VEGF) therapies are not options, standard treatment would be 'optimised standard of care', which could include laser therapy as a maintenance treatment. The Committee was aware of the publication of guidelines from the Royal College of Ophthalmologists suggesting the use of fluocinolone for some people and understood that there are currently no standard treatments for people with chronic diabetic macular oedema after other therapies have failed. The Committee discussed the likely place of fluocinolone acetonide intravitreal implant in clinical practice. It heard from the clinical specialists that because fluocinolone acetonide intravitreal implant is a sustained‑release low‑dose long‑acting steroid, it has clear advantages over other steroid implants, which are not licensed for the treatment of diabetic macular oedema. However, the Committee understood that there are significant side effects associated with the use of a steroid in the eye, especially the acceleration of cataract development and increased rates of raised intraocular pressure, and that these still occur with fluocinolone acetonide intravitreal implant. The Committee discussed whether the use of fluocinolone acetonide intravitreal implant in one eye could be associated with cataract development in the other eye. It understood from the manufacturer that it was not aware of any evidence suggesting this. Further, it heard that fluocinolone was not detectable in the blood. The Committee also heard from the clinical specialists that there is a spectrum of severity of diabetic macular oedema, and steroid treatment might be useful in those with more severe diabetic macular oedema if other treatments (including laser therapy) have failed and cataracts have already been removed. It understood that based on existing NICE guidance and clinical practice the patient population that would be considered for fluocinolone acetonide intravitreal implant would be those for whom laser photocoagulation and anti‑VEGF therapies had failed. # Clinical effectiveness The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of fluocinolone acetonide intravitreal implant. The Committee noted that the main sources of evidence were the FAME A and B randomised controlled trials, which enrolled people with diabetic macular oedema and included a preplanned analysis defined by the median duration of diabetic macular oedema, which had been used to identify a subgroup of people with chronic diabetic macular oedema (that is, of more than 3 years' duration). It noted that in the FAME trials, patients were only treated in 1 eye and that the majority of patients were treated in their worse‑seeing eye. The Committee noted that fluocinolone acetonide intravitreal implant was associated with statistically significant gains in the proportion of patients with chronic diabetic macular oedema who had a more than 15‑letter increase in best corrected visual acuity (BCVA) from baseline compared with the sham injection group. It also noted that mean change in BCVA from baseline at month 36 of the FAME trials was statistically significantly greater in the fluocinolone acetonide intravitreal implant group compared with the sham injection group. The Committee concluded that fluocinolone acetonide intravitreal implant showed greater clinical effectiveness than sham injection in people with chronic diabetic macular oedema. The Committee discussed the characteristics of the FAME trial population and how these related to the patient group specified in the marketing authorisation for fluocinolone acetonide intravitreal implant and to the group of patients likely to receive treatment in UK clinical practice. The Committee noted that the efficacy data submitted were based on a subgroup defined as having chronic disease with a duration of longer than 3 years, rather than as unresponsive to available therapies as specified in the marketing authorisation. The Committee further noted that some patients included received additional treatments during the trials such as laser photocoagulation and anti‑VEGF injections. The Committee discussed the concerns that this implied that in the FAME trials fluocinolone acetonide intravitreal implant was not being used as specified in the marketing authorisation. The Committee noted the manufacturer's submission and comments on the appraisal consultation document stating that the patients in the FAME trials had poor visual acuity, and that the patients in the comparator arm had disease that was responding poorly to the background therapies when given in the trial. However, the Committee remained concerned that the data from the FAME trials did not specifically reflect a group of patients who had disease that was insufficiently responsive to other therapies because people in the FAME trials did not necessarily have disease that was unresponsive to treatment with anti‑VEGF or laser photocoagulation before randomisation. The Committee considered that this could affect the levels of response observed in clinical practice because one of the mechanisms of action of corticosteroids was to act on VEGF. It noted comments received on the appraisal consultation document that studies of other intravitreal corticosteroids (such as triamcinolone) have shown a beneficial effect on macular oedema when used after anti‑VEGF treatments. The Committee remained concerned that the data from the trials may not be fully representative of the group of people who would be receiving fluocinolone acetonide intravitreal implant in UK clinical practice. However, it concluded that although there is uncertainty about the generalisability of the trial data to UK clinical practice, fluocinolone acetonide intravitreal implant is likely to be clinically effective in this population. The Committee considered the manufacturer's approach to conducting an indirect comparison of fluocinolone acetonide intravitreal implant and laser photocoagulation using the FAME trials and the DRCR Protocol B study (2008). The Committee was aware of the Evidence Review Group's (ERG's) concerns over the value of the indirect comparison given the absence of a common comparator to link the FAME studies with the identified DRCR Protocol B study. It also noted that the retinopathy in patients included in the DRCR study was not as severe as in the FAME trials; that 40% of the DRCR population was laser‑naive; and that in the DRCR study there was no stipulation on duration of diabetic macular oedema at randomisation. The Committee concluded that the indirect comparison could not be interpreted with confidence and in any case was inappropriate to the scope for this appraisal, which considered fluocinolone acetonide intravitreal implant when diabetic macular oedema has been insufficiently responsive to available therapies. The Committee considered the evidence for adverse events associated with fluocinolone acetonide intravitreal implant. It was aware that fluocinolone acetonide intravitreal implant was associated with the formation or progression of cataract. It noted that although there were similar rates of pre‑existing cataract between the 2 trial groups (77.9% and 77.0%) among people who were phakic (still had their natural lens) at baseline, cataract surgery was needed by a greater percentage (85.1% versus 36.4%) of these people in the fluocinolone acetonide intravitreal implant group than in the sham injection group. The Committee heard from clinical specialists that the majority of people with chronic diabetic macular oedema would be likely to develop cataracts at some stage but that fluocinolone acetonide intravitreal implant might accelerate this. The Committee also noted that administration of fluocinolone acetonide intravitreal implant was associated with increased intraocular pressure: 5.3% of people in the fluocinolone group needed intraocular pressure‑lowering surgery compared with 0% in the sham injection group. The Committee heard from clinical specialists that intraocular pressure‑lowering surgery was a particular concern and for this reason, in addition to the associated acceleration of cataract development, clinicians would be likely to use fluocinolone acetonide intravitreal implant conservatively and be reluctant to use it too early in the treatment pathway. The Committee concluded that it was appropriate to take account of these adverse events when considering the approach to economic modelling. # Cost effectiveness The Committee considered the manufacturer's economic model and sensitivity analyses, and discussed the key parameters used in it. The Committee noted the sensitivity of the model to the assumptions about the relationship between a person's treated eye and their overall visual acuity, the number of fluocinolone acetonide intravitreal implant treatments in the first 3 years, assumptions about the benefits of treatment after month 36, the rate of re‑treatment, and the source of health‑related quality of life values. The Committee concluded that the cost‑effectiveness estimates were most sensitive to the source of health‑related quality of life values, the assumption that a person's overall visual acuity related only to their treated eye, and the assumption that all treated eyes were better‑seeing eyes. The Committee considered the ERG's critique of the manufacturer's original base‑case results. It was aware that the ERG had made a series of explorations using the manufacturer's original base‑case incremental cost‑effectiveness ratio (ICER) of £22,600 per quality‑adjusted life year (QALY) gained as a starting point. The Committee noted that by correcting an error relating to the application of annual discontinuation rates in the model, and by changing the formulae for averaging male and female mortality rates and for calculating the percentage of patients remaining on fluocinolone acetonide intravitreal implant beyond 9 years, the ERG's revisions increased the manufacturer's original base‑case ICER from £22,700 to £26,500 per QALY gained for fluocinolone acetonide intravitreal implant compared with optimised standard of care without the patient access scheme. The Committee agreed that the ERG's initial error corrections to the model were appropriate. The Committee went on to consider the ERG's further explorations to the original model, which were included in the manufacturer's revised model submitted for the rapid review: aligning assumptions about the rate of laser administrations per patient in the optimised standard of care group for year 1 of the model with the trial data applying revised unit costs for some adverse events revising the assumptions about the extrapolation of benefits beyond 3 years in the model applying an adjusted bilateral treatment rate in the fluocinolone acetonide intravitreal implant group of 85.2% of the treatment rate in the optimised standard of care group use of a 10‑letters response criterion applying the absolute cost and quality of life uplift associated with bilateral treatment in the optimised standard of care group to the patients in the fluocinolone group needing bilateral treatment but for whom it was contraindicated applying the cost of blindness when only the treated eye fell below a BCVA of 35 letters rather than both eyes.The Committee concluded that the above amendments to the assumptions in the economic model submitted by the manufacturer for the rapid review were reasonable. The Committee discussed the assumption in the model that 20% of patients were treated in their best‑seeing eye, 40% in their worse‑seeing eye and 40% of patients were treated in both eyes. The Committee noted the manufacturer's comment on the appraisal consultation document that in the FAME trials the majority of the patients had their worse‑seeing eye treated because of ethical considerations but that in clinical practice, more patients would be treated in their best‑seeing eye because this is more likely to protect functional vision. The Committee agreed that this could be the case but considered that currently there is a lack of evidence. It concluded that the assumption of 20% of the patients being treated in their best‑seeing eye, 40% in their worse‑seeing eye and 40% of patients receiving bilateral treatment was reasonable. The Committee discussed the use of second and subsequent fluocinolone acetonide intravitreal implants and the assumption in the model of re‑treatment only after 36 months. It noted that the summary of product characteristics states that an additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema. The Committee heard from the manufacturer that this wording was included in the summary of product characteristics because patients in the FAME trials could receive a further implant after 12 months. However, subsequent research showed that the effect of the corticosteroid should last 36 months. The Committee understood from the manufacturer that it does not promote having the implants more frequently than once every 36 months and that there are currently no data available demonstrating further benefit from reimplantation. The Committee accepted the assumption in the model of no more than 1 implant every 36 months. The Committee discussed the fact that the model did not apply quality of life detriments to adverse events such as cataracts, glaucoma or raised intraocular pressure. The Committee noted the manufacturer's rationale that the impact of adverse events such as cataract formation on visual acuity was incorporated in the overall utility measures, that the application of these decrements would be short in duration and therefore have a minimal impact on the ICERs, and that the decrements associated with surgery would depend on when a patient chose to have surgery. Nevertheless, the Committee concluded that if disutilities associated with operations, procedures and hospital attendances (such as cataract removal, glaucoma surgery, retinal detachment surgery, vitrectomy and treatment of endophthalmitis) had been taken into account the ICERs would increase. The Committee discussed the utility values for the better‑seeing eye used in the economic model. The Committee noted that the manufacturer's original analyses had been based on Brown et al. (2000) utilities. It further noted that the ERG's explorations of the manufacturer's original model retained the Brown et al. (2000) utility values, and also explored the effect of applying utility values from Brown et al. (1999) and from a regression analysis in the manufacturer's submission for NICE technology appraisal guidance 237. The Committee agreed that the utility values may vary in their appropriateness in being applied to people with chronic diabetic macular oedema. It accepted that the utility values from the manufacturer's submission for NICE technology appraisal guidance 237 were relatively insensitive to changes in visual acuity and therefore ICERs using these utilities may be numerically too high. The Committee discussed further the relative merits of Brown et al. (1999) and Brown et al. (2000). It was aware that the Brown et al. (1999) utility values were based on a larger population with a mix of eye diseases whereas the Brown et al. (2000) study was based on a smaller population with age‑related macular oedema (but not diabetic macular oedema). It noted that the data from Brown et al. (2000) included a large drop in utility values between some health states, which may have arisen from the smaller patient numbers in each health state. It also noted that utility values from Brown et al. (2000) for the best health states were higher than would be expected for people with chronic diabetic macular oedema, who are usually older people with comorbidities and this, in turn, increased the uncertainty around the validity of this source of utility values. The Committee heard from the ERG that Brown et al. (2002) found no difference in the reduction in the quality of life associated with similar levels of visual acuity loss depending on the causes of vision impairment. The Committee considered the manufacturer's rationale for using Brown et al. (2000) values based on the higher proportion of patients with oedema compared with Brown et al. (1999). It also noted that the manufacturer restated in its comment on the appraisal consultation document that Brown et al. (2000) represents a more accurate source of utility values for people with diabetic macular oedema. However, the Committee was not persuaded that this outweighed the benefits of the larger sample size and the associated finer delineation of utilities possible with larger patient numbers. The Committee concluded that there were limitations to using the available utility values to model the health‑related quality of life of the group of people with chronic diabetic macular oedema. However, of the available source of utility values, Brown et al. (1999) had advantages because of the size of the sample included in the study. Because there were some uncertainties about the most appropriate source of utility values for this patient population the Committee agreed to consider a range of ICERs based on both Brown et al. (1999) and Brown et al. (2000). The Committee noted that the manufacturer had also included analyses using utility values from Czoski‑Murray et al. (2009) and Heintz et al. (2012). The Committee discussed the appropriateness of using the values from Heintz et al. (2012) and considered that the very slight differences between utilities for the loss of better‑seeing eye vision relative to worse‑seeing eye vision lacked face validity. The Committee then discussed the utility values presented in Czoski‑Murray (2009). It understood that the source of utility values had been considered for the appraisal of Ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance 237, replaced by NICE technology appraisal guidance 274) and noted that using these utility values resulted in ICERs in between the ones obtained using Brown et al. (1999) and Brown et al. (2000). The Committee agreed to consider Czoski‑Murray et al. (2009) as another source of utility values for this appraisal. The Committee discussed the most appropriate adjustments needed to the better‑seeing eye utility values in the model when the worse‑seeing eye or both eyes were treated. The Committee considered the 6 scenario analyses carried out by the ERG (see section 3.38) which varied the health‑related quality of life impact of changes in the vision of the worse‑seeing eye and the resultant QALY gain associated with treatment of the worse‑seeing eye or both eyes. The Committee understood the concerns of the ERG about using the Heintz et al. (2012) data to calculate the amount of gain from treating the worse‑seeing eye, because of the small numbers of patients in some of the visual acuity levels and also because the manufacturer's calculation did not account for visual acuity in the better‑seeing eye being correlated with visual acuity in the worse‑seeing eye. The Committee also discussed the utilities for worse‑seeing eyes in Brown et al. (1999) and heard from the ERG about an additional study, Sahel et al. (2007), which also showed that the visual acuity in the worse‑seeing eye has little impact on health‑related quality of life unless it is severely affected. The Committee was aware that there could be psychological benefits from treating the worse‑seeing eye that had not been captured in the calculation of the QALY. However, the Committee noted that the FAME trials collected data (with a majority of worse‑seeing eyes) on the effect of visual impairment on quality of life using the disease‑specific VFQ‑25 questionnaire, and that this had shown no difference between the groups treated with fluocinolone acetonide intravitreal implant and those treated with sham injection. On balance, the Committee considered scenario analysis 3 (which assumed that changes in vision for people treated in their worse‑seeing eye had 30% of the health‑related quality of life impact of the same change in vision from treating their better‑seeing eye) to be the most appropriate for decision‑making. The Committee was not persuaded that 30% was an unreasonable reflection of the clinical situation for people with chronic diabetic macular oedema and noted that this was also consistent with previous appraisals. The Committee then considered the cost‑effectiveness results based on data from the FAME trials for all patients with chronic diabetic macular oedema taking into account its concerns (sections 4.9–4.18). The Committee noted that the most plausible ICER for fluocinolone acetonide intravitreal implant compared with optimised standard of care in the original guidance was at least £47,600 using the utilities from Brown et al. (2000) and £80,000 using the utilities from Brown et al. (1999) per QALY gained. The Committee noted that with the patient access scheme the ICERs were reduced to £37,600 using the utilities from Brown et al. (2000), £42,700 using the utilities from Czoski‑Murray et al. (2009) and £63,500 using the utilities from Brown et al. (1999) per QALY gained. The Committee considered that the lowest of these estimates remained over £30,000 per QALY gained and therefore outside the range normally considered cost effective (£20,000–£30,000 per QALY gained). It also noted that there was substantial uncertainty in these estimates, particularly in the extent to which the results of the clinical trial data included in the analyses could be applied to the population of people who would receive treatment in clinical practice. The Committee concluded that fluocinolone acetonide intravitreal implant could not be recommended as a cost‑effective use of NHS resources for treating people with chronic diabetic macular oedema that is insufficiently responsive to available therapies. The Committee discussed the subgroup of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens. The Committee acknowledged that this is an identifiable subgroup of people with chronic diabetic macular oedema. The Committee noted that the numbers of patients in the subgroup were approximately half the chronic diabetic macular oedema population in the FAME trials and that the clinical effectiveness in terms of 15‑letter gain in visual acuity in this subgroup was numerically worse than that in the total population (albeit with wide confidence intervals). The Committee considered that the comparatively small numbers of such patients in the FAME trials led to uncertainty in the estimates of clinical effectiveness for this group and thus in the estimates from the economic modelling but accepted that the subgroup proposed was reasonable. The Committee also considered that its concerns about the extent to which the data for the subgroup were representative of the group of people who would receive fluocinolone acetonide intravitreal implants in UK clinical practice remained valid (section 4.6). However, on balance, the Committee concluded that fluocinolone acetonide intravitreal implant had been shown to be clinically effective in this subgroup of people. The Committee considered the cost effectiveness of fluocinolone acetonide intravitreal implant in the pseudophakic subgroup. It noted that the most plausible ICER for this subgroup in NICE technology appraisal guidance 271 was between £29,700 per QALY gained using the utilities from Brown et al. (2000) and £50,600 using the utilities from Brown et al. (1999). The Committee noted that with the patient access scheme, the ICERs presented by the ERG were £30,000 per QALY gained using the utilities from Brown et al. (1999), £21,000 per QALY gained using the utilities from Czoski‑Murray et al. (2009) and £17,500 per QALY gained using the utilities from Brown et al. (2000). The Committee considered that the most plausible estimates of cost effectiveness would be in the upper end of this range, and that there was significant uncertainty around this estimate. The Committee was persuaded that the technology had been shown to meet a clinical need in people whose disease is unresponsive to available therapies. On balance, the Committee concluded that fluocinolone acetonide intravitreal implant could be a cost‑effective use of NHS resources and recommended it as an option for people with chronic diabetic macular oedema that is insufficiently responsive to available therapies and if the implant is to be used in an eye with an intraocular (pseudophakic) lens. # Summary of Appraisal Committee's key conclusions TA301 Appraisal title: Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy (rapid review of technology appraisal 271) Section Key conclusion Fluocinolone acetonide intravitreal implant is recommended as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if the implant is to be used in an eye with an intraocular (pseudophakic) lens and the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme. The Committee considered that the lowest of ICERs with the patient access scheme for people with chronic diabetic macular oedema remained over £30,000 per QALY gained and therefore outside the range normally considered cost‑effective (£20,000–£30,000 per QALY gained). The Committee concluded that fluocinolone acetonide intravitreal implant was not recommended as a cost‑effective use of NHS resources for treating people with chronic diabetic macular oedema that is insufficiently responsive to available therapies. The Committee noted that for the pseudophakic subgroup, the ICERs with the patient access scheme checked by the ERG were between £30,000 per QALY gained using the utilities from Brown et al. (1999) and £17,500 per QALY gained with the utilities from Brown et al. (2000). It was persuaded that the technology had been shown to meet a clinical need in people whose disease is unresponsive to available therapies. The Committee concluded that fluocinolone acetonide intravitreal implant was a cost‑effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments The Committee was aware of comments from patient experts describing the significant negative impact that visual impairment has on the physical and emotional wellbeing of people with diabetic macular oedema. The Committee was aware that Ranibizumab for treating diabetic macular oedema (NICE technology appraisal guidance 274) is the only NICE guidance relating specifically to treating diabetic macular oedema and that it does not cover the treatment of people with unresponsive disease. The Committee understood that there are currently no standard treatments for people with chronic diabetic macular oedema after other therapies have failed. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits? The Committee heard from the clinical specialists that because fluocinolone acetonide intravitreal implant is a sustained‑release low‑dose long‑acting steroid, it has clear advantages over other steroid implants, which the Committee was aware are not licensed for the treatment of diabetic macular oedema. What is the position of the treatment in the pathway of care for the condition? The Committee noted that the marketing authorisation for fluocinolone acetonide intravitreal implant specified its use only when diabetic macular oedema was insufficiently responsive to available therapies and that this population was not covered by NICE technology appraisal guidance 274. It understood that based on existing NICE guidance and clinical practice the patient population that would be considered for fluocinolone acetonide intravitreal implant would be those for whom laser photocoagulation and anti‑VEGF therapies had failed. Adverse reactions The Committee noted that the significant side effects associated with the use of a steroid in the eye, especially the acceleration of cataract development and increased rates of raised intraocular pressure, still occur with fluocinolone acetonide intravitreal implant. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee noted that the main sources of evidence were the FAME A and B randomised controlled trials. The Committee noted the DRCR Protocol B study used by the manufacturer in its indirect comparison. The Committee was aware of the ERG's concerns about the indirect comparison and concluded that it could not be interpreted with confidence and was inappropriate to the scope of this appraisal. Relevance to general clinical practice in the NHS The Committee noted that the efficacy data submitted were based on a subgroup defined as having chronic disease with a duration of longer than 3 years, rather than as unresponsive to available therapies as specified in the marketing authorisation. The Committee further noted that some patients included in the trials received additional treatments during the trial such as laser photocoagulation and anti‑VEGF injections, and that this implied that in the FAME trials fluocinolone acetonide intravitreal implant was not being used as specified in the marketing authorisation. However, it concluded that although there is uncertainty about the generalisability of the trial data to UK clinical practice, fluocinolone acetonide intravitreal implant is likely to be clinically effective in this population. Uncertainties generated by the evidence The Committee was concerned that the data from the FAME trials did not reflect a group of patients who had disease that was insufficiently responsive to other therapies because people in the FAME trials did not necessarily have disease that was unresponsive to treatment with anti‑VEGF or laser photocoagulation before randomisation. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee discussed the subgroup of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens. The Committee considered that the comparatively small numbers of such patients in the FAME trials led to uncertainty in the estimates of clinical effectiveness for this group and thus in the estimates from the economic modelling but accepted that the subgroup proposed was reasonable. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that fluocinolone acetonide intravitreal implant showed greater clinical effectiveness than sham injection in people with chronic diabetic macular oedema. The Committee concluded that fluocinolone acetonide intravitreal implant had been shown to be clinically effective in the subgroup of people who had a pseudophakic lens. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the manufacturer´s model and the ERG's critique submitted for the rapid review. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee concluded that the manufacturer's model did not take into account the disutilities associated with operations, procedures and hospital attendances which if taken into account would cause the ICER to be even higher. The Committee concluded that there were limitations to using the available utilities to model the health‑related quality of life of the group of people with chronic diabetic macular oedema. The Committee considered that the comparatively small numbers of patients who had a pseudophakic lens in the FAME trials led to uncertainty in the estimates of clinical effectiveness for this group and thus in the estimates from the economic modelling. Incorporation of health‑related quality‑of‑life benefits and utility values Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered? The Committee concluded that there were limitations to using the available utilities to model the health‑related quality of life of the group of people with chronic diabetic macular oedema and agreed to consider a range of ICERs based on both Brown et al. (1999) and Brown et al. (2000). The Committee noted that the manufacturer had also included analyses using utility values from Czoski‑Murray et al. (2009) and Heintz et al. (2012). The Committee discussed the appropriateness of using the values from Heintz et al. (2012) and considered that the very slight differences between utilities for the loss of better‑seeing eye vision relative to worse‑seeing eye vision lacked face validity. It understood that the utility values from Czoski‑Murray et al. (2009) had been considered for the appraisal of ranibizumab for the treatment of diabetic macular oedema and agreed to consider it as another source of utility values for this appraisal. Are there specific groups of people for whom the technology is particularly cost effective? The Committee discussed the subgroup of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens and concluded that it was a cost‑effective use of NHS resources. What are the key drivers of cost effectiveness? The Committee concluded that the cost‑effectiveness estimates were most sensitive to the source of health‑related quality of life values and the assumption that a person's overall visual acuity related only to their treated eye. Most likely cost‑effectiveness estimate (given as an ICER) The Committee noted that for all patients with chronic diabetic macular oedema, with the patient access scheme, the ICERs were £37,600 using the utilities from Brown et al. (2000), £42,700 using the utilities from Czoski‑Murray et al. (2009) and £63,500 using the utilities from Brown et al. (1999) per QALY gained. The Committee noted that for the pseudophakic subgroup, the ICERs with the patient access scheme presented by the ERG were £30,000 per QALY gained using the utilities from Brown et al. (1999), £21,000 per QALY gained with the utilities from Czoski‑Murray et al. (2009) and £17,500 per QALY gained with the utilities from Brown et al. (2000). Additional factors taken into account Patient access schemes (PPRS) The manufacturer of fluocinolone acetonide intravitreal implant has agreed a patient access scheme with the Department of Health in which fluocinolone acetonide intravitreal implant will be available with a discount (see section 5.3). The details of the scheme were provided as commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. End‑of‑life considerations Not applicable. Equalities considerations and social value judgements The Committee concluded there were no issues relating to the equalities legislation, and there was no need to alter or add to its recommendations. # Recommendations for further research Further research is recommended to resolve uncertainties about the cost effectiveness of fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema. This should focus on a group of patients whose condition is unresponsive to other available therapies, and include measures of efficacy and health‑related quality of life. Research should focus on identifying appropriate utility values, taking into account the utility values for different levels of visual acuity and the relative relationship in utility values from treating the best‑seeing and the worse‑seeing eye. The appropriateness of generalising utility values from one group of eye conditions to another group would also be of value.# Related NICE guidance Details are correct at the time of publication. Further information is available on the NICE website. # Published Aflibercept solution for injection for treating wet age\u2011\related macular degeneration. NICE technology appraisal guidance 294 (2013). Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 283 (2013). Ranibizumab for treating diabetic macular oedema (rapid review of technology appraisal guidance 237) . NICE technology appraisal guidance 274 (2013). Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229 (2011). Type 2 diabetes: the management of type 2 diabetes. NICE clinical guideline 87 (2009). Ranibizumab and pegaptanib for the treatment of age\u2011\related macular degeneration. NICE technology appraisal guidance 155 (2008). Type 1 diabetes. NICE clinical guideline 15 (2004).# Review of guidance The guidance on this technology will be considered for review by the Guidance Executive in November 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew Dillon Chief ExecutiveNovember 2013# Changes after publication July 2015: Cross reference to summary of product characteristics added to section 2.1.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It replaces NICE technology appraisal guidance 271 (published January 2013). TA271 did not recommend fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema considered insufficiently responsive to available therapies. The updated guidance recommends fluocinolone acetonide intravitreal implant as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if the implant is to be used in an eye with an intraocular (pseudophakic) lens and the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme. This guidance has been incorporated into the NICE pathway on diabetes along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978‑1‑4731‑0368‑9	{'Guidance': 'This guidance replaces NICE technology appraisal guidance\xa0271 issued in January\xa02013.\n\nThe review of fluocinolone acetonide intravitreal implant for treatment of chronic diabetic macular oedema after an inadequate response to prior therapy has resulted in a change in the guidance. See About this guidance for more information.\n\nFluocinolone acetonide intravitreal implant is recommended as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if:\n\nthe implant is to be used in an eye with an intraocular (pseudophakic) lens and\n\nthe manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme.', 'The technology ': "Fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) contains a corticosteroid that has anti‑inflammatory and anti‑vascular endothelial growth factor (anti‑VEGF) properties. It is administered by intravitreal injection. Each implant contains 190\xa0micrograms of fluocinolone acetonide, releasing 0.2\xa0micrograms/day for approximately 36\xa0months. Fluocinolone acetonide intravitreal implant has a marketing authorisation for 'the treatment of vision impairment associated with chronic diabetic macular oedema considered insufficiently responsive to available therapies'. The summary of product characteristics states that administration in both eyes concurrently is not recommended (see summary of product characteristics sections\xa04.2 and 4.4).\n\nThe summary of product characteristics lists the following adverse reactions for fluocinolone acetonide intravitreal implant: cataract, increased intraocular pressure, floaters (myodesopsia), retinal detachments, vitreous haemorrhages or detachments, glaucoma and endophthalmitis. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nFluocinolone acetonide intravitreal implant is available in a 190‑microgram implant at a price of £5500 (excluding VAT; 'British National Formulary' [BNF] 65th\xa0edition). Costs may vary in different settings because of negotiated procurement discounts.\n\nThe manufacturer of fluocinolone acetonide intravitreal implant has agreed a patient access scheme with the Department of Health in which fluocinolone acetonide intravitreal implant will be available with a discount (see section\xa05.3). The details of the scheme were provided as commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (section\xa09) considered evidence submitted by the manufacturer of fluocinolone acetonide intravitreal implant and a review of this submission by the Evidence Review Group (ERG; section\xa010).\n\nThe manufacturer submitted evidence on the clinical and cost effectiveness of fluocinolone acetonide intravitreal implant compared with optimised standard of care and laser photocoagulation monotherapy. The manufacturer did not provide any specific analyses comparing fluocinolone acetonide intravitreal implant with triamcinolone alone or the anti‑vascular endothelial growth factor (anti‑VEGF) treatments bevacizumab and ranibizumab alone.\n\nThe main source of evidence in the manufacturer's submission was a preplanned analysis of data from the FAME\xa0A and B randomised controlled trials that evaluated the safety and efficacy of fluocinolone acetonide intravitreal implant for treating diabetic macular oedema. The preplanned analysis focused on duration of diabetic macular oedema, analysing patients who had had the condition for durations above and below the median separately. When the trial was unblinded the median duration was determined to be 3\xa0years. The subgroup in the submission was patients with duration of diabetic macular oedema over 3\xa0years (the manufacturer calculated the duration of diabetic macular oedema as the year of randomisation to treatment minus the year of diagnosis of the disease plus\xa01).\n\nFAME A and B were 2\xa0identical, randomised, double‑blinded, sham injection‑controlled multicentre trials conducted over 36\xa0months. The results of the trials were combined and presented in the submission as a single analysis. Patients were randomised 1:2:2 to sham injection, 0.2\xa0micrograms/day (low‑dose) or 0.5\xa0micrograms/day (high‑dose) fluocinolone acetonide intravitreal implant. Participants in the trials were adults with diabetic macular oedema who were aged between 18\xa0and 85, who had received at least 1\xa0previous laser treatment, whose best corrected visual acuity (BCVA) was ≥19 to ≤68\xa0letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, and whose central retinal thickness was 250\xa0microns or more at baseline. Exclusion criteria were intraocular pressure over 21\xa0mmHg, and systolic blood pressure over 180\xa0mmHg or diastolic blood pressure over 105\xa0mmHg.\n\nIn both groups (sham injection and low‑ or high‑dose implant) additional treatment with laser photocoagulation was given as needed after week\xa06. Approximately 61% of the sham injection group and 41% of the fluocinolone acetonide intravitreal implant group received treatment with laser photocoagulation during the study. The mean number of laser treatments was 1.4\xa0and 0.8\xa0in the sham injection and fluocinolone acetonide intravitreal implant groups respectively. Re‑treatment with fluocinolone acetonide intravitreal implant was offered at any time after the month\xa012 assessments if patients experienced vision loss (5\xa0letters or more) or retinal thickening of 50\xa0microns or more compared with their best status in the previous 12\xa0months.\n\nPatients in both groups also received a range of therapies not allowed in the study protocol. These included intravitreal steroids (triamcinolone and dexamethasone), anti‑VEGF therapy, vitrectomies and posterior sub‑Tenon steroids. The number of off‑protocol treatments was higher in the sham injection group than in the fluocinolone acetonide intravitreal implant group (117 compared with 48); approximately 35% of patients in the sham injection group and 13% of patients in the fluocinolone acetonide intravitreal implant group received at least 1\xa0off‑protocol treatment. Data from these patients were included in the analysis population.\n\nThe primary outcome reported in the FAME trials was the proportion of people with an improvement of 15\xa0or more letters from baseline BCVA at month\xa024. Secondary outcomes included:\n\nmean change in BCVA\n\nmean change in excess retinal thickness\n\npercentage with 3‑step (15\xa0letters or more) worsening of ETDRS\n\npercentage needing laser photocoagulation.\n\nThere were 956\xa0patients enrolled in the FAME trials. Of these, 536\xa0formed the subgroup of patients with chronic diabetic macular oedema for longer than 3\xa0years. Of this subgroup of patients comprehensive data were presented by the manufacturer for the 0.2\xa0micrograms/day implant group only, because only the low dose has been licensed. The resulting number of patients with chronic diabetic macular oedema in the subgroup that formed the basis of the manufacturer's submission was\xa0321 (209\xa0in the 0.2\xa0micrograms/day implant group and 112\xa0in the sham injection group).\n\nThe mean age of the patients was 62.9\xa0years in the sham injection group (n=112) and 63.7\xa0years in the 0.2\xa0micrograms/day implant group (n=209). In the trials, the majority of patients had chronic diabetic macular oedema in both eyes at baseline, but only 1\xa0eye was treated. In most cases, the worse‑seeing eye was treated.\n\nAt month\xa024, the proportions of patients with chronic diabetic macular oedema who had a ≥15\xa0letter increase from baseline BCVA were 13.4% and 34.4% in the sham injection and 0.2\xa0micrograms/day implant groups respectively (p<0.001). The proportions of patients who had a ≥15\xa0letter improvement in BCVA at month\xa036 (13.4% and 34.0% respectively [p<0.001]) were comparable to those observed in month\xa024. There were numerical increases in mean change in BCVA from baseline in the 0.2\xa0micrograms/day implant group compared with the sham injection group at all evaluations (12\xa0through to 36\xa0months); this was statistically significant at months\xa030 and\xa036. At month\xa036, there was a mean improvement of 7.6\xa0letters in the 0.2\xa0micrograms/day implant treatment group compared with 1.8\xa0letters in the sham injection group (p<0.004).\n\nThe FAME trials included an assessment of health‑related quality of life using the Visual Function Questionnaire‑25\xa0(VFQ‑25) at baseline and months\xa024 and\xa036. These data were provided in the clinical study reports of the FAME trials. The manufacturer stated that the VFQ‑25 was not used in the economic model because it measures overall visual function which is driven by vision in the better‑seeing eye, whereas in the FAME trials, the majority of patients had their worse‑seeing eye treated. The VFQ‑25 values are marked by the manufacturer as academic in confidence and therefore not presented here.\n\nThe manufacturer also included laser photocoagulation monotherapy as a relevant comparator for fluocinolone acetonide intravitreal implant. The manufacturer conducted a literature search and identified 1\xa0relevant study: DRCR Protocol\xa0B (2008). This study was a phase\xa03, multicentre, randomised clinical trial conducted in the USA to compare intravitreal triamcinolone with focal/grid laser photocoagulation in patients with diabetic macular oedema. The manufacturer noted that the severity of diabetic macular oedema in the DRCR study was not as great as in the FAME trials. Of the DRCR population, approximately 40% of people had not had their disease treated with laser and there was no stipulation on duration of diabetic macular oedema at randomisation. A comparison of outcomes data as reported in the DRCR and FAME clinical trials was presented. The manufacturer did not use any statistical methods to compare the data indirectly. The manufacturer noted that the proportion of people with a ≥15\xa0letter improvement in BCVA in the FAME trials at month\xa036 demonstrated a numerical difference in favour of fluocinolone acetonide intravitreal implant (34.0% compared with 18% for laser photocoagulation at 24\xa0months in the DRCR Protocol\xa0B study).\n\nThe manufacturer's submission included data from the FAME trials for ocular adverse events in people with chronic diabetic macular oedema (duration of 3\xa0years or longer). The data suggested that fluocinolone acetonide intravitreal implant is associated with the formation or progression of cataract and increased intraocular pressure. In the FAME trials, 34.4% (72/209) of patients in the fluocinolone acetonide intravitreal implant group experienced increased intraocular pressure or ocular hypertension compared with 14.3% (16/112) in the sham injection group. At baseline, 58.9% (66/112) of people in the sham injection group and 54.5% (114/209) in the fluocinolone intravitreal implant group were phakic (still had their natural lens). Of those who were phakic at baseline, 77.9% of the fluocinolone acetonide intravitreal implant group and 77.0% of the sham injection group had a pre‑existing cataract. Cataract surgery was needed by 85.1% (97/114) of the fluocinolone acetonide intravitreal implant group and 36.4% (24/66) of the sham injection group who were phakic at baseline.\n\nThe manufacturer provided a subgroup analysis of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens (that is, they had already had an operation for cataract removal and had been fitted with an intraocular lens to replace the natural crystalline lens) at entry into the FAME trials. The manufacturer considered the overall treatment effect in this subgroup to be similar to that for the phakic population; however, increased benefits arose through the removal of a known adverse event (advancement of cataract development) and removal of the costs associated with cataract surgery. Of the people with chronic diabetic macular oedema, there were 46\xa0(41.1%) who had a pseudophakic lens in the sham injection group and 95\xa0(45.5%) in the 0.2\xa0micrograms/day fluocinolone‑treated group. For this subgroup, at 36\xa0months, 31.6% in the fluocinolone‑treated group and 17.4% in the sham injection group had a greater than 15‑letter increase from baseline BCVA, giving a difference of 14.2% (95%\xa0CI 28.6% to −0.2%).\n\nThe economic evidence provided by the manufacturer in its submission comprised a literature review (which identified no relevant published cost‑effectiveness studies) and a de‑novo cost–utility analysis. The manufacturer's economic evaluation compared fluocinolone acetonide intravitreal implant with the comparator ('optimised standard of care') in the FAME trials for a cohort of patients with chronic diabetic macular oedema. The model also included a comparison of fluocinolone acetonide intravitreal implant with laser photocoagulation using data for laser photocoagulation from the DRCR Protocol\xa0B study.\n\nThe manufacturer's model included 14\xa0health states (13\xa0BCVA health states and death) which were defined by bands of 5\xa0ETDRS letters in the treated eye. Utility values associated with the 13\xa0BCVA‑related health states captured the effect of varying degrees of visual gain or loss on patients' quality of life. The model structure made no distinction between treatment of the better‑seeing eye and the worse‑seeing eye. The model had a 15‑year time horizon and a quarterly cycle length, with costs and benefits both being discounted at 3.5%. For the first 3\xa0years, the distribution of patients across health states was drawn directly from the FAME trials data. Beyond 3\xa0years, a Markov model structure was adopted with transition probabilities being applied.\n\nThe base‑case analysis assumed that 1\xa0fluocinolone acetonide intravitreal implant is needed every 3\xa0years. Patients needed to have gained 5\xa0or more ETDRS letters of visual acuity between baseline and month\xa036 to receive a further implant at month\xa036. In addition, using data from the FAME trials the manufacturer applied a drop‑out rate (for those who withdrew consent, were lost to follow‑up or died) to the patients receiving fluocinolone acetonide intravitreal implant who were re‑treated at the end of the first 36\xa0months (these details are marked by the manufacturer as commercial in confidence and therefore not presented here). This adjusted re‑treatment rate was applied equally to each health state. Patients in both the fluocinolone group and the optimised standard of care group also received laser treatments based on rates from the FAME trials, and in the first 3\xa0years could receive other therapies including triamcinolone, ranibizumab, bevacizumab and dexamethasone, again based on rates in the FAME trials.\n\nIn the base‑case analysis, it was assumed that 35% of patients would receive bilateral treatment in the optimised standard of care group. The manufacturer assumed that bilateral treatment would be contraindicated for patients treated in the first eye with fluocinolone acetonide intravitreal implant who had a subsequent rise in intraocular pressure greater than 30\xa0mmHg. Therefore the bilateral treatment rate in the fluocinolone group was reduced based on the proportion of patients with raised intraocular pressure observed in the FAME trials.\n\nThe clinical efficacy data from the FAME trials were used directly to calculate the number of patients in each of the model health states in each quarter for the first 3\xa0years. Changes after 3\xa0years were extrapolated from the FAME trials data. The FAME data were divided into patients whose disease had responded to and not responded to treatment based on the ETDRS 5‑letter criteria. Data were then analysed to determine the numbers of patients whose vision improved or worsened by at least 5\xa0letters each quarter. The average net changes in the last 4\xa0quarters of the FAME trials were used in the model to extrapolate improvements in vision beyond 3\xa0years. For patients receiving another implant at 36\xa0months, the model assumed that 5% of patients in each health state would improve by 5\xa0letters every quarter. For patients not receiving a further implant at 36\xa0months, the model assumed that 3% of patients in each health state would experience a transition to a lower health state every quarter. In the optimised standard of care group and laser group, the model assumed that 3% of patients in each health state would have a worsening in vision of 5\xa0letters and therefore move to a worse health state every quarter.\n\nThe manufacturer did not consider it appropriate to include the VFQ‑25 values in the economic model because VFQ‑25 is driven by vision in the better‑seeing eye, whereas in the FAME trials, the majority of patients had their worse‑seeing eye treated (these values are marked by the manufacturer as academic in confidence and are therefore not presented here). Furthermore, the manufacturer stated that a mapping exercise was not considered because there was not a universally accepted mapping process to convert VFQ‑25 data to utility scores.\n\nThe manufacturer conducted a systematic review to identify utility values reported in the literature for populations with visual impairment. The review of the articles included diabetic macular oedema and other disorders affecting visual acuity (such as age‑related macular degeneration). Based on the data available, the manufacturer chose to use time trade‑off data from Brown et al. (2000) as the source of utility values for its submission. Brown et al. (2000) was a US study that measured utility values in 5\xa0groups according to visual acuity in the better‑seeing eye in a population of patients with age‑related macular degeneration. The values estimated by Brown et al. (2000) and the values used within the model ranged from 0.40\xa0in the lowest health state (<20\xa0ETDRS letters) to 0.89\xa0in the highest health state (≥75\xa0ETDRS letters). The Brown et al. (2000) study did not report utility weights in patients with BCVAs between 35\xa0and 50, and therefore the unweighted averages of the utility weights above and below this range were assumed.\n\nFor patients who received treatment in both eyes, a 25% bilateral treatment quality‑adjusted life year (QALY) uplift was also applied to the aggregate QALYs.\n\nThe model did not consider utility decrements due to adverse events, or procedures and interventions for the adverse events. The manufacturer stated that because the utility was calculated for BCVA values, and the BCVA values were based on the trial data, the impact on patient vision of adverse events such as cataract formation was reflected in the BCVA of the treated eye.\n\nThe model included the costs of fluocinolone acetonide intravitreal implant as well as laser and other therapies at the rates observed in the FAME trials. Adverse event costs were also included. The manufacturer applied an annual cost of blindness of £6298 to the proportion of patients whose treated‑eye BCVA fell below 35\xa0letters.\n\nIn its deterministic base case, based on an incremental cost of £11,330\xa0and an incremental QALY value of 0.500, the manufacturer estimated an incremental cost‑effectiveness ratio (ICER) without the patient access scheme of £22,655\xa0per QALY gained for fluocinolone acetonide intravitreal implant compared with optimised standard of care.\n\nFollowing a request for clarification from the ERG the manufacturer provided a revised analysis. The manufacturer acknowledged that the health‑related quality of life values from Brown et al. (2000) may not apply to patients having their worse‑seeing eye treated. The manufacturer therefore used revised health‑related quality of life values to reflect a weighted average of values for people having their worse‑ and better‑seeing eyes treated, taken from a study by Heintz et al. (2012).\n\nAs well as changing health‑related quality of life values, the manufacturer's revised analysis also amended: male and female mortality rates to revise the pooled annual all‑cause mortality risk, the proportion of patients needing bilateral treatment, the percentage of patients needing bilateral treatment and for whom a second fluocinolone acetonide intravitreal implant treatment was not contraindicated, the quality of life uplift from bilateral treatment to 10%, and the unadjusted response rate in the fluocinolone group to a rate based upon a 10‑letter re‑treatment criterion.\n\nThe manufacturer's amendments reduced the estimate of cost effectiveness for fluocinolone acetonide intravitreal implant compared with optimised standard of care from £22,655\xa0to £19,268\xa0per QALY gained without the patient access scheme, based on an incremental cost of £11,927\xa0and an incremental QALY value of 0.619.\n\n# ERG comments on the manufacturer's submission\n\nThe ERG commented that the 3‑year data used to inform the first 3\xa0years of the economic model were robust, although the more usual modelling approach would have been to use transition probability matrices. The structure of the model means it cannot be manipulated during this 3‑year period to explore different scenarios.\n\nThe ERG commented that it would have been more appropriate for the manufacturer to use a model structure that modelled patients as having 2\xa0eyes, rather than undertaking an ad hoc adjustment to the output of a model in which patients only had 1\xa0eye. The ERG noted that the FAME trials had a reasonable proportion of patients who had their better‑seeing eye treated, and that the rate of chronic diabetic macular oedema in the other eye was high.\n\nThe ERG also noted that the distribution between health states for patients whose disease had responded to and not responded to fluocinolone acetonide intravitreal implant at 36\xa0months was modelled as being a constant percentage of the overall patient distribution at 36\xa0months. The ERG commented that this approach was not justified, and could lead to bias in the estimates of cost effectiveness for fluocinolone acetonide intravitreal implant.\n\nThe ERG noted that the manufacturer's base‑case model applied a re‑treatment criterion of a minimum 5‑letter improvement between baseline and 36\xa0months. The ERG commented that a more realistic criterion might be a minimum 10‑letter improvement between baseline and 36\xa0months, which the manufacturer applied in response to the clarification request from the ERG. However, the ERG commented that this only changed the number of patients not receiving another fluocinolone acetonide intravitreal implant at 36\xa0months and did not affect their distribution across health states.\n\nIn the manufacturer's submission clinical effectiveness beyond 3\xa0years was extrapolated from the FAME trials data. The ERG commented that rather than including the proportions of patients whose disease improved or worsened each quarter of a year, the proportions were netted. The ERG considered that the reasons for analysing the data in this way were unclear.\n\nThe ERG commented that because in the FAME trials patients had only 1\xa0eye treated, assumptions were needed about rates of bilateral treatment. In the base‑case analysis, it was assumed that 35% of patients would need bilateral treatment; this percentage was increased in the revised analysis (these details are marked by the manufacturer as academic in confidence and therefore not presented here). The ERG considered that the manufacturer's revision was too high because a proportion of patients would not have visual impairment in both eyes because of diabetic macular oedema, and a proportion would not be able to have both eyes treated because of raised intraocular pressure or other reasons.\n\nThe ERG commented that there was considerable uncertainty about the appropriateness of the utility values used in the model. The original submission used utility values that related to sight in the better‑seeing eye. The ERG considered there were limitations in the data (based on Heintz et al. 2012) used in the revised analysis because these provided only 3\xa0quality of life values over 13\xa0health states, were based on small patient numbers, and were non‑monotonic.\n\n# Exploratory analyses by the ERG\n\nInitially, the ERG made a series of revisions to address what it considered to be possible errors in the model. These were:\n\na change to the formulae for averaging mortality between male and female rates\n\na change to the formulae for applying the yearly natural discontinuation rate (the detail of which is commercial in confidence) in the cohort flow cells\n\na change to the formula for the percentage of patients remaining on fluocinolone acetonide intravitreal implant after year\xa09.The cumulative impact of correcting the 3\xa0errors was to increase the ICER without the patient access scheme from £22,655\xa0to £26,526\xa0per QALY gained for fluocinolone acetonide intravitreal implant compared with optimised standard of care.\n\nThe ERG also conducted additional exploratory analyses changing:\n\nhow the cost of fluorescein angiography needed before each laser administration was applied in the model\n\nthe number of laser administrations per patient\n\nthe unit costs for adverse event procedures\n\nhow the proportions of people whose disease improved and worsened each quarter year after 36\xa0months was calculated\n\nthe rate of bilateral treatment\n\nthe cost of blindness\n\nthe cost and quality of life uplift applied for bilateral treatment for patients in the fluocinolone group whose condition needed bilateral treatment but for whom a second implant was contraindicated.The cumulative impact of these changes resulted in ICERs of £37,740\xa0for the 5‑letter response criterion (with an incremental cost of £14,569\xa0and an incremental QALY of 0.386) and £35,940\xa0for the 10‑letter response criterion (with an incremental cost of £12,736\xa0and an incremental QALY of 0.354) without the patient access scheme.\n\nThe ERG also conducted further exploratory sensitivity analyses with a particular focus on the source of utility values. These additional analyses modelled the impact of changes in the BCVA of the better‑seeing eye using Brown et al. (1999). This US study of 325\xa0patients measured utility values in 12\xa0groups according to visual acuity in the better‑seeing eye in a population of patients with impaired vision in at least 1\xa0eye. The values estimated by Brown et al. (1999) used within the model vary from 0.54\xa0in the lowest health state (<20\xa0ETDRS letters) to 0.89\xa0in the highest health state (≥75\xa0ETDRS letters), giving a range of 0.350\xa0across the health states of the model. The ERG commented that if its cost‑effectiveness estimates without the patient access scheme for fluocinolone acetonide intravitreal implant compared with optimised standard of care were used as a starting point (£37,740\xa0per QALY gained for the 5‑letter response criterion and £35,940\xa0per QALY gained for the 10‑letter response criterion), applying the health‑related quality of life values taken from Brown et al. (1999) would suggest cost‑effectiveness estimates of £66,744\xa0per QALY gained (5‑letter response criterion) and £64,249\xa0per QALY gained (10‑letter response criterion).\n\nThe ERG explored the effect of using health‑related quality of life values from a regression analysis in the manufacturer's submission for Ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance\xa0237, replaced by technology appraisal guidance 274), and from Brown et al. (1999) and Brown et al. (2000). The ERG noted that there was uncertainty around the health‑related quality of life impact resulting from changes in the BCVA of the worse‑seeing eye, and presented 6\xa0scenario analyses to take this into account in conjunction with the 3\xa0different sources of utility values:\n\nScenario analysis 1: A flat health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have no impact.\n\nScenario analysis 2: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 15% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 15% of 0.350\xa0which equals 0.053.\n\nScenario analysis 3: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 30% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 30% of 0.350 which equals 0.105.\n\nScenario analysis 4: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 50% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 50% of 0.350 which equals 0.175.\n\nScenario analysis 5: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 70% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 70% of 0.350 which equals 0.245.\n\nScenario analysis 6: A health‑related quality of life function where changes in the BCVA of the worse‑seeing eye have 100% of the range of changes in the BCVA of the better‑seeing eye: that is, a range of 0.350.\n\nThe ERG also assumed that 20% and 40% of people received unilateral treatment in their better‑seeing eye and worse‑seeing eye respectively. For the fluocinolone group it was further assumed that 34% of people received bilateral treatment with fluocinolone acetonide intravitreal implant (that is, in both eyes), whereas 6% received treatment with fluocinolone acetonide intravitreal implant in the first eye but not in the second eye. In the optimised standard of care group, the ERG similarly assumed that 20% and 40% of people received unilateral treatment in their better‑seeing and worse‑seeing eye respectively; whereas 40% of people were assumed to receive treatment in both eyes.\n\nThe ERG completed sensitivity analyses without the patient access scheme. Using Brown et al. (1999), the ICERs (based on a 10‑letter response criterion and including a bilateral benefit) ranged from £48,533\xa0per QALY gained (scenario analysis\xa06, where changes in the BCVA of the worse‑seeing eye have 100% of the range of changes in the BCVA of the better‑seeing eye, that is, a range of 0.350) to £110,730\xa0per QALY gained (scenario analysis\xa01, where changes in the BCVA of the worse‑seeing eye are assumed to have no impact). Using Brown et al. (2000), the equivalent ICERs ranged between £30,910 and £61,942\xa0per QALY gained for fluocinolone acetonide intravitreal implant compared with optimised standard of care. Using the utility values derived from the manufacturer's submission for NICE technology appraisal guidance 237, based upon the 10‑letter response criterion and including a bilateral benefit, the ICERs ranged from £69,802 (scenario analysis\xa06) to £251,686 per QALY gained (scenario analysis\xa01). Using a 10‑letter response criterion, including a bilateral benefit and assuming scenario analysis\xa03 the ICER values were £47,604\xa0per QALY gained using Brown et al. (2000) utilities and £80,037\xa0per QALY gained using Brown et al. (1999) utilities.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report for NICE technology appraisal guidance 271.\n\n# Rapid review of NICE technology appraisal guidance\xa0271: patient access scheme\n\nIn NICE technology appraisal guidance 271, fluocinolone acetonide intravitreal implant was not recommended for treating chronic diabetic macular oedema. After publication, the manufacturer agreed a patient access scheme with the Department of Health and submitted revised analyses to be considered in a rapid review of the original guidance.\n\nThe manufacturer presented analyses for the full population of people with chronic diabetic macular oedema and for the subgroup of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens. In the revised economic model the manufacturer included:\n\nBCVA patient distributions in the extrapolation from month\xa036 onwards that were specific to a patient's response status\n\nBCVA patient distributions in the extrapolation for the pseudophakic subgroup that were based on the final 30\xa0months of observations from the FAME trials, and BCVA patient distributions for the full chronic diabetic macular oedema population that were based on the final 12\xa0months of observations\n\nanalyses using utility values from Brown et al. (1999) and Brown et al. (2000), as well as an analysis using utilities from Czoski‑Murray et al. (2009) (used in NICE technology appraisal guidance 237, replaced by technology appraisal guidance 274)\n\nan assumption that changes in vision for people treated in their worse‑seeing eye had 30% of the health‑related quality of life impact of the same change in vision from treating their best‑seeing eye\n\nan assumption that 20% of patients are unilaterally treated in the best‑seeing eye, 40% of patients are unilaterally treated in the worst‑seeing eye, and the remaining 40% of patients receive bilateral treatment.\n\nThe manufacturer also clarified some characteristics of the people enrolled in the FAME trials. It stated that people in the trials were as severely affected as patients who would receive fluocinolone acetonide intravitreal implant in routine clinical practice. It stated that in clinical practice, a BCVA of 20/80 is generally considered poor and insufficiently responsive to treatment. It noted that in the FAME trials 59% of the patients with chronic diabetic macular oedema had vision of 20/80\xa0or worse at baseline. Of these, 42.7% and 12.7% of patients had a 15‑letter gain in the fluocinolone acetonide intravitreal implant and optimised standard of care groups respectively (p<0.001). The manufacturer also stated that in the FAME trials all patients had at least 1\xa0prior macular laser treatment before randomisation. It noted that in the optimised standard of care group, people with diabetic macular oedema for more than 3\xa0years showed lower levels of response (13.4% of patients) than people with diabetic macular oedema for less than 3\xa0years (27.8% of patients); whereas in the fluocinolone acetonide intravitreal implant group, people with diabetic macular oedema for more than 3 years showed higher levels of response (34% of patients) than people with diabetic macular oedema for less than 3\xa0years (22.3% of patients). The manufacturer considered that fluocinolone acetonide intravitreal implant provided significant additive benefit for people with chronic diabetic macular oedema whose disease was responding insufficiently to other therapies.\n\nThe manufacturer presented the results for the comparison between fluocinolone acetonide intravitreal implant and optimised standard of care with the patient access scheme for the whole population with chronic diabetic macular oedema and for the subgroup of people with a pseudophakic lens. The ICERs for the whole population with the patient access scheme were £37,630\xa0using the utilities from Brown et al. (2000) and £63,472\xa0using the utilities from Brown et al. (1999) per QALY gained. The ICER using the utilities from Czoski‑Murray et al. (2009) was £42,663\xa0per QALY gained. In the pseudophakic subgroup the ICERs were £17,639 using the utilities from Brown et al. (2000) and £30,296 using the utilities from Brown et al. (1999) per QALY gained. Using the utilities form Czosky‑Murray et al. (2009) the ICER was £19,884\xa0per QALY gained.\n\nThe manufacturer carried out a sensitivity analysis assuming that patients would not be re‑treated with fluocinolone acetonide intravitreal implant automatically at month 36. Re‑treatment would only take place if there was a response to treatment and a BCVA less than\xa020/32 at month\xa036. These analyses resulted in small reductions in the ICERs. With the patient access scheme, the ICERs for the chronic diabetic macular oedema population were £34,668 using utilities from Brown et al. (2000) and £57,476 using utilities from Brown et al. (1999) per QALY gained. In the pseudophakic subgroup, the ICERs were £16,642 using the utilities from Brown et al. (2000) and £28,584 using the utilities from Brown et al. (1999) per QALY gained.\n\n# Comments on the manufacturer's rapid review submission by the Evidence Review Group\n\nThe ERG stated that there continued to be uncertainty about the best source of utilities to be used in the model. It noted that utilities from Brown et al. (1999) represented a more diverse group of patients with different eye conditions, all of whom were visually impaired with vision of at best 20/40\xa0in at least 1\xa0eye. The ERG considered that utilities from Brown et al. (1999) may be preferable to those from Brown et al. (2000) because Brown et al. (1999) included more patients, which allows a finer gradation of utility estimates for a given BCVA. The number of patients for a given BCVA band was also higher in Brown et al. (1999). The ERG also noted that one‑third of patients in Brown et al. (1999) had diabetes compared with none in Brown et al. (2000).\n\nThe ERG commented that it was unable to source the utility values from Czoski‑Murray et al. (2009) used by the manufacturer. The ERG applied the Czoski‑Murray utility function adjusted for an average age of 63 and found similar ranges to those used by the manufacturer. The ERG noted that patients included in Czoski‑Murray et al. (2009) used contact lenses to simulate different degrees of visual loss. It also noted that the duration of the simulated visual impairment was short, and so the utility values may not apply to patients with longer duration of visual loss.\n\nThe ERG commented that the differences between the ICERs for the whole chronic diabetic macular oedema population and the pseudophakic subgroup were in part driven by differences in the distribution of patients across health states. The ERG noted that there were uncertainties around these distributions because for the pseudophakic subgroup, the difference in the baseline distributions between the fluocinolone group and the optimised standard of care group may indicate a breakdown in randomisation. It also noted that there were differences in the 36‑month patient distributions within the optimised standard of care group, between the full chronic diabetic macular oedema population and the pseudophakic subgroup. The ERG commented on the importance of these patient distributions because they are the basis for the extrapolations in the model.\n\nThe ERG checked the manufacturer's ICERs and found minor differences in the values. The ERG commented that there were some small changes made to response rates and drop‑out rates that had not been previously applied in the model. The ERG also commented that there were some errors in the adverse effect cost calculations, but correcting for these had little impact on the ICERs. The deterministic ICERs from the ERG check with the patient access scheme for the chronic diabetic macular oedema population were £64,549 and £37,996\xa0per QALY gained using Brown et al. (1999) and Brown et al. (2000) utilities respectively. For the pseudophakic subgroup, the ICERs with the patient access scheme were £30,025 (using Brown et al. utilities), £21,027 (using Czoski‑Murray utilities) and £17,487 (using Brown et al. utilities) per QALY gained.\n\nThe ERG noted that the manufacturer presented a sensitivity analysis that assumed that patients would be re‑treated at month\xa036 only if their disease responded to fluocinolone and they had a BCVA <20/32. The ERG commented that this change only affected costs in the fluocinolone acetonide intravitreal implant group without any clinical impact of these patients stopping treatment. It also stated that the impact on costs may be underestimated as the re‑treatment adjustment was only applied to the second re‑treatment with fluocinolone acetonide intravitreal implant (at month\xa036) but not to subsequent re‑treatments.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of fluocinolone acetonide intravitreal implant, having considered evidence on the nature of chronic diabetic macular oedema after an inadequate response to prior therapy and the value placed on the benefits of fluocinolone acetonide intravitreal implant by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the causes of diabetic macular oedema, and recognised the importance of good control of blood glucose, blood pressure and blood lipids in reducing the risk of diabetic macular oedema, the progression of diabetic macular oedema and other complications. The Committee discussed the impact of visual impairment on people with diabetic macular oedema. It was aware of comments from patient experts describing the significant negative impact that visual impairment has on the physical and emotional wellbeing of people with diabetic macular oedema. The Committee noted that people with diabetes manage some aspects of their own condition and that visual impairment can affect their ability to do this. This in turn can increase the risk of long‑term disease complications such as kidney disease, cardiovascular disease and amputations. The Committee also heard from clinical specialists that chronic diabetic macular oedema tends to be a bilateral condition (that is, affecting both eyes) with the potential risk of losing sight in both eyes. The clinical specialists stated that chronic diabetic macular oedema therefore affects the quality of life of people with the condition by causing visual impairment and also that of their carers because of loss of independence. The Committee noted comments from clinical specialists which highlighted that several studies have reported depression in people with chronic diabetic macular oedema. The Committee recognised the impact of visual impairment on people with diabetic macular oedema, particularly those with chronic diabetic macular oedema that is not responsive to available therapies.\n\nThe Committee discussed the current management of diabetic macular oedema. The Committee was aware that Ranibizumab for treating diabetic macular oedema (NICE technology appraisal guidance\xa0274) is the only NICE guidance relating specifically to treating diabetic macular oedema. It noted that the marketing authorisation for fluocinolone acetonide intravitreal implant specified its use only when diabetic macular oedema was insufficiently responsive to available therapies and that this population was not covered by NICE technology appraisal guidance\xa0274. The Committee heard from the clinical specialists that when anti‑vascular endothelial growth factor (anti‑VEGF) therapies are not options, standard treatment would be 'optimised standard of care', which could include laser therapy as a maintenance treatment. The Committee was aware of the publication of guidelines from the Royal College of Ophthalmologists suggesting the use of fluocinolone for some people and understood that there are currently no standard treatments for people with chronic diabetic macular oedema after other therapies have failed.\n\nThe Committee discussed the likely place of fluocinolone acetonide intravitreal implant in clinical practice. It heard from the clinical specialists that because fluocinolone acetonide intravitreal implant is a sustained‑release low‑dose long‑acting steroid, it has clear advantages over other steroid implants, which are not licensed for the treatment of diabetic macular oedema. However, the Committee understood that there are significant side effects associated with the use of a steroid in the eye, especially the acceleration of cataract development and increased rates of raised intraocular pressure, and that these still occur with fluocinolone acetonide intravitreal implant. The Committee discussed whether the use of fluocinolone acetonide intravitreal implant in one eye could be associated with cataract development in the other eye. It understood from the manufacturer that it was not aware of any evidence suggesting this. Further, it heard that fluocinolone was not detectable in the blood. The Committee also heard from the clinical specialists that there is a spectrum of severity of diabetic macular oedema, and steroid treatment might be useful in those with more severe diabetic macular oedema if other treatments (including laser therapy) have failed and cataracts have already been removed. It understood that based on existing NICE guidance and clinical practice the patient population that would be considered for fluocinolone acetonide intravitreal implant would be those for whom laser photocoagulation and anti‑VEGF therapies had failed.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of fluocinolone acetonide intravitreal implant. The Committee noted that the main sources of evidence were the FAME\xa0A and B randomised controlled trials, which enrolled people with diabetic macular oedema and included a preplanned analysis defined by the median duration of diabetic macular oedema, which had been used to identify a subgroup of people with chronic diabetic macular oedema (that is, of more than 3\xa0years' duration). It noted that in the FAME trials, patients were only treated in 1\xa0eye and that the majority of patients were treated in their worse‑seeing eye. The Committee noted that fluocinolone acetonide intravitreal implant was associated with statistically significant gains in the proportion of patients with chronic diabetic macular oedema who had a more than 15‑letter increase in best corrected visual acuity (BCVA) from baseline compared with the sham injection group. It also noted that mean change in BCVA from baseline at month\xa036 of the FAME trials was statistically significantly greater in the fluocinolone acetonide intravitreal implant group compared with the sham injection group. The Committee concluded that fluocinolone acetonide intravitreal implant showed greater clinical effectiveness than sham injection in people with chronic diabetic macular oedema.\n\nThe Committee discussed the characteristics of the FAME trial population and how these related to the patient group specified in the marketing authorisation for fluocinolone acetonide intravitreal implant and to the group of patients likely to receive treatment in UK clinical practice. The Committee noted that the efficacy data submitted were based on a subgroup defined as having chronic disease with a duration of longer than 3\xa0years, rather than as unresponsive to available therapies as specified in the marketing authorisation. The Committee further noted that some patients included received additional treatments during the trials such as laser photocoagulation and anti‑VEGF injections. The Committee discussed the concerns that this implied that in the FAME trials fluocinolone acetonide intravitreal implant was not being used as specified in the marketing authorisation. The Committee noted the manufacturer's submission and comments on the appraisal consultation document stating that the patients in the FAME trials had poor visual acuity, and that the patients in the comparator arm had disease that was responding poorly to the background therapies when given in the trial. However, the Committee remained concerned that the data from the FAME trials did not specifically reflect a group of patients who had disease that was insufficiently responsive to other therapies because people in the FAME trials did not necessarily have disease that was unresponsive to treatment with anti‑VEGF or laser photocoagulation before randomisation. The Committee considered that this could affect the levels of response observed in clinical practice because one of the mechanisms of action of corticosteroids was to act on VEGF. It noted comments received on the appraisal consultation document that studies of other intravitreal corticosteroids (such as triamcinolone) have shown a beneficial effect on macular oedema when used after anti‑VEGF treatments. The Committee remained concerned that the data from the trials may not be fully representative of the group of people who would be receiving fluocinolone acetonide intravitreal implant in UK clinical practice. However, it concluded that although there is uncertainty about the generalisability of the trial data to UK clinical practice, fluocinolone acetonide intravitreal implant is likely to be clinically effective in this population.\n\nThe Committee considered the manufacturer's approach to conducting an indirect comparison of fluocinolone acetonide intravitreal implant and laser photocoagulation using the FAME trials and the DRCR Protocol B study (2008). The Committee was aware of the Evidence Review Group's (ERG's) concerns over the value of the indirect comparison given the absence of a common comparator to link the FAME studies with the identified DRCR Protocol B study. It also noted that the retinopathy in patients included in the DRCR study was not as severe as in the FAME trials; that 40% of the DRCR population was laser‑naive; and that in the DRCR study there was no stipulation on duration of diabetic macular oedema at randomisation. The Committee concluded that the indirect comparison could not be interpreted with confidence and in any case was inappropriate to the scope for this appraisal, which considered fluocinolone acetonide intravitreal implant when diabetic macular oedema has been insufficiently responsive to available therapies.\n\nThe Committee considered the evidence for adverse events associated with fluocinolone acetonide intravitreal implant. It was aware that fluocinolone acetonide intravitreal implant was associated with the formation or progression of cataract. It noted that although there were similar rates of pre‑existing cataract between the 2\xa0trial groups (77.9% and 77.0%) among people who were phakic (still had their natural lens) at baseline, cataract surgery was needed by a greater percentage (85.1% versus 36.4%) of these people in the fluocinolone acetonide intravitreal implant group than in the sham injection group. The Committee heard from clinical specialists that the majority of people with chronic diabetic macular oedema would be likely to develop cataracts at some stage but that fluocinolone acetonide intravitreal implant might accelerate this. The Committee also noted that administration of fluocinolone acetonide intravitreal implant was associated with increased intraocular pressure: 5.3% of people in the fluocinolone group needed intraocular pressure‑lowering surgery compared with 0% in the sham injection group. The Committee heard from clinical specialists that intraocular pressure‑lowering surgery was a particular concern and for this reason, in addition to the associated acceleration of cataract development, clinicians would be likely to use fluocinolone acetonide intravitreal implant conservatively and be reluctant to use it too early in the treatment pathway. The Committee concluded that it was appropriate to take account of these adverse events when considering the approach to economic modelling.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model and sensitivity analyses, and discussed the key parameters used in it. The Committee noted the sensitivity of the model to the assumptions about the relationship between a person's treated eye and their overall visual acuity, the number of fluocinolone acetonide intravitreal implant treatments in the first 3\xa0years, assumptions about the benefits of treatment after month\xa036, the rate of re‑treatment, and the source of health‑related quality of life values. The Committee concluded that the cost‑effectiveness estimates were most sensitive to the source of health‑related quality of life values, the assumption that a person's overall visual acuity related only to their treated eye, and the assumption that all treated eyes were better‑seeing eyes.\n\nThe Committee considered the ERG's critique of the manufacturer's original base‑case results. It was aware that the ERG had made a series of explorations using the manufacturer's original base‑case incremental cost‑effectiveness ratio (ICER) of £22,600\xa0per quality‑adjusted life year (QALY) gained as a starting point. The Committee noted that by correcting an error relating to the application of annual discontinuation rates in the model, and by changing the formulae for averaging male and female mortality rates and for calculating the percentage of patients remaining on fluocinolone acetonide intravitreal implant beyond 9\xa0years, the ERG's revisions increased the manufacturer's original base‑case ICER from £22,700 to £26,500\xa0per QALY gained for fluocinolone acetonide intravitreal implant compared with optimised standard of care without the patient access scheme. The Committee agreed that the ERG's initial error corrections to the model were appropriate.\n\nThe Committee went on to consider the ERG's further explorations to the original model, which were included in the manufacturer's revised model submitted for the rapid review:\n\naligning assumptions about the rate of laser administrations per patient in the optimised standard of care group for year\xa01 of the model with the trial data\n\napplying revised unit costs for some adverse events\n\nrevising the assumptions about the extrapolation of benefits beyond 3\xa0years in the model\n\napplying an adjusted bilateral treatment rate in the fluocinolone acetonide intravitreal implant group of 85.2% of the treatment rate in the optimised standard of care group\n\nuse of a 10‑letters response criterion\n\napplying the absolute cost and quality of life uplift associated with bilateral treatment in the optimised standard of care group to the patients in the fluocinolone group needing bilateral treatment but for whom it was contraindicated\n\napplying the cost of blindness when only the treated eye fell below a BCVA of 35\xa0letters rather than both eyes.The Committee concluded that the above amendments to the assumptions in the economic model submitted by the manufacturer for the rapid review were reasonable.\n\nThe Committee discussed the assumption in the model that 20% of patients were treated in their best‑seeing eye, 40% in their worse‑seeing eye and 40% of patients were treated in both eyes. The Committee noted the manufacturer's comment on the appraisal consultation document that in the FAME trials the majority of the patients had their worse‑seeing eye treated because of ethical considerations but that in clinical practice, more patients would be treated in their best‑seeing eye because this is more likely to protect functional vision. The Committee agreed that this could be the case but considered that currently there is a lack of evidence. It concluded that the assumption of 20% of the patients being treated in their best‑seeing eye, 40% in their worse‑seeing eye and 40% of patients receiving bilateral treatment was reasonable.\n\nThe Committee discussed the use of second and subsequent fluocinolone acetonide intravitreal implants and the assumption in the model of re‑treatment only after 36\xa0months. It noted that the summary of product characteristics states that an additional implant may be administered after 12\xa0months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema. The Committee heard from the manufacturer that this wording was included in the summary of product characteristics because patients in the FAME trials could receive a further implant after 12\xa0months. However, subsequent research showed that the effect of the corticosteroid should last 36\xa0months. The Committee understood from the manufacturer that it does not promote having the implants more frequently than once every 36\xa0months and that there are currently no data available demonstrating further benefit from reimplantation. The Committee accepted the assumption in the model of no more than 1\xa0implant every 36\xa0months.\n\nThe Committee discussed the fact that the model did not apply quality of life detriments to adverse events such as cataracts, glaucoma or raised intraocular pressure. The Committee noted the manufacturer's rationale that the impact of adverse events such as cataract formation on visual acuity was incorporated in the overall utility measures, that the application of these decrements would be short in duration and therefore have a minimal impact on the ICERs, and that the decrements associated with surgery would depend on when a patient chose to have surgery. Nevertheless, the Committee concluded that if disutilities associated with operations, procedures and hospital attendances (such as cataract removal, glaucoma surgery, retinal detachment surgery, vitrectomy and treatment of endophthalmitis) had been taken into account the ICERs would increase.\n\nThe Committee discussed the utility values for the better‑seeing eye used in the economic model. The Committee noted that the manufacturer's original analyses had been based on Brown et al. (2000) utilities. It further noted that the ERG's explorations of the manufacturer's original model retained the Brown et al. (2000) utility values, and also explored the effect of applying utility values from Brown et al. (1999) and from a regression analysis in the manufacturer's submission for NICE technology appraisal guidance 237. The Committee agreed that the utility values may vary in their appropriateness in being applied to people with chronic diabetic macular oedema. It accepted that the utility values from the manufacturer's submission for NICE technology appraisal guidance\xa0237 were relatively insensitive to changes in visual acuity and therefore ICERs using these utilities may be numerically too high.\n\nThe Committee discussed further the relative merits of Brown et al. (1999) and Brown et al. (2000). It was aware that the Brown et al. (1999) utility values were based on a larger population with a mix of eye diseases whereas the Brown et al. (2000) study was based on a smaller population with age‑related macular oedema (but not diabetic macular oedema). It noted that the data from Brown et al. (2000) included a large drop in utility values between some health states, which may have arisen from the smaller patient numbers in each health state. It also noted that utility values from Brown et al. (2000) for the best health states were higher than would be expected for people with chronic diabetic macular oedema, who are usually older people with comorbidities and this, in turn, increased the uncertainty around the validity of this source of utility values. The Committee heard from the ERG that Brown et al. (2002) found no difference in the reduction in the quality of life associated with similar levels of visual acuity loss depending on the causes of vision impairment. The Committee considered the manufacturer's rationale for using Brown et al. (2000) values based on the higher proportion of patients with oedema compared with Brown et al. (1999). It also noted that the manufacturer restated in its comment on the appraisal consultation document that Brown et al. (2000) represents a more accurate source of utility values for people with diabetic macular oedema. However, the Committee was not persuaded that this outweighed the benefits of the larger sample size and the associated finer delineation of utilities possible with larger patient numbers. The Committee concluded that there were limitations to using the available utility values to model the health‑related quality of life of the group of people with chronic diabetic macular oedema. However, of the available source of utility values, Brown et al. (1999) had advantages because of the size of the sample included in the study. Because there were some uncertainties about the most appropriate source of utility values for this patient population the Committee agreed to consider a range of ICERs based on both Brown et al. (1999) and Brown et al. (2000).\n\nThe Committee noted that the manufacturer had also included analyses using utility values from Czoski‑Murray et al. (2009) and Heintz et al. (2012). The Committee discussed the appropriateness of using the values from Heintz et al. (2012) and considered that the very slight differences between utilities for the loss of better‑seeing eye vision relative to worse‑seeing eye vision lacked face validity. The Committee then discussed the utility values presented in Czoski‑Murray (2009). It understood that the source of utility values had been considered for the appraisal of Ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance\xa0237, replaced by NICE technology appraisal guidance 274) and noted that using these utility values resulted in ICERs in between the ones obtained using Brown et al. (1999) and Brown et al. (2000). The Committee agreed to consider Czoski‑Murray et al. (2009) as another source of utility values for this appraisal.\n\nThe Committee discussed the most appropriate adjustments needed to the better‑seeing eye utility values in the model when the worse‑seeing eye or both eyes were treated. The Committee considered the 6\xa0scenario analyses carried out by the ERG (see section 3.38) which varied the health‑related quality of life impact of changes in the vision of the worse‑seeing eye and the resultant QALY gain associated with treatment of the worse‑seeing eye or both eyes. The Committee understood the concerns of the ERG about using the Heintz et al. (2012) data to calculate the amount of gain from treating the worse‑seeing eye, because of the small numbers of patients in some of the visual acuity levels and also because the manufacturer's calculation did not account for visual acuity in the better‑seeing eye being correlated with visual acuity in the worse‑seeing eye. The Committee also discussed the utilities for worse‑seeing eyes in Brown et al. (1999) and heard from the ERG about an additional study, Sahel et al. (2007), which also showed that the visual acuity in the worse‑seeing eye has little impact on health‑related quality of life unless it is severely affected. The Committee was aware that there could be psychological benefits from treating the worse‑seeing eye that had not been captured in the calculation of the QALY. However, the Committee noted that the FAME trials collected data (with a majority of worse‑seeing eyes) on the effect of visual impairment on quality of life using the disease‑specific VFQ‑25\xa0questionnaire, and that this had shown no difference between the groups treated with fluocinolone acetonide intravitreal implant and those treated with sham injection. On balance, the Committee considered scenario analysis\xa03 (which assumed that changes in vision for people treated in their worse‑seeing eye had 30% of the health‑related quality of life impact of the same change in vision from treating their better‑seeing eye) to be the most appropriate for decision‑making. The Committee was not persuaded that 30% was an unreasonable reflection of the clinical situation for people with chronic diabetic macular oedema and noted that this was also consistent with previous appraisals.\n\nThe Committee then considered the cost‑effectiveness results based on data from the FAME trials for all patients with chronic diabetic macular oedema taking into account its concerns (sections 4.9–4.18). The Committee noted that the most plausible ICER for fluocinolone acetonide intravitreal implant compared with optimised standard of care in the original guidance was at least £47,600 using the utilities from Brown et al. (2000) and £80,000 using the utilities from Brown et al. (1999) per QALY gained. The Committee noted that with the patient access scheme the ICERs were reduced to £37,600 using the utilities from Brown et al. (2000), £42,700 using the utilities from Czoski‑Murray et al. (2009) and £63,500 using the utilities from Brown et al. (1999) per QALY gained. The Committee considered that the lowest of these estimates remained over £30,000\xa0per QALY gained and therefore outside the range normally considered cost effective (£20,000–£30,000\xa0per QALY gained). It also noted that there was substantial uncertainty in these estimates, particularly in the extent to which the results of the clinical trial data included in the analyses could be applied to the population of people who would receive treatment in clinical practice. The Committee concluded that fluocinolone acetonide intravitreal implant could not be recommended as a cost‑effective use of NHS resources for treating people with chronic diabetic macular oedema that is insufficiently responsive to available therapies.\n\nThe Committee discussed the subgroup of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens. The Committee acknowledged that this is an identifiable subgroup of people with chronic diabetic macular oedema. The Committee noted that the numbers of patients in the subgroup were approximately half the chronic diabetic macular oedema population in the FAME trials and that the clinical effectiveness in terms of 15‑letter gain in visual acuity in this subgroup was numerically worse than that in the total population (albeit with wide confidence intervals). The Committee considered that the comparatively small numbers of such patients in the FAME trials led to uncertainty in the estimates of clinical effectiveness for this group and thus in the estimates from the economic modelling but accepted that the subgroup proposed was reasonable. The Committee also considered that its concerns about the extent to which the data for the subgroup were representative of the group of people who would receive fluocinolone acetonide intravitreal implants in UK clinical practice remained valid (section\xa04.6). However, on balance, the Committee concluded that fluocinolone acetonide intravitreal implant had been shown to be clinically effective in this subgroup of people.\n\nThe Committee considered the cost effectiveness of fluocinolone acetonide intravitreal implant in the pseudophakic subgroup. It noted that the most plausible ICER for this subgroup in NICE technology appraisal guidance 271 was between £29,700 per QALY gained using the utilities from Brown et al. (2000) and £50,600 using the utilities from Brown et al. (1999). The Committee noted that with the patient access scheme, the ICERs presented by the ERG were £30,000 per QALY gained using the utilities from Brown et al. (1999), £21,000\xa0per QALY gained using the utilities from Czoski‑Murray et al. (2009) and £17,500 per QALY gained using the utilities from Brown et al. (2000). The Committee considered that the most plausible estimates of cost effectiveness would be in the upper end of this range, and that there was significant uncertainty around this estimate. The Committee was persuaded that the technology had been shown to meet a clinical need in people whose disease is unresponsive to available therapies. On balance, the Committee concluded that fluocinolone acetonide intravitreal implant could be a cost‑effective use of NHS resources and recommended it as an option for people with chronic diabetic macular oedema that is insufficiently responsive to available therapies and if the implant is to be used in an eye with an intraocular (pseudophakic) lens.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA301\n\nAppraisal title: Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy (rapid review of technology appraisal 271)\n\nSection\n\nKey conclusion\n\nFluocinolone acetonide intravitreal implant is recommended as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if the implant is to be used in an eye with an intraocular (pseudophakic) lens and the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme.\n\nThe Committee considered that the lowest of ICERs with the patient access scheme for people with chronic diabetic macular oedema remained over £30,000\xa0per QALY gained and therefore outside the range normally considered cost‑effective (£20,000–£30,000\xa0per QALY gained). The Committee concluded that fluocinolone acetonide intravitreal implant was not recommended as a cost‑effective use of NHS resources for treating people with chronic diabetic macular oedema that is insufficiently responsive to available therapies.\n\nThe Committee noted that for the pseudophakic subgroup, the ICERs with the patient access scheme checked by the ERG were between £30,000\xa0per QALY gained using the utilities from Brown et al. (1999) and £17,500\xa0per QALY gained with the utilities from Brown et al. (2000). It was persuaded that the technology had been shown to meet a clinical need in people whose disease is unresponsive to available therapies. The Committee concluded that fluocinolone acetonide intravitreal implant was a cost‑effective use of NHS resources.\n\n, 4.19, 4.21\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee was aware of comments from patient experts describing the significant negative impact that visual impairment has on the physical and emotional wellbeing of people with diabetic macular oedema.\n\nThe Committee was aware that Ranibizumab for treating diabetic macular oedema (NICE technology appraisal guidance\xa0274) is the only NICE guidance relating specifically to treating diabetic macular oedema and that it does not cover the treatment of people with unresponsive disease. The Committee understood that there are currently no standard treatments for people with chronic diabetic macular oedema after other therapies have failed.\n\n, 4.3\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee heard from the clinical specialists that because fluocinolone acetonide intravitreal implant is a sustained‑release low‑dose long‑acting steroid, it has clear advantages over other steroid implants, which the Committee was aware are not licensed for the treatment of diabetic macular oedema.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee noted that the marketing authorisation for fluocinolone acetonide intravitreal implant specified its use only when diabetic macular oedema was insufficiently responsive to available therapies and that this population was not covered by NICE technology appraisal guidance 274. It understood that based on existing NICE guidance and clinical practice the patient population that would be considered for fluocinolone acetonide intravitreal implant would be those for whom laser photocoagulation and anti‑VEGF therapies had failed.\n\n, 4.4\n\nAdverse reactions\n\nThe Committee noted that the significant side effects associated with the use of a steroid in the eye, especially the acceleration of cataract development and increased rates of raised intraocular pressure, still occur with fluocinolone acetonide intravitreal implant.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted that the main sources of evidence were the FAME\xa0A and B randomised controlled trials.\n\nThe Committee noted the DRCR Protocol B study used by the manufacturer in its indirect comparison. The Committee was aware of the ERG's concerns about the indirect comparison and concluded that it could not be interpreted with confidence and was inappropriate to the scope of this appraisal.\n\n, 4.7\n\nRelevance to general clinical practice in the NHS\n\nThe Committee noted that the efficacy data submitted were based on a subgroup defined as having chronic disease with a duration of longer than 3\xa0years, rather than as unresponsive to available therapies as specified in the marketing authorisation. The Committee further noted that some patients included in the trials received additional treatments during the trial such as laser photocoagulation and anti‑VEGF injections, and that this implied that in the FAME trials fluocinolone acetonide intravitreal implant was not being used as specified in the marketing authorisation. However, it concluded that although there is uncertainty about the generalisability of the trial data to UK clinical practice, fluocinolone acetonide intravitreal implant is likely to be clinically effective in this population.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee was concerned that the data from the FAME trials did not reflect a group of patients who had disease that was insufficiently responsive to other therapies because people in the FAME trials did not necessarily have disease that was unresponsive to treatment with anti‑VEGF or laser photocoagulation before randomisation.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee discussed the subgroup of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens. The Committee considered that the comparatively small numbers of such patients in the FAME trials led to uncertainty in the estimates of clinical effectiveness for this group and thus in the estimates from the economic modelling but accepted that the subgroup proposed was reasonable.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that fluocinolone acetonide intravitreal implant showed greater clinical effectiveness than sham injection in people with chronic diabetic macular oedema.\n\nThe Committee concluded that fluocinolone acetonide intravitreal implant had been shown to be clinically effective in the subgroup of people who had a pseudophakic lens.\n\n, 4.20\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the manufacturer´s model and the ERG's critique submitted for the rapid review.\n\n, 4.10\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee concluded that the manufacturer's model did not take into account the disutilities associated with operations, procedures and hospital attendances which if taken into account would cause the ICER to be even higher.\n\nThe Committee concluded that there were limitations to using the available utilities to model the health‑related quality of life of the group of people with chronic diabetic macular oedema.\n\nThe Committee considered that the comparatively small numbers of patients who had a pseudophakic lens in the FAME trials led to uncertainty in the estimates of clinical effectiveness for this group and thus in the estimates from the economic modelling.\n\n, 4.16, 4.20\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee concluded that there were limitations to using the available utilities to model the health‑related quality of life of the group of people with chronic diabetic macular oedema and agreed to consider a range of ICERs based on both Brown et al. (1999) and Brown et al. (2000).\n\nThe Committee noted that the manufacturer had also included analyses using utility values from Czoski‑Murray et al. (2009) and Heintz et al. (2012). The Committee discussed the appropriateness of using the values from Heintz et al. (2012) and considered that the very slight differences between utilities for the loss of better‑seeing eye vision relative to worse‑seeing eye vision lacked face validity. It understood that the utility values from Czoski‑Murray et al. (2009) had been considered for the appraisal of ranibizumab for the treatment of diabetic macular oedema and agreed to consider it as another source of utility values for this appraisal.\n\n, 4.17\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee discussed the subgroup of people with chronic diabetic macular oedema who had treatment in an eye with a pseudophakic lens and concluded that it was a cost‑effective use of NHS resources.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee concluded that the cost‑effectiveness estimates were most sensitive to the source of health‑related quality of life values and the assumption that a person's overall visual acuity related only to their treated eye.\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe Committee noted that for all patients with chronic diabetic macular oedema, with the patient access scheme, the ICERs were £37,600 using the utilities from Brown et al. (2000), £42,700 using the utilities from Czoski‑Murray et al. (2009) and £63,500 using the utilities from Brown et al. (1999) per QALY gained.\n\nThe Committee noted that for the pseudophakic subgroup, the ICERs with the patient access scheme presented by the ERG were £30,000 per QALY gained using the utilities from Brown et al. (1999), £21,000 per QALY gained with the utilities from Czoski‑Murray et al. (2009) and £17,500 per QALY gained with the utilities from Brown et al. (2000).\n\n, 4.21\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer of fluocinolone acetonide intravitreal implant has agreed a patient access scheme with the Department of Health in which fluocinolone acetonide intravitreal implant will be available with a discount (see section\xa05.3). The details of the scheme were provided as commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd‑of‑life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee concluded there were no issues relating to the equalities legislation, and there was no need to alter or add to its recommendations.\n\n", 'Recommendations for further research ': 'Further research is recommended to resolve uncertainties about the cost effectiveness of fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema. This should focus on a group of patients whose condition is unresponsive to other available therapies, and include measures of efficacy and health‑related quality of life. Research should focus on identifying appropriate utility values, taking into account the utility values for different levels of visual acuity and the relative relationship in utility values from treating the best‑seeing and the worse‑seeing eye. The appropriateness of generalising utility values from one group of eye conditions to another group would also be of value.', 'Related NICE guidance': 'Details are correct at the time of publication. Further information is available on the NICE website.\n\n# Published\n\nAflibercept solution for injection for treating wet age\\u2011\\related macular degeneration. NICE technology appraisal guidance 294\xa0(2013).\n\nRanibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 283\xa0(2013).\n\nRanibizumab for treating diabetic macular oedema (rapid review of technology appraisal guidance 237)\n . NICE technology appraisal guidance 274\xa0(2013).\n\nDexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229\xa0(2011).\n\nType 2 diabetes: the management of type 2 diabetes. NICE clinical guideline 87\xa0(2009).\n\nRanibizumab and pegaptanib for the treatment of age\\u2011\\related macular degeneration. NICE technology appraisal guidance 155\xa0(2008).\n\nType 1 diabetes. NICE clinical guideline 15\xa0(2004).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in November 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon Chief ExecutiveNovember 2013', 'Changes after publication': 'July 2015: Cross reference to summary of product characteristics added to section\xa02.1.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt replaces NICE technology appraisal guidance 271 (published January 2013). TA271 did not recommend fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema considered insufficiently responsive to available therapies. The updated guidance recommends fluocinolone acetonide intravitreal implant as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if the implant is to be used in an eye with an intraocular (pseudophakic) lens and the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme.\n\nThis guidance has been incorporated into the NICE pathway on diabetes along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978‑1‑4731‑0368‑9'}	https://www.nice.org.uk/guidance/ta301	Evidence-based recommendations on fluocinolone acetonide intravitreal implant (Iluvien) for treating chronic diabetic macular oedema in adults.
ab7dd8ea0f7f82873b8f75e689f6bad506f759c4	nice	Canakinumab for treating systemic juvenile idiopathic arthritis (terminated appraisal)	Canakinumab for treating systemic juvenile idiopathic arthritis (terminated appraisal) # Background The manufacturer of canakinumab (Novartis) was invited to submit evidence for this single technology appraisal in November 2013. The manufacturer informed NICE that it had decided not to provide an evidence submission because it does not believe that sufficient data are available to inform a robust health technology assessment of canakinumab for the patients with systemic juvenile idiopathic arthritis who are likely to be considered for treatment in UK clinical practice. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of canakinumab for treating systemic juvenile idiopathic arthritis. If, after doing this, organisations still wish to consider canakinumab for treating systemic juvenile idiopathic arthritis, they should follow the advice set out in the Department of Health's Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance, which outlines the approach that should be adopted in circumstances in which NICE guidance is unavailable. NICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission. # Related NICE guidance For information about NICE guidance that has been issued or is in development, see the NICE website. ## Published Tocilizumab for the treatment of systemic juvenile idiopathic arthritis. NICE technology appraisal guidance 238 (2011). Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0373-3	{'Background': 'The manufacturer of canakinumab (Novartis) was invited to submit evidence for this single technology appraisal in November\xa02013.\n\nThe manufacturer informed NICE that it had decided not to provide an evidence submission because it does not believe that sufficient data are available to inform a robust health technology assessment of canakinumab for the patients with systemic juvenile idiopathic arthritis who are likely to be considered for treatment in UK clinical practice.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': "NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of canakinumab for treating systemic juvenile idiopathic arthritis. If, after doing this, organisations still wish to consider canakinumab for treating systemic juvenile idiopathic arthritis, they should follow the advice set out in the Department of Health's Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance, which outlines the approach that should be adopted in circumstances in which NICE guidance is unavailable.\n\nNICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission.\n\n# Related NICE guidance\n\nFor information about NICE guidance that has been issued or is in development, see the NICE website.\n\n## Published\n\nTocilizumab for the treatment of systemic juvenile idiopathic arthritis. NICE technology appraisal guidance\xa0238 (2011).\n\nCopyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0373-3"}	https://www.nice.org.uk/guidance/ta302
014fea1c39d9641312590c221fdfcc9b212c596a	nice	Implantation of a duodenal–jejunal bypass sleeve for managing obesity	Implantation of a duodenal–jejunal bypass sleeve for managing obesity # Recommendations Current evidence on the safety and efficacy of implantation of a duodenal–jejunal bypass sleeve (DJBS) for managing obesity is limited in quality and quantity. Therefore, this procedure should only be used in the context of research. Clinicians should review local clinical outcomes and enter details about all patients undergoing implantation of a DJBS for managing obesity onto the National Bariatric Surgery Register when the facility for this is available. Well-controlled studies are needed to support the current limited evidence on weight loss in the short term. They should document patient selection, all complications (while the device is in place and after its removal) and technical problems associated with placing and removing the device.# Indications and current treatments Obesity is defined as a body mass index (BMI) of 30 kg/m2 or more. It is a risk factor for comorbidities such as type 2 diabetes, coronary heart disease and hypertension. Weight loss reduces the risks of comorbidities and improves long-term survival. Obesity is managed by dietary advice, exercise, lifestyle changes and medication. Bariatric surgery is considered as a treatment option in selected patients whose BMI is over 40 kg/m2, or over 35 kg/m2 for patients with other significant comorbidities, if they have not lost enough weight using non‑surgical measures. Surgical procedures aim to help patients lose weight by restricting the size of the stomach (for example, gastric banding or sleeve gastrectomy) and/or by decreasing the patient's capacity to absorb food (for example, Roux-en-Y gastric bypass or biliopancreatic diversion).# The procedure Endoscopic implantation of a duodenal–jejunal bypass sleeve (DJBS) is a minimally invasive procedure that has been used to promote weight loss in patients with obesity and with a view to improving comorbidities, including diabetes. The procedure is done with the patient under general anaesthesia or sedation, using image guidance. The sleeve is positioned endoscopically (via the mouth). Using a delivery catheter, a capsule containing a single-use impermeable DJBS is positioned in the duodenal bulb just distal to the pylorus and is secured there using an integral spring metal anchor. The sleeve is advanced distally into the jejunum with the aid of a tension wire which is part of the introducer device. It extends approximately 60 cm down the small intestine and forms a barrier between food and the intestinal wall, delaying the mixing of digestive enzymes with the food. After the procedure, patients are placed on a diet that typically involves progression from fluids to semi-solid foods, before returning to solid foods. After a maximum of a year, the sleeve is removed under sedation, using endoscopy and image guidance. The anchor incorporates a drawstring mechanism that enables it to be collapsed and partly withdrawn into a plastic hood fitted to the endoscope. The entire device is then withdrawn.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. A randomised controlled trial (RCT) of 56 patients with obesity comparing duodenal–jejunal bypass sleeve (DJBS) (n=27) against sham endoscopy (n=29) reported a significantly higher percentage of excess weight loss at 12-week follow-up for the DJBS group (n=13) than for the sham endoscopy group (n=24): 11.9±1.4% and 2.7±2.0% respectively (p=0.001). A case series of 42 patients with obesity treated by DJBS reported 47.0±4.4% (p<0.0001) excess weight loss at 52-week follow-up. An RCT of 18 patients with obesity and type 2 diabetes comparing DJBS (n=12) against sham endoscopy (n=6) reported that glycosylated haemoglobin (HbA1c) values decreased by 1.3±0.9% for the DJBS group and by 0.8±0.3% in the sham endoscopy group (p>0.05) at 12-week follow-up. At 24-week follow-up, the HbA1c had decreased by 2.4±0.7% in the DJBS group and by 0.8±0.4% in the sham endoscopy group (p>0.05). These differences were not statistically significant. The case series of 42 patients with obesity treated by DJBS reported significant reductions from baseline in total cholesterol (from 197±7 mg/dL to 161±8 mg/dL; p<0.0001), triglycerides (from 160±16 mg/dL to 115±11 mg/dL; p=0.002) and blood pressure (systolic from 134±3 mmHg to 125±2 mmHg and diastolic from 85±1 mmHg to 71±2 mmHg ) at 52-week follow-up. Implantation failure was reported in 20% (4/25) of patients because of a short duodenal bulb (n=3) or a combination of patient anatomy and investigator inexperience (n=1) in the RCT of 56 patients. The case series of 42 patients with obesity reported that, without any kind of maintenance programme, patients who completed 52 weeks of follow-up regained a mean of 4.4 kg 6 months after removal of the DJBS. A case series of 22 patients with obesity and type 2 diabetes reported that improvement in HbA1c levels continued for up to 6 months after device removal in 11 patients (mean percentage decrease 1.7±0.7%). The specialist advisers listed an additional key efficacy outcome measure as patient-reported quality of life.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. Gastrointestinal bleeding with haematemesis was reported in 14% (3/21) of patients at 11, 25 and 43 days after the procedure in the duodenal–jejunal bypass sleeve (DJBS) group of the randomised controlled trial (RCT) of 56 patients. The devices were removed. One patient needed sclerotherapy and endoscopic clips and 2 did not need further interventions to stop the bleeding. Device migration was reported in 41% (5/12) of patients in the DJBS group (4 because of anchor migration and 1 because of 'device turning or migration') during 12 weeks of follow-up in the RCT of 18 patients. All the devices were removed. Three patients presented with symptoms (1 with moderate pain, 1 with nausea, and 1 with vomiting and abdominal pain). Two patients had no symptoms, but device migration was noted at follow-up endoscopy (n=1) and at time of device removal (n=1). Sleeve obstruction with severe nausea and vomiting on day 30 was reported in 1 patient in the RCT of 40 patients. Symptoms resolved after removal of the device. One pharyngeal mucosal tear and 1 oesophageal mucosal tear occurred during device removal in a case series of 12 patients. Further intervention was not needed. Nausea and upper abdominal pain were reported in 77% (20/26) and 50% (13/26) of patients respectively (mainly in the first week after the procedure) in the DJBS group of the RCT of 41 patients. All events resolved with medication. Continuous epigastric pain was reported in 1 patient in the RCT of 41 patients. This resolved after removal of the device at 3 months. Pseudopolyp formation and implant site inflammation were noted during explantation or at follow-up endoscopy in 50% (13/26) and 38% (10/26) in the DJBS group of the RCT of 41 patients. The specialist advisers listed anecdotal adverse events as multiple linear ulcerated areas with perforation in the proximal jejunum, erosion of the duodenal wall, device malplacement, misplacement of the endoscope hood in the pharynx during endoscopic removal of the device, and inability to remove an obstructed and migrated device endoscopically (needing a laparotomy for removal). The specialist advisers listed theoretical adverse events as implantation failure; perforation of the oesophagus, stomach, duodenum or proximal jejunum and consequent laparotomy; and reduced absorption of dietary calcium and iron.# Further information # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0370-2	{'Recommendations': 'Current evidence on the safety and efficacy of implantation of a duodenal–jejunal bypass sleeve (DJBS) for managing obesity is limited in quality and quantity. Therefore, this procedure should only be used in the context of research.\n\nClinicians should review local clinical outcomes and enter details about all patients undergoing implantation of a DJBS for managing obesity onto the National Bariatric Surgery Register when the facility for this is available.\n\nWell-controlled studies are needed to support the current limited evidence on weight loss in the short term. They should document patient selection, all complications (while the device is in place and after its removal) and technical problems associated with placing and removing the device.', 'Indications and current treatments': "Obesity is defined as a body mass index (BMI) of 30\xa0kg/m2\xa0or more. It is a risk factor for comorbidities such as type\xa02\xa0diabetes, coronary heart disease and hypertension. Weight loss reduces the risks of comorbidities and improves long-term survival.\n\nObesity is managed by dietary advice, exercise, lifestyle changes and medication. Bariatric surgery is considered as a treatment option in selected patients whose BMI is over 40\xa0kg/m2, or over 35\xa0kg/m2\xa0for patients with other significant comorbidities, if they have not lost enough weight using non‑surgical measures.\n\nSurgical procedures aim to help patients lose weight by restricting the size of the stomach (for example, gastric banding or sleeve gastrectomy) and/or by decreasing the patient's capacity to absorb food (for example, Roux-en-Y gastric bypass or biliopancreatic diversion).", 'The procedure': 'Endoscopic implantation of a duodenal–jejunal bypass sleeve (DJBS) is a minimally invasive procedure that has been used to promote weight loss in patients with obesity and with a view to improving comorbidities, including diabetes.\n\nThe procedure is done with the patient under general anaesthesia or sedation, using image guidance. The sleeve is positioned endoscopically (via the mouth). Using a delivery catheter, a capsule containing a single-use impermeable DJBS is positioned in the duodenal bulb just distal to the pylorus and is secured there using an integral spring metal anchor. The sleeve is advanced distally into the jejunum with the aid of a tension wire which is part of the introducer device. It extends approximately 60\xa0cm down the small intestine and forms a barrier between food and the intestinal wall, delaying the mixing of digestive enzymes with the food.\n\nAfter the procedure, patients are placed on a diet that typically involves progression from fluids to semi-solid foods, before returning to solid foods.\n\nAfter a maximum of a year, the sleeve is removed under sedation, using endoscopy and image guidance. The anchor incorporates a drawstring mechanism that enables it to be collapsed and partly withdrawn into a plastic hood fitted to the endoscope. The entire device is then withdrawn.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nA randomised controlled trial (RCT) of 56\xa0patients with obesity comparing duodenal–jejunal bypass sleeve (DJBS) (n=27) against sham endoscopy (n=29) reported a significantly higher percentage of excess weight loss at 12-week follow-up for the DJBS group (n=13) than for the sham endoscopy group (n=24): 11.9±1.4% and 2.7±2.0% respectively (p=0.001). A case series of 42\xa0patients with obesity treated by DJBS reported 47.0±4.4% (p<0.0001) excess weight loss at 52-week follow-up.\n\nAn RCT of 18\xa0patients with obesity and type\xa02\xa0diabetes comparing DJBS (n=12) against sham endoscopy (n=6) reported that glycosylated haemoglobin (HbA1c) values decreased by 1.3±0.9% for the DJBS group and by 0.8±0.3% in the sham endoscopy group (p>0.05) at 12-week follow-up. At 24-week follow-up, the HbA1c had decreased by 2.4±0.7% in the DJBS group and by 0.8±0.4% in the sham endoscopy group (p>0.05). These differences were not statistically significant.\n\nThe case series of 42\xa0patients with obesity treated by DJBS reported significant reductions from baseline in total cholesterol (from 197±7\xa0mg/dL to 161±8\xa0mg/dL; p<0.0001), triglycerides (from 160±16\xa0mg/dL to 115±11\xa0mg/dL; p=0.002) and blood pressure (systolic from 134±3\xa0mmHg to 125±2\xa0mmHg [p=0.01] and diastolic from 85±1\xa0mmHg to 71±2\xa0mmHg [p<0.0001]) at 52-week follow-up.\n\nImplantation failure was reported in 20% (4/25) of patients because of a short duodenal bulb (n=3) or a combination of patient anatomy and investigator inexperience (n=1) in the RCT of 56\xa0patients.\n\nThe case series of 42\xa0patients with obesity reported that, without any kind of maintenance programme, patients who completed 52\xa0weeks of follow-up regained a mean of 4.4\xa0kg 6\xa0months after removal of the DJBS.\n\nA case series of 22\xa0patients with obesity and type\xa02\xa0diabetes reported that improvement in HbA1c levels continued for up to 6\xa0months after device removal in 11\xa0patients (mean percentage decrease 1.7±0.7%).\n\nThe specialist advisers listed an additional key efficacy outcome measure as patient-reported quality of life.', 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nGastrointestinal bleeding with haematemesis was reported in 14% (3/21) of patients at 11, 25\xa0and 43\xa0days after the procedure in the duodenal–jejunal bypass sleeve (DJBS) group of the randomised controlled trial (RCT) of 56\xa0patients. The devices were removed. One patient needed sclerotherapy and endoscopic clips and 2\xa0did not need further interventions to stop the bleeding.\n\nDevice migration was reported in 41% (5/12) of patients in the DJBS group (4\xa0because of anchor migration and 1\xa0because of 'device turning or migration') during 12\xa0weeks of follow-up in the RCT of 18\xa0patients. All the devices were removed. Three patients presented with symptoms (1\xa0with moderate pain, 1\xa0with nausea, and 1\xa0with vomiting and abdominal pain). Two patients had no symptoms, but device migration was noted at follow-up endoscopy (n=1) and at time of device removal (n=1).\n\nSleeve obstruction with severe nausea and vomiting on day\xa030\xa0was reported in 1\xa0patient in the RCT of 40\xa0patients. Symptoms resolved after removal of the device.\n\nOne pharyngeal mucosal tear and 1\xa0oesophageal mucosal tear occurred during device removal in a case series of 12\xa0patients. Further intervention was not needed.\n\nNausea and upper abdominal pain were reported in 77% (20/26) and 50% (13/26) of patients respectively (mainly in the first week after the procedure) in the DJBS group of the RCT of 41\xa0patients. All events resolved with medication. Continuous epigastric pain was reported in 1\xa0patient in the RCT of 41\xa0patients. This resolved after removal of the device at 3\xa0months.\n\nPseudopolyp formation and implant site inflammation were noted during explantation or at follow-up endoscopy in 50% (13/26) and 38% (10/26) in the DJBS group of the RCT of 41\xa0patients.\n\nThe specialist advisers listed anecdotal adverse events as multiple linear ulcerated areas with perforation in the proximal jejunum, erosion of the duodenal wall, device malplacement, misplacement of the endoscope hood in the pharynx during endoscopic removal of the device, and inability to remove an obstructed and migrated device endoscopically (needing a laparotomy for removal). The specialist advisers listed theoretical adverse events as implantation failure; perforation of the oesophagus, stomach, duodenum or proximal jejunum and consequent laparotomy; and reduced absorption of dietary calcium and iron.", 'Further information': '# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0370-2'}	https://www.nice.org.uk/guidance/ipg471
05c239f3e9a17bc2f428f12e319c6e60ac8422a6	nice	Negative pressure wound therapy for the open abdomen	Negative pressure wound therapy for the open abdomen # Recommendations This document replaces previous guidance on negative pressure wound therapy for the open abdomen (interventional procedure guidance 322). Current evidence on the safety and efficacy of negative pressure wound therapy (NPWT) for the open abdomen is adequate to support the use of this procedure provided that normal arrangements are in place for consent, audit and clinical governance. NPWT for the open abdomen should only be carried out by healthcare professionals with specific training in the procedure: it should be done in accordance with the manufacturer's instructions when commercial products are used. NICE encourages further research into the role of NPWT for the open abdomen. Patient selection should be documented and research should report on efficacy outcomes such as impact on wound care and healing rates, and duration of hospital stay.# Indications and current treatments Negative pressure wound therapy (NPWT) for the open abdomen may be used to manage open abdominal wounds (laparostomy) in which the gut and other intraperitoneal organs are exposed. These patients can be divided into 3 groups:(a) patients who have had surgery that did not involve the gastrointestinal tract, and in whom delayed primary closure is planned within about 1 week (for example, after 'damage-control' surgery for trauma or repair of a ruptured abdominal aneurysm)(b) patients who have had gastrointestinal tract surgery for the management of abdominal sepsis associated with severe gastrointestinal disease (including anastomotic dehiscence, visceral perforation or inflammatory bowel disease) or severe pancreatitis(c) patients who have had abdominal wound dehiscence.Intestinal fistulae may occur in any of these groups, either before or after use of NPWT is considered. Open abdomens may be managed in a number of different ways, including application of a 'Bogota bag', systems with a 'zipper' allowing lavage, or various types of dressings. NPWT is an alternative to these methods. All of these techniques may be used as a prelude to delayed primary closure of the abdomen (especially in group (a) above). Alternatively, split-thickness skin grafts, mesh repair, muscle flaps or a combination of these may be used to close the abdomen (referred to in some of the published evidence as fascial closure).# The procedure The aims of negative pressure wound therapy (NPWT) for the open abdomen include removing infected material and helping nursing care by reducing escape of fluid; its use may also influence the possibility of delayed primary closure. NPWT uses a sealed suction system to remove exudate and infected material from the abdominal cavity. The systems and techniques used vary widely, but the underlying principle is that the abdominal contents are covered with a foam sponge or other porous dressing (for example, gauze), with a membrane between the sponge/dressing and the abdominal contents. The entire wound and surrounding skin are covered with an adhesive transparent membrane, which is perforated by a drainage tube attached to the suction system. This applies negative pressure and removes fluid, at the same time preventing escape of fluid, because the membrane adheres to the skin all the way around the wound. A sensing device (a pad placed on top of the foam dressing) may be used to ensure that the prescribed amount of negative pressure is being applied to the wound. Several different commercial systems are available for NPWT, each of which requires specific training for safe and effective use. A number of non-commercial systems have also been described.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. A meta-analysis of 4303 patients reported delayed primary fascial closure rates of 58% (95% confidence interval 51 to 65) for negative pressure wound therapy (NPWT), 78% (95% CI 56 to 94) for Wittmann patch, 44% (95% CI 27 to 61) for zipper, 36% (95% CI 26 to 46) for mesh, 28% (95% CI 8 to 55) for Bogota bag and 13% (95% CI 3 to 28) for packing. A non-randomised comparative study of 578 patients treated by NPWT or other temporary abdominal closure techniques reported delayed primary fascial closure rates of 45% (84/187) and 61% (114/187) respectively (p=0.002, matched pair analysis). The non-randomised comparative study of 578 patients treated by NPWT or other temporary abdominal closure techniques reported that 14% (27/187) and 11% (20/187) of patients respectively needed prosthetic replacement of the abdominal wall (p=0.28, matched pair analysis). A case series of 111 patients reported that 7% (8/111) of patients needed abdominal wall reconstruction with a polypropylene mesh. The specialist advisers listed key efficacy outcomes as reduction of exudate from the open abdomen, early fascial closure, shorter length of hospital stay, lower mortality, lower rate of secondary procedures to reconstruct the abdominal wall and improvement in patients' quality of life.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. Mortality of 22% (95% confidence interval 18 to 28) for negative pressure wound therapy (NPWT), 33% (95% CI 25 to 42) for packing, 30% (95% CI 24 to 37) for mesh, 30% (95% CI 23 to 36) for zipper, 28% (95% CI 20 to 37) for Bogota bag and 16% (95% CI 5 to 30) for Wittmann patch were reported in the meta-analysis of 4303 patients. Mortality of 26% (48/187) for patients treated by NPWT and 29% (55/187) for patients treated by other temporary abdominal closure techniques (p=0.40, matched pair analysis) were reported in the non-randomised comparative study of 578 patients. Mortality of 30% (33/111) was reported in the case series of 111 patients. Fistulae were reported in 7% (95% CI 5 to 9) of patients treated by NPWT compared with 13% (95% CI 5 to 23) treated by zipper, 11% (95% CI 6 to 16) treated by packing, 8% (95% CI 5 to 10) treated by mesh, 8% (95% CI 2 to 16) treated by Bogota bag and 3% (95% CI 1 to 5) treated by Wittmann patch in the meta-analysis of 4303 patients. Intestinal fistulae were reported in 8% (15/187) of patients treated by NPWT and in 10% (18/187) of patients treated by other techniques (p=0.58, matched pair analysis) in the non-randomised comparative study of 578 patients. Intestinal fistulae that were considered possibly to be related to NPWT were reported in 7% (8/111) of patients in the case series of 111 patients (7 occurred during treatment and 1 after treatment). Intestinal failure (defined as the need for parenteral nutrition for more than 28 days) was reported in 15% (28/187) of patients treated by NPWT and in 15% (28/187) of patients treated by other techniques (p=1.00, matched pair analysis) in the non-randomised comparative study of 578 patients. Abscess was reported in 4% (95% CI 2 to 7) of patients treated by NPWT compared with 16% (95% CI 4 to 19) treated by zipper, 12% (95% CI 1 to 31) treated by Bogota bag, 9% (95% CI 5 to 13) treated by mesh, 7% (95% CI 2 to 16) treated by packing and 2% (95% CI 0.1 to 8) treated by Wittmann patch, in the meta-analysis of 4303 patients. Abdominal abscess was reported in 5% (5/111) of patients in the case series of 111 patients (1 occurred during treatment and 4 after treatment). Intervention to control bleeding was reported in 12% (23/187) of patients treated by NPWT and in 17% (31/187) of patients treated by other techniques (p=0.25, matched pair analysis) in the non-randomised comparative study of 578 patients. The specialist advisers stated that it could sometimes be difficult to remove the foam component of NPWT because of granulation tissue that had anchored it to the wound. In addition to the adverse events described above, the specialist advisers drew attention to pain as an adverse event reported in the literature. They listed theoretical adverse events as bowel perforation, and in the longer term an increased risk of cancerous cell regeneration.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. It updates and replaces NICE interventional procedure guidance 322. We have produced a summary of this guidance for patients and carers. Changes after publication December 2013: minor maintenance Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0286-6	{'Recommendations': "This document replaces previous guidance on negative pressure wound therapy for the open abdomen (interventional procedure guidance\xa0322).\n\nCurrent evidence on the safety and efficacy of negative pressure wound therapy (NPWT) for the open abdomen is adequate to support the use of this procedure provided that normal arrangements are in place for consent, audit and clinical governance.\n\nNPWT for the open abdomen should only be carried out by healthcare professionals with specific training in the procedure: it should be done in accordance with the manufacturer's instructions when commercial products are used.\n\nNICE encourages further research into the role of NPWT for the open abdomen. Patient selection should be documented and research should report on efficacy outcomes such as impact on wound care and healing rates, and duration of hospital stay.", 'Indications and current treatments': "Negative pressure wound therapy (NPWT) for the open abdomen may be used to manage open abdominal wounds (laparostomy) in which the gut and other intraperitoneal organs are exposed. These patients can be divided into 3\xa0groups:(a) patients who have had surgery that did not involve the gastrointestinal tract, and in whom delayed primary closure is planned within about 1\xa0week (for example, after 'damage-control' surgery for trauma or repair of a ruptured abdominal aneurysm)(b) patients who have had gastrointestinal tract surgery for the management of abdominal sepsis associated with severe gastrointestinal disease (including anastomotic dehiscence, visceral perforation or inflammatory bowel disease) or severe pancreatitis(c) patients who have had abdominal wound dehiscence.Intestinal fistulae may occur in any of these groups, either before or after use of NPWT is considered.\n\nOpen abdomens may be managed in a number of different ways, including application of a 'Bogota bag', systems with a 'zipper' allowing lavage, or various types of dressings. NPWT is an alternative to these methods. All of these techniques may be used as a prelude to delayed primary closure of the abdomen (especially in group (a) above). Alternatively, split-thickness skin grafts, mesh repair, muscle flaps or a combination of these may be used to close the abdomen (referred to in some of the published evidence as fascial closure).", 'The procedure': 'The aims of negative pressure wound therapy (NPWT) for the open abdomen include removing infected material and helping nursing care by reducing escape of fluid; its use may also influence the possibility of delayed primary closure.\n\nNPWT uses a sealed suction system to remove exudate and infected material from the abdominal cavity. The systems and techniques used vary widely, but the underlying principle is that the abdominal contents are covered with a foam sponge or other porous dressing (for example, gauze), with a membrane between the sponge/dressing and the abdominal contents. The entire wound and surrounding skin are covered with an adhesive transparent membrane, which is perforated by a drainage tube attached to the suction system. This applies negative pressure and removes fluid, at the same time preventing escape of fluid, because the membrane adheres to the skin all the way around the wound. A sensing device (a pad placed on top of the foam dressing) may be used to ensure that the prescribed amount of negative pressure is being applied to the wound.\n\nSeveral different commercial systems are available for NPWT, each of which requires specific training for safe and effective use. A number of non-commercial systems have also been described.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nA meta-analysis of 4303\xa0patients reported delayed primary fascial closure rates of 58% (95% confidence interval [CI] 51 to 65) for negative pressure wound therapy (NPWT), 78% (95% CI 56 to 94) for Wittmann patch, 44% (95% CI 27 to 61) for zipper, 36% (95% CI 26 to 46) for mesh, 28% (95% CI 8 to 55) for Bogota bag and 13% (95% CI 3 to 28) for packing. A\xa0non-randomised comparative study of 578\xa0patients treated by NPWT or other temporary abdominal closure techniques reported delayed primary fascial closure rates of 45% (84/187) and 61% (114/187) respectively (p=0.002, matched pair analysis).\n\nThe non-randomised comparative study of 578\xa0patients treated by NPWT or other temporary abdominal closure techniques reported that 14% (27/187) and 11% (20/187) of patients respectively needed prosthetic replacement of the abdominal wall (p=0.28, matched pair analysis). A case series of 111\xa0patients reported that 7% (8/111) of patients needed abdominal wall reconstruction with a polypropylene mesh.\n\nThe specialist advisers listed key efficacy outcomes as reduction of exudate from the open abdomen, early fascial closure, shorter length of hospital stay, lower mortality, lower rate of secondary procedures to reconstruct the abdominal wall and improvement in patients' quality of life.", 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nMortality of 22% (95% confidence interval [CI] 18 to 28) for negative pressure wound therapy (NPWT), 33% (95% CI 25 to 42) for packing, 30% (95% CI 24 to 37) for mesh, 30% (95% CI 23 to 36) for zipper, 28% (95% CI 20 to 37) for Bogota bag and 16% (95% CI 5 to 30) for Wittmann patch were reported in the meta-analysis of 4303\xa0patients. Mortality of 26% (48/187) for patients treated by NPWT and 29% (55/187) for patients treated by other temporary abdominal closure techniques (p=0.40, matched pair analysis) were reported in the non-randomised comparative study of 578\xa0patients. Mortality of 30% (33/111) was reported in the case series of 111\xa0patients.\n\nFistulae were reported in 7% (95% CI 5 to 9) of patients treated by NPWT compared with 13% (95% CI 5 to 23) treated by zipper, 11% (95% CI 6 to 16) treated by packing, 8% (95% CI 5 to 10) treated by mesh, 8% (95% CI 2 to 16) treated by Bogota bag and 3% (95% CI 1 to 5) treated by Wittmann patch in the meta-analysis of 4303\xa0patients. Intestinal fistulae were reported in 8% (15/187) of patients treated by NPWT and in 10% (18/187) of patients treated by other techniques (p=0.58, matched pair analysis) in the non-randomised comparative study of 578\xa0patients. Intestinal fistulae that were considered possibly to be related to NPWT were reported in 7% (8/111) of patients in the case series of 111\xa0patients (7\xa0occurred during treatment and 1 after treatment).\n\nIntestinal failure (defined as the need for parenteral nutrition for more than 28\xa0days) was reported in 15% (28/187) of patients treated by NPWT and in 15% (28/187) of patients treated by other techniques (p=1.00, matched pair analysis) in the non-randomised comparative study of 578\xa0patients.\n\nAbscess was reported in 4% (95% CI 2 to 7) of patients treated by NPWT compared with 16% (95% CI 4 to 19) treated by zipper, 12% (95% CI 1 to 31) treated by Bogota bag, 9% (95% CI 5 to 13) treated by mesh, 7% (95% CI 2 to 16) treated by packing and 2% (95% CI 0.1 to 8) treated by Wittmann patch, in the meta-analysis of 4303\xa0patients. Abdominal abscess was reported in 5% (5/111) of patients in the case series of 111\xa0patients (1\xa0occurred during treatment and 4\xa0after treatment).\n\nIntervention to control bleeding was reported in 12% (23/187) of patients treated by NPWT and in 17% (31/187) of patients treated by other techniques (p=0.25, matched pair analysis) in the non-randomised comparative study of 578\xa0patients.\n\nThe specialist advisers stated that it could sometimes be difficult to remove the foam component of NPWT because of granulation tissue that had anchored it to the wound. In addition to the adverse events described above, the specialist advisers drew attention to pain as an adverse event reported in the literature. They listed theoretical adverse events as bowel perforation, and in the longer term an increased risk of cancerous cell regeneration.', 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 322.\n\nWe have produced a summary of this guidance for patients and carers.\n\nChanges after publication\n\nDecember 2013: minor maintenance\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0286-6'}	https://www.nice.org.uk/guidance/ipg467
7c5f295ae34baddec6c1e9dd3aaa3c5722219d57	nice	Phrenic nerve transfer in brachial plexus injury	Phrenic nerve transfer in brachial plexus injury # Recommendations The limited quantity of evidence on the efficacy of phrenic nerve transfer in brachial plexus injury shows useful recovery of arm function in some patients, but there is very little information about long-term functional and quality-of-life outcomes, and evidence on safety shows some impairment of respiratory function. However, patients with brachial plexus injuries are often very disabled and treatment options may be limited. Therefore, this procedure may be used with normal arrangements for clinical governance, consent and audit. During the consent process patients should be informed, in particular, that the procedure may not restore useful function in the arm and that it may compromise respiratory function. Patient selection and treatment should only be carried out in units that specialise in the management of complex brachial plexus injuries and offer a full range of treatment options.# Indications and current treatments Brachial plexus injuries are typically caused by traction of the arm at birth and by road traffic accidents. They result in loss of sensation and movement in all or part of the arm and can be associated with severe pain. The exact symptoms depend on the severity and location of the injury. Brachial plexus injuries in which the nerves are injured but still intact are usually managed by conservative care, including physiotherapy. If the plexus has been disrupted then surgical repair is considered. This may be possible by direct suture, or it may involve the use of nerve grafts if the nerve ends are separated. If neither of these is possible, for example in nerve root avulsion, nerve transfer (neurotisation) can be done, in which a healthy nerve to a different muscle is joined to a damaged nerve, to re-innervate the affected arm muscle. A variety of nerves may be used for this kind of procedure, including intercostal nerves, the spinal accessory nerve, the phrenic nerve and the motor branches of the cervical plexus. Sometimes, free muscle or tendon transfer is done in combination with nerve transfer to re-innervate the forearm muscles.# The procedure The procedure is performed with the patient under general anaesthesia, by a supraclavicular approach. The brachial plexus is explored and the root avulsion confirmed. The phrenic nerve is identified in the neck on the surface of the scalenus anterior muscle, or in the chest thorascopically to provide a longer segment for grafting. Phrenic nerve function is confirmed by neurophysiology. The nerve is divided, transferred and joined to the distal segment of the selected damaged nerve either directly or via an interposition graft if necessary. The aim of the procedure is to re-innervate the target muscles and improve arm function. Postoperatively, a head and shoulder spica may be applied for several weeks to avoid tension on the nerve transfer. Specialist rehabilitation is provided to maximise the recovery of useful arm function. Phrenic nerve transfer may be combined with other donor nerve transfers at the same time or in stages.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. A quasi-randomised study comparing phrenic nerve transfer (PNT; n=17) against intercostal nerve transfer (n=19) to the musculocutaneous nerve in 36 patients reported that motor recovery of biceps occurred significantly later in the PNT group (mean 262 days) than in the intercostal nerve transfer group (mean 195 days; p=0.03). Biceps muscle motor recovery to Medical Research Council (MRC) grade 3 (able to overcome gravity) or greater strength was reported in 29% (5/17) of patients in the PNT group and 53% (10/19) of patients in the intercostal nerve transfer group at 1-year follow-up. In the PNT group 23% (4/17) of patients had no recovery, but all patients in the intercostal nerve transfer group regained some muscle motor function, and after rehabilitation could separate breathing from biceps function. A case series of 40 patients treated by PNT to the anterior division of the upper trunk of the brachial plexus to restore elbow flexion reported that the biceps muscle strength recovered to MRC grade 3 or greater in 83% (33/40) of patients at an average follow-up of 28.2 months. Recovery to MRC grade 3 or greater strength occurred in 91% (29/32) of patients aged under 40 years, and in 50% (4/8) of patients aged 40 years and over. For patients who had the procedure more than 1 year after the injury, the recovery rate was 25% (1/4 patients). A retrospective case series of 180 patients treated by PNT to the musculocutaneous nerve followed up 65 patients for more than 2 years. The study reported that 85% (55/65) of patients regained biceps muscle power to MRC grade 3 or greater strength. The average time taken for restoration of muscle strength to MRC grade 3 was 9.5 months. Longer delays in treatment were associated with lower levels of recovery. Patients who had a nerve graft had similar results to patients who had a direct nerve transfer. Poor results were seen in patients with severe crush injuries and associated fractures in the shoulder region. The specialist advisers listed key efficacy outcomes as restoration of muscle function or joint movement/elbow flexion, shoulder stability, control of re-innervated muscles and functional scores such as DASH (Disabilities of the Arm, Shoulder and Hand) and QALY (quality-adjusted life year) measures.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. A retrospective comparative study of 42 patients comparing phrenic nerve transfer (PNT; n=19) against PNT with multiple intercostal nerve transfer (PNT+MIT; n=23) reported that a certain degree of hemidiaphragm elevation (a mean of 1–1.5 intercostal spaces) was observed in 90% (38/42) of patients at a mean follow-up of 10 years. Diaphragmatic excursion was reduced by a mean of 0.5–1 intercostal spaces in both the groups after the procedures. Hemidiaphragm elevation and movement reduction did not worsen as the number of intercostal nerves used increased from 2–4 in the PNT+MIT group, or if both procedures were done at the same stage or performed at an interval of 1–2 months. A case series of 19 patients treated by PNT+MIT reported persistent ipsilateral diaphragmatic paralysis in all patients for up to 36 months (p<0.01). The quasi-randomised study of 36 patients comparing PNT (n=17) against intercostal nerve transfer (n=19) reported that pulmonary function (forced vital capacity, forced expiratory volume in 1 second, vital capacity and tidal volume) was significantly lower in the PNT group than in the intercostal nerve transfer group throughout 1 year of follow-up. Body position had a significant effect on forced vital capacity in the PNT group but no effect in the intercostal nerve transfer group. The retrospective case series of 180 patients of whom 65 patients were followed up for more than 2 years reported that pulmonary function tests in 19 patients (including forced vital capacity, total lung capacity, functional residual capacity, vital capacity and maximum ventilation volume) showed decreased pulmonary function during the first year after PNT surgery, improving to normal values by 2 years. The case series of 19 patients who had PNT+MIT reported mild dyspnoea on exertion in 42% (8/19) of patients at 6-month follow-up (p<0.05), which resolved by 1-year follow-up. The specialist advisers listed theoretical adverse events as chest wall deformity, herniation, basal atelectasis/collapse, poor voluntary control of muscles innervated by the transfer and failure to re-innervate target muscles due to proximal injury to the phrenic nerve.# Further information # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0356-6	{'Recommendations': 'The limited quantity of evidence on the efficacy of phrenic nerve transfer in brachial plexus injury shows useful recovery of arm function in some patients, but there is very little information about long-term functional and quality-of-life outcomes, and evidence on safety shows some impairment of respiratory function. However, patients with brachial plexus injuries are often very disabled and treatment options may be limited. Therefore, this procedure may be used with normal arrangements for clinical governance, consent and audit.\n\nDuring the consent process patients should be informed, in particular, that the procedure may not restore useful function in the arm and that it may compromise respiratory function.\n\nPatient selection and treatment should only be carried out in units that specialise in the management of complex brachial plexus injuries and offer a full range of treatment options.', 'Indications and current treatments': 'Brachial plexus injuries are typically caused by traction of the arm at birth and by road traffic accidents. They result in loss of sensation and movement in all or part of the arm and can be associated with severe pain. The exact symptoms depend on the severity and location of the injury.\n\nBrachial plexus injuries in which the nerves are injured but still intact are usually managed by conservative care, including physiotherapy. If the plexus has been disrupted then surgical repair is considered. This may be possible by direct suture, or it may involve the use of nerve grafts if the nerve ends are separated. If neither of these is possible, for example in nerve root avulsion, nerve transfer (neurotisation) can be done, in which a healthy nerve to a different muscle is joined to a damaged nerve, to re-innervate the affected arm muscle. A variety of nerves may be used for this kind of procedure, including intercostal nerves, the spinal accessory nerve, the phrenic nerve and the motor branches of the cervical plexus. Sometimes, free muscle or tendon transfer is done in combination with nerve transfer to re-innervate the forearm muscles.', 'The procedure': 'The procedure is performed with the patient under general anaesthesia, by a supraclavicular approach. The brachial plexus is explored and the root avulsion confirmed. The phrenic nerve is identified in the neck on the surface of the scalenus anterior muscle, or in the chest thorascopically to provide a longer segment for grafting. Phrenic nerve function is confirmed by neurophysiology. The nerve is divided, transferred and joined to the distal segment of the selected damaged nerve either directly or via an interposition graft if necessary. The aim of the procedure is to re-innervate the target muscles and improve arm function.\n\nPostoperatively, a head and shoulder spica may be applied for several weeks to avoid tension on the nerve transfer. Specialist rehabilitation is provided to maximise the recovery of useful arm function.\n\nPhrenic nerve transfer may be combined with other donor nerve transfers at the same time or in stages.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nA quasi-randomised study comparing phrenic nerve transfer (PNT; n=17) against intercostal nerve transfer (n=19) to the musculocutaneous nerve in 36\xa0patients reported that motor recovery of biceps occurred significantly later in the PNT group (mean 262\xa0days) than in the intercostal nerve transfer group (mean 195\xa0days; p=0.03). Biceps muscle motor recovery to Medical Research Council (MRC) grade\xa03 (able to overcome gravity) or greater strength was reported in 29% (5/17) of patients in the PNT group and 53% (10/19) of patients in the intercostal nerve transfer group at 1-year follow-up. In the PNT group 23% (4/17) of patients had no recovery, but all patients in the intercostal nerve transfer group regained some muscle motor function, and after rehabilitation could separate breathing from biceps function.\n\nA case series of 40\xa0patients treated by PNT to the anterior division of the upper trunk of the brachial plexus to restore elbow flexion reported that the biceps muscle strength recovered to MRC grade\xa03 or greater in 83% (33/40) of patients at an average follow-up of 28.2\xa0months. Recovery to MRC grade\xa03 or greater strength occurred in 91% (29/32) of patients aged under 40\xa0years, and in 50% (4/8) of patients aged 40\xa0years and over. For patients who had the procedure more than 1\xa0year after the injury, the recovery rate was 25% (1/4 patients).\n\nA retrospective case series of 180\xa0patients treated by PNT to the musculocutaneous nerve followed up 65\xa0patients for more than 2\xa0years. The study reported that 85% (55/65) of patients regained biceps muscle power to MRC grade\xa03 or greater strength. The average time taken for restoration of muscle strength to MRC grade\xa03 was 9.5\xa0months. Longer delays in treatment were associated with lower levels of recovery. Patients who had a nerve graft had similar results to patients who had a direct nerve transfer. Poor results were seen in patients with severe crush injuries and associated fractures in the shoulder region.\n\nThe specialist advisers listed key efficacy outcomes as restoration of muscle function or joint movement/elbow flexion, shoulder stability, control of re-innervated muscles and functional scores such as DASH (Disabilities of the Arm, Shoulder and Hand) and QALY (quality-adjusted life year) measures.', 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nA retrospective comparative study of 42\xa0patients comparing phrenic nerve transfer (PNT; n=19) against PNT with multiple intercostal nerve transfer (PNT+MIT; n=23) reported that a certain degree of hemidiaphragm elevation (a mean of 1–1.5\xa0intercostal spaces) was observed in 90% (38/42) of patients at a mean follow-up of 10\xa0years. Diaphragmatic excursion was reduced by a mean of 0.5–1\xa0intercostal spaces in both the groups after the procedures. Hemidiaphragm elevation and movement reduction did not worsen as the number of intercostal nerves used increased from 2–4 in the PNT+MIT group, or if both procedures were done at the same stage or performed at an interval of 1–2\xa0months.\n\nA case series of 19\xa0patients treated by PNT+MIT reported persistent ipsilateral diaphragmatic paralysis in all patients for up to 36\xa0months (p<0.01).\n\nThe quasi-randomised study of 36\xa0patients comparing PNT (n=17) against intercostal nerve transfer (n=19) reported that pulmonary function (forced vital capacity, forced expiratory volume in 1\xa0second, vital capacity and tidal volume) was significantly lower in the PNT group than in the intercostal nerve transfer group throughout 1\xa0year of follow-up. Body position had a significant effect on forced vital capacity in the PNT group but no effect in the intercostal nerve transfer group.\n\nThe retrospective case series of 180\xa0patients of whom 65\xa0patients were followed up for more than 2\xa0years reported that pulmonary function tests in 19\xa0patients (including forced vital capacity, total lung capacity, functional residual capacity, vital capacity and maximum ventilation volume) showed decreased pulmonary function during the first year after PNT surgery, improving to normal values by 2\xa0years.\n\nThe case series of 19\xa0patients who had PNT+MIT reported mild dyspnoea on exertion in 42% (8/19) of patients at 6-month follow-up (p<0.05), which resolved by 1-year follow-up.\n\nThe specialist advisers listed theoretical adverse events as chest wall deformity, herniation, basal atelectasis/collapse, poor voluntary control of muscles innervated by the transfer and failure to re-innervate target muscles due to proximal injury to the phrenic nerve.', 'Further information': '# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0356-6'}	https://www.nice.org.uk/guidance/ipg468
0a04e25ce61051258de0e3733876c054996563f4	nice	Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C	Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C Evidence-based recommendations on peginterferon alfa (Pegasys) and ribavirin for people with mild chronic hepatitis C. # Guidance This is an extension of the guidance given in Hepatitis C - pegylated interferons, ribavirin and alfa interferon (NICE technology appraisal guidance 75). This guidance and TA75 have been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200) and 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300). For details, see 'About this guidance'. Combination therapy, comprising peginterferon alfa-2a and ribavirin or peginterferon alfa-2b and ribavirin, is recommended, within the licensed indications of these drugs, for the treatment of mild chronic hepatitis C. Monotherapy with peginterferon alfa-2a or peginterferon alfa-2b is recommended, within the licensed indications of these drugs, for the treatment of mild chronic hepatitis C for people who are unable to tolerate ribavirin, or for whom ribavirin is contraindicated. The decision on whether a person with mild chronic hepatitis C should be treated immediately or should wait until the disease has reached a moderate stage ('watchful waiting') should be made by the person after fully informed consultation with the responsible clinician. The decision to treat need not depend on a liver biopsy to determine the stage of the disease if treatment is initiated immediately. However, a biopsy may be recommended by the clinician for other reasons or if a strategy of watchful waiting is chosen. This recommendation has been updated and replaced by NICE technology appraisal guidance 200 ( 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' This recommendation has been updated and replaced by NICE technology appraisal guidance 200 ( 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' This recommendation has been partially updated and replaced by NICE technology appraisal guidance 300 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' ). There is insufficient evidence to recommend combination therapy or monotherapy with peginterferon alfa for people who have had a liver transplant.# Clinical need and practice Chronic hepatitis C is a disease of the liver caused by the hepatitis C virus. Generally the virus is transmitted parenterally, but the natural history of the disease is not completely understood. The virus is primarily acquired through percutaneous exposure to contaminated blood. Since the viral inactivation programme was implemented in the mid-1980s and blood donor screening started in 1991, the transmission of HCV in the UK, via transfusion of blood, blood products or organ transplantation, has all but ceased. However, injecting drug use, cosmetic and other practices involving percutaneous exposure remain common routes of transmission. HCV prevalence is correlated with markers of sexual activity, but HCV incidence in monogamous heterosexual partners of infected people is extremely low. There is a transmission rate of about 6% from mother to child if the mother is an HCV carrier. Concomitant HIV infection increases the risk of transmission. People infected with HCV are often asymptomatic, but about 20% will develop overt hepatitis. Many people who are chronically infected will experience non-specific symptoms including malaise, weakness and anorexia. About 80% of those exposed go on to develop chronic hepatitis. The rate of progression of the disease is slow but variable, usually taking about 20–50 years from the time of infection. About 30% of those who are infected develop cirrhosis within 20–30 years, and a small percentage of these people are at a high risk of developing hepatocellular carcinoma. A third may never progress to cirrhosis or will not progress for at least 50 years. Some people with end-stage liver disease or hepatocellular carcinoma may need liver transplantation. The effectiveness of treatment is related to the genotype of the virus. Six major genetic types of HCV have been found. Genotype 1 is the most common in the UK, accounting for about 40–50% of cases. Genotypes 2 and 3 contribute another 40–50%; and genotypes 4, 5 and 6 constitute the remainder, about 5%. Recent estimates suggest that approximately 200,000 to 500,000 people are infected with HCV in England and Wales. (In 2005, the Department of Health estimated that only 47,000 people with HCV infection had been diagnosed and only 7000 had been treated.) There is also great variation in prevalence between subgroups of the population: 0.04% in blood donors, 0.4% in people attending antenatal clinics in inner London, 1% in people attending genitourinary clinics and up to 50% in intravenous drug users attending drug abuse clinics. Because it is not possible in the short term to directly measure the effectiveness of treatment in reducing progression to cirrhosis and hepatocellular carcinoma, three surrogate markers have been used in trials: hepatic histology virological loss of HCV-RNA (by quantitative polymerase chain reaction) levels of alanine aminotransferase (an enzyme that indicates the presence of liver inflammation). The previous NICE guidance (TA 75) applies only to people with moderate or severe chronic hepatitis C, which is defined as histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation of the liver. For the majority of people with moderate or severe hepatitis C, the standard treatment is combination therapy with ribavirin and either peginterferon alfa-2a or peginterferon alfa-2b. Monotherapy with peginterferon alfa is used only for people unable to tolerate ribavirin. In trials for people with moderate or severe hepatitis C, about 75–85% of people with HCV genotype 2 or 3 had a sustained virological response 6 months after finishing a course of treatment with peginterferon alfa and ribavirin. For people with genotype 1, the rate of sustained virological response was about 40–50%, while for the three less common genotypes (4, 5 and 6) the rate appears to be between those for genotype 1 and genotypes 2 or 3. For people with moderate or severe disease and with genotype 2 or 3, the maximum rate of sustained virological response is attained after 24 weeks of treatment. Further treatment does not increase the rate, so treatment beyond 24 weeks is not advised. For people with the other genotypes, it may take longer than 24 weeks to gain a sustained virological response, so the standard treatment length is 48 weeks. However, if no virological response has occurred by 12 weeks of treatment, a sustained response is unlikely to occur. Hence, it is recommended that people who do not attain a sufficient virological response by 12 weeks should not receive a further 36 weeks of treatment. People infected with genotypes 2 or 3 do not need a test of virological response at 12 weeks, because almost all respond by that time. Peginterferons are formed by attaching strands of polyethylene glycol (PEG) to the interferon molecules. This slows the rate of absorption and excretion of interferon, reducing the fluctuations in serum concentrations that occur with unmodified interferon. The pegylation process increases the half-life of the interferon molecule in the body: in the case of peginterferon alfa-2a from about 4 hours to between 50 and 130 hours, and for peginterferon alfa-2b from about 4 hours to about 40 hours. Accordingly, people treated with peginterferon alfa need injections only once a week, compared with three times a week for people treated with non-pegylated interferon, referred to in this guidance as 'interferon'. In addition, clinical trials suggest that response rates to interferon among people with moderate or severe disease are significantly lower than response rates to peginterferon therapy. Standard haematological tests and blood chemistry (that is, full blood count and differential platelet count, liver function tests, uric acid, serum bilirubin and serum creatinine) are necessary for all patients being considered for combination therapy. The HCV genotype with which the person is infected should be determined for all candidates for combination therapy. Liver biopsy has played a role in helping to determine disease staging, but it is no longer considered necessary for people with HCV of genotypes 2 and 3, or if biopsy poses an increased risk. Patients should be seen weekly for the first 4 weeks of treatment and then monthly for 6 months to check for haemolysis and changes in thyroid activity. Both pegylated interferon and interferon give rise to flu-like symptoms in many people. Ribavirin leads, in a proportion of cases, to anaemia, pruritus, rash, insomnia and dyspnoea. For full details of side effects and contraindications, see the summary of product characteristics for each drug. The standard measurement of the effectiveness of treatment, in people with chronic hepatitis C, is the virological response rate sustained for 6 months (known as the sustained virological response rate). This is defined as the proportion of people in whom the virus is undetectable in blood samples 6 months after treatment has been completed. A direct measure of viral activity is viral load, which is the number of copies of the virus in a given quantity of blood. Although a high viral load is likely to mean that the liver deteriorates more quickly than it does under the influence of a low viral load, the relationship is not a simple one, and some people live with high viral loads for many years without progressing from mild disease to moderate disease. A person is classified as having mild, moderate or severe chronic hepatitis C based on the extent of liver damage. If there is a sufficient need to know the extent of liver disease, this may be determined histologically by liver biopsy. The main indicator of liver damage is the degree of fibrosis, although the degree of necroinflammation also contributes to the diagnosis. At a time before the treatment of mild chronic hepatitis C was routinely considered, it was the practice to perform a liver biopsy before prescribing interferon alfa or peginterferon alfa to determine whether a person with chronic hepatitis C had reached a moderate or severe stage of the disease. Initiating treatment at an earlier stage means this is no longer necessary.# The technology The objective of this appraisal is to compare the use of peginterferon therapy (in combination with ribavirin or as monotherapy) in mild chronic hepatitis C with the current practice of deferring treatment until the disease has progressed to moderate or severe. Current practice and the technology are described in section 2 above. Peginterferon alfa-2a (Pegasys) and ribavirin (Copegus) are manufactured by Roche. For genotypes 2 and 3, the licensed regimen is peginterferon alfa-2a 180 micrograms once per week plus ribavirin 800 mg/dayfor 24 weeks. This course of therapy costs £5019 (excluding VAT; 'British national formulary', 50th edition). For genotypes 1, 4, 5 and 6, the regimen is peginterferon alfa-2a 180 micrograms once per week for 48 weeks plus ribavirin 1000 mg/day (for people weighing less than 75 kg) or 1200 mg/day (for those weighing 75 kg or more) for the same length of time as peginterferon alfa. The cost is £10,963 or £11,889 for 48 weeks depending on body weight. For peginterferon monotherapy, the cost of treatment is £6339 (for 12 months) for all genotypes. Peginterferon alfa-2b (ViraferonPeg) and ribavirin (Rebetol) are produced by Schering-Plough. For genotypes 2 and 3, the licensed regimen is peginterferon alfa-2b 1.5 micrograms/kg/week plus ribavirin 800 mg/day (for people weighing less than 65 kg) or 1000 mg/day (for those weighing 65–85 kg) or 1200 mg/day (for those weighing more than 85 kg) for 24 weeks. The cost of a course is £6734 for a person of an average weight of 79 kg (excluding VAT; 'British national formulary', 50th edition). Costs may vary in different settings because of negotiated procurement discounts. The marketing authorisation for peginterferon alfa-2b in combination with ribavirin has been varied and now allows for 24 weeks of treatment in people with genotype 1 (low viral load) who have responded sufficiently to treatment at 4 weeks. The cost is £6734 for a person of average weight (79 kg). For people with genotype 1 (high viral load) and optionally for those with low viral load, the cost for 48 weeks of treatment is £13,468 for a person of average weight (excluding VAT; 'British national formulary', 50th edition). Costs may vary in different settings because of negotiated procurement discounts. For genotypes 5 and 6, the regimen (and associated cost) is as for genotypes 1 and 4 (high viral load). Costs may vary in different settings because of negotiated procurement discounts. The cost of treatment for 24 weeks with peginterferon alfa-2b monotherapy is £1657 (0.5 micrograms/kg/week) or £2652 (1.0 micrograms/kg/week) and for 48 weeks is £3314 (0.5 micrograms/kg/week) or £5303 (1.0 micrograms/kg/week) (excluding VAT; 'British national formulary', 50th edition). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (see appendix B). # Clinical effectiveness Three trials of peginterferon alfa-2a and five trials of interferon alfa-2b that included people with chronic hepatitis C, at least 70% of whom had mild disease, were included in the assessment report. All studies included the combination with ribavirin in at least one arm. The comparators in the trials varied. Two of the three peginterferon alfa-2a studies compared longer courses (48 weeks) with shorter courses (24 weeks); the third compared peginterferon alfa-2a with non-pegylated interferon alfa-2a. No studies compared the strategies of early treatment of mild disease with a strategy of watchful waiting and treatment for those who progress to moderate or severe disease. Because this is the primary comparison of interest in this appraisal, results for the comparator arms in the studies in section 4.1.4 are not reported here. ## Peginterferon alfa-2a plus ribavirin HCV genotypes 2 and 3 The three trials of peginterferon alfa-2a plus ribavirin in people with genotypes 2 and 3 yielded sustained virological response rates of 72–84% after 24 weeks of treatment and rates of 78–80% after 48 weeks of treatment. For people infected with these genotypes, there was no statistically significant difference between the rates after 24 weeks of treatment or after 48 weeks. These results are consistent with those for studies conducted in people with moderate or severe chronic hepatitis C; in the previous appraisal (TA 75), the corresponding rate of sustained virological response in different trials that included people with both mild and moderate or severe disease was 79%. In people infected with genotype 1, peginterferon alfa-2a plus ribavirin yielded sustained virological response rates of 13–42% after 24 weeks of treatment and 40–52% after 48 weeks. In this group, the additional 24 weeks of treatment statistically significantly increased the rate of sustained response. ## Peginterferon alfa-2b plus ribavirin Although there was no trial of peginterferon alfa-2b combination therapy that met the Assessment Group's criteria for inclusion of trials of people with mild chronic hepatitis C, one study included 1014 (of 1530) participants who had been documented as having no or minimal fibrosis. In this study, a sustained virological response occurred in 57% of participants with no or minimal fibrosis (that is, with mild disease) who received 'high-dose' peginterferon alfa‑2b (1.5 micrograms/kg/week for 48 weeks) plus ribavirin. This compares with a rate of 44% among those who had bridging fibrosis or cirrhosis (that is, moderate or severe disease) who received high-dose peginterferon alfa-2b. In people who received 'low-dose' peginterferon alfa-2b (1.5 micrograms/kg/week for 4 weeks, then 0.5 micrograms/kg/week for 48 weeks) plus ribavirin, a sustained virological response rate of 51% was recorded among those with mild disease compared with 43% among those with moderate or severe disease. Results by genotype were not reported. The rate of sustained virological response was statistically significantly higher among participants on high-dose (but not low-dose) peginterferon alfa-2b combination therapy than among patients on non-pegylated interferon alfa-2b plus ribavirin. ## Monotherapy trials People who are unable to take ribavirin and are treated with monotherapy with peginterferon alfa or non-pegylated interferon alfa have much lower response rates than people treated with combination therapy. One trial of 159 people compared response rates with three different regimens of peginterferon alfa-2a with one of interferon alfa-2a. Rates of sustained virological response were 3% for interferon alfa-2a and between 10% and 29% for peginterferon alfa-2a, depending on the dose. Altogether, 82% of participants were classified as having mild chronic hepatitis C. Another trial of 1219 people compared response rates for three different regimens of peginterferon alfa-2b and one of interferon alfa-2b. Altogether, 83% of participants in this study were classified as having mild disease. Rates of sustained virological response were 12% for those treated with interferon alfa-2b and between 18 and 23% for those treated with peginterferon alfa-2b, depending on the dose. ## Summary Taken as a whole, the evidence for combination therapy and monotherapy, and for pegylated and non-pegylated interferon alfa-2a and pegylated and non-pegylated interferon alfa-2b, suggests that rates of sustained virological response among patients with mild disease are about the same as those among patients with moderate or severe disease. Combination therapy with peginterferon alfa (2a or 2b) and ribavirin produces higher rates of sustained virological response than combination therapy with non-pegylated interferon alfa (2a or 2b). Monotherapy with pegylated interferon alfa-2a or alfa-2b produces higher response rates than monotherapy with non-pegylated interferon alfa. # Cost effectiveness The assessment report found six studies examining the cost effectiveness of treatment for people with mild disease. Three of these studies compared interferon combination therapy with no treatment rather than with delayed treatment. These three studies showed that interferon combination therapy was cost effective when compared with standard care (all estimated mean incremental cost-effectiveness ratios were less than £10,000 per quality-adjusted life year ). Two studies compared early treatment with peginterferon alfa combination therapy with delayed treatment. They showed that, for genotypes 2 and 3, early treatment is apparently cost effective when compared with delayed treatment, but the case for early treatment for genotype 1 is less clear. The model employed in the Roche submission determined the cost effectiveness of peginterferon alfa-2a plus ribavirin against no treatment. The estimated mean cost per QALY for treating people with mild disease was £1000 for genotypes 2 and 3, and £4000 for genotype 1. The model employed in the Schering-Plough submission determined the cost effectiveness of peginterferon alfa-2b plus ribavirin against no treatment. The model is academic-in-confidence. The estimated mean cost per QALY for treating mild chronic hepatitis C was £1000 for genotypes 2 and 3, and £3000 for genotype 1. The model developed by the Assessment Group incorporated seven health states: remission, mild disease, moderate disease, compensated cirrhosis, decompensated cirrhosis, liver cancer and liver transplantation. It used rates of sustained virological response from the manufacturers' submissions and transition rates between the seven health states from a number of sources. For example, the estimated transition rate from mild to moderate disease as used in the model was 2.5% per year, which was obtained from observational data relating to 373 cases from a routine practice in a hospital in London between 1990 and 2001. Health-state utilities and costs were estimated from the UK mild hepatitis C trial. For comparability with the previous review, benefits were discounted at 1.5% per year and costs at 6%, with a sensitivity analysis at 3.5% for both costs and benefits. ## Non-1 genotype HCV For people with non-1 genotype infection, the base case estimated mean ICER for deferring treatment with peginterferon alfa‑2a combination therapy until the disease reaches the moderate or severe stage relative to best supportive care (no treatment) is £1300 per QALY. The corresponding ICER for peginterferon alfa-2b plus ribavirin is £1400. This analysis confirms that the strategy of treating people with moderate or severe disease is cost effective compared with not treating them at all. The estimated mean ICERs for early treatment with peginterferon alfa in combination with ribavirin are £3700 for peginterferon alfa-2a and £4300 for peginterferon alfa-2b, when compared with deferring treatment until the disease reaches the moderate-to-severe stage in people with non-1 genotype infection. This analysis shows that treatment of mild disease is cost effective compared with waiting until the patient reaches the moderate stage of the disease. These are the key cost-effectiveness estimates for this appraisal. Further analysis shows that combination therapy with pegylated interferon is cost effective when compared with the corresponding non-pegylated therapy for treating people with mild disease. ## Genotype 1 HCV For people with genotype 1 infection, the base case estimated mean ICER is £6900 per QALY for watchful waiting followed by treatment with peginterferon alfa-2a combination therapy when the disease reaches the moderate or severe stage, relative to best supportive care (no treatment). The corresponding ICER for peginterferon alfa-2b plus ribavirin is £4700. This analysis confirms that the strategy of treating only moderate or severe disease is cost effective compared with not treating the infection at all. For people with genotype 1 infection, the estimated mean ICERs for early treatment with peginterferon alfa in combination with ribavirin are £10,300 for peginterferon alfa-2a and £8300 for peginterferon alfa-2b when compared with deferring treatment until the disease reaches the moderate-to-severe stage, and reflecting the early stopping rules recommended in the summary of product characteristics for peginterferon alfa-2a. This analysis shows that treating mild disease is very likely to be cost effective compared with waiting until the patient reaches the moderate stage. These are the key cost-effectiveness estimates for this appraisal. Further analysis shows that pegylated interferon combination therapy is cost effective when compared with the corresponding non-pegylated therapy for treating people with mild disease. ## Monotherapy: all genotypes In people unable to take ribavirin, monotherapy with peginterferon may be used. The estimated mean ICER for early treatment with peginterferon alfa monotherapy is £3000 per QALY for peginterferon alfa-2a and £2300 for peginterferon alfa-2b against the same treatment deferred until a later stage. ## Sensitivity analyses Estimated mean ICERs are even lower using current stopping rules, whereby treatment is stopped at 12 weeks if a 100-fold reduction in viral load has not occurred. Sensitivity analyses conducted in the assessment report do not lead to ICERs of more than £20,000 except when the average age of patients is increased by 15 years. # Consideration of the evidence The Committee reviewed the data on the clinical effectiveness and cost effectiveness of interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C, having considered evidence on the nature of the condition and the value placed on the benefits of this treatment by people with the condition (or who have had the condition), those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. The Committee heard from clinical and patient experts that studies show the quality of life of people with mild disease, even in the absence of histological evidence of definitive liver disease, is on average lower than that of people who have had mild disease and who have been cleared of the virus. The experts advised the Committee that such a difference in quality of life is an important contributor to the benefit of early treatment of mild disease. The Committee also heard from the experts that sustained virological response, when the virus is undetectable 6 months after treatment has finished, is maintained for 10 years in more than 90% of people. Additionally, it is unusual for re-infection with HCV to occur after a sustained virological response has been achieved. These observations were consistent with the assumptions of the cost-effectiveness model used in the assessment report. Therefore, the Committee concluded that the model inputs were appropriate in these respects. The Committee understood that about half of the approximately 3000 people in England and Wales who are treated each year have a sustained virological response and are effectively cured, but that the number of new cases is greater than the number of people being cured. Therefore, the number of people with the disease is still rising. The Committee heard that early treatment of people with chronic hepatitis C in the general population could potentially reduce the likelihood of the spread of infection and that this would lead to a better estimate of cost effectiveness than that demonstrated in the models, in which the effect of the spread of infection had not been considered. The Committee considered that, although the predicted effectiveness of the treatment of mild disease in a clinical setting was not as high as the average efficacy seen in the clinical trials, this difference was not likely to affect the importance of the therapy or overall cost effectiveness. The Committee discussed a recent change in the UK marketing authorisation for peginterferon alfa-2b for people with genotype 1 (and by extension, genotype 4) and low viral loads (less than 600,000 IU/ml). This change allows combination therapy to be stopped at 24 weeks rather than continue to 48 weeks. The Committee has not reviewed the clinical effectiveness evidence for this modification of the marketing authorisation, so is not able to comment specifically on it. However, the Committee did note the caution carried in the marketing authorisation regarding the possibility that there may be a lower rate of sustained viral response if treatment is limited to 24 weeks. Nevertheless, if the success rate for sustained viral response were not to be affected by the shortening of the treatment period, the Committee recognised that this regimen would be cost effective compared with the 48-week treatment. The Committee considered that an important question was whether it is cost effective to treat immediately people who have mild chronic hepatitis C with peginterferon alfa plus ribavirin or to wait until their disease reaches the moderate stage ('watchful waiting'). The Committee disregarded the manufacturers' models, which they considered had not made the relevant comparison. The Committee understood that, if the rate of progression to moderate disease were sufficiently low, it might be better not to subject all people with mild disease to the side effects of combination therapy because few might progress to moderate disease or beyond. The Committee discussed the progression rates (from mild to moderate disease). The Committee was told that there is no way of knowing which patients are likely to progress from mild disease to moderate disease, but that progression is somewhat slower for younger people, for those who have been infected for a shorter time, for females and for certain ethnic groups. The Committee considered at length the progression rates assumed in the assessment report model, and noted that these were from clinical trials of people who presented for treatment. The Committee appreciated that this may represent a small proportion of the total number thought to be infected with HCV and that people who were asymptomatic and had not sought treatment may experience a different rate of progression, on average, from those who had sought treatment. The Committee accepted that low rates of progression would mean that treating people with mild disease may affect the overall cost effectiveness of early treatment when compared with watchful waiting. The Committee considered that although low progression rates may exist among the population of all people with mild disease, it was likely that the progression rates found in clinical studies and used in the cost-effectiveness analysis might only be applicable to people with mild disease who present for treatment. Therefore, the Committee concluded that the estimated ICERs in the clinical setting currently pertaining in England and Wales would be acceptable. However, the Committee recognised that if a much higher proportion of people with mild disease were to be diagnosed (for example, from a screening programme), the average progression rate of such a group could be so low that it might no longer be optimal to offer early treatment. That is, the Committee considered that the cost effectiveness of treating all people with mild disease identified as a result of a screening programme has yet to be proven, and that this guidance to treat people with mild disease might not necessarily apply to a screened population. The Committee considered estimates used in the economic models of improvements in quality of life for people receiving treatment for mild disease and whether these improvements were importantly different between mild and moderate disease. The Committee heard that many people infected with chronic hepatitis C believe that they are stigmatised and discriminated against, which further reduces their quality of life. Clearing the disease could thus be associated with improvements that may not be reflected in economic models, and this could lead to an underestimate of the benefits of treatment. The Committee was persuaded that the estimated ICERs for combination therapy or monotherapy with peginterferon alfa for mild disease remained below £26,000 per QALY even if only very small improvements in quality of life (1%) were considered. This was the same for all genotypes. The estimated ICER could be as high as £42,000 per QALY for genotype 1 (the genotype with the highest estimated ICER) only when there was assumed to be no improvement in quality of life when mild disease was cleared. The Committee was not persuaded that this latter scenario was appropriate, so accepted the range of predicted ICERs less than £26,000 per QALY. The Committee was persuaded by the experts that the previous guidance (TA 75) on treating people with moderate chronic hepatitis C who continue to use intravenous drugs and/or misuse alcohol and people co-infected with HIV should be extended to members of all such groups who have mild disease. Thus, the Committee concluded that, with respect to those continuing to use intravenous drugs, in naturalistic settings, the rate of discontinuation of treatment would not be so great as to prevent the treatment being cost effective. In addition, with respect to people who continue consuming alcohol, the Committee considered that continued alcohol consumption is not in itself an absolute contraindication to therapy, but it should be emphasised as an important contributory factor to the development of liver disease and should be taken into account in advice and information given by the clinical team. The Committee was mindful that the guidance on recommending treatment for mild disease caused by all genotypes would mean that liver biopsy will no longer be required to diagnose the severity of the disease before treatment can be initiated. It was felt that this would increase the uptake of treatment among people unwilling to undergo this procedure. Additionally, it would reduce the cost of disease management somewhat and avoid the pain and complications associated with liver biopsy. However, the Committee heard from a clinical expert that the number of biopsies carried out in people with chronic hepatitis C may not fall a great deal because biopsies would still be recommended for reasons not directly related to the decision to initiate therapy. Treatment with combination peginterferon therapy has side effects, and the Committee appreciated that some people with mild disease may decide, in consultation with their clinician, to wait until they reach the moderate stage of the disease before beginning treatment. The Committee understood that, although people opting to begin treatment with combination therapy immediately may not need a liver biopsy, the situation may be different for people who opt to defer therapy. Clinicians will need to discuss the possible need for liver biopsy with people who opt to defer treatment. It should be explained that biopsy is used to determine whether a person has progressed to the moderate stage of the disease. The Committee decided that the previous guidance on moderate or severe disease (TA 75) should be retained for mild disease with respect to: the length of treatment for different genotypes; people requiring monotherapy; and second courses of treatment. The Committee did not believe that there was sufficient evidence to recommend combination therapy or monotherapy with peginterferon alfa for people with mild chronic hepatitis C who are under the age of 18 years, or those who have had a liver transplant.# Recommendations for further research Research is needed on the quality of life and progression rates among a random sample of people with mild disease compared with people presenting for treatment. This research might also include retrospective studies of progression among people who have already been diagnosed for reasons other than having symptoms of the disease.# Related guidance NICE has issued the following related technology appraisal guidance. Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B. NICE technology appraisal guidance no. 96 (2006). Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C. NICE technology appraisal guidance no. 75 (2004).# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. This technology appraisal and TA 75 will be considered together for review in November 2007. Andrew DillonChief ExecutiveAugust 2006# Appendix C. Detail on criteria for audit of the use of peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C # Possible objectives for an audit An audit on the use of peginterferon alfa and ribavirin in the treatment of mild chronic hepatitis C could be carried out to ensure that the therapy is used appropriately. # Possible patients to be included in the audit An audit could be carried out on a reasonable number of people being treated for mild chronic hepatitis C. Because there is insufficient evidence to recommend combination therapy or monotherapy with peginterferon alfa for people with mild chronic hepatitis C who are under the age of 18 years or who have had a liver transplant, these people should be excluded from this audit. Where a large number of people are being treated, a representative sampling strategy is suggested. # Measures that could be used as a basis for an audit The measures that could be used in an audit of peginterferon alfa and ribavirin in the treatment of mild chronic hepatitis C are as follows. Criterion Standard Exception Definition of terms . A person with mild chronic hepatitis C is treated with combination therapy comprising peginterferon alfa-2a and ribavirin or peginterferon alfa-2b and ribavirin, within their licensed indications % of people with mild chronic hepatitis C who present for treatment A. If a woman is pregnant or breastfeeding B. If ribavirin is contraindicated or is not tolerated (see criterion 2) For contraindications to ribavirin and symptoms of intolerance, see the summary of product characteristics. . A person with mild chronic hepatitis C who is unable to tolerate or has a contraindication to ribavirin is treated with monotherapy with peginterferon alfa-2a or peginterferon alfa-2b, within their licensed indications % of people with mild chronic hepatitis C who are unable to tolerate or have a contraindication to ribavirin and who present for treatment None For contraindications to ribavirin and symptoms of intolerance, see the summary of product characteristics. . A person with mild chronic hepatitis C makes the decision on immediate treatment with combination therapy or monotherapy or waiting until the disease has reached a moderate stage after fully informed consultation with the responsible clinician % of people with mild chronic hepatitis C who present for treatment None 'Waiting until the disease has reached a moderate stage' can be referred to as 'watchful waiting.' Clinicians will need to agree on how the patient's decision and the fully informed consultation with the responsible clinician are documented, for audit purposes. The patient should understand that liver biopsy to determine the stage of the disease is not required if treatment is initiated immediately but biopsy may be recommended by the clinician for other reasons or if treatment is delayed. . For a person with mild chronic hepatitis C who has been treated with a first course of either combination therapy or monotherapy with peginterferon alfa and who has not had an early response, second or subsequent courses of treatment are provided. % of people with mild chronic hepatitis C who have had combination therapy or monotherapy with peginterferon alfa but who have not had an early response None 'Early response' is as defined in the above measures, that is, the person's viral load has fallen to less than 1% of the initial level. # Calculation of compliance Compliance (%) with each measure described in the table above is calculated as follows. Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed x 100 Number of patients to whom the measure applies Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Changes after publication March 2012: minor maintenance. November 2013: partial update.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This is an extension of the guidance given in Hepatitis C - pegylated interferons, ribavirin and alfa interferon (NICE technology appraisal guidance 75). NICE issued guidance on the use of interferon alfa, pegylated interferon alfa (peginterferon alfa) and ribavirin in the treatment of people with moderate to severe chronic hepatitis C in January 2004 (NICE technology appraisal guidance 75; TA75). The evidence in this appraisal relates to the extension of this treatment to people with mild chronic hepatitis C. For people with moderate or severe disease, the guidance in TA75 still stands. This guidance and TA75 have been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200) and 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300). We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2006. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This is an extension of the guidance given in Hepatitis C - pegylated interferons, ribavirin and alfa interferon (NICE technology appraisal guidance 75).\n\nThis guidance and TA75 have been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200) and 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300).\n\nFor details, see 'About this guidance'.\n\nCombination therapy, comprising peginterferon alfa-2a and ribavirin or peginterferon alfa-2b and ribavirin, is recommended, within the licensed indications of these drugs, for the treatment of mild chronic hepatitis C.\n\nMonotherapy with peginterferon alfa-2a or peginterferon alfa-2b is recommended, within the licensed indications of these drugs, for the treatment of mild chronic hepatitis C for people who are unable to tolerate ribavirin, or for whom ribavirin is contraindicated.\n\nThe decision on whether a person with mild chronic hepatitis C should be treated immediately or should wait until the disease has reached a moderate stage ('watchful waiting') should be made by the person after fully informed consultation with the responsible clinician. The decision to treat need not depend on a liver biopsy to determine the stage of the disease if treatment is initiated immediately. However, a biopsy may be recommended by the clinician for other reasons or if a strategy of watchful waiting is chosen.\n\nThis recommendation has been updated and replaced by NICE technology appraisal guidance 200 (\n 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C'\n ).\n\nThis recommendation has been updated and replaced by NICE technology appraisal guidance 200 (\n 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C'\n ).\n\nThis recommendation has been partially updated and replaced by NICE technology appraisal guidance 300\n (\n 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people'\n \n ). There is insufficient evidence to recommend combination therapy or monotherapy with peginterferon alfa for people who have had a liver transplant.", 'Clinical need and practice': "Chronic hepatitis C is a disease of the liver caused by the hepatitis C virus. Generally the virus is transmitted parenterally, but the natural history of the disease is not completely understood. The virus is primarily acquired through percutaneous exposure to contaminated blood. Since the viral inactivation programme was implemented in the mid-1980s and blood donor screening started in 1991, the transmission of HCV in the UK, via transfusion of blood, blood products or organ transplantation, has all but ceased. However, injecting drug use, cosmetic and other practices involving percutaneous exposure remain common routes of transmission. HCV prevalence is correlated with markers of sexual activity, but HCV incidence in monogamous heterosexual partners of infected people is extremely low. There is a transmission rate of about 6% from mother to child if the mother is an HCV carrier. Concomitant HIV infection increases the risk of transmission.\n\nPeople infected with HCV are often asymptomatic, but about 20% will develop overt hepatitis. Many people who are chronically infected will experience non-specific symptoms including malaise, weakness and anorexia. About 80% of those exposed go on to develop chronic hepatitis. The rate of progression of the disease is slow but variable, usually taking about 20–50 years from the time of infection. About 30% of those who are infected develop cirrhosis within 20–30\xa0years, and a small percentage of these people are at a high risk of developing hepatocellular carcinoma. A third may never progress to cirrhosis or will not progress for at least 50 years. Some people with end-stage liver disease or hepatocellular carcinoma may need liver transplantation.\n\nThe effectiveness of treatment is related to the genotype of the virus. Six major genetic types of HCV have been found. Genotype 1 is the most common in the UK, accounting for about 40–50% of cases. Genotypes 2 and 3 contribute another 40–50%; and genotypes 4, 5 and 6 constitute the remainder, about 5%.\n\nRecent estimates suggest that approximately 200,000 to 500,000 people are infected with HCV in England and Wales. (In 2005, the Department of Health estimated that only 47,000 people with HCV infection had been diagnosed and only 7000 had been treated.) There is also great variation in prevalence between subgroups of the population: 0.04% in blood donors, 0.4% in people attending antenatal clinics in inner London, 1% in people attending genitourinary clinics and up to 50% in intravenous drug users attending drug abuse clinics.\n\nBecause it is not possible in the short term to directly measure the effectiveness of treatment in reducing progression to cirrhosis and hepatocellular carcinoma, three surrogate markers have been used in trials:\n\nhepatic histology\n\nvirological loss of HCV-RNA (by quantitative polymerase chain reaction)\n\nlevels of alanine aminotransferase (an enzyme that indicates the presence of liver inflammation).\n\nThe previous NICE guidance (TA 75) applies only to people with moderate or severe chronic hepatitis C, which is defined as histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation of the liver. For the majority of people with moderate or severe hepatitis C, the standard treatment is combination therapy with ribavirin and either peginterferon alfa-2a or peginterferon alfa-2b. Monotherapy with peginterferon alfa is used only for people unable to tolerate ribavirin.\n\nIn trials for people with moderate or severe hepatitis C, about 75–85% of people with HCV genotype 2 or 3 had a sustained virological response 6\xa0months after finishing a course of treatment with peginterferon\xa0alfa and ribavirin. For people with genotype 1, the rate of sustained virological response was about 40–50%, while for the three less common genotypes (4, 5 and 6) the rate appears to be between those for genotype 1 and genotypes 2 or 3.\n\nFor people with moderate or severe disease and with genotype 2 or 3, the maximum rate of sustained virological response is attained after 24 weeks of treatment. Further treatment does not increase the rate, so treatment beyond 24 weeks is not advised. For people with the other genotypes, it may take longer than 24 weeks to gain a sustained virological response, so the standard treatment length is 48 weeks. However, if no virological response has occurred by 12 weeks of treatment, a sustained response is unlikely to occur. Hence, it is recommended that people who do not attain a sufficient virological response by 12\xa0weeks should not receive a further 36 weeks of treatment. People infected with genotypes 2 or 3 do not need a test of virological response at 12 weeks, because almost all respond by that time.\n\nPeginterferons are formed by attaching strands of polyethylene glycol (PEG) to the interferon molecules. This slows the rate of absorption and excretion of interferon, reducing the fluctuations in serum concentrations that occur with unmodified interferon. The pegylation process increases the half-life of the interferon molecule in the body: in the case of peginterferon alfa-2a from about 4 hours to between 50 and 130\xa0hours, and for peginterferon alfa-2b from about 4\xa0hours to about 40\xa0hours. Accordingly, people treated with peginterferon alfa need injections only once a week, compared with three times a week for people treated with non-pegylated interferon, referred to in this guidance as 'interferon'. In addition, clinical trials suggest that response rates to interferon among people with moderate or severe disease are significantly lower than response rates to peginterferon therapy.\n\nStandard haematological tests and blood chemistry (that is, full blood count and differential platelet count, liver function tests, uric acid, serum bilirubin and serum creatinine) are necessary for all patients being considered for combination therapy. The HCV genotype with which the person is infected should be determined for all candidates for combination therapy. Liver biopsy has played a role in helping to determine disease staging, but it is no longer considered necessary for people with HCV of genotypes 2 and 3, or if biopsy poses an increased risk. Patients should be seen weekly for the first 4\xa0weeks of treatment and then monthly for 6\xa0months to check for haemolysis and changes in thyroid activity.\n\nBoth pegylated interferon and interferon give rise to flu-like symptoms in many people. Ribavirin leads, in a proportion of cases, to anaemia, pruritus, rash, insomnia and dyspnoea. For full details of side effects and contraindications, see the summary of product characteristics for each drug.\n\nThe standard measurement of the effectiveness of treatment, in people with chronic hepatitis\xa0C, is the virological response rate sustained for 6\xa0months (known as the sustained virological response rate). This is defined as the proportion of people in whom the virus is undetectable in blood samples 6\xa0months after treatment has been completed.\n\nA direct measure of viral activity is viral load, which is the number of copies of the virus in a given quantity of blood. Although a high viral load is likely to mean that the liver deteriorates more quickly than it does under the influence of a low viral load, the relationship is not a simple one, and some people live with high viral loads for many years without progressing from mild disease to moderate disease.\n\nA person is classified as having mild, moderate or severe chronic hepatitis C based on the extent of liver damage. If there is a sufficient need to know the extent of liver disease, this may be determined histologically by liver biopsy. The main indicator of liver damage is the degree of fibrosis, although the degree of necroinflammation also contributes to the diagnosis.\n\nAt a time before the treatment of mild chronic hepatitis C was routinely considered, it was the practice to perform a liver biopsy before prescribing interferon alfa or peginterferon alfa to determine whether a person with chronic hepatitis C had reached a moderate or severe stage of the disease. Initiating treatment at an earlier stage means this is no longer necessary.", 'The technology': "The objective of this appraisal is to compare the use of peginterferon therapy (in combination with ribavirin or as monotherapy) in mild chronic hepatitis C with the current practice of deferring treatment until the disease has progressed to moderate or severe. Current practice and the technology are described in section 2 above.\n\nPeginterferon alfa-2a (Pegasys) and ribavirin (Copegus) are manufactured by Roche. For genotypes 2 and 3, the licensed regimen is peginterferon\xa0alfa-2a 180\xa0micrograms once per week plus ribavirin 800\xa0mg/dayfor 24 weeks. This course of therapy costs £5019 (excluding VAT; 'British national formulary', 50th edition). For genotypes 1, 4, 5 and 6, the regimen is peginterferon\xa0alfa-2a 180\xa0micrograms once per week for 48\xa0weeks plus ribavirin 1000\xa0mg/day (for people weighing less than\xa075\xa0kg) or 1200\xa0mg/day (for those weighing\xa075\xa0kg or more) for the same length of time as peginterferon\xa0alfa. The cost is £10,963 or £11,889 for 48 weeks depending on body weight. For peginterferon monotherapy, the cost of treatment is £6339 (for 12 months) for all genotypes.\n\nPeginterferon alfa-2b (ViraferonPeg) and ribavirin (Rebetol) are produced by Schering-Plough. For genotypes 2 and 3, the licensed regimen is peginterferon\xa0alfa-2b 1.5 micrograms/kg/week plus ribavirin 800\xa0mg/day (for people weighing less than\xa065\xa0kg) or 1000\xa0mg/day (for those weighing 65–85\xa0kg) or 1200\xa0mg/day (for those weighing more than\xa085\xa0kg) for 24\xa0weeks. The cost of a course is £6734 for a person of an average weight of 79\xa0kg (excluding VAT; 'British national formulary', 50th edition). Costs may vary in different settings because of negotiated procurement discounts.\n\nThe marketing authorisation for peginterferon alfa-2b in combination with ribavirin has been varied and now allows for 24 weeks of treatment in people with genotype 1 (low viral load) who have responded sufficiently to treatment at 4 weeks. The cost is £6734 for a person of average weight (79 kg). For people with genotype 1 (high viral load) and optionally for those with low viral load, the cost for 48 weeks of treatment is £13,468 for a person of average weight (excluding VAT; 'British national formulary', 50th edition). Costs may vary in different settings because of negotiated procurement discounts.\n\nFor genotypes 5 and 6, the regimen (and associated cost) is as for genotypes 1 and 4 (high viral load). Costs may vary in different settings because of negotiated procurement discounts.\n\nThe cost of treatment for 24 weeks with peginterferon alfa-2b monotherapy is £1657 (0.5\xa0micrograms/kg/week) or £2652 (1.0 micrograms/kg/week) and for 48 weeks is £3314 (0.5\xa0micrograms/kg/week) or £5303 (1.0\xa0micrograms/kg/week) (excluding VAT; 'British national formulary', 50th edition). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (see appendix B).\n\n# Clinical effectiveness\n\nThree trials of peginterferon\xa0alfa-2a and five trials of interferon alfa-2b that included people with chronic hepatitis C, at least 70% of whom had mild disease, were included in the assessment report. All studies included the combination with ribavirin in at least one arm. The comparators in the trials varied. Two of the three peginterferon\xa0alfa-2a studies compared longer courses (48 weeks) with shorter courses (24 weeks); the third compared peginterferon\xa0alfa-2a with non-pegylated interferon alfa-2a.\n\nNo studies compared the strategies of early treatment of mild disease with a strategy of watchful waiting and treatment for those who progress to moderate or severe disease. Because this is the primary comparison of interest in this appraisal, results for the comparator arms in the studies in section\xa04.1.4 are not reported here.\n\n## Peginterferon alfa-2a plus ribavirin\n\nHCV genotypes 2 and 3\n\nThe three trials of peginterferon\xa0alfa-2a plus ribavirin in people with genotypes 2 and 3 yielded sustained virological response rates of 72–84% after 24 weeks of treatment and rates of 78–80% after 48 weeks of treatment. For people infected with these genotypes, there was no statistically significant difference between the rates after 24 weeks of treatment or after 48 weeks. These results are consistent with those for studies conducted in people with moderate or severe chronic hepatitis C; in the previous appraisal (TA\xa075), the corresponding rate of sustained virological response in different trials that included people with both mild and moderate or severe disease was 79%.\n\nIn people infected with genotype 1, peginterferon\xa0alfa-2a plus ribavirin yielded sustained virological response rates of 13–42% after 24 weeks of treatment and 40–52% after 48 weeks. In this group, the additional 24\xa0weeks of treatment statistically significantly increased the rate of sustained response.\n\n## Peginterferon alfa-2b plus ribavirin\n\nAlthough there was no trial of peginterferon\xa0alfa-2b combination therapy that met the Assessment Group's criteria for inclusion of trials of people with mild chronic hepatitis C, one study included 1014 (of 1530) participants who had been documented as having no or minimal fibrosis. In this study, a sustained virological response occurred in 57% of participants with no or minimal fibrosis (that is, with mild disease) who received 'high-dose' peginterferon alfa‑2b (1.5\xa0micrograms/kg/week for 48 weeks) plus ribavirin. This compares with a rate of 44% among those who had bridging fibrosis or cirrhosis (that is, moderate or severe disease) who received high-dose peginterferon alfa-2b. In people who received 'low-dose' peginterferon alfa-2b (1.5\xa0micrograms/kg/week for 4 weeks, then 0.5\xa0micrograms/kg/week for 48\xa0weeks) plus ribavirin, a sustained virological response rate of 51% was recorded among those with mild disease compared with 43% among those with moderate or severe disease. Results by genotype were not reported. The rate of sustained virological response was statistically significantly higher among participants on high-dose (but not low-dose) peginterferon alfa-2b combination therapy than among patients on non-pegylated interferon alfa-2b plus ribavirin.\n\n## Monotherapy trials\n\nPeople who are unable to take ribavirin and are treated with monotherapy with peginterferon\xa0alfa or non-pegylated interferon\xa0alfa have much lower response rates than people treated with combination therapy. One trial of 159 people compared response rates with three different regimens of peginterferon alfa-2a with one of interferon alfa-2a. Rates of sustained virological response were 3% for interferon alfa-2a and between 10% and 29% for peginterferon alfa-2a, depending on the dose. Altogether, 82% of participants were classified as having mild chronic hepatitis C.\n\nAnother trial of 1219 people compared response rates for three different regimens of peginterferon\xa0alfa-2b and one of interferon alfa-2b. Altogether, 83% of participants in this study were classified as having mild disease. Rates of sustained virological response were 12% for those treated with interferon alfa-2b and between 18 and 23% for those treated with peginterferon alfa-2b, depending on the dose.\n\n## Summary\n\nTaken as a whole, the evidence for combination therapy and monotherapy, and for pegylated and non-pegylated interferon alfa-2a and pegylated and non-pegylated interferon alfa-2b, suggests that rates of sustained virological response among patients with mild disease are about the same as those among patients with moderate or severe disease. Combination therapy with peginterferon\xa0alfa (2a or 2b) and ribavirin produces higher rates of sustained virological response than combination therapy with non-pegylated interferon alfa (2a or 2b). Monotherapy with pegylated interferon alfa-2a or alfa-2b produces higher response rates than monotherapy with non-pegylated interferon alfa.\n\n# Cost effectiveness\n\nThe assessment report found six studies examining the cost effectiveness of treatment for people with mild disease. Three of these studies compared interferon combination therapy with no treatment rather than with delayed treatment. These three studies showed that interferon combination therapy was cost effective when compared with standard care (all estimated mean incremental cost-effectiveness ratios [ICERs] were less than £10,000 per quality-adjusted life year [QALY]). Two studies compared early treatment with peginterferon\xa0alfa combination therapy with delayed treatment. They showed that, for genotypes 2 and 3, early treatment is apparently cost effective when compared with delayed treatment, but the case for early treatment for genotype 1 is less clear.\n\nThe model employed in the Roche submission determined the cost effectiveness of peginterferon\xa0alfa-2a plus ribavirin against no treatment. The estimated mean cost per QALY for treating people with mild disease was £1000 for genotypes 2 and 3, and £4000 for genotype\xa01.\n\nThe model employed in the Schering-Plough submission determined the cost effectiveness of peginterferon\xa0alfa-2b plus ribavirin against no treatment. The model is academic-in-confidence. The estimated mean cost per QALY for treating mild chronic hepatitis C was £1000 for genotypes 2 and 3, and £3000 for genotype\xa01.\n\nThe model developed by the Assessment Group incorporated seven health states: remission, mild disease, moderate disease, compensated cirrhosis, decompensated cirrhosis, liver cancer and liver transplantation. It used rates of sustained virological response from the manufacturers' submissions and transition rates between the seven health states from a number of sources. For example, the estimated transition rate from mild to moderate disease as used in the model was 2.5% per year, which was obtained from observational data relating to 373 cases from a routine practice in a hospital in London between 1990 and 2001. Health-state utilities and costs were estimated from the UK mild hepatitis C trial. For comparability with the previous review, benefits were discounted at 1.5% per year and costs at 6%, with a sensitivity analysis at 3.5% for both costs and benefits.\n\n## Non-1 genotype HCV\n\nFor people with non-1 genotype infection, the base case estimated mean ICER for deferring treatment with peginterferon\xa0alfa‑2a combination therapy until the disease reaches the moderate or severe stage relative to best supportive care (no treatment) is £1300 per QALY. The corresponding ICER for peginterferon\xa0alfa-2b plus ribavirin is £1400. This analysis confirms that the strategy of treating people with moderate or severe disease is cost effective compared with not treating them at all.\n\nThe estimated mean ICERs for early treatment with peginterferon\xa0alfa in combination with ribavirin are £3700 for peginterferon\xa0alfa-2a and £4300 for peginterferon\xa0alfa-2b, when compared with deferring treatment until the disease reaches the moderate-to-severe stage in people with non-1 genotype infection. This analysis shows that treatment of mild disease is cost effective compared with waiting until the patient reaches the moderate stage of the disease. These are the key cost-effectiveness estimates for this appraisal.\n\nFurther analysis shows that combination therapy with pegylated interferon is cost effective when compared with the corresponding non-pegylated therapy for treating people with mild disease.\n\n## Genotype 1 HCV\n\nFor people with genotype 1 infection, the base case estimated mean ICER is £6900 per QALY for watchful waiting followed by treatment with peginterferon\xa0alfa-2a combination therapy when the disease reaches the moderate or severe stage, relative to best supportive care (no treatment). The corresponding ICER for peginterferon\xa0alfa-2b plus ribavirin is £4700. This analysis confirms that the strategy of treating only moderate or severe disease is cost effective compared with not treating the infection at all.\n\nFor people with genotype 1 infection, the estimated mean ICERs for early treatment with peginterferon\xa0alfa in combination with ribavirin are £10,300 for peginterferon\xa0alfa-2a and £8300 for peginterferon\xa0alfa-2b when compared with deferring treatment until the disease reaches the moderate-to-severe stage, and reflecting the early stopping rules recommended in the summary of product characteristics for peginterferon alfa-2a. This analysis shows that treating mild disease is very likely to be cost effective compared with waiting until the patient reaches the moderate stage. These are the key cost-effectiveness estimates for this appraisal.\n\nFurther analysis shows that pegylated interferon combination therapy is cost effective when compared with the corresponding non-pegylated therapy for treating people with mild disease.\n\n## Monotherapy: all genotypes\n\nIn people unable to take ribavirin, monotherapy with peginterferon may be used. The estimated mean ICER for early treatment with peginterferon\xa0alfa monotherapy is £3000 per QALY for peginterferon\xa0alfa-2a and £2300 for peginterferon alfa-2b against the same treatment deferred until a later stage.\n\n## Sensitivity analyses\n\nEstimated mean ICERs are even lower using current stopping rules, whereby treatment is stopped at 12 weeks if a 100-fold reduction in viral load has not occurred.\n\nSensitivity analyses conducted in the assessment report do not lead to ICERs of more than £20,000 except when the average age of patients is increased by 15 years.\n\n# Consideration of the evidence\n\nThe Committee reviewed the data on the clinical effectiveness and cost effectiveness of interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C, having considered evidence on the nature of the condition and the value placed on the benefits of this treatment by people with the condition (or who have had the condition), those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee heard from clinical and patient experts that studies show the quality of life of people with mild disease, even in the absence of histological evidence of definitive liver disease, is on average lower than that of people who have had mild disease and who have been cleared of the virus. The experts advised the Committee that such a difference in quality of life is an important contributor to the benefit of early treatment of mild disease.\n\nThe Committee also heard from the experts that sustained virological response, when the virus is undetectable 6 months after treatment has finished, is maintained for 10 years in more than 90% of people. Additionally, it is unusual for re-infection with HCV to occur after a sustained virological response has been achieved. These observations were consistent with the assumptions of the cost-effectiveness model used in the assessment report. Therefore, the Committee concluded that the model inputs were appropriate in these respects.\n\nThe Committee understood that about half of the approximately 3000 people in England and Wales who are treated each year have a sustained virological response and are effectively cured, but that the number of new cases is greater than the number of people being cured. Therefore, the number of people with the disease is still rising.\n\nThe Committee heard that early treatment of people with chronic hepatitis\xa0C in the general population could potentially reduce the likelihood of the spread of infection and that this would lead to a better estimate of cost effectiveness than that demonstrated in the models, in which the effect of the spread of infection had not been considered.\n\nThe Committee considered that, although the predicted effectiveness of the treatment of mild disease in a clinical setting was not as high as the average efficacy seen in the clinical trials, this difference was not likely to affect the importance of the therapy or overall cost effectiveness.\n\nThe Committee discussed a recent change in the UK marketing authorisation for peginterferon alfa-2b for people with genotype 1 (and by extension, genotype 4) and low viral loads (less than\xa0600,000\xa0IU/ml). This change allows combination therapy to be stopped at 24 weeks rather than continue to 48\xa0weeks. The Committee has not reviewed the clinical effectiveness evidence for this modification of the marketing authorisation, so is not able to comment specifically on it. However, the Committee did note the caution carried in the marketing authorisation regarding the possibility that there may be a lower rate of sustained viral response if treatment is limited to 24 weeks. Nevertheless, if the success rate for sustained viral response were not to be affected by the shortening of the treatment period, the Committee recognised that this regimen would be cost effective compared with the 48-week treatment.\n\nThe Committee considered that an important question was whether it is cost effective to treat immediately people who have mild chronic hepatitis C with peginterferon alfa plus ribavirin or to wait until their disease reaches the moderate stage ('watchful waiting'). The Committee disregarded the manufacturers' models, which they considered had not made the relevant comparison. The Committee understood that, if the rate of progression to moderate disease were sufficiently low, it might be better not to subject all people with mild disease to the side effects of combination therapy because few might progress to moderate disease or beyond.\n\nThe Committee discussed the progression rates (from mild to moderate disease). The Committee was told that there is no way of knowing which patients are likely to progress from mild disease to moderate disease, but that progression is somewhat slower for younger people, for those who have been infected for a shorter time, for females and for certain ethnic groups. The Committee considered at length the progression rates assumed in the assessment report model, and noted that these were from clinical trials of people who presented for treatment. The Committee appreciated that this may represent a small proportion of the total number thought to be infected with HCV and that people who were asymptomatic and had not sought treatment may experience a different rate of progression, on average, from those who had sought treatment. The Committee accepted that low rates of progression would mean that treating people with mild disease may affect the overall cost effectiveness of early treatment when compared with watchful waiting. The Committee considered that although low progression rates may exist among the population of all people with mild disease, it was likely that the progression rates found in clinical studies and used in the cost-effectiveness analysis might only be applicable to people with mild disease who present for treatment. Therefore, the Committee concluded that the estimated ICERs in the clinical setting currently pertaining in England and Wales would be acceptable.\n\nHowever, the Committee recognised that if a much higher proportion of people with mild disease were to be diagnosed (for example, from a screening programme), the average progression rate of such a group could be so low that it might no longer be optimal to offer early treatment. That is, the Committee considered that the cost effectiveness of treating all people with mild disease identified as a result of a screening programme has yet to be proven, and that this guidance to treat people with mild disease might not necessarily apply to a screened population.\n\nThe Committee considered estimates used in the economic models of improvements in quality of life for people receiving treatment for mild disease and whether these improvements were importantly different between mild and moderate disease. The Committee heard that many people infected with chronic hepatitis C believe that they are stigmatised and discriminated against, which further reduces their quality of life. Clearing the disease could thus be associated with improvements that may not be reflected in economic models, and this could lead to an underestimate of the benefits of treatment. The Committee was persuaded that the estimated ICERs for combination therapy or monotherapy with peginterferon alfa for mild disease remained below £26,000 per QALY even if only very small improvements in quality of life (1%) were considered. This was the same for all genotypes. The estimated ICER could be as high as £42,000 per QALY for genotype 1 (the genotype with the highest estimated ICER) only when there was assumed to be no improvement in quality of life when mild disease was cleared. The Committee was not persuaded that this latter scenario was appropriate, so accepted the range of predicted ICERs less than £26,000 per QALY.\n\nThe Committee was persuaded by the experts that the previous guidance (TA\xa075) on treating people with moderate chronic hepatitis C who continue to use intravenous drugs and/or misuse alcohol and people co-infected with HIV should be extended to members of all such groups who have mild disease. Thus, the Committee concluded that, with respect to those continuing to use intravenous drugs, in naturalistic settings, the rate of discontinuation of treatment would not be so great as to prevent the treatment being cost effective. In addition, with respect to people who continue consuming alcohol, the Committee considered that continued alcohol consumption is not in itself an absolute contraindication to therapy, but it\xa0should be emphasised as an important contributory factor to the development of liver disease and should be taken into account in advice and information given by the clinical team.\n\nThe Committee was mindful that the guidance on recommending treatment for mild disease caused by all genotypes would mean that liver biopsy will no longer be required to diagnose the severity of the disease before treatment can be initiated. It was felt that this would increase the uptake of treatment among people unwilling to undergo this procedure. Additionally, it would reduce the cost of disease management somewhat and avoid the pain and complications associated with liver biopsy. However, the Committee heard from a clinical expert that the number of biopsies carried out in people with chronic hepatitis C may not fall a great deal because biopsies would still be recommended for reasons not directly related to the decision to initiate therapy.\n\nTreatment with combination peginterferon therapy has side effects, and the Committee appreciated that some people with mild disease may decide, in consultation with their clinician, to wait until they reach the moderate stage of the disease before beginning treatment. The Committee understood that, although people opting to begin treatment with combination therapy immediately may not need a liver biopsy, the situation may be different for people who opt to defer therapy. Clinicians will need to discuss the possible need for liver biopsy with people who opt to defer treatment. It should be explained that biopsy is used to determine whether a person has progressed to the moderate stage of the disease.\n\nThe Committee decided that the previous guidance on moderate or severe disease (TA\xa075) should be retained for mild disease with respect to: the length of treatment for different genotypes; people requiring monotherapy; and second courses of treatment. The Committee did not believe that there was sufficient evidence to recommend combination therapy or monotherapy with peginterferon alfa for people with mild chronic hepatitis C who are under the age of 18 years, or those who have had a liver transplant.", 'Recommendations for further research': 'Research is needed on the quality of life and progression rates among a random sample of people with mild disease compared with people presenting for treatment. This research might also include retrospective studies of progression among people who have already been diagnosed for reasons other than having symptoms of the disease.', 'Related guidance': 'NICE has issued the following related technology appraisal guidance.\n\nAdefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis\xa0B. NICE technology appraisal guidance no. 96 (2006).\n\nInterferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C. NICE technology appraisal guidance no.\xa075 (2004).', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThis technology appraisal and TA 75 will be considered together for review in November 2007.\n\nAndrew DillonChief ExecutiveAugust 2006', 'Appendix C. Detail on criteria for audit of the use of peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C ': "# Possible objectives for an audit\n\nAn audit on the use of peginterferon alfa and ribavirin in the treatment of mild chronic hepatitis C could be carried out to ensure that the therapy is used appropriately.\n\n# Possible patients to be included in the audit\n\nAn audit could be carried out on a reasonable number of people being treated for mild chronic hepatitis C. Because there is insufficient evidence to recommend combination therapy or monotherapy with peginterferon alfa for people with mild chronic hepatitis C who are under the age of 18 years or who have had a liver transplant, these people should be excluded from this audit. Where a large number of people are being treated, a representative sampling strategy is suggested.\n\n# Measures that could be used as a basis for an audit\n\nThe measures that could be used in an audit of peginterferon alfa and ribavirin in the treatment of mild chronic hepatitis C are as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. A person with mild chronic hepatitis C is treated with combination therapy comprising peginterferon alfa-2a and ribavirin or peginterferon alfa-2b and ribavirin, within their licensed indications\n\n% of people with mild chronic hepatitis C who present for treatment\n\nA. If a woman is pregnant or breastfeeding\n\nB. If ribavirin is contraindicated or is not tolerated (see criterion 2)\n\nFor contraindications to ribavirin and symptoms of intolerance, see the summary of product characteristics.\n\n. A person with mild chronic hepatitis C who is unable to tolerate or has a contraindication to ribavirin is treated with monotherapy with peginterferon alfa-2a or peginterferon alfa-2b, within their licensed indications\n\n% of people with mild chronic hepatitis C who are unable to tolerate or have a contraindication to ribavirin and who present for treatment\n\nNone\n\nFor contraindications to ribavirin and symptoms of intolerance, see the summary of product characteristics.\n\n\n\n. A person with mild chronic hepatitis C makes the decision on immediate treatment with combination therapy or monotherapy or waiting until the disease has reached a moderate stage after fully informed consultation with the responsible clinician\n\n\n\n% of people with mild chronic hepatitis C who present for treatment\n\nNone\n\n'Waiting until the disease has reached a moderate stage' can be referred to as 'watchful waiting.'\n\nClinicians will need to agree on how the patient's decision and the fully informed consultation with the responsible clinician are documented, for audit purposes. The patient should understand that liver biopsy to determine the stage of the disease is not required if treatment is initiated immediately but biopsy may be recommended by the clinician for other reasons or if treatment is delayed.\n\n. For a person with mild chronic hepatitis C who has been treated with a first course of either combination therapy or monotherapy with peginterferon alfa and who has not had an early response, second or subsequent courses of treatment are provided.\n\n% of people with mild chronic hepatitis C who have had combination therapy or monotherapy with peginterferon alfa but who have not had an early response\n\nNone\n\n'Early response' is as defined in the above measures, that is, the person's viral load has fallen to less than 1% of the initial level.\n\n# Calculation of compliance\n\nCompliance (%) with each measure described in the table above is calculated as follows.\n\nNumber of patients whose care is consistent with the criterion plus number of patients who meet any exception listed\n\n\n\nx 100\n\nNumber of patients to whom the measure applies\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.", 'Changes after publication': 'March 2012: minor maintenance.\n\nNovember 2013: partial update.', 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis is an extension of the guidance given in Hepatitis C - pegylated interferons, ribavirin and alfa interferon (NICE technology appraisal guidance 75).\n\nNICE issued guidance on the use of interferon alfa, pegylated interferon alfa (peginterferon alfa) and ribavirin in the treatment of people with moderate to severe chronic hepatitis\xa0C in January 2004 (NICE technology appraisal guidance\xa075; TA75). The evidence in this appraisal relates to the extension of this treatment to people with mild chronic hepatitis\xa0C. For people with moderate or severe disease, the guidance in TA75 still stands.\n\nThis guidance and TA75 have been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200) and 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300).\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2006. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}	https://www.nice.org.uk/guidance/ta106	Evidence-based recommendations on peginterferon alfa (Pegasys) and ribavirin for people with mild chronic hepatitis C.
c39756807c1fb3281d39c6d80674eabd73145aa7	nice	Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C	Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C Evidence-based recommendations on interferon alfa (Pegasys or ViraferonPeg) and ribavirin for people with chronic hepatitis C. # Guidance This guidance replaces 'Hepatitis C - alpha interferon and ribavirin' (NICE Technology Appraisal Guidance No. 14 issued in October 2000). This guidance is extended by 'Hepatitis C – peginterferon alfa and ribavirin (TA106). This guidance has been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200) and 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300). Combination therapy with peginterferon alfa and ribavirin is recommended within its licensed indications for the treatment of people aged 18 years and over with moderate to severe chronic hepatitis C (CHC), defined as histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation. Separate recommendations for treating chronic hepatitis C in children and young people with peginterferon alfa and ribavirin have been published in NICE technology appraisal guidance 300 ('Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people'). People with moderate to severe CHC are suitable for treatment if they have: not previously been treated with interferon alfa or peginterferon alfa, or been treated previously with interferon alfa (as monotherapy or in combination therapy), and/or this part-recommendation has been updated and replaced by NICE technology appraisal guidance 200 People currently being treated with interferon alfa, either as combination therapy or monotherapy, may be switched to the corresponding therapy with peginterferon alfa. Treatment for the groups identified in Sections 1.1 and 1.2 should be as follows. People infected with hepatitis C virus (HCV) of genotype 2 and/or 3 should be treated for 24 weeks. For people infected with HCV of genotype 1, 4, 5 or 6, initial treatment should be for 12 weeks. Only people showing, at 12 weeks, a reduction in viral load to less than 1% of its level at the start of treatment (at least a 2-log reduction, see Section 4.1.2.5) should continue treatment until 48 weeks. For people in whom viral load at 12 weeks exceeds 1% of its level at the start of treatment, treatment should be discontinued. People infected with more than one genotype that includes one or more of genotypes 1, 4, 5, or 6 should be treated as for genotype 1.Recommendation 4.1 still applies for people who are treated with standard courses of combination therapy, but has been replaced by NICE technology appraisal guidance 200 (TA200) for people who are eligible for shortened courses of combination therapy (as described in recommendation 1.2 of TA200). People satisfying the conditions in Sections 1.1 and 1.2 but for whom ribavirin is contraindicated or is not tolerated should be treated with peginterferon alfa monotherapy. Regardless of genotype, individuals should be tested for viral load at 12 weeks, and if the viral load has reduced to less than 1% of its level at the start of treatment, treatment should be continued for a total of 48 weeks. If viral load has not fallen to this extent, treatment should stop at 12 weeks. People for whom liver biopsy poses a substantial risk (such as those with haemophilia, or those who have experienced an adverse event after undergoing a previous liver biopsy), and people with symptoms of extra-hepatic HCV infection sufficient to impair quality of life, may be treated on clinical grounds without prior histological classification. There is insufficient evidence to recommend combination therapy using peginterferon alfa or interferon alfa in people who: this part-recommendation has been updated and replaced by NICE technology appraisal guidance 200 this part-recommendation has been updated and replaced by NICE technology appraisal guidance 300 have had a liver transplantation. Treatment of CHC recurrence after liver transplantation (whether or not the person had been treated with interferon alfa or peginterferon alfa therapy at any time before transplantation) should be considered as experimental and carried out only in the context of a clinical trial.# Clinical need and practice Chronic hepatitis C (CHC) is a disease of the liver caused by the hepatitis C virus (HCV). Generally, the virus is transmitted by blood-to-blood contact. Before the introduction of screening in 1991 it was also spread through blood transfusions. Before the viral inactivation programme in the mid-1980s it was also spread through blood products. HCV can be acquired by people who inject drugs through the sharing of needles. There is a small risk of infection associated with tattooing, electrolysis, body piercing and acupuncture. Infection through sexual intercourse can also occur. There is a transmission rate of about 6% from mother to child if the mother is an HCV carrier. Concomitant HIV infection is thought to increase the risk of transmission. People are often asymptomatic after exposure to the virus, but about 20% will develop acute hepatitis; some of them will experience malaise, weakness and anorexia. Up to 85% of those exposed do not clear the virus and go on to develop CHC. Progression of the disease occurs over 20–50 years. About 5–30% of people initially infected will develop cirrhosis within 20 years and a small percentage of these are at high risk of developing hepatocellular carcinoma. One-third may never progress to cirrhosis or will not progress for at least 50 years. Some people with end-stage liver disease or hepatocellular carcinoma may require liver transplantation. Six major genetic types of HCV have been identified. Genotype 1 (G1) is the most common in the UK, and is found in about 40–50% of cases. Genotypes 2 and 3 (G2/3) contribute another 40–50%, and genotypes 4, 5 and 6 constitute the remainder of about 5%. Response to treatment varies between different genotypes. G1 is relatively more common among people infected through blood products, and G2/3 is relatively more common among people who inject themselves with illicit drugs. Many individuals with HCV infection do not display symptoms. However, non-specific symptoms, such as fatigue, irritability, nausea, muscle ache, anorexia, abdominal discomfort and pain in the upper right quadrant, have been reported even in the absence of secondary pathology. If cirrhosis develops, people may have severe symptoms and complications. Estimates of prevalence for hepatitis C in England and Wales vary considerably. The extant NICE guidance (see Section 8.1) puts the figure between 200,000 and 400,000, whereas the Assessment Report suggests between 50,000 and 500,000. There is also great variation in prevalence between certain subgroups of the population: 0.04% in blood donors, 0.4% in people attending antenatal clinics (in London), 1% in people attending genito-urinary clinics and up to 50% in injecting drug users. About two-thirds of people with HCV infection are men, mainly because more men inject themselves with illicit drugs, but also because there are far more men than women with haemophilia. Because it is not possible to measure directly the effectiveness of treatment in reducing progression to cirrhosis and hepatocellular carcinoma in the short term, three surrogate markers have been used in trials: hepatic histology; virological loss of HCV-RNA (measured by the polymerase chain reaction, PCR); and levels of alanine aminotransferase (ALT, an enzyme that indicates liver inflammation). The primary aim of treatment for people with CHC is to clear HCV (defined as undetectable HCV-RNA in the serum) for at least 6 months after treatment cessation, in order to improve quality of life for patients and reduce the risk of cirrhosis and hepatocellular carcinoma. The diagnosis of hepatitis C causes considerable anxiety to people. It is generally accepted, though without formal trial evidence, that all people diagnosed with the condition should receive adequate advice and information from a healthcare professional with knowledge and experience in the field. The current standard treatment for moderate and severe chronic HCV infection is combination treatment with interferon alfa and ribavirin, except for people who cannot tolerate ribavirin, when interferon alfa monotherapy is used (Section 8.1 references the NICE guidance that is replaced by this guidance). The precise antiviral mode of action of interferon alfa is unknown. However, it appears to alter host-cell metabolism. It is available in the UK in two forms, interferon alfa-2a (Roferon A, Roche) and interferon alfa-2b (Viraferon, Schering-Plough). Interferon alfa is eliminated from the body rapidly, having a plasma half-life of only about 4 hours. To maintain effectiveness against HCV, doses must be administered by injection on a minimum of 3 days a week. The duration of monotherapy treatment is 48 weeks. For monotherapy, more than half of people who clear the virus after treatment relapse within 6 months of treatment cessation, but for those who remain clear after 6 months, about 90% remain so after 6 years. Thus, for this group, treatment may be called a cure. The dosage for interferon alfa treatment is usually 3 million units three times per week by subcutaneous injection. Injections are administered by clinical staff or by the patient after adequate training. People who respond usually do so within 12–16 weeks. Those who respond continue with this dose of interferon alfa for 48 weeks. Many, but not all, people find interferon alfa therapy very hard to tolerate. After each injection, they may suffer influenza-like symptoms, and up to one-half of all people treated suffer from fatigue, headaches, pyrexia (fever), myalgia (aches and pains), insomnia and/or nausea. About one-quarter suffer hair loss, arthralgia (pain in the joints), rigors, irritability, pruritus (itching), depression, dermatitis and/or decreased appetite. There are significant problems of dropout and non-adherence with treatment as a result. Dropout rates of 7–14% have occurred. Figures on adherence are more difficult to quantify. In the late 1990s, combination treatment of interferon alfa and ribavirin commenced, following trials that showed that, although ribavirin alone showed no activity against HCV, the effect of the combination of ribavirin with interferon alfa was much enhanced compared with that of interferon alfa alone. Since the introduction of combination therapy, monotherapy is used only for people unable to tolerate ribavirin. Ribavirin (Copegus, Roche; Rebetol, Schering-Plough) is a nucleoside analogue with a broad spectrum of antiviral activity against RNA viruses. It is licensed for use in combination with interferon alfa-2a or interferon alfa-2b for treatment of CHC in: adult patients with histologically proven, previously untreated CHC, without liver decompensation, who are positive for serum HCV-RNA and who have fibrosis or high inflammatory activity adult patients with CHC who have previously responded (with normalisation of ALT at the end of treatment) to interferon alfa but subsequently relapsed. Ribavirin is administered orally, usually in divided doses (200 mg per capsule or tablet). The dosage varies according to the patient's weight. Regular monitoring of full blood count to detect haemolytic anaemia is needed in order to judge whether to reduce or cease ribavirin treatment. Ribavirin is contraindicated in pregnancy and breastfeeding, in severe debilitating medical conditions (particularly of the heart, blood, kidneys and liver), in haemoglobinopathies and in the presence of autoimmune diseases or severe psychiatric conditions. It may also cause haemolytic anaemia, for which close monitoring is required and a reduction in dose or cessation of treatment may be necessary. Adverse effects related to combination therapy are similar in type and frequency to those of interferon alfa monotherapy and include influenza-like symptoms (fatigue, headache and fever), decreases in haematological parameters (neutrophil, white blood cell and platelet counts), gastrointestinal complaints (anorexia and nausea), dermatological symptoms (alopecia) and psychiatric disturbances (depression and anxiety). The trials indicate that discontinuation of treatment is more frequent (10–20%) for combination therapy than for monotherapy. Studies of combination therapy show that haematological events were the most common reason for either study withdrawal or dose reduction. Standard treatment with interferon alfa combination therapy is either for 24 weeks (for people with G2/3) or for 48 weeks (for people with G1). Treatment with interferon alfa monotherapy or combination therapy is not licensed for people younger than 18 years of age. The following factors affect the efficacy of treatment. Genotype of the virus. This is the most important determinant of efficacy of treatment. High viral load. The higher the viral load, the lower the proportion of people with HCV who have a sustained virological response (SVR), all other things being equal. High viral load is the second most important determinant of efficacy of treatment. Age. Younger people fare better than older people. This may be because older people tend to have been infected for longer, although there appears to be an independent factor beyond that. The period between infection and treatment. Longer delays appear to adversely affect the efficacy of treatment. Weight. People who weigh more than the average have a lower response rate to treatment than those who weigh less than the average, when the dosages of interferon alfa (and ribavirin for combination therapy) are fixed. Fibrosis and cirrhosis of the liver (which act as markers for the damage done by the virus). The greater the damage, the less likely it is that the body can rid itself of the virus. The pre-treatment ALT level. The higher the pre-treatment ALT level, the lower the probability of treatment success. Racial group. Studies in the USA have shown that black people had a poorer response to treatment than white people, but there is no evidence of the impact of ethnicity in a UK setting. Gender. Women respond somewhat better than men to fixed doses (though evidence suggests that this may be due to women's lower average weight, and hence to the effective dose per kilogram). Because HCV and HIV share common routes of transmission, many people with HIV are also infected with HCV. In these people, hepatitis C is a leading cause of death. It appears that HIV is associated with an acceleration of liver disease caused by HCV. Treatment of co-infected people is complicated by the possibility of adverse drug interactions, particularly with ribavirin. Studies show that treatment of people co-infected with HIV and HCV with interferon alfa combination therapy results in worthwhile (if somewhat lower) clearance rates of HCV than in people with HCV but not HIV. This is likely to be attributable to higher discontinuation rates and problems of drug interactions. A 4-week cycle of interferon alfa at 3 million units three times a week costs around £200. Ribavirin for the same period costs from about £350 to £500. (All prices exclude VAT, British National Formulary 45th edition.) Therefore, 24 weeks of combination therapy of interferon alfa plus ribavirin will cost around £4000 (excluding monitoring costs). The cost of treatment depends on which of interferon alfa-2a or interferon alfa-2b is used, and on weight, because the accompanying ribavirin dose is differentially weight-related. The value of triple therapy (combination therapy of interferon alfa and ribavirin plus amantadine) has to be fully assessed.# The technology Two product licences for a new form of interferon alfa, pegylated interferon alfa (called peginterferon alfa), have now been granted, both for use as monotherapy and for combination therapy with ribavirin in adults with hepatitis C. The pegylated form of interferon alfa contains an essentially inert 'tail', the function of which is to slow down the rate at which the body eliminates the molecule, enabling dosing to be less frequent. Of the two forms of pegylated interferon, peginterferon alfa-2a has a 40 kD branched chain polyethylene glycol molecule attached to the interferon with a stable bond. Peginterferon alfa-2b has a linear 12 kD polyethylene glycol chain that is attached via an unstable bond that breaks down in solution, releasing interferon alfa-2b. Ribavirin doses for combination therapy are as follows. In conjunction with peginterferon alfa-2a (as for interferon alfa-2a), people who have HCV genotype 1 or 4 (and usually those who have genotype 5 or 6) and who weigh less than 75 kg take 1000 mg daily of ribavirin in divided doses. People who weigh more than 75 kg take 1200 mg ribavirin daily in divided doses. For people with HCV genotype 2 or 3 (and less usually those who have genotype 5 or 6) the dose of ribavirin is 800 mg daily in divided doses. In conjunction with peginterferon alfa-2b (as for interferon alfa-2b) and regardless of genotype, people who weigh less than 65 kg take 800 mg of ribavirin daily in divided doses, people who weigh 65–85 kg take 1000 mg daily in divided doses, and people who weigh more than 85 kg take 1200 mg daily in divided doses. Peginterferon alfa has a much longer plasma half-life (50–130 hours for peginterferon alfa-2a and about 40 hours for peginterferon alfa-2b) than interferon alfa. It therefore needs to be injected only once per week, and the aggregate dose per month can be lower than for interferon, reducing most side effects. However, data show a higher incidence of neutropenia and thrombocytopenia for peginterferon alfa as either monotherapy or combination therapy than for the corresponding treatment regimen with interferon alfa. These adverse events may be managed by dose reduction. For people who are considered for peginterferon alfa combination therapy, standard haematological tests and blood chemistry (full blood count and differential platelet count, liver function tests, uric acid, serum bilirubin, serum creatinine, and electrolyte concentrations) are necessary for all people before initiating therapy. The HCV genotype is also determined and baseline viral load established. Liver biopsy is undertaken, if there are no increased risks, in order to assess liver scarring and necro-inflammation according to an accepted severity scale. This is important in determining the need for treatment for people with significant fibrosis and necro-inflammation. People are seen weekly for 4 weeks, and then monthly during treatment, to check for side effects such as haemolysis, neutropenia, thyroid changes, depression and retinopathy. Both peginterferon alfa-2a and alfa-2b are administered once a week by subcutaneous injection. The dose for peginterferon alfa-2a is 180 μg for either monotherapy or combination therapy. The dose for peginterferon alfa-2b is 1.5 μg per kg body weight (combination therapy), and either 0.5 μg or 1.0 μg per kg body weight (monotherapy). Substituting peginterferon alfa for interferon alfa increases the 4-week cost of the interferon component from about £200 to about £550. Thus, a 24-week course of combination therapy with peginterferon alfa will cost about £6000. For monotherapy, the 24-week costs for interferon alfa and peginterferon alfa are about £1200 and £3200, respectively. The cost of a 48-week course is double that of a 24-week course. (All prices exclude VAT, British National Formulary 45th edition.) Costs may vary in different settings because of negotiated procurement discounts. In pregnant or breastfeeding women, treatment with peginterferon alfa is contraindicated. Treatment with ribavirin is also contraindicated for these groups. For full details of side effects and contraindications of peginterferon alfa and of ribavirin, see the Summary of Product Characteristics.# Evidence and interpretation The Appraisal Committee (Appendix A) considered evidence from a number of sources (see Appendix B). # Clinical effectiveness The standard measurement of effectiveness of treatment of CHC is the virological response rate sustained for 6 months, called the SVR. SVR has been shown to closely reflect biopsy and ALT results taken from the same people at the same time. ## Peginterferon alfa combination therapy versus interferon alfa combination therapy The effectiveness of peginterferon alfa and ribavirin combination therapy, compared with interferon alfa and ribavirin combination therapy, for patients being treated with interferon alfa or peginterferon alfa for the first time has been investigated in two randomised controlled trials (RCTs) lasting 48 weeks. One trial used ribavirin and peginterferon alfa-2a (n = 1121) and the other used ribavirin and peginterferon alfa-2b (n = 1530). The results were broadly similar. For the first trial, peginterferon alfa-2a in combination with ribavirin yielded an SVR of 56% versus 44% for interferon alfa-2b in combination (95% confidence interval on the difference of 12 percentage points is 5 to 19 percentage points). In the second trial, the intention-to-treat analysis (which included patients taking ribavirin at lower than the licensed dose) of peginterferon alfa-2b in combination with ribavirin, the SVR was 54% versus 47% for interferon alfa-2b in combination (95% CI on the difference of 7 percentage points is 0.4 to 12.7 percentage points). In this arm of the study, all patients received 800 mg of ribavirin with 1.5 μg per kg body weight of peginterferon alfa-2b. The effect of ribavirin dose adjusted according to body weight was analysed in a subset of 188 of these patients. In this sub-population, the SVR for peginterferon alfa-2b in combination was 61% versus 47% for interferon alfa-2b in combination (95% CI on the difference of 14 percentage points is 5 to 22 percentage points). The licence for peginterferon alfa-2b combination therapy is based on this weight-adjusted ribavirin dosage. The Assessment Report recognises that the treatments with peginterferon alfa-2a and alfa-2b (both in combination with ribavirin) may be different and that there are differences between the trial populations. However, it shows that, if the results of the trials of these two treatments are pooled, peginterferon alfa combination therapy yields an SVR of 56% on an intention-to-treat basis, whereas the interferon alfa combination yields an SVR of 47% on the same basis. The difference (9 percentage points) has a 95% CI from 5 to 13 percentage points. A second trial of peginterferon alfa-2a combination therapy has so far been reported in abstract form only. It extends the knowledge gained from the first trial by comparing different doses of ribavirin and lengths of treatment. Broadly, it confirms the results of the first trial using peginterferon alfa-2a. (Further results are currently commercial-in-confidence.) The SVR in each of the two fully reported trials varied with both the baseline viral load and the genotype of the HCV. When there were more than 2 million copies of the virus in each millilitre of a patient's blood, the SVR was significantly lower than when there were fewer than 2 million copies. This was true for both arms of both of the trials. SVRs for patients infected with HCV G1 are much lower than those for G2/3, whereas SVRs for genotypes 4, 5 and 6 (when they are known) appear to be between those of the more prevalent genotypes. For G1, SVRs for peginterferon alfa-2a combination therapy were 46%, compared with 36% for interferon alfa-2a combination therapy. When peginterferon alfa-2b combination therapy and interferon alfa-2b combination therapy were compared, the SVR values were 42% and 33%, respectively, on an intention-to-treat basis. On a weight-based ribavirin dosage, they were 48% and 34%, respectively. For G2/3, the SVR for peginterferon alfa-2a combination therapy was 76%, compared with 61% for the interferon alfa-2a therapy. When the peginterferon alfa-2b and interferon alfa-2b combination therapies were compared, the SVR values were 82% and 79%, respectively, on an intention-to-treat basis. On a weight-based ribavirin dosage, they were 88% and 80%, respectively. Patients infected with HCV G2/3 respond to combination treatment with peginterferon alfa-2a in 95% of cases or more, and in about 80% of cases the response is sustained 6 months after treatment has finished. These rates are achieved after 24 weeks of treatment and are not increased by prolonging treatment for a further 24 weeks. For G1, however, the SVR after 48 weeks of treatment is much higher than that for 24 weeks of treatment, even though it is of the order of only 40–50%. This pattern follows that of combination therapy with interferon alfa-2a and interferon alfa-2b. After 12 weeks of treatment, the viral load in people who eventually have an SVR after 24 or 48 weeks' treatment is generally reduced by a factor of 100 or more. That is, for every 1000 copies of the virus in the blood at the beginning of treatment, there would be 10 or fewer copies at the end of 12 weeks' treatment. This is known as a 2-log reduction. For patients infected with HCV G2/3, more than 99% will respond with a 2-log reduction at 12 weeks. About 80% will eventually have an SVR. Of the very small number of patients not responding at 12 weeks, very few (perhaps less than 0.5% of the group that started treatment) have an SVR. For genotypes 1, 4, 5 and 6 (together called G1+), only 70–80% have a 2-log reduction at 12 weeks and, of these, about 60% (40–50% of the total group) have an SVR. Of the 20–30% that are non-responders at 12 weeks, few (perhaps 0.5% of those originally treated) go on to have an SVR. Data from a subgroup of people with cirrhosis or bridging fibrosis and G2/3 in a recent trial of peginterferon alfa-2a, details of which are still confidential until its full publication, suggest that treatment beyond 24 weeks does not result in an increase in the SVR. ## Peginterferon alfa monotherapy versus interferon alfa monotherapy The Assessment Report found four RCTs that compared peginterferon alfa monotherapy with interferon alfa monotherapy. Three of these trials, involving about 960 people, were conducted with peginterferon alfa-2a, and one trial, involving more than 1200 people, was conducted with peginterferon alfa-2b. SVRs were much lower than for combination therapy. Peginterferon alfa-2a yielded a 36% pooled response, compared with 14% for interferon alfa-2a, whereas the SVR values for peginterferon alfa-2b versus interferon alfa-2b were 23% and 12%, respectively. Different doses of peginterferon alfa were used in three of the four trials, which occurred at different stages of drug development. All trials were 48 weeks in duration; hence the shorter treatment possibility for G2/3 was not tested. ## Re-treatment of non-responders The Assessment Report found 10 RCTs, involving some 860 people, that compared interferon alfa combination therapy with interferon alfa monotherapy for the re-treatment of non-responders to interferon alfa monotherapy. Of those re-treated with monotherapy, only 7 out of 413 had a virological response at the end of the trial, whereas for combination therapy, 53 out of 449 had such a response. For studies including both failure to respond and relapses from previous monotherapy, there were 16 responses out of 323 for monotherapy, compared with 75 out of 330 for combination therapy. The differences between the success rates for monotherapy compared with combination therapy are marked, although the percentage of successes when re-treating people failing to respond to monotherapy with combination therapy is only of the order of 10%. Data for re-treatment with peginterferon alfa combination therapy for people previously treated with interferon alfa monotherapy or combination therapy is still tentative. ## Adherence Three studies (one published and one unpublished study of peginterferon alfa combination therapy, and one study of peginterferon alfa monotherapy) have retrospectively examined satisfactory adherence, defined as adhering to the designated dosing pattern at least 80% of the time. All studies show that SVR is significantly higher among people with G1 who show satisfactory adherence. For people with G2/3, one of the three studies also shows that SVR is significantly higher among those with satisfactory adherence. ## Other patient subgroups: haemophilia Many people with haemophilia were infected by blood products, in most cases by HCV G1. Many cases of G1 did not respond to monotherapy, or relapsed within 6 months. Small studies showed that a small but significant proportion of these relapses and treatment failures responded to peginterferon alfa combination therapy. ## Other patient subgroups: HIV comorbidity It is not unusual for people with HCV to be co-infected with HIV, because of their common transmission routes. Several patient submissions, one manufacturer and the Assessment Report examined this set of circumstances. In people infected with both viruses, the rate of progression of CHC is much faster. Several small trials have been conducted, all involving interferon alfa-2b, which show that the SVRs are of the order of 30% lower (for example, 35% instead of 50%) for people co-infected with HIV than for those without HIV. There is no evidence that interferon alfa interacts with drugs taken for HIV, but there is evidence that ribavirin could do so when taken with peginterferon alfa, and may prove toxic. Additional care is called for when monitoring people receiving medication for HIV co-infection. ## Other patient subgroups: injecting drug users Current injecting drug users can have high rates of discontinuation in trials, and thus do not achieve success rates in trials with interferon alfa therapy as high as those obtained by other participants. However, there is evidence that where adherence is achieved, success rates are not significantly different. ## Other patient subgroups: people with continued alcohol consumption Alcohol consumption of more than 7 units per week not only increases liver damage for those infected with HCV, but also adversely affects its treatment. ## Other patient subgroups: liver transplants People with CHC who require a liver transplant usually develop the disease in the new liver. Very limited data (six people) showed that four people responded to peginterferon alfa-2b combination therapy. ## Other patient subgroups: age, gender and ethnicity Some differences have been observed in the success of treatment between people of different ages, between men and women, and between people of different ethnicity. These differences are relatively small compared with those resulting from viral genotype or viral load. ## Other patient subgroups: mild CHC and acute hepatitis C Trials in people with mild disease have not yet reported. Treatment of mild CHC is outside of the scope of this appraisal. Acute infection is not covered by this appraisal. One trial has shown better clearance if HCV infection is treated immediately after onset, but it may not be possible to generalise its results to most people infected with HCV. # Cost effectiveness ## Peginterferon alfa combination therapy versus interferon alfa combination therapy The Assessment Report shows that peginterferon alfa combination therapy is a very cost effective intervention compared with interferon alfa combination therapy. For G2/3, given the very high sustained success rates at 24 weeks, treatment is cost effective at 24 weeks but not thereafter. For G1, 48-week treatment is cost effective compared with stopping therapy after 24 weeks. See Table 1. ## Table 1: Cost effectiveness of combination therapy for different HCV genotypes Comparison Genotype Treatment length (weeks) Estimated incremental cost/QALY (1) Peginterferon alfa combination vs interferon alfa combination £4000 to £11,000 (2) Peginterferon alfa combination vs interferon alfa combination (3) Peginterferon alfa combination vs interferon alfa combination £7000 to £38,000 (4) Peginterferon alfa combination (24 weeks) vs peginterferon alfa combination (48 weeks) Not 1 vs 48 £69,000 to negative benefits compared with24 week treatment (5) Peginterferon combination (24 weeks) vs peginterferon combination (48 weeks) vs 48 £15,000 to £19,000 compared with 24 week treatment Notes on Table 1: The estimated incremental cost/QALY figures were obtained from the Assessment Report using a modelling approach. Rows (1) and (3): use data from the pivotal trials of peginterferon/interferon alfa-2a and of alfa-2b. The estimates differ because they are based on (a) different trials and (b) different doses of ribavirin. Row (2): Uses data from the pivotal trial of peginterferon/interferon alfa-2b. Rows (4) and (5): use data from an unpublished trial of peginterferon/interferon alfa-2a submitted in confidence by the manufacturer, for different doses of ribavirin. The genotype 'not 1' essentially refers to genotypes 2 and 3, as the numbers of those in genotypes 4, 5 and 6 were small. In the Assessment Report, the estimates of incremental cost effectiveness ratios by viral genotype differ depending on thetype of peginterferon alfa or interferon alfa and the dose of ribavirin. For G1, the estimated cost per quality-adjusted life ear (QALY) gained of peginterferon alfa combination therapy compared with the corresponding interferon alfa combination therapy for 48 weeks' treatment ranges from £4000 to £11,000. For G2/3, the corresponding figures are £7000 to £38,000. For monotherapy, all treatments are for 48 weeks (see Table 2). ## Table 2: Cost effectiveness of monotherapy for different HCV Comparison Genotype Estimated incremental cost/QALY Peginterferon alfa monotherapy vs interferon alfa monotherapy Peginterferon alfa monotherapy vs interferon alfa monotherapy and 3 Peginterferon alfa monotherapy vs interferon alfa monotherapy Note on Table 2: The estimated incremental costs per QALY gained were obtained from the Assessment Report, based on a modelling approach using SVRs taken from a meta-analysis. The manufacturers' models are similar in structure to that of the Assessment Report, and the estimates of cost effectiveness derived from them show even lower costs per QALY. In one instance, this can be explained in part by the longer time horizon (expected lifetime, as opposed to 30 years). The Assessment Report shows that testing viral load at 12 weeks for G1+ and stopping treatment for people who do not exhibit a 2-log reduction in viral load is cost effective compared with continuing treatment. Some 20-30% of people infected with G1+ do not respond at 12 weeks, and of these, less than 2% will eventually have an SVR. The cost per QALY gained from continuing treatment for the non-responders at 12 weeks is estimated to be £227,000. This is not the case for G2/3; there are very few non-responders at 12 weeks. The cost effectiveness of treating with peginterferon combination therapy non-responders to interferon monotherapy has been estimated to be £3000 per QALY against no treatment. For non-responders to interferon combination therapy, it is £9000 per QALY against no treatment. # Consideration of the evidence The Committee reviewed the evidence available on the clinical and cost effectiveness of treatment with interferon alfa and peginterferon alfa and ribavirin in CHC, having considered evidence on the nature of the condition and the value placed by users on the benefits of interferon and peginterferon alfa and ribavirin from people with CHC, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. The Committee considered that peginterferon alfa combination therapy was both clinically and cost effective compared with interferon alfa combination therapy. Additionally, peginterferon alfa monotherapy was both clinically and cost effective compared with interferon alfa monotherapy. The Committee concluded that peginterferon alfa therapy should therefore supersede treatment using interferon alfa for all people unless particular side-effect considerations (neutropenia and thrombocytopenia risk) favour interferon alfa (without pegylation). The Committee also concluded that combination therapy should be used rather than monotherapy, except for people for whom ribavirin is contraindicated or cannot be tolerated. The Committee gave careful consideration to the differential efficacy of treatment for patients infected with the different HCV genotypes. On the basis of the evidence reviewed, the Committee concluded that patients infected with HCV G2/3 should be considered differently from those with G1, and genotypes 4, 5 and 6 should be treated as for G1. For combination therapy, people with G2/3 should receive 24 weeks' treatment, whereas people with all other genotypes who have demonstrated a sufficient initial response should receive 48 weeks' treatment. For combination therapy, the Committee discussed the requirement for testing for viral load at 12 weeks after the initiation of treatment as a means of assessing response. For G2/3, the number of non-respondents at this stage was such a small proportion that testing them to exclude further treatment was not considered cost effective. For all other genotypes, because the proportion of non-responders was much higher than for G2/3, the viral load response at 12 weeks is important to inform the need for treatment up to 48 weeks. The Committee further considered the clinical and cost effectiveness of peginterferon alfa-2a versus peginterferon alfa-2b. Although it was aware that the two drugs had different dosage regimens and pharmacokinetic profiles, it considered that, in the absence of any head-to-head trials and on the basis of expert opinion received, the evidence was insufficient to recommend one of these products over the other. The Committee concluded that it would be important for clinicians to have the choice of either product in order to target different groups of people under particular clinical circumstances. The Committee, in this context, gave consideration to genotypes 2 and 3. The Committee noted that the SVRs for peginterferon alfa-2a were 15 percentage points above those for interferon alfa-2b, whereas for peginterferon alfa-2b, the SVRs were only 3 percentage points above those for interferon alfa-2b. However, the Committee considered the response of the former control group to be relatively low, whereas that of the latter control group was relatively high. It also noted that, when the weight-related dosage of ribavirin (on which the peginterferon alfa-2b licence is based) was considered, the relative efficacy of peginterferon alfa-2b compared with interferon alfa-2b was more marked. The Committee therefore considered that the apparent differences in response between the two forms of peginterferon for G2/3 should not result in a differential recommendation. The Committee considered the use of peginterferon alfa for combination therapy in groups of people with HCV infection that were not represented in the pivotal clinical trials. These included people with haemophilia and people co-infected with HIV. The Committee concluded that, based on the evidence available, there was no reason to make any different provision for these groups. It did, however, note that there might be occasions where ribavirin may interact with medication for HIV, necessitating either a change in the latter or a switch to peginterferon alfa monotherapy. For combination therapy, the Committee considered the differences in treatment efficacy for people of different age, gender and ethnicity, and decided that, where sufficient evidence existed, the efficacy differences were not great enough to give rise to a different recommendation for any of these subgroups. The Committee heard that, although injecting drug users with HCV might, on average, seek treatment less frequently than other people with HCV, those who do seek treatment have similar adherence rates to other people with HCV. Furthermore, the evidence provided by the experts persuaded the Committee that current information indicated that HCV re-infection rates for people on interferon or peginterferon therapy were low in those who continue to inject illicit drugs. Thus, although rates of discontinuation of injecting drug users in trials have been high, the Committee was prepared to accept that in naturalistic settings, the rate of discontinuation would not be so great as to prevent the treatment being cost effective. The Committee heard that continued alcohol consumption even at levels of intake much lower than the recommended maximum levels for the general population might be harmful for people with CHC-induced liver disease. This is because of the effect of alcohol on the progression of liver disease and also because alcohol reduces the efficacy of peginterferon/interferon alfa as therapy for CHC. The Committee considered that continued alcohol consumption was, however, not in itself an absolute contraindication to therapy but should be emphasised as an important factor to be taken into account in advice and information given by the clinical team. The Committee carefully considered the situation of people who had already been treated with peginterferon or interferon alfa. Evidence shows that for those treated with interferon alfa monotherapy who had either not responded, or had responded but then relapsed, further treatment with combination therapy (with either peginterferon or interferon alfa) will be cost effective, although not as cost effective as for people not previously treated. The Assessment Group produced a further modelling analysis which assumed that re-treatment with peginterferon alfa combination, for those who had already undergone interferon alfa combination therapy, would yield an SVR equal to the difference between the SVRs of the two therapies. This analysis suggested that it could be cost effective to re-treat those previously treated with interferon alfa combination therapy who had relapsed or who had not responded. The Committee, after also receiving expert clinical advice on this matter and recognising the great uncertainty surrounding these estimates, decided that these groups of people should be suitable for treatment. The Committee reached the same conclusion for the few, if any, people previously treated without sustained virological response with peginterferon alfa monotherapy. However, it decided that there was no clinical or modelling evidence, or expert opinion, to support re-treatment of people who had previously been treated with peginterferon alfa combination therapy. For people unable to take ribavirin, the Committee decided that peginterferon alfa monotherapy should be the treatment of choice, because it is both clinically and cost effective compared with interferon alfa monotherapy, despite lower clearance rates of the virus than for combination therapy. All people taking peginterferon alfa monotherapy should receive treatment for 48 weeks, regardless of genotype, because it was noted that there is currently no evidence for the effectiveness of a shorter period (24 weeks) of treatment. The requirement for 12 weeks' viral load testing was also considered for this group, and it was concluded that it should apply to people with every HCV genotype. Although there was no direct evidence of the cost effectiveness for this recommendation, it could reasonably be assumed that viral testing at 12 weeks would be at least as cost effective as in combination therapy, and there was no evidence to support G2/3 being treated any differently from other genotypes. The provisos for combination therapy in Section 4.3.3 (except for the 24-week treatment for G2/3), and Sections 4.3.5 to 4.3.9, also apply to treatment with monotherapy. The Committee considered the treatment of people classified on the basis of liver biopsy as having mild chronic CHC. It was aware that there were two trials of people with mild disease that would shortly be reporting. The correct and cost-effective management of this group was considered very important and, although people with mild disease represent a small subgroup of the current RCT evidence base, it was decided that waiting for the current specific trials to report would provide a more robust basis on which to provide guidance to the NHS. The Committee discussed the question of the need for liver biopsy at some length. It concluded that, because the basis for the original guidance (see Section 8.1) required the definition of the extent of liver disease, the requirement for biopsy before deciding on appropriate therapy should remain. It was persuaded that alternative non-invasive tests of liver function could not currently be relied upon to act as appropriate surrogates for direct histological examination. However, the Committee considered that, in due course, the result of the trials in mild disease might affect this requirement. The Committee believed that there were grounds for making exceptions for people with haemophilia and risk of bleeding or with a previous adverse reaction to liver biopsy, and for those with extra-hepatic symptoms sufficient to merit treatment. The Committee considered that the effective delivery of the guidance in Section 1 would be critically dependent on the existence of a properly structured clinical environment for people with CHC. Thus, it concluded that the decision to undertake therapy should only be initiated by a physician with specialist knowledge of the treatment of CHC. Additionally it is important that a clinical team including specialist nurses is available for lifestyle advice to facilitate the informed decision of the individual to undertake treatment and to help him or her successfully complete the course of therapy.# Recommendations for further research Current trials involving peginterferon alfa for people with moderate or severe chronic CHC are reported in Appendix 11 of the Assessment Report. These consist of one trial of a triple therapy, five trials of combination therapy, two of monotherapy, five of co-infected populations and one to assess the long-term SVR in children. Trials for people with mild chronic CHC are also near completion. In addition, a randomised controlled trial of combination therapy involving pegylated interferon alfa-2a versus alfa-2b is being planned. A well-constructed trial of peginterferon alfa combination therapy versus other therapies involving interferon alfa is needed in children with chronic CHC.# Implications for the NHS The total budgetary impact of combination therapy depends on a number of factors: prevalence, proportion of people diagnosed, proportion of the people diagnosed who attend for assessment, and the proportion considered suitable for treatment, as well as the proportions who actually take up therapy and complete it. It also depends on whether peginterferon alfa combination treatment is being compared with interferon alfa combination therapy, peginterferon alfa or interferon alfa monotherapy, or no treatment. Currently, only about 2000 people in England and Wales each year are being treated for HCV infection with some form of interferon or peginterferon alfa therapy. On the basis that all these people will eventually receive peginterferon alfa combination therapy, that the numbers being treated do not change with time, and that peginterferon alfa combination therapy costs about £3200 more per patient than interferon alfa combination therapy, the additional drug expenditure would be up to £6.4 million per year. However, it is likely first, that the number of people able to benefit from treatment (injecting drug users and people who have had an alcohol problem) will be increased as a consequence of this guidance, and second, that the number of people seeking treatment will increase as education about the condition increases and as people become aware of improvements in treatment. This would significantly increase drug expenditure. Testing people with G1+ infection at 12 weeks and ending treatment for those who are not responding to therapy would cut the additional costs by about 16%, or about £1 million. There will also be a re-treatment cost for non-responders to previous therapy. The numbers of people involved are not known with any degree of certainty. The following assumptions have been made: people have not had an SVR to monotherapy and have not subsequently been treated with a combination therapy are still alive and would wish to undertake peginterferon alfa combination therapy % are G1+ and 40% are G2/3 half of the people with G1+ respond after 12 weeks and are treated for 48 weeks at a cost of £12,000 each the other half of the people with G1+ are treated for 16 weeks at a cost of £4000 each the people with G2/3 are treated for 24 weeks at a cost of £6000 each the number of people who have been treated with previous interferon combination therapy but who have either not responded or have relapsed is 2000, of whom 75% (1500) are G1+ and 25% (500) are G2/3 -f the G1+ and 400 of the G2/3 seek re-treatment % of the G1+ group respond after 12 weeks and are treated for 48 weeks at a cost of £12,000 each; the 75% that does not respond are treated for 16 weeks the G2/3 group is treated for 24 weeks at a cost of £6000 each. The drug cost, compared with no interferon treatment, would be approximately £1.8 million for people who have had previous monotherapy treatment and a further £8.4 million for people who have had previous combination therapy treatment. This is likely to be spread over about 2 years, equating to £5.1 million per year. The total increased drug cost for the next 2 years would therefore be about £10.5 million per year. Should people seeking re-treatment delay further treatment, the costs per year would be lower than £10.5 million per year, but would be spread over a longer time period. This estimation procedure ignores other costs, such as the cost of testing for genotype and viral load, but also ignores the additional potential treatment offsets down the line.# Related guidance This guidance is a review of and an extension to: National Institute for Clinical Excellence (2000) Guidance on the use of ribavirin and interferon alpha for hepatitis C. NICE Technology Appraisal No. 14. London: National Institute for Clinical Excellence.# Review of guidance The use of this technology for mild CHC (and any consequent changes that this may have on this guidance) will be considered after the publication of the results of the two relevant clinical trials, and at the earliest in August 2004. The full guidance will be reviewed in November 2006. Andrew DillonChief ExecutiveJanuary 2004# Appendix C. Detail on criteria for audit of the use of interferon alfa (pegylated and non-pegylated) and ribavirin in the treatment of chronic hepatitis C # Possible objectives for an audit An audit on the use of pegylated and non-pegylated interferon alfa and ribavirin in the treatment of CHC could be carried out to ensure that combination therapy is used appropriately. # Possible patients to be included in the audit An audit could be carried out on a reasonable number of people being treated for CHC, for audit purposes. If a large number of people is being treated, a representative sampling strategy is suggested. # Measures that could be used as a basis for audit The measures that could be used in an audit of pegylated and non-pegylated interferon alfa and ribavirin in the treatment of CHC are as follows. Criterion Standard Exception Definition of terms . An individual with moderate to severe CHC and who is aged 18 years or older is provided with peginterferon alfa and ribavirin combination therapy within licensed indications if he or she meets one of the following: a. has not been treated previously with interferon alfa or peginterferon alfa or b. has been treated previously or is currently being treated with interferon alfa monotherapy or combination therapy or c. has been previously treated with peginterferon alfa monotherapy only and either responded at the end of treatment but subsequently relapsed, or who was not responding at the end of treatment % of individuals who meet one of a–c A. Peginterferon alfa is contra-indicated; in particular, the patient is pregnant or breastfeeding B. Ribavirin is contraindicated or is not tolerated, in which case the individual is: ) treated with peginterferon alfa monotherapy and ) tested for viral load at 12 weeks of treatment and ) treated for 48 weeks if the viral load has reduced to less than 1% of its level at the start of treatment or discontinued treatment if the viral load exceeds 1% of its level at the start of treatment Pegylated interferon alfa includes peginterferon alfa-2a and peginterferon alfa-2b. 'Moderate to severe CHC' means there is histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation. See criterion 3 for exceptions for carrying out a liver biopsy for this purpose. Clinicians will need to agree locally on how to measure compliance with licensed indications, for audit purposes and will need to agree on how to define lack of response to treatment (for 1c) for audit purposes. For exception B, contraindications include: pregnancy, breastfeeding, the presence of severe debilitating medical conditions (particularly of the heart, blood, kidneys or liver), haemoglobinopathies, the presence of autoimmune diseases, severe psychiatric conditions, or haemolytic anaemia. For the exception, 'not tolerated' can include: influenza-like symptoms (fatigue, headache and fever), decreases in haematological parameters (neutrophil, white blood cell or platelet counts); gastrointestinal complaints such as anorexia or nausea, dermatological symptoms including alopecia, and psychiatric disturbances including depression or anxiety. . An individual who meets 1a–c above is treated as follows: a. for 24 weeks if the individual is infected with HCV of genotypes and/or 3 or b. for 12 weeks if the individual is infected with CHC of genotypes 1, 4, 5 or 6 and for 48 weeks if the individual is infected with HCV of genotypes 1, 4, 5 or 6 and the viral load at 12 weeks has reduced to less than 1% of its level at the start of treatment or treatment is discontinued after 12 weeks if the individual is infected with HCV of genotypes 1, 4, 5 or 6 and viral load at 12 weeks exceeds 1% of its level at the start of treatment. % of individuals in 1a–c above None If an individual is infected with more than one genotype, including at least one of genotypes 1, , 5 or 6, treatment should follow 2b and c. 'Reduced to less than 1% of the level at the start of treatment' = at least a 2-log reduction . A liver biopsy is carried out on each individual receiving any kind of interferon therapy. % of individuals in 1a–c above A. Liver biopsy poses a significant risk B. The individual has symptoms of severe extra-hepatic HCV infection sufficient to impair quality of life For exception A, conditions include haemophilia and individuals who have experienced an adverse event after undergoing a previous liver biopsy. Clinicians will need to agree locally on how to define severe extra-hepatic HCV infection and quality-of-life impairment, for audit purposes # Calculation of compliance Compliance (%) with each measure described in the table above is calculated as follows. Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed x 100 Number of patients to whom the measure applies Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Changes after publication November 2013: This guidance has been partially updated by 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300). March 2012: minor maintenance. September 2010: This guidance has been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200).# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance replaces 'Hepatitis C - alpha interferon and ribavirin' (NICE Technology Appraisal Guidance No. 14 issued in October 2000). This guidance is extended by 'Hepatitis C – peginterferon alfa and ribavirin (TA106). This guidance has been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200) and 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300). We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance replaces 'Hepatitis C - alpha interferon and ribavirin' (NICE Technology Appraisal Guidance No. 14 issued in October 2000). This guidance is extended by 'Hepatitis C – peginterferon alfa and ribavirin (TA106).\n\nThis guidance has been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200) and 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300).\n\nCombination therapy with peginterferon alfa and ribavirin is recommended within its licensed indications for the treatment of people aged 18 years and over with moderate to severe chronic hepatitis C (CHC), defined as histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation. Separate recommendations for treating chronic hepatitis C in children and young people with peginterferon alfa and ribavirin have been published in NICE technology appraisal guidance 300 ('Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people').\n\nPeople with moderate to severe CHC are suitable for treatment if they have:\n\nnot previously been treated with interferon alfa or peginterferon alfa, or\n\nbeen treated previously with interferon alfa (as monotherapy or in combination therapy), and/or\n\nthis part-recommendation has been updated and replaced by \n NICE technology appraisal guidance 200\n .\n\nPeople currently being treated with interferon alfa, either as combination therapy or monotherapy, may be switched to the corresponding therapy with peginterferon alfa.\n\nTreatment for the groups identified in Sections 1.1 and 1.2 should be as follows.\n\nPeople infected with hepatitis C virus (HCV) of genotype 2 and/or 3 should be treated for 24 weeks.\n\nFor people infected with HCV of genotype 1, 4, 5 or 6, initial treatment should be for 12 weeks. Only people showing, at 12 weeks, a reduction in viral load to less than 1% of its level at the start of treatment (at least a 2-log reduction, see Section 4.1.2.5) should continue treatment until 48 weeks. For people in whom viral load at 12 weeks exceeds 1% of its level at the start of treatment, treatment should be discontinued.\n\nPeople infected with more than one genotype that includes one or more of genotypes 1, 4, 5, or 6 should be treated as for genotype 1.Recommendation 4.1 still applies for people who are treated with standard courses of combination therapy, but has been replaced by NICE technology appraisal guidance 200 (TA200) for people who are eligible for shortened courses of combination therapy (as described in recommendation 1.2 of TA200).\n\nPeople satisfying the conditions in Sections 1.1 and 1.2 but for whom ribavirin is contraindicated or is not tolerated should be treated with peginterferon alfa monotherapy. Regardless of genotype, individuals should be tested for viral load at 12 weeks, and if the viral load has reduced to less than 1% of its level at the start of treatment, treatment should be continued for a total of 48 weeks. If viral load has not fallen to this extent, treatment should stop at 12 weeks.\n\nPeople for whom liver biopsy poses a substantial risk (such as those with haemophilia, or those who have experienced an adverse event after undergoing a previous liver biopsy), and people with symptoms of extra-hepatic HCV infection sufficient to impair quality of life, may be treated on clinical grounds without prior histological classification.\n\nThere is insufficient evidence to recommend combination therapy using peginterferon alfa or interferon alfa in people who:\n\nthis part-recommendation has been updated and replaced by\n NICE technology appraisal guidance 200\n\nthis part-recommendation has been updated and replaced by \n NICE technology appraisal guidance 300\n\nhave had a liver transplantation. Treatment of CHC recurrence after liver transplantation (whether or not the person had been treated with interferon alfa or peginterferon alfa therapy at any time before transplantation) should be considered as experimental and carried out only in the context of a clinical trial.", 'Clinical need and practice': "Chronic hepatitis C (CHC) is a disease of the liver caused by the hepatitis C virus (HCV). Generally, the virus is transmitted by blood-to-blood contact. Before the introduction of screening in 1991 it was also spread through blood transfusions. Before the viral inactivation programme in the mid-1980s it was also spread through blood products. HCV can be acquired by people who inject drugs through the sharing of needles. There is a small risk of infection associated with tattooing, electrolysis, body piercing and acupuncture. Infection through sexual intercourse can also occur. There is a transmission rate of about 6% from mother to child if the mother is an HCV carrier. Concomitant HIV infection is thought to increase the risk of transmission.\n\nPeople are often asymptomatic after exposure to the virus, but about 20% will develop acute hepatitis; some of them will experience malaise, weakness and anorexia. Up to 85% of those exposed do not clear the virus and go on to develop CHC. Progression of the disease occurs over 20–50 years. About 5–30% of people initially infected will develop cirrhosis within 20 years and a small percentage of these are at high risk of developing hepatocellular carcinoma. One-third may never progress to cirrhosis or will not progress for at least 50 years. Some people with end-stage liver disease or hepatocellular carcinoma may require liver transplantation.\n\nSix major genetic types of HCV have been identified. Genotype 1 (G1) is the most common in the UK, and is found in about 40–50% of cases. Genotypes 2 and 3 (G2/3) contribute another 40–50%, and genotypes 4, 5 and 6 constitute the remainder of about 5%. Response to treatment varies between different genotypes. G1 is relatively more common among people infected through blood products, and G2/3 is relatively more common among people who inject themselves with illicit drugs.\n\nMany individuals with HCV infection do not display symptoms. However, non-specific symptoms, such as fatigue, irritability, nausea, muscle ache, anorexia, abdominal discomfort and pain in the upper right quadrant, have been reported even in the absence of secondary pathology. If cirrhosis develops, people may have severe symptoms and complications.\n\nEstimates of prevalence for hepatitis C in England and Wales vary considerably. The extant NICE guidance (see Section 8.1) puts the figure between 200,000 and 400,000, whereas the Assessment Report suggests between 50,000 and 500,000. There is also great variation in prevalence between certain subgroups of the population: 0.04% in blood donors, 0.4% in people attending antenatal clinics (in London), 1% in people attending genito-urinary clinics and up to 50% in injecting drug users.\n\nAbout two-thirds of people with HCV infection are men, mainly because more men inject themselves with illicit drugs, but also because there are far more men than women with haemophilia.\n\nBecause it is not possible to measure directly the effectiveness of treatment in reducing progression to cirrhosis and hepatocellular carcinoma in the short term, three surrogate markers have been used in trials: hepatic histology; virological loss of HCV-RNA (measured by the polymerase chain reaction, PCR); and levels of alanine aminotransferase (ALT, an enzyme that indicates liver inflammation).\n\nThe primary aim of treatment for people with CHC is to clear HCV (defined as undetectable HCV-RNA in the serum) for at least 6 months after treatment cessation, in order to improve quality of life for patients and reduce the risk of cirrhosis and hepatocellular carcinoma.\n\nThe diagnosis of hepatitis C causes considerable anxiety to people. It is generally accepted, though without formal trial evidence, that all people diagnosed with the condition should receive adequate advice and information from a healthcare professional with knowledge and experience in the field.\n\nThe current standard treatment for moderate and severe chronic HCV infection is combination treatment with interferon alfa and ribavirin, except for people who cannot tolerate ribavirin, when interferon alfa monotherapy is used (Section 8.1 references the NICE guidance that is replaced by this guidance). The precise antiviral mode of action of interferon alfa is unknown. However, it appears to alter host-cell metabolism. It is available in the UK in two forms, interferon alfa-2a (Roferon A, Roche) and interferon alfa-2b (Viraferon, Schering-Plough).\n\nInterferon alfa is eliminated from the body rapidly, having a plasma half-life of only about 4 hours. To maintain effectiveness against HCV, doses must be administered by injection on a minimum of 3 days a week.\n\nThe duration of monotherapy treatment is 48 weeks. For monotherapy, more than half of people who clear the virus after treatment relapse within 6 months of treatment cessation, but for those who remain clear after 6 months, about 90% remain so after 6 years. Thus, for this group, treatment may be called a cure. The dosage for interferon alfa treatment is usually 3 million units three times per week by subcutaneous injection. Injections are administered by clinical staff or by the patient after adequate training. People who respond usually do so within 12–16 weeks. Those who respond continue with this dose of interferon alfa for 48 weeks.\n\nMany, but not all, people find interferon alfa therapy very hard to tolerate. After each injection, they may suffer influenza-like symptoms, and up to one-half of all people treated suffer from fatigue, headaches, pyrexia (fever), myalgia (aches and pains), insomnia and/or nausea. About one-quarter suffer hair loss, arthralgia (pain in the joints), rigors, irritability, pruritus (itching), depression, dermatitis and/or decreased appetite. There are significant problems of dropout and non-adherence with treatment as a result. Dropout rates of 7–14% have occurred. Figures on adherence are more difficult to quantify.\n\nIn the late 1990s, combination treatment of interferon alfa and ribavirin commenced, following trials that showed that, although ribavirin alone showed no activity against HCV, the effect of the combination of ribavirin with interferon alfa was much enhanced compared with that of interferon alfa alone. Since the introduction of combination therapy, monotherapy is used only for people unable to tolerate ribavirin.\n\nRibavirin (Copegus, Roche; Rebetol, Schering-Plough) is a nucleoside analogue with a broad spectrum of antiviral activity against RNA viruses. It is licensed for use in combination with interferon alfa-2a or interferon alfa-2b for treatment of CHC in:\n\nadult patients with histologically proven, previously untreated CHC, without liver decompensation, who are positive for serum HCV-RNA and who have fibrosis or high inflammatory activity\n\nadult patients with CHC who have previously responded (with normalisation of ALT at the end of treatment) to interferon alfa but subsequently relapsed.\n\nRibavirin is administered orally, usually in divided doses (200 mg per capsule or tablet). The dosage varies according to the patient's weight. Regular monitoring of full blood count to detect haemolytic anaemia is needed in order to judge whether to reduce or cease ribavirin treatment.\n\nRibavirin is contraindicated in pregnancy and breastfeeding, in severe debilitating medical conditions (particularly of the heart, blood, kidneys and liver), in haemoglobinopathies and in the presence of autoimmune diseases or severe psychiatric conditions. It may also cause haemolytic anaemia, for which close monitoring is required and a reduction in dose or cessation of treatment may be necessary.\n\nAdverse effects related to combination therapy are similar in type and frequency to those of interferon alfa monotherapy and include influenza-like symptoms (fatigue, headache and fever), decreases in haematological parameters (neutrophil, white blood cell and platelet counts), gastrointestinal complaints (anorexia and nausea), dermatological symptoms (alopecia) and psychiatric disturbances (depression and anxiety). The trials indicate that discontinuation of treatment is more frequent (10–20%) for combination therapy than for monotherapy. Studies of combination therapy show that haematological events were the most common reason for either study withdrawal or dose reduction.\n\nStandard treatment with interferon alfa combination therapy is either for 24 weeks (for people with G2/3) or for 48 weeks (for people with G1).\n\nTreatment with interferon alfa monotherapy or combination therapy is not licensed for people younger than 18 years of age.\n\nThe following factors affect the efficacy of treatment.\n\nGenotype of the virus. This is the most important determinant of efficacy of treatment.\n\nHigh viral load. The higher the viral load, the lower the proportion of people with HCV who have a sustained virological response (SVR), all other things being equal. High viral load is the second most important determinant of efficacy of treatment.\n\nAge. Younger people fare better than older people. This may be because older people tend to have been infected for longer, although there appears to be an independent factor beyond that.\n\nThe period between infection and treatment. Longer delays appear to adversely affect the efficacy of treatment.\n\nWeight. People who weigh more than the average have a lower response rate to treatment than those who weigh less than the average, when the dosages of interferon alfa (and ribavirin for combination therapy) are fixed.\n\nFibrosis and cirrhosis of the liver (which act as markers for the damage done by the virus). The greater the damage, the less likely it is that the body can rid itself of the virus.\n\nThe pre-treatment ALT level. The higher the pre-treatment ALT level, the lower the probability of treatment success.\n\nRacial group. Studies in the USA have shown that black people had a poorer response to treatment than white people, but there is no evidence of the impact of ethnicity in a UK setting.\n\nGender. Women respond somewhat better than men to fixed doses (though evidence suggests that this may be due to women's lower average weight, and hence to the effective dose per kilogram).\n\nBecause HCV and HIV share common routes of transmission, many people with HIV are also infected with HCV. In these people, hepatitis C is a leading cause of death. It appears that HIV is associated with an acceleration of liver disease caused by HCV. Treatment of co-infected people is complicated by the possibility of adverse drug interactions, particularly with ribavirin. Studies show that treatment of people co-infected with HIV and HCV with interferon alfa combination therapy results in worthwhile (if somewhat lower) clearance rates of HCV than in people with HCV but not HIV. This is likely to be attributable to higher discontinuation rates and problems of drug interactions.\n\nA 4-week cycle of interferon alfa at 3 million units three times a week costs around £200. Ribavirin for the same period costs from about £350 to £500. (All prices exclude VAT, British National Formulary 45th edition.) Therefore, 24 weeks of combination therapy of interferon alfa plus ribavirin will cost around £4000 (excluding monitoring costs). The cost of treatment depends on which of interferon alfa-2a or interferon alfa-2b is used, and on weight, because the accompanying ribavirin dose is differentially weight-related.\n\nThe value of triple therapy (combination therapy of interferon alfa and ribavirin plus amantadine) has to be fully assessed.", 'The technology': "Two product licences for a new form of interferon alfa, pegylated interferon alfa (called peginterferon alfa), have now been granted, both for use as monotherapy and for combination therapy with ribavirin in adults with hepatitis C. The pegylated form of interferon alfa contains an essentially inert 'tail', the function of which is to slow down the rate at which the body eliminates the molecule, enabling dosing to be less frequent. Of the two forms of pegylated interferon, peginterferon alfa-2a has a 40 kD branched chain polyethylene glycol molecule attached to the interferon with a stable bond. Peginterferon alfa-2b has a linear 12 kD polyethylene glycol chain that is attached via an unstable bond that breaks down in solution, releasing interferon alfa-2b.\n\nRibavirin doses for combination therapy are as follows. In conjunction with peginterferon alfa-2a (as for interferon alfa-2a), people who have HCV genotype 1 or 4 (and usually those who have genotype 5 or 6) and who weigh less than 75 kg take 1000 mg daily of ribavirin in divided doses. People who weigh more than 75 kg take 1200 mg ribavirin daily in divided doses. For people with HCV genotype 2 or 3 (and less usually those who have genotype 5 or 6) the dose of ribavirin is 800 mg daily in divided doses. In conjunction with peginterferon alfa-2b (as for interferon alfa-2b) and regardless of genotype, people who weigh less than 65 kg take 800 mg of ribavirin daily in divided doses, people who weigh 65–85 kg take 1000 mg daily in divided doses, and people who weigh more than 85 kg take 1200 mg daily in divided doses.\n\nPeginterferon alfa has a much longer plasma half-life (50–130 hours for peginterferon alfa-2a and about 40 hours for peginterferon alfa-2b) than interferon alfa. It therefore needs to be injected only once per week, and the aggregate dose per month can be lower than for interferon, reducing most side effects. However, data show a higher incidence of neutropenia and thrombocytopenia for peginterferon alfa as either monotherapy or combination therapy than for the corresponding treatment regimen with interferon alfa. These adverse events may be managed by dose reduction.\n\nFor people who are considered for peginterferon alfa combination therapy, standard haematological tests and blood chemistry (full blood count and differential platelet count, liver function tests, uric acid, serum bilirubin, serum creatinine, and electrolyte concentrations) are necessary for all people before initiating therapy. The HCV genotype is also determined and baseline viral load established. Liver biopsy is undertaken, if there are no increased risks, in order to assess liver scarring and necro-inflammation according to an accepted severity scale. This is important in determining the need for treatment for people with significant fibrosis and necro-inflammation. People are seen weekly for 4 weeks, and then monthly during treatment, to check for side effects such as haemolysis, neutropenia, thyroid changes, depression and retinopathy.\n\nBoth peginterferon alfa-2a and alfa-2b are administered once a week by subcutaneous injection. The dose for peginterferon alfa-2a is 180 μg for either monotherapy or combination therapy. The dose for peginterferon alfa-2b is 1.5 μg per kg body weight (combination therapy), and either 0.5 μg or 1.0 μg per kg body weight (monotherapy).\n\nSubstituting peginterferon alfa for interferon alfa increases the 4-week cost of the interferon component from about £200 to about £550. Thus, a 24-week course of combination therapy with peginterferon alfa will cost about £6000. For monotherapy, the 24-week costs for interferon alfa and peginterferon alfa are about £1200 and £3200, respectively. The cost of a 48-week course is double that of a 24-week course. (All prices exclude VAT, British National Formulary 45th edition.) Costs may vary in different settings because of negotiated procurement discounts.\n\nIn pregnant or breastfeeding women, treatment with peginterferon alfa is contraindicated. Treatment with ribavirin is also contraindicated for these groups. For full details of side effects and contraindications of peginterferon alfa and of ribavirin, see the Summary of Product Characteristics.", 'Evidence and interpretation': "The Appraisal Committee (Appendix A) considered evidence from a number of sources (see Appendix B).\n\n# Clinical effectiveness\n\nThe standard measurement of effectiveness of treatment of CHC is the virological response rate sustained for 6 months, called the SVR. SVR has been shown to closely reflect biopsy and ALT results taken from the same people at the same time.\n\n## Peginterferon alfa combination therapy versus interferon alfa combination therapy\n\nThe effectiveness of peginterferon alfa and ribavirin combination therapy, compared with interferon alfa and ribavirin combination therapy, for patients being treated with interferon alfa or peginterferon alfa for the first time has been investigated in two randomised controlled trials (RCTs) lasting 48 weeks. One trial used ribavirin and peginterferon alfa-2a (n = 1121) and the other used ribavirin and peginterferon alfa-2b (n = 1530). The results were broadly similar. For the first trial, peginterferon alfa-2a in combination with ribavirin yielded an SVR of 56% versus 44% for interferon alfa-2b in combination (95% confidence interval [CI] on the difference of 12 percentage points is 5 to 19 percentage points). In the second trial, the intention-to-treat analysis (which included patients taking ribavirin at lower than the licensed dose) of peginterferon alfa-2b in combination with ribavirin, the SVR was 54% versus 47% for interferon alfa-2b in combination (95% CI on the difference of 7 percentage points is 0.4 to 12.7 percentage points). In this arm of the study, all patients received 800 mg of ribavirin with 1.5 μg per kg body weight of peginterferon alfa-2b. The effect of ribavirin dose adjusted according to body weight was analysed in a subset of 188 of these patients. In this sub-population, the SVR for peginterferon alfa-2b in combination was 61% versus 47% for interferon alfa-2b in combination (95% CI on the difference of 14 percentage points is 5 to 22 percentage points). The licence for peginterferon alfa-2b combination therapy is based on this weight-adjusted ribavirin dosage. The Assessment Report recognises that the treatments with peginterferon alfa-2a and alfa-2b (both in combination with ribavirin) may be different and that there are differences between the trial populations. However, it shows that, if the results of the trials of these two treatments are pooled, peginterferon alfa combination therapy yields an SVR of 56% on an intention-to-treat basis, whereas the interferon alfa combination yields an SVR of 47% on the same basis. The difference (9 percentage points) has a 95% CI from 5 to 13 percentage points. A second trial of peginterferon alfa-2a combination therapy has so far been reported in abstract form only. It extends the knowledge gained from the first trial by comparing different doses of ribavirin and lengths of treatment. Broadly, it confirms the results of the first trial using peginterferon alfa-2a. (Further results are currently commercial-in-confidence.)\n\nThe SVR in each of the two fully reported trials varied with both the baseline viral load and the genotype of the HCV. When there were more than 2 million copies of the virus in each millilitre of a patient's blood, the SVR was significantly lower than when there were fewer than 2 million copies. This was true for both arms of both of the trials.\n\nSVRs for patients infected with HCV G1 are much lower than those for G2/3, whereas SVRs for genotypes 4, 5 and 6 (when they are known) appear to be between those of the more prevalent genotypes. For G1, SVRs for peginterferon alfa-2a combination therapy were 46%, compared with 36% for interferon alfa-2a combination therapy. When peginterferon alfa-2b combination therapy and interferon alfa-2b combination therapy were compared, the SVR values were 42% and 33%, respectively, on an intention-to-treat basis. On a weight-based ribavirin dosage, they were 48% and 34%, respectively. For G2/3, the SVR for peginterferon alfa-2a combination therapy was 76%, compared with 61% for the interferon alfa-2a therapy. When the peginterferon alfa-2b and interferon alfa-2b combination therapies were compared, the SVR values were 82% and 79%, respectively, on an intention-to-treat basis. On a weight-based ribavirin dosage, they were 88% and 80%, respectively.\n\nPatients infected with HCV G2/3 respond to combination treatment with peginterferon alfa-2a in 95% of cases or more, and in about 80% of cases the response is sustained 6 months after treatment has finished. These rates are achieved after 24 weeks of treatment and are not increased by prolonging treatment for a further 24 weeks. For G1, however, the SVR after 48 weeks of treatment is much higher than that for 24 weeks of treatment, even though it is of the order of only 40–50%. This pattern follows that of combination therapy with interferon alfa-2a and interferon alfa-2b.\n\nAfter 12 weeks of treatment, the viral load in people who eventually have an SVR after 24 or 48 weeks' treatment is generally reduced by a factor of 100 or more. That is, for every 1000 copies of the virus in the blood at the beginning of treatment, there would be 10 or fewer copies at the end of 12 weeks' treatment. This is known as a 2-log reduction.\n\nFor patients infected with HCV G2/3, more than 99% will respond with a 2-log reduction at 12 weeks. About 80% will eventually have an SVR. Of the very small number of patients not responding at 12 weeks, very few (perhaps less than 0.5% of the group that started treatment) have an SVR. For genotypes 1, 4, 5 and 6 (together called G1+), only 70–80% have a 2-log reduction at 12 weeks and, of these, about 60% (40–50% of the total group) have an SVR. Of the 20–30% that are non-responders at 12 weeks, few (perhaps 0.5% of those originally treated) go on to have an SVR.\n\nData from a subgroup of people with cirrhosis or bridging fibrosis and G2/3 in a recent trial of peginterferon alfa-2a, details of which are still confidential until its full publication, suggest that treatment beyond 24 weeks does not result in an increase in the SVR.\n\n## Peginterferon alfa monotherapy versus interferon alfa monotherapy\n\nThe Assessment Report found four RCTs that compared peginterferon alfa monotherapy with interferon alfa monotherapy. Three of these trials, involving about 960 people, were conducted with peginterferon alfa-2a, and one trial, involving more than 1200 people, was conducted with peginterferon alfa-2b. SVRs were much lower than for combination therapy. Peginterferon alfa-2a yielded a 36% pooled response, compared with 14% for interferon alfa-2a, whereas the SVR values for peginterferon alfa-2b versus interferon alfa-2b were 23% and 12%, respectively. Different doses of peginterferon alfa were used in three of the four trials, which occurred at different stages of drug development. All trials were 48 weeks in duration; hence the shorter treatment possibility for G2/3 was not tested.\n\n## Re-treatment of non-responders\n\nThe Assessment Report found 10 RCTs, involving some 860 people, that compared interferon alfa combination therapy with interferon alfa monotherapy for the re-treatment of non-responders to interferon alfa monotherapy. Of those re-treated with monotherapy, only 7 out of 413 had a virological response at the end of the trial, whereas for combination therapy, 53 out of 449 had such a response. For studies including both failure to respond and relapses from previous monotherapy, there were 16 responses out of 323 for monotherapy, compared with 75 out of 330 for combination therapy. The differences between the success rates for monotherapy compared with combination therapy are marked, although the percentage of successes when re-treating people failing to respond to monotherapy with combination therapy is only of the order of 10%.\n\nData for re-treatment with peginterferon alfa combination therapy for people previously treated with interferon alfa monotherapy or combination therapy is still tentative.\n\n## Adherence\n\nThree studies (one published and one unpublished study of peginterferon alfa combination therapy, and one study of peginterferon alfa monotherapy) have retrospectively examined satisfactory adherence, defined as adhering to the designated dosing pattern at least 80% of the time. All studies show that SVR is significantly higher among people with G1 who show satisfactory adherence. For people with G2/3, one of the three studies also shows that SVR is significantly higher among those with satisfactory adherence.\n\n## Other patient subgroups: haemophilia\n\nMany people with haemophilia were infected by blood products, in most cases by HCV G1. Many cases of G1 did not respond to monotherapy, or relapsed within 6 months. Small studies showed that a small but significant proportion of these relapses and treatment failures responded to peginterferon alfa combination therapy.\n\n## Other patient subgroups: HIV comorbidity\n\nIt is not unusual for people with HCV to be co-infected with HIV, because of their common transmission routes. Several patient submissions, one manufacturer and the Assessment Report examined this set of circumstances.\n\nIn people infected with both viruses, the rate of progression of CHC is much faster.\n\nSeveral small trials have been conducted, all involving interferon alfa-2b, which show that the SVRs are of the order of 30% lower (for example, 35% instead of 50%) for people co-infected with HIV than for those without HIV.\n\nThere is no evidence that interferon alfa interacts with drugs taken for HIV, but there is evidence that ribavirin could do so when taken with peginterferon alfa, and may prove toxic. Additional care is called for when monitoring people receiving medication for HIV co-infection.\n\n## Other patient subgroups: injecting drug users\n\nCurrent injecting drug users can have high rates of discontinuation in trials, and thus do not achieve success rates in trials with interferon alfa therapy as high as those obtained by other participants. However, there is evidence that where adherence is achieved, success rates are not significantly different.\n\n## Other patient subgroups: people with continued alcohol consumption\n\nAlcohol consumption of more than 7 units per week not only increases liver damage for those infected with HCV, but also adversely affects its treatment.\n\n## Other patient subgroups: liver transplants\n\nPeople with CHC who require a liver transplant usually develop the disease in the new liver. Very limited data (six people) showed that four people responded to peginterferon alfa-2b combination therapy.\n\n## Other patient subgroups: age, gender and ethnicity\n\nSome differences have been observed in the success of treatment between people of different ages, between men and women, and between people of different ethnicity. These differences are relatively small compared with those resulting from viral genotype or viral load.\n\n## Other patient subgroups: mild CHC and acute hepatitis C\n\nTrials in people with mild disease have not yet reported. Treatment of mild CHC is outside of the scope of this appraisal.\n\nAcute infection is not covered by this appraisal. One trial has shown better clearance if HCV infection is treated immediately after onset, but it may not be possible to generalise its results to most people infected with HCV.\n\n# Cost effectiveness\n\n## Peginterferon alfa combination therapy versus interferon alfa combination therapy\n\nThe Assessment Report shows that peginterferon alfa combination therapy is a very cost effective intervention compared with interferon alfa combination therapy. For G2/3, given the very high sustained success rates at 24 weeks, treatment is cost effective at 24 weeks but not thereafter. For G1, 48-week treatment is cost effective compared with stopping therapy after 24 weeks. See Table 1.\n\n## Table 1: Cost effectiveness of combination therapy for different HCV genotypes\n\nComparison\n\nGenotype\n\nTreatment length (weeks)\n\nEstimated incremental cost/QALY\n\n(1) Peginterferon alfa combination vs interferon alfa combination\n\n\n\n\n\n£4000 to £11,000\n\n(2) Peginterferon alfa combination vs interferon alfa combination\n\n–6\n\n\n\n£9000\n\n(3) Peginterferon alfa combination vs interferon alfa combination\n\n–3\n\n\n\n£7000 to £38,000\n\n(4) Peginterferon alfa combination (24 weeks) vs peginterferon alfa combination (48 weeks)\n\n\n\nNot 1\n\nvs 48\n\n£69,000 to negative benefits compared with24 week treatment\n\n(5) Peginterferon combination (24 weeks) vs peginterferon combination (48 weeks)\n\n\n\nvs 48\n\n£15,000 to £19,000 compared with 24 week treatment\n\nNotes on Table 1: The estimated incremental cost/QALY figures were obtained from the Assessment Report using a modelling approach.\n\nRows (1) and (3): use data from the pivotal trials of peginterferon/interferon alfa-2a and of alfa-2b. The estimates differ because they are based on (a) different trials and (b) different doses of ribavirin.\n\nRow (2): Uses data from the pivotal trial of peginterferon/interferon alfa-2b.\n\nRows (4) and (5): use data from an unpublished trial of peginterferon/interferon alfa-2a submitted in confidence by the manufacturer, for different doses of ribavirin. The genotype 'not 1' essentially refers to genotypes 2 and 3, as the numbers of those in genotypes 4, 5 and 6 were small.\n\nIn the Assessment Report, the estimates of incremental cost effectiveness ratios by viral genotype differ depending on thetype of peginterferon alfa or interferon alfa and the dose of ribavirin. For G1, the estimated cost per quality-adjusted life ear (QALY) gained of peginterferon alfa combination therapy compared with the corresponding interferon alfa combination therapy for 48 weeks' treatment ranges from £4000 to £11,000. For G2/3, the corresponding figures are £7000 to £38,000.\n\nFor monotherapy, all treatments are for 48 weeks (see Table 2).\n\n## Table 2: Cost effectiveness of monotherapy for different HCV\n\nComparison\n\nGenotype\n\nEstimated incremental cost/QALY\n\n\n\nPeginterferon alfa monotherapy vs interferon alfa monotherapy\n\n\n\n£19,000\n\nPeginterferon alfa monotherapy vs interferon alfa monotherapy\n\nand 3\n\n£7000\n\nPeginterferon alfa monotherapy vs interferon alfa monotherapy\n\n–6\n\n£2000\n\nNote on Table 2: The estimated incremental costs per QALY gained were obtained from the Assessment Report, based on a modelling approach using SVRs taken from a meta-analysis.\n\nThe manufacturers' models are similar in structure to that of the Assessment Report, and the estimates of cost effectiveness derived from them show even lower costs per QALY. In one instance, this can be explained in part by the longer time horizon (expected lifetime, as opposed to 30 years).\n\nThe Assessment Report shows that testing viral load at 12 weeks for G1+ and stopping treatment for people who do not exhibit a 2-log reduction in viral load is cost effective compared with continuing treatment. Some 20-30% of people infected with G1+ do not respond at 12 weeks, and of these, less than 2% will eventually have an SVR. The cost per QALY gained from continuing treatment for the non-responders at 12 weeks is estimated to be £227,000. This is not the case for G2/3; there are very few non-responders at 12 weeks.\n\nThe cost effectiveness of treating with peginterferon combination therapy non-responders to interferon monotherapy has been estimated to be £3000 per QALY against no treatment. For non-responders to interferon combination therapy, it is £9000 per QALY against no treatment.\n\n# Consideration of the evidence\n\nThe Committee reviewed the evidence available on the clinical and cost effectiveness of treatment with interferon alfa and peginterferon alfa and ribavirin in CHC, having considered evidence on the nature of the condition and the value placed by users on the benefits of interferon and peginterferon alfa and ribavirin from people with CHC, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee considered that peginterferon alfa combination therapy was both clinically and cost effective compared with interferon alfa combination therapy. Additionally, peginterferon alfa monotherapy was both clinically and cost effective compared with interferon alfa monotherapy. The Committee concluded that peginterferon alfa therapy should therefore supersede treatment using interferon alfa for all people unless particular side-effect considerations (neutropenia and thrombocytopenia risk) favour interferon alfa (without pegylation). The Committee also concluded that combination therapy should be used rather than monotherapy, except for people for whom ribavirin is contraindicated or cannot be tolerated.\n\nThe Committee gave careful consideration to the differential efficacy of treatment for patients infected with the different HCV genotypes. On the basis of the evidence reviewed, the Committee concluded that patients infected with HCV G2/3 should be considered differently from those with G1, and genotypes 4, 5 and 6 should be treated as for G1. For combination therapy, people with G2/3 should receive 24 weeks' treatment, whereas people with all other genotypes who have demonstrated a sufficient initial response should receive 48 weeks' treatment.\n\nFor combination therapy, the Committee discussed the requirement for testing for viral load at 12 weeks after the initiation of treatment as a means of assessing response. For G2/3, the number of non-respondents at this stage was such a small proportion that testing them to exclude further treatment was not considered cost effective. For all other genotypes, because the proportion of non-responders was much higher than for G2/3, the viral load response at 12 weeks is important to inform the need for treatment up to 48 weeks.\n\nThe Committee further considered the clinical and cost effectiveness of peginterferon alfa-2a versus peginterferon alfa-2b. Although it was aware that the two drugs had different dosage regimens and pharmacokinetic profiles, it considered that, in the absence of any head-to-head trials and on the basis of expert opinion received, the evidence was insufficient to recommend one of these products over the other. The Committee concluded that it would be important for clinicians to have the choice of either product in order to target different groups of people under particular clinical circumstances. The Committee, in this context, gave consideration to genotypes 2 and 3. The Committee noted that the SVRs for peginterferon alfa-2a were 15 percentage points above those for interferon alfa-2b, whereas for peginterferon alfa-2b, the SVRs were only 3 percentage points above those for interferon alfa-2b. However, the Committee considered the response of the former control group to be relatively low, whereas that of the latter control group was relatively high. It also noted that, when the weight-related dosage of ribavirin (on which the peginterferon alfa-2b licence is based) was considered, the relative efficacy of peginterferon alfa-2b compared with interferon alfa-2b was more marked. The Committee therefore considered that the apparent differences in response between the two forms of peginterferon for G2/3 should not result in a differential recommendation.\n\nThe Committee considered the use of peginterferon alfa for combination therapy in groups of people with HCV infection that were not represented in the pivotal clinical trials. These included people with haemophilia and people co-infected with HIV. The Committee concluded that, based on the evidence available, there was no reason to make any different provision for these groups. It did, however, note that there might be occasions where ribavirin may interact with medication for HIV, necessitating either a change in the latter or a switch to peginterferon alfa monotherapy.\n\nFor combination therapy, the Committee considered the differences in treatment efficacy for people of different age, gender and ethnicity, and decided that, where sufficient evidence existed, the efficacy differences were not great enough to give rise to a different recommendation for any of these subgroups.\n\nThe Committee heard that, although injecting drug users with HCV might, on average, seek treatment less frequently than other people with HCV, those who do seek treatment have similar adherence rates to other people with HCV. Furthermore, the evidence provided by the experts persuaded the Committee that current information indicated that HCV re-infection rates for people on interferon or peginterferon therapy were low in those who continue to inject illicit drugs. Thus, although rates of discontinuation of injecting drug users in trials have been high, the Committee was prepared to accept that in naturalistic settings, the rate of discontinuation would not be so great as to prevent the treatment being cost effective.\n\nThe Committee heard that continued alcohol consumption even at levels of intake much lower than the recommended maximum levels for the general population might be harmful for people with CHC-induced liver disease. This is because of the effect of alcohol on the progression of liver disease and also because alcohol reduces the efficacy of peginterferon/interferon alfa as therapy for CHC. The Committee considered that continued alcohol consumption was, however, not in itself an absolute contraindication to therapy but should be emphasised as an important factor to be taken into account in advice and information given by the clinical team.\n\nThe Committee carefully considered the situation of people who had already been treated with peginterferon or interferon alfa. Evidence shows that for those treated with interferon alfa monotherapy who had either not responded, or had responded but then relapsed, further treatment with combination therapy (with either peginterferon or interferon alfa) will be cost effective, although not as cost effective as for people not previously treated. The Assessment Group produced a further modelling analysis which assumed that re-treatment with peginterferon alfa combination, for those who had already undergone interferon alfa combination therapy, would yield an SVR equal to the difference between the SVRs of the two therapies. This analysis suggested that it could be cost effective to re-treat those previously treated with interferon alfa combination therapy who had relapsed or who had not responded. The Committee, after also receiving expert clinical advice on this matter and recognising the great uncertainty surrounding these estimates, decided that these groups of people should be suitable for treatment. The Committee reached the same conclusion for the few, if any, people previously treated without sustained virological response with peginterferon alfa monotherapy. However, it decided that there was no clinical or modelling evidence, or expert opinion, to support re-treatment of people who had previously been treated with peginterferon alfa combination therapy.\n\nFor people unable to take ribavirin, the Committee decided that peginterferon alfa monotherapy should be the treatment of choice, because it is both clinically and cost effective compared with interferon alfa monotherapy, despite lower clearance rates of the virus than for combination therapy. All people taking peginterferon alfa monotherapy should receive treatment for 48 weeks, regardless of genotype, because it was noted that there is currently no evidence for the effectiveness of a shorter period (24 weeks) of treatment. The requirement for 12 weeks' viral load testing was also considered for this group, and it was concluded that it should apply to people with every HCV genotype. Although there was no direct evidence of the cost effectiveness for this recommendation, it could reasonably be assumed that viral testing at 12 weeks would be at least as cost effective as in combination therapy, and there was no evidence to support G2/3 being treated any differently from other genotypes. The provisos for combination therapy in Section 4.3.3 (except for the 24-week treatment for G2/3), and Sections 4.3.5 to 4.3.9, also apply to treatment with monotherapy.\n\nThe Committee considered the treatment of people classified on the basis of liver biopsy as having mild chronic CHC. It was aware that there were two trials of people with mild disease that would shortly be reporting. The correct and cost-effective management of this group was considered very important and, although people with mild disease represent a small subgroup of the current RCT evidence base, it was decided that waiting for the current specific trials to report would provide a more robust basis on which to provide guidance to the NHS.\n\nThe Committee discussed the question of the need for liver biopsy at some length. It concluded that, because the basis for the original guidance (see Section 8.1) required the definition of the extent of liver disease, the requirement for biopsy before deciding on appropriate therapy should remain. It was persuaded that alternative non-invasive tests of liver function could not currently be relied upon to act as appropriate surrogates for direct histological examination. However, the Committee considered that, in due course, the result of the trials in mild disease might affect this requirement. The Committee believed that there were grounds for making exceptions for people with haemophilia and risk of bleeding or with a previous adverse reaction to liver biopsy, and for those with extra-hepatic symptoms sufficient to merit treatment.\n\nThe Committee considered that the effective delivery of the guidance in Section 1 would be critically dependent on the existence of a properly structured clinical environment for people with CHC. Thus, it concluded that the decision to undertake therapy should only be initiated by a physician with specialist knowledge of the treatment of CHC. Additionally it is important that a clinical team including specialist nurses is available for lifestyle advice to facilitate the informed decision of the individual to undertake treatment and to help him or her successfully complete the course of therapy.", 'Recommendations for further research': 'Current trials involving peginterferon alfa for people with moderate or severe chronic CHC are reported in Appendix 11 of the Assessment Report. These consist of one trial of a triple therapy, five trials of combination therapy, two of monotherapy, five of co-infected populations and one to assess the long-term SVR in children. Trials for people with mild chronic CHC are also near completion. In addition, a randomised controlled trial of combination therapy involving pegylated interferon alfa-2a versus alfa-2b is being planned.\n\nA well-constructed trial of peginterferon alfa combination therapy versus other therapies involving interferon alfa is needed in children with chronic CHC.', 'Implications for the NHS': 'The total budgetary impact of combination therapy depends on a number of factors: prevalence, proportion of people diagnosed, proportion of the people diagnosed who attend for assessment, and the proportion considered suitable for treatment, as well as the proportions who actually take up therapy and complete it. It also depends on whether peginterferon alfa combination treatment is being compared with interferon alfa combination therapy, peginterferon alfa or interferon alfa monotherapy, or no treatment.\n\nCurrently, only about 2000 people in England and Wales each year are being treated for HCV infection with some form of interferon or peginterferon alfa therapy. On the basis that all these people will eventually receive peginterferon alfa combination therapy, that the numbers being treated do not change with time, and that peginterferon alfa combination therapy costs about £3200 more per patient than interferon alfa combination therapy, the additional drug expenditure would be up to £6.4 million per year. However, it is likely first, that the number of people able to benefit from treatment (injecting drug users and people who have had an alcohol problem) will be increased as a consequence of this guidance, and second, that the number of people seeking treatment will increase as education about the condition increases and as people become aware of improvements in treatment. This would significantly increase drug expenditure.\n\nTesting people with G1+ infection at 12 weeks and ending treatment for those who are not responding to therapy would cut the additional costs by about 16%, or about £1 million.\n\nThere will also be a re-treatment cost for non-responders to previous therapy. The numbers of people involved are not known with any degree of certainty. The following assumptions have been made:\n\npeople have not had an SVR to monotherapy and have not subsequently been treated with a combination therapy\n\nare still alive and would wish to undertake peginterferon alfa combination therapy\n\n% are G1+ and 40% are G2/3\n\nhalf of the people with G1+ respond after 12 weeks and are treated for 48 weeks at a cost of £12,000 each\n\nthe other half of the people with G1+ are treated for 16 weeks at a cost of £4000 each\n\nthe people with G2/3 are treated for 24 weeks at a cost of £6000 each\n\nthe number of people who have been treated with previous interferon combination therapy but who have either not responded or have relapsed is 2000, of whom 75% (1500) are G1+ and 25% (500) are G2/3\n\nof the G1+ and 400 of the G2/3 seek re-treatment\n\n% of the G1+ group respond after 12 weeks and are treated for 48 weeks at a cost of £12,000 each; the 75% that does not respond are treated for 16 weeks\n\nthe G2/3 group is treated for 24 weeks at a cost of £6000 each.\n\nThe drug cost, compared with no interferon treatment, would be approximately £1.8 million for people who have had previous monotherapy treatment and a further £8.4 million for people who have had previous combination therapy treatment. This is likely to be spread over about 2 years, equating to £5.1 million per year. The total increased drug cost for the next 2 years would therefore be about £10.5 million per year. Should people seeking re-treatment delay further treatment, the costs per year would be lower than £10.5 million per year, but would be spread over a longer time period.\n\nThis estimation procedure ignores other costs, such as the cost of testing for genotype and viral load, but also ignores the additional potential treatment offsets down the line.', 'Related guidance': 'This guidance is a review of and an extension to:\n\nNational Institute for Clinical Excellence (2000) Guidance on the use of ribavirin and interferon alpha for hepatitis C. NICE Technology Appraisal No. 14. London: National Institute for Clinical Excellence.', 'Review of guidance': 'The use of this technology for mild CHC (and any consequent changes that this may have on this guidance) will be considered after the publication of the results of the two relevant clinical trials, and at the earliest in August 2004. The full guidance will be reviewed in November 2006.\n\nAndrew DillonChief ExecutiveJanuary 2004', 'Appendix C. Detail on criteria for audit of the use of interferon alfa (pegylated and non-pegylated) and ribavirin in the treatment of chronic hepatitis C': "# Possible objectives for an audit\n\nAn audit on the use of pegylated and non-pegylated interferon alfa and ribavirin in the treatment of CHC could be carried out to ensure that combination therapy is used appropriately.\n\n# Possible patients to be included in the audit\n\nAn audit could be carried out on a reasonable number of people being treated for CHC, for audit purposes. If a large number of people is being treated, a representative sampling strategy is suggested.\n\n# Measures that could be used as a basis for audit\n\nThe measures that could be used in an audit of pegylated and non-pegylated interferon alfa and ribavirin in the treatment of CHC are as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. An individual with moderate to severe CHC and who is aged 18 years or older is provided with peginterferon alfa and ribavirin combination therapy within licensed indications if he or she meets one of the following:\n\na. has not been treated previously\n\nwith interferon alfa or peginterferon alfa or\n\nb. has been treated previously or is currently being treated with interferon alfa monotherapy or combination therapy or\n\nc. has been previously treated with peginterferon alfa monotherapy only and either responded at the end of treatment but subsequently relapsed, or who was not responding at the end of treatment\n\n% of individuals who meet one of a–c\n\nA. Peginterferon alfa is contra-indicated; in particular, the patient is pregnant or breastfeeding\n\nB. Ribavirin is contraindicated or is not tolerated, in which case the individual is:\n\n) treated with peginterferon alfa monotherapy and\n\n) tested for viral load at 12 weeks of treatment and\n\n) treated for 48 weeks if the viral load has reduced to less than 1% of its level at the start of treatment or discontinued treatment if the viral load exceeds 1% of its level at the start of treatment\n\nPegylated interferon alfa includes peginterferon alfa-2a and peginterferon alfa-2b.\n\n'Moderate to severe CHC' means there is histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation. See criterion 3 for exceptions for carrying out a liver biopsy for this purpose.\n\nClinicians will need to agree locally on how to measure compliance with licensed indications, for audit purposes and will need to agree on how to define lack of response to treatment (for 1c) for audit purposes.\n\nFor exception B, contraindications include: pregnancy, breastfeeding, the presence of severe debilitating medical conditions (particularly of the heart, blood, kidneys or liver), haemoglobinopathies, the presence of autoimmune diseases, severe psychiatric conditions, or haemolytic anaemia.\n\nFor the exception, 'not tolerated' can include: influenza-like symptoms (fatigue, headache and fever), decreases in haematological parameters (neutrophil, white blood cell or platelet counts); gastrointestinal complaints such as anorexia or nausea, dermatological symptoms including alopecia, and psychiatric disturbances including depression or anxiety.\n\n. An individual who meets 1a–c above is treated as follows:\n\na. for 24 weeks if the individual is\n\ninfected with HCV of genotypes and/or 3 or\n\nb. for 12 weeks if the individual is infected with CHC of genotypes 1, 4, 5 or 6 and for 48 weeks if the individual is infected with HCV of genotypes 1, 4, 5 or 6 and the viral load at 12 weeks has reduced to less than 1% of its level at the start of treatment or treatment is discontinued after 12 weeks if the individual is infected with HCV of genotypes 1, 4, 5 or 6 and viral load at 12 weeks exceeds 1% of its level at the start of treatment.\n\n% of individuals in 1a–c above\n\nNone\n\nIf an individual is infected with more than one genotype, including at least one of genotypes 1,\n\n, 5 or 6, treatment should follow 2b and c.\n\n'Reduced to less than 1% of the level at the start of treatment' = at least a 2-log reduction\n\n. A liver biopsy is carried out on each individual receiving any kind of interferon therapy.\n\n% of individuals in 1a–c above\n\nA. Liver biopsy poses a significant risk\n\nB. The individual has symptoms of severe extra-hepatic HCV infection sufficient to impair quality of life\n\nFor exception A, conditions include haemophilia and individuals who have experienced an adverse event after undergoing a previous liver biopsy.\n\nClinicians will need to agree locally on how to define severe extra-hepatic HCV infection and quality-of-life impairment, for audit purposes\n\n# Calculation of compliance\n\nCompliance (%) with each measure described in the table above is calculated as follows.\n\nNumber of patients whose care is consistent with the criterion plus number of patients who meet any exception listed\n\nx 100\n\nNumber of patients to whom the measure applies\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.", 'Changes after publication': "November 2013: This guidance has been partially updated by 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300).\n\nMarch 2012: minor maintenance.\n\nSeptember 2010: This guidance has been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200).", 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance replaces 'Hepatitis C - alpha interferon and ribavirin' (NICE Technology Appraisal Guidance No. 14 issued in October 2000). This guidance is extended by 'Hepatitis C – peginterferon alfa and ribavirin (TA106).\n\nThis guidance has been partially updated by 'Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C' (NICE technology appraisal guidance 200) and 'Peginterferon alfa and ribavirin for treating chronic hepatitis C in children and young people' (NICE technology appraisal guidance 300).\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2004. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}	https://www.nice.org.uk/guidance/ta75	Evidence-based recommendations on interferon alfa (Pegasys or ViraferonPeg) and ribavirin for people with chronic hepatitis C.
8d2e23c631db37da92f5abe753cc4fce5464afb9	nice	Weight management: lifestyle services for overweight or obese children and young people	Weight management: lifestyle services for overweight or obese children and young people This guideline covers lifestyle weight management services for children and young people aged under 18 who are overweight or obese. It advises how to deliver effective weight management programmes that support children and young people to change their lifestyle and manage their weight. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The Programme Development Group (PDG) considers that the recommendations are likely to be cost effective. The evidence underpinning the recommendations is listed in the evidence section and the full evidence reviews, economic modelling report, expert papers and commissioned report. For the research recommendations, see Recommendations for research and Gaps in the evidence respectively. The recommendations in this guidance cover lifestyle weight management services for overweight and obese children and young people aged under 18. However, no evidence was identified about the effectiveness of such programmes specifically aimed at children under 6. The absence of such programmes from the recommendations is a result of this lack of evidence and should not be taken as a judgement on whether or not they are effective and cost effective. The recommendations are for commissioners in local authorities and the NHS and providers of community-based services that take a 'lifestyle' approach to helping overweight or obese children and young people manage their weight. They are also for health professionals and people working with children and young people. Although local terminology varies, these are sometimes called tier 2 services and are just 1 part of a comprehensive approach to preventing and treating obesity. The guidance may also be of interest to children and young people, their parents, carers, families and other members of the public. The guidance complements but does not replace NICE guidance on obesity, body mass index and waist circumference among minority ethnic groups, how local communities can prevent obesity, physical activity for children and young people, and weight management in pregnancy. (For further details, see the NICE topic page on obesity.) # Principles of weight management for children and young people Assessing the body mass index (BMI) of children is more complicated than for adults because it changes as they grow and mature. In addition, growth patterns differ between boys and girls. Thresholds that take into account a child's age and sex are used to assess whether their BMI is too high or too low. These are usually derived from a reference population, known as a child growth reference, with the data presented in BMI centile charts. In a clinical assessment, a child or young person on or above the 98th centile is classified as obese. A child or young person on or above the 91st centile, but below the 98th centile, is classified as overweight. Several classification systems are used in the UK to define 'obesity' and 'overweight' in children. In the analysis of population surveys such as the National Child Measurement Programme and the Health Survey for England (HSE), children over the 85th centile, and on or below the 95th centile, are classified as being 'overweight'. Children over the 95th centile are classified as being 'obese'. However, the NCMP uses the clinical cut-off points described above when providing feedback about the BMI of individual children to parents and carers. When monitoring and comparing groups of children and young people BMI z scores may be used. These are a measure of how many standard deviations a child or young person's BMI is above or below the average BMI for their age and gender. In this guidance, the term BMI centile is used in recommendations that focus on working with individual children or young people. 'BMI z score' is used in recommendations relating to monitoring and research. Further information can be found in the Nation Obesity Observatory's simple guide to classifying BMI in children. # Lifestyle weight management programmes Many lifestyle weight management programmes aim to maintain the growing child's existing weight in the short term, as they grow taller. This is an appropriate short-term aim, because it will result in an improved BMI over time, and is often described as 'growing into their weight'. Young people who are overweight or obese and are no longer growing taller will ultimately need to lose weight to improve their BMI. However, preventing further weight gain while they gain the knowledge and skills they need to make lifestyle changes, may be an appropriate short-term aim. These changes then need to become firmly established habits over the long term. # Whose health will benefit? Children and young people who are overweight or obese. # Recommendation 1 Planning lifestyle weight management services for children and young people ## Who should take action? Directors of public health and public health teams working on obesity and child health and wellbeing. Health and wellbeing boards. Local authority commissioners. Clinical commissioning groups. NHS England. Public Health England. Children's services. ## What action should they take? Ensure family-based, multi-component lifestyle weight management services for children and young people are available as part of a community-wide, multi-agency approach to promoting a healthy weight and preventing and managing obesity. These services should contain the core elements described in recommendation 3. They should be provided as part of a locally agreed obesity care or weight management pathway. Dedicate long-term resources to support the development, implementation, delivery, promotion, monitoring and evaluation of these services. See recommendation 7 in NICE's guideline on obesity: working with local communities and principle 7 in NICE's guideline on behaviour change: general approaches. Use data from the joint strategic needs assessment and the National Child Measurement Programme to identify local need. See recommendation 1 in NICE's guideline on obesity: working with local communities. # Recommendation 2 Commissioning lifestyle weight management programmes for children and young people ## Who should take action? Directors of public health and public health teams working on obesity and child health and wellbeing. Health and wellbeing boards. Local authority commissioners. Clinical commissioning groups. NHS England. Public Health England. Children's services. ## What action should they take? Identify needs using the joint strategic needs assessment. Use community engagement techniques with local families to identify any barriers and facilitators discouraging or encouraging the uptake and completion of programmes. Commission lifestyle weight management services to meet the needs of local children and young people, including those of different ages, different stages of development and from different cultural backgrounds. Services should be in line with the health and wellbeing strategy. Consider how best to provide services for overweight or obese children and young people with special needs or disabilities. For example, through specific programmes where these are available. Or by making reasonable adaptations to mainstream programmes (including training staff) and evaluating them. Ensure there is an appropriate interface with specialist obesity services to help those with more complex needs manage their weight. Ensure all lifestyle weight management programmes are designed and developed with input from a multidisciplinary team and have taken into account the views of children, young people and their families. The team should include professionals who specialise in children, young people and weight management. These include the following: a state registered dietitian or registered nutritionist a physical activity specialist a behaviour-change expert, such as a health promotion specialist (for physical activity, a sport and exercise psychologist may be appropriate) a health or clinical psychologist, or a child or adolescent psychiatrist, to provide expertise in mental wellbeing a paediatrician or paediatric nurse. Ensure programme content is regularly reviewed and updated by the multidisciplinary team. Ensure providers can demonstrate that staff are trained to deliver the specific programme commissioned and are experienced in working with children, young people and their families. Ensure sufficient resources are dedicated to monitoring and evaluation. Ensure there are clearly defined programme objectives, outputs, outcomes and monitoring and evaluation requirements in programme specifications and in contracts. Contracts should also specify any at-risk groups that should be targeted, such as black and minority ethnic groups, or children and young people from low-income families or neighbourhoods. Ensure key performance indicators are agreed with programme providers, including the proportion of sessions that must be attended to complete the programme (see recommendation 15). Ensure the contract or programme specification requires that height and weight are measured and that both BMI and BMI for age and gender (BMI z score) are recorded. All children and young people should be measured at the following times: at recruitment to the programme at completion of the programme months after completing the programme year after completing the programme. For recommendations for providers, see recommendations 3, 5, 10 and 14. See also recommendation 10 in NICE's guideline on obesity: working with local communities. # Recommendation 3 Lifestyle weight management programmes: core components ## Who should take action? Providers of lifestyle weight management programmes. ## What action should they take? Ensure all lifestyle weight management programmes for overweight and obese children and young people are multi-component. They should focus on: diet and healthy eating habits physical activity reducing the amount of time spent being sedentary strategies for changing the behaviour of the child or young person and all close family members. Ensure the following core components, developed with the input of a multidisciplinary team (see recommendation 2) are included: Behaviour-change techniques to increase motivation and confidence in the ability to change. This includes strategies to help the family identify how changes can be implemented and sustained at home. Positive parenting skills training, including problem-solving skills, to support changes in behaviour. An emphasis on the importance of encouraging all family members to eat healthily and to be physically active, regardless of their weight. A tailored plan to meet individual needs, appropriate to the child or young person's age, gender, ethnicity, cultural background, economic and family circumstances, any special needs and how obese or overweight they are. This should include helping them and their family to set goals, monitor progress against them and provide feedback (see recommendation 4). Information and help to master skills in, for example, how to interpret nutritional labelling and how to modify culturally appropriate recipes on a budget. Help to identify opportunities to become less sedentary and to build physical activity into their daily life (for example, by walking to school and through active play). A range of physical activities (such as games, dancing and aerobics) that the children or young people enjoy and that can help them gradually become more active. Information for family members who may not attend the programme itself to explain the programme's aims and objectives and how they can provide support. Ongoing support and follow-up for participants who have completed the programme. # Recommendation 4 Developing a tailored plan to meet individual needs ## Who should take action? Providers of lifestyle weight management programmes. ## What action should they take? Assess each child or young person for obesity-associated diseases or conditions (comorbidities). Use a locally approved comorbidities assessment tool, where available. Assessment is particularly important if the child or young person and their family have self-referred to the programme, or have not been assessed by a health professional. Refer them to their GP if any concerns are identified. Identify whether the child or young person's mental wellbeing is affected by their weight. For example, whether there are any signs of psychological distress, depression, bulimia, self-harming or other mental health problems related to their weight. Identify whether their weight is a consequence of circumstances that have affected their mental wellbeing. (For example, if they have experienced bereavement or have caring responsibilities.) If concerns about their mental wellbeing are identified refer the child or young person to their GP for assessment and treatment and, if appropriate, for onward referral to child and adolescent mental health services (CAMHS). (Note: such concerns may be identified at any stage of a weight management programme.) Take account of the child or young person's self-esteem, self-perception and any previous attempts to manage their weight. Provide opportunities, in either a group or one-to-one session, for them to talk about any victimisation or distress if they wish. (This includes any history of bullying or teasing.) Find out whether the family recognises that their child is overweight or obese and the potential benefits of managing their weight. Discuss the family's history of attempts to manage their weight, and their existing knowledge of, and attitudes towards, food, physical activity and the amount of time spent being sedentary. Weigh, measure, determine and record the child or young person's BMI. Offer to do the same for parents, carers and other family members. Measurements should be undertaken by staff who have been trained using standard protocols (see recommendation 11). They should use validated, transportable instruments that are regularly calibrated. Emphasise that the programme may benefit the whole family. In addition, offer information about local lifestyle weight management services to adult family members who are overweight or obese. Encourage children and young people from around the age of 12 (depending on their ability and stage of development) to monitor their eating, physical activity and any sedentary behaviour. For example, encourage them to keep a record of time spent watching television or playing computer games, and what they snack on and when, to identify areas that need addressing. For younger children, parents and carers should monitor these behaviours, with the involvement of the child according to their age and stage of development. Work with children from around the age of 12 (depending on their ability and stage of development) to identify situations in which it would be possible for them to eat more healthily or to become less sedentary and more active. For example, this might involve gradually reducing TV viewing at certain times and replacing this with more active pastimes. Work with the parents and carers of younger children to achieve the same. Aim to gradually increase the amount of moderate to vigorous-intensity physical activity programme participants do every day. Focus on activities they enjoy and that are easily accessible. This includes activities that can be built into daily life, such as active play, walking or cycling. Aim to achieve the age-specific UK physical activity guidelines. Agree dietary changes that are age-appropriate, affordable, culturally sensitive and consistent with healthy eating advice. Ensure nutrient needs for growth and development are met by including healthier choices, in appropriate amounts, from each of the food groups (see NHS Eatwell plate). Changes to diet should take into account the child or young person's likes and dislikes. Manage expectations of what can be realistically achieved over the duration of the programme. Small but realistic goals should be mutually agreed with the child or young person and their family. These should relate to goals that they value and that motivate them to attend. Work with participants and their families to regularly monitor progress against the goals and provide feedback. Praise progress and achievements and update the goals as the child or young person progresses through the programme. If they do not meet their goals, discuss the possible causes for this and modify them if necessary. Stress the importance of maintaining changes, no matter how small, over the longer term. Encourage participants to take up offers of ongoing support (see recommendation 10). # Recommendation 5 Encouraging adherence to lifestyle weight management programmes ## Who should take action? Providers of lifestyle weight management programmes. ## What action should they take? Offer programmes to groups of children or young people and their families. Where necessary, offer programmes to individual families, if this better meets their needs and preferences. For example, some families may prefer to attend individual sessions initially and attend group sessions as their confidence and self-esteem grows. Offer a range of programmes for children and young people of different ages and at different stages of development. If group sessions are offered, work with groups of peers and their parents or carers. Note, some adolescents may respond better to programmes if their sessions are separate from those for their parents and carers. Offer programmes in venues that have the necessary facilities, are easily accessible and where the child or young person and their family feel comfortable. For example, use local community venues that have space for physical activities or games, and that can be reached quickly and easily by walking, cycling or using public transport. Offer programmes at a range of times that are convenient for families with children of different ages and for working parents and carers. For example, some sessions could be offered in the evenings or at weekends. Adopt a flexible approach so that participants can accommodate other commitments. They may also prefer to attend programmes more frequently initially and less frequently as their skills and confidence in making changes grows. For example, use rolling programmes that allow participants to start at different points and cover the same material but not necessarily in the same order. Emphasise the importance of parental (or carer) support and their commitment to adhere to the programme. Stress that this support and commitment should extend beyond the duration of the programme itself and that outcomes will be reviewed for at least the first year after completion. Maintain regular contact with participants. Promptly follow up those who miss sessions to establish why and to restore commitment. Focus on participants from disadvantaged groups and those who miss sessions early on in the programme. Try to retain the same team of staff throughout each cycle of the programme. # Recommendation 6 Raising awareness of lifestyle weight management programmes: commissioners and programme providers ## Who should take action? Directors of public health and their teams. Local authority commissioners. NHS commissioners. NHS and local authority communications teams. Providers of lifestyle weight management programmes. ## What action should they take? Local authorities should ensure an up-to-date list of local lifestyle weight management programmes for children and young people is maintained. This should form part of a list of services commissioned for the local obesity care or weight management pathway. It should be regularly disseminated, or accessible to organisations in the public, community and voluntary sectors. Use children's centres, libraries, the local media, professional and voluntary organisations working with children and young people and schools to raise awareness of lifestyle weight management programmes. Any publicity should clearly describe: who the programme is for (age range, any eligibility criteria and the level of parental involvement needed) how to enrol (including whether participants can self-refer or need a formal referral from a health professional) programme aims type of activities involved (to alleviate any anxieties about the unknown and to ensure expectations are realistic): 'healthy living' and any fun aspects should be emphasised time and location, length of each session and number of sessions. Commissioners, public health teams and providers should raise awareness of the programmes among health professionals who may refer children and young people. This includes GPs and staff involved in the National Child Measurement Programme and the Healthy Child Programme. For example, the programme could be publicised through health professional networks and by offering training sessions on the programmes and how to make referrals. # Recommendation 7 Raising awareness of lifestyle weight management programmes: health professionals, other professionals and voluntary organisations ## Who should take action? Health professionals, in particular, GPs, dietitians, health visitors, school nurses and those involved in delivering the National Child Measurement Programme and the Healthy Child Programme. Schools, colleges, early years organisations, children's centres and looked-after children's teams and other professionals who work with children and young people. For example, youth workers, social workers, and pastoral care workers. ## What action should they take? Health professionals should tell the parents or carers of children and young people who have been identified as being overweight or obese about local lifestyle weight management programmes. They should explain what these involve and how they can take part (including whether or not they can self-refer). Other professionals who work with children and young people should raise awareness of lifestyle weight management programmes for overweight and obese children and young people. They should also raise awareness of how to enrol on them. # Recommendation 8 Formal referrals to lifestyle weight management programmes ## Who should take action? Children's community nurses, dietetic teams, GPs, health visitors, primary care teams, obesity specialists, paediatricians, school nurses and school healthcare teams. ## What action should they take? Where there are concerns about a child or young person's weight, weigh them in light clothing on clinically approved, regularly calibrated scales. In children older than 2 years, measure their height using a stadiometer. (See the National Obesity Observatory's standard evaluation framework for weight management interventions, for practical advice on weighing and measuring children). Use the UK growth charts for children aged 4 years and older to determine BMI centile for their age and gender. Use the UK-WHO 0 to 4 years growth chart to determine if children younger than 4 are a healthy weight. Record this in the child or young person's health record. Take account of their BMI centile, any obesity-associated diseases or conditions (comorbidities) they may have, or family medical history, and any psychosocial considerations, to determine whether referral to a lifestyle weight management programme is clinically appropriate. Use tact and diplomacy to find out if the family and the child or young person accepts that the child or young person is overweight or obese. If they do accept this and it is clinically appropriate to refer them to a lifestyle weight management programme, explain the potential benefits they will gain – and the risks of not addressing their child's weight. In addition: identify and address any fears or concerns the child, young person or their family may have about attending (for example, fears of being the largest child on the programme, of having to do very strenuous activities, or being stigmatised for attending) give the family information about the programme, or tell them where they can get this information explain what can be realistically expected in terms of results over the duration of the programme itself (for example, explain that for growing children, maintaining their existing weight may be a realistic short-term aim) explain that the more sessions of a programme they attend, the greater the likelihood of success. Assess whether the child or young person and their family are ready and willing to be referred. If they are ready, refer them to an effective lifestyle weight management programme (see recommendation 3). If the family is not ready to attend a programme: tell them how they can enrol in the future (including the fact that they can self-refer if this is possible) -ffer a follow-up appointment in 3 or 6 months, according to their preference provide them with, or point them to, information and advice on healthy eating, physical activity and how to reduce sedentary behaviour (examples include: the NHS Eatwell plate, UK physical activity guidelines and the Change4Life). If children or young people need specialist support to manage their weight, refer them to specialist obesity services (if available) or to paediatric services. If there are concerns about the child or young person's mental wellbeing related to their weight, use the local pathway to refer them to CAMHS. Ensure their GP is informed. # Recommendation 9 Providing ongoing support: health professionals ## Who should take action? Children's community nurses, dietetic teams, GPs, health visitors, members of primary care teams, obesity specialists, paediatricians and school nurses and school healthcare teams. ## What action should they take? Health professionals should use feedback from the programmes to help regularly monitor progress and provide ongoing support. They should acknowledge that: for children who are growing taller, avoiding further weight gain is a realistic short-term aim that can have a positive impact in the longer term for young people who are no longer growing taller, ultimately they need to lose weight to improve their BMI, and they should also aim to acquire the knowledge and skills they need to make long-term behaviour changes it is important to maintain changes in behaviour once the programme is completed improvements in diet and physical activity can have positive health benefits, independent of any effect on weight or BMI improvements in psychosocial outcomes (such as sense of wellbeing, self-efficacy, self-esteem and self-perception) are considered important health benefits for overweight and obese children and young people. After the programme has been completed, health professionals should continue to monitor the child or young person's BMI centile when the opportunity arises and at 6 months and 1 year after they complete the programme. If the child or young person's BMI centile begins to increase, or if they or their parents or carers express concerns about their weight (or sustaining changes in their behaviour), discuss the possible causes. If necessary, consider another referral to the same or an alternative lifestyle weight management programme that may better address the needs of the family. Or consider referral to specialist obesity services (if available), or to a paediatrician. # Recommendation 10 Providing ongoing support: lifestyle weight management programmes ## Who should take action? Providers of lifestyle weight management programmes. ## What action should they take? With the participants' consent, providers should send feedback to their referring GP or healthcare professional. Offer all participants ongoing support when they have completed the programme. This support should be offered for at least the first year and longer, if possible, depending on the family's needs. Offer a range of options including follow-up sessions at different times and in easily accessible and acceptable venues. Tell participants about local services and activities that may provide further support to help them manage their weight, for example, local leisure services and walking or cycling groups. # Recommendation 11 Lifestyle weight management programme staff: training ## Who should take action? Providers of lifestyle weight management programmes. ## What action should they take? Ensure staff are trained to deliver the weight management programme they will be working on. Ensure the training has been developed with the input of, and is regularly reviewed by, a multi-disciplinary team of professionals (see recommendation 2). Ensure staff training needs are regularly reviewed and addressed. Ensure programme staff treat overweight and obese children, young people and their families with empathy, by making them aware of: the reasons why some children and young people may have difficulty managing their weight the experiences they may face in relation to their weight the anxieties they and their families may have about attending the programme the way in which obesity is perceived by different communities the issues they may need to consider to ensure activities are culturally acceptable. Train staff: to accurately measure and record height and weight and to determine BMI centile using age- and gender-specific charts to help parents and carers recognise that their child is overweight or obese and the benefits of addressing their weight to use a locally approved comorbidities assessment tool, where available, to determine whether lifestyle weight management programmes are appropriate, or whether they should see their GP for a referral to a specialist obesity service or other specialist services (for example, paediatric services) to identify any concerns about a child or young person's mental wellbeing and how to refer them to their GP for onward referral to CAMHS in how to comply with statutory requirements and local policies relating to safeguarding and information governance. # Recommendation 12 Lifestyle weight management programme staff: knowledge and skills ## Who should take action? Providers of lifestyle weight management programmes. ## What action should they take? Ensure staff have the necessary knowledge and skills to deliver multi-component programmes to children, young people and their families. This includes knowledge and skills in relation to: childhood obesity management, diet and physical activity. It may also include training in behaviour-change techniques and psychological approaches (for example, motivational interviewing). Ensure there are staff available who can provide parenting skills training. Also ensure there are staff trained in practical food preparation. Ensure staff are able to empathise and communicate effectively with the family. They should be able to work collaboratively with them and tailor interventions for individual needs. They should also be able to lead group work and set an appropriate pace when delivering the programme. In addition, they should be able to judge when changes in behaviour have become embedded, before introducing further changes. Ensure staff can review progress and provide constructive feedback. They should be able to help children, young people and their families to identify possible reasons for relapse and use problem-solving techniques to address these. Identify any gaps in staff knowledge or skills (or a lack of confidence). Address any gaps through training. # Recommendation 13 Training in how to make referrals to a lifestyle weight management programme ## Who should take action? Employers. Professional bodies responsible for setting competencies and designing continuous professional development programmes for health professionals. ## What action should they take? Ensure health professionals: Understand why some children and young people may have difficulty managing their weight and the experiences that they may face in relation to their weight. Are aware of how obesity is viewed in different cultures and the issues they may need to consider to ensure any recommended activities are culturally acceptable. See NICE's guideline on promoting physical activity for children and young people. Can accurately measure and record height and weight and determine BMI centile, using age- and gender-specific charts. Can raise the issue of weight management confidently and sensitively. They should be able to help parents and carers identify when their child is overweight or obese and understand the benefits of addressing their weight. Are familiar with the local obesity care or weight management pathway and any locally approved comorbidities assessment tools. Can assess whether referral to a lifestyle weight management service is appropriate, or whether they should be referred to specialist obesity services or other specialist services (for example, paediatric services). Can identify suitable lifestyle weight management programmes for children, young people and their families and can provide them with information and ongoing support (see recommendations 9 and 10). # Recommendation 14 Supporting lifestyle weight management programme staff and those making programme referrals ## Who should take action? Employers of staff working on, or referring children and young people to, lifestyle weight management programmes. Providers of lifestyle weight management programmes. ## What action should they take? If those involved in referring to, or delivering, lifestyle weight management programmes lack the confidence and skills to discuss weight management, offer them support and training. If staff identify that the reason for their lack of confidence is a result of being overweight or obese themselves, offer them access to weight management programmes. See also recommendation 9 in NICE's guideline on obesity: working with local communities. # Recommendation 15 Monitoring and evaluating programmes ## Who should take action? Directors of public health and public health teams working on obesity and child health and wellbeing. Health and wellbeing boards. Local authority commissioners. Clinical commissioning groups. NHS England. Providers of lifestyle weight management programmes. ## What action should they take? Ensure monitoring focuses on sustaining changes in the longer term. Include the following in the data reported: numbers recruited, percentage completing the programme and percentage followed up at 6 months and at 1 year after completing the programme for all those recruited, BMI and BMI z score a) at recruitment to the programme b) at completion of the programme c) 6 months after completing the programme and d) 1 year after completing the programme. Ensure other measured outcomes reflect the aim of the programme and relate to factors that can support or contribute towards a reduction in BMI. These could include: improvements in diet and physical activity, a reduction in sedentary behaviour and improvements in self-esteem. (See National Obesity Observatory's standard evaluation framework for weight management interventions for examples of other possible outcome measures.) Ensure data collection tools are validated for the age range or population group the programme addresses and are feasible and affordable in practice settings. Do not rely on self-reported measures of height or weight, or interpretations of BMI based on them. Monitor any variation in the numbers recruited, numbers completing and the proportion of people retained by the programme, according to population subgroup. Collect data on: Variations in outcomes, according to age, gender, ethnicity and socioeconomic status (for example, as indicated by the postcode of participants), so that the impact on health inequalities can be assessed. The route through which participants were referred to programmes including any self-referrals. Use this information to identify areas where awareness of available programmes is low and where referral rates might be increased. The views of participants: areas they found helpful and areas for improvement. Ensure the views of everyone who has participated are collected (including those who did not complete the programme). The views of staff delivering the programme and of those referring participants to it. Use the information to identify any practical or process issues that may need addressing. Commissioners should evaluate the service using data on outcomes and the cost of promotion and delivery. Commissioners should regularly review monitoring and evaluation data and use it to amend and improve the service. See also recommendation 10 in NICE's guideline on obesity: working with local communities# Public health need and practice # Obesity and overweight statistics In 2011 in England, around 3 out of 10 boys and girls aged 2 to 15 years were either overweight or obese. The proportion of those who are overweight has remained largely unchanged since the mid-1990s. However, childhood obesity has risen by around 1 percentage point every 2 years up to 2007 (NHS Information Centre 2013; Department of Health 2011). In the 2011/2012 school year, around 23% of children in reception and 34% in year 6 were either overweight or obese. Around 9.5% and 19%, respectively, were obese. The prevalence of obesity was linked with socioeconomic deprivation and was more prevalent in urban areas. Obesity was also more prevalent among children from black, Asian, 'mixed' and 'other' minority ethnic groups than among their white counterparts (NHS Information Centre 2012). Although the prevalence of obesity now appears to be levelling off, in 2011 around 17% of boys and just under 16% of girls aged 2 to 15 years were classed as obese (NHS Information Centre 2013). Up to 79% of children who are obese in their early teens are likely to remain obese as adults (Chief Medical Officer 2008). Consequently, they will be at greater risk of conditions such as type 2 diabetes, coronary heart disease and some cancers in adulthood (Foresight 2007). Studies have also shown that a child with at least 1 obese parent is more likely to be obese themselves (Perez-Pastor et al. 2009). # Childhood obesity and health Various diseases or conditions (comorbidities) may be associated with obesity in childhood. Of these, type 2 diabetes is a particular concern. It usually occurs in middle aged and older people and is associated with being overweight or obese. However, over the past decade, more younger people and children (some as young as 7) are being diagnosed with this condition (Diabetes UK 2011). Being overweight as a child has also been associated with other cardiovascular risk factors in childhood or early adulthood (Craig et al. 2008; Logue and Sattar 2011). Other conditions associated with childhood obesity include: non-alcoholic fatty liver disease (Wei et al. 2011); gall stones (Koebnick et al. 2012); asthma and sleep-disordered breathing, including sleep apnoea (Figueroa-Munoz et al. 2001); and musculoskeletal conditions (Murray and Wilson 2008, Taylor et al 2006). In addition, there is evidence that childhood obesity impacts on self-esteem and quality of life (Griffiths et al. 2010). In adolescence, it has been associated with depression (Sjoberg et al. 2005). Overweight and obese children are likely to experience bullying and stigma (Griffiths et al. 2006) which can also impact on their self-esteem. Some of these issues may, in turn, lead to under-achievement at school (Bromfield 2009). # Weight management programmes The 'Healthy child programme for 5- to 19‑year-olds' recommends that overweight or obese children should be referred to appropriate weight management services to help them achieve and maintain a healthier weight (Department of Health 2009). Such programmes can also help improve self-esteem (Lowry et al. 2007). In addition, they have the potential to help improve how they see themselves which may, in turn, enhance their future wellbeing (even if weight loss is not apparent in the short term) (Griffiths et al. 2010). In 2008, an estimated 314 to 375 weight management programmes for children were operating in England (Aicken et al. 2008). Lifestyle approaches focus on diet, physical activity, behaviour change or any combination of these factors. They may include programmes, courses or clubs (including online services) that are: designed for overweight or obese children and young people or for their parents, carers or families designed primarily for adults but which accept, or may be used by, children and young people provided by the public, private or voluntary sector, in the community or in (or via) primary care organisations. Some were small local schemes, others were available on a regional or national basis – such as those listed in the Department of Health's 'Child weight management programme and training providers framework' (Cross Government Obesity Unit 2009). # Financial consequences of childhood obesity Unless obesity is addressed in childhood, most of the financial consequences are likely to be incurred when treating and managing the obesity-associated diseases or conditions (comorbidities) that arise in adulthood. (These include type 2 diabetes, coronary heart disease and some cancers.)# Considerations # Introduction The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations, as follows. Please note: this section does not contain the recommendations. # The evidence The PDG highlighted the need for greater consistency in reported outcome measures and the time points at which they are recorded, to allow for better comparison of the effectiveness and cost effectiveness of interventions. In many studies, there was a lack of detail on the content of the intervention. This made it difficult to compare different approaches or methods and to determine which elements of 'multi-component' interventions contribute to overall effectiveness. Review 1 included studies from the UK, Western Europe, North America, Australia and New Zealand, because the potential applicability of the findings to the UK was considered to be high. The UK evidence included some lower quality, relatively small, uncontrolled studies. However, such studies were valuable in indicating a general 'direction of travel' in terms of the effectiveness of interventions. Limited data were available for children and young people of specific ages. No studies were found in which children younger than 6 were specifically targeted. Although several programmes had a lower age limit (of between 3 and 5 years), none of the studies provided data separately for this age group. Most programmes aimed at very young children appeared to be aimed at all children, rather than those who were overweight or obese. Study participants were predominantly female. Only 2 studies included more boys than girls and, in most cases, there were at least 20% more girls than boys. However, the PDG noted from expert testimony and experience that, in the 'real world', there tends to be a more even mix of boys and girls among programme participants. Nevertheless, the importance of identifying barriers to involving more boys in intervention studies was noted. There were limited and contradictory data on the impact of lifestyle weight management programmes according to socioeconomic group. In most studies, children and young people were from middle-income families. In the 2 UK studies that did have significant numbers from low-income families, no association was found between outcomes and socioeconomic group. However, a US study found that participation led to greater reductions in body mass index (BMI) z scores among those from higher income families. No data were available on the effectiveness or cost effectiveness of lifestyle weight management services for children and young people with special needs. Nor were any data available on the barriers and facilitators to implementing lifestyle weight management services for this group. The PDG noted this gap in the evidence base and has made recommendations for research in this area. Review 1 considered the reported follow-up data for participants in the included studies. It did not consider any secondary prevention or weight maintenance programmes for children or young people who have previously been obese or overweight. There is also a lack of information on the views of those who do not take part or who drop out early from a lifestyle weight management programme. This is an important omission, because there is an association between BMI adjusted for age and sex (BMI z score) at baseline and drop-out rates. It is possible, therefore, that review 2 may not have fully captured the views of children and young people with higher BMI scores. Review 2 focused on the views of children, young people and their families about weight management programmes. It did not capture their views or experiences of the referral process. # Family-based approach There is strong evidence from review 1 to suggest that targeting both parents and children, or whole families, is effective in reducing BMI z scores by the end the programme. In addition, the evidence on interventions involving families showed no negative effects on wellbeing and, in some cases, showed positive effects. A report commissioned for the PDG identified that it is more common for adolescents to attend programmes alone, or for parental attendance to be optional. That is despite evidence showing that parental or family involvement contributes to success in weight management. The recommendations for a whole-family approach therefore apply to older children and adolescents. However, the PDG acknowledged that flexibility is important as young people and older children become more independent, because some young people and some older children may prefer to attend separate sessions from their parents or carers. (This might be on a group or an individual basis.) Many overweight and obese children and young people may have, or come from a family with, a history of failed attempts to manage their weight. The Group noted the importance of exploring this shared history, along with family attitudes towards diet, physical activity and the amount of time spent being sedentary. Efforts to manage a child or young person's weight are not always supported, and are sometimes undermined, by members of the wider family. This is possibly because of a lack of understanding of the aims of lifestyle weight management programmes and the importance of managing the weight of obese or overweight children and young people. The PDG was aware that some family members may not attend the programme with the child or young person. (This may be true for non-resident parents, step-parents and grandparents.) With this in mind, the Group noted the importance of gaining the wider family's understanding and support and has made a recommendation to this effect. # Tailoring programmes The PDG noted that lifestyle weight management programmes were often 'bought in' by commissioners and were rarely tailored to meet local needs. As a result, the recommendations highlight the importance of assessing local needs and ensuring programmes are tailored to address those needs. Because of a dearth of evidence, the PDG has been unable to make age-specific recommendations. However, the Group does stress the importance of tailoring programmes according to age and stage of development. The PDG did not make specific recommendations for children and young people with severe obesity. However, the Group was aware that some of them may attend a lifestyle weight management programme. For example, families may self-refer to these services, or they may be referred by health professionals following treatment at a specialist obesity service. Or they may attend a lifestyle weight management service (to support lifestyle changes) and also receive individual specialist support. The PDG highlighted the importance of developing an individually tailored plan that includes appropriate goals for all children and young people, including those from this group. # Determining whether a child is overweight or obese The PDG recognised that although BMI is a practical estimate of overweight in children and young people, it is not a direct measure of adiposity. It acknowledged that it may be less accurate and need to be interpreted with caution in children and young people who are muscular or in those with earlier than average pubertal development. In addition, the Group was aware that there is evidence that adults from black and minority ethnic groups are at risk of obesity-associated conditions and diseases (comorbidities), such as type 2 diabetes, at a lower BMI than the white European population. However, it was beyond the remit of this guidance to assess whether the same applies to children and young people. # Referring on to specialist services The PDG recognised that complex obesity (in which someone who is obese also has obesity-associated diseases or conditions ) can occur at any level of obesity (although this is more likely, as BMI increases). That is why the Group recommended the use of a comorbidity assessment tool. The aim was to ensure that, if necessary, children and young people are referred on for specialist support. However, the PDG was unable to identify an appropriate assessment tool for use by lifestyle weight management services. The Group viewed development of such a tool as a priority and made a research recommendation to this effect. The PDG heard from expert testimony that overweight and obese children are often victimised and that this can lead to depression. The Group also heard that emotional and behavioural problems and impaired quality of life have been observed in obese pre-school children. Behaviours such as binge eating are also more likely in obese adolescents than in adolescents of a healthy weight. Treatment of these conditions was beyond the scope of this guidance. However, the PDG noted the importance of ensuring that any such potential issues are identified and that the child or young person is referred on for specialist support if necessary. # Children and young people with special needs The PDG was aware that some children and young people with disabilities, learning difficulties or other special needs may have particular problems managing their weight. This may be because of their underlying condition, or because their physical activity is limited. The PDG also recognised the importance of ensuring they have access to appropriate services to help them manage their weight. In addition, it acknowledged the statutory duty upon public bodies to look at ways of ensuring equal access to services. The PDG noted that many overweight or obese children and young people with more complex needs will need the support of a specialist obesity service or other specialist services to help manage their weight. However, members also noted that some providers have developed lifestyle weight management programmes for children and young people with mild to moderate learning difficulties or for disabled children. Others have adapted existing programmes and trained staff to accommodate their needs. The PDG welcomed such approaches and encouraged evaluation of them. # Encouraging adherence to programmes The PDG was particularly concerned about the practical issues that may prevent potential participants from taking part in, or continuing to attend, a lifestyle weight management programme. This includes the location and type of venue where programmes are delivered and participants' need to accommodate other family commitments. Evidence from review 2 highlighted how important it is to ensure the family and the child or young person recognise and accept that they are overweight or obese. Conversely, a lack of recognition or denial that the child or young person is overweight or obese can hinder uptake and adherence to a lifestyle weight management programme. The recommendations reflect this finding, including a recommendation for further research as to how this may be best achieved. The PDG debated whether lifestyle weight management services should be offered to groups of families or to families on an individual basis. Evidence shows that both approaches are effective in reducing BMI adjusted for age and sex (BMI z scores). The PDG noted from expert testimony that group sessions can provide a good opportunity to see how others with similar goals have succeeded. They also provide peer support to build the child or young person's self-belief that they, too, can succeed. The PDG acknowledged that individual sessions were likely to be more resource intensive. However, the Group was aware that some children and young people may not feel able to discuss or address their weight in a group setting. For this reason, the PDG recommended flexibility as necessary. # Behaviour-change techniques The PDG heard from expert testimony that behaviour-change techniques are effective in lifestyle weight management programmes for children and young people and are widely used. (This includes self-monitoring, stimulus control and goal-setting.) A 'package' of these techniques is usually included in the programme, because it is not known how much each element contributes to effectiveness. The PDG has therefore made a recommendation for more research in this area. The PDG heard that aspects of cognitive behavioural therapy are used by some lifestyle weight management programmes, usually with older children or adolescents. This therapy focuses on understanding unhelpful or inaccurate thought processes, then changing behaviour to encourage new ways of thinking. It is usually delivered by staff who have received specialist training. However, current evidence does not allow conclusions to be drawn on its effectiveness. # Increasing uptake of programmes Review 2 identified a lack of awareness of the availability of lifestyle weight management programmes among health professionals. In addition, the former Childhood Obesity National Support Team found that programmes frequently ran below capacity. The PDG was therefore aware of the need to increase both self-referrals and referrals by health professionals – including the need to agree clear referral pathways. The PDG identified a wide range of 'actors' who could raise awareness of lifestyle weight management programmes. In particular, the PDG noted that staff conducting the National Child Measurement Programme were in an ideal position to direct parents and carers to these programmes for advice and support. The key aims of the Healthy Child Programme: pregnancy and the first 5 years of life include early recognition of risk factors for obesity, prevention and early intervention. The Programme's approach is consistent with this guidance. For example, it recommends working in partnership with the family, setting achievable goals and exploring earlier life experiences in relation to obesity. The PDG recognised the important contribution that staff delivering the Healthy Child Programme could make in raising awareness of, and formally referring children and their families to, lifestyle weight management programmes. It also recognised their potential role in providing ongoing support. # Training and support Review 2 and the former National Support Team for Childhood Obesity findings both highlighted the need to train lifestyle weight management programme staff and health professionals referring people to the programmes. The PDG noted that staff may lack the confidence and skills to raise the issue of weight management with potential participants and identified this as a training need. In addition, the National Support Team for Childhood Obesity found that a lack of confidence to deliver weight management interventions was sometimes linked to the programme staffs' own unhealthy weight. The PDG noted the need to offer these staff support to manage their weight. # Sustaining behaviour changes The PDG did not make recommendations regarding the optimal length of programmes. A meta-analysis conducted for review 1 showed that the duration of programmes was associated with improved BMI z scores in programmes lasting between 8 and 24 months. However, once the programme was completed, the effect disappeared over time and was non-significant at 6 months after completion. The PDG therefore stressed the importance of ongoing support and follow-up once programmes are completed. The PDG has recommended that participants completing programmes are given information about relevant local support services. However, the Group has not made recommendations regarding those services because this is beyond the scope of the guidance. It noted that a number of pieces of NICE guidance have made recommendations in this area (see NICE's topic page on obesity). The PDG noted that many lifestyle weight management services for children and young people were often commissioned in isolation and in response to a short-term funding opportunity. The Group highlighted the importance of commissioning these services as part of a wider, more sustainable approach to preventing and treating obesity. This approach is reflected in this guidance. It is also addressed in detail by NICE's guideline on obesity: working with local communities. # Monitoring, evaluation and setting outcome measures The PDG noted there had been little robust monitoring and evaluation of lifestyle weight management programmes. The Group also noted that new local authority responsibilities for public health may be an opportunity to embed monitoring requirements into service specifications and contracts. Periodic evaluations into planning and commissioning strategies may also be possible. The PDG debated at length the choice of suitable outcome measures for lifestyle weight management programmes for children and young people. The Group agreed that the primary goal, in the longer term, is to reduce BMI for age and sex (BMI z scores). However, it was aware that, in practice, most programmes run for only around 8 to 12 weeks – and substantial reductions in that time may be difficult to achieve. A report commissioned for the PDG identified unrealistic outcome measures as a barrier to providers working effectively with commissioners. Nevertheless, the PDG was aware that a reduction in BMI for age and sex is sometimes used by commissioners as a key performance indicator. Financial penalties may, in some cases, be attached to failure of providers to achieve this outcome. The PDG recognised that maintaining weight (and preventing further weight gain) is the short-term aim of many lifestyle weight management programmes for children and young people. The rationale is that if the child maintains their weight as they grow in height over time, their BMI will be reduced. The PDG acknowledged that young people who are no longer growing taller will ultimately need to lose weight to improve their BMI. However, the Group also recognised that this takes time. Members considered that an appropriate short-term aim may be to avoid further weight gain while the young person acquires the skills and knowledge they need to make behavioural changes. Over time, as the changes to their behaviour become established, there should be a positive effect on their BMI. The PDG felt it was very important to sustain any positive outcomes beyond the duration of a lifestyle weight management programme. Therefore, the Group placed an emphasis on sustaining long-term change. The PDG recognised the importance of retaining participants in the programme. This is based on evidence that the greater the proportion of total programme sessions a child or young person attends, the more likely they are to succeed. This is reflected in a number of recommendations. # Economic considerations The economic model defines a child or young person as overweight if their BMI (adjusted for age and sex) lies between the 85th and 95th centiles of the UK 1990 centile chart. These centiles correspond to BMI z scores of 1 and 2 respectively for the UK 1990 centile chart. They are used for defining whether someone is overweight or obese in population studies and for monitoring populations, rather than for the clinical management of individuals. In the model, a child or young person whose BMI (adjusted for age and sex) lies between the 95th and the 99.5th centile is defined as obese; children and young people above the 99.5th centile are described as 'morbidly obese'. How the average weight of children of a particular age and sex changes over time can be referred to as their 'weight trajectory'. All other factors being equal, the BMI z score of this group of children will be maintained. So the aim of programmes for overweight or obese children and young people is to help them make changes so that they move to a lower weight trajectory. This might be achieved by: losing weight; by maintaining weight as a child grows in height; or by gaining less weight than would have been expected. In all cases, they will weigh less than would have otherwise been expected over the same time period. The economic model estimated that interventions costing £100 per person would usually be cost effective from a public sector perspective. This would be the case if a group of overweight or obese children could be moved to a lower average weight trajectory and this was maintained throughout life. (This is true for a weight loss of as little as 0.5%.) Interventions that permanently lower weight trajectory by an average 3% are estimated to be cost effective, if their average cost is less than £1000 per child. The cost effectiveness of interventions for children and young people who are morbidly obese, as defined by the model, was unclear. The PDG concluded that interventions for children who are morbidly obese would need to lower their BMI z score considerably to be worth doing. There was little evidence on whether children and young people can maintain for life the lower weight trajectory they may achieve during a lifestyle weight management programme. If they do, the economic model concludes that interventions that cause very small average decreases in weight trajectory will be worth undertaking. However, if the weight is regained quickly and they revert to their previous weight trajectory, then the intervention is estimated not to be cost effective. For example, the model looked at an intervention for overweight boys or girls aged from 12 to 17 that cost an average £437 per person. To be cost effective, their average weight trajectory, following an initial average weight loss of 5% of body weight, must lie below what it would have been without the intervention for at least 11 years. If the weight of each participant in a lifestyle weight management programme is reduced by an average of 0.5% – and the post-intervention weight trajectory is maintained for life – the model estimates that interventions costing up to about £500 per child will be cost effective for both girls and boys and for each category of overweight and obesity. Interventions costing £2000 per child are estimated to need weight losses of 3 to 5%, maintained for life, to be cost effective for children who are borderline overweight, but of 2% (maintained for life) for children who are obese or morbidly obese. The model assumes a discount rate of 3.5% per year for both costs and health benefits. Most of the health benefits of providing a lifestyle weight management programme for overweight and obese children and young people accrue in the later stages of life. As a result of discounting, these benefits are given a relatively low value compared with a health benefit that is immediate. Reducing the discount rate to 1.5% per year has the effect of increasing the present value of future health benefits considerably, and thus improves cost effectiveness.# Recommendations for research The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects. # Recommendation 1 Research studies and trials ## Who should take action? Research councils, commissioners and funders. ## What action should they take? Research studies and trials of lifestyle weight management programmes for children and young people who are obese or overweight should: Standardise outcome measures to assess effectiveness. Outcomes should be reported on an 'intention to treat' basis (as opposed to reporting outcomes for programme completers only). They should include: changes in body mass index (BMI) z score, as the primary outcome measure factors that affect weight (matching these to the intervention objectives) for example, measures of self-efficacy, changes in diet, physical activity and time spent being sedentary and measures of wellbeing. Standardise the time points at which outcome measures are reported and followed up. They should include, as a minimum: at baseline, completion of the intervention and at 6 months and at 1 year after completing the intervention. Report in detail the components of the intervention. This should include: what is done, to whom, by whom, in which setting, and when and how? Include an appropriate comparator group and report the components above. If a randomised controlled trial is not possible, alternative research designs should be considered. Report attrition (drop-out) rates, follow up non-completers and investigate the causes of attrition. Also should investigate the causes of low uptake and how these might be addressed. Be sufficiently powered to detect effects. If possible, use only standardised validated tools (appropriate for the study sample) to collect data, for example, a validated food frequency questionnaire to investigate dietary intake. If validated tools for secondary measures do not exist, a tool to measure the outcome (for example, physical activity) should be developed as part of the study. Include the collection and analysis of qualitative data to allow a process evaluation of the intervention. These data should include the referral process and experiences of both programme staff and participants. Include the collection of cost data to allow cost effectiveness to be evaluated. Report any unexpected effects or outcomes. # Recommendation 2 Longer-term programme evaluation ## Who should take action? Research councils, commissioners and funders. ## What action should they take? Consider funding longer term research studies and trials of lifestyle weight management programmes for children and young people who are obese or overweight. Ideally studies should last between 5 and 10 years. # Recommendation 3 Barriers and facilitators ## Who should take action? Research councils, commissioners and funders. Researchers and investigators. ## What action should they take? Determine any variation in the barriers to, and facilitators for, participating in lifestyle weight management programmes for overweight and obese children and young people and their families (including beliefs about obesity). Include: ethnicity and cultural aspects socioeconomic group gender (boys in particular) age. Ask parents, carers and families of children younger than 6 what factors encourage or discourage overweight and obese children to participate (or not) in lifestyle weight management programmes. Determine how these might be addressed. Investigate the barriers to, and facilitators for, implementing lifestyle weight management services for overweight and obese children and young people with special needs. Determine how these might be addressed. # Recommendation 4 Weight management programmes ## Who should take action? Research councils, commissioners and funders. Researchers and investigators. ## What action should they take? Consider which components of multi-component interventions determine effectiveness and cost effectiveness. Investigate effective and cost-effective approaches to lifestyle weight management for children younger than 6 years. Investigate effective and cost-effective approaches to lifestyle weight management for children and young people with special needs. How can their needs, and the needs of their families, best be met? What training would staff need to deliver such interventions? Determine the long-term effectiveness of programmes. Do children and young people who have lost or maintained their weight in a lifestyle weight management programme maintain this in the long term and, if so, for how long? What programme characteristics facilitate longer term effectiveness? Examine how best to communicate the individual measures of the National Child Measurement Programme to parents and carers to ensure they take action, as needed, without causing distress. Investigate how to encourage parents and carers to take responsibility for their child's weight management. This includes how best to help parents, carers and families recognise when children and young people are overweight or obese. It also includes how to encourage parents and carers to participate in programmes. Investigate what impact parents and carers have on the outcomes of programmes. Examine who is best placed to deliver lifestyle weight management programmes (including lay people) for children and young people and what their training needs are. Investigate effective and appropriate ways of getting children and young people involved in lifestyle weight management programmes. This might include use of new technology such as texting or phone apps. Investigate and develop a comorbidity assessment tool for use by lifestyle weight management services, to ensure that, if necessary, children and young people are referred for specialist support. More detail identified during development of this guidance is provided in Gaps in the evidence.# Glossary # Behaviour-change techniques Behaviour-change techniques are techniques aimed at changing the way someone acts (and so, logically, their thinking patterns). In this case, the changes relate to dietary intake and eating behaviour, physical activity and sedentary behaviour. # Body mass index (BMI) z score BMI z score is a measure of how many standard deviations a child or young person's BMI is above or below the average BMI for their age and gender. (This is based on a reference population known as a child growth reference.) For instance, a z score of 1.5 indicates that a child is 1.5 standard deviations above the average value, and a z score of -1.5 indicates a child is 1.5 standard deviations below the average value. The advantage of using BMI z scores, instead of BMI, is that it allows direct comparison of BMI (and any changes in BMI) across different ages and by gender. This term is sometimes used interchangeably with 'BMI standard deviation score' (BMI SDS). See the National Obesity Observatory's simple guide to classifying body mass index in children. Care is needed when interpreting BMI z scores using the UK 1990 centile charts for black, Asian and other minority ethnic groups. There is evidence to suggest that adults from these groups are at risk of obesity-associated conditions and diseases at a lower BMI than the white population. See NICE's guideline on obesity: identification, assessment and management. However, there are no growth reference charts for children from minority ethnic groups. (For more details on the differences in BMI thresholds as a trigger for disease among children in these groups, see the National Obesity Observatory's report on obesity and ethnicity.) # Body mass index (BMI) Body mass index is defined as a person's weight in kilograms divided by the square of their height in metres and is reported in units of kg/m2. Specific cut-off points are used to assess whether a person is a healthy weight, underweight, overweight or obese. For children and young people these are related to age and gender. # Child and adolescent mental health services (CAMHS) Child and adolescent mental health services are specialist mental health services for children and young people. # Clinical commissioning groups Clinical commissioning groups (CCGs) are responsible for commissioning a range of healthcare services for children and adults. This includes specialist obesity services (sometimes called tier 3 services). The groups do not directly commission lifestyle weight management services (sometimes called tier 2 services). Rather, they work with local authorities to coordinate and integrate planning and commissioning through the health and wellbeing board. # Comorbidities Comorbidities are diseases or conditions that someone has in addition to the health problem being studied or treated. Some comorbidities, such as type 2 diabetes, are associated with being overweight or obese, because the risk of developing them increases with an increasing BMI. # Complex obesity Complex obesity occurs when someone who is obese has additional and related diseases or conditions, for example, type 2 diabetes. It can also occur when obesity results from an underlying condition, for example, an endocrine disease or condition, or when it is associated with various syndromes (such as Prader-Willi syndrome). Complex obesity can occur regardless how obese the person is, although it is more likely as BMI increases. # Evaluation Evaluation involves assessing whether an intervention is meeting its objectives. This might include outcomes (for example, effectiveness in terms of BMI z score reduction or value for money). It might also include evaluation of processes (for example, how successful recruitment is or how acceptable the intervention is to participants). # Health and wellbeing boards Health and wellbeing boards are based in upper tier and unitary local authorities. They aim to improve health and care services and the health and wellbeing of local people. They bring together key commissioners in the locality, including representatives of clinical commissioning groups, public health, children's services and adult social services. They include at least 1 elected councillor and a representative of HealthWatch. The board develops a health and wellbeing strategy for the local area. This is based on an assessment of local needs, including a joint strategic needs assessment. # Joint strategic needs assessments (JSNAs) Joint strategic needs assessments (JSNAs) identify the current and future health needs of a local population. They are used as the basis for the priorities and targets set. # Lifestyle weight management programmes In this guidance, lifestyle weight management programmes refer to programmes that focus on diet, physical activity, behaviour change or any combination of these elements. # Lifestyle weight management services In this guidance, lifestyle weight management services (sometimes called tier 2 services) refer to services that help people in a particular geographical location who are overweight or obese. The service can be made up of 1 or more lifestyle weight management programmes. The programmes are usually based in the community and may be run by the public, private or voluntary sector. # Local authority commissioners Local authorities commission some public health services for children and young people aged 5 to 19 years. They have a mandatory responsibility to deliver the National Child Measurement Programme. They also commission non-mandatory services such as school nursing and community-based weight management services. # Monitoring Monitoring involves routine collection, analysis and reporting of a set of data to assess the performance of a weight management programme according to the service specification and intended health outcomes. # National Child Measurement Programme The National Child Measurement Programme (NCMP) measures the weight and height of children in reception class (aged 4 to 5) and Year 6 (aged 10 to 11). The aim is to assess the prevalence of obesity and overweight among children of primary school age, by local authority area. These data can be used at a national level to support local public health initiatives and inform local services for children. # NHS England NHS England commissions primary care, clinical and specialised services. It also commissions public health services for children aged 0 to 5 years (including health visiting and much of the Healthy Child Programme). In 2015, the organisation's public health services transfer to local authorities. # Obesity care or weight management pathway An obesity care or weight management pathway represents the various routes through local services that an individual child or young person might follow to help them manage their weight. A comprehensive obesity care or weight management pathway spans both prevention and treatment, offering services at different levels or 'tiers'. Children and young people may move between these services. In adult obesity care pathways, there may also be a further tier focusing on surgical treatment (sometimes called tier 4 services). Surgery is recommended for children and young people only in exceptional circumstances, see NICE's guideline on obesity prevention. # Physical activity Physical activity includes the full range of human movement. It includes everyday activities such as walking or cycling for everyday journeys, active play, work-related activity, active recreation (such as working out in a gym), dancing, gardening or playing active games, as well as organised and competitive sport. # Positive parenting skills training Positive parenting skills training is training for parents and carers that aims to improve children and young peoples' behaviour. It fosters effective boundary setting and the need to reward and praise children in a way that promotes positive relationships and self-esteem. # Providers of lifestyle weight management programmes Providers of lifestyle weight management programmes are private, public or voluntary sector organisations offering lifestyle weight management services in the community or in (or via) primary care settings. # Public Health England Public Health England is an executive agency of the Department of Health. It provides advice and expertise to local authorities, NHS England and clinical commissioning groups on the commissioning of public health services. # Rolling programmes Rolling programmes are lifestyle weight management programmes that run on a continuous basis. Participants can start and end the programme at different points, covering the same material over the same number of weeks or months, but not necessarily in the same order. An advantage is that participants referred part way through a programme cycle do not have to wait for it to be completed and a new one to start before they join. # Sedentary behaviour Sedentary behaviour describes activities that do not increase energy expenditure much above resting levels. Sedentary activities include sitting, lying down and sleeping. Associated activities, such as watching television, are also sedentary. # Specialist obesity services In this guidance, specialist obesity services (sometimes called tier 3 services) usually refer to clinical treatments provided by specialist services. This may include the use of drugs. These services could be for children or young people with severe or complex obesity, or with other special needs. # Stimulus control Stimulus control relates to the way someone's behaviour changes as a result of a particular trigger. For example, having the television on can encourage someone to sit and watch it (that is, adopt sedentary behaviour); turning it off could encourage them to do something that is more physically active. Or if a person trying to manage their weight finds it hard to resist high fat or sugary snacks, family members could be asked not to eat those snacks around that person. # Universal obesity prevention services In this guidance, universal obesity prevention services (sometimes called tier 1 services) refer to activities to help prevent everyone, regardless of their weight, from becoming overweight or obese. These universal services help raise awareness of the importance of maintaining a healthy weight. They also develop and promote services, facilities and policies that enable children, young people and their families to eat more healthily and be more physically active. For example, by providing walking and cycling routes and safe areas for active play, or by working with caterers in schools, colleges and early years organisations to improve the food choices on offer. # UK 1990 centile charts UK 1990 centile charts, also referred to as the British 1990 growth reference (UK90), are charts used for children aged 4 years and older to determine whether their BMI is appropriate for their age and gender. See the National Obesity Observatory's simple guide to classifying body mass index in children.# References Aicken C, Arai L, Roberts H (2008) Schemes to promote healthy weight among obese and overweight children in England. London: EPPI Centre, Social Science Research Unit Bromfield PV (2009) Childhood obesity: psychosocial outcomes and the role of weight bias and stigma. Educational Psychology in Practice 25: 193–209 Chief Medical Officer (2008) The Chief Medical Officer's report 2007. Under their skins: tackling the health of the teenage nation. London: Department of Health Craig L, Love J, Ratcliffe B et al. (2008) Overweight and cardiovascular risk factors in 4–18 year olds. Obesity Facts 1: 237–42 Cross Government Obesity Unit (2009) Healthy weight, healthy lives: child weight management programme and training providers network. London: Department of Health Department of Health (2011) Healthy lives, healthy people: a call to action on obesity in England. London: Department of Health Department of Health (2009) Healthy child programme: from 5 to 19 years old. London: Department of Health Diabetes UK (2011) Diabetes in the UK 2011/2012: key statistics on diabetes. Figueroa-Munoz JI, Chinn S, Rona RJ et al. (2001) Association between obesity and asthma in 4–11 year old children in the UK. Thorax 56: 133–7 Foresight (2007) Tackling obesities: future choices. London: Government Office for Science Griffiths LJ, Parsons TJ, Hill AJ (2010) Self-esteem and quality of life in obese children and adolescents: a systematic review. International Journal of Pediatric Obesity 5: 282–304 Griffiths LJ, Wolke D, Page AS et al. (2006) Obesity and bullying: different effects for boys and girls. Archives of Disease in Childhood 91: 121–5 Koebnick C, Smith N, Black MH et al. (2012) Paediatric obesity and gallstone disease. Journal of Paediatric Gastroenterology and Nutrition 55: 328–33 Logue J, Sattar N (2011) Childhood obesity: a ticking time bomb for cardiovascular disease? Nature 90: 174–8 Lowry KW, Sallinen, BJ, Janicke, DM (2007) The effects of weight management programs on self-esteem in pediatric overweight populations. Journal of Pediatric Psychology 32: 1179–95 Murray AW, Wilson NIL, et al. (2008) Changing incidence of slipped capital femoral epiphysis. A relationship with obesity? The Journal of Bone and Joint Surgery 90-B: 92–4 NHS Information Centre (2013) Statistics on obesity, physical activity and diet: England. London: The Health and Social Care Information Centre NHS Information Centre (2012) National child measurement programme: England, 2011/12 school year. London: Department of Health Perez-Pastor EM, Metcalf BS, Hosking J et al. (2009) Assortative weight gain in mother-daughter and father-son pairs: an emerging source of childhood obesity. Longitudinal study of trios (EarlyBird 43). International Journal of Obesity 33: 727–35 Sjoberg RL, Nilsson KW, Leppert J (2005) Obesity, shame, and depression in school-aged children: A population based study. Pediatrics 116: e389–92 Taylor ED, Theim KR, Mirch MC et al. (2006) Orthopedic complications of overweight in children and adolescence. Pediatrics 117: 2167–74 Wei C, Ford A, Hunt L et al. (2011) Abnormal liver function in children with metabolic syndrome from a UK based obesity clinic. Archives of Disease in Childhood 96: 1003–7# Summary of the methods used to develop this guidance # Introduction The reviews, commissioned report and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations. All supporting documents are listed in About this guidance. # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were: How effective and cost effective are lifestyle weight management programmes in helping overweight or obese children and young people to achieve and maintain a healthy weight? What are the essential components of an effective and cost-effective weight management programme for overweight and obese children and young people? The subsidiary questions were: . How does effectiveness and cost effectiveness vary for different population groups? (Examples may include children and young people from different black and minority ethnic groups, from low-income groups, of different ages or genders, or with special needs.) . What are the most effective and cost-effective ways of addressing and sustaining behavioural change among overweight and obese children and young people using community-based weight management programmes? . How does the inclusion of parents, carers and the wider family impact on the effectiveness of community-based weight management programmes for children and young people? . What barriers and facilitators affect the delivery of effective weight management programmes for children and young people and how do they vary for different population groups? . What are the views, perceptions and beliefs of the children, young people and their families who use weight management services? . What are the views, perceptions and beliefs of the staff responsible for commissioning and delivering weight management services to children and young people? . How can more overweight and obese children and young people be encouraged to join, and adhere to, lifestyle weight management programmes? These questions were made more specific for each evidence review. # Reviewing the evidence ## Effectiveness reviews One review of effectiveness and cost effectiveness was conducted (Review 1). A number of databases were searched in May 2012 for relevant studies published in English from January 2000. See the review for details of the databases searched. In addition, randomised controlled trials (RCTs), economic evaluations and views studies published between 1990 and 1999 were identified and included using 'snowballing' methods. (Systematic reviews, reference list checking and citation tracking were 'unpicked' from the Scopus and Science Citation Index databases.) NICE also issued a call for evidence from registered stakeholders in May 2012. Studies were included in the effectiveness and cost-effectiveness review if they: covered children and young people aged below 18 years who were overweight or obese, or their parents, carers and families considered lifestyle weight management programmes for obese and overweight children and young people that focus on diet, physical activity or behaviour change, or any combination of these factors measured changes in weight, diet, physical activity, wellbeing or satisfaction with the service were carried out in the UK (any study design) were RCTs and quasi-RCTs (randomisation method unclear) of 100 or more participants from Australia, Canada, New Zealand, the US and other western European countries reported health economic outcomes. Studies were excluded if they: focused on young women under 18 who were pregnant were RCTs involving a population of less than 40 focused on clinical treatment of obesity. See evidence review 1: effectiveness and cost effectiveness of lifestyle weight management services for children and young people. ## Other reviews One review of barriers and facilitators to implementing lifestyle weight management programmes for children and young people was conducted (review 2). The same databases and websites were searched as for review 1. ## Selection criteria Studies were included in the review if they: considered lifestyle weight management programmes for obese and overweight children and young people that focused on diet, physical activity or behaviour change, or any combination of these factors were qualitative, survey and other observational studies of the barriers and facilitators to delivering such interventions or the views, perceptions and beliefs of those using and delivering them were conducted in Australia, Canada, New Zealand, the US or western Europe Studies were excluded if they: focused on young women under 18 who were pregnant focused on clinical treatment of obesity reported intrapersonal barriers and facilitators to losing or managing weight not associated with the participation in, or delivery of, weight management programmes were quantitative studies that did not measure attitudes (for example, correlation studies). See evidence review 2: the barriers and facilitators to implementing lifestyle weight management programmes for children and young people. ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in Methods for the development of NICE public health guidance. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. − Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. The evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable). ## Summarising the evidence and making evidence statements The review data were summarised in evidence tables (see full reviews). The findings from the reviews and expert reports were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see About this guidance). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope. # Commissioned report A short report was commissioned on practical and process issues related to the provision of lifestyle weight management services for children and young people. It synthesised responses to a questionnaire submitted by service providers. See the commissioned report on practical and process issues in the provision of lifestyle weight management services for children and young people. # Cost effectiveness The existing cost-effectiveness evidence was reviewed as part of evidence review 1: effectiveness and cost effectiveness of lifestyle weight management services for children and young people. In addition, an economic model was constructed. The results are reported in: Managing overweight and obesity among children: report on economic modelling and cost consequence analysis. This was produced by M Brown, T Marsh, K Rtveladze (all from the UK Health Forum, formerly the National Heart Forum) and R Fordham, M Suhrcke, D Turner, R Little and O Filani (all from the University of East Anglia). # How the PDG formulated the recommendations At its meetings in July, October and December 2012 and January, February and July 2013, the Programme Development Group (PDG) considered the evidence, expert reports and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guidance. The PDG developed recommendations through informal consensus, based on the following criteria: Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. Where possible, recommendations were linked to an evidence statement(s) (see the evidence section for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).# The evidence This section lists the evidence statements from 2 reviews provided by external contractors (see the section on what evidence is the guidance based on?) and links them to the relevant recommendations. (See the section on summary of the methods used to develop this guidance for the key to quality assessments.) This section also lists 6 expert papers and 1 report commissioned by the Programme Development Group (PDG) and their links to the recommendations and sets out a brief summary of findings from the economic analysis. The evidence statements are short summaries of evidence, in a review. Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document. Evidence statement number 1.2.3 indicates that the linked statement is numbered 2.3 in review 1. Evidence statement number 2.1.1 indicates that the linked statement is numbered 1.1 in review 2. EP1 indicates that expert paper 1 is linked to a recommendation and CR1 indicates that the commissioned report is linked to a recommendation. See the full reviews, expert reports, commissioned report and economic analysis. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: evidence statements 1.1.10, 1.1.16, 1.1.33, 1.1.34, 1.1.35, 1.1.36, 1.2.3; EP1 Recommendation 2: evidence statements 2.1.40, 2.1.41, 2.1.42; EP1, EP2, EP4, CR1; IDE. Recommendation 3: evidence statements 1.1.10, 1.1.16, 1.1.33, 1.1.34, 1.2.2, 1.2.3, 1.4.1, 1.4.2, 2.1.13, 2.1.14, 2.1.15, 2.1.16, 2.1.17, 2.1.23, 2.1.25, 2.1.26, 2.1.27, 2.1.32, 2.1.33, 2.1.34; EP3, EP5, EP6 Recommendation 4: evidence statements 1.1.14, 1.2.3, 1.4.1, 1.4.2, 2.1.5, 2.1.8, 2.1.10, 2.1.13, 2.1.15, 2.1.25, 2.1.26, 2.1.27, 2.1.31, 2.1.33, 2.2.4, 2.2.5; EP3, EP6; IDE Recommendation 5: evidence statements 1.1.10, 1.1.16, 1.2.3, 1.4.3, 2.1.12, 2.1.13, 2.1.15, 2.1.22, 2.1.23, 2.1.24, 2.1.28, 2.1.29, 2.1.30, 2.1.38, 2.1.39, 2.2.4, 2.2.5; EP5, CR1, IDE Recommendation 6: evidence statements 2.1.11, 2.1.18, 2.1.19, 2.1.20, 2.1.32; EP1, CR1; IDE Recommendation 7: evidence statements 2.1.18, 2.1.19; 2.1.20; EP1; IDE Recommendation 8: evidence statements 1.2.7, 1.4.3, 2.1.4, 2.1.7, 2.1.8, 2.1.9, 2.1.10, 2.1.11, 2.1.14, 2.1.16, 2.1.19; EP1, EP3, CR1; IDE Recommendation 9: evidence statements 1.1.33, 1.1.34, 1.4.1, 1.4.2, 1.4.3, 2.1.1, 2.1.2, 2.1.3, 2.1.4, 2.1.34; EP3, CR1; IDE Recommendation 10: evidence statements 1.1.33, 1.1.34, 1.4.1, 1.4.2, 2.1.34, 2.1.35, 2.1.36, 2.1.37; CR1; IDE Recommendation 11: evidence statements 2.1.8, 2.1.10, 2.1.11, 2.1.38, 2.1.39, 2.1.41, 2.1.42; EP1, EP5, CR1; IDE Recommendation 12: evidence statements 2.1.38, 2.1.39, 2.1.41, 2.1.42; EP1, EP3, EP5, EP6, CR1; IDE Recommendation13: evidence statements 1.2.4, 2.1.8, 2.1.10, 2.1.19; EP1; IDE Recommendation 14: EP1; IDE Recommendation 15: evidence statements 1.4.1, 1.4.2; EP1, EP4, EP5 CR1; IDE # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style. ## Evidence statement 1.1.10 Child and parent/carer interventions – anthropometric outcomes There is strong evidence from 8 studies (3 randomised controlled trials , 2 RCTs, 2 quasi-RCTs and 1 uncontrolled before-after study) that child/adolescent and parent interventions result in significant decreases in body mass index (BMI) z score based on baseline to follow-up within group measures. This evidence is directly applicable because the studies were carried out in community settings in the USA, Australia and the UK. ## Evidence statement 1.1.14 Child and parent/carer interventions – wellbeing outcomes There is strong evidence from 2 (++) RCTs that group-based behaviour-change interventions directed at children/adolescents and parents have significant beneficial effects on some psychosocial outcomes. One (++) RCT showed a group difference at 18 months for body satisfaction (p=0.026) and appearance (p=0.019) although no group differences on other psychosocial outcomes. A second (++) RCT showed group difference at 12 months for scholastic competence (p=0.049), but not other psychosocial outcomes. Two hundred and eight overweight adolescent females aged 12 to 17 received a 5‑month intervention delivered by nutritionists, health educators and clinical psychologists. Dietitians delivered a 2‑year intervention to 151 overweight and obese adolescents (52% female). This evidence is directly applicable because studies were conducted in community settings respectively in the USA, Australia and the UK. ## Evidence statement 1.1.16 Family interventions – anthropometric outcomes There is strong evidence from 18 papers on 17 studies (5 RCTs, 4 RCTs, 1 quasi-RCT, 1 quasi-RCT and 6 UBAs) that, for overweight and obese children and adolescents, whole family interventions whether directed at individual families or group-based result in significant decreases in BMI z score based on baseline to follow-up for within group measures. All but 1 UBA (which focused on diet and physical activity) and 1 quasi-RCT (behaviour change only) assess the effectiveness of multi-component interventions focusing on behaviour change. This evidence is applicable because all studies are community-based, 11 were conducted in the UK, 3 in the USA, 2 in Australia and 1 in Italy. ## Evidence statement 1.1.33 Meta-analyses: child and parent or whole family interventions – anthropometric outcomes A meta-analysis of 8 studies (4 RCTs, 3 RCTs and 1 quasi-RCT) estimated the overall effectiveness of interventions directed at children and parents/carers or whole family versus no or minimal control outcomes immediately post intervention as a significant reduction in BMI standardised mean difference (SMD) of −0.22 (−0.33 to −0.10). This evidence is directly applicable because the studies were conducted in the UK and other similar community-based settings. ## Evidence statement 1.1.34 Meta-analyses: child and parent or whole family interventions – anthropometric outcomes A meta-analysis of 11 studies (7 RCTs; 3 RCTs and 1 quasi-RCT) estimated the overall effectiveness of interventions directed at children and parents/carers or whole family versus no or minimal control outcomes at longer-term follow up (6 months or more) as a non-significant reduction in BMI SMD of −0.01 (−0.11 to 0.08). This evidence is directly applicable because the studies were conducted in the UK or other similar community-based settings. ## Evidence statement 1.1.35 Cost effectiveness Evidence from 7 short-term health economic analyses suggests that lifestyle weight management programmes will result in an increased cost to the NHS in terms of BMI z score gains when compared with routine care in the short term. However, overall small (and in some cases, non-significant) improvements in BMI z scores can be achieved. All studies were applicable in terms of setting and participants, but data from short-term studies are limited in applicability to life-time cost estimates and assessed as partially applicable. Some studies provided cost data only and there was no assessment of their applicability or study limitations. ## Evidence statement 1.1.36 cost effectiveness Three extrapolation models of programmes suggest interventions that lead to even small reductions in BMI can be cost effective in the long term at conventional cost-effectiveness thresholds, provided the short-term effects on BMI, observed in trials, are sustained into adulthood. The evidence from these studies is directly applicable but there are potentially serious limitations to the studies. ## Evidence statement 1.2.2 Parenting skills. There is strong evidence from 2 RCTs (both ) that interventions involving group-based general parenting skills training for parents of overweight and obese children aged 6 to 9 years and 5 to 9 years are effective in improving BMI z scores. Adding intensive lifestyle education to the parenting skills training does not appear to result in significantly greater improvements in BMI z scores, food intake or physical activity measures or parenting outcomes. Both interventions were delivered over 6 months by dietitians. This evidence is directly applicable because the studies were conducted in community settings in Australia. ## Evidence statement 1.2.3 Involvement of family There is strong evidence, post intervention, to suggest that targeting both parents and children (8 studies: 3 RCTs, 2 RCTs, 2 quasi-RCTs and 1 UBA) or whole families (18 papers from 17 studies: 5 RCTs, 4 RCTs, 1 quasi-RCT, 1 quasi-RCT and 6 UBAs) is effective in reducing within group BMI z scores. For those studies with follow up of 6 months or more there were no clear differences. Evidence from child-only interventions (1 RCT, 1 RCT and 1 CBA) and parent-only interventions (2 RCTs, 2 RCTs and 1 cluster RCT) is limited and inconsistent. ## Evidence statement 1.2.4 Referral method There is strong evidence from a meta-analysis of 12 studies, of which 2 studies examined specialist referral, to suggest that interventions that involve specialist medical referral to a programme compared with self, GP, school or a mixture of referral methods show greater improvements in BMI z scores at end of intervention (SMD of −0.41; 95% confidence interval of −0.64 to −0.17). The studies in the meta-analysis were conducted in applicable community settings. ## Evidence statement 1.2.7 Intensity of intervention There is moderate evidence from 1 (−) RCT and 1 (++) RCT that children who attend 75% or more of the high intensity programme sessions offered, showed greater improvements in weight outcomes than those attending fewer sessions. One further ongoing (++) RCT found that following up CBT therapy with telephone or text coaching was not more beneficial to BMI z scores, diet, physical activity and psychosocial outcomes than CBT alone. The studies in both meta-analysis were conducted in community settings in the USA and Australia. ## Evidence statement 1.4.1 Most effective ways of sustaining long-term effects There is inconsistent evidence as to whether the effects of weight management programmes are sustained long term. There is strong evidence from meta-analyses of 18 programmes (10 RCTs , 5 RCTs, 3 quasi-RCTs – 1 , 2 ) with BMI z outcomes, indicating improvements decrease the longer the length of follow-up. The evidence is directly applicable because all studies were conducted in community settings in the UK or other similar countries and are directly applicable. ## Evidence statement 1.4.2 Most effective ways of sustaining long-term effects Considering BMI plus other outcomes, there is inconsistent evidence from 5 (++) RCTs, 1 (+) RCT, 1 (+) quasi-RCT and 1 UBA as to whether the effects of weight management programmes are sustained long term. It is not possible to determine which intervention components resulted in sustained outcomes. The evidence is directly applicable because all studies were conducted in community settings in the UK or other similar countries. ## Evidence statement 1.4.3 Duration of interventions A meta-analysis of 8 studies (4 RCTs, 3 RCTs, 1 RCT) indicated that duration of intervention is associated with improved between-group BMI z outcomes at the end of the intervention for programmes of 8 to 24 months. There were no significant between group differences in BMI z scores associated with studies of a shorter duration. Between-group differences diminished over time and were not significant at 6 months. The evidence is directly applicable as the studies were conducted in the UK and the USA. ## Evidence statement 2.1.1 Facilitator: weight management goals There is evidence from 5 qualitative studies (4 and 1 ) that the desire to lose weight or prevent further weight gain was a motivator for programme users to join and continue attendance at lifestyle weight management programmes. In 8 studies, perceived improvements in children's and/or young people's weight management outcomes were described by programme providers (1 qualitative study) and programme users (1 qualitative, 4 qualitative, and 2 process evaluations). This evidence is directly applicable because the studies were conducted in community-based settings in the UK or other similar countries (USA). ## Evidence statement 2.1.2 Facilitator: health improvement goals Health improvement or prevention of future health problems were described as incentives to joining weight management programmes by children and families in 6 qualitative studies (2 , 3 and 1 ). Providers in 1 (+) qualitative study and programme users in 4 studies (3 process evaluations, 1 qualitative study) perceived health improvements as a consequence of attending weight management programmes. This evidence is directly applicable because studies were conducted in the UK in community-based settings. ## Evidence statement 2.1.3 Facilitator: healthier lifestyle behaviour Weight management programmes were perceived to improve children's lifestyle behaviours, such as healthier diet and increased physical activity, by programme providers in 2 process evaluations, and also by programme users in 5 studies (1 qualitative, 2 qualitative, 1 qualitative and 1 process evaluation). The evidence is directly applicable because the studies were conducted in the UK in community-based settings. ## Evidence statement 2.1.4 Barrier: lack of programme impact on weight management Concerns that programmes were not helping children achieve weight management goals were expressed by providers in 1 (−) qualitative study and by parents in 1 (+) qualitative study. In both studies the weight outcome was described in terms of weight loss, without reference to the wider aims of most weight management programmes to slow further weight gain so that BMI z scores improve as children grow. Also, children in 1 (++) qualitative study stated that weight gain prompted feelings of embarrassment and shame, and led to non-attendance at booked appointments. There were different views between studies and between the participants of the same studies as to whether weight was the most important outcome. Two (+) qualitative studies suggested psychological wellbeing was of equal or greater importance to parents, whereas weight outcomes appeared more important to some children in 2 (+) qualitative studies and to parents in 1 (−) qualitative study. This evidence is directly applicable because the studies were conducted in community settings in the UK and Sweden. ## Evidence statement 2.1.5 Facilitator: psychological wellbeing and social outcomes Improved psychological wellbeing such as confidence and self-esteem, or improved social outcomes such as reduced bullying and making friends, were strong motivators for programme participation among children and their families in 10 studies (2 qualitative, 6 qualitative, and 2 qualitative). Programmes were perceived to be successful in improving these outcomes in 12 studies (2 qualitative, 4 qualitative, 2 qualitative, 4 process evaluations). Two studies suggested that improvements in these outcomes were sufficient to maintain engagement with programmes despite lack of weight management. This evidence is directly applicable because the studies were conducted in community settings in the UK or similar countries (the USA, Sweden, Australia). ## Evidence statement 2.1.7 Facilitator: children's motivation to manage weight High levels of children's motivation to manage weight was reported in 6 qualitative studies (3 , 2 and 1 ) and helped promote participation in weight management programmes. This evidence is directly applicable because the studies were conducted in community settings in the UK or similar countries (the USA, Sweden). ## Evidence statement 2.1.8 Facilitator: awareness and acceptance of children being overweight or obese Children, their families and providers emphasised that awareness and acceptance of children being overweight or obese was a facilitator to programme adherence. This was evidenced in 6 qualitative studies (3 , 2 , 1 ). This evidence is directly applicable because the studies were conducted in community settings in the UK or similar countries (United States, Sweden). ## Evidence statement 2.1.9 Barrier: lack of children's motivation Programme users and providers shared views that children's lack of motivation was a barrier to uptake of lifestyle weight management programmes. This was described in 1 (+) qualitative study and 1 process evaluation. Lack of motivation was also described by programme users and providers as a barrier to programme adherence in 7 studies (1 qualitative, 3 qualitative, 1 cross-sectional, 1 qualitative, and 1 process evaluation). This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Australia, Sweden, Canada, the USA). ## Evidence statement 2.1.10 Barrier: lack of awareness and acceptance of children being overweight or obese Family and provider perspectives in 5 studies (1 qualitative, 2 qualitative, 1 cross-sectional and 1 qualitative study) indicated that some families do not acknowledge or recognise that their child is overweight or obese, which hindered programme uptake and adherence. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Canada, Belgium). ## Evidence statement 2.1.11 Barrier: children's and their parents' apprehension A strong theme identified in 5 qualitative studies (1 , 3 and 1 ) was the anxiety and apprehension described by children and parents about joining weight management programmes. Concerns manifested as general fears of the unknown (for example, anxieties of meeting new people, struggling to make friends or worries of being the largest on the programme). In addition, there were reports in 3 qualitative studies (1 , 2 ) and 1 process evaluation of programme users having negative perceptions of the programme characteristics and eligibility criteria before starting the intervention. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (USA). ## Evidence statement 2.1.12 Barrier: individual and family demands Parents and children described a range of individual and family demands, such as busy lifestyles, homework, work or family commitments. These were indicated as obstacles to programme uptake or adherence in 10 studies (2 qualitative, 3 qualitative, 1 cross-sectional, 1 cross-sectional, 1 qualitative and 2 process evaluations). This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Australia, Canada, Iceland, Belgium.). ## Evidence statement 2.1.13 Facilitator: parental support Both providers and children were reported as believing parental support to be an important facilitator of successful lifestyle weight management interventions. High levels of parental support and their role in children's weight management was described in 5 qualitative studies (1 , 3 , 1 ). A (+) cross-sectional study identified parents' motivation for treatment as a statistically significant predictor of programme completion. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (the USA, Belgium). ## Evidence statement 2.1.14 Facilitator: parental motivation Parental motivation was perceived to be a critical factor in children's successful engagement with weight management programmes, as evidenced in 7 studies: 3 qualitative (2 , 1 ); 3 cross-sectional surveys (2 , 1 ) and 1 process evaluation. Perceptions of high levels of parental motivation were reported in 3 studies, primarily from parents whereas providers acknowledged high parent motivation in only 1 study. Two studies found a statistically significant association between motivated parents and either programme uptake or completion. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Belgium, Australia, the USA). ## Evidence statement 2.1.15 Barrier: lack of parental support Providers reported a lack of parental support acting as a barrier to children's weight management in 4 qualitative studies (1 , 2 , 1 ). Three of these studies described provider perceptions that parents did not realise their role as agents of change and they looked to the programme to solve children's weight management difficulties. This evidence is directly applicable because studies were conducted in the UK in a community setting. ## Evidence statement 2.1.16 Barrier: lack of parental motivation Programme providers described how low parental motivation hindered children's weight management in 1 (+) qualitative study, 1 (−) qualitative study and 1 process evaluation. In addition, a small proportion of parents (4.7%) cited lack of family readiness to change as a reason for dropping out of a lifestyle weight management programme in 1 (−) cross-sectional study. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Belgium, USA). ## Evidence statement 2.1.17 Barrier: lack of support from other family members Children and parents described situations in which other family members (either partners or members outside of the nucleus family such as grandparents) did not support, and even sabotaged, children's weight management attempts. This was described in 8 qualitative studies (2 , 4 , 1 ). This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (USA). ## Evidence statement 2.1.18 Barrier: lack of awareness Both providers and programme users identified a lack of awareness of local weight management programmes. Providers considered poor programme publicity to be the reason why potential users were unaware of the programme in 1 process evaluation. Programme users also reflected on the lack of programme awareness among children and families in 4 qualitative studies (1 , 3 ). Providers and users also referred to health professionals' lack of programme awareness in 1 process evaluation and 1 qualitative study. This evidence is directly applicable because all studies were conducted in UK community settings. ## Evidence statement 2.1.19 Role of health professionals Both programme users and providers felt that health professionals such as GPs, nurses and health visitors should raise awareness or refer children to lifestyle weight management programmes. However, varying opinions were offered on whether this was being sufficiently implemented. Examples of awareness-raising by other professionals were reported by providers or programme users in 2 (+) qualitative studies, 1 (−) qualitative study and 1 process evaluation. However, providers in 3 studies (1 qualitative, 2 process evaluations) and programme users in 1 (+) qualitative study, described circumstances in which children were not referred, or inappropriate referrals were made. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (USA). ## Evidence statement 2.1.20 Facilitator: recruitment suggestions Programme users and providers offered varied suggestions for future programme recruitment strategies in 8 studies (2 qualitative, 4 process evaluations, 2 qualitative). Increasing referral routes, recruiting through schools and family support workers, was suggested by both programme providers and users; advertising in local media was suggested by providers and users. Providers also mentioned ensuring programme aims and characteristics were sufficiently described and offering rolling programmes that allow families to join on an ongoing basis. Users felt that emphasising the healthy living and fun aspects of programmes rather than weight management would promote uptake. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (USA). ## Evidence statement 2.1.22 Facilitator: venue Programme users valued the comfortable and welcoming environment of their programme venues in 2 (+) qualitative studies, which were either located in a clinic or at schools. Community settings and schools were suggested by providers and programme users as suitable venues in 1 (++) qualitative study and 2 process evaluations. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada). ## Evidence statement 2.1.23 Facilitator: family involvement Providers, children and families valued a delivery approach that incorporated family involvement in lifestyle weight management programmes, perceiving it to facilitate behaviour change. Users expressed these views in 11 studies (2 qualitative, 4 qualitative, and 5 process evaluations) and providers in 3 studies (1 qualitative study, 1 qualitative study and 1 process evaluation). Regarding specific parenting education sessions, users in receipt of these interventions liked the emphasis on positive parenting and separate children and parent sessions addressing the same topic as each other. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia, Canada, USA). ## Evidence statement 2.1.24 Facilitator: group intervention sessions with peers There was evidence from 13 studies (2 qualitative, 3 qualitative, 3 qualitative, 5 process evaluations) that group-based sessions and interaction with peers were highly valued by children and parents. Interventions incorporating group sessions or peer interactions were perceived to be opportunities to share experiences, and give and receive support from people facing similar problems. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Sweden). ## Evidence statement 2.1.25 Facilitator: goal setting Programme users and providers shared the view that the use of goal setting (which may or may not also involve rewards) was a beneficial feature of interventions, and emphasised the importance of frequent but small and realistic goals. This was evidenced in 11 studies (2 qualitative, 6 qualitative, and 3 process evaluations). This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, USA). ## Evidence statement 2.1.26 Facilitator: user-tailored interventions Programme users and providers highly valued the interventions that were tailored to the user in 9 studies (6 qualitative: 2 , 2 , 2 ; 1 cross-sectional survey and 2 process evaluations). Interventions were viewed positively if they were tailored to different population groups of children (for example, age, gender, ethnicity) by parents, providers and children. There was a strong emphasis on the value of interventions addressing the individual personal needs of programme users. Programme users commented on the importance of identifying and adjusting interventions to the needs, goals, motives or existing knowledge of individual participants. Providers in 1 study recommended tailoring programmes to children's age, ethnicity, degree of obesity and their readiness for change. Authors in 1 study also commented on the benefits of collaborating with families to create individual goals and strategies. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, USA and Sweden). ## Evidence statement 2.1.27 Facilitator: monitoring and feedback There was evidence from 10 studies that regular monitoring and feedback of weight management progress was highly valued by programme users and providers (2 qualitative, 4 qualitative, 2 qualitative studies, and 2 process evaluations). This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Sweden). ## Evidence statement 2.1.28 Facilitators: scheduling suggestions Suggestions for improving programme scheduling were offered by programme users and providers in 9 studies (1 qualitative, 2 qualitative, 1 qualitative, 1 cross-sectional survey and 4 process evaluations). More flexible appointment times, such as in the evening or weekends were suggested by programme users and providers. Programme users also wanted increased frequency of appointments to maintain their motivation. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia, USA). ## Evidence statement 2.1.29 Barrier: inconvenient intervention scheduling Scheduling of interventions (for example, timing, length of individual sessions) were important influences on programme users but no clear consensus was described on what the scheduling should be. Potential users cited inconvenient timing of programmes as a reason for not joining programmes in 1 (−) qualitative study and 2 process evaluations. Programme attendees also reported difficult scheduling as a barrier to continued participation in 10 studies (2 qualitative studies, 2 qualitative studies, 1 cross-sectional survey, 3 process evaluations, 1 cross-sectional and 1 qualitative study). Programme users in 1 survey disagreed on how the frequency of appointments resulted in their attendance or drop-out. 11.6% dropped out of programmes because appointments were not frequent enough, whereas 7% stated they were too frequent. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia, Canada, USA). ## Evidence statement 2.1.30 Barrier: venue location Negative comments regarding programme venues were expressed in 6 studies (3 qualitative, 1 qualitative, 1 cross-sectional survey and 1 process evaluation). Challenges relating to locations being too far away, difficult to reach, or hindered by traffic problems at peak times were described by both providers and users. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada and USA). ## Evidence statement 2.1.31 Barrier: challenges in goal setting Challenges of setting goals within programmes were highlighted by users and providers in 3 studies (1 qualitative, and 2 process evaluations). Programme users spoke negatively about too many goals being set, long-term goals not being revisited or monitored or goals not being matched to those valued by the child. Providers described difficulties in designing goals for users. This evidence is directly applicable because all studies conducted in community settings in the UK or similar countries (Sweden, Australia). ## Evidence statement 2.1.32 Facilitator: practical intervention elements A recurring theme within studies was that programme users particularly liked the practical elements of their intervention sessions, as evidenced in 11 studies: 7 qualitative (1 , 4 , 2 ) and 4 process evaluations. Regarding dietary components, children and/or parents enjoyed cookery lessons in particular or wanted the programme to incorporate more of these. Specific directive information was also valued, including the provision of recipes, eating plans or messages that 'told them what to do'. Education on food in supermarkets was also valued, with 1 study suggesting that education on labels should be followed up with trips to the supermarket. Regarding physical activity education, children consistently commented on enjoying games and physical exercise sessions, and views indicated they would like more activities within the intervention. Some parents also wanted more exercise sessions, although some parents expressed negative views of physical activity sessions. Variety in the available activities was also valued. This evidence is directly applicable because all studies were conducted in community settings in the UK. ## Evidence statement 2.1.33 Facilitator: behavioural change components Parents and children had positive views of the behavioural change elements in the programmes they received, evidenced in 7 studies: 5 qualitative (1 , 2 , 2 ) and 2 process evaluations. Positive comments were made regarding: understanding the 'how and why' of their eating behaviour, learning about their feelings and being able to talk about how they feel, or learning about stress and how to cope with it. One study reported that users believed lifestyle weight management programmes should include physical activity, nutrition and psychological components. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, the USA). ## Evidence statement 2.1.34 Barrier: relevance of intervention to home life Seven studies described children's and/or their families' concerns with the relevance and ease of managing their weight outside in their home life or after leaving their programme (4 , 1 , 1 qualitative and 1 cross-sectional study). This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Belgium). ## Evidence statement 2.1.35 Facilitator: post-intervention support and follow-up Seven studies (1 qualitative, 2 qualitative, 2 qualitative, 2 process evaluations) identified that the continuation of professional support following completion of the programme was important to users. Families wanted support to continue and thought it would be helpful for ensuring that weight management goals were continued. Very little detail was provided regarding the forms this support should take. Parents in 1 study suggested follow-up letters, meetings or continuation sessions. Parents in another study proposed a long-term financial subsidy to encourage children and young people to maintain participation in formal activities. This evidence is directly applicable because all studies were conducted in UK community settings. ## Evidence statement 2.1.36 Facilitator: personal strategies to sustain weight management behaviour Parents in 3 studies (2 qualitative, 1 process evaluation) described a range of strategies they employed to facilitate continuation of their children's weight management behaviour. These included staying consistent, setting planned routines, enjoying their new healthy lifestyle, and seeking additional support. This evidence is directly applicable because all studies were conducted in the UK community settings. ## Evidence statement 2.1.37 Barrier: attendance at follow-up sessions Despite strong support for professional follow-up after completion of weight management programmes, children and parent views in 3 studies suggested that the content and timing of potential support may affect the uptake of sessions if they did not appeal to programme users or conflicted with their competing interests. This was indicated in 3 qualitative studies: (1 , 1 and 1 ). This evidence is directly applicable because studies were conducted in the UK community settings or similar countries (Canada). ## Evidence statement 2.1.38 Facilitator: building good child/family-provider relationships There was evidence from 15 studies (3 qualitative, 6 qualitative, 4 process evaluations, and 2 qualitative) of children's and parents' perspectives, that provider characteristics were key factors for continued participation in weight management programmes and behaviour change attempts. Valued characteristics included the encouraging, non-judgemental tone of providers, and continuity of staff. Parents also appreciated the role providers had in acting as voices of authority that parents could rely on to educate children. Provider perspectives in 2 of these studies also suggested that staff were aware of the importance of establishing good relationships with programme users and their families. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, Sweden, the USA Australia). ## Evidence statement 2.1.39 Barrier: negative opinions of providers' characteristics Six studies (2 qualitative, 2 qualitative, 1 process evaluation, 1 qualitative) described how negative opinions of provider dynamics influenced user engagement. Children and parents provided examples of poor user-provider relationships and suggested they hindered engagement with programmes or weight management behaviour Providers also recognised the negative effect bad relationships with users and staff discontinuity could have on programme adherence. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, Sweden). ## Evidence statement 2.1.40 Facilitator: collaborative multi-disciplinary teams Three studies (1 qualitative study, 1 process evaluation and 1 cross-sectional survey) indicated that providers highly valued working within effective collaborative multidisciplinary teams. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia). ## Evidence statement 2.1.41 Facilitator: provider highly valued opportunities for training Three studies (1 qualitative, 1 process evaluation and 1 cross-sectional survey) reported that providers were keen to receive relevant training that would help them gain necessary skills to effectively deliver interventions. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia). ## Evidence statement 2.1.42 Barrier: provider gaps in knowledge Three studies (1 qualitative study, 1 cross-sectional study and 1 process evaluation) referred to providers' perceptions of their skills and knowledge. Three studies indicated some providers felt unqualified to deliver interventions, specifically interventions that were broad in their nature, or were delivered to a varying user group who sometimes had complex psychosocial needs. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia). ## Evidence statement 2.2.4 Pre-adolescent children (6 to 13 years) A wide range of themes was described in 16 studies of school-age children: 7 qualitative (3 , 3 , 1 ), 1 (+) correlation, 2 cross-sectional, 6 process evaluations. However, none of the studies were designed to explore differences in barriers and facilitators compared with other age groups. Commonly shared facilitators across studies were the importance of non-weight outcomes such as psychological wellbeing, social outcomes such as making friends and reduced bullying; interventions with a whole-family approach; positive provider characteristics; group-based sessions with peers; regular monitoring and feedback; and post-intervention support. Commonly shared barriers across studies were poor relationships of providers with children and/or their parents. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, Australia, the USA, Iceland, Belgium). ## Evidence statement 2.2.5 Adolescents A wide range of themes was described in 10 studies of adolescents (2 qualitative, 3 qualitative, 1 cross-sectional survey, 4 process evaluations). However, none of the studies were designed to explore differences in barriers and facilitators for adolescents when compared with other age groups. Facilitators shared across 3 or more studies were the importance of psychological wellbeing as an outcome and positive provider characteristics. Commonly shared barriers across studies were: perceived lack of parental support and concern regarding unintended consequences of weight management programmes. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia the USA and Sweden). ## Expert papers and commissioned report Expert papers 1 to 6. Commissioned report. For details, see the section on what evidence is the guidance based on? # Economic modelling The economic model considered the BMI trajectory of children in 3 different age groups (2 to 5 years, 7 to 11 years and 12 to 17 years). It considered boys and girls separately. It also considered 3 starting weights for each age group and both sexes. The starting weights considered were: the borderline between healthy weight and overweight, between overweight and obese, and between obese and what the model called morbidly obese. The model examined what happened to each cohort if there were no intervention. It estimated the average (mean) weight and quality of life for the cohort on an annual basis and its expected life expectancy. It also estimated the costs of any health problems they would face during their lifetime. The model was then set up to answer 2 questions: What would happen to the quality of life and the life expectancy of each of these groups of children or young adults if an intervention from the evidence review were applied? How would the future costs of treating diseases change as the result of the intervention? The difference between the subsequent lifelong pathways of these 2 hypothetical situations (that is, 'with an intervention' and 'without an intervention') was expressed in terms of quality-adjusted life years (QALYs) gained from the intervention. It was also expressed in terms of the cost of the intervention less the future costs saved. An intervention is generally considered to be cost effective if the cost per QALY gained is less than about £20,000 to £30,000. The model estimated that an intervention costing £100 per person would be cost effective if a child or young person could be moved to a lower weight trajectory (as little as 0.5% lower) than it would have been without the intervention. However, this would be the case only if the 0.5% weight difference were to be maintained throughout life. If, on average, they regained the weight within 10 years or less it is estimated that the intervention would no longer be cost effective.# Gaps in the evidence The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence and expert comment. These gaps are set out below. . There is a lack of data on how to involve male children and young men in lifestyle weight management programmes. (Source: evidence review 1) . There is a lack of data on effective lifestyle weight management programmes for children and young people with disabilities, learning difficulties or other special needs. (Source: evidence reviews 1 and 2) . There is a lack of data on effective and cost-effective approaches to weight management for children younger than 6 years, including the views of their parents and families. In addition, there is a lack of data on the barriers to, and facilitators for, encouraging these children to complete a lifestyle weight management programme. (Source: evidence reviews 1 and 2) . There is a lack of data on how the barriers to, and facilitators for, participating in a lifestyle weight management programme vary according to socioeconomic group, ethnicity, gender and age. (Source: evidence review 2) . There is a lack of standardised reporting for the behavioural therapy and cognitive behavioural therapy (CBT) components used by programme developers. This makes it difficult to evaluate these components of a lifestyle weight management programme. (Source: expert paper 6) . There is a lack of evidence on the lifetime effects of weight management programmes. (Such data are crucial for assessing cost effectiveness.) (Source: Economic modelling report) The Committee made 4 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in Recommendations for research.# About this guidance # What evidence is the guidance based on? The evidence that the Programme Development Group (PDG) considered included: Evidence reviews: Review 1: 'Effectiveness and cost effectiveness of lifestyle weight management services for children and young people', was carried out by Support Unit for Research Evidence (SURE), Cardiff University. The principal authors were: Fiona Morgan, Alison Weightman, (SURE, Cardiff University) Sarah Whitehead (DECIPHer, Cardiff University) and Sinead Brophy (DECIPHer, Swansea University). Review 2: 'The barriers and facilitators to implementing lifestyle weight management programmes for children and young people', was carried out by SURE, Cardiff University. The principal authors were: Ruth Turley, Alison Weightman, (SURE, Cardiff University), Elizabeth Halstead (Bangor University) and Helen Morgan (SURE, Cardiff University). Economic modelling: 'Managing overweight and obesity among children economic modelling report', was carried out by the UK Health Forum, (formerly the National Heart Forum) and the University of East Anglia. The principal authors were: Martin Brown, Tim Marsh and Ketevan Rtveladze (UK Health Forum) and Ric Fordham (University of East Anglia). Commissioned report: 'Practical and process issues in the provision of lifestyle weight management services for children and young people', was carried out by GK Research. The author was Graham Kelly. Expert papers: Expert paper 1: 'Findings of the former Childhood Obesity National Support Team' by Kim Hastie, Head of former Childhood Obesity National Support Team. Expert paper 2 'Implications of the transition of public health responsibilities to local government' by Helen Walters, Greater London Authority Expert paper 3 'Psychological considerations for lifestyle weight management programmes for children and young people, and the use of behaviour change theories' by Andrew Hill, University of Leeds Expert paper 4 'Choosing outcome measures for lifestyle weight management programmes for children' by Maria Bryant, University of Leeds Expert paper 5 'A population-level evaluation of a family-based community intervention for childhood overweight and obesity' by Catherine Law and Helen Roberts, Institute of Child Health, University College, London Expert paper 6 'Effective Behavioural Components for Childhood weight management programmes' by Pinki Sahota, Leeds Metropolitan University. In some cases, the evidence was insufficient and the PDG has made recommendations for future research.# Finding more information To find NICE guidance on related topics, including guidance in development, see the NICE topic page on obesity. For full details of the evidence and the guideline committee's discussions, see the evidence reviews and expert papers. You can also find information about how the guideline was developed, including details of the Programme Development Group. NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice. ISBN 978-1-4731-0330-6	{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe Programme Development Group (PDG) considers that the recommendations are likely to be cost effective.\n\nThe evidence underpinning the recommendations is listed in the evidence section and the full evidence reviews, economic modelling report, expert papers and commissioned report. For the research recommendations, see Recommendations for research and Gaps in the evidence respectively.\n\nThe recommendations in this guidance cover lifestyle weight management services for overweight and obese children and young people aged under\xa018. However, no evidence was identified about the effectiveness of such programmes specifically aimed at children under\xa06. The absence of such programmes from the recommendations is a result of this lack of evidence and should not be taken as a judgement on whether or not they are effective and cost effective.\n\nThe recommendations are for commissioners in local authorities and the NHS and providers of community-based services that take a 'lifestyle' approach to helping overweight or obese children and young people manage their weight. They are also for health professionals and people working with children and young people.\n\nAlthough local terminology varies, these are sometimes called tier 2 services and are just 1 part of a comprehensive approach to preventing and treating obesity.\n\nThe guidance may also be of interest to children and young people, their parents, carers, families and other members of the public.\n\nThe guidance complements but does not replace NICE guidance on obesity, body mass index and waist circumference among minority ethnic groups, how local communities can prevent obesity, physical activity for children and young people, and weight management in pregnancy. (For further details, see the NICE topic page on obesity.)\n\n# Principles of weight management for children and young people\n\nAssessing the body mass index (BMI) of children is more complicated than for adults because it changes as they grow and mature. In addition, growth patterns differ between boys and girls.\n\nThresholds that take into account a child's age and sex are used to assess whether their BMI is too high or too low. These are usually derived from a reference population, known as a child growth reference, with the data presented in BMI centile charts. In a clinical assessment, a child or young person on or above the 98th centile is classified as obese. A child or young person on or above the 91st centile, but below the 98th centile, is classified as overweight. Several classification systems are used in the UK to define 'obesity' and 'overweight' in children. In the analysis of population surveys such as the National Child Measurement Programme and the Health Survey for England (HSE), children over the 85th centile, and on or below the 95th centile, are classified as being 'overweight'. Children over the 95th centile are classified as being 'obese'. However, the NCMP uses the clinical cut-off points described above when providing feedback about the BMI of individual children to parents and carers.\n\nWhen monitoring and comparing groups of children and young people BMI\xa0z scores may be used. These are a measure of how many standard deviations a child or young person's BMI is above or below the average BMI for their age and gender.\n\nIn this guidance, the term BMI centile is used in recommendations that focus on working with individual children or young people. 'BMI\xa0z score' is used in recommendations relating to monitoring and research.\n\nFurther information can be found in the Nation Obesity Observatory's simple guide to classifying BMI in children.\n\n# Lifestyle weight management programmes\n\nMany lifestyle weight management programmes aim to maintain the growing child's existing weight in the short term, as they grow taller. This is an appropriate short-term aim, because it will result in an improved BMI over time, and is often described as 'growing into their weight'.\n\nYoung people who are overweight or obese and are no longer growing taller will ultimately need to lose weight to improve their BMI. However, preventing further weight gain while they gain the knowledge and skills they need to make lifestyle changes, may be an appropriate short-term aim. These changes then need to become firmly established habits over the long term.\n\n# Whose health will benefit?\n\nChildren and young people who are overweight or obese.\n\n# Recommendation 1 Planning lifestyle weight management services for children and young people\n\n## Who should take action?\n\nDirectors of public health and public health teams working on obesity and child health and wellbeing.\n\nHealth and wellbeing boards.\n\nLocal authority commissioners.\n\nClinical commissioning groups.\n\nNHS England.\n\nPublic Health England.\n\nChildren's services.\n\n## What action should they take?\n\nEnsure family-based, multi-component lifestyle weight management services for children and young people are available as part of a community-wide, multi-agency approach to promoting a healthy weight and preventing and managing obesity. These services should contain the core elements described in recommendation 3. They should be provided as part of a locally agreed obesity care or weight management pathway.\n\nDedicate long-term resources to support the development, implementation, delivery, promotion, monitoring and evaluation of these services. See recommendation 7 in NICE's guideline on obesity: working with local communities and principle 7 in NICE's guideline on behaviour change: general approaches.\n\nUse data from the joint strategic needs assessment and the National Child Measurement Programme to identify local need. See recommendation 1 in NICE's guideline on obesity: working with local communities.\n\n# Recommendation 2 Commissioning lifestyle weight management programmes for children and young people\n\n## Who should take action?\n\nDirectors of public health and public health teams working on obesity and child health and wellbeing.\n\nHealth and wellbeing boards.\n\nLocal authority commissioners.\n\nClinical commissioning groups.\n\nNHS England.\n\nPublic Health England.\n\nChildren's services.\n\n## What action should they take?\n\nIdentify needs using the joint strategic needs assessment. Use community engagement techniques with local families to identify any barriers and facilitators discouraging or encouraging the uptake and completion of programmes.\n\nCommission lifestyle weight management services to meet the needs of local children and young people, including those of different ages, different stages of development and from different cultural backgrounds. Services should be in line with the health and wellbeing strategy.\n\nConsider how best to provide services for overweight or obese children and young people with special needs or disabilities. For example, through specific programmes where these are available. Or by making reasonable adaptations to mainstream programmes (including training staff) and evaluating them. Ensure there is an appropriate interface with specialist obesity services to help those with more complex needs manage their weight.\n\nEnsure all lifestyle weight management programmes are designed and developed with input from a multidisciplinary team and have taken into account the views of children, young people and their families. The team should include professionals who specialise in children, young people and weight management. These include the following:\n\n\n\na state registered dietitian or registered nutritionist\n\na physical activity specialist\n\na behaviour-change expert, such as a health promotion specialist (for physical activity, a sport and exercise psychologist may be appropriate)\n\na health or clinical psychologist, or a child or adolescent psychiatrist, to provide expertise in mental wellbeing\n\na paediatrician or paediatric nurse.\n\n\n\nEnsure programme content is regularly reviewed and updated by the multidisciplinary team.\n\nEnsure providers can demonstrate that staff are trained to deliver the specific programme commissioned and are experienced in working with children, young people and their families.\n\nEnsure sufficient resources are dedicated to monitoring and evaluation.\n\nEnsure there are clearly defined programme objectives, outputs, outcomes and monitoring and evaluation requirements in programme specifications and in contracts. Contracts should also specify any at-risk groups that should be targeted, such as black and minority ethnic groups, or children and young people from low-income families or neighbourhoods.\n\nEnsure key performance indicators are agreed with programme providers, including the proportion of sessions that must be attended to complete the programme (see recommendation 15).\n\nEnsure the contract or programme specification requires that height and weight are measured and that both BMI and BMI for age and gender (BMI\xa0z score) are recorded. All children and young people should be measured at the following times:\n\n\n\nat recruitment to the programme\n\nat completion of the programme\n\nmonths after completing the programme\n\nyear after completing the programme.\n\n\n\nFor recommendations for providers, see recommendations 3, 5, 10 and 14.\n\nSee also recommendation 10 in NICE's guideline on obesity: working with local communities.\n\n# Recommendation 3 Lifestyle weight management programmes: core components\n\n## Who should take action?\n\nProviders of lifestyle weight management programmes.\n\n## What action should they take?\n\nEnsure all lifestyle weight management programmes for overweight and obese children and young people are multi-component. They should focus on:\n\n\n\ndiet and healthy eating habits\n\nphysical activity\n\nreducing the amount of time spent being sedentary\n\nstrategies for changing the behaviour of the child or young person and all close family members.\n\n\n\nEnsure the following core components, developed with the input of a multidisciplinary team (see recommendation 2) are included:\n\n\n\nBehaviour-change techniques to increase motivation and confidence in the ability to change. This includes strategies to help the family identify how changes can be implemented and sustained at home.\n\nPositive parenting skills training, including problem-solving skills, to support changes in behaviour.\n\nAn emphasis on the importance of encouraging all family members to eat healthily and to be physically active, regardless of their weight.\n\nA tailored plan to meet individual needs, appropriate to the child or young person's age, gender, ethnicity, cultural background, economic and family circumstances, any special needs and how obese or overweight they are. This should include helping them and their family to set goals, monitor progress against them and provide feedback (see recommendation 4).\n\nInformation and help to master skills in, for example, how to interpret nutritional labelling and how to modify culturally appropriate recipes on a budget.\n\nHelp to identify opportunities to become less sedentary and to build physical activity into their daily life (for example, by walking to school and through active play).\n\nA range of physical activities (such as games, dancing and aerobics) that the children or young people enjoy and that can help them gradually become more active.\n\nInformation for family members who may not attend the programme itself to explain the programme's aims and objectives and how they can provide support.\n\nOngoing support and follow-up for participants who have completed the programme.\n\n\n\n# Recommendation 4 Developing a tailored plan to meet individual needs\n\n## Who should take action?\n\nProviders of lifestyle weight management programmes.\n\n## What action should they take?\n\nAssess each child or young person for obesity-associated diseases or conditions (comorbidities). Use a locally approved comorbidities assessment tool, where available. Assessment is particularly important if the child or young person and their family have self-referred to the programme, or have not been assessed by a health professional. Refer them to their GP if any concerns are identified.\n\nIdentify whether the child or young person's mental wellbeing is affected by their weight. For example, whether there are any signs of psychological distress, depression, bulimia, self-harming or other mental health problems related to their weight.\n\nIdentify whether their weight is a consequence of circumstances that have affected their mental wellbeing. (For example, if they have experienced bereavement or have caring responsibilities.)\n\nIf concerns about their mental wellbeing are identified refer the child or young person to their GP for assessment and treatment and, if appropriate, for onward referral to child and adolescent mental health services (CAMHS). (Note: such concerns may be identified at any stage of a weight management programme.)\n\nTake account of the child or young person's self-esteem, self-perception and any previous attempts to manage their weight. Provide opportunities, in either a group or one-to-one session, for them to talk about any victimisation or distress if they wish. (This includes any history of bullying or teasing.)\n\nFind out whether the family recognises that their child is overweight or obese and the potential benefits of managing their weight. Discuss the family's history of attempts to manage their weight, and their existing knowledge of, and attitudes towards, food, physical activity and the amount of time spent being sedentary.\n\nWeigh, measure, determine and record the child or young person's BMI. Offer to do the same for parents, carers and other family members. Measurements should be undertaken by staff who have been trained using standard protocols (see recommendation 11).\n\nThey should use validated, transportable instruments that are regularly calibrated.\n\nEmphasise that the programme may benefit the whole family. In addition, offer information about local lifestyle weight management services to adult family members who are overweight or obese.\n\nEncourage children and young people from around the age of 12 (depending on their ability and stage of development) to monitor their eating, physical activity and any sedentary behaviour. For example, encourage them to keep a record of time spent watching television or playing computer games, and what they snack on and when, to identify areas that need addressing. For younger children, parents and carers should monitor these behaviours, with the involvement of the child according to their age and stage of development.\n\nWork with children from around the age of 12 (depending on their ability and stage of development) to identify situations in which it would be possible for them to eat more healthily or to become less sedentary and more active. For example, this might involve gradually reducing TV viewing at certain times and replacing this with more active pastimes. Work with the parents and carers of younger children to achieve the same.\n\nAim to gradually increase the amount of moderate to vigorous-intensity physical activity programme participants do every day. Focus on activities they enjoy and that are easily accessible. This includes activities that can be built into daily life, such as active play, walking or cycling. Aim to achieve the age-specific UK physical activity guidelines.\n\nAgree dietary changes that are age-appropriate, affordable, culturally sensitive and consistent with healthy eating advice. Ensure nutrient needs for growth and development are met by including healthier choices, in appropriate amounts, from each of the food groups (see NHS Eatwell plate). Changes to diet should take into account the child or young person's likes and dislikes.\n\nManage expectations of what can be realistically achieved over the duration of the programme. Small but realistic goals should be mutually agreed with the child or young person and their family. These should relate to goals that they value and that motivate them to attend.\n\nWork with participants and their families to regularly monitor progress against the goals and provide feedback. Praise progress and achievements and update the goals as the child or young person progresses through the programme. If they do not meet their goals, discuss the possible causes for this and modify them if necessary.\n\nStress the importance of maintaining changes, no matter how small, over the longer term. Encourage participants to take up offers of ongoing support (see recommendation 10).\n\n# Recommendation 5 Encouraging adherence to lifestyle weight management programmes\n\n## Who should take action?\n\nProviders of lifestyle weight management programmes.\n\n## What action should they take?\n\nOffer programmes to groups of children or young people and their families. Where necessary, offer programmes to individual families, if this better meets their needs and preferences. For example, some families may prefer to attend individual sessions initially and attend group sessions as their confidence and self-esteem grows.\n\nOffer a range of programmes for children and young people of different ages and at different stages of development. If group sessions are offered, work with groups of peers and their parents or carers. Note, some adolescents may respond better to programmes if their sessions are separate from those for their parents and carers.\n\nOffer programmes in venues that have the necessary facilities, are easily accessible and where the child or young person and their family feel comfortable. For example, use local community venues that have space for physical activities or games, and that can be reached quickly and easily by walking, cycling or using public transport.\n\nOffer programmes at a range of times that are convenient for families with children of different ages and for working parents and carers. For example, some sessions could be offered in the evenings or at weekends.\n\nAdopt a flexible approach so that participants can accommodate other commitments. They may also prefer to attend programmes more frequently initially and less frequently as their skills and confidence in making changes grows. For example, use rolling programmes that allow participants to start at different points and cover the same material but not necessarily in the same order.\n\nEmphasise the importance of parental (or carer) support and their commitment to adhere to the programme. Stress that this support and commitment should extend beyond the duration of the programme itself and that outcomes will be reviewed for at least the first year after completion.\n\nMaintain regular contact with participants. Promptly follow up those who miss sessions to establish why and to restore commitment. Focus on participants from disadvantaged groups and those who miss sessions early on in the programme.\n\nTry to retain the same team of staff throughout each cycle of the programme.\n\n# Recommendation 6 Raising awareness of lifestyle weight management programmes: commissioners and programme providers\n\n## Who should take action?\n\nDirectors of public health and their teams.\n\nLocal authority commissioners.\n\nNHS commissioners.\n\nNHS and local authority communications teams.\n\nProviders of lifestyle weight management programmes.\n\n## What action should they take?\n\nLocal authorities should ensure an up-to-date list of local lifestyle weight management programmes for children and young people is maintained. This should form part of a list of services commissioned for the local obesity care or weight management pathway. It should be regularly disseminated, or accessible to organisations in the public, community and voluntary sectors.\n\nUse children's centres, libraries, the local media, professional and voluntary organisations working with children and young people and schools to raise awareness of lifestyle weight management programmes. Any publicity should clearly describe:\n\n\n\nwho the programme is for (age range, any eligibility criteria and the level of parental involvement needed)\n\nhow to enrol (including whether participants can self-refer or need a formal referral from a health professional)\n\nprogramme aims\n\ntype of activities involved (to alleviate any anxieties about the unknown and to ensure expectations are realistic): 'healthy living' and any fun aspects should be emphasised\n\ntime and location, length of each session and number of sessions.\n\n\n\nCommissioners, public health teams and providers should raise awareness of the programmes among health professionals who may refer children and young people. This includes GPs and staff involved in the National Child Measurement Programme and the Healthy Child Programme. For example, the programme could be publicised through health professional networks and by offering training sessions on the programmes and how to make referrals.\n\n# Recommendation 7 Raising awareness of lifestyle weight management programmes: health professionals, other professionals and voluntary organisations\n\n## Who should take action?\n\nHealth professionals, in particular, GPs, dietitians, health visitors, school nurses and those involved in delivering the National Child Measurement Programme and the Healthy Child Programme.\n\nSchools, colleges, early years organisations, children's centres and looked-after children's teams and other professionals who work with children and young people. For example, youth workers, social workers, and pastoral care workers.\n\n## What action should they take?\n\nHealth professionals should tell the parents or carers of children and young people who have been identified as being overweight or obese about local lifestyle weight management programmes. They should explain what these involve and how they can take part (including whether or not they can self-refer).\n\nOther professionals who work with children and young people should raise awareness of lifestyle weight management programmes for overweight and obese children and young people. They should also raise awareness of how to enrol on them.\n\n# Recommendation 8 Formal referrals to lifestyle weight management programmes\n\n## Who should take action?\n\nChildren's community nurses, dietetic teams, GPs, health visitors, primary care teams, obesity specialists, paediatricians, school nurses and school healthcare teams.\n\n## What action should they take?\n\nWhere there are concerns about a child or young person's weight, weigh them in light clothing on clinically approved, regularly calibrated scales. In children older than 2\xa0years, measure their height using a stadiometer. (See the National Obesity Observatory's standard evaluation framework for weight management interventions, for practical advice on weighing and measuring children).\n\nUse the UK growth charts for children aged 4\xa0years and older to determine BMI centile for their age and gender. Use the UK-WHO 0 to 4\xa0years growth chart to determine if children younger than\xa04 are a healthy weight. Record this in the child or young person's health record.\n\nTake account of their BMI centile, any obesity-associated diseases or conditions (comorbidities) they may have, or family medical history, and any psychosocial considerations, to determine whether referral to a lifestyle weight management programme is clinically appropriate.\n\nUse tact and diplomacy to find out if the family and the child or young person accepts that the child or young person is overweight or obese. If they do accept this and it is clinically appropriate to refer them to a lifestyle weight management programme, explain the potential benefits they will gain – and the risks of not addressing their child's weight. In addition:\n\n\n\nidentify and address any fears or concerns the child, young person or their family may have about attending (for example, fears of being the largest child on the programme, of having to do very strenuous activities, or being stigmatised for attending)\n\ngive the family information about the programme, or tell them where they can get this information\n\nexplain what can be realistically expected in terms of results over the duration of the programme itself (for example, explain that for growing children, maintaining their existing weight may be a realistic short-term aim)\n\nexplain that the more sessions of a programme they attend, the greater the likelihood of success.\n\n\n\nAssess whether the child or young person and their family are ready and willing to be referred. If they are ready, refer them to an effective lifestyle weight management programme (see recommendation 3).\n\nIf the family is not ready to attend a programme:\n\n\n\ntell them how they can enrol in the future (including the fact that they can self-refer if this is possible)\n\noffer a follow-up appointment in 3 or 6 months, according to their preference\n\nprovide them with, or point them to, information and advice on healthy eating, physical activity and how to reduce sedentary behaviour (examples include: the NHS Eatwell plate, UK physical activity guidelines and the Change4Life).\n\n\n\nIf children or young people need specialist support to manage their weight, refer them to specialist obesity services (if available) or to paediatric services.\n\nIf there are concerns about the child or young person's mental wellbeing related to their weight, use the local pathway to refer them to CAMHS. Ensure their GP is informed.\n\n# Recommendation 9 Providing ongoing support: health professionals\n\n## Who should take action?\n\nChildren's community nurses, dietetic teams, GPs, health visitors, members of primary care teams, obesity specialists, paediatricians and school nurses and school healthcare teams.\n\n## What action should they take?\n\nHealth professionals should use feedback from the programmes to help regularly monitor progress and provide ongoing support. They should acknowledge that:\n\n\n\nfor children who are growing taller, avoiding further weight gain is a realistic short-term aim that can have a positive impact in the longer term\n\nfor young people who are no longer growing taller, ultimately they need to lose weight to improve their BMI, and they should also aim to acquire the knowledge and skills they need to make long-term behaviour changes\n\nit is important to maintain changes in behaviour once the programme is completed\n\nimprovements in diet and physical activity can have positive health benefits, independent of any effect on weight or BMI\n\nimprovements in psychosocial outcomes (such as sense of wellbeing, self-efficacy, self-esteem and self-perception) are considered important health benefits for overweight and obese children and young people.\n\n\n\nAfter the programme has been completed, health professionals should continue to monitor the child or young person's BMI centile when the opportunity arises and at 6\xa0months and 1\xa0year after they complete the programme.\n\nIf the child or young person's BMI centile begins to increase, or if they or their parents or carers express concerns about their weight (or sustaining changes in their behaviour), discuss the possible causes. If necessary, consider another referral to the same or an alternative lifestyle weight management programme that may better address the needs of the family. Or consider referral to specialist obesity services (if available), or to a paediatrician.\n\n# Recommendation 10 Providing ongoing support: lifestyle weight management programmes\n\n## Who should take action?\n\nProviders of lifestyle weight management programmes.\n\n## What action should they take?\n\nWith the participants' consent, providers should send feedback to their referring GP or healthcare professional.\n\nOffer all participants ongoing support when they have completed the programme. This support should be offered for at least the first year and longer, if possible, depending on the family's needs. Offer a range of options including follow-up sessions at different times and in easily accessible and acceptable venues.\n\nTell participants about local services and activities that may provide further support to help them manage their weight, for example, local leisure services and walking or cycling groups.\n\n# Recommendation 11 Lifestyle weight management programme staff: training\n\n## Who should take action?\n\nProviders of lifestyle weight management programmes.\n\n## What action should they take?\n\nEnsure staff are trained to deliver the weight management programme they will be working on. Ensure the training has been developed with the input of, and is regularly reviewed by, a multi-disciplinary team of professionals (see recommendation 2). Ensure staff training needs are regularly reviewed and addressed.\n\nEnsure programme staff treat overweight and obese children, young people and their families with empathy, by making them aware of:\n\n\n\nthe reasons why some children and young people may have difficulty managing their weight\n\nthe experiences they may face in relation to their weight\n\nthe anxieties they and their families may have about attending the programme\n\nthe way in which obesity is perceived by different communities\n\nthe issues they may need to consider to ensure activities are culturally acceptable.\n\n\n\nTrain staff:\n\n\n\nto accurately measure and record height and weight and to determine BMI centile using age- and gender-specific charts\n\nto help parents and carers recognise that their child is overweight or obese and the benefits of addressing their weight\n\nto use a locally approved comorbidities assessment tool, where available, to determine whether lifestyle weight management programmes are appropriate, or whether they should see their GP for a referral to a specialist obesity service or other specialist services (for example, paediatric services)\n\nto identify any concerns about a child or young person's mental wellbeing and how to refer them to their GP for onward referral to CAMHS\n\nin how to comply with statutory requirements and local policies relating to safeguarding and information governance.\n\n\n\n# Recommendation 12 Lifestyle weight management programme staff: knowledge and skills\n\n## Who should take action?\n\nProviders of lifestyle weight management programmes.\n\n## What action should they take?\n\nEnsure staff have the necessary knowledge and skills to deliver multi-component programmes to children, young people and their families. This includes knowledge and skills in relation to: childhood obesity management, diet and physical activity. It may also include training in behaviour-change techniques and psychological approaches (for example, motivational interviewing).\n\nEnsure there are staff available who can provide parenting skills training. Also ensure there are staff trained in practical food preparation.\n\nEnsure staff are able to empathise and communicate effectively with the family. They should be able to work collaboratively with them and tailor interventions for individual needs. They should also be able to lead group work and set an appropriate pace when delivering the programme. In addition, they should be able to judge when changes in behaviour have become embedded, before introducing further changes.\n\nEnsure staff can review progress and provide constructive feedback. They should be able to help children, young people and their families to identify possible reasons for relapse and use problem-solving techniques to address these.\n\nIdentify any gaps in staff knowledge or skills (or a lack of confidence). Address any gaps through training.\n\n# Recommendation 13 Training in how to make referrals to a lifestyle weight management programme\n\n## Who should take action?\n\nEmployers.\n\nProfessional bodies responsible for setting competencies and designing continuous professional development programmes for health professionals.\n\n## What action should they take?\n\nEnsure health professionals:\n\nUnderstand why some children and young people may have difficulty managing their weight and the experiences that they may face in relation to their weight.\n\nAre aware of how obesity is viewed in different cultures and the issues they may need to consider to ensure any recommended activities are culturally acceptable. See NICE's guideline on promoting physical activity for children and young people.\n\nCan accurately measure and record height and weight and determine BMI centile, using age- and gender-specific charts.\n\nCan raise the issue of weight management confidently and sensitively. They should be able to help parents and carers identify when their child is overweight or obese and understand the benefits of addressing their weight.\n\nAre familiar with the local obesity care or weight management pathway and any locally approved comorbidities assessment tools.\n\nCan assess whether referral to a lifestyle weight management service is appropriate, or whether they should be referred to specialist obesity services or other specialist services (for example, paediatric services).\n\nCan identify suitable lifestyle weight management programmes for children, young people and their families and can provide them with information and ongoing support (see recommendations 9 and 10).\n\n# Recommendation 14 Supporting lifestyle weight management programme staff and those making programme referrals\n\n## Who should take action?\n\nEmployers of staff working on, or referring children and young people to, lifestyle weight management programmes.\n\nProviders of lifestyle weight management programmes.\n\n## What action should they take?\n\nIf those involved in referring to, or delivering, lifestyle weight management programmes lack the confidence and skills to discuss weight management, offer them support and training.\n\nIf staff identify that the reason for their lack of confidence is a result of being overweight or obese themselves, offer them access to weight management programmes.\n\nSee also recommendation 9 in NICE's guideline on obesity: working with local communities.\n\n# Recommendation 15 Monitoring and evaluating programmes\n\n## Who should take action?\n\nDirectors of public health and public health teams working on obesity and child health and wellbeing.\n\nHealth and wellbeing boards.\n\nLocal authority commissioners.\n\nClinical commissioning groups.\n\nNHS England.\n\nProviders of lifestyle weight management programmes.\n\n## What action should they take?\n\nEnsure monitoring focuses on sustaining changes in the longer term. Include the following in the data reported:\n\n\n\nnumbers recruited, percentage completing the programme and percentage followed up at 6\xa0months and at 1\xa0year after completing the programme\n\nfor all those recruited, BMI and BMI\xa0z score a) at recruitment to the programme b) at completion of the programme c) 6\xa0months after completing the programme and d) 1\xa0year after completing the programme.\n\n\n\nEnsure other measured outcomes reflect the aim of the programme and relate to factors that can support or contribute towards a reduction in BMI. These could include: improvements in diet and physical activity, a reduction in sedentary behaviour and improvements in self-esteem. (See National Obesity Observatory's standard evaluation framework for weight management interventions for examples of other possible outcome measures.)\n\nEnsure data collection tools are validated for the age range or population group the programme addresses and are feasible and affordable in practice settings. Do not rely on self-reported measures of height or weight, or interpretations of BMI based on them.\n\nMonitor any variation in the numbers recruited, numbers completing and the proportion of people retained by the programme, according to population subgroup.\n\nCollect data on:\n\n\n\nVariations in outcomes, according to age, gender, ethnicity and socioeconomic status (for example, as indicated by the postcode of participants), so that the impact on health inequalities can be assessed.\n\nThe route through which participants were referred to programmes including any self-referrals. Use this information to identify areas where awareness of available programmes is low and where referral rates might be increased.\n\nThe views of participants: areas they found helpful and areas for improvement. Ensure the views of everyone who has participated are collected (including those who did not complete the programme).\n\nThe views of staff delivering the programme and of those referring participants to it. Use the information to identify any practical or process issues that may need addressing.\n\n\n\nCommissioners should evaluate the service using data on outcomes and the cost of promotion and delivery.\n\nCommissioners should regularly review monitoring and evaluation data and use it to amend and improve the service.\n\nSee also recommendation 10 in NICE's guideline on obesity: working with local communities", 'Public health need and practice': "# Obesity and overweight statistics\n\nIn 2011 in England, around 3 out of 10 boys and girls aged 2 to 15\xa0years were either overweight or obese. The proportion of those who are overweight has remained largely unchanged since the mid-1990s. However, childhood obesity has risen by around 1\xa0percentage point every 2\xa0years up to 2007 (NHS Information Centre 2013; Department of Health 2011).\n\nIn the 2011/2012 school year, around 23% of children in reception and 34% in year\xa06 were either overweight or obese. Around 9.5% and 19%, respectively, were obese. The prevalence of obesity was linked with socioeconomic deprivation and was more prevalent in urban areas. Obesity was also more prevalent among children from black, Asian, 'mixed' and 'other' minority ethnic groups than among their white counterparts (NHS Information Centre 2012).\n\nAlthough the prevalence of obesity now appears to be levelling off, in 2011 around 17% of boys and just under 16% of girls aged 2 to 15\xa0years were classed as obese (NHS Information Centre 2013).\n\nUp to 79% of children who are obese in their early teens are likely to remain obese as adults (Chief Medical Officer 2008). Consequently, they will be at greater risk of conditions such as type 2 diabetes, coronary heart disease and some cancers in adulthood (Foresight 2007). Studies have also shown that a child with at least 1 obese parent is more likely to be obese themselves (Perez-Pastor et al. 2009).\n\n# Childhood obesity and health\n\nVarious diseases or conditions (comorbidities) may be associated with obesity in childhood. Of these, type\xa02 diabetes is a particular concern. It usually occurs in middle aged and older people and is associated with being overweight or obese. However, over the past decade, more younger people and children (some as young as 7) are being diagnosed with this condition (Diabetes UK 2011).\n\nBeing overweight as a child has also been associated with other cardiovascular risk factors in childhood or early adulthood (Craig et al. 2008; Logue and Sattar 2011). Other conditions associated with childhood obesity include: non-alcoholic fatty liver disease (Wei et al. 2011); gall stones (Koebnick et al. 2012); asthma and sleep-disordered breathing, including sleep apnoea (Figueroa-Munoz et al. 2001); and musculoskeletal conditions (Murray and Wilson 2008, Taylor et al 2006).\n\nIn addition, there is evidence that childhood obesity impacts on self-esteem and quality of life (Griffiths et al. 2010). In adolescence, it has been associated with depression (Sjoberg et al. 2005).\n\nOverweight and obese children are likely to experience bullying and stigma (Griffiths et al. 2006) which can also impact on their self-esteem. Some of these issues may, in turn, lead to under-achievement at school (Bromfield 2009).\n\n# Weight management programmes\n\nThe 'Healthy child programme for 5- to 19‑year-olds' recommends that overweight or obese children should be referred to appropriate weight management services to help them achieve and maintain a healthier weight (Department of Health 2009).\n\nSuch programmes can also help improve self-esteem (Lowry et al. 2007). In addition, they have the potential to help improve how they see themselves which may, in turn, enhance their future wellbeing (even if weight loss is not apparent in the short term) (Griffiths et al. 2010).\n\nIn 2008, an estimated 314 to 375 weight management programmes for children were operating in England (Aicken et al. 2008). Lifestyle approaches focus on diet, physical activity, behaviour change or any combination of these factors. They may include programmes, courses or clubs (including online services) that are:\n\ndesigned for overweight or obese children and young people or for their parents, carers or families\n\ndesigned primarily for adults but which accept, or may be used by, children and young people\n\nprovided by the public, private or voluntary sector, in the community or in (or via) primary care organisations.\n\nSome were small local schemes, others were available on a regional or national basis – such as those listed in the Department of Health's 'Child weight management programme and training providers framework' (Cross Government Obesity Unit 2009).\n\n# Financial consequences of childhood obesity\n\nUnless obesity is addressed in childhood, most of the financial consequences are likely to be incurred when treating and managing the obesity-associated diseases or conditions (comorbidities) that arise in adulthood. (These include type\xa02 diabetes, coronary heart disease and some cancers.)", 'Considerations': "# Introduction\n\nThe Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations, as follows. Please note: this section does not contain the recommendations.\n\n# The evidence\n\nThe PDG highlighted the need for greater consistency in reported outcome measures and the time points at which they are recorded, to allow for better comparison of the effectiveness and cost effectiveness of interventions.\n\nIn many studies, there was a lack of detail on the content of the intervention. This made it difficult to compare different approaches or methods and to determine which elements of 'multi-component' interventions contribute to overall effectiveness.\n\nReview 1 included studies from the UK, Western Europe, North America, Australia and New Zealand, because the potential applicability of the findings to the UK was considered to be high. The UK evidence included some lower quality, relatively small, uncontrolled studies. However, such studies were valuable in indicating a general 'direction of travel' in terms of the effectiveness of interventions.\n\nLimited data were available for children and young people of specific ages. No studies were found in which children younger than 6 were specifically targeted. Although several programmes had a lower age limit (of between 3 and 5\xa0years), none of the studies provided data separately for this age group. Most programmes aimed at very young children appeared to be aimed at all children, rather than those who were overweight or obese. Study participants were predominantly female. Only 2 studies included more boys than girls and, in most cases, there were at least 20% more girls than boys. However, the PDG noted from expert testimony and experience that, in the 'real world', there tends to be a more even mix of boys and girls among programme participants. Nevertheless, the importance of identifying barriers to involving more boys in intervention studies was noted.\n\nThere were limited and contradictory data on the impact of lifestyle weight management programmes according to socioeconomic group. In most studies, children and young people were from middle-income families. In the 2 UK studies that did have significant numbers from low-income families, no association was found between outcomes and socioeconomic group. However, a US study found that participation led to greater reductions in body mass index (BMI) z scores among those from higher income families.\n\nNo data were available on the effectiveness or cost effectiveness of lifestyle weight management services for children and young people with special needs. Nor were any data available on the barriers and facilitators to implementing lifestyle weight management services for this group. The PDG noted this gap in the evidence base and has made recommendations for research in this area.\n\nReview 1 considered the reported follow-up data for participants in the included studies. It did not consider any secondary prevention or weight maintenance programmes for children or young people who have previously been obese or overweight. There is also a lack of information on the views of those who do not take part or who drop out early from a lifestyle weight management programme. This is an important omission, because there is an association between BMI adjusted for age and sex (BMI z score) at baseline and drop-out rates. It is possible, therefore, that review 2 may not have fully captured the views of children and young people with higher BMI scores. Review 2 focused on the views of children, young people and their families about weight management programmes. It did not capture their views or experiences of the referral process.\n\n# Family-based approach\n\nThere is strong evidence from review 1 to suggest that targeting both parents and children, or whole families, is effective in reducing BMI z scores by the end the programme. In addition, the evidence on interventions involving families showed no negative effects on wellbeing and, in some cases, showed positive effects.\n\nA report commissioned for the PDG identified that it is more common for adolescents to attend programmes alone, or for parental attendance to be optional. That is despite evidence showing that parental or family involvement contributes to success in weight management. The recommendations for a whole-family approach therefore apply to older children and adolescents. However, the PDG acknowledged that flexibility is important as young people and older children become more independent, because some young people and some older children may prefer to attend separate sessions from their parents or carers. (This might be on a group or an individual basis.)\n\nMany overweight and obese children and young people may have, or come from a family with, a history of failed attempts to manage their weight. The Group noted the importance of exploring this shared history, along with family attitudes towards diet, physical activity and the amount of time spent being sedentary.\n\nEfforts to manage a child or young person's weight are not always supported, and are sometimes undermined, by members of the wider family. This is possibly because of a lack of understanding of the aims of lifestyle weight management programmes and the importance of managing the weight of obese or overweight children and young people. The PDG was aware that some family members may not attend the programme with the child or young person. (This may be true for non-resident parents, step-parents and grandparents.) With this in mind, the Group noted the importance of gaining the wider family's understanding and support and has made a recommendation to this effect.\n\n# Tailoring programmes\n\nThe PDG noted that lifestyle weight management programmes were often 'bought in' by commissioners and were rarely tailored to meet local needs. As a result, the recommendations highlight the importance of assessing local needs and ensuring programmes are tailored to address those needs.\n\nBecause of a dearth of evidence, the PDG has been unable to make age-specific recommendations. However, the Group does stress the importance of tailoring programmes according to age and stage of development.\n\nThe PDG did not make specific recommendations for children and young people with severe obesity. However, the Group was aware that some of them may attend a lifestyle weight management programme. For example, families may self-refer to these services, or they may be referred by health professionals following treatment at a specialist obesity service. Or they may attend a lifestyle weight management service (to support lifestyle changes) and also receive individual specialist support. The PDG highlighted the importance of developing an individually tailored plan that includes appropriate goals for all children and young people, including those from this group.\n\n# Determining whether a child is overweight or obese\n\nThe PDG recognised that although BMI is a practical estimate of overweight in children and young people, it is not a direct measure of adiposity. It acknowledged that it may be less accurate and need to be interpreted with caution in children and young people who are muscular or in those with earlier than average pubertal development. In addition, the Group was aware that there is evidence that adults from black and minority ethnic groups are at risk of obesity-associated conditions and diseases (comorbidities), such as type 2 diabetes, at a lower BMI than the white European population. However, it was beyond the remit of this guidance to assess whether the same applies to children and young people.\n\n# Referring on to specialist services\n\nThe PDG recognised that complex obesity (in which someone who is obese also has obesity-associated diseases or conditions [comorbidities]) can occur at any level of obesity (although this is more likely, as BMI increases). That is why the Group recommended the use of a comorbidity assessment tool. The aim was to ensure that, if necessary, children and young people are referred on for specialist support. However, the PDG was unable to identify an appropriate assessment tool for use by lifestyle weight management services. The Group viewed development of such a tool as a priority and made a research recommendation to this effect.\n\nThe PDG heard from expert testimony that overweight and obese children are often victimised and that this can lead to depression. The Group also heard that emotional and behavioural problems and impaired quality of life have been observed in obese pre-school children. Behaviours such as binge eating are also more likely in obese adolescents than in adolescents of a healthy weight. Treatment of these conditions was beyond the scope of this guidance. However, the PDG noted the importance of ensuring that any such potential issues are identified and that the child or young person is referred on for specialist support if necessary.\n\n# Children and young people with special needs\n\nThe PDG was aware that some children and young people with disabilities, learning difficulties or other special needs may have particular problems managing their weight. This may be because of their underlying condition, or because their physical activity is limited. The PDG also recognised the importance of ensuring they have access to appropriate services to help them manage their weight. In addition, it acknowledged the statutory duty upon public bodies to look at ways of ensuring equal access to services.\n\nThe PDG noted that many overweight or obese children and young people with more complex needs will need the support of a specialist obesity service or other specialist services to help manage their weight. However, members also noted that some providers have developed lifestyle weight management programmes for children and young people with mild to moderate learning difficulties or for disabled children. Others have adapted existing programmes and trained staff to accommodate their needs. The PDG welcomed such approaches and encouraged evaluation of them.\n\n# Encouraging adherence to programmes\n\nThe PDG was particularly concerned about the practical issues that may prevent potential participants from taking part in, or continuing to attend, a lifestyle weight management programme. This includes the location and type of venue where programmes are delivered and participants' need to accommodate other family commitments.\n\nEvidence from review 2 highlighted how important it is to ensure the family and the child or young person recognise and accept that they are overweight or obese. Conversely, a lack of recognition or denial that the child or young person is overweight or obese can hinder uptake and adherence to a lifestyle weight management programme. The recommendations reflect this finding, including a recommendation for further research as to how this may be best achieved.\n\nThe PDG debated whether lifestyle weight management services should be offered to groups of families or to families on an individual basis. Evidence shows that both approaches are effective in reducing BMI adjusted for age and sex (BMI\xa0z scores). The PDG noted from expert testimony that group sessions can provide a good opportunity to see how others with similar goals have succeeded. They also provide peer support to build the child or young person's self-belief that they, too, can succeed. The PDG acknowledged that individual sessions were likely to be more resource intensive. However, the Group was aware that some children and young people may not feel able to discuss or address their weight in a group setting. For this reason, the PDG recommended flexibility as necessary.\n\n# Behaviour-change techniques\n\nThe PDG heard from expert testimony that behaviour-change techniques are effective in lifestyle weight management programmes for children and young people and are widely used. (This includes self-monitoring, stimulus control and goal-setting.) A 'package' of these techniques is usually included in the programme, because it is not known how much each element contributes to effectiveness. The PDG has therefore made a recommendation for more research in this area.\n\nThe PDG heard that aspects of cognitive behavioural therapy are used by some lifestyle weight management programmes, usually with older children or adolescents. This therapy focuses on understanding unhelpful or inaccurate thought processes, then changing behaviour to encourage new ways of thinking. It is usually delivered by staff who have received specialist training. However, current evidence does not allow conclusions to be drawn on its effectiveness.\n\n# Increasing uptake of programmes\n\nReview 2 identified a lack of awareness of the availability of lifestyle weight management programmes among health professionals. In addition, the former Childhood Obesity National Support Team found that programmes frequently ran below capacity. The PDG was therefore aware of the need to increase both self-referrals and referrals by health professionals – including the need to agree clear referral pathways.\n\nThe PDG identified a wide range of 'actors' who could raise awareness of lifestyle weight management programmes. In particular, the PDG noted that staff conducting the National Child Measurement Programme were in an ideal position to direct parents and carers to these programmes for advice and support.\n\nThe key aims of the Healthy Child Programme: pregnancy and the first 5 years of life include early recognition of risk factors for obesity, prevention and early intervention. The Programme's approach is consistent with this guidance. For example, it recommends working in partnership with the family, setting achievable goals and exploring earlier life experiences in relation to obesity. The PDG recognised the important contribution that staff delivering the Healthy Child Programme could make in raising awareness of, and formally referring children and their families to, lifestyle weight management programmes. It also recognised their potential role in providing ongoing support.\n\n# Training and support\n\nReview 2 and the former National Support Team for Childhood Obesity findings both highlighted the need to train lifestyle weight management programme staff and health professionals referring people to the programmes.\n\nThe PDG noted that staff may lack the confidence and skills to raise the issue of weight management with potential participants and identified this as a training need. In addition, the National Support Team for Childhood Obesity found that a lack of confidence to deliver weight management interventions was sometimes linked to the programme staffs' own unhealthy weight. The PDG noted the need to offer these staff support to manage their weight.\n\n# Sustaining behaviour changes\n\nThe PDG did not make recommendations regarding the optimal length of programmes. A meta-analysis conducted for review\xa01 showed that the duration of programmes was associated with improved BMI z scores in programmes lasting between 8 and 24\xa0months. However, once the programme was completed, the effect disappeared over time and was non-significant at 6\xa0months after completion. The PDG therefore stressed the importance of ongoing support and follow-up once programmes are completed.\n\nThe PDG has recommended that participants completing programmes are given information about relevant local support services. However, the Group has not made recommendations regarding those services because this is beyond the scope of the guidance. It noted that a number of pieces of NICE guidance have made recommendations in this area (see NICE's topic page on obesity).\n\nThe PDG noted that many lifestyle weight management services for children and young people were often commissioned in isolation and in response to a short-term funding opportunity. The Group highlighted the importance of commissioning these services as part of a wider, more sustainable approach to preventing and treating obesity. This approach is reflected in this guidance. It is also addressed in detail by NICE's guideline on obesity: working with local communities.\n\n# Monitoring, evaluation and setting outcome measures\n\nThe PDG noted there had been little robust monitoring and evaluation of lifestyle weight management programmes. The Group also noted that new local authority responsibilities for public health may be an opportunity to embed monitoring requirements into service specifications and contracts. Periodic evaluations into planning and commissioning strategies may also be possible.\n\nThe PDG debated at length the choice of suitable outcome measures for lifestyle weight management programmes for children and young people. The Group agreed that the primary goal, in the longer term, is to reduce BMI for age and sex (BMI z scores). However, it was aware that, in practice, most programmes run for only around 8 to 12\xa0weeks – and substantial reductions in that time may be difficult to achieve.\n\nA report commissioned for the PDG identified unrealistic outcome measures as a barrier to providers working effectively with commissioners. Nevertheless, the PDG was aware that a reduction in BMI for age and sex is sometimes used by commissioners as a key performance indicator. Financial penalties may, in some cases, be attached to failure of providers to achieve this outcome.\n\nThe PDG recognised that maintaining weight (and preventing further weight gain) is the short-term aim of many lifestyle weight management programmes for children and young people. The rationale is that if the child maintains their weight as they grow in height over time, their BMI will be reduced. The PDG acknowledged that young people who are no longer growing taller will ultimately need to lose weight to improve their BMI. However, the Group also recognised that this takes time. Members considered that an appropriate short-term aim may be to avoid further weight gain while the young person acquires the skills and knowledge they need to make behavioural changes. Over time, as the changes to their behaviour become established, there should be a positive effect on their BMI.\n\nThe PDG felt it was very important to sustain any positive outcomes beyond the duration of a lifestyle weight management programme. Therefore, the Group placed an emphasis on sustaining long-term change.\n\nThe PDG recognised the importance of retaining participants in the programme. This is based on evidence that the greater the proportion of total programme sessions a child or young person attends, the more likely they are to succeed. This is reflected in a number of recommendations.\n\n# Economic considerations\n\nThe economic model defines a child or young person as overweight if their BMI (adjusted for age and sex) lies between the 85th and 95th centiles of the UK 1990 centile chart. These centiles correspond to BMI z scores of 1 and 2 respectively for the UK 1990 centile chart. They are used for defining whether someone is overweight or obese in population studies and for monitoring populations, rather than for the clinical management of individuals. In the model, a child or young person whose BMI (adjusted for age and sex) lies between the 95th and the 99.5th centile is defined as obese; children and young people above the 99.5th centile are described as 'morbidly obese'.\n\nHow the average weight of children of a particular age and sex changes over time can be referred to as their 'weight trajectory'. All other factors being equal, the BMI\xa0z score of this group of children will be maintained. So the aim of programmes for overweight or obese children and young people is to help them make changes so that they move to a lower weight trajectory. This might be achieved by: losing weight; by maintaining weight as a child grows in height; or by gaining less weight than would have been expected. In all cases, they will weigh less than would have otherwise been expected over the same time period.\n\nThe economic model estimated that interventions costing £100 per person would usually be cost effective from a public sector perspective. This would be the case if a group of overweight or obese children could be moved to a lower average weight trajectory and this was maintained throughout life. (This is true for a weight loss of as little as 0.5%.) Interventions that permanently lower weight trajectory by an average 3% are estimated to be cost effective, if their average cost is less than £1000 per child.\n\nThe cost effectiveness of interventions for children and young people who are morbidly obese, as defined by the model, was unclear. The PDG concluded that interventions for children who are morbidly obese would need to lower their BMI z score considerably to be worth doing.\n\nThere was little evidence on whether children and young people can maintain for life the lower weight trajectory they may achieve during a lifestyle weight management programme. If they do, the economic model concludes that interventions that cause very small average decreases in weight trajectory will be worth undertaking. However, if the weight is regained quickly and they revert to their previous weight trajectory, then the intervention is estimated not to be cost effective. For example, the model looked at an intervention for overweight boys or girls aged from 12 to 17 that cost an average £437 per person. To be cost effective, their average weight trajectory, following an initial average weight loss of 5% of body weight, must lie below what it would have been without the intervention for at least 11\xa0years.\n\nIf the weight of each participant in a lifestyle weight management programme is reduced by an average of 0.5% – and the post-intervention weight trajectory is maintained for life – the model estimates that interventions costing up to about £500 per child will be cost effective for both girls and boys and for each category of overweight and obesity. Interventions costing £2000 per child are estimated to need weight losses of 3 to 5%, maintained for life, to be cost effective for children who are borderline overweight, but of 2% (maintained for life) for children who are obese or morbidly obese.\n\nThe model assumes a discount rate of 3.5% per year for both costs and health benefits. Most of the health benefits of providing a lifestyle weight management programme for overweight and obese children and young people accrue in the later stages of life. As a result of discounting, these benefits are given a relatively low value compared with a health benefit that is immediate. Reducing the discount rate to 1.5% per year has the effect of increasing the present value of future health benefits considerably, and thus improves cost effectiveness.", 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects.\n\n# Recommendation 1 Research studies and trials\n\n## Who should take action?\n\nResearch councils, commissioners and funders.\n\n## What action should they take?\n\nResearch studies and trials of lifestyle weight management programmes for children and young people who are obese or overweight should:\n\nStandardise outcome measures to assess effectiveness. Outcomes should be reported on an 'intention to treat' basis (as opposed to reporting outcomes for programme completers only). They should include:\n\n\n\nchanges in body mass index (BMI)\xa0z score, as the primary outcome measure\n\nfactors that affect weight (matching these to the intervention objectives) for example, measures of self-efficacy, changes in diet, physical activity and time spent being sedentary and measures of wellbeing.\n\n\n\nStandardise the time points at which outcome measures are reported and followed up. They should include, as a minimum: at baseline, completion of the intervention and at 6\xa0months and at 1\xa0year after completing the intervention.\n\nReport in detail the components of the intervention. This should include: what is done, to whom, by whom, in which setting, and when and how?\n\nInclude an appropriate comparator group and report the components above. If a randomised controlled trial is not possible, alternative research designs should be considered.\n\nReport attrition (drop-out) rates, follow up non-completers and investigate the causes of attrition. Also should investigate the causes of low uptake and how these might be addressed.\n\nBe sufficiently powered to detect effects.\n\nIf possible, use only standardised validated tools (appropriate for the study sample) to collect data, for example, a validated food frequency questionnaire to investigate dietary intake. If validated tools for secondary measures do not exist, a tool to measure the outcome (for example, physical activity) should be developed as part of the study.\n\nInclude the collection and analysis of qualitative data to allow a process evaluation of the intervention. These data should include the referral process and experiences of both programme staff and participants.\n\nInclude the collection of cost data to allow cost effectiveness to be evaluated.\n\nReport any unexpected effects or outcomes.\n\n# Recommendation 2 Longer-term programme evaluation\n\n## Who should take action?\n\nResearch councils, commissioners and funders.\n\n## What action should they take?\n\nConsider funding longer term research studies and trials of lifestyle weight management programmes for children and young people who are obese or overweight. Ideally studies should last between 5 and 10\xa0years.\n\n# Recommendation 3 Barriers and facilitators\n\n## Who should take action?\n\nResearch councils, commissioners and funders.\n\nResearchers and investigators.\n\n## What action should they take?\n\nDetermine any variation in the barriers to, and facilitators for, participating in lifestyle weight management programmes for overweight and obese children and young people and their families (including beliefs about obesity). Include:\n\n\n\nethnicity and cultural aspects\n\nsocioeconomic group\n\ngender (boys in particular)\n\nage.\n\n\n\nAsk parents, carers and families of children younger than 6 what factors encourage or discourage overweight and obese children to participate (or not) in lifestyle weight management programmes. Determine how these might be addressed.\n\nInvestigate the barriers to, and facilitators for, implementing lifestyle weight management services for overweight and obese children and young people with special needs. Determine how these might be addressed.\n\n# Recommendation 4 Weight management programmes\n\n## Who should take action?\n\nResearch councils, commissioners and funders.\n\nResearchers and investigators.\n\n## What action should they take?\n\nConsider which components of multi-component interventions determine effectiveness and cost effectiveness.\n\nInvestigate effective and cost-effective approaches to lifestyle weight management for children younger than 6\xa0years.\n\nInvestigate effective and cost-effective approaches to lifestyle weight management for children and young people with special needs. How can their needs, and the needs of their families, best be met? What training would staff need to deliver such interventions?\n\nDetermine the long-term effectiveness of programmes. Do children and young people who have lost or maintained their weight in a lifestyle weight management programme maintain this in the long term and, if so, for how long? What programme characteristics facilitate longer term effectiveness?\n\nExamine how best to communicate the individual measures of the National Child Measurement Programme to parents and carers to ensure they take action, as needed, without causing distress.\n\nInvestigate how to encourage parents and carers to take responsibility for their child's weight management. This includes how best to help parents, carers and families recognise when children and young people are overweight or obese. It also includes how to encourage parents and carers to participate in programmes.\n\nInvestigate what impact parents and carers have on the outcomes of programmes.\n\nExamine who is best placed to deliver lifestyle weight management programmes (including lay people) for children and young people and what their training needs are.\n\nInvestigate effective and appropriate ways of getting children and young people involved in lifestyle weight management programmes. This might include use of new technology such as texting or phone apps.\n\nInvestigate and develop a comorbidity assessment tool for use by lifestyle weight management services, to ensure that, if necessary, children and young people are referred for specialist support.\n\nMore detail identified during development of this guidance is provided in Gaps in the evidence.", 'Glossary': "# Behaviour-change techniques\n\nBehaviour-change techniques are techniques aimed at changing the way someone acts (and so, logically, their thinking patterns). In this case, the changes relate to dietary intake and eating behaviour, physical activity and sedentary behaviour.\n\n# Body mass index (BMI)\xa0z score\n\nBMI\xa0z score is a measure of how many standard deviations a child or young person's BMI is above or below the average BMI for their age and gender. (This is based on a reference population known as a child growth reference.) For instance, a z score of 1.5 indicates that a child is 1.5 standard deviations above the average value, and a z score of -1.5 indicates a child is 1.5 standard deviations below the average value.\n\nThe advantage of using BMI\xa0z scores, instead of BMI, is that it allows direct comparison of BMI (and any changes in BMI) across different ages and by gender. This term is sometimes used interchangeably with 'BMI standard deviation score' (BMI\xa0SDS). See the National Obesity Observatory's simple guide to classifying body mass index in children.\n\nCare is needed when interpreting BMI\xa0z scores using the UK 1990 centile charts for black, Asian and other minority ethnic groups. There is evidence to suggest that adults from these groups are at risk of obesity-associated conditions and diseases at a lower BMI than the white population. See NICE's guideline on obesity: identification, assessment and management. However, there are no growth reference charts for children from minority ethnic groups. (For more details on the differences in BMI thresholds as a trigger for disease among children in these groups, see the National Obesity Observatory's report on obesity and ethnicity.)\n\n# Body mass index (BMI)\n\nBody mass index is defined as a person's weight in kilograms divided by the square of their height in metres and is reported in units of kg/m2. Specific cut-off points are used to assess whether a person is a healthy weight, underweight, overweight or obese. For children and young people these are related to age and gender.\n\n# Child and adolescent mental health services (CAMHS)\n\nChild and adolescent mental health services are specialist mental health services for children and young people.\n\n# Clinical commissioning groups\n\nClinical commissioning groups (CCGs) are responsible for commissioning a range of healthcare services for children and adults. This includes specialist obesity services (sometimes called tier 3 services). The groups do not directly commission lifestyle weight management services (sometimes called tier 2 services). Rather, they work with local authorities to coordinate and integrate planning and commissioning through the health and wellbeing board.\n\n# Comorbidities\n\nComorbidities are diseases or conditions that someone has in addition to the health problem being studied or treated. Some comorbidities, such as type\xa02 diabetes, are associated with being overweight or obese, because the risk of developing them increases with an increasing BMI.\n\n# Complex obesity\n\nComplex obesity occurs when someone who is obese has additional and related diseases or conditions, for example, type 2 diabetes. It can also occur when obesity results from an underlying condition, for example, an endocrine disease or condition, or when it is associated with various syndromes (such as Prader-Willi syndrome). Complex obesity can occur regardless how obese the person is, although it is more likely as BMI increases.\n\n# Evaluation\n\nEvaluation involves assessing whether an intervention is meeting its objectives. This might include outcomes (for example, effectiveness in terms of BMI z score reduction or value for money). It might also include evaluation of processes (for example, how successful recruitment is or how acceptable the intervention is to participants).\n\n# Health and wellbeing boards\n\nHealth and wellbeing boards are based in upper tier and unitary local authorities. They aim to improve health and care services and the health and wellbeing of local people. They bring together key commissioners in the locality, including representatives of clinical commissioning groups, public health, children's services and adult social services. They include at least 1 elected councillor and a representative of HealthWatch. The board develops a health and wellbeing strategy for the local area. This is based on an assessment of local needs, including a joint strategic needs assessment.\n\n# Joint strategic needs assessments (JSNAs)\n\nJoint strategic needs assessments (JSNAs) identify the current and future health needs of a local population. They are used as the basis for the priorities and targets set.\n\n# Lifestyle weight management programmes\n\nIn this guidance, lifestyle weight management programmes refer to programmes that focus on diet, physical activity, behaviour change or any combination of these elements.\n\n# Lifestyle weight management services\n\nIn this guidance, lifestyle weight management services (sometimes called tier 2 services) refer to services that help people in a particular geographical location who are overweight or obese. The service can be made up of 1 or more lifestyle weight management programmes. The programmes are usually based in the community and may be run by the public, private or voluntary sector.\n\n# Local authority commissioners\n\nLocal authorities commission some public health services for children and young people aged 5\xa0to 19\xa0years. They have a mandatory responsibility to deliver the National Child Measurement Programme. They also commission non-mandatory services such as school nursing and community-based weight management services.\n\n# Monitoring\n\nMonitoring involves routine collection, analysis and reporting of a set of data to assess the performance of a weight management programme according to the service specification and intended health outcomes.\n\n# National Child Measurement Programme\n\nThe National Child Measurement Programme (NCMP) measures the weight and height of children in reception class (aged 4\xa0to\xa05) and Year\xa06 (aged 10\xa0to\xa011). The aim is to assess the prevalence of obesity and overweight among children of primary school age, by local authority area. These data can be used at a national level to support local public health initiatives and inform local services for children.\n\n# NHS England\n\nNHS England commissions primary care, clinical and specialised services. It also commissions public health services for children aged 0\xa0to 5\xa0years (including health visiting and much of the Healthy Child Programme). In 2015, the organisation's public health services transfer to local authorities.\n\n# Obesity care or weight management pathway\n\nAn obesity care or weight management pathway represents the various routes through local services that an individual child or young person might follow to help them manage their weight. A comprehensive obesity care or weight management pathway spans both prevention and treatment, offering services at different levels or 'tiers'. Children and young people may move between these services. In adult obesity care pathways, there may also be a further tier focusing on surgical treatment (sometimes called tier\xa04 services). Surgery is recommended for children and young people only in exceptional circumstances, see NICE's guideline on obesity prevention.\n\n# Physical activity\n\nPhysical activity includes the full range of human movement. It includes everyday activities such as walking or cycling for everyday journeys, active play, work-related activity, active recreation (such as working out in a gym), dancing, gardening or playing active games, as well as organised and competitive sport.\n\n# Positive parenting skills training\n\nPositive parenting skills training is training for parents and carers that aims to improve children and young peoples' behaviour. It fosters effective boundary setting and the need to reward and praise children in a way that promotes positive relationships and self-esteem.\n\n# Providers of lifestyle weight management programmes\n\nProviders of lifestyle weight management programmes are private, public or voluntary sector organisations offering lifestyle weight management services in the community or in (or via) primary care settings.\n\n# Public Health England\n\nPublic Health England is an executive agency of the Department of Health. It provides advice and expertise to local authorities, NHS England and clinical commissioning groups on the commissioning of public health services.\n\n# Rolling programmes\n\nRolling programmes are lifestyle weight management programmes that run on a continuous basis. Participants can start and end the programme at different points, covering the same material over the same number of weeks or months, but not necessarily in the same order. An advantage is that participants referred part way through a programme cycle do not have to wait for it to be completed and a new one to start before they join.\n\n# Sedentary behaviour\n\nSedentary behaviour describes activities that do not increase energy expenditure much above resting levels. Sedentary activities include sitting, lying down and sleeping. Associated activities, such as watching television, are also sedentary.\n\n# Specialist obesity services\n\nIn this guidance, specialist obesity services (sometimes called tier 3 services) usually refer to clinical treatments provided by specialist services. This may include the use of drugs. These services could be for children or young people with severe or complex obesity, or with other special needs.\n\n# Stimulus control\n\nStimulus control relates to the way someone's behaviour changes as a result of a particular trigger. For example, having the television on can encourage someone to sit and watch it (that is, adopt sedentary behaviour); turning it off could encourage them to do something that is more physically active. Or if a person trying to manage their weight finds it hard to resist high fat or sugary snacks, family members could be asked not to eat those snacks around that person.\n\n# Universal obesity prevention services\n\nIn this guidance, universal obesity prevention services (sometimes called tier 1 services) refer to activities to help prevent everyone, regardless of their weight, from becoming overweight or obese. These universal services help raise awareness of the importance of maintaining a healthy weight. They also develop and promote services, facilities and policies that enable children, young people and their families to eat more healthily and be more physically active. For example, by providing walking and cycling routes and safe areas for active play, or by working with caterers in schools, colleges and early years organisations to improve the food choices on offer.\n\n# UK 1990 centile charts\n\nUK 1990 centile charts, also referred to as the British 1990 growth reference (UK90), are charts used for children aged 4 years and older to determine whether their BMI is appropriate for their age and gender. See the National Obesity Observatory's simple guide to classifying body mass index in children.", 'References': "Aicken C, Arai L, Roberts H (2008) Schemes to promote healthy weight among obese and overweight children in England. London: EPPI Centre, Social Science Research Unit\n\nBromfield PV (2009) Childhood obesity: psychosocial outcomes and the role of weight bias and stigma. Educational Psychology in Practice 25: 193–209\n\nChief Medical Officer (2008) The Chief Medical Officer's report 2007. Under their skins: tackling the health of the teenage nation. London: Department of Health\n\nCraig L, Love J, Ratcliffe B et al. (2008) Overweight and cardiovascular risk factors in 4–18 year olds. Obesity Facts 1: 237–42\n\nCross Government Obesity Unit (2009) Healthy weight, healthy lives: child weight management programme and training providers network. London: Department of Health\n\nDepartment of Health (2011) Healthy lives, healthy people: a call to action on obesity in England. London: Department of Health\n\nDepartment of Health (2009) Healthy child programme: from 5 to 19 years old. London: Department of Health\n\nDiabetes UK (2011) Diabetes in the UK 2011/2012: key statistics on diabetes. [online]\n\nFigueroa-Munoz JI, Chinn S, Rona RJ et al. (2001) Association between obesity and asthma in 4–11 year old children in the UK. Thorax 56: 133–7\n\nForesight (2007) Tackling obesities: future choices. London: Government Office for Science\n\nGriffiths LJ, Parsons TJ, Hill AJ (2010) Self-esteem and quality of life in obese children and adolescents: a systematic review. International Journal of Pediatric Obesity 5: 282–304\n\nGriffiths LJ, Wolke D, Page AS et al. (2006) Obesity and bullying: different effects for boys and girls. Archives of Disease in Childhood 91: 121–5\n\nKoebnick C, Smith N, Black MH et al. (2012) Paediatric obesity and gallstone disease. Journal of Paediatric Gastroenterology and Nutrition 55: 328–33\n\nLogue J, Sattar N (2011) Childhood obesity: a ticking time bomb for cardiovascular disease? Nature 90: 174–8\n\nLowry KW, Sallinen, BJ, Janicke, DM (2007) The effects of weight management programs on self-esteem in pediatric overweight populations. Journal of Pediatric Psychology 32: 1179–95\n\nMurray AW, Wilson NIL, et al. (2008) Changing incidence of slipped capital femoral epiphysis. A relationship with obesity? The Journal of Bone and Joint Surgery 90-B: 92–4\n\nNHS Information Centre (2013) Statistics on obesity, physical activity and diet: England. London: The Health and Social Care Information Centre\n\nNHS Information Centre (2012) National child measurement programme: England, 2011/12 school year. London: Department of Health\n\nPerez-Pastor EM, Metcalf BS, Hosking J et al. (2009) Assortative weight gain in mother-daughter and father-son pairs: an emerging source of childhood obesity. Longitudinal study of trios (EarlyBird 43). International Journal of Obesity 33: 727–35\n\nSjoberg RL, Nilsson KW, Leppert J (2005) Obesity, shame, and depression in school-aged children: A population based study. Pediatrics 116: e389–92\n\nTaylor ED, Theim KR, Mirch MC et al. (2006) Orthopedic complications of overweight in children and adolescence. Pediatrics 117: 2167–74\n\nWei C, Ford A, Hunt L et al. (2011) Abnormal liver function in children with metabolic syndrome from a UK based obesity clinic. Archives of Disease in Childhood 96: 1003–7", 'Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews, commissioned report and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in About this guidance.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were:\n\nHow effective and cost effective are lifestyle weight management programmes in helping overweight or obese children and young people to achieve and maintain a healthy weight?\n\nWhat are the essential components of an effective and cost-effective weight management programme for overweight and obese children and young people?\n\nThe subsidiary questions were:\n\n. How does effectiveness and cost effectiveness vary for different population groups? (Examples may include children and young people from different black and minority ethnic groups, from low-income groups, of different ages or genders, or with special needs.)\n\n. What are the most effective and cost-effective ways of addressing and sustaining behavioural change among overweight and obese children and young people using community-based weight management programmes?\n\n. How does the inclusion of parents, carers and the wider family impact on the effectiveness of community-based weight management programmes for children and young people?\n\n. What barriers and facilitators affect the delivery of effective weight management programmes for children and young people and how do they vary for different population groups?\n\n. What are the views, perceptions and beliefs of the children, young people and their families who use weight management services?\n\n. What are the views, perceptions and beliefs of the staff responsible for commissioning and delivering weight management services to children and young people?\n\n. How can more overweight and obese children and young people be encouraged to join, and adhere to, lifestyle weight management programmes?\n\nThese questions were made more specific for each evidence review.\n\n# Reviewing the evidence\n\n## Effectiveness reviews\n\nOne review of effectiveness and cost effectiveness was conducted (Review\xa01).\n\nA number of databases were searched in May 2012 for relevant studies published in English from January 2000. See the review for details of the databases searched.\n\nIn addition, randomised controlled trials (RCTs), economic evaluations and views studies published between 1990 and 1999 were identified and included using 'snowballing' methods. (Systematic reviews, reference list checking and citation tracking were 'unpicked' from the Scopus and Science Citation Index databases.)\n\nNICE also issued a call for evidence from registered stakeholders in May\xa02012.\n\nStudies were included in the effectiveness and cost-effectiveness review if they:\n\ncovered children and young people aged below 18\xa0years who were overweight or obese, or their parents, carers and families\n\nconsidered lifestyle weight management programmes for obese and overweight children and young people that focus on diet, physical activity or behaviour change, or any combination of these factors\n\nmeasured changes in weight, diet, physical activity, wellbeing or satisfaction with the service\n\nwere carried out in the UK (any study design)\n\nwere RCTs and quasi-RCTs (randomisation method unclear) of 100 or more participants from Australia, Canada, New Zealand, the US and other western European countries\n\nreported health economic outcomes.\n\nStudies were excluded if they:\n\nfocused on young women under\xa018 who were pregnant\n\nwere RCTs involving a population of less than 40\n\nfocused on clinical treatment of obesity.\n\nSee evidence review\xa01: effectiveness and cost effectiveness of lifestyle weight management services for children and young people.\n\n## Other reviews\n\nOne review of barriers and facilitators to implementing lifestyle weight management programmes for children and young people was conducted (review 2).\n\nThe same databases and websites were searched as for review 1.\n\n## Selection criteria\n\nStudies were included in the review if they:\n\nconsidered lifestyle weight management programmes for obese and overweight children and young people that focused on diet, physical activity or behaviour change, or any combination of these factors\n\nwere qualitative, survey and other observational studies of the barriers and facilitators to delivering such interventions or the views, perceptions and beliefs of those using and delivering them\n\nwere conducted in Australia, Canada, New Zealand, the US or western Europe\n\nStudies were excluded if they:\n\nfocused on young women under\xa018 who were pregnant\n\nfocused on clinical treatment of obesity\n\nreported intrapersonal barriers and facilitators to losing or managing weight not associated with the participation in, or delivery of, weight management programmes\n\nwere quantitative studies that did not measure attitudes (for example, correlation studies).\n\nSee evidence review\xa02: the barriers and facilitators to implementing lifestyle weight management programmes for children and young people.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in Methods for the development of NICE public health guidance. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n− Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nThe evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable).\n\n## Summarising the evidence and making evidence statements\n\nThe review data were summarised in evidence tables (see full reviews).\n\nThe findings from the reviews and expert reports were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see About this guidance). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Commissioned report\n\nA short report was commissioned on practical and process issues related to the provision of lifestyle weight management services for children and young people. It synthesised responses to a questionnaire submitted by service providers. See the commissioned report on practical and process issues in the provision of lifestyle weight management services for children and young people.\n\n# Cost effectiveness\n\nThe existing cost-effectiveness evidence was reviewed as part of evidence review\xa01: effectiveness and cost effectiveness of lifestyle weight management services for children and young people.\n\nIn addition, an economic model was constructed. The results are reported in: Managing overweight and obesity among children: report on economic modelling and cost consequence analysis. This was produced by M Brown, T Marsh, K Rtveladze (all from the UK Health Forum, formerly the National Heart Forum) and R Fordham, M Suhrcke, D Turner, R Little and O Filani (all from the University of East Anglia).\n\n# How the PDG formulated the recommendations\n\nAt its meetings in July, October and December 2012 and January, February and July 2013, the Programme Development Group (PDG) considered the evidence, expert reports and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nThe PDG developed recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to an evidence statement(s) (see the evidence section for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).", 'The evidence': "This section lists the evidence statements from 2 reviews provided by external contractors (see the section on what evidence is the guidance based on?) and links them to the relevant recommendations. (See the section on summary of the methods used to develop this guidance for the key to quality assessments.)\n\nThis section also lists 6 expert papers and 1 report commissioned by the Programme Development Group (PDG) and their links to the recommendations and sets out a brief summary of findings from the economic analysis.\n\nThe evidence statements are short summaries of evidence, in a review. Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document.\n\nEvidence statement number 1.2.3 indicates that the linked statement is numbered 2.3 in review\xa01. Evidence statement number 2.1.1 indicates that the linked statement is numbered 1.1 in review\xa02. EP1 indicates that expert paper\xa01 is linked to a recommendation and CR1 indicates that the commissioned report is linked to a recommendation.\n\nSee the full reviews, expert reports, commissioned report and economic analysis. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: evidence statements 1.1.10, 1.1.16, 1.1.33, 1.1.34, 1.1.35, 1.1.36, 1.2.3; EP1\n\nRecommendation 2: evidence statements 2.1.40, 2.1.41, 2.1.42; EP1, EP2, EP4, CR1; IDE.\n\nRecommendation 3: evidence statements 1.1.10, 1.1.16, 1.1.33, 1.1.34, 1.2.2, 1.2.3, 1.4.1, 1.4.2, 2.1.13, 2.1.14, 2.1.15, 2.1.16, 2.1.17, 2.1.23, 2.1.25, 2.1.26, 2.1.27, 2.1.32, 2.1.33, 2.1.34; EP3, EP5, EP6\n\nRecommendation 4: evidence statements 1.1.14, 1.2.3, 1.4.1, 1.4.2, 2.1.5, 2.1.8, 2.1.10, 2.1.13, 2.1.15, 2.1.25, 2.1.26, 2.1.27, 2.1.31, 2.1.33, 2.2.4, 2.2.5; EP3, EP6; IDE\n\nRecommendation 5: evidence statements 1.1.10, 1.1.16, 1.2.3, 1.4.3, 2.1.12, 2.1.13, 2.1.15, 2.1.22, 2.1.23, 2.1.24, 2.1.28, 2.1.29, 2.1.30, 2.1.38, 2.1.39, 2.2.4, 2.2.5; EP5, CR1, IDE\n\nRecommendation 6: evidence statements 2.1.11, 2.1.18, 2.1.19, 2.1.20, 2.1.32; EP1, CR1; IDE\n\nRecommendation 7: evidence statements 2.1.18, 2.1.19; 2.1.20; EP1; IDE\n\nRecommendation 8: evidence statements 1.2.7, 1.4.3, 2.1.4, 2.1.7, 2.1.8, 2.1.9, 2.1.10, 2.1.11, 2.1.14, 2.1.16, 2.1.19; EP1, EP3, CR1; IDE\n\nRecommendation 9: evidence statements 1.1.33, 1.1.34, 1.4.1, 1.4.2, 1.4.3, 2.1.1, 2.1.2, 2.1.3, 2.1.4, 2.1.34; EP3, CR1; IDE\n\nRecommendation 10: evidence statements 1.1.33, 1.1.34, 1.4.1, 1.4.2, 2.1.34, 2.1.35, 2.1.36, 2.1.37; CR1; IDE\n\nRecommendation 11: evidence statements 2.1.8, 2.1.10, 2.1.11, 2.1.38, 2.1.39, 2.1.41, 2.1.42; EP1, EP5, CR1; IDE\n\nRecommendation 12: evidence statements 2.1.38, 2.1.39, 2.1.41, 2.1.42; EP1, EP3, EP5, EP6, CR1; IDE\n\nRecommendation13: evidence statements 1.2.4, 2.1.8, 2.1.10, 2.1.19; EP1; IDE\n\nRecommendation 14: EP1; IDE\n\nRecommendation 15: evidence statements 1.4.1, 1.4.2; EP1, EP4, EP5 CR1; IDE\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement 1.1.10 Child and parent/carer interventions – anthropometric outcomes\n\nThere is strong evidence from 8 studies (3 [++] randomised controlled trials [RCTs], 2 [+] RCTs, 2 [−] quasi-RCTs and 1 [−] uncontrolled before-after [UBA] study) that child/adolescent and parent interventions result in significant decreases in body mass index (BMI)\xa0z score based on baseline to follow-up within group measures. This evidence is directly applicable because the studies were carried out in community settings in the USA, Australia and the UK.\n\n## Evidence statement 1.1.14 Child and parent/carer interventions – wellbeing outcomes\n\nThere is strong evidence from 2 (++) RCTs that group-based behaviour-change interventions directed at children/adolescents and parents have significant beneficial effects on some psychosocial outcomes. One (++) RCT showed a group difference at 18 months for body satisfaction (p=0.026) and appearance (p=0.019) although no group differences on other psychosocial outcomes. A second (++) RCT showed group difference at 12\xa0months for scholastic competence (p=0.049), but not other psychosocial outcomes. Two hundred and eight overweight adolescent females aged 12\xa0to\xa017 received a 5‑month intervention delivered by nutritionists, health educators and clinical psychologists. Dietitians delivered a 2‑year intervention to 151 overweight and obese adolescents (52% female). This evidence is directly applicable because studies were conducted in community settings respectively in the USA, Australia and the UK.\n\n## Evidence statement 1.1.16 Family interventions – anthropometric outcomes\n\nThere is strong evidence from 18 papers on 17 studies (5 [++] RCTs, 4 [+] RCTs, 1 [+] quasi-RCT, 1 [−] quasi-RCT and 6 [−] UBAs) that, for overweight and obese children and adolescents, whole family interventions whether directed at individual families or group-based result in significant decreases in BMI\xa0z score based on baseline to follow-up for within group measures. All but 1 UBA (which focused on diet and physical activity) and 1 quasi-RCT (behaviour change only) assess the effectiveness of multi-component interventions focusing on behaviour change. This evidence is applicable because all studies are community-based, 11 were conducted in the UK, 3 in the USA, 2 in Australia and 1 in Italy.\n\n## Evidence statement 1.1.33 Meta-analyses: child and parent or whole family interventions – anthropometric outcomes\n\nA meta-analysis of 8 studies (4 [++] RCTs, 3 [+] RCTs and 1 [−] quasi-RCT) estimated the overall effectiveness of interventions directed at children and parents/carers or whole family versus no or minimal control outcomes immediately post intervention as a significant reduction in BMI standardised mean difference (SMD) of −0.22 (−0.33 to −0.10). This evidence is directly applicable because the studies were conducted in the UK and other similar community-based settings.\n\n## Evidence statement 1.1.34 Meta-analyses: child and parent or whole family interventions – anthropometric outcomes\n\nA meta-analysis of 11 studies (7 [++] RCTs; 3 [+] RCTs and 1 [−] quasi-RCT) estimated the overall effectiveness of interventions directed at children and parents/carers or whole family versus no or minimal control outcomes at longer-term follow up (6 months or more) as a non-significant reduction in BMI SMD of −0.01 (−0.11 to 0.08). This evidence is directly applicable because the studies were conducted in the UK or other similar community-based settings.\n\n## Evidence statement 1.1.35 Cost effectiveness\n\nEvidence from 7 short-term health economic analyses suggests that lifestyle weight management programmes will result in an increased cost to the NHS in terms of BMI\xa0z score gains when compared with routine care in the short term. However, overall small (and in some cases, non-significant) improvements in BMI\xa0z scores can be achieved. All studies were applicable in terms of setting and participants, but data from short-term studies are limited in applicability to life-time cost estimates and assessed as partially applicable. Some studies provided cost data only and there was no assessment of their applicability or study limitations.\n\n## Evidence statement 1.1.36 cost effectiveness\n\nThree extrapolation models of programmes suggest interventions that lead to even small reductions in BMI can be cost effective in the long term at conventional cost-effectiveness thresholds, provided the short-term effects on BMI, observed in trials, are sustained into adulthood. The evidence from these studies is directly applicable but there are potentially serious limitations to the studies.\n\n## Evidence statement 1.2.2 Parenting skills.\n\nThere is strong evidence from 2 RCTs (both [++]) that interventions involving group-based general parenting skills training for parents of overweight and obese children aged 6\xa0to 9\xa0years and 5\xa0to 9\xa0years are effective in improving BMI z scores. Adding intensive lifestyle education to the parenting skills training does not appear to result in significantly greater improvements in BMI\xa0z scores, food intake or physical activity measures or parenting outcomes. Both interventions were delivered over 6\xa0months by dietitians. This evidence is directly applicable because the studies were conducted in community settings in Australia.\n\n## Evidence statement 1.2.3 Involvement of family\n\nThere is strong evidence, post intervention, to suggest that targeting both parents and children (8 studies: 3 [++] RCTs, 2 [+] RCTs, 2 [−] quasi-RCTs and 1 [−] UBA) or whole families (18 papers from 17 studies: 5 [++] RCTs, 4 [+] RCTs, 1 [+] quasi-RCT, 1 [−] quasi-RCT and 6 [−] UBAs) is effective in reducing within group BMI\xa0z scores. For those studies with follow up of 6\xa0months or more there were no clear differences. Evidence from child-only interventions (1 [++] RCT, 1 [+] RCT and 1 [−] CBA) and parent-only interventions (2 [++] RCTs, 2 [+] RCTs and 1 [−] cluster RCT) is limited and inconsistent.\n\n## Evidence statement 1.2.4 Referral method\n\nThere is strong evidence from a meta-analysis of 12 studies, of which 2 studies examined specialist referral, to suggest that interventions that involve specialist medical referral to a programme compared with self, GP, school or a mixture of referral methods show greater improvements in BMI\xa0z scores at end of intervention (SMD of −0.41; 95% confidence interval [CI] of −0.64 to −0.17). The studies in the meta-analysis were conducted in applicable community settings.\n\n## Evidence statement 1.2.7 Intensity of intervention\n\nThere is moderate evidence from 1 (−) RCT and 1 (++) RCT that children who attend 75% or more of the high intensity programme sessions offered, showed greater improvements in weight outcomes than those attending fewer sessions. One further ongoing (++) RCT found that following up CBT therapy with telephone or text coaching was not more beneficial to BMI\xa0z scores, diet, physical activity and psychosocial outcomes than CBT alone. The studies in both meta-analysis were conducted in community settings in the USA and Australia.\n\n## Evidence statement 1.4.1 Most effective ways of sustaining long-term effects\n\nThere is inconsistent evidence as to whether the effects of weight management programmes are sustained long term. There is strong evidence from meta-analyses of 18 programmes (10 [++] RCTs [11 papers], 5 [+] RCTs, 3 quasi-RCTs – 1 [+], 2 [−]) with BMI z outcomes, indicating improvements decrease the longer the length of follow-up. The evidence is directly applicable because all studies were conducted in community settings in the UK or other similar countries and are directly applicable.\n\n## Evidence statement 1.4.2 Most effective ways of sustaining long-term effects\n\nConsidering BMI plus other outcomes, there is inconsistent evidence from 5 (++) RCTs, 1 (+) RCT, 1 (+) quasi-RCT and 1 [−] UBA as to whether the effects of weight management programmes are sustained long term. It is not possible to determine which intervention components resulted in sustained outcomes. The evidence is directly applicable because all studies were conducted in community settings in the UK or other similar countries.\n\n## Evidence statement 1.4.3 Duration of interventions\n\nA meta-analysis of 8 studies (4 [++] RCTs, 3 [+] RCTs, 1 [−] RCT) indicated that duration of intervention is associated with improved between-group BMI\xa0z outcomes at the end of the intervention for programmes of 8\xa0to 24\xa0months. There were no significant between group differences in BMI\xa0z scores associated with studies of a shorter duration. Between-group differences diminished over time and were not significant at 6\xa0months. The evidence is directly applicable as the studies were conducted in the UK and the USA.\n\n## Evidence statement 2.1.1 Facilitator: weight management goals\n\nThere is evidence from 5 qualitative studies (4 [+] and 1 [−]) that the desire to lose weight or prevent further weight gain was a motivator for programme users to join and continue attendance at lifestyle weight management programmes. In 8 studies, perceived improvements in children's and/or young people's weight management outcomes were described by programme providers (1 [+] qualitative study) and programme users (1 [++] qualitative, 4 [+] qualitative, and 2 process evaluations). This evidence is directly applicable because the studies were conducted in community-based settings in the UK or other similar countries (USA).\n\n## Evidence statement 2.1.2 Facilitator: health improvement goals\n\nHealth improvement or prevention of future health problems were described as incentives to joining weight management programmes by children and families in 6 qualitative studies (2 [++], 3 [+] and 1 [−]). Providers in 1 (+) qualitative study and programme users in 4 studies (3 process evaluations, 1 [+] qualitative study) perceived health improvements as a consequence of attending weight management programmes. This evidence is directly applicable because studies were conducted in the UK in community-based settings.\n\n## Evidence statement 2.1.3 Facilitator: healthier lifestyle behaviour\n\nWeight management programmes were perceived to improve children's lifestyle behaviours, such as healthier diet and increased physical activity, by programme providers in 2 process evaluations, and also by programme users in 5 studies (1 [++] qualitative, 2 [+] qualitative, 1 [−] qualitative and 1 process evaluation). The evidence is directly applicable because the studies were conducted in the UK in community-based settings.\n\n## Evidence statement 2.1.4 Barrier: lack of programme impact on weight management\n\nConcerns that programmes were not helping children achieve weight management goals were expressed by providers in 1 (−) qualitative study and by parents in 1 (+) qualitative study. In both studies the weight outcome was described in terms of weight loss, without reference to the wider aims of most weight management programmes to slow further weight gain so that BMI\xa0z scores improve as children grow. Also, children in 1 (++) qualitative study stated that weight gain prompted feelings of embarrassment and shame, and led to non-attendance at booked appointments. There were different views between studies and between the participants of the same studies as to whether weight was the most important outcome. Two (+) qualitative studies suggested psychological wellbeing was of equal or greater importance to parents, whereas weight outcomes appeared more important to some children in 2 (+) qualitative studies and to parents in 1 (−) qualitative study. This evidence is directly applicable because the studies were conducted in community settings in the UK and Sweden.\n\n## Evidence statement 2.1.5 Facilitator: psychological wellbeing and social outcomes\n\nImproved psychological wellbeing such as confidence and self-esteem, or improved social outcomes such as reduced bullying and making friends, were strong motivators for programme participation among children and their families in 10 studies (2 [++] qualitative, 6 [+] qualitative, and 2 [−] qualitative). Programmes were perceived to be successful in improving these outcomes in 12 studies (2 [++] qualitative, 4 [+] qualitative, 2 [−] qualitative, 4 process evaluations). Two studies suggested that improvements in these outcomes were sufficient to maintain engagement with programmes despite lack of weight management. This evidence is directly applicable because the studies were conducted in community settings in the UK or similar countries (the USA, Sweden, Australia).\n\n## Evidence statement 2.1.7 Facilitator: children's motivation to manage weight\n\nHigh levels of children's motivation to manage weight was reported in 6 qualitative studies (3 [++], 2 [+] and 1 [−]) and helped promote participation in weight management programmes. This evidence is directly applicable because the studies were conducted in community settings in the UK or similar countries (the USA, Sweden).\n\n## Evidence statement 2.1.8 Facilitator: awareness and acceptance of children being overweight or obese\n\nChildren, their families and providers emphasised that awareness and acceptance of children being overweight or obese was a facilitator to programme adherence. This was evidenced in 6 qualitative studies (3 [++], 2 [+], 1 [−]). This evidence is directly applicable because the studies were conducted in community settings in the UK or similar countries (United States, Sweden).\n\n## Evidence statement 2.1.9 Barrier: lack of children's motivation\n\nProgramme users and providers shared views that children's lack of motivation was a barrier to uptake of lifestyle weight management programmes. This was described in 1 (+) qualitative study and 1 process evaluation. Lack of motivation was also described by programme users and providers as a barrier to programme adherence in 7 studies (1 [++] qualitative, 3 [+] qualitative, 1 [−] cross-sectional, 1 [−] qualitative, and 1 process evaluation). This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Australia, Sweden, Canada, the USA).\n\n## Evidence statement 2.1.10 Barrier: lack of awareness and acceptance of children being overweight or obese\n\nFamily and provider perspectives in 5 studies (1 [++] qualitative, 2 [+] qualitative, 1 [+] cross-sectional and 1 [−] qualitative study) indicated that some families do not acknowledge or recognise that their child is overweight or obese, which hindered programme uptake and adherence. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Canada, Belgium).\n\n## Evidence statement 2.1.11 Barrier: children's and their parents' apprehension\n\nA strong theme identified in 5 qualitative studies (1 [++], 3 [+] and 1 [−]) was the anxiety and apprehension described by children and parents about joining weight management programmes. Concerns manifested as general fears of the unknown (for example, anxieties of meeting new people, struggling to make friends or worries of being the largest on the programme). In addition, there were reports in 3 qualitative studies (1 [+], 2 [−]) and 1 process evaluation of programme users having negative perceptions of the programme characteristics and eligibility criteria before starting the intervention. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (USA).\n\n## Evidence statement 2.1.12 Barrier: individual and family demands\n\nParents and children described a range of individual and family demands, such as busy lifestyles, homework, work or family commitments. These were indicated as obstacles to programme uptake or adherence in 10 studies (2 [++] qualitative, 3 [+] qualitative, 1 [+] cross-sectional, 1 [−] cross-sectional, 1 [−] qualitative and 2 process evaluations). This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Australia, Canada, Iceland, Belgium.).\n\n## Evidence statement 2.1.13 Facilitator: parental support\n\nBoth providers and children were reported as believing parental support to be an important facilitator of successful lifestyle weight management interventions. High levels of parental support and their role in children's weight management was described in 5 qualitative studies (1 [++], 3 [+], 1 [−]). A (+) cross-sectional study identified parents' motivation for treatment as a statistically significant predictor of programme completion. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (the USA, Belgium).\n\n## Evidence statement 2.1.14 Facilitator: parental motivation\n\nParental motivation was perceived to be a critical factor in children's successful engagement with weight management programmes, as evidenced in 7 studies: 3 qualitative (2 [+], 1 [−]); 3 cross-sectional surveys (2 [+], 1 [−]) and 1 process evaluation. Perceptions of high levels of parental motivation were reported in 3 studies, primarily from parents whereas providers acknowledged high parent motivation in only 1 study. Two studies found a statistically significant association between motivated parents and either programme uptake or completion. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Belgium, Australia, the USA).\n\n## Evidence statement 2.1.15 Barrier: lack of parental support\n\nProviders reported a lack of parental support acting as a barrier to children's weight management in 4 qualitative studies (1 [++], 2 [+], 1 [−]). Three of these studies described provider perceptions that parents did not realise their role as agents of change and they looked to the programme to solve children's weight management difficulties. This evidence is directly applicable because studies were conducted in the UK in a community setting.\n\n## Evidence statement 2.1.16 Barrier: lack of parental motivation\n\nProgramme providers described how low parental motivation hindered children's weight management in 1 (+) qualitative study, 1 (−) qualitative study and 1 process evaluation. In addition, a small proportion of parents (4.7%) cited lack of family readiness to change as a reason for dropping out of a lifestyle weight management programme in 1 (−) cross-sectional study. This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (Belgium, USA).\n\n## Evidence statement 2.1.17 Barrier: lack of support from other family members\n\nChildren and parents described situations in which other family members (either partners or members outside of the nucleus family such as grandparents) did not support, and even sabotaged, children's weight management attempts. This was described in 8 qualitative studies (2 [++], 4 [+], 1 [−]). This evidence is directly applicable because studies were conducted in community settings in the UK or similar countries (USA).\n\n## Evidence statement 2.1.18 Barrier: lack of awareness\n\nBoth providers and programme users identified a lack of awareness of local weight management programmes. Providers considered poor programme publicity to be the reason why potential users were unaware of the programme in 1 process evaluation. Programme users also reflected on the lack of programme awareness among children and families in 4 qualitative studies (1 [+], 3 [−]). Providers and users also referred to health professionals' lack of programme awareness in 1 process evaluation and 1 qualitative study. This evidence is directly applicable because all studies were conducted in UK community settings.\n\n## Evidence statement 2.1.19 Role of health professionals\n\nBoth programme users and providers felt that health professionals such as GPs, nurses and health visitors should raise awareness or refer children to lifestyle weight management programmes. However, varying opinions were offered on whether this was being sufficiently implemented. Examples of awareness-raising by other professionals were reported by providers or programme users in 2 (+) qualitative studies, 1 (−) qualitative study and 1 process evaluation. However, providers in 3 studies (1 [+] qualitative, 2 process evaluations) and programme users in 1 (+) qualitative study, described circumstances in which children were not referred, or inappropriate referrals were made. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (USA).\n\n## Evidence statement 2.1.20 Facilitator: recruitment suggestions\n\nProgramme users and providers offered varied suggestions for future programme recruitment strategies in 8 studies (2 [++] qualitative, 4 process evaluations, 2 [−] qualitative). Increasing referral routes, recruiting through schools and family support workers, was suggested by both programme providers and users; advertising in local media was suggested by providers and users. Providers also mentioned ensuring programme aims and characteristics were sufficiently described and offering rolling programmes that allow families to join on an ongoing basis. Users felt that emphasising the healthy living and fun aspects of programmes rather than weight management would promote uptake. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (USA).\n\n## Evidence statement 2.1.22 Facilitator: venue\n\nProgramme users valued the comfortable and welcoming environment of their programme venues in 2 (+) qualitative studies, which were either located in a clinic or at schools. Community settings and schools were suggested by providers and programme users as suitable venues in 1 (++) qualitative study and 2 process evaluations. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada).\n\n## Evidence statement 2.1.23 Facilitator: family involvement\n\nProviders, children and families valued a delivery approach that incorporated family involvement in lifestyle weight management programmes, perceiving it to facilitate behaviour change. Users expressed these views in 11 studies (2 [++] qualitative, 4 [+] qualitative, and 5 process evaluations) and providers in 3 studies (1 [++] qualitative study, 1 [−] qualitative study and 1 process evaluation). Regarding specific parenting education sessions, users in receipt of these interventions liked the emphasis on positive parenting and separate children and parent sessions addressing the same topic as each other. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia, Canada, USA).\n\n## Evidence statement 2.1.24 Facilitator: group intervention sessions with peers\n\nThere was evidence from 13 studies (2 [++] qualitative, 3 [+] qualitative, 3 [−] qualitative, 5 process evaluations) that group-based sessions and interaction with peers were highly valued by children and parents. Interventions incorporating group sessions or peer interactions were perceived to be opportunities to share experiences, and give and receive support from people facing similar problems. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Sweden).\n\n## Evidence statement 2.1.25 Facilitator: goal setting\n\nProgramme users and providers shared the view that the use of goal setting (which may or may not also involve rewards) was a beneficial feature of interventions, and emphasised the importance of frequent but small and realistic goals. This was evidenced in 11 studies (2 [++] qualitative, 6 [+] qualitative, and 3 process evaluations). This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, USA).\n\n## Evidence statement 2.1.26 Facilitator: user-tailored interventions\n\nProgramme users and providers highly valued the interventions that were tailored to the user in 9 studies (6 qualitative: 2 [++], 2 [+], 2 [−]; 1 [+] cross-sectional survey and 2 process evaluations).\n\nInterventions were viewed positively if they were tailored to different population groups of children (for example, age, gender, ethnicity) by parents, providers and children. There was a strong emphasis on the value of interventions addressing the individual personal needs of programme users. Programme users commented on the importance of identifying and adjusting interventions to the needs, goals, motives or existing knowledge of individual participants. Providers in 1 study recommended tailoring programmes to children's age, ethnicity, degree of obesity and their readiness for change. Authors in 1 study also commented on the benefits of collaborating with families to create individual goals and strategies. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, USA and Sweden).\n\n## Evidence statement 2.1.27 Facilitator: monitoring and feedback\n\nThere was evidence from 10 studies that regular monitoring and feedback of weight management progress was highly valued by programme users and providers (2 [++] qualitative, 4 [+] qualitative, 2 [−] qualitative studies, and 2 process evaluations). This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Sweden).\n\n## Evidence statement 2.1.28 Facilitators: scheduling suggestions\n\nSuggestions for improving programme scheduling were offered by programme users and providers in 9 studies (1 [++] qualitative, 2 [+] qualitative, 1 [+] qualitative, 1 [+] cross-sectional survey and 4 process evaluations). More flexible appointment times, such as in the evening or weekends were suggested by programme users and providers. Programme users also wanted increased frequency of appointments to maintain their motivation. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia, USA).\n\n## Evidence statement 2.1.29 Barrier: inconvenient intervention scheduling\n\nScheduling of interventions (for example, timing, length of individual sessions) were important influences on programme users but no clear consensus was described on what the scheduling should be.\n\nPotential users cited inconvenient timing of programmes as a reason for not joining programmes in 1 (−) qualitative study and 2 process evaluations. Programme attendees also reported difficult scheduling as a barrier to continued participation in 10 studies (2 [++] qualitative studies, 2 [+] qualitative studies, 1 [+] cross-sectional survey, 3 process evaluations, 1 [−] cross-sectional and 1 [−] qualitative study). Programme users in 1 survey disagreed on how the frequency of appointments resulted in their attendance or drop-out. 11.6% dropped out of programmes because appointments were not frequent enough, whereas 7% stated they were too frequent. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia, Canada, USA).\n\n## Evidence statement 2.1.30 Barrier: venue location\n\nNegative comments regarding programme venues were expressed in 6 studies (3 [+] qualitative, 1 [−] qualitative, 1 [−] cross-sectional survey and 1 process evaluation). Challenges relating to locations being too far away, difficult to reach, or hindered by traffic problems at peak times were described by both providers and users. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada and USA).\n\n## Evidence statement 2.1.31 Barrier: challenges in goal setting\n\nChallenges of setting goals within programmes were highlighted by users and providers in 3 studies (1 [++] qualitative, and 2 process evaluations). Programme users spoke negatively about too many goals being set, long-term goals not being revisited or monitored or goals not being matched to those valued by the child. Providers described difficulties in designing goals for users. This evidence is directly applicable because all studies conducted in community settings in the UK or similar countries (Sweden, Australia).\n\n## Evidence statement 2.1.32 Facilitator: practical intervention elements\n\nA recurring theme within studies was that programme users particularly liked the practical elements of their intervention sessions, as evidenced in 11 studies: 7 qualitative (1 [++], 4 [+], 2 [−]) and 4 process evaluations.\n\nRegarding dietary components, children and/or parents enjoyed cookery lessons in particular or wanted the programme to incorporate more of these. Specific directive information was also valued, including the provision of recipes, eating plans or messages that 'told them what to do'. Education on food in supermarkets was also valued, with 1 study suggesting that education on labels should be followed up with trips to the supermarket.\n\nRegarding physical activity education, children consistently commented on enjoying games and physical exercise sessions, and views indicated they would like more activities within the intervention. Some parents also wanted more exercise sessions, although some parents expressed negative views of physical activity sessions. Variety in the available activities was also valued. This evidence is directly applicable because all studies were conducted in community settings in the UK.\n\n## Evidence statement 2.1.33 Facilitator: behavioural change components\n\nParents and children had positive views of the behavioural change elements in the programmes they received, evidenced in 7 studies: 5 qualitative (1 [++], 2 [+], 2 [−]) and 2 process evaluations. Positive comments were made regarding: understanding the 'how and why' of their eating behaviour, learning about their feelings and being able to talk about how they feel, or learning about stress and how to cope with it. One study reported that users believed lifestyle weight management programmes should include physical activity, nutrition and psychological components. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, the USA).\n\n## Evidence statement 2.1.34 Barrier: relevance of intervention to home life\n\nSeven studies described children's and/or their families' concerns with the relevance and ease of managing their weight outside in their home life or after leaving their programme (4 [++], 1 [+], 1 [−] qualitative and 1 [+] cross-sectional study). This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Belgium).\n\n## Evidence statement 2.1.35 Facilitator: post-intervention support and follow-up\n\nSeven studies (1 [++] qualitative, 2 [+] qualitative, 2 [−] qualitative, 2 process evaluations) identified that the continuation of professional support following completion of the programme was important to users. Families wanted support to continue and thought it would be helpful for ensuring that weight management goals were continued.\n\nVery little detail was provided regarding the forms this support should take. Parents in 1 study suggested follow-up letters, meetings or continuation sessions. Parents in another study proposed a long-term financial subsidy to encourage children and young people to maintain participation in formal activities.\n\nThis evidence is directly applicable because all studies were conducted in UK community settings.\n\n## Evidence statement 2.1.36 Facilitator: personal strategies to sustain weight management behaviour\n\nParents in 3 studies (2 [+] qualitative, 1 process evaluation) described a range of strategies they employed to facilitate continuation of their children's weight management behaviour. These included staying consistent, setting planned routines, enjoying their new healthy lifestyle, and seeking additional support. This evidence is directly applicable because all studies were conducted in the UK community settings.\n\n## Evidence statement 2.1.37 Barrier: attendance at follow-up sessions\n\nDespite strong support for professional follow-up after completion of weight management programmes, children and parent views in 3 studies suggested that the content and timing of potential support may affect the uptake of sessions if they did not appeal to programme users or conflicted with their competing interests. This was indicated in 3 qualitative studies: (1 [++], 1 [+] and 1 [−]). This evidence is directly applicable because studies were conducted in the UK community settings or similar countries (Canada).\n\n## Evidence statement 2.1.38 Facilitator: building good child/family-provider relationships\n\nThere was evidence from 15 studies (3 [++] qualitative, 6 [+] qualitative, 4 process evaluations, and 2 [−] qualitative) of children's and parents' perspectives, that provider characteristics were key factors for continued participation in weight management programmes and behaviour change attempts. Valued characteristics included the encouraging, non-judgemental tone of providers, and continuity of staff. Parents also appreciated the role providers had in acting as voices of authority that parents could rely on to educate children. Provider perspectives in 2 of these studies also suggested that staff were aware of the importance of establishing good relationships with programme users and their families. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, Sweden, the USA Australia).\n\n## Evidence statement 2.1.39 Barrier: negative opinions of providers' characteristics\n\nSix studies (2 [++] qualitative, 2 [+] qualitative, 1 process evaluation, 1 [−] qualitative) described how negative opinions of provider dynamics influenced user engagement. Children and parents provided examples of poor user-provider relationships and suggested they hindered engagement with programmes or weight management behaviour Providers also recognised the negative effect bad relationships with users and staff discontinuity could have on programme adherence. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, Sweden).\n\n## Evidence statement 2.1.40 Facilitator: collaborative multi-disciplinary teams\n\nThree studies (1 [+] qualitative study, 1 process evaluation and 1 [+] cross-sectional survey) indicated that providers highly valued working within effective collaborative multidisciplinary teams. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia).\n\n## Evidence statement 2.1.41 Facilitator: provider highly valued opportunities for training\n\nThree studies (1 [+] qualitative, 1 process evaluation and 1 [+] cross-sectional survey) reported that providers were keen to receive relevant training that would help them gain necessary skills to effectively deliver interventions. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia).\n\n## Evidence statement 2.1.42 Barrier: provider gaps in knowledge\n\nThree studies (1 [+] qualitative study, 1 [+] cross-sectional study and 1 process evaluation) referred to providers' perceptions of their skills and knowledge. Three studies indicated some providers felt unqualified to deliver interventions, specifically interventions that were broad in their nature, or were delivered to a varying user group who sometimes had complex psychosocial needs. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia).\n\n## Evidence statement 2.2.4 Pre-adolescent children (6\xa0to 13\xa0years)\n\nA wide range of themes was described in 16 studies of school-age children: 7 qualitative (3 [++], 3 [+], 1 [−]), 1 (+) correlation, 2 cross-sectional, 6 process evaluations. However, none of the studies were designed to explore differences in barriers and facilitators compared with other age groups.\n\nCommonly shared facilitators across studies were the importance of non-weight outcomes such as psychological wellbeing, social outcomes such as making friends and reduced bullying; interventions with a whole-family approach; positive provider characteristics; group-based sessions with peers; regular monitoring and feedback; and post-intervention support. Commonly shared barriers across studies were poor relationships of providers with children and/or their parents. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Canada, Australia, the USA, Iceland, Belgium).\n\n## Evidence statement 2.2.5 Adolescents\n\nA wide range of themes was described in 10 studies of adolescents (2 [++] qualitative, 3 [+] qualitative, 1 [+] cross-sectional survey, 4 process evaluations). However, none of the studies were designed to explore differences in barriers and facilitators for adolescents when compared with other age groups. Facilitators shared across 3 or more studies were the importance of psychological wellbeing as an outcome and positive provider characteristics. Commonly shared barriers across studies were: perceived lack of parental support and concern regarding unintended consequences of weight management programmes. This evidence is directly applicable because all studies were conducted in community settings in the UK or similar countries (Australia the USA and Sweden).\n\n## Expert papers and commissioned report\n\nExpert papers 1\xa0to\xa06.\n\nCommissioned report.\n\nFor details, see the section on what evidence is the guidance based on?\n\n# Economic modelling\n\nThe economic model considered the BMI trajectory of children in 3 different age groups (2\xa0to 5\xa0years, 7\xa0to 11\xa0years and 12\xa0to 17\xa0years). It considered boys and girls separately. It also considered 3 starting weights for each age group and both sexes. The starting weights considered were: the borderline between healthy weight and overweight, between overweight and obese, and between obese and what the model called morbidly obese.\n\nThe model examined what happened to each cohort if there were no intervention. It estimated the average (mean) weight and quality of life for the cohort on an annual basis and its expected life expectancy. It also estimated the costs of any health problems they would face during their lifetime. The model was then set up to answer 2\xa0questions:\n\nWhat would happen to the quality of life and the life expectancy of each of these groups of children or young adults if an intervention from the evidence review were applied?\n\nHow would the future costs of treating diseases change as the result of the intervention?\n\nThe difference between the subsequent lifelong pathways of these 2 hypothetical situations (that is, 'with an intervention' and 'without an intervention') was expressed in terms of quality-adjusted life years (QALYs) gained from the intervention. It was also expressed in terms of the cost of the intervention less the future costs saved. An intervention is generally considered to be cost effective if the cost per QALY gained is less than about £20,000 to £30,000.\n\nThe model estimated that an intervention costing £100 per person would be cost effective if a child or young person could be moved to a lower weight trajectory (as little as 0.5% lower) than it would have been without the intervention. However, this would be the case only if the 0.5% weight difference were to be maintained throughout life. If, on average, they regained the weight within 10\xa0years or less it is estimated that the intervention would no longer be cost effective.", 'Gaps in the evidence': 'The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence and expert comment. These gaps are set out below.\n\n. There is a lack of data on how to involve male children and young men in lifestyle weight management programmes.\n\n(Source: evidence review 1)\n\n. There is a lack of data on effective lifestyle weight management programmes for children and young people with disabilities, learning difficulties or other special needs.\n\n(Source: evidence reviews 1 and 2)\n\n. There is a lack of data on effective and cost-effective approaches to weight management for children younger than 6 years, including the views of their parents and families. In addition, there is a lack of data on the barriers to, and facilitators for, encouraging these children to complete a lifestyle weight management programme.\n\n(Source: evidence reviews 1 and 2)\n\n. There is a lack of data on how the barriers to, and facilitators for, participating in a lifestyle weight management programme vary according to socioeconomic group, ethnicity, gender and age.\n\n(Source: evidence review 2)\n\n. There is a lack of standardised reporting for the behavioural therapy and cognitive behavioural therapy (CBT) components used by programme developers. This makes it difficult to evaluate these components of a lifestyle weight management programme.\n\n(Source: expert paper 6)\n\n. There is a lack of evidence on the lifetime effects of weight management programmes. (Such data are crucial for assessing cost effectiveness.)\n\n(Source: Economic modelling report)\n\nThe Committee made 4 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in Recommendations for research.', 'About this guidance': "# What evidence is the guidance based on?\n\nThe evidence that the Programme Development Group (PDG) considered included:\n\nEvidence reviews:\n\n\n\nReview 1: 'Effectiveness and cost effectiveness of lifestyle weight management services for children and young people', was carried out by Support Unit for Research Evidence (SURE), Cardiff University. The principal authors were: Fiona Morgan, Alison Weightman, (SURE, Cardiff University) Sarah Whitehead (DECIPHer, Cardiff University) and Sinead Brophy (DECIPHer, Swansea University).\n\nReview 2: 'The barriers and facilitators to implementing lifestyle weight management programmes for children and young people', was carried out by SURE, Cardiff University. The principal authors were: Ruth Turley, Alison Weightman, (SURE, Cardiff University), Elizabeth Halstead (Bangor University) and Helen Morgan (SURE, Cardiff University).\n\n\n\nEconomic modelling: 'Managing overweight and obesity among children economic modelling report', was carried out by the UK Health Forum, (formerly the National Heart Forum) and the University of East Anglia. The principal authors were: Martin Brown, Tim Marsh and Ketevan Rtveladze (UK Health Forum) and Ric Fordham (University of East Anglia).\n\nCommissioned report: 'Practical and process issues in the provision of lifestyle weight management services for children and young people', was carried out by GK Research. The author was Graham Kelly.\n\nExpert papers:\n\n\n\nExpert paper 1: 'Findings of the former Childhood Obesity National Support Team' by Kim Hastie, Head of former Childhood Obesity National Support Team.\n\nExpert paper 2 'Implications of the transition of public health responsibilities to local government' by Helen Walters, Greater London Authority\n\nExpert paper 3 'Psychological considerations for lifestyle weight management programmes for children and young people, and the use of behaviour change theories' by Andrew Hill, University of Leeds\n\nExpert paper 4 'Choosing outcome measures for lifestyle weight management programmes for children' by Maria Bryant, University of Leeds\n\nExpert paper 5 'A population-level evaluation of a family-based community intervention for childhood overweight and obesity' by Catherine Law and Helen Roberts, Institute of Child Health, University College, London\n\nExpert paper 6 'Effective Behavioural Components for Childhood weight management programmes' by Pinki Sahota, Leeds Metropolitan University.\n\n\n\nIn some cases, the evidence was insufficient and the PDG has made recommendations for future research.", 'Finding more information': "To find NICE guidance on related topics, including guidance in development, see the NICE topic page on obesity.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews and expert papers. You can also find information about how the guideline was developed, including\xa0details of the Programme Development Group.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.\n\nISBN 978-1-4731-0330-6"}	https://www.nice.org.uk/guidance/ph47	This guideline covers lifestyle weight management services for children and young people aged under 18 who are overweight or obese. It advises how to deliver effective weight management programmes that support children and young people to change their lifestyle and manage their weight.
1c21bdf094953235389ffb68f9e84a0e70df0460	nice	Ocriplasmin for treating vitreomacular traction	Ocriplasmin for treating vitreomacular traction Evidence-based recommendations on ocriplasmin (Jetrea) for treating vitreomacular traction in adults. # Guidance Ocriplasmin is recommended as an option for treating vitreomacular traction in adults, only if: an epiretinal membrane is not presentand they have a stage 2 full-thickness macular hole with a diameter of 400 micrometres or less and/or they have severe symptoms.# The technology Ocriplasmin (Jetrea, Inceptua) is a truncated form of human plasmin, manufactured using recombinant DNA technology. It is 'indicated in adults for the treatment of vitreomacular traction (VMT), including when associated with macular hole (MH) of diameter less than or equal to 400 microns'. It is administered by intravitreal injection at a dose of 0.125 mg. Repeated injections into the same eye are not recommended. The summary of product characteristics lists the following adverse reactions for ocriplasmin: vitreous floaters, eye pain, photopsia, and conjunctival haemorrhage resulting from the injection procedure. Most of these reactions were non‑serious, mild in intensity and resolved within 2 to 3 weeks. For full details of adverse reactions and contraindications, see the summary of product characteristics. The cost of an ocriplasmin injection is £2500 (excluding VAT, ocriplasmin concentrate 0.5 mg in 0.2 ml solution; MIMS, July 2013; from September 2018, this was replaced with ready-diluted 0.375 mg/0.3 ml solution). Because repeat injections are not recommended, this is the cost for a full course of treatment. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (section 6) considered evidence submitted by the manufacturer of ocriplasmin and a review of this submission by the Evidence Review Group (ERG; section 7). # Clinical effectiveness ## Background to the clinical evidence The manufacturer's systematic literature review identified 2 randomised controlled trials that were relevant to the decision problem: TG‑MV‑006 and TG‑MV‑007. The data from these trials were assessed individually and as an integrated dataset. Three non‑randomised controlled trials (TG‑MV‑001, TG‑MV‑008 and TG‑MV‑010) provided relevant safety and pharmacokinetic data. TG‑MV‑006 was a randomised, placebo‑controlled, double‑blind trial conducted in the USA. People with vitreomacular traction were randomised to receive either a single injection of ocriplasmin (n=219), or a placebo injection of saline (n=107), and were followed up over 6 months. Inclusion criteria included a best corrected visual acuity (BCVA) of 20/25 or worse in the study eye, and 20/800 or better in the non‑study eye. Exclusion criteria included a macular hole larger than 400 micrometres and previous vitrectomy in the study eye. At baseline 27.3% had a full‑thickness (stage 2) macular hole, 72.7% had vitreomacular traction (which could include a stage 1 macular hole), 37.1% had an epiretinal membrane, and 79.4% had an expected need for a vitrectomy. The mean BCVA score at baseline was 64.8 (standard deviation 10.53). TG‑MV‑007 was a randomised, placebo‑controlled, double‑blind trial conducted in the USA and Europe (including the UK). People with vitreomacular traction were randomised to receive either a single injection of ocriplasmin (n=245), or a placebo injection of saline (n=81), and were followed up over 6 months. Inclusion criteria included a BCVA of 20/25 or worse in the study eye and 20/800 or better in the non‑study eye. Exclusion criteria included a macular hole larger than 400 micrometres and previous vitrectomy in the study eye. At baseline, 19.6% had a full‑thickness (stage 2) macular hole, 80.4% had vitreomacular traction (which could include a stage 1 macular hole), 40.2% had an epiretinal membrane, and 88.7% had an expected need for a vitrectomy. The mean BCVA score at baseline was 63.8 (standard deviation 13.20). The primary outcome of TG‑MV‑006 and TG‑MV‑007 was the proportion of patients with non‑surgical resolution of focal vitreomacular adhesion at day 28 post‑injection, as determined by masked central reading centre optical coherence tomography (OCT) evaluation. Secondary outcomes included the proportion of patients with total posterior vitreous detachment (PVD) at day 28, proportion of full‑thickness (stage 2) macular holes that closed without vitrectomy, proportion of patients not needing vitrectomy, an improvement of at least 2 or 3 lines in BCVA without need for vitrectomy, improvement in mean BCVA, and improvement in the 25‑item Visual Function Questionnaire (VFQ‑25). Safety outcomes included adverse events, with special attention to ocular events, such as worsening visual acuity (VA), worsening macular oedema, vitreous haemorrhage, retinal tear, retinal detachment, increase in ocular inflammation and intraocular pressure increases. ## Clinical trial results The manufacturer presented the whole population results from TG‑MV‑006 and TG‑MV‑007 (see section 3.6), as well as the following subgroups: VMT without ERM (vitreomacular traction without an epiretinal membrane); this included people with a stage 1 macular hole (see section 3.7) VMT with ERM (vitreomacular traction with an epiretinal membrane); this included people with a stage 1 macular hole (see section 3.8) VMT with MH (vitreomacular traction with a stage 2 macular hole); this included people with an epiretinal membrane (see section 3.9). Data from both the clinical trials and the integrated analyses were presented for the whole population. The proportion of patients with vitreomacular traction resolution was statistically significantly greater in the ocriplasmin arm than the placebo arm for both trials and in the integrated analyses for the whole population (TG‑MV‑006: 27.9% and 13.1% respectively, 95% confidence interval 6.0 to 23.5, p=0.003; TG‑MV‑007: 25.3% and 6.2% respectively, 95% CI 11.6 to 26.7, p<0.001; integrated analysis: 26.5% and 10.1% respectively, 95% CI 10.5 to 22.3, p<0.001). The proportion of patients with total PVD by day 28 was statistically significantly greater in the ocriplasmin than the placebo arm for both trials in the whole population (TG‑MV‑006: 16.4% and 6.5% respectively, 95% CI 3.1 to 16.7, p=0.0014; TG‑MV‑007: 10.6% and 0% respectively, 95% CI 6.8 to 14.5, p<0.001). The manufacturer presented data on the VMT without ERM subgroup. The integrated analyses showed that the proportion of patients with vitreomacular traction resolution or total PVD by day 28 was statistically significantly greater in the ocriplasmin arm than the placebo arm (vitreomacular traction resolution: placebo 7.7%, ocriplasmin 29.8%, p<0.001; total PVD: placebo 2.6%, ocriplasmin 17.0%, p<0.001). Further secondary outcomes did not show a statistically significant difference between the treatment arms but did favour ocriplasmin (proportion of patients who received a vitrectomy by month 6: placebo 15.4%, ocriplasmin 8.0%, p=0.091; mean change in VA from baseline at day 28: placebo 2.5 letters, ocriplasmin 2.6 letters, p=0.890; mean change in VA from baseline at month 6: placebo 2.8 letters, ocriplasmin 3.1 letters, p=0.728). At month 6 more patients treated with ocriplasmin than placebo had gained letters, on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale (at least 10 letters gained: placebo 15.4%, ocriplasmin 25.5%, p=0.051; at least 15 letters gained: placebo 5.1%, ocriplasmin 10.1%, p=0.140. However, more patients treated with ocriplasmin had lost letters (at least 10 letters lost: placebo 3.8%, ocriplasmin 6.9%, p=0.381; at least 15 letters lost: placebo 1.3%, ocriplasmin 5.9%, p=0.121). The manufacturer presented data on the VMT with ERM subgroup. The integrated analyses showed that there was no statistically significant difference between the placebo and ocriplasmin arm for any of the outcomes, and that the differences were small (proportion of patients with vitreomacular traction resolution by day 28: placebo 1.6%, ocriplasmin 7.8%, p=0.085; proportion of patients with total PVD by day 28: placebo 1.6%, ocriplasmin 3.6%, p=0.444; proportion of patients who received a vitrectomy by month 6: placebo 17.5%, ocriplasmin 11.4%, p=0.231; mean change in VA from baseline at day 28: placebo 2.7 letters, ocriplasmin 1.9 letters, p=0.325; mean change in VA from baseline at month 6: placebo 2.3 letters, ocriplasmin 2.0 letters p=0.685). At month 6 more patients treated with ocriplasmin than placebo had gained letters. However, more patients treated with ocriplasmin had lost letters (at least 10 letters gained: placebo 9.5%, ocriplasmin 20.5%, p=0.058; at least 15 letters gained: placebo 3.2%, ocriplasmin 4.8%, p=0.625; at least 10 letters lost: placebo 1.6%, ocriplasmin 8.4%, p=0.052; at least 15 letters lost: placebo 0%, ocriplasmin 4.8%, p=0.069). The manufacturer presented data on the VMT with MH subgroup. The integrated analyses showed that the proportions of patients with vitreomacular traction resolution, total PVD or macular hole closure without vitrectomy by day 28, or macular hole closure without vitrectomy by month 6, were statistically significantly greater in the ocriplasmin arm than the placebo arm (vitreomacular traction resolution: placebo 25.5%, ocriplasmin 50.0%, p=0.006; total PVD: placebo 8.5%, ocriplasmin 22.6%, p=0.033; macular hole closure at day 28: placebo 10.6%, ocriplasmin 40.6%, p<0.001; macular hole closure at month 6: placebo 17.0%, ocriplasmin 40.6%, p<0.001). Further secondary outcomes did not show a statistically significant difference between the treatment arms but did favour ocriplasmin (proportion of patients who received vitrectomy by month 6: placebo 57.4%, ocriplasmin 44.3%, p=0.157; mean change in VA from baseline at day 28: placebo 3.0 letters, ocriplasmin 3.9 letters, p=0.691; mean change in VA from baseline at month 6: placebo 2.3 letters, ocriplasmin 6.8 letters, p=0.126). At month 6, the proportion of patients gaining letters and patients losing letters favoured ocriplasmin (at least 10 letters gained: placebo 30.4%, ocriplasmin 44.3%, p=0.104; at least 15 letters gained: placebo 13.0%, ocriplasmin 27.4%, p=0.063; at least 10 letters lost: placebo 15.2%, ocriplasmin 8.5%, p=0.233; at least 15 letters lost: placebo 10.9%, ocriplasmin 6.6%, p=0.421). ## Health‑related quality-of-life results Health‑related quality-of-life data were collected during the TG‑MV‑006 and TG‑MV‑007 trials using the VFQ‑25. The VFQ‑25 has 12 subscales that measure the influence of visual disability and visual symptoms on generic health domains such as emotional wellbeing, social functioning, sense of independence, and other task‑oriented domains related to daily visual functioning (such as driving). The manufacturer presented the integrated analyses of these data for the whole population. In the ocriplasmin group, mean increases (representing improvements) were observed across all of the subscale and composite scores at month 6, and were numerically better than the placebo arm. A clinically meaningful improvement in the VFQ‑25 composite score (minimum clinically important difference: 3.6) was observed in a significantly larger proportion of the ocriplasmin group (35.9%) than the placebo group (22.7%, p=0.0016). The mean change from baseline in VFQ‑25 composite score at 6 months was significantly greater in the ocriplasmin group (3.4) than the placebo group (0.7, p=0.007). The general vision subscale score improved more in the ocriplasmin group than the placebo group (placebo 2.1, ocriplasmin 6.1, p=0.024). This score was affected by the primary efficacy outcome (vitreomacular adhesion resolution): in the ocriplasmin group, mean improvement from baseline in the general vision subscale score was 8.4 for patients who had vitreomacular adhesion resolution, and 5.3 for those who did not. The mean improvement from baseline in the composite score was 5.7 among patients who had vitreomacular adhesion resolution and 2.6 for those who did not. The manufacturer presented a meta‑analysis that showed statistically significant improvements in VFQ‑25 outcomes (expressed as a difference in means) with ocriplasmin in general vision, distance activities, dependency, and composite scores. ## Adverse events of treatment The manufacturer presented pooled adverse event data from 7 clinical trials because TG‑MV‑006 and TG‑MV‑007 were not powered to detect significant differences in treatment‑related adverse events. The pooled trials were TG‑MV‑001, TG‑MV‑002, TG‑MV‑003, TG‑MV‑004, TG‑MV‑006, TG‑MV‑007 and TG‑MV‑010. The adverse events were mainly ocular events. The incidence of serious adverse events was similar between placebo (TG‑MV‑006 and TG‑MV‑007 12.8%, all studies 13.8%) and ocriplasmin (TG‑MV‑006 and TG‑MV‑007 13.3%, all studies 13.5%). The only suspected adverse drug reaction that appeared to be dose dependent was vitreous floaters. The most common serious adverse event reported in the study eye was macular hole, which was less common in the ocriplasmin group than in the placebo group (4.7% and 6.5% respectively in all studies combined). The manufacturer stated that most adverse events were non‑serious, mild in intensity, and resolved, and therefore were not considered to be clinically significant. # Cost effectiveness The cost‑effectiveness evidence presented by the manufacturer consisted of a systematic literature review and a de novo model. The literature review was to identify all existing studies of the cost effectiveness of any intervention in patients with vitreomacular traction (including vitreomacular traction associated with a macular hole or epiretinal membrane). The systematic review did not identify any relevant cost‑effectiveness studies, so the manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of ocriplasmin compared with 'watch and wait' in patients with VMT with ERM, VMT without ERM, and VMT with MH. ## Model structure The manufacturer's model had 2 components: a short‑term decision tree and a long‑term extrapolation Markov model. The short‑term decision tree covered the first 6 months of treatment, and was predominantly based on clinical trial data pooled from TG‑MV‑006 and TG‑MV‑007. It had monthly cycles. The short‑term decision tree determined the starting position of patients in the long‑term extrapolation Markov model, which started at 6 months post‑treatment and then had a lifetime time horizon. The Markov model applied 3-monthly cycles for the first 2 to 5 years. After 2 years (or 5 years in the sensitivity analysis) annual cycles were used, therefore assuming events such as vitrectomy and spontaneous resolution would occur before this. The manufacturer's model covered the population stated in the scope and the marketing authorisation (that is, adults with vitreomacular traction, including when associated with macular hole of diameter less than or equal to 400 microns). However, the manufacturer modelled 3 different subgroups of this population, which were defined by baseline characteristics: VMT without ERM, VMT with ERM (the VMT subgroups included patients with stage 1 macular holes), and VMT with MH (macular holes were stage 2; this group included people with an epiretinal membrane). There were 2 short‑term decision tree models used, one for the VMT with MH group and one for the other 2 subgroups. The structure of the long‑term extrapolation Markov model was the same for all 3 subgroups. The manufacturer's short‑term decision tree for patients with VMT (with or without ERM) had the following decision nodes: non‑surgical vitreomacular traction resolution (at day 28 or month 6), visual acuity health state 1 to 6 (see section 3.15), vitrectomy, macular hole at month 6. The manufacturer's short‑term decision tree for patients with VMT with MH had the following decision nodes: non‑surgical macular hole resolution (at day 28 or month 6), vitrectomy (first or second), macular hole closed, non‑surgical vitreomacular traction resolution at month 6. The manufacturer assumed that macular hole closure would lead to vitreomacular traction resolution. Patients finished the decision tree in 1 of 6 different health states, which were in the long‑term Markov model. These health states were: resolved (vitreomacular traction and macular hole), vitreomacular traction unresolved without macular hole, vitreomacular traction unresolved with macular hole, vitreomacular traction resolved with macular hole (no vitrectomies), vitreomacular traction resolved with macular hole (1 vitrectomy) or vitreomacular traction resolved with macular hole (2 vitrectomies). The manufacturer's long‑term Markov model also had a 'death' state. Patients transitioned to another health state as a result of the following events: spontaneous vitreomacular traction and/or macular hole resolution, resolution of vitreomacular traction and/or macular hole through vitrectomy, failure of vitrectomy to resolve macular hole, spontaneous development of a macular hole, or death (see sections 3.16 and 3.19 for model transitions). There were 2 assumptions in the model that were based only on the manufacturer's clinical expert opinion: There is a maximum of 2 vitrectomies. This is based on clinical expert opinion that the probability of having a third vitrectomy was very low. Vitrectomies are 100% effective at treating vitreomacular traction, and therefore a second one is only used to close a persistent macular hole. Within each health state of the long‑term extrapolation Markov model (other than death) there were 6 sub‑states that represented levels of visual acuity, called the vision health states. Patients could move in any direction through the vision health states because they could improve or deteriorate. These health states were determined by the patients' BCVA in terms of ETDRS letters read: VA1: 76 to 100 letters, VA2: 66 to 75 letters, VA3: 56 to 65 letters, VA4: 46 to 55 letters, VA5: 36 to 45 letters, VA6: 0 to 35 letters. ## Model transitions The transitions between health states in the manufacturer's decision tree and Markov models were calculated from the integrated phase 3 trial data (from TG‑MV‑006/007), with the following exceptions: probability of opting for a second vitrectomy (75%), probability of success of second vitrectomy (50% of success rate of first vitrectomy ). Each of these were based on manufacturer expert opinion. The mortality rates applied in the manufacturer's model were based on VA state. For VA1 to 5, the mortality rate of the general population was used, taken from England and Wales interim life tables 2008–2010, from the Office of National Statistics. These were weighted according to sex. For a best‑seeing eye VA6 score, which represented severe visual impairment, the manufacturer used a mortality hazard rate of 1.54 from a US study (Christ et al. 2008). As described in 3.15, the manufacturer's Markov model included visual acuity states within each health state. At the start of the model, the distribution of patients across the visual acuity states was estimated using an ordered logit model based on trial data (TG‑MV‑006 and TG‑MV‑007). This was assumed to be the same for both treatment arms (ocriplasmin and placebo). The presence of a macular hole affected the visual acuity state distribution, with more patients with a macular hole having VA3–VA6 scores than those without. Patients could move between any visual acuity state (representing improving or declining visual acuity) within the model. The transition probabilities between visual acuity states were assumed to be different depending on whether vitreomacular adhesion/traction was resolved or remained unresolved, and it was assumed that the presence of a macular hole did not affect the rate of visual acuity change. The transition probabilities between visual acuity states were based on estimates from the literature that relate to changes over time in the general population for patients with resolved vitreomacular traction, and in patients with persistent vitreomacular traction for unresolved vitreomacular traction. The manufacturer's submission recognised that after specific events there would be an initial change in vision that would be different from changes observed in the general population over time. The manufacturer therefore included within the model visual acuity transitions after a specific event for 1 cycle. The events that were modelled were vitreomacular traction resolution only, macular hole closure only, vitreomacular traction resolution and macular hole closure and vitreomacular traction progression to macular hole. The corresponding transition probabilities were calculated from the integrated phase 3 clinical trial data (TG‑MV‑006 and TG‑MV‑007) using an ordered logit model (except for the macular hole opening, for which calibration was used). ## Utility values and adverse events The manufacturer applied utility values to each of the visual acuity states in the model. These were derived from a study that used contact lenses to simulate the effects of visual impairment caused by age‑related macular degeneration. The study grouped patients into 4 categories, according to their best‑seeing eye, and a time trade‑off instrument was used to elicit utilities from the general UK population. Because the manufacturer's model used 6 visual acuity states, the utility values from the study were adapted to fit the 6 visual acuity states in the model. In addition, because the study was based on the best‑seeing eye only, a matrix was developed to account for the visual acuity state of both the best- and worst-seeing eye. The utility for each visual acuity combination (for example, VA1 and VA1, or VA1 and VA2) was then estimated. The adverse events included in the manufacturer's model were modelled as occurring post‑vitrectomy or post‑ocriplasmin. These included retinal tear (13.23% and 0.22%, respectively), retinal detachment (13.23% and 0.43% respectively), elevated intraocular pressure (26.46% and 2.37% respectively) and vitreous haemorrhage (3.31% and 0.22% respectively). The probabilities of these events occurring were estimated using the integrated clinical trials data (TG‑MV‑006 and TG‑MV‑007). Many patients develop cataracts after vitrectomy, therefore the manufacturer's model included a 96% probability (determined from published data) of developing cataracts after having a vitrectomy. The proportions of people in each subgroup who could develop cataracts (who have not had previous cataract surgery) were 59% for VMT with ERM, 63.9% for VMT without ERM and 79.1% for VMT with MH. The manufacturer accounted for adverse events by applying disutility values. A disutility for metamorphopsia (0.017), which has a significant impact on quality of life, was derived from the literature and included in the manufacturer's model. Disutility values derived from the literature were also applied to each of the adverse events captured in the model (see section 3.21): retinal detachment (0.13 for 1 month), vitreous haemorrhage (0.02 for 1 month) and cataract (0.14 for 6 months). Disutility values for retinal tear and increased intraocular pressure were not identified in the literature and therefore no disutility was applied to these. Disutilities were all applied during 1 cycle, with an exception made for metamorphopsia, which persisted until vitreomacular traction resolved. Disutilities were normalised to a 3‑month cycle length. Vitrectomy surgery is associated with a post‑surgery reduction in health‑related quality of life which was accounted for in the model by transitioning to the visual acuity state VA6 for 2 weeks (rather than applying a disutility value). ## Costs applied in the model The manufacturer's model included the following costs: ocriplasmin (£2500), ocriplasmin administration (£117), surgery (vitrectomy and cataract ), follow‑up visits (£80), OCT (£54.29), annual cost of blindness (£6496), and costs of adverse events (retinal detachment , retinal tears , increased intraocular pressure , vitreous haemorrhage ). The manufacturer used NHS reference costs to estimate the cost of vitrectomy surgery, cataract surgery, administration of ocriplasmin, follow‑up visits, retinal detachment, and vitreous haemorrhage. The annual cost of blindness was estimated from the Personal Social Services Research Unit (PSSRU) costs of Health and Social Care and accounts for residential care (£18,191 for 30% of blind patients), community care (£8195 for 6% of blind patients), depression (£539 for 39% of blind patients), and hip replacement (£6728 for 5% of blind patients). The cost of OCT was taken from the literature, and the costs of retinal tears and increased ocular pressure were taken from NICE submissions. The model base case assumes 1 follow‑up visit per 3 months, 1 OCT per 3 months, 4 post‑vitrectomy follow‑up visits, 4 OCTs post‑vitrectomy, 2 follow‑up visits post‑ocriplasmin injection and 1 OCT post‑ocriplasmin injection. These visit estimates are based on clinical expert advice. ## Manufacturer's base‑case incremental cost‑effectiveness ratio (ICER), sensitivity and scenario analyses The manufacturer presented a base‑case ICER for each patient subgroup. The ICER for ocriplasmin compared with 'watch and wait' in the VMT without ERM subgroup was £18,481 per quality‑adjusted life year (QALY) gained (incremental cost: £1880.67, incremental QALY: 0.1018), for VMT with ERM it was £67,119 per QALY gained (incremental cost: £2487.13, incremental QALY: 0.0371) and for VMT with MH it was £21,593 per QALY gained (incremental cost: £1752.90, incremental QALY: 0.0812). The manufacturer estimated that the probability of ocriplasmin being cost effective, if the maximum acceptable ICER was £20,000 or £30,000 per QALY gained, compared with 'watch and wait' was: 51% and 80% respectively for VMT without ERM; 0% and 2% respectively for VMT with ERM; and 46% and 72% respectively for VMT with MH. The manufacturer conducted univariate sensitivity analyses for each of the subgroups. For the VMT without ERM and VMT with ERM subgroups the model outcomes were most sensitive to the inputs determining non‑surgical resolution of vitreomacular traction at 6 months and 28 days. The QALY discount rate was also an important driver for these subgroups. For the VMT with MH subgroup, the model outcomes were most sensitive to the inputs that determined non‑surgical macular hole closure, cataract disutility and the chance of macular hole closure post‑vitrectomy. The manufacturer also conducted scenario analyses to investigate the following: The time limit of vitrectomy. It was assumed that vitrectomies would occur within 2 years in the base case and therefore the model applied a 3‑month cycle length for 2 years and an annual cycle length thereafter. The 3‑month cycles enable rapid changes in visual acuity in response to vitrectomy. By changing the length of time the model was running at 3‑monthly cycles from 2 years in the base case to 1 or 5 years, the manufacturer could investigate the impact of changing the time period for vitrectomy. The impact of treating patients with a macular hole earlier than usual with a vitrectomy by assessing the cost effectiveness at day 28 of ocriplasmin compared with vitrectomy. Accounting for the lack of mortality in the decision tree part of the model by doubling mortality in the first year of the Markov model. Using visual acuity state transitions derived from a study by Van der Pols et al. (2000) on British patients, rather than Finnish patients as in the base case. Applying the same rate of visual acuity decline whether vitreomacular traction was resolved or not, by using the transition rates from Laitinen et al. (2005) for all visual acuity health states. Using spontaneous vitreomacular traction resolution rates from the literature rather than the clinical trial. Applying utility values derived from patients with age‑related macular degeneration in the US, rather than utilities derived from the general UK population as in the base case. The impact of modelling the best or worst‑seeing eye only, rather than accounting for both eyes. Applying an alternative metamorphopsia disutility value of 0.14, derived using the EQ‑5D, rather than 0.017 from the literature as used in the base case. The different scenarios had different impacts on the 3 subgroups. Two scenarios increased the ICER the most. These increased the ICER substantially from the manufacturer's base case for the VMT without ERM and VMT with ERM subgroups and resulted in small increases for the VMT with MH group: making the long‑term vision transition rates equal whether vitreomacular traction had resolved or not VMT without ERM: £44,489 per QALY gained (incremental cost £2235, incremental QALY 0.050) VMT with ERM: £142,347 per QALY gained (incremental cost £2599, incremental QALY 0.018) VMT with MH: £21,723 per QALY gained (incremental cost £1754, incremental QALY 0.081) using a 16.5% rate of spontaneous resolution VMT without ERM: £67,320 per QALY gained (incremental cost £2257, incremental QALY 0.034) VMT with ERM: £230,656 per QALY gained (incremental cost £2575, incremental QALY 0.011) VMT with MH: £21,615 per QALY gained (incremental cost £1753, incremental QALY 0.081). Applying a different metamorphopsia disutility value reduced the ICER substantially from the manufacturer's base case in all 3 subgroups: VMT without ERM: £12,190 per QALY gained (incremental cost £1881, incremental QALY 0.154) VMT with ERM £42,388 per QALY gained (incremental cost £2487, incremental QALY 0.059) VMT with MH £17,837 per QALY gained (incremental cost £1753, incremental QALY 0.098). Modelling only the best‑seeing eye reduced the ICER and modelling only the worst‑seeing eye increased the ICER in all 3 subgroups, with a large impact for both analyses in the VMT with ERM subgroup. Using utility values derived from UK patients increased the ICER for all 3 subgroups, with a substantial increase in the VMT with ERM subgroup. Changing the time limit of vitrectomy had little impact on the VMT with MH subgroup but for both the VMT without ERM and VMT with ERM subgroups using 1 year substantially decreased the ICER, and using 5 years substantially increased the ICER. The other scenario analyses had only a small impact on the ICERs. # Evidence Review Group comments ## Clinical effectiveness The ERG reviewed the manufacturer's literature review and considered that the manufacturer was likely to have identified all the randomised controlled trial evidence relevant to the decision problem. The ERG reviewed the designs of TG‑MV‑006 and TG‑MV‑007. It noted that the patients in the placebo group had undergone an injection, which was an invasive procedure, rather than having been initially observed without treatment, as is typical in UK clinical practice. The ERG noted that the visual acuity of patients enrolled on the trials, with the exception of those with a macular hole, was better than would be seen in clinical practice for patients with vitreomacular traction and/or macular hole who would normally be offered vitrectomy. The ERG identified this as a limitation of the data because efficacy may be affected by disease severity. The ERG noted that the primary outcome of non‑surgical resolution of vitreomacular adhesion is a surrogate outcome for preventing deteriorating vision, which can result from untreated and progressive vitreomacular traction. The ERG commented that there is limited evidence on the validity of non‑surgical resolution of vitreomacular adhesion as a surrogate for preventing deteriorating visual function. The ERG noted that adverse events reported in the pooled results of 7 completed clinical trials (the 'safety set') were consistent with the vitreolytic activity of the drug or method of administration and most were mild, or moderate and transient. However, the ERG commented that none of the safety set of trials, which ocriplasmin's safety profile is based on, was designed to assess safety outcomes with sufficient power to detect differences in incidence rates. This safety set can only detect adverse events with an incidence greater than 0.4% because of the uneven randomisation ratios. ## Cost effectiveness The ERG considered the modelling approach presented by the manufacturer to be appropriate and stated that it enabled important anatomical and visual outcomes to be simultaneously captured in the short and long term. The ERG reviewed the model, and considered many of the approaches, assumptions and data sources applied by the manufacturer to be reasonable. The ERG identified some areas of uncertainty in the manufacturer's model, which it investigated, if it was possible, in exploratory analyses. Three scenarios had a large impact on the ICER: applying a different rate of probability for cataracts (see 3.38) enabling cataract and vitrectomy surgery to be done simultaneously (see section 3.39) applying a different macular hole vitrectomy success rate (see section 3.40). ## Evidence Review Group's exploratory analyses Most of the ERG's exploratory analyses did not affect the manufacturer's base-case ICERs (see section 3.25) for the subgroups substantially. The resulting ICERs were in the following ranges: VMT without ERM: base case: £18,481 per QALY gained range: £17,733 to £18,986 per QALY gained VMT with ERM: base case: £67,119 per QALY gained range: £64,331 to £67,666 per QALY gained VMT with MH: base case: £21,593 per QALY gained range: £20,551 to £22,985 per QALY gained. The ERG explored the rate of cataracts after vitrectomy. The ERG noted that a study of the National Ophthalmology Database identified that 64.6% of eyes that had a macular hole operation (without combined or previous cataract surgery) needed lens removal within 1 year of vitrectomy, which was much lower than the 96% applied in the model by the manufacturer (to non‑pseudophakic eyes only). Applying this new rate increased the ICER of each subgroup by at least £1000 (VMT without ERM: from £18,481 to £19,858 per QALY gained ; VMT with ERM: £67,119 to £71,737 per QALY gained ; VMT with MH: from £21,593 to £28,289 per QALY gained ). The ERG conducted a sensitivity analysis around this and applied an 88.8% and 92.0% probability of cataract. This increased the manufacturer's base‑case ICER, but to a lesser extent than applying the 64.6% probability. Applying an 88.8% probability of cataract increased the manufacturer's base‑case ICER to: VMT without ERM: £18,782 per QALY gained (incremental cost £1885, incremental QALY 0.100); VMT with ERM: £68,127 per QALY gained (incremental cost £2489, incremental QALY 0.037); VMT with MH: £22,863 per QALY gained (incremental cost £1765, incremental QALY 0.077). Applying a 92.0% probability of cataract increased the manufacturer's base‑case ICER to: VMT without ERM: £18,647 per QALY gained (incremental cost £1883, incremental QALY 0.101); VMT with ERM: £67,675 per QALY gained (incremental cost £2488, incremental QALY 0.037); VMT with MH: £22,283 per QALY gained (incremental cost £1760, incremental QALY 0.079). The ERG explored the impact of combining vitrectomy and cataract surgery. The ERG received advice from clinical specialists highlighting that, as a result of the high incidence of cataract formation after vitrectomy, lens removal is frequently combined with vitrectomy as a preventative measure. The ERG noted that this was not accounted for in the manufacturer's model. Furthermore, the ERG noted that Jackson et al. (2013) report that 40.5% of patients undergoing macular hole vitrectomy had combined lens removal. Therefore, to investigate the potential impact of combined surgery on the manufacturer's ICERs, the ERG further reduced the probability of cataract surgery by 40.5%. The ICER of each subgroup increased (VMT without ERM: from £18,481 to £20,212 per QALY gained ; VMT with ERM: £67,119 to £72,929 per QALY gained ; VMT with MH: from £21,593 to £30,458 per QALY gained ). The ERG explored the success rate of macular hole vitrectomy in the manufacturer's model. The ERG noted that 82% of vitrectomies to treat macular hole are assumed to be successful (based on trial data) in the manufacturer's base‑case economic analyses. However, expert clinical opinion highlighted that, in patients with a macular hole of 400 micrometres or less, success after vitrectomy involving internal limiting membrane peeling is over 90%. Therefore the ERG carried out a sensitivity analysis assuming 95.8% of macular hole vitrectomies are successful. The ICER associated with each subgroup increased, most notably in patients with a macular hole (VMT without ERM: from £18,481 to £19,250 per QALY gained ; VMT with ERM: from £67,119 to £69,588 per QALY gained ; VMT with MH: from £21,593 to £26,854 per QALY gained ). The ERG estimated a revised (deterministic) base‑case ICER for each subgroup that took into account all of the exploratory analyses detailed in sections 3.37 to 3.40, and used a probability of cataract of 64.6%. The resulting ICERs were: VMT without ERM £20,861 per QALY gained (incremental costs £2082, incremental QALY 0.100) VMT with ERM £69,694 per QALY gained (incremental costs £2568, incremental QALY 0.037) VMT with MH £56,137 per QALY gained (incremental costs £2132, incremental QALY 0.038). The ERG commented that there were other areas of uncertainty that could affect the ICER, including: The uncertainty associated with the clinical data because patients receiving a placebo injection had been used to represent the outcomes of 'watch and wait' patients. The ERG concluded that this was likely to bias against ocriplasmin, and that the ICER would be expected to decrease (in all subgroups) if this was addressed. The health states modelled did not include epiretinal membrane. The ERG stated that this would affect only the VMT with ERM subgroup but would be likely to increase the ICER in this subgroup. Differences in the results and baseline characteristics within and between the relevant clinical trials (TG‑MV‑006 and TG‑MV‑007). The ERG concluded that any bias was likely to be against ocriplasmin and therefore the ICER would be expected to decrease if baseline characteristics for these subgroups were balanced. The manufacturer conservatively assuming long‑term vision decline was the same for all patients with unresolved vitreomacular traction, regardless of whether they had a macular hole or not. The ERG stated that the ICER would be expected to decrease if visual decline was different for vitreomacular traction patients with or without a macular hole but that the impact was not quantifiable for any of the subgroups. The manufacturer assuming the quality of life impact of metamorphopsia is the same for both vitreomacular traction and macular hole, and applies to patients whose vitreomacular traction is unresolved, or whose macular hole is open. The ERG considered these assumptions to be potentially inaccurate because the patient population in Fukeda et al. (2009) continued to have symptoms of metamorphopsia after vitrectomy to close the macular hole. This suggests the possibility of metamorphopsia in patients with resolved vitreomacular traction, which clinical specialist advice highlighted may be a result of a persistent epiretinal membrane (not accounted for in the manufacturer's model). The ERG concluded that the impact of accounting for metamorphopsia in patients with resolved vitreomacular traction was not quantifiable but that any bias was likely to be small and against ocriplasmin. The ICER would be expected to decrease if a lower disutility for metamorphopsia was applied in patients with vitreomacular traction alone (no macular hole). The fact that the manufacturer provided no rationale for not including an increased mortality risk in patients with 'some' visual impairment. The ERG anticipated that the impact on the ICER of incorporating an increased mortality risk for patients with visual impairment in their worst‑seeing eye was likely to be small, and that the direction of any bias was unclear. The ERG reviewed the scenario presented by the manufacturer in which long‑term vision outcomes were assumed to be equivalent, whether vitreomacular traction was resolved or unresolved. It noted that this increased the ICER substantially (see section 3.28). The ERG agreed with the manufacturer and stated that, based on the ERG's clinical specialist opinion, this scenario was unlikely. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ocriplasmin having considered evidence on the nature of vitreomacular traction and the value placed on the benefits of ocriplasmin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee considered the current management of vitreomacular traction and the likely place of ocriplasmin in clinical practice; noting that the scope of the appraisal and the marketing authorisation for ocriplasmin is 'indicated in adults for the treatment of vitreomacular traction, including when associated with macular hole of diameter less than or equal to 400 microns'. The clinical specialists explained that vitreomacular traction was managed differently depending on whether or not a stage 2 macular hole was present. They said that patients who presented with a stage 2 macular hole would be listed for surgery because delaying surgery could lead to poorer outcomes for these patients and stage 2 macular holes rarely resolve spontaneously. The Committee heard from the clinical specialists that if ocriplasmin was recommended for use, patients with a stage 2 macular hole would still be listed for surgery, without delay, and ocriplasmin would be administered to patients during the period before surgery (in UK clinical practice this can be a number of weeks or months). The clinical specialists stated that for patients who have vitreomacular traction without a macular hole, or with a stage 1 macular hole, delaying surgery in general does not have an impact on long‑term outcomes and that many of these patients will not need surgery. The clinical specialists explained that some patients would need surgery and in these patients if ocriplasmin was available it would be offered as an alternative to surgery. Furthermore, they commented that some patients would have severe distressing symptoms (such as metamorphopsia and low visual acuity), but would not be eligible for surgery, and that if ocriplasmin was available it would be offered to these patients instead of 'watch and wait'. The Committee acknowledged that about 80% of the patients in the trials had an expected need for vitrectomy at baseline, and therefore the patients in the trials were those with severe distressing symptoms and/or those who were eligible for surgery. The Committee concluded that the treatment pathway varies depending on the presence or absence of a stage 2 macular hole. If a stage 2 macular hole is present, ocriplasmin would be used during the wait for surgery, without delaying surgery. If a stage 2 macular hole is not present, ocriplasmin would be used as an alternative to surgery, or as an alternative to 'watch and wait' for people who have severe distressing symptoms. The Committee discussed vitrectomy surgery in UK clinical practice. The clinical specialists explained that there were risks involved with the surgery, including the potential to damage the eye and reduce visual acuity. Clinical specialists stated that a treatment that could avoid vitrectomy surgery would be beneficial for patients. The Committee also heard from the patient expert who described her experience of vitrectomy surgery and the anxiety and trauma it could cause. The patient expert explained that the recovery period after surgery was worse than the surgery itself because she had to lie in a face down position for up to a week. She described this as being very difficult and uncomfortable, and said that it felt suffocating. She commented that she would choose a treatment that involved an injection over vitrectomy surgery. The Committee recognised this, but also understood that face down positioning for recovery is being used less often, and for shorter periods. The Committee acknowledged that, although vitrectomy surgery was effective in resolving vitreomacular traction and the recovery time after surgery was short, the recovery was an unpleasant process for patients, and surgery also had risks and could damage the eye. The Committee concluded that an alternative treatment for vitreomacular traction would be welcomed by clinicians and patients. The Committee considered the impact of vitreomacular traction on the everyday life of patients. It heard from the patient expert about the problems associated with vitreomacular traction, including difficulties with reading, cooking, watching television and driving that prevented them from enjoying these activities. The Committee understood from the patient expert that the effects of metamorphopsia and macular holes were very disturbing. The patient described seeing straight lines as wavy, and objects disappearing from view. The Committee concluded that resolving vitreomacular traction without the need for surgery would be beneficial to the wellbeing of patients with vitreomacular traction. # Clinical effectiveness The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ocriplasmin. The Committee acknowledged that 3 subgroups were presented by the manufacturer (VMT without ERM , VMT with ERM , and VMT with MH ). It noted that the evidence was from the TG‑MV‑006 and TG‑MV‑007 trials and it discussed the outcomes in these trials. The Committee acknowledged that the outcomes presented by the manufacturer were in line with the scope issued by NICE, and that they included vitreomacular traction resolution, posterior vitreous detachment (PVD), vitrectomy, visual acuity changes and macular hole closure. The Committee noted that although there was a statistically significant benefit with ocriplasmin compared with placebo in terms of vitreomacular traction resolution and total PVD at day 28 in the VMT without ERM and VMT with MH subgroups, this did not translate into a statistically significant visual acuity benefit (see sections 3.7 and 3.9). The clinical specialists explained that visual acuity was not a complete or accurate measure of the vision impairment experienced with vitreomacular traction. This is because measured visual acuity may not be affected by the presence of a macular hole or metamorphopsia: although the patient has distorted vision, they may still be able to read a letter on an eye chart successfully. The clinical specialists therefore explained that anatomical measures such as vitreomacular traction resolution or total PVD were a better way to measure the benefit of the treatment, and that from their experience approximately 70–80% of metamorphopsia resolved with vitreomacular traction resolution. The Committee accepted that the anatomical outcomes of vitreomacular traction resolution and total PVD were appropriate measures for assessing the effectiveness of ocriplasmin. The Committee considered the results from the trials in the manufacturer's submission. The Committee noted that the efficacy of ocriplasmin was not the same for all the subgroups evaluated. The Committee acknowledged that ocriplasmin was associated with a statistically significant improvement in vitreomacular traction resolution and total PVD at 28 days in the VMT without ERM (see section 3.7) and VMT with MH (see section 3.9) subgroups. However, in the VMT with ERM subgroup, the effect of ocriplasmin in terms of these outcomes was small and not statistically significant (see section 3.8). The Committee heard from the clinical specialists that they did not consider ocriplasmin to have a place in the treatment of patients with vitreomacular traction and an epiretinal membrane because it was not clinically effective in these patients. The Committee recognised that the VMT with MH group included people with ERM, and that because of the small sample size of this group (n=23) analyses had not been presented by the manufacturer. The Committee took into account the data from the VMT with ERM subgroup and the opinion of the clinical specialists and concluded that ocriplasmin was unlikely to be clinically effective in people with ERM in any of the subgroups, including VMT with MH. The Committee concluded that ocriplasmin was clinically effective, in terms of vitreomacular traction resolution and total PVD at 28 days in the subgroups VMT without ERM and VMT with MH, but not in the subgroup VMT with ERM, and it was unlikely to be clinically effective in terms of these outcomes in the VMT with MH subgroup who had ERM. The Committee discussed whether the comparator arm in the clinical trials was relevant to clinical practice in the UK. It noted that a placebo injection was used in the trials instead of the UK clinical practice of 'watch and wait'. It heard from clinical specialists that an injection of saline into the eye sometimes resolves vitreomacular traction, and that it could also provoke macular hole development. Therefore it was likely that the placebo injection could lead to total PVD, or to the creation of a macular hole. The clinical specialists commented that this was supported by the spontaneous resolution rates observed in the placebo arm of the trials (approximately 10%) because they were much higher than they observe in clinical practice (approximately 2% to 5%). The Committee concluded that the placebo injection in the clinical trials was not equivalent to 'watch and wait' and that it was plausible that the efficacy of ocriplasmin would have been greater if it had been compared with the UK clinical practice of 'watch and wait'. The Committee considered the differences between the trials and clinical practice in the UK. The clinical specialists noted that access to surgery may have been quicker in the trials than in clinical practice. It discussed that patients in the trials may be operated on immediately, while in clinical practice there could be a waiting time of several weeks or months. The Committee agreed that this difference could lead to an underestimation of the benefit of ocriplasmin because the wait for surgery can result in a poorer outcome for patients in clinical practice than observed in the trial. The Committee concluded that the benefit of ocriplasmin may have been underestimated because there was a shorter waiting period for vitrectomy in the clinical trials. The Committee considered the impact of ocriplasmin on all of the outcomes measured in the trials. The Committee noted that the trial results were limited to 6 months after the injection and therefore the long‑term impact was unknown. However, it heard from clinical specialists that once traction was relieved the condition was generally stable, and therefore it was plausible that any benefits relating to ocriplasmin would be expected to last beyond the 6‑month clinical trial period. The Committee concluded that the clinical effectiveness of ocriplasmin was likely to be durable in the long term. The Committee considered the adverse events that were associated with ocriplasmin. It noted that adverse events were mainly ocular events and that the incidence of serious adverse events was similar between ocriplasmin and placebo. The Committee acknowledged that the most common serious adverse event reported in the study eye was macular hole, which was more common in the placebo group than in the ocriplasmin group. The Committee understood that most adverse events were non-serious, mild in intensity and generally resolved. It concluded that ocriplasmin was similar to placebo in terms of adverse events. # Cost effectiveness The Committee considered the cost‑effectiveness evidence presented in the manufacturer's submission, including the base‑case incremental cost‑effectiveness ratios (ICERs), the sensitivity and scenario analyses, the Evidence Review Group's (ERG's) critique of the manufacturer's evidence, and comments raised during consultation on the appraisal consultation document (ACD). The Committee considered the 3 subgroups presented by the manufacturer in turn, as detailed below. The Committee considered the available cost‑effectiveness evidence for ocriplasmin in the VMT without ERM subgroup. The Committee discussed the potential for ocriplasmin to be used earlier than surgery would normally be used, in patients with distressing symptoms (for example metamorphopsia or low visual acuity), and was satisfied that this was captured in the model. It discussed the manufacturer's base‑case ICER of £18,500 per quality‑adjusted life year (QALY) gained. It noted that in the ERG's exploratory analysis (see sections 3.37 to 3.41) the ICERs were in the range of £17,700 to £20,200 per QALY gained, and that the ERG base-case ICER was £20,900 per QALY gained. The Committee recognised that this subgroup represents people with vitreomacular traction without an epiretinal membrane or a stage 2 macular hole who would be eligible for vitrectomy surgery, or people with severe distressing symptoms who would not be eligible for surgery. The Committee concluded that ocriplasmin was a cost‑effective option for the treatment of people with vitreomacular traction without an epiretinal membrane, and without a stage 2 macular hole. The Committee considered the available cost‑effectiveness evidence of ocriplasmin in the VMT with ERM subgroup. The Committee noted that ocriplasmin was not associated with a statistically significant improvement in vitreomacular traction resolution and total PVD at 28 days in the VMT with ERM subgroup (see section 3.8), and that any differences observed between ocriplasmin and placebo were small. Taking into account these data and the view of the clinical specialists that ocriplasmin was not effective in patients with ERM, the Committee concluded that the use of ocriplasmin in people with vitreomacular traction with an epiretinal membrane, but without a stage 2 macular hole, was not a cost‑effective use of NHS resources. The Committee considered the cost effectiveness of ocriplasmin in the VMT with MH subgroup. It noted the manufacturer's base‑case ICER of £21,600 per QALY gained. It discussed the manufacturer's sensitivity and scenario analysis (see sections 3.25 to 3.30), and the ERG critique of the manufacturer's model. It noted the uncertainties in the model, which had potentially substantial impacts on the manufacturer's ICER: The impact of combining vitrectomy and cataract surgery (see section 4.15). The rate of cataracts (see section 4.16). The macular hole vitrectomy success rate (see section 4.17). The metamorphopsia utility value (see section 4.18).The Committee also discussed additional comments that were raised during ACD consultation (see section 4.19) and that could impact on the ICER, including: The number of optical coherence tomography (OCT) and follow‑up visits post‑vitrectomy. The retinal detachment rate. The retinal tear rate. The rate of visual decline not accounting for a macular hole.The Committee's discussion and conclusion are summarised in the paragraphs below. The Committee considered the VMT and MH subgroup and the assumption in the manufacturer's model that vitrectomy and cataract surgery would not be performed at the same time. The Committee heard from clinical specialists that combining vitrectomy surgery and cataract surgery into one procedure is common practice in the UK. It noted that the risk of cataracts forming after vitrectomy surgery is greater than 90%. However, the clinical specialists explained that the main driver for performing the 2 operations at the same time was constrained capacity in hospital eye departments rather than improved outcomes. The Committee agreed that combining vitrectomy and cataract surgery was done in clinical practice, and therefore should be included in the model. It noted that combining vitrectomy and cataract surgery increased the ICER for the VMT with MH subgroup from £21,600 to approximately £30,500 per QALY gained. The Committee noted that no disutility had been applied by the manufacturer to the model to account for the addition of cataract removal to vitrectomy surgery, and concluded that applying a disutility would reduce the ICER marginally to under £30,500 per QALY gained. The Committee discussed the VMT and MH subgroup further, and the rate that was applied in the manufacturer's model for developing a cataract after vitrectomy. The Committee noted from the ERG's critique that as the rate of developing a post‑surgical cataract is reduced, the ICER for ocriplasmin increases. The Committee heard from clinical specialists that the overall chance of developing a cataract was likely to be greater than 90%. It commented further that the annual rate of 64.6% (estimating an ICER of £28,300 per QALY gained for the VMT and MH subgroup) modelled by the ERG was likely to be lower than observed in UK clinical practice, and that the rate modelled by the manufacturer (96% annual rate, ICER £21,600 per QALY gained for the VMT with MH subgroup) was likely to be higher than observed in UK clinical practice. The Committee concluded that the rate of developing a cataract in UK clinical practice was likely to be lower than the manufacturer's value. The Committee discussed the success rates of macular hole vitrectomy applied to the VMT with MH subgroup in the manufacturer's model (82%) and applied in the ERG's exploratory analyses (95.8%). It noted that for the VMT with MH subgroup, applying the higher rate increased the ICER from £21,600 to £26,900 per QALY gained. The Committee heard from clinical specialists that the success rate generally ranged from 80 to 90% and acknowledged the comments raised during ACD consultation that supported the ERG's macular hole vitrectomy success rate. The Committee therefore considered the rate applied by the ERG to be the most appropriate. The Committee concluded that the macular hole vitrectomy success rate was likely to be higher than that modelled in the manufacturer's base case and that this would increase the ICER. The Committee noted from the manufacturer's scenario analysis in the VMT with MH subgroup that changing the metamorphopsia utility value had an impact on the manufacturer's base‑case ICER. It understood that the manufacturer's base case applied a disutility value of 0.017 and that the manufacturer's scenario analysis, using a value of 0.14, reduced the ICER in all 3 subgroups substantially (see section 3.29). The Committee heard from clinical specialists that the utility gained from resolving metamorphopsia could be equivalent to going up 2 visual acuity states. The Committee considered that this was equivalent to approximately 0.03 utilities, based on the utility values used in the manufacturer's model. The Committee concluded that the disutility value applied in the manufacturer's model underestimated the disutility of metamorphopsia and that applying a higher disutility value would reduce the ICER, although the level of impact remained unclear. The Committee considered the comments that were received during ACD consultation. It noted that the number of OCT and follow‑up visits post‑vitrectomy may have been overestimated in the manufacturer's base case for the VMT with MH subgroup. The Committee was aware that the ERG had done a sensitivity analysis that reduced the number of OCT and follow‑up visits from 4 to 2, and that this increased the ICER by a small amount: from £21,600 to £22,500 per QALY gained. The Committee also discussed comments received during consultation that a retinal detachment rate of 13.23% in the manufacturer's base case seemed high and a rate of 5.4% was more representative of clinical practice. In addition, a retinal tear rate with ocriplasmin of 0.22% had been used in the manufacturer's base case rather than a rate of 1.3%, which has been published. The Committee considered the impact on the ICER of the different rates of retinal detachment and retinal tear and recognised that the ICER would increase by a small amount. Finally, the Committee also noted comments received during consultation that in the manufacturer's base case visual decline was assumed to be the same whether or not a macular hole was present. The Committee understood from the ERG that the ICER would reduce if visual decline was different for people with or without a macular hole. The Committee concluded that reducing the number of OCT and follow‑up visits and applying different rates for retinal detachment and retinal tear would lead to small increases in the ICER, but that accounting for a greater rate of visual decline with a macular hole would reduce the ICER. The Committee considered whether an ocriplasmin injection is an innovative treatment. The Committee agreed with the clinical specialists and manufacturer that the ocriplasmin injection provided a step change in treating patients with vitreomacular traction compared with current practice in vitrectomy and 'watch and wait'. The Committee acknowledged that no significant or substantial health‑related benefits were identified that were not included in the economic model. Therefore the Committee agreed that the ocriplasmin injection was innovative and it would consider an ICER at the top end of the range that would normally be considered a cost effective use of NHS resources (£20,000 to 30,000 per QALY gained). In summary, the Committee considered the manufacturer's base‑case ICERs, the sensitivity and scenario analyses presented by the manufacturer, the ERG's critique and exploratory analyses, and comments raised during consultation for each of the subgroups presented that make up the marketing authorisation. The Committee considered the use of ocriplasmin to treat vitreomacular traction without an epiretinal membrane or a stage 2 macular hole and concluded that the ICER was likely to be no greater than £20,900 per QALY gained (as presented by the ERG, see section 3.41). It agreed therefore that ocriplasmin was a cost‑effective use of NHS resources for treating vitreomacular traction in people with vitreomacular traction without an epiretinal membrane. The Committee considered the use of ocriplasmin to treat vitreomacular traction with an epiretinal membrane, but without a stage 2 macular hole, and recognised that ocriplasmin was not clinically effective or cost effective for these people (see section 3.8 and 3.41). The Committee therefore concluded that ocriplasmin could not be considered a cost‑effective use of NHS resources for treating people with vitreomacular traction and an epiretinal membrane, without a stage 2 macular hole. The Committee considered the use of ocriplasmin to treat vitreomacular traction with a stage 2 macular hole. The Committee agreed that the preferred assumption was to include combined cataract and vitrectomy surgery (see section 4.15), and noted the associated ICER was approximately £30,500 per QALY gained. It considered that in clinical practice the effectiveness of ocriplasmin might be greater than that seen in the trials because patients would have to wait longer for surgery and would not benefit from a placebo injection (see section 4.7). The Committee recognised that this would lower the ICER to below £30,500 per QALY gained. The Committee also considered that addressing uncertainties in the model could both increase and decrease the ICER (increase it by: increasing the macular hole vitrectomy success rate , reducing the post vitrectomy cataract rate , increasing the retinal tear rate with ocriplasmin , decreasing the retinal detachment rate with vitrectomy and decreasing the post‑vitrectomy OCT and follow‑up visits ; decrease it by: accounting for greater disutility values associated with both metamorphopsia and combined surgery , accounting for a greater rate of visual decline with a macular hole , and accounting for the active placebo comparison ). The Committee recognised that ocriplasmin was unlikely to be clinically effective in patients who have an epiretinal membrane and a stage 2 macular hole (see section 4.6). Having taken into account all of the evidence submitted (from the manufacturer and the ERG), and comments received during ACD consultation, the Committee concluded that on balance the ICER was likely to be lower than £30,500 per QALY gained and therefore ocriplasmin was a cost‑effective use of NHS resources for treating people with vitreomacular traction and a stage 2 macular hole without an epiretinal membrane. The Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. No equality issues were raised during the appraisal process or at the Committee meetings, and therefore the Committee concluded that no alterations or additions to its recommendations were needed. # Summary of Appraisal Committee's key conclusions TA297 Appraisal title: Ocriplasmin for treating vitreomacular traction Section Key conclusion Ocriplasmin is recommended as an option for treating vitreomacular traction in adults, only if an epiretinal membrane is not present and they have a stage 2 full-thickness macular hole with a diameter of 400 micrometres or less and/or they have severe symptoms. The Committee understood that the treatment pathway, and therefore the use of ocriplasmin, varies depending on the presence or absence of a stage 2 macular hole. If a stage 2 macular hole is present, the Committee acknowledged that ocriplasmin would be used during the wait for surgery, without delaying surgery. However, if a stage 2 macular hole is not present, the Committee recognised that ocriplasmin would be offered as an alternative to surgery, or as an alternative to 'watch and wait' for people who have severe distressing symptoms but are not eligible for surgery. The Committee concluded that ocriplasmin was clinically and cost effective in the VMT without ERM (vitreomacular traction without an epiretinal membrane), and VMT with MH (vitreomacular traction with a stage 2 macular hole) subgroups. The Committee recognised that in the VMT with ERM (vitreomacular traction with an epiretinal membrane) subgroup, the effect of ocriplasmin was small and not statistically significant. The Committee heard from the clinical specialists that they did not consider ocriplasmin to have a place in the treatment of patients with vitreomacular traction and an epiretinal membrane because it was not clinically effective in these patients. The Committee recognised that the VMT with MH group included people with an epiretinal membrane, and taking into account the data from the VMT with ERM subgroup and the opinion of the clinical specialists it concluded that ocriplasmin was unlikely to be clinically or cost effective in people with an epiretinal membrane in any of the subgroups, including VMT with MH. Current practice Clinical need of patients, including the availability of alternative treatments The Committee understood that vitreomacular traction is managed differently depending on whether or not a stage 2 macular hole is present; if a stage 2 macular hole is present, ocriplasmin would be used during the wait for surgery, without delaying surgery; if a stage 2 macular hole is not present, ocriplasmin would be used as an alternative to surgery, or as an alternative to 'watch and wait' for people who have severe distressing symptoms. The Committee understood that, although vitrectomy surgery is effective in resolving vitreomacular traction and the recovery time after surgery is short, the recovery is an unpleasant process for patients, and that surgery has risks and could damage the eye. The Committee concluded that an alternative treatment for vitreomacular traction would be welcomed by clinicians and patients. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits? The Committee agreed with the clinical specialists that the ocriplasmin injection provided a step change in treating patients with vitreomacular traction because it provides an alternative to 'watch and wait' and/or surgery. The Committee concluded that it was innovative. What is the position of the treatment in the pathway of care for the condition? The Committee understood that in UK clinical practice patients who have a stage 2 macular hole would be listed for surgery and ocriplasmin would be administered during the period before surgery, without delaying surgery. For patients without a macular hole, ocriplasmin would be offered as an alternative to surgery, or as an alternative to 'watch and wait' for people who have severe distressing symptoms. Adverse reactions The Committee understood that adverse event rates were similar between placebo and ocriplasmin and that most were non‑serious, mild in intensity, and resolved, and therefore were not considered to be clinically significant. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee acknowledged that all the relevant evidence was likely to have been identified by the manufacturer and that the evidence to support the clinical effectiveness was from the TG‑MV‑006 and TG‑MV‑007 trials. The Committee understood that the evidence presented by the manufacturer matched the decision problem. Relevance to general clinical practice in the NHS The Committee discussed the comparator arm in the trials and noted that a placebo injection was used in the trials instead of the UK clinical practice of 'watch and wait'. The Committee concluded that the placebo injection in the clinical trials was not equivalent to 'watch and wait' and that it was plausible that the efficacy of ocriplasmin would have been greater if it had been compared with the UK clinical practice of 'watch and wait'. Uncertainties generated by the evidence The Committee recognised 2 key uncertainties in the clinical evidence: The comparator in the trials was a placebo injection rather than 'watch and wait'. Patients may have had a shorter waiting period before vitrectomy in the clinical trial than would be expected in clinical practice. The Committee concluded that the efficacy of ocriplasmin may have been underestimated because of these uncertainties. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The manufacturer presented 3 different subgroups, for which there was differential effectiveness. The Committee took into account the data from the VMT with ERM subgroup and the opinion of the clinical specialists and concluded that ocriplasmin was unlikely to be clinically effective in people with an epiretinal membrane in any of the subgroups, including VMT with MH. The Committee concluded that ocriplasmin was clinically effective in the subgroups VMT without ERM and VMT with MH, but not in the subgroup VMT with ERM, and was unlikely to be clinically effective in those in the VMT with MH subgroup who had an epiretinal membrane. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that there was a statistically significant benefit in terms of vitreomacular traction resolution and total posterior vitreous detachment at day 28 in the VMT without ERM and VMT with MH subgroups. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the cost‑effectiveness evidence presented in the manufacturer's submission, including the base‑case incremental cost-effectiveness ratios (ICERs), the sensitivity and scenario analyses, as well as the Evidence Review Group's (ERG) critique of the manufacturer's evidence. The Committee understood that the modelling approach presented by the manufacturer was appropriate and that the assumptions and data sources were reasonable. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee considered important areas of uncertainty in the model: The assumption that vitrectomy and cataract surgery would be completed separately, and that when the model accounted for combined surgery a disutility value to account for the addition of cataract removal to surgery was not added. The cataract rate. The macular hole vitrectomy success rate. The metamorphopsia disutility value. The number of optical coherence tomography and follow‑up visits post‑vitrectomy. The retinal detachment and retinal tear rate. The rate of visual decline not accounting for a macular hole. Incorporation of health‑related quality‑of‑life benefits and utility values Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered? The Committee agreed with clinical specialists that the ocriplasmin injection provided a step change in treating patients with vitreomacular traction because it provides an alternative to 'watch and wait' and/or surgery. The Committee concluded that it was innovative. The Committee recognised that the benefit of this may not have been captured in the quality-adjusted life year (QALY) calculation. Are there specific groups of people for whom the technology is particularly cost effective? The Committee understood that there was not a group of people for whom ocriplasmin was particularly cost effective. However, it recognised that ocriplasmin was not clinically effective (in terms of total posterior vitreous detachment and vitreomacular traction resolution by day 28) for patients with vitreomacular traction and epiretinal membrane, without a stage 2 macular hole. In addition, it concluded, taking into account the views of clinical specialists and the data from the VMT with ERM subgroup, that ocriplasmin was unlikely to be clinically effective (in terms of total PVD and vitreomacular traction resolution by day 28) for patients with vitreomacular traction, an epiretinal membrane and a stage 2 macular hole. It therefore concluded that ocriplasmin was not cost effective for these groups. What are the key drivers of cost effectiveness? For the VMT without ERM and VMT with ERM subgroups the model outcomes were most sensitive to the inputs determining non‑surgical resolution of vitreomacular traction at 6 months and 28 days. The QALY discount rate was also an important driver for these subgroups. For the VMT with MH subgroup, the model outcomes were most sensitive to the inputs that determined non‑surgical macular hole closure, cataract disutility and the change of macular hole closure post‑vitrectomy. Most likely cost‑effectiveness estimate (given as an ICER) The Committee considered the use of ocriplasmin to treat vitreomacular traction without an epiretinal membrane or a stage 2 macular hole and concluded that the ICER was likely to be no greater than £20,900 per QALY gained (as presented by the ERG). It agreed therefore that ocriplasmin was a cost-effective use of NHS resources for treating vitreomacular traction in people without an epiretinal membrane. The Committee considered the use of ocriplasmin to treat vitreomacular traction with an epiretinal membrane but without a stage 2 macular hole and recognised that ocriplasmin was not clinically effective or cost effective for these people. The Committee therefore concluded that ocriplasmin could not be considered a cost-effective use of NHS resources for treating people with vitreomacular traction and an epiretinal membrane, without a stage 2 macular hole. The Committee considered the use of ocriplasmin to treat vitreomacular traction with a stage 2 macular hole. The Committee agreed that the preferred assumption was to include combined cataract and vitrectomy surgery, and noted the associated ICER was approximately £30,500 per QALY gained. The Committee also considered that addressing uncertainties in the model could both increase and decrease the ICER. The Committee recognised that ocriplasmin was unlikely to be clinically effective in patients who have an epiretinal membrane and a stage 2 macular hole. Having taken into account all of the evidence submitted (from the manufacturer and the ERG), and comments received during consultation, the Committee concluded that on balance the ICER was likely to be lower than £30,500 per QALY gained and therefore ocriplasmin was a cost-effective use of NHS resources for treating people with vitreomacular traction and a stage 2 macular hole without an epiretinal membrane. Additional factors taken into account Equalities considerations and social value judgements No equality issues within the scope of this appraisal were raised during the appraisal process or at the Committee meetings.	{'Guidance': 'Ocriplasmin is recommended as an option for treating vitreomacular traction in adults, only if:\n\nan epiretinal membrane is not presentand\n\nthey have a stage\xa02 full-thickness macular hole with a diameter of 400\xa0micrometres or less and/or\n\nthey have severe symptoms.', 'The technology ': "Ocriplasmin (Jetrea, Inceptua) is a truncated form of human plasmin, manufactured using recombinant DNA technology. It is 'indicated in adults for the treatment of vitreomacular traction (VMT), including when associated with macular hole (MH) of diameter less than or equal to 400\xa0microns'. It is administered by intravitreal injection at a dose of 0.125\xa0mg. Repeated injections into the same eye are not recommended.\n\nThe summary of product characteristics lists the following adverse reactions for ocriplasmin: vitreous floaters, eye pain, photopsia, and conjunctival haemorrhage resulting from the injection procedure. Most of these reactions were non‑serious, mild in intensity and resolved within 2 to 3\xa0weeks. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe cost of an ocriplasmin injection is £2500 (excluding VAT, ocriplasmin concentrate 0.5\xa0mg in 0.2\xa0ml solution; MIMS, July\xa02013; from September 2018, this was replaced with ready-diluted 0.375\xa0mg/0.3\xa0ml solution). Because repeat injections are not recommended, this is the cost for a full course of treatment. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (section\xa06) considered evidence submitted by the manufacturer of ocriplasmin and a review of this submission by the Evidence Review Group (ERG; section\xa07).\n\n# Clinical effectiveness\n\n## Background to the clinical evidence\n\nThe manufacturer's systematic literature review identified 2\xa0randomised controlled trials that were relevant to the decision problem: TG‑MV‑006 and TG‑MV‑007. The data from these trials were assessed individually and as an integrated dataset. Three non‑randomised controlled trials (TG‑MV‑001, TG‑MV‑008 and TG‑MV‑010) provided relevant safety and pharmacokinetic data.\n\nTG‑MV‑006 was a randomised, placebo‑controlled, double‑blind trial conducted in the USA. People with vitreomacular traction were randomised to receive either a single injection of ocriplasmin (n=219), or a placebo injection of saline (n=107), and were followed up over 6\xa0months. Inclusion criteria included a best corrected visual acuity (BCVA) of 20/25 or worse in the study eye, and 20/800 or better in the non‑study eye. Exclusion criteria included a macular hole larger than 400\xa0micrometres and previous vitrectomy in the study eye. At baseline 27.3% had a full‑thickness (stage\xa02) macular hole, 72.7% had vitreomacular traction (which could include a stage\xa01 macular hole), 37.1% had an epiretinal membrane, and 79.4% had an expected need for a vitrectomy. The mean BCVA score at baseline was 64.8 (standard deviation\xa010.53).\n\nTG‑MV‑007 was a randomised, placebo‑controlled, double‑blind trial conducted in the USA and Europe (including the UK). People with vitreomacular traction were randomised to receive either a single injection of ocriplasmin (n=245), or a placebo injection of saline (n=81), and were followed up over 6\xa0months. Inclusion criteria included a BCVA of 20/25 or worse in the study eye and 20/800 or better in the non‑study eye. Exclusion criteria included a macular hole larger than 400\xa0micrometres and previous vitrectomy in the study eye. At baseline, 19.6% had a full‑thickness (stage\xa02) macular hole, 80.4% had vitreomacular traction (which could include a stage\xa01 macular hole), 40.2% had an epiretinal membrane, and 88.7% had an expected need for a vitrectomy. The mean BCVA score at baseline was 63.8 (standard deviation\xa013.20).\n\nThe primary outcome of TG‑MV‑006 and TG‑MV‑007 was the proportion of patients with non‑surgical resolution of focal vitreomacular adhesion at day\xa028 post‑injection, as determined by masked central reading centre optical coherence tomography (OCT) evaluation. Secondary outcomes included the proportion of patients with total posterior vitreous detachment (PVD) at day\xa028, proportion of full‑thickness (stage\xa02) macular holes that closed without vitrectomy, proportion of patients not needing vitrectomy, an improvement of at least 2 or 3\xa0lines in BCVA without need for vitrectomy, improvement in mean BCVA, and improvement in the 25‑item Visual Function Questionnaire (VFQ‑25). Safety outcomes included adverse events, with special attention to ocular events, such as worsening visual acuity (VA), worsening macular oedema, vitreous haemorrhage, retinal tear, retinal detachment, increase in ocular inflammation and intraocular pressure increases.\n\n## Clinical trial results\n\nThe manufacturer presented the whole population results from TG‑MV‑006 and TG‑MV‑007 (see section\xa03.6), as well as the following subgroups:\n\nVMT without ERM (vitreomacular traction without an epiretinal membrane); this included people with a stage\xa01 macular hole (see section\xa03.7)\n\nVMT with ERM (vitreomacular traction with an epiretinal membrane); this included people with a stage\xa01 macular hole (see section\xa03.8)\n\nVMT with MH (vitreomacular traction with a stage\xa02 macular hole); this included people with an epiretinal membrane (see section\xa03.9).\n\nData from both the clinical trials and the integrated analyses were presented for the whole population. The proportion of patients with vitreomacular traction resolution was statistically significantly greater in the ocriplasmin arm than the placebo arm for both trials and in the integrated analyses for the whole population (TG‑MV‑006: 27.9% and 13.1% respectively, 95%\xa0confidence interval [CI] 6.0 to 23.5, p=0.003; TG‑MV‑007: 25.3% and 6.2% respectively, 95% CI\xa011.6 to 26.7, p<0.001; integrated analysis: 26.5% and 10.1% respectively, 95% CI\xa010.5 to 22.3, p<0.001). The proportion of patients with total PVD by day\xa028 was statistically significantly greater in the ocriplasmin than the placebo arm for both trials in the whole population (TG‑MV‑006: 16.4% and 6.5% respectively, 95% CI\xa03.1 to 16.7, p=0.0014; TG‑MV‑007: 10.6% and 0% respectively, 95% CI\xa06.8 to 14.5, p<0.001).\n\nThe manufacturer presented data on the VMT without ERM subgroup. The integrated analyses showed that the proportion of patients with vitreomacular traction resolution or total PVD by day\xa028 was statistically significantly greater in the ocriplasmin arm than the placebo arm (vitreomacular traction resolution: placebo 7.7%, ocriplasmin 29.8%, p<0.001; total PVD: placebo 2.6%, ocriplasmin 17.0%, p<0.001). Further secondary outcomes did not show a statistically significant difference between the treatment arms but did favour ocriplasmin (proportion of patients who received a vitrectomy by month\xa06: placebo 15.4%, ocriplasmin 8.0%, p=0.091; mean change in VA from baseline at day\xa028: placebo 2.5\xa0letters, ocriplasmin 2.6\xa0letters, p=0.890; mean change in VA from baseline at month\xa06: placebo 2.8\xa0letters, ocriplasmin 3.1\xa0letters, p=0.728). At month\xa06 more patients treated with ocriplasmin than placebo had gained letters, on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale (at least 10\xa0letters gained: placebo 15.4%, ocriplasmin 25.5%, p=0.051; at least 15\xa0letters gained: placebo 5.1%, ocriplasmin 10.1%, p=0.140. However, more patients treated with ocriplasmin had lost letters (at least 10\xa0letters lost: placebo 3.8%, ocriplasmin 6.9%, p=0.381; at least 15\xa0letters lost: placebo 1.3%, ocriplasmin 5.9%, p=0.121).\n\nThe manufacturer presented data on the VMT with ERM subgroup. The integrated analyses showed that there was no statistically significant difference between the placebo and ocriplasmin arm for any of the outcomes, and that the differences were small (proportion of patients with vitreomacular traction resolution by day\xa028: placebo 1.6%, ocriplasmin 7.8%, p=0.085; proportion of patients with total PVD by day\xa028: placebo 1.6%, ocriplasmin 3.6%, p=0.444; proportion of patients who received a vitrectomy by month\xa06: placebo 17.5%, ocriplasmin 11.4%, p=0.231; mean change in VA from baseline at day\xa028: placebo 2.7\xa0letters, ocriplasmin 1.9\xa0letters, p=0.325; mean change in VA from baseline at month\xa06: placebo 2.3\xa0letters, ocriplasmin 2.0\xa0letters p=0.685). At month\xa06 more patients treated with ocriplasmin than placebo had gained letters. However, more patients treated with ocriplasmin had lost letters (at least 10\xa0letters gained: placebo 9.5%, ocriplasmin 20.5%, p=0.058; at least 15\xa0letters gained: placebo 3.2%, ocriplasmin 4.8%, p=0.625; at least 10\xa0letters lost: placebo 1.6%, ocriplasmin 8.4%, p=0.052; at least 15\xa0letters lost: placebo 0%, ocriplasmin 4.8%, p=0.069).\n\nThe manufacturer presented data on the VMT with MH subgroup. The integrated analyses showed that the proportions of patients with vitreomacular traction resolution, total PVD or macular hole closure without vitrectomy by day\xa028, or macular hole closure without vitrectomy by month\xa06, were statistically significantly greater in the ocriplasmin arm than the placebo arm (vitreomacular traction resolution: placebo 25.5%, ocriplasmin 50.0%, p=0.006; total PVD: placebo 8.5%, ocriplasmin 22.6%, p=0.033; macular hole closure at day\xa028: placebo 10.6%, ocriplasmin 40.6%, p<0.001; macular hole closure at month\xa06: placebo 17.0%, ocriplasmin 40.6%, p<0.001). Further secondary outcomes did not show a statistically significant difference between the treatment arms but did favour ocriplasmin (proportion of patients who received vitrectomy by month\xa06: placebo 57.4%, ocriplasmin 44.3%, p=0.157; mean change in VA from baseline at day\xa028: placebo 3.0\xa0letters, ocriplasmin 3.9\xa0letters, p=0.691; mean change in VA from baseline at month\xa06: placebo 2.3\xa0letters, ocriplasmin 6.8\xa0letters, p=0.126). At month\xa06, the proportion of patients gaining letters and patients losing letters favoured ocriplasmin (at least 10\xa0letters gained: placebo 30.4%, ocriplasmin 44.3%, p=0.104; at least 15\xa0letters gained: placebo 13.0%, ocriplasmin 27.4%, p=0.063; at least 10\xa0letters lost: placebo 15.2%, ocriplasmin 8.5%, p=0.233; at least 15\xa0letters lost: placebo 10.9%, ocriplasmin 6.6%, p=0.421).\n\n## Health‑related quality-of-life results\n\nHealth‑related quality-of-life data were collected during the TG‑MV‑006 and TG‑MV‑007 trials using the VFQ‑25. The VFQ‑25 has 12\xa0subscales that measure the influence of visual disability and visual symptoms on generic health domains such as emotional wellbeing, social functioning, sense of independence, and other task‑oriented domains related to daily visual functioning (such as driving). The manufacturer presented the integrated analyses of these data for the whole population. In the ocriplasmin group, mean increases (representing improvements) were observed across all of the subscale and composite scores at month\xa06, and were numerically better than the placebo arm. A clinically meaningful improvement in the VFQ‑25 composite score (minimum clinically important difference: 3.6) was observed in a significantly larger proportion of the ocriplasmin group (35.9%) than the placebo group (22.7%, p=0.0016). The mean change from baseline in VFQ‑25 composite score at 6\xa0months was significantly greater in the ocriplasmin group (3.4) than the placebo group (0.7, p=0.007). The general vision subscale score improved more in the ocriplasmin group than the placebo group (placebo 2.1, ocriplasmin 6.1, p=0.024). This score was affected by the primary efficacy outcome (vitreomacular adhesion resolution): in the ocriplasmin group, mean improvement from baseline in the general vision subscale score was 8.4 for patients who had vitreomacular adhesion resolution, and 5.3 for those who did not. The mean improvement from baseline in the composite score was 5.7 among patients who had vitreomacular adhesion resolution and 2.6 for those who did not. The manufacturer presented a meta‑analysis that showed statistically significant improvements in VFQ‑25 outcomes (expressed as a difference in means) with ocriplasmin in general vision, distance activities, dependency, and composite scores.\n\n## Adverse events of treatment\n\nThe manufacturer presented pooled adverse event data from 7\xa0clinical trials because TG‑MV‑006 and TG‑MV‑007 were not powered to detect significant differences in treatment‑related adverse events. The pooled trials were TG‑MV‑001, TG‑MV‑002, TG‑MV‑003, TG‑MV‑004, TG‑MV‑006, TG‑MV‑007 and TG‑MV‑010. The adverse events were mainly ocular events. The incidence of serious adverse events was similar between placebo (TG‑MV‑006 and TG‑MV‑007 12.8%, all studies 13.8%) and ocriplasmin (TG‑MV‑006 and TG‑MV‑007 13.3%, all studies 13.5%). The only suspected adverse drug reaction that appeared to be dose dependent was vitreous floaters. The most common serious adverse event reported in the study eye was macular hole, which was less common in the ocriplasmin group than in the placebo group (4.7% and 6.5% respectively in all studies combined). The manufacturer stated that most adverse events were non‑serious, mild in intensity, and resolved, and therefore were not considered to be clinically significant.\n\n# Cost effectiveness\n\nThe cost‑effectiveness evidence presented by the manufacturer consisted of a systematic literature review and a de novo model. The literature review was to identify all existing studies of the cost effectiveness of any intervention in patients with vitreomacular traction (including vitreomacular traction associated with a macular hole or epiretinal membrane). The systematic review did not identify any relevant cost‑effectiveness studies, so the manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of ocriplasmin compared with 'watch and wait' in patients with VMT with ERM, VMT without ERM, and VMT with MH.\n\n## Model structure\n\nThe manufacturer's model had 2\xa0components: a short‑term decision tree and a long‑term extrapolation Markov model. The short‑term decision tree covered the first 6\xa0months of treatment, and was predominantly based on clinical trial data pooled from TG‑MV‑006 and TG‑MV‑007. It had monthly cycles. The short‑term decision tree determined the starting position of patients in the long‑term extrapolation Markov model, which started at 6\xa0months post‑treatment and then had a lifetime time horizon. The Markov model applied 3-monthly cycles for the first 2 to 5\xa0years. After 2\xa0years (or 5\xa0years in the sensitivity analysis) annual cycles were used, therefore assuming events such as vitrectomy and spontaneous resolution would occur before this.\n\nThe manufacturer's model covered the population stated in the scope and the marketing authorisation (that is, adults with vitreomacular traction, including when associated with macular hole of diameter less than or equal to 400\xa0microns). However, the manufacturer modelled 3\xa0different subgroups of this population, which were defined by baseline characteristics: VMT without ERM, VMT with ERM (the VMT subgroups included patients with stage\xa01 macular holes), and VMT with MH (macular holes were stage\xa02; this group included people with an epiretinal membrane). There were 2\xa0short‑term decision tree models used, one for the VMT with MH group and one for the other 2\xa0subgroups. The structure of the long‑term extrapolation Markov model was the same for all 3\xa0subgroups. The manufacturer's short‑term decision tree for patients with VMT (with or without ERM) had the following decision nodes: non‑surgical vitreomacular traction resolution (at day\xa028 or month\xa06), visual acuity health state 1 to 6 (see section\xa03.15), vitrectomy, macular hole at month\xa06. The manufacturer's short‑term decision tree for patients with VMT with MH had the following decision nodes: non‑surgical macular hole resolution (at day\xa028 or month\xa06), vitrectomy (first or second), macular hole closed, non‑surgical vitreomacular traction resolution at month\xa06. The manufacturer assumed that macular hole closure would lead to vitreomacular traction resolution. Patients finished the decision tree in 1 of 6\xa0different health states, which were in the long‑term Markov model. These health states were: resolved (vitreomacular traction and macular hole), vitreomacular traction unresolved without macular hole, vitreomacular traction unresolved with macular hole, vitreomacular traction resolved with macular hole (no vitrectomies), vitreomacular traction resolved with macular hole (1\xa0vitrectomy) or vitreomacular traction resolved with macular hole (2\xa0vitrectomies). The manufacturer's long‑term Markov model also had a 'death' state. Patients transitioned to another health state as a result of the following events: spontaneous vitreomacular traction and/or macular hole resolution, resolution of vitreomacular traction and/or macular hole through vitrectomy, failure of vitrectomy to resolve macular hole, spontaneous development of a macular hole, or death (see sections\xa03.16 and\xa03.19 for model transitions). There were 2\xa0assumptions in the model that were based only on the manufacturer's clinical expert opinion:\n\nThere is a maximum of 2\xa0vitrectomies. This is based on clinical expert opinion that the probability of having a third vitrectomy was very low.\n\nVitrectomies are 100% effective at treating vitreomacular traction, and therefore a second one is only used to close a persistent macular hole.\n\nWithin each health state of the long‑term extrapolation Markov model (other than death) there were 6\xa0sub‑states that represented levels of visual acuity, called the vision health states. Patients could move in any direction through the vision health states because they could improve or deteriorate. These health states were determined by the patients' BCVA in terms of ETDRS letters read: VA1: 76 to 100\xa0letters, VA2: 66 to 75\xa0letters, VA3: 56 to 65\xa0letters, VA4: 46 to 55\xa0letters, VA5: 36 to 45\xa0letters, VA6: 0 to 35\xa0letters.\n\n## Model transitions\n\nThe transitions between health states in the manufacturer's decision tree and Markov models were calculated from the integrated phase\xa03 trial data (from TG‑MV‑006/007), with the following exceptions: probability of opting for a second vitrectomy (75%), probability of success of second vitrectomy (50% of success rate of first vitrectomy [probability of macular hole closure post‑vitrectomy was estimated as 82%]). Each of these were based on manufacturer expert opinion.\n\nThe mortality rates applied in the manufacturer's model were based on VA state. For VA1 to 5, the mortality rate of the general population was used, taken from England and Wales interim life tables 2008–2010, from the Office of National Statistics. These were weighted according to sex. For a best‑seeing eye VA6 score, which represented severe visual impairment, the manufacturer used a mortality hazard rate of 1.54 from a US study (Christ et al. 2008).\n\nAs described in\xa03.15, the manufacturer's Markov model included visual acuity states within each health state. At the start of the model, the distribution of patients across the visual acuity states was estimated using an ordered logit model based on trial data (TG‑MV‑006 and TG‑MV‑007). This was assumed to be the same for both treatment arms (ocriplasmin and placebo). The presence of a macular hole affected the visual acuity state distribution, with more patients with a macular hole having VA3–VA6 scores than those without.\n\nPatients could move between any visual acuity state (representing improving or declining visual acuity) within the model. The transition probabilities between visual acuity states were assumed to be different depending on whether vitreomacular adhesion/traction was resolved or remained unresolved, and it was assumed that the presence of a macular hole did not affect the rate of visual acuity change. The transition probabilities between visual acuity states were based on estimates from the literature that relate to changes over time in the general population for patients with resolved vitreomacular traction, and in patients with persistent vitreomacular traction for unresolved vitreomacular traction. The manufacturer's submission recognised that after specific events there would be an initial change in vision that would be different from changes observed in the general population over time. The manufacturer therefore included within the model visual acuity transitions after a specific event for 1\xa0cycle. The events that were modelled were vitreomacular traction resolution only, macular hole closure only, vitreomacular traction resolution and macular hole closure and vitreomacular traction progression to macular hole. The corresponding transition probabilities were calculated from the integrated phase\xa03 clinical trial data (TG‑MV‑006 and TG‑MV‑007) using an ordered logit model (except for the macular hole opening, for which calibration was used).\n\n## Utility values and adverse events\n\nThe manufacturer applied utility values to each of the visual acuity states in the model. These were derived from a study that used contact lenses to simulate the effects of visual impairment caused by age‑related macular degeneration. The study grouped patients into 4\xa0categories, according to their best‑seeing eye, and a time trade‑off instrument was used to elicit utilities from the general UK population. Because the manufacturer's model used 6\xa0visual acuity states, the utility values from the study were adapted to fit the 6\xa0visual acuity states in the model. In addition, because the study was based on the best‑seeing eye only, a matrix was developed to account for the visual acuity state of both the best- and worst-seeing eye. The utility for each visual acuity combination (for example, VA1 and VA1, or VA1 and VA2) was then estimated.\n\nThe adverse events included in the manufacturer's model were modelled as occurring post‑vitrectomy or post‑ocriplasmin. These included retinal tear (13.23% and 0.22%, respectively), retinal detachment (13.23% and 0.43% respectively), elevated intraocular pressure (26.46% and 2.37% respectively) and vitreous haemorrhage (3.31% and 0.22% respectively). The probabilities of these events occurring were estimated using the integrated clinical trials data (TG‑MV‑006 and TG‑MV‑007).\n\nMany patients develop cataracts after vitrectomy, therefore the manufacturer's model included a 96% probability (determined from published data) of developing cataracts after having a vitrectomy. The proportions of people in each subgroup who could develop cataracts (who have not had previous cataract surgery) were 59% for VMT with ERM, 63.9% for VMT without ERM and 79.1% for VMT with MH.\n\nThe manufacturer accounted for adverse events by applying disutility values. A disutility for metamorphopsia (0.017), which has a significant impact on quality of life, was derived from the literature and included in the manufacturer's model. Disutility values derived from the literature were also applied to each of the adverse events captured in the model (see section\xa03.21): retinal detachment (0.13 for 1\xa0month), vitreous haemorrhage (0.02 for 1\xa0month) and cataract (0.14 for 6\xa0months). Disutility values for retinal tear and increased intraocular pressure were not identified in the literature and therefore no disutility was applied to these. Disutilities were all applied during 1\xa0cycle, with an exception made for metamorphopsia, which persisted until vitreomacular traction resolved. Disutilities were normalised to a 3‑month cycle length. Vitrectomy surgery is associated with a post‑surgery reduction in health‑related quality of life which was accounted for in the model by transitioning to the visual acuity state VA6 for 2\xa0weeks (rather than applying a disutility value).\n\n## Costs applied in the model\n\nThe manufacturer's model included the following costs: ocriplasmin (£2500), ocriplasmin administration (£117), surgery (vitrectomy [£2191] and cataract [£851]), follow‑up visits (£80), OCT (£54.29), annual cost of blindness (£6496), and costs of adverse events (retinal detachment [£2012], retinal tears [£424], increased intraocular pressure [£40.65], vitreous haemorrhage [£1852]). The manufacturer used NHS reference costs to estimate the cost of vitrectomy surgery, cataract surgery, administration of ocriplasmin, follow‑up visits, retinal detachment, and vitreous haemorrhage. The annual cost of blindness was estimated from the Personal Social Services Research Unit (PSSRU) costs of Health and Social Care and accounts for residential care (£18,191 for 30% of blind patients), community care (£8195 for 6% of blind patients), depression (£539 for 39% of blind patients), and hip replacement (£6728 for 5% of blind patients). The cost of OCT was taken from the literature, and the costs of retinal tears and increased ocular pressure were taken from NICE submissions. The model base case assumes 1\xa0follow‑up visit per 3\xa0months, 1\xa0OCT per 3\xa0months, 4\xa0post‑vitrectomy follow‑up visits, 4\xa0OCTs post‑vitrectomy, 2\xa0follow‑up visits post‑ocriplasmin injection and 1\xa0OCT post‑ocriplasmin injection. These visit estimates are based on clinical expert advice.\n\n## Manufacturer's base‑case incremental cost‑effectiveness ratio (ICER), sensitivity and scenario analyses\n\nThe manufacturer presented a base‑case ICER for each patient subgroup. The ICER for ocriplasmin compared with 'watch and wait' in the VMT without ERM subgroup was £18,481 per quality‑adjusted life year (QALY) gained (incremental cost: £1880.67, incremental QALY: 0.1018), for VMT with ERM it was £67,119 per QALY gained (incremental cost: £2487.13, incremental QALY: 0.0371) and for VMT with MH it was £21,593 per QALY gained (incremental cost: £1752.90, incremental QALY: 0.0812). The manufacturer estimated that the probability of ocriplasmin being cost effective, if the maximum acceptable ICER was £20,000 or £30,000 per QALY gained, compared with 'watch and wait' was: 51% and 80% respectively for VMT without ERM; 0% and 2% respectively for VMT with ERM; and 46% and 72% respectively for VMT with MH.\n\nThe manufacturer conducted univariate sensitivity analyses for each of the subgroups. For the VMT without ERM and VMT with ERM subgroups the model outcomes were most sensitive to the inputs determining non‑surgical resolution of vitreomacular traction at 6\xa0months and 28\xa0days. The QALY discount rate was also an important driver for these subgroups. For the VMT with MH subgroup, the model outcomes were most sensitive to the inputs that determined non‑surgical macular hole closure, cataract disutility and the chance of macular hole closure post‑vitrectomy.\n\nThe manufacturer also conducted scenario analyses to investigate the following:\n\nThe time limit of vitrectomy. It was assumed that vitrectomies would occur within 2\xa0years in the base case and therefore the model applied a 3‑month cycle length for 2\xa0years and an annual cycle length thereafter. The 3‑month cycles enable rapid changes in visual acuity in response to vitrectomy. By changing the length of time the model was running at 3‑monthly cycles from 2\xa0years in the base case to 1 or 5\xa0years, the manufacturer could investigate the impact of changing the time period for vitrectomy.\n\nThe impact of treating patients with a macular hole earlier than usual with a vitrectomy by assessing the cost effectiveness at day\xa028 of ocriplasmin compared with vitrectomy.\n\nAccounting for the lack of mortality in the decision tree part of the model by doubling mortality in the first year of the Markov model.\n\nUsing visual acuity state transitions derived from a study by Van der Pols et al. (2000) on British patients, rather than Finnish patients as in the base case.\n\nApplying the same rate of visual acuity decline whether vitreomacular traction was resolved or not, by using the transition rates from Laitinen et al. (2005) for all visual acuity health states.\n\nUsing spontaneous vitreomacular traction resolution rates from the literature rather than the clinical trial.\n\nApplying utility values derived from patients with age‑related macular degeneration in the US, rather than utilities derived from the general UK population as in the base case.\n\nThe impact of modelling the best or worst‑seeing eye only, rather than accounting for both eyes.\n\nApplying an alternative metamorphopsia disutility value of 0.14, derived using the EQ‑5D, rather than 0.017 from the literature as used in the base case.\n\nThe different scenarios had different impacts on the 3\xa0subgroups. Two scenarios increased the ICER the most. These increased the ICER substantially from the manufacturer's base case for the VMT without ERM and VMT with ERM subgroups and resulted in small increases for the VMT with MH group:\n\nmaking the long‑term vision transition rates equal whether vitreomacular traction had resolved or not\n\n\n\nVMT without ERM: £44,489 per QALY gained (incremental cost £2235, incremental QALY 0.050)\n\nVMT with ERM: £142,347 per QALY gained (incremental cost £2599, incremental QALY 0.018)\n\nVMT with MH: £21,723 per QALY gained (incremental cost £1754, incremental QALY 0.081)\n\n\n\nusing a 16.5% rate of spontaneous resolution\n\n\n\nVMT without ERM: £67,320 per QALY gained (incremental cost £2257, incremental QALY 0.034)\n\nVMT with ERM: £230,656 per QALY gained (incremental cost £2575, incremental QALY 0.011)\n\nVMT with MH: £21,615 per QALY gained (incremental cost £1753, incremental QALY 0.081).\n\n\n\nApplying a different metamorphopsia disutility value reduced the ICER substantially from the manufacturer's base case in all 3\xa0subgroups:\n\nVMT without ERM: £12,190 per QALY gained (incremental cost £1881, incremental QALY 0.154)\n\nVMT with ERM £42,388 per QALY gained (incremental cost £2487, incremental QALY 0.059)\n\nVMT with MH £17,837 per QALY gained (incremental cost £1753, incremental QALY 0.098).\n\nModelling only the best‑seeing eye reduced the ICER and modelling only the worst‑seeing eye increased the ICER in all 3\xa0subgroups, with a large impact for both analyses in the VMT with ERM subgroup. Using utility values derived from UK patients increased the ICER for all 3\xa0subgroups, with a substantial increase in the VMT with ERM subgroup. Changing the time limit of vitrectomy had little impact on the VMT with MH subgroup but for both the VMT without ERM and VMT with ERM subgroups using 1\xa0year substantially decreased the ICER, and using 5\xa0years substantially increased the ICER. The other scenario analyses had only a small impact on the ICERs.\n\n# Evidence Review Group comments\n\n## Clinical effectiveness\n\nThe ERG reviewed the manufacturer's literature review and considered that the manufacturer was likely to have identified all the randomised controlled trial evidence relevant to the decision problem. The ERG reviewed the designs of TG‑MV‑006 and TG‑MV‑007. It noted that the patients in the placebo group had undergone an injection, which was an invasive procedure, rather than having been initially observed without treatment, as is typical in UK clinical practice.\n\nThe ERG noted that the visual acuity of patients enrolled on the trials, with the exception of those with a macular hole, was better than would be seen in clinical practice for patients with vitreomacular traction and/or macular hole who would normally be offered vitrectomy. The ERG identified this as a limitation of the data because efficacy may be affected by disease severity.\n\nThe ERG noted that the primary outcome of non‑surgical resolution of vitreomacular adhesion is a surrogate outcome for preventing deteriorating vision, which can result from untreated and progressive vitreomacular traction. The ERG commented that there is limited evidence on the validity of non‑surgical resolution of vitreomacular adhesion as a surrogate for preventing deteriorating visual function.\n\nThe ERG noted that adverse events reported in the pooled results of 7\xa0completed clinical trials (the 'safety set') were consistent with the vitreolytic activity of the drug or method of administration and most were mild, or moderate and transient. However, the ERG commented that none of the safety set of trials, which ocriplasmin's safety profile is based on, was designed to assess safety outcomes with sufficient power to detect differences in incidence rates. This safety set can only detect adverse events with an incidence greater than 0.4% because of the uneven randomisation ratios.\n\n## Cost effectiveness\n\nThe ERG considered the modelling approach presented by the manufacturer to be appropriate and stated that it enabled important anatomical and visual outcomes to be simultaneously captured in the short and long term. The ERG reviewed the model, and considered many of the approaches, assumptions and data sources applied by the manufacturer to be reasonable.\n\nThe ERG identified some areas of uncertainty in the manufacturer's model, which it investigated, if it was possible, in exploratory analyses. Three\xa0scenarios had a large impact on the ICER:\n\napplying a different rate of probability for cataracts (see\xa03.38)\n\nenabling cataract and vitrectomy surgery to be done simultaneously (see section\xa03.39)\n\napplying a different macular hole vitrectomy success rate (see section\xa03.40).\n\n## Evidence Review Group's exploratory analyses\n\nMost of the ERG's exploratory analyses did not affect the manufacturer's base-case ICERs (see section\xa03.25) for the subgroups substantially. The resulting ICERs were in the following ranges:\n\nVMT without ERM:\n\n\n\nbase case: £18,481 per QALY gained\n\nrange: £17,733 to £18,986 per QALY gained\n\n\n\nVMT with ERM:\n\n\n\nbase case: £67,119 per QALY gained\n\nrange: £64,331 to £67,666 per QALY gained\n\n\n\nVMT with MH:\n\n\n\nbase case: £21,593 per QALY gained\n\nrange: £20,551 to £22,985 per QALY gained.\n\n\n\nThe ERG explored the rate of cataracts after vitrectomy. The ERG noted that a study of the National Ophthalmology Database identified that 64.6% of eyes that had a macular hole operation (without combined or previous cataract surgery) needed lens removal within 1\xa0year of vitrectomy, which was much lower than the 96% applied in the model by the manufacturer (to non‑pseudophakic eyes only). Applying this new rate increased the ICER of each subgroup by at least £1000 (VMT without ERM: from £18,481 to £19,858 per QALY gained [incremental cost £1899, incremental QALY 0.096]; VMT with ERM: £67,119 to £71,737 per QALY gained [incremental cost £2494, incremental QALY 0.035]; VMT with MH: from £21,593 to £28,289 per QALY gained [incremental cost £1806, incremental QALY 0.064]). The ERG conducted a sensitivity analysis around this and applied an 88.8% and 92.0% probability of cataract. This increased the manufacturer's base‑case ICER, but to a lesser extent than applying the 64.6% probability. Applying an 88.8% probability of cataract increased the manufacturer's base‑case ICER to: VMT without ERM: £18,782 per QALY gained (incremental cost £1885, incremental QALY 0.100); VMT with ERM: £68,127 per QALY gained (incremental cost £2489, incremental QALY 0.037); VMT with MH: £22,863 per QALY gained (incremental cost £1765, incremental QALY 0.077). Applying a 92.0% probability of cataract increased the manufacturer's base‑case ICER to: VMT without ERM: £18,647 per QALY gained (incremental cost £1883, incremental QALY 0.101); VMT with ERM: £67,675 per QALY gained (incremental cost £2488, incremental QALY 0.037); VMT with MH: £22,283 per QALY gained (incremental cost £1760, incremental QALY 0.079).\n\nThe ERG explored the impact of combining vitrectomy and cataract surgery. The ERG received advice from clinical specialists highlighting that, as a result of the high incidence of cataract formation after vitrectomy, lens removal is frequently combined with vitrectomy as a preventative measure. The ERG noted that this was not accounted for in the manufacturer's model. Furthermore, the ERG noted that Jackson et al. (2013) report that 40.5% of patients undergoing macular hole vitrectomy had combined lens removal. Therefore, to investigate the potential impact of combined surgery on the manufacturer's ICERs, the ERG further reduced the probability of cataract surgery by 40.5%. The ICER of each subgroup increased (VMT without ERM: from £18,481 to £20,212 per QALY gained [incremental cost £1904, incremental QALY 0.094]; VMT with ERM: £67,119 to £72,929 per QALY gained [incremental cost £2496, incremental QALY 0.034]; VMT with MH: from £21,593 to £30,458 per QALY gained [incremental cost £1818, incremental QALY 0.060]).\n\nThe ERG explored the success rate of macular hole vitrectomy in the manufacturer's model. The ERG noted that 82% of vitrectomies to treat macular hole are assumed to be successful (based on trial data) in the manufacturer's base‑case economic analyses. However, expert clinical opinion highlighted that, in patients with a macular hole of 400\xa0micrometres or less, success after vitrectomy involving internal limiting membrane peeling is over 90%. Therefore the ERG carried out a sensitivity analysis assuming 95.8% of macular hole vitrectomies are successful. The ICER associated with each subgroup increased, most notably in patients with a macular hole (VMT without ERM: from £18,481 to £19,250 per QALY gained [incremental cost £1911, incremental QALY 0.099]; VMT with ERM: from £67,119 to £69,588 per QALY gained [incremental cost £2501, incremental QALY 0.036]; VMT with MH: from £21,593 to £26,854 per QALY gained [incremental cost £1847, incremental QALY 0.069]).\n\nThe ERG estimated a revised (deterministic) base‑case ICER for each subgroup that took into account all of the exploratory analyses detailed in sections\xa03.37 to 3.40, and used a probability of cataract of 64.6%. The resulting ICERs were:\n\nVMT without ERM £20,861 per QALY gained (incremental costs £2082, incremental QALY 0.100)\n\nVMT with ERM £69,694 per QALY gained (incremental costs £2568, incremental QALY 0.037)\n\nVMT with MH £56,137 per QALY gained (incremental costs £2132, incremental QALY 0.038).\n\nThe ERG commented that there were other areas of uncertainty that could affect the ICER, including:\n\nThe uncertainty associated with the clinical data because patients receiving a placebo injection had been used to represent the outcomes of 'watch and wait' patients. The ERG concluded that this was likely to bias against ocriplasmin, and that the ICER would be expected to decrease (in all subgroups) if this was addressed.\n\nThe health states modelled did not include epiretinal membrane. The ERG stated that this would affect only the VMT with ERM subgroup but would be likely to increase the ICER in this subgroup.\n\nDifferences in the results and baseline characteristics within and between the relevant clinical trials (TG‑MV‑006 and TG‑MV‑007). The ERG concluded that any bias was likely to be against ocriplasmin and therefore the ICER would be expected to decrease if baseline characteristics for these subgroups were balanced.\n\nThe manufacturer conservatively assuming long‑term vision decline was the same for all patients with unresolved vitreomacular traction, regardless of whether they had a macular hole or not. The ERG stated that the ICER would be expected to decrease if visual decline was different for vitreomacular traction patients with or without a macular hole but that the impact was not quantifiable for any of the subgroups.\n\nThe manufacturer assuming the quality of life impact of metamorphopsia is the same for both vitreomacular traction and macular hole, and applies to patients whose vitreomacular traction is unresolved, or whose macular hole is open. The ERG considered these assumptions to be potentially inaccurate because the patient population in Fukeda et al. (2009) continued to have symptoms of metamorphopsia after vitrectomy to close the macular hole. This suggests the possibility of metamorphopsia in patients with resolved vitreomacular traction, which clinical specialist advice highlighted may be a result of a persistent epiretinal membrane (not accounted for in the manufacturer's model). The ERG concluded that the impact of accounting for metamorphopsia in patients with resolved vitreomacular traction was not quantifiable but that any bias was likely to be small and against ocriplasmin. The ICER would be expected to decrease if a lower disutility for metamorphopsia was applied in patients with vitreomacular traction alone (no macular hole).\n\nThe fact that the manufacturer provided no rationale for not including an increased mortality risk in patients with 'some' visual impairment. The ERG anticipated that the impact on the ICER of incorporating an increased mortality risk for patients with visual impairment in their worst‑seeing eye was likely to be small, and that the direction of any bias was unclear.\n\nThe ERG reviewed the scenario presented by the manufacturer in which long‑term vision outcomes were assumed to be equivalent, whether vitreomacular traction was resolved or unresolved. It noted that this increased the ICER substantially (see section\xa03.28). The ERG agreed with the manufacturer and stated that, based on the ERG's clinical specialist opinion, this scenario was unlikely.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ocriplasmin having considered evidence on the nature of vitreomacular traction and the value placed on the benefits of ocriplasmin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the current management of vitreomacular traction and the likely place of ocriplasmin in clinical practice; noting that the scope of the appraisal and the marketing authorisation for ocriplasmin is 'indicated in adults for the treatment of vitreomacular traction, including when associated with macular hole of diameter less than or equal to 400\xa0microns'. The clinical specialists explained that vitreomacular traction was managed differently depending on whether or not a stage\xa02 macular hole was present.\n\nThey said that patients who presented with a stage\xa02 macular hole would be listed for surgery because delaying surgery could lead to poorer outcomes for these patients and stage\xa02 macular holes rarely resolve spontaneously. The Committee heard from the clinical specialists that if ocriplasmin was recommended for use, patients with a stage\xa02 macular hole would still be listed for surgery, without delay, and ocriplasmin would be administered to patients during the period before surgery (in UK clinical practice this can be a number of weeks or months).\n\nThe clinical specialists stated that for patients who have vitreomacular traction without a macular hole, or with a stage\xa01 macular hole, delaying surgery in general does not have an impact on long‑term outcomes and that many of these patients will not need surgery. The clinical specialists explained that some patients would need surgery and in these patients if ocriplasmin was available it would be offered as an alternative to surgery. Furthermore, they commented that some patients would have severe distressing symptoms (such as metamorphopsia [distorted vision in which straight lines appear wavy] and low visual acuity), but would not be eligible for surgery, and that if ocriplasmin was available it would be offered to these patients instead of 'watch and wait'. The Committee acknowledged that about 80% of the patients in the trials had an expected need for vitrectomy at baseline, and therefore the patients in the trials were those with severe distressing symptoms and/or those who were eligible for surgery.\n\nThe Committee concluded that the treatment pathway varies depending on the presence or absence of a stage\xa02 macular hole. If a stage\xa02 macular hole is present, ocriplasmin would be used during the wait for surgery, without delaying surgery. If a stage\xa02 macular hole is not present, ocriplasmin would be used as an alternative to surgery, or as an alternative to 'watch and wait' for people who have severe distressing symptoms.\n\nThe Committee discussed vitrectomy surgery in UK clinical practice. The clinical specialists explained that there were risks involved with the surgery, including the potential to damage the eye and reduce visual acuity. Clinical specialists stated that a treatment that could avoid vitrectomy surgery would be beneficial for patients. The Committee also heard from the patient expert who described her experience of vitrectomy surgery and the anxiety and trauma it could cause. The patient expert explained that the recovery period after surgery was worse than the surgery itself because she had to lie in a face down position for up to a week. She described this as being very difficult and uncomfortable, and said that it felt suffocating. She commented that she would choose a treatment that involved an injection over vitrectomy surgery. The Committee recognised this, but also understood that face down positioning for recovery is being used less often, and for shorter periods. The Committee acknowledged that, although vitrectomy surgery was effective in resolving vitreomacular traction and the recovery time after surgery was short, the recovery was an unpleasant process for patients, and surgery also had risks and could damage the eye. The Committee concluded that an alternative treatment for vitreomacular traction would be welcomed by clinicians and patients.\n\nThe Committee considered the impact of vitreomacular traction on the everyday life of patients. It heard from the patient expert about the problems associated with vitreomacular traction, including difficulties with reading, cooking, watching television and driving that prevented them from enjoying these activities. The Committee understood from the patient expert that the effects of metamorphopsia and macular holes were very disturbing. The patient described seeing straight lines as wavy, and objects disappearing from view. The Committee concluded that resolving vitreomacular traction without the need for surgery would be beneficial to the wellbeing of patients with vitreomacular traction.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ocriplasmin. The Committee acknowledged that 3\xa0subgroups were presented by the manufacturer (VMT without ERM [vitreomacular traction without an epiretinal membrane], VMT with ERM [vitreomacular traction with an epiretinal membrane], and VMT with MH [vitreomacular traction with a stage\xa02 macular hole]). It noted that the evidence was from the TG‑MV‑006 and TG‑MV‑007 trials and it discussed the outcomes in these trials. The Committee acknowledged that the outcomes presented by the manufacturer were in line with the scope issued by NICE, and that they included vitreomacular traction resolution, posterior vitreous detachment (PVD), vitrectomy, visual acuity changes and macular hole closure. The Committee noted that although there was a statistically significant benefit with ocriplasmin compared with placebo in terms of vitreomacular traction resolution and total PVD at day\xa028 in the VMT without ERM and VMT with MH subgroups, this did not translate into a statistically significant visual acuity benefit (see sections\xa03.7 and\xa03.9). The clinical specialists explained that visual acuity was not a complete or accurate measure of the vision impairment experienced with vitreomacular traction. This is because measured visual acuity may not be affected by the presence of a macular hole or metamorphopsia: although the patient has distorted vision, they may still be able to read a letter on an eye chart successfully. The clinical specialists therefore explained that anatomical measures such as vitreomacular traction resolution or total PVD were a better way to measure the benefit of the treatment, and that from their experience approximately 70–80% of metamorphopsia resolved with vitreomacular traction resolution. The Committee accepted that the anatomical outcomes of vitreomacular traction resolution and total PVD were appropriate measures for assessing the effectiveness of ocriplasmin.\n\nThe Committee considered the results from the trials in the manufacturer's submission. The Committee noted that the efficacy of ocriplasmin was not the same for all the subgroups evaluated. The Committee acknowledged that ocriplasmin was associated with a statistically significant improvement in vitreomacular traction resolution and total PVD at 28\xa0days in the VMT without ERM (see section\xa03.7) and VMT with MH (see section\xa03.9) subgroups. However, in the VMT with ERM subgroup, the effect of ocriplasmin in terms of these outcomes was small and not statistically significant (see section\xa03.8). The Committee heard from the clinical specialists that they did not consider ocriplasmin to have a place in the treatment of patients with vitreomacular traction and an epiretinal membrane because it was not clinically effective in these patients. The Committee recognised that the VMT with MH group included people with ERM, and that because of the small sample size of this group (n=23) analyses had not been presented by the manufacturer. The Committee took into account the data from the VMT with ERM subgroup and the opinion of the clinical specialists and concluded that ocriplasmin was unlikely to be clinically effective in people with ERM in any of the subgroups, including VMT with MH. The Committee concluded that ocriplasmin was clinically effective, in terms of vitreomacular traction resolution and total PVD at 28\xa0days in the subgroups VMT without ERM and VMT with MH, but not in the subgroup VMT with ERM, and it was unlikely to be clinically effective in terms of these outcomes in the VMT with MH subgroup who had ERM.\n\nThe Committee discussed whether the comparator arm in the clinical trials was relevant to clinical practice in the UK. It noted that a placebo injection was used in the trials instead of the UK clinical practice of 'watch and wait'. It heard from clinical specialists that an injection of saline into the eye sometimes resolves vitreomacular traction, and that it could also provoke macular hole development. Therefore it was likely that the placebo injection could lead to total PVD, or to the creation of a macular hole. The clinical specialists commented that this was supported by the spontaneous resolution rates observed in the placebo arm of the trials (approximately 10%) because they were much higher than they observe in clinical practice (approximately 2% to 5%). The Committee concluded that the placebo injection in the clinical trials was not equivalent to 'watch and wait' and that it was plausible that the efficacy of ocriplasmin would have been greater if it had been compared with the UK clinical practice of 'watch and wait'.\n\nThe Committee considered the differences between the trials and clinical practice in the UK. The clinical specialists noted that access to surgery may have been quicker in the trials than in clinical practice. It discussed that patients in the trials may be operated on immediately, while in clinical practice there could be a waiting time of several weeks or months. The Committee agreed that this difference could lead to an underestimation of the benefit of ocriplasmin because the wait for surgery can result in a poorer outcome for patients in clinical practice than observed in the trial. The Committee concluded that the benefit of ocriplasmin may have been underestimated because there was a shorter waiting period for vitrectomy in the clinical trials.\n\nThe Committee considered the impact of ocriplasmin on all of the outcomes measured in the trials. The Committee noted that the trial results were limited to 6\xa0months after the injection and therefore the long‑term impact was unknown. However, it heard from clinical specialists that once traction was relieved the condition was generally stable, and therefore it was plausible that any benefits relating to ocriplasmin would be expected to last beyond the 6‑month clinical trial period. The Committee concluded that the clinical effectiveness of ocriplasmin was likely to be durable in the long term.\n\nThe Committee considered the adverse events that were associated with ocriplasmin. It noted that adverse events were mainly ocular events and that the incidence of serious adverse events was similar between ocriplasmin and placebo. The Committee acknowledged that the most common serious adverse event reported in the study eye was macular hole, which was more common in the placebo group than in the ocriplasmin group. The Committee understood that most adverse events were non-serious, mild in intensity and generally resolved. It concluded that ocriplasmin was similar to placebo in terms of adverse events.\n\n# Cost effectiveness\n\nThe Committee considered the cost‑effectiveness evidence presented in the manufacturer's submission, including the base‑case incremental cost‑effectiveness ratios (ICERs), the sensitivity and scenario analyses, the Evidence Review Group's (ERG's) critique of the manufacturer's evidence, and comments raised during consultation on the appraisal consultation document (ACD). The Committee considered the 3\xa0subgroups presented by the manufacturer in turn, as detailed below.\n\nThe Committee considered the available cost‑effectiveness evidence for ocriplasmin in the VMT without ERM subgroup. The Committee discussed the potential for ocriplasmin to be used earlier than surgery would normally be used, in patients with distressing symptoms (for example metamorphopsia or low visual acuity), and was satisfied that this was captured in the model. It discussed the manufacturer's base‑case ICER of £18,500 per quality‑adjusted life year (QALY) gained. It noted that in the ERG's exploratory analysis (see sections\xa03.37 to\xa03.41) the ICERs were in the range of £17,700 to £20,200 per QALY gained, and that the ERG base-case ICER was £20,900 per QALY gained. The Committee recognised that this subgroup represents people with vitreomacular traction without an epiretinal membrane or a stage\xa02 macular hole who would be eligible for vitrectomy surgery, or people with severe distressing symptoms who would not be eligible for surgery. The Committee concluded that ocriplasmin was a cost‑effective option for the treatment of people with vitreomacular traction without an epiretinal membrane, and without a stage\xa02 macular hole.\n\nThe Committee considered the available cost‑effectiveness evidence of ocriplasmin in the VMT with ERM subgroup. The Committee noted that ocriplasmin was not associated with a statistically significant improvement in vitreomacular traction resolution and total PVD at 28\xa0days in the VMT with ERM subgroup (see section\xa03.8), and that any differences observed between ocriplasmin and placebo were small. Taking into account these data and the view of the clinical specialists that ocriplasmin was not effective in patients with ERM, the Committee concluded that the use of ocriplasmin in people with vitreomacular traction with an epiretinal membrane, but without a stage\xa02 macular hole, was not a cost‑effective use of NHS resources.\n\nThe Committee considered the cost effectiveness of ocriplasmin in the VMT with MH subgroup. It noted the manufacturer's base‑case ICER of £21,600 per QALY gained. It discussed the manufacturer's sensitivity and scenario analysis (see sections\xa03.25 to\xa03.30), and the ERG critique of the manufacturer's model. It noted the uncertainties in the model, which had potentially substantial impacts on the manufacturer's ICER:\n\nThe impact of combining vitrectomy and cataract surgery (see section\xa04.15).\n\nThe rate of cataracts (see section\xa04.16).\n\nThe macular hole vitrectomy success rate (see section\xa04.17).\n\nThe metamorphopsia utility value (see section\xa04.18).The Committee also discussed additional comments that were raised during ACD consultation (see section\xa04.19) and that could impact on the ICER, including:\n\nThe number of optical coherence tomography (OCT) and follow‑up visits post‑vitrectomy.\n\nThe retinal detachment rate.\n\nThe retinal tear rate.\n\nThe rate of visual decline not accounting for a macular hole.The Committee's discussion and conclusion are summarised in the paragraphs below.\n\nThe Committee considered the VMT and MH subgroup and the assumption in the manufacturer's model that vitrectomy and cataract surgery would not be performed at the same time. The Committee heard from clinical specialists that combining vitrectomy surgery and cataract surgery into one procedure is common practice in the UK. It noted that the risk of cataracts forming after vitrectomy surgery is greater than 90%. However, the clinical specialists explained that the main driver for performing the 2\xa0operations at the same time was constrained capacity in hospital eye departments rather than improved outcomes. The Committee agreed that combining vitrectomy and cataract surgery was done in clinical practice, and therefore should be included in the model. It noted that combining vitrectomy and cataract surgery increased the ICER for the VMT with MH subgroup from £21,600 to approximately £30,500 per QALY gained. The Committee noted that no disutility had been applied by the manufacturer to the model to account for the addition of cataract removal to vitrectomy surgery, and concluded that applying a disutility would reduce the ICER marginally to under £30,500 per QALY gained.\n\nThe Committee discussed the VMT and MH subgroup further, and the rate that was applied in the manufacturer's model for developing a cataract after vitrectomy. The Committee noted from the ERG's critique that as the rate of developing a post‑surgical cataract is reduced, the ICER for ocriplasmin increases. The Committee heard from clinical specialists that the overall chance of developing a cataract was likely to be greater than 90%. It commented further that the annual rate of 64.6% (estimating an ICER of £28,300 per QALY gained for the VMT and MH subgroup) modelled by the ERG was likely to be lower than observed in UK clinical practice, and that the rate modelled by the manufacturer (96% annual rate, ICER £21,600 per QALY gained for the VMT with MH subgroup) was likely to be higher than observed in UK clinical practice. The Committee concluded that the rate of developing a cataract in UK clinical practice was likely to be lower than the manufacturer's value.\n\nThe Committee discussed the success rates of macular hole vitrectomy applied to the VMT with MH subgroup in the manufacturer's model (82%) and applied in the ERG's exploratory analyses (95.8%). It noted that for the VMT with MH subgroup, applying the higher rate increased the ICER from £21,600 to £26,900 per QALY gained. The Committee heard from clinical specialists that the success rate generally ranged from 80 to 90% and acknowledged the comments raised during ACD consultation that supported the ERG's macular hole vitrectomy success rate. The Committee therefore considered the rate applied by the ERG to be the most appropriate. The Committee concluded that the macular hole vitrectomy success rate was likely to be higher than that modelled in the manufacturer's base case and that this would increase the ICER.\n\nThe Committee noted from the manufacturer's scenario analysis in the VMT with MH subgroup that changing the metamorphopsia utility value had an impact on the manufacturer's base‑case ICER. It understood that the manufacturer's base case applied a disutility value of 0.017 and that the manufacturer's scenario analysis, using a value of 0.14, reduced the ICER in all 3\xa0subgroups substantially (see section\xa03.29). The Committee heard from clinical specialists that the utility gained from resolving metamorphopsia could be equivalent to going up 2\xa0visual acuity states. The Committee considered that this was equivalent to approximately 0.03\xa0utilities, based on the utility values used in the manufacturer's model. The Committee concluded that the disutility value applied in the manufacturer's model underestimated the disutility of metamorphopsia and that applying a higher disutility value would reduce the ICER, although the level of impact remained unclear.\n\nThe Committee considered the comments that were received during ACD consultation. It noted that the number of OCT and follow‑up visits post‑vitrectomy may have been overestimated in the manufacturer's base case for the VMT with MH subgroup. The Committee was aware that the ERG had done a sensitivity analysis that reduced the number of OCT and follow‑up visits from\xa04 to\xa02, and that this increased the ICER by a small amount: from £21,600 to £22,500 per QALY gained. The Committee also discussed comments received during consultation that a retinal detachment rate of 13.23% in the manufacturer's base case seemed high and a rate of 5.4% was more representative of clinical practice. In addition, a retinal tear rate with ocriplasmin of 0.22% had been used in the manufacturer's base case rather than a rate of 1.3%, which has been published. The Committee considered the impact on the ICER of the different rates of retinal detachment and retinal tear and recognised that the ICER would increase by a small amount. Finally, the Committee also noted comments received during consultation that in the manufacturer's base case visual decline was assumed to be the same whether or not a macular hole was present. The Committee understood from the ERG that the ICER would reduce if visual decline was different for people with or without a macular hole. The Committee concluded that reducing the number of OCT and follow‑up visits and applying different rates for retinal detachment and retinal tear would lead to small increases in the ICER, but that accounting for a greater rate of visual decline with a macular hole would reduce the ICER.\n\nThe Committee considered whether an ocriplasmin injection is an innovative treatment. The Committee agreed with the clinical specialists and manufacturer that the ocriplasmin injection provided a step change in treating patients with vitreomacular traction compared with current practice in vitrectomy and 'watch and wait'. The Committee acknowledged that no significant or substantial health‑related benefits were identified that were not included in the economic model. Therefore the Committee agreed that the ocriplasmin injection was innovative and it would consider an ICER at the top end of the range that would normally be considered a cost effective use of NHS resources (£20,000 to 30,000 per QALY gained).\n\nIn summary, the Committee considered the manufacturer's base‑case ICERs, the sensitivity and scenario analyses presented by the manufacturer, the ERG's critique and exploratory analyses, and comments raised during consultation for each of the subgroups presented that make up the marketing authorisation.\n\nThe Committee considered the use of ocriplasmin to treat vitreomacular traction without an epiretinal membrane or a stage\xa02 macular hole and concluded that the ICER was likely to be no greater than £20,900 per QALY gained (as presented by the ERG, see section\xa03.41). It agreed therefore that ocriplasmin was a cost‑effective use of NHS resources for treating vitreomacular traction in people with vitreomacular traction without an epiretinal membrane.\n\nThe Committee considered the use of ocriplasmin to treat vitreomacular traction with an epiretinal membrane, but without a stage\xa02 macular hole, and recognised that ocriplasmin was not clinically effective or cost effective for these people (see section\xa03.8 and\xa03.41). The Committee therefore concluded that ocriplasmin could not be considered a cost‑effective use of NHS resources for treating people with vitreomacular traction and an epiretinal membrane, without a stage\xa02 macular hole.\n\nThe Committee considered the use of ocriplasmin to treat vitreomacular traction with a stage\xa02 macular hole. The Committee agreed that the preferred assumption was to include combined cataract and vitrectomy surgery (see section\xa04.15), and noted the associated ICER was approximately £30,500 per QALY gained. It considered that in clinical practice the effectiveness of ocriplasmin might be greater than that seen in the trials because patients would have to wait longer for surgery and would not benefit from a placebo injection (see section\xa04.7). The Committee recognised that this would lower the ICER to below £30,500 per QALY gained. The Committee also considered that addressing uncertainties in the model could both increase and decrease the ICER (increase it by: increasing the macular hole vitrectomy success rate [see section\xa04.17], reducing the post vitrectomy cataract rate [see section\xa04.16], increasing the retinal tear rate with ocriplasmin [see section\xa04.19], decreasing the retinal detachment rate with vitrectomy [see section\xa04.19] and decreasing the post‑vitrectomy OCT and follow‑up visits [see section\xa04.19]; decrease it by: accounting for greater disutility values associated with both metamorphopsia and combined surgery [see sections\xa04.15 and\xa04.18], accounting for a greater rate of visual decline with a macular hole [see section\xa04.19], and accounting for the active placebo comparison [see section\xa04.7]). The Committee recognised that ocriplasmin was unlikely to be clinically effective in patients who have an epiretinal membrane and a stage\xa02 macular hole (see section\xa04.6). Having taken into account all of the evidence submitted (from the manufacturer and the ERG), and comments received during ACD consultation, the Committee concluded that on balance the ICER was likely to be lower than £30,500 per QALY gained and therefore ocriplasmin was a cost‑effective use of NHS resources for treating people with vitreomacular traction and a stage\xa02 macular hole without an epiretinal membrane.\n\nThe Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. No equality issues were raised during the appraisal process or at the Committee meetings, and therefore the Committee concluded that no alterations or additions to its recommendations were needed.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA297\n\nAppraisal title: Ocriplasmin for treating vitreomacular traction\n\nSection\n\nKey conclusion\n\nOcriplasmin is recommended as an option for treating vitreomacular traction in adults, only if\n\nan epiretinal membrane is not present\n\nand\n\nthey have a stage\xa02 full-thickness macular hole with a diameter of 400\xa0micrometres or less and/or\n\nthey have severe symptoms.\n\nThe Committee understood that the treatment pathway, and therefore the use of ocriplasmin, varies depending on the presence or absence of a stage\xa02 macular hole. If a stage\xa02 macular hole is present, the Committee acknowledged that ocriplasmin would be used during the wait for surgery, without delaying surgery. However, if a stage\xa02 macular hole is not present, the Committee recognised that ocriplasmin would be offered as an alternative to surgery, or as an alternative to 'watch and wait' for people who have severe distressing symptoms but are not eligible for surgery.\n\nThe Committee concluded that ocriplasmin was clinically and cost effective in the VMT without ERM (vitreomacular traction without an epiretinal membrane), and VMT with MH (vitreomacular traction with a stage 2 macular hole) subgroups.\n\nThe Committee recognised that in the VMT with ERM (vitreomacular traction with an epiretinal membrane) subgroup, the effect of ocriplasmin was small and not statistically significant. The Committee heard from the clinical specialists that they did not consider ocriplasmin to have a place in the treatment of patients with vitreomacular traction and an epiretinal membrane because it was not clinically effective in these patients. The Committee recognised that the VMT with MH group included people with an epiretinal membrane, and taking into account the data from the VMT with ERM subgroup and the opinion of the clinical specialists it concluded that ocriplasmin was unlikely to be clinically or cost effective in people with an epiretinal membrane in any of the subgroups, including VMT with MH.\n\n, 4.2, 4.6, 4.12, 4.13, 4.21\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee understood that vitreomacular traction is managed differently depending on whether or not a stage\xa02 macular hole is present; if a stage\xa02 macular hole is present, ocriplasmin would be used during the wait for surgery, without delaying surgery; if a stage\xa02 macular hole is not present, ocriplasmin would be used as an alternative to surgery, or as an alternative to 'watch and wait' for people who have severe distressing symptoms.\n\nThe Committee understood that, although vitrectomy surgery is effective in resolving vitreomacular traction and the recovery time after surgery is short, the recovery is an unpleasant process for patients, and that surgery has risks and could damage the eye. The Committee concluded that an alternative treatment for vitreomacular traction would be welcomed by clinicians and patients.\n\n, 4.3\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee agreed with the clinical specialists that the ocriplasmin injection provided a step change in treating patients with vitreomacular traction because it provides an alternative to 'watch and wait' and/or surgery. The Committee concluded that it was innovative.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee understood that in UK clinical practice patients who have a stage\xa02 macular hole would be listed for surgery and ocriplasmin would be administered during the period before surgery, without delaying surgery. For patients without a macular hole, ocriplasmin would be offered as an alternative to surgery, or as an alternative to 'watch and wait' for people who have severe distressing symptoms.\n\n\n\nAdverse reactions\n\nThe Committee understood that adverse event rates were similar between placebo and ocriplasmin and that most were non‑serious, mild in intensity, and resolved, and therefore were not considered to be clinically significant.\n\n, 4.10\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee acknowledged that all the relevant evidence was likely to have been identified by the manufacturer and that the evidence to support the clinical effectiveness was from the TG‑MV‑006 and TG‑MV‑007 trials. The Committee understood that the evidence presented by the manufacturer matched the decision problem.\n\n, 4.5\n\nRelevance to general clinical practice in the NHS\n\nThe Committee discussed the comparator arm in the trials and noted that a placebo injection was used in the trials instead of the UK clinical practice of 'watch and wait'. The Committee concluded that the placebo injection in the clinical trials was not equivalent to 'watch and wait' and that it was plausible that the efficacy of ocriplasmin would have been greater if it had been compared with the UK clinical practice of 'watch and wait'.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee recognised 2\xa0key uncertainties in the clinical evidence:\n\nThe comparator in the trials was a placebo injection rather than 'watch and wait'.\n\nPatients may have had a shorter waiting period before vitrectomy in the clinical trial than would be expected in clinical practice.\n\nThe Committee concluded that the efficacy of ocriplasmin may have been underestimated because of these uncertainties.\n\n, 4.8\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe manufacturer presented 3\xa0different subgroups, for which there was differential effectiveness. The Committee took into account the data from the VMT with ERM subgroup and the opinion of the clinical specialists and concluded that ocriplasmin was unlikely to be clinically effective in people with an epiretinal membrane in any of the subgroups, including VMT with MH. The Committee concluded that ocriplasmin was clinically effective in the subgroups VMT without ERM and VMT with MH, but not in the subgroup VMT with ERM, and was unlikely to be clinically effective in those in the VMT with MH subgroup who had an epiretinal membrane.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that there was a statistically significant benefit in terms of vitreomacular traction resolution and total posterior vitreous detachment at day\xa028 in the VMT without ERM and VMT with MH subgroups.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the cost‑effectiveness evidence presented in the manufacturer's submission, including the base‑case incremental cost-effectiveness ratios (ICERs), the sensitivity and scenario analyses, as well as the Evidence Review Group's (ERG) critique of the manufacturer's evidence. The Committee understood that the modelling approach presented by the manufacturer was appropriate and that the assumptions and data sources were reasonable.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered important areas of uncertainty in the model:\n\nThe assumption that vitrectomy and cataract surgery would be completed separately, and that when the model accounted for combined surgery a disutility value to account for the addition of cataract removal to surgery was not added.\n\nThe cataract rate.\n\nThe macular hole vitrectomy success rate.\n\nThe metamorphopsia disutility value.\n\nThe number of optical coherence tomography and follow‑up visits post‑vitrectomy.\n\nThe retinal detachment and retinal tear rate.\n\nThe rate of visual decline not accounting for a macular hole.\n\n, 4.15, 4.16, 4.17, 4.18\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee agreed with clinical specialists that the ocriplasmin injection provided a step change in treating patients with vitreomacular traction because it provides an alternative to 'watch and wait' and/or surgery. The Committee concluded that it was innovative. The Committee recognised that the benefit of this may not have been captured in the quality-adjusted life year (QALY) calculation.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee understood that there was not a group of people for whom ocriplasmin was particularly cost effective. However, it recognised that ocriplasmin was not clinically effective (in terms of total posterior vitreous detachment [PVD] and vitreomacular traction resolution by day\xa028) for patients with vitreomacular traction and epiretinal membrane, without a stage\xa02 macular hole. In addition, it concluded, taking into account the views of clinical specialists and the data from the VMT with ERM subgroup, that ocriplasmin was unlikely to be clinically effective (in terms of total PVD and vitreomacular traction resolution by day\xa028) for patients with vitreomacular traction, an epiretinal membrane and a stage\xa02 macular hole. It therefore concluded that ocriplasmin was not cost effective for these groups.\n\n, 3.9, 4.6, 4.13, 4.21\n\nWhat are the key drivers of cost effectiveness?\n\nFor the VMT without ERM and VMT with ERM subgroups the model outcomes were most sensitive to the inputs determining non‑surgical resolution of vitreomacular traction at 6\xa0months and 28\xa0days. The QALY discount rate was also an important driver for these subgroups. For the VMT with MH subgroup, the model outcomes were most sensitive to the inputs that determined non‑surgical macular hole closure, cataract disutility and the change of macular hole closure post‑vitrectomy.\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe Committee considered the use of ocriplasmin to treat vitreomacular traction without an epiretinal membrane or a stage 2 macular hole and concluded that the ICER was likely to be no greater than £20,900 per QALY gained (as presented by the ERG). It agreed therefore that ocriplasmin was a cost-effective use of NHS resources for treating vitreomacular traction in people without an epiretinal membrane.\n\nThe Committee considered the use of ocriplasmin to treat vitreomacular traction with an epiretinal membrane but without a stage 2 macular hole and recognised that ocriplasmin was not clinically effective or cost effective for these people. The Committee therefore concluded that ocriplasmin could not be considered a cost-effective use of NHS resources for treating people with vitreomacular traction and an epiretinal membrane, without a stage 2 macular hole.\n\nThe Committee considered the use of ocriplasmin to treat vitreomacular traction with a stage\xa02 macular hole. The Committee agreed that the preferred assumption was to include combined cataract and vitrectomy surgery, and noted the associated ICER was approximately £30,500 per QALY gained. The Committee also considered that addressing uncertainties in the model could both increase and decrease the ICER. The Committee recognised that ocriplasmin was unlikely to be clinically effective in patients who have an epiretinal membrane and a stage 2 macular hole. Having taken into account all of the evidence submitted (from the manufacturer and the ERG), and comments received during consultation, the Committee concluded that on balance the ICER was likely to be lower than £30,500 per QALY gained and therefore ocriplasmin was a cost-effective use of NHS resources for treating people with vitreomacular traction and a stage\xa02 macular hole without an epiretinal membrane.\n\n\n\nAdditional factors taken into account\n\nEqualities considerations and social value judgements\n\nNo equality issues within the scope of this appraisal were raised during the appraisal process or at the Committee meetings.\n\n"}	https://www.nice.org.uk/guidance/ta297	Evidence-based recommendations on ocriplasmin (Jetrea) for treating vitreomacular traction in adults.
2830a4947d681738596c8f6211c990bedf8b1c72	nice	Faecal calprotectin diagnostic tests for inflammatory diseases of the bowel	Faecal calprotectin diagnostic tests for inflammatory diseases of the bowel Evidence-based recommendations on faecal calprotectin tests for distinguishing between inflammatory bowel diseases (such as Crohn’s disease and ulcerative colitis) and non-inflammatory bowel diseases (such as irritable bowel syndrome). # Recommendations Faecal calprotectin testing is recommended as an option to support clinicians with the differential diagnosis of inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) in adults with recent onset lower gastrointestinal symptoms for whom specialist assessment is being considered, if: cancer is not suspected, having considered the risk factors (for example, age) described in the NICE guideline on suspected cancer and appropriate quality assurance processes and locally agreed care pathways are in place for the testing. Faecal calprotectin testing is recommended as an option to support clinicians with the differential diagnosis of IBD or non‑IBD (including IBS) in children with suspected IBD who have been referred for specialist assessment, if: appropriate quality assurance processes and locally agreed care pathways are in place for the testing.# The technologies Several technologies that measure the level of calprotectin in stool samples (faecal calprotectin) were evaluated, including fully quantitative laboratory-based tests, fully quantitative rapid tests and semi-quantitative point‑of‑care tests. Faecal calprotectin is excreted in excess into the intestinal lumen during the inflammatory process and so can act as a marker for inflammatory diseases of the lower gastrointestinal tract. The tests are intended to help distinguish between inflammatory bowel diseases and non‑inflammatory bowel diseases. Additional details are provided in section 4.# Clinical need and practice # The problem addressed The aim of this evaluation was to examine the clinical and cost effectiveness of faecal calprotectin tests to help differentiate between non‑inflammatory disorders such as irritable bowel syndrome (IBS) and inflammatory disorders such as inflammatory bowel disease (IBD) in people presenting with any of the following lower gastrointestinal symptoms for at least 6 weeks: abdominal pain or discomfort, bloating, or change in bowel habit. Patients with IBD need to be referred to specialist care (most likely, gastroenterology) for further investigation. The External Assessment Group suggested that, in adults, the distinction between IBD and IBS is likely to be most clinically useful. It was also suggested that children presenting with these symptoms can have a different range of conditions than adults, and the most clinically useful distinction in children was thought to be between IBD and non‑IBD. # The conditions ## Background, epidemiology and incidence Chronic abdominal pain or discomfort, with diarrhoea or constipation, are common. The symptoms can be caused by several different conditions, including IBD, of which ulcerative colitis and Crohn's disease are the most common, and IBS. Lower bowel symptoms are very common in general practice. They are most often associated with IBS. However, the symptoms can be caused by IBD, which can lead to serious complications. For example, over 50% of people with Crohn's disease need surgery within 10 years of diagnosis. It is important to distinguish IBD from non‑IBD, such as IBS, so that the conditions can be appropriately managed and monitored. IBD is characterised by inflammation of the bowel, which is not seen in most patients with IBS. IBS is a functional bowel disorder characterised by frequent bouts of bowel disturbance, abdominal pain and discomfort, and bloating. There is no clear cause, no distinctive pathology and treatment is symptomatic. Exacerbations may be triggered by diet or stress. Physiological studies often show an increase in bowel sensitivity, and the condition may be associated with abnormal muscle activity in the wall of the bowel. It is troublesome and can interfere with activities of daily life, although it does not usually cause serious morbidity. The NICE guideline on irritable bowel syndrome in adults suggests a prevalence of between 10% and 20% in the general population. Prevalence figures can vary depending on the diagnostic criteria used, which may account for the range of reported values. The true prevalence of IBS may be higher than estimated because many people with IBS symptoms do not seek medical advice; the NICE guideline cites NHS Direct online data that suggest 75% of people using this service rely on self-care. IBS most commonly affects people between the ages of 20 and 30 years and is twice as common in women as in men. Recent evidence shows that there is also a significant prevalence of IBS in older people. In terms of non‑IBD conditions, the percentage of people with IBS is greater in adults than children. IBD is the term normally given to a group of conditions that involves inflammation of the gastrointestinal tract, such as Crohn's disease and ulcerative colitis. These conditions can sometimes have serious complications, including a high risk of surgery and an increased risk of colorectal cancer. In both ulcerative colitis and Crohn's disease, some people have active disease but no symptoms. Ulcerative colitis and Crohn's disease are the 2 most common forms of IBD. The incidence of ulcerative colitis is approximately 10–20 per 100,000 per year, with a reported prevalence of 100–200 per 100,000 people. The incidence of Crohn's disease is around 5–10 per 100,000 per year (and thought to be increasing), with a prevalence of 50–100 per 100,000 people. There is little gender difference in the prevalence of IBD, but it is more common in white people than in African‑Caribbean people or those of Asian origin. The condition is most prevalent in Jewish people of European origin. The ratio of Crohn's disease to ulcerative colitis varies between adults and children. In adults, the ratio of Crohn's disease to ulcerative colitis is 2:3, while the ratio in children is much higher (2.3:1). Ulcerative colitis: is a relapsing and remitting disease characterised by inflammation of the colon, sometimes intense, with bloody diarrhoea, but more often milder. The cause is not known, but some people seem to be more genetically susceptible than others; around 10% of people with ulcerative colitis have a first‑degree relative with the condition. There may be an abnormal immune response to the natural bacteria that live in the gut. Sometimes, ulcerative colitis occurs after an episode of gastroenteritis caused by organisms such as Salmonella, Shigella and Campylobacter. However, in this case, the condition is more commonly triggered by resulting changes in the natural gut flora than by the direct effects of these organisms. Crohn's disease: can present in different ways, depending on which part of the intestinal tract is affected. Like ulcerative colitis, it is a relapsing and remitting inflammatory disease. However, it can be a much more extensive disease and can affect any part of the gastrointestinal tract. The cause is unknown, but there is a genetic susceptibility. Like ulcerative colitis, it can occur after infectious gastroenteritis and is associated with disturbances in the natural gut flora. The highest incidence of Crohn's disease is in the 15–30 year age range, but 20–30% of people with the condition are younger than 20 years and onset occurs in people younger than 17 years about 25% of the time. The incidence of Crohn's disease in the general population has been increasing both within the UK and internationally. The pattern of symptoms in children is different from that in adults. The largest prospective survey in the UK and Ireland was carried out by the British Paediatric Surveillance Unit, the British Society of Gastroenterology Research Unit and the Paediatric Register of IBD. The commonest presenting symptoms of Crohn's disease are abdominal pain, weight loss and diarrhoea, but 44% of children in the survey did not report diarrhoea, and only 25% reported all 3 together. Other symptoms at presentation included lethargy and anorexia. Paediatric IBD is often more extensive at diagnosis than in adults. ## Prognosis IBS is not associated with the development of serious comorbidities, and there is no indication that it is linked with a worse prognosis compared with the general population. However, IBS can be painful, disrupt normal activities and reduce quality of life. For example, Spiegel et al. (2009) reported that quality of life in people with IBS is reduced by 26% on average and by 30% if the condition is severe when compared with a person at full health. Quality of life is reduced because of disturbed work and sleep, and anxiety. People with IBS can have symptoms for many years. IBD can be painful, disrupt normal activities and reduce quality of life, particularly during periods of active disease. For example, Stark et al. (2010) reported that quality of life is reduced by an average of 16% (by 9% for those in remission and by 29% for those with active disease) in people with ulcerative colitis, and reduced by an average of 23% (by 11% for those in remission and by 39% for those with active disease) in people with Crohn's disease when compared with a person at full health. Ulcerative colitis: at first presentation, most patients have mild disease and only 10% have severe disease. About 50% will continue to have mild disease or be in remission but, in about 20% of patients, ulcerative colitis will be chronic and continuous, and be more likely to become extensive throughout the colon. Ordas et al. (2012) noted that, 10 years after onset, 20–30% of patients will have needed removal of the colon (colectomy). Ford and Talley (2013) estimated a lower colectomy rate of around 10%. The risk of mortality does not seem to be raised in people with ulcerative colitis compared with the general population. Crohn's disease: the outlook in Crohn's disease is worse than in ulcerative colitis. Only 10% of people with this condition have prolonged remission. Ford and Talley (2013) estimated that approximately 20% need hospital admission each year, and 50% will need surgery within 10 years of diagnosis. Life expectancy is slightly decreased in people with Crohn's disease compared with the general population (Baumgart and Sandborn 2012). There are 3 main serious intestinal complications in Crohn's disease. One is stricture (narrowing) of the bowel, which can lead to intestinal obstruction, so Crohn's disease can present as an 'acute abdomen' needing surgery, sometimes mimicking appendicitis. Another is fistulas, which are abnormal connections between sections of the bowel, or between the bowel and bladder. The third is colorectal cancer, and surveillance for this is needed. # The diagnostic and care pathways ## Diagnosis of IBS and IBD The symptoms of lower gastrointestinal disorders (including IBD and IBS) can be sufficiently similar to sometimes make diagnosis difficult. Tests are often carried out to exclude conditions rather than to diagnose them, leading to repeat visits and investigations. In most cases the diagnosis of IBS can be made on the basis of clinical history alone. The NICE guideline on irritable bowel syndrome in adults recommends that people presenting with abdominal pain or discomfort, bloating or a change in bowel habit for at least 6 months should be asked if they have any red flag indicators such as unexplained weight loss. They should also be clinically tested for red flag indicators, including anaemia, rectal masses, inflammatory biomarkers for IBD (faecal calprotectin is not specifically mentioned) and late onset (older than 60 years) change in bowel habits. Presence of any of these indicators should result in a referral to secondary care for further investigation. Therefore, patients presenting with symptoms or test results indicative of IBD are referred to secondary care for specialist investigation (most likely to a gastroenterology clinic). If there are no red flag indicators to cause concern, the NICE guideline on irritable bowel syndrome in adults states that patients who meet the IBS diagnostic criteria should receive the following laboratory tests to exclude other diagnoses: full blood count erythrocyte sedimentation rate or plasma viscosity C-reactive protein antibody testing for coeliac disease (endomysial antibodies or tissue transglutaminase antibody). Of these, the 2 main tests for inflammation are erythrocyte sedimentation rate and C‑reactive protein. However, these tests can be influenced by non‑intestinal diseases and can lack diagnostic accuracy. Therefore, while both tests can identify inflammation, they cannot localise it to the bowel. As a result, many patients are referred for further investigation involving endoscopy, which may not be needed. The NICE guideline on irritable bowel syndrome in adults states that an endoscopy (and a range of other tests) is not needed to confirm the diagnosis of IBS. Most people diagnosed with IBS at this stage are managed in primary care. People with lower bowel symptoms are likely to be referred to secondary care when there is uncertainty about the diagnosis, or a high clinical suspicion of IBD that needs further investigation. British Society of Gastroenterology guidelines on IBS (2007) suggest that tests conducted in secondary care are largely based on the likely differential diagnosis. Initial laboratory tests in secondary care include full blood count, erythrocyte sedimentation rate, C‑reactive protein, endomysial antibodies and tissue transglutaminase antibody. These tests may already have been done at the request of primary care. The next level of investigation involves endoscopy and imaging. British Society of Gastroenterology guidelines on IBD (2011) state that 'the diagnosis of IBD is confirmed by clinical evaluation and a combination of biochemical, endoscopic, radiological, histological, or nuclear medicine based investigations'. Initial laboratory investigations in common practice include full blood count, erythrocyte sedimentation rate, C‑reactive protein and other tests such as kidney function tests. The guidelines state: 'faecal calprotectin is accurate in detecting colonic inflammation and can help identify functional diarrhoea'. The next level of investigation involves endoscopy (with or without a biopsy), histology and imaging. Endoscopy can be colonoscopy, involving inspection of the whole colon; sigmoidoscopy, inspecting only the distal part of the bowel (the sigmoid colon); or gastroscopy, visualising the oesophagus, stomach and upper part of the small bowel. There are some sections of the small bowel that cannot currently be reached by widely available forms of endoscopy. Options then include capsule camera endoscopy (the 'camera pill'), and imaging methods including ultrasound and MRI. Therefore, the British Society of Gastroenterology guidelines suggest that patients with symptoms indicative of IBD or IBS presenting in secondary care follow a similar diagnostic pathway of initial investigations before receiving endoscopy (second level of testing). As in primary care, erythrocyte sedimentation rate and C‑reactive protein are the main markers used to measure intestinal inflammation. A UK and Ireland survey found that delays in diagnosis of Crohn's disease in children were common; 18% had had a pre‑diagnosis symptom for 1 to 3 years, and 9% had had one for more than 3 years. Only 9% had isolated small bowel disease. ## Differential diagnosis IBS is often diagnosed on the basis of signs and symptoms, without a need for further investigations, but distinction from IBD on clinical grounds is not always possible. Blood tests that show the presence of inflammation (erythrocyte sedimentation rate and C‑reactive protein) have been used as an aid to diagnosis, but may be abnormal because of other, non-gastrointestinal conditions, and can be normal in people with IBD. Until recently, colonoscopy in specialist care has often been needed to distinguish between IBD and IBS. This is an invasive and unpleasant investigation needing sedation, and is usually carried out on a day‑case basis. In younger patients, over 60% of colonoscopies are normal. ## Management The aetiology of IBS has not yet been established and, as a result, management focuses on the relief of symptoms. The symptom profile can vary and can need a combination of different interventions to achieve effective relief. These include watchful waiting, diet and lifestyle interventions, patient education and self‑help, drugs, behavioural and psychological therapies, and complementary and alternative therapies. Drugs include antispasmodic agents, laxatives, antimotility agents and, as second‑line treatment, antidepressants. The treatment of IBS often requires trials of different therapies because some do not improve symptoms. The process of trying different therapies may take several months; the significance of this is that the patient may have IBD and there may be a delay before the correct diagnosis is suspected and the patient is referred for specialist investigation. The treatments and the aims of management for IBD have changed in recent years. Schoepfer et al. (2012) comment that the aims have evolved from relieving symptoms towards mucosal healing. They consider that this shift has been driven by the arrival of new medications such as the anti‑tumour necrosis factor (anti‑TNF) drugs, which can induce and maintain mucosal healing. The aim of treatment in active disease is to secure and maintain remission. Management involves diet and lifestyle interventions, drugs and surgery to induce and maintain remission. Drugs include aminosalicylates, corticosteroids, thiopurines, disease-modifying anti-rheumatic drugs (such as methotrexate), immunosuppressants (such as ciclosporin) and anti‑TNF drugs (such as infliximab). There is an increased risk of colorectal cancer, so surveillance is part of patient care.# The diagnostic tests # The interventions Several faecal calprotectin tests are available to the NHS in England, including fully quantitative laboratory-based technologies (many of which use an enzyme‑linked immunosorbent assay platform), fully quantitative rapid tests and semi-quantitative point‑of‑care tests (POCTs). Rapid tests have not been characterised as POCTs in this assessment because they need a dedicated reader to process the tests but with appropriate training and quality assurance processes they may be appropriate for use in point‑of‑care settings. In principle, all technologies can be used to provide a faecal calprotectin testing service to either primary or secondary care. Manufacturer Test Platform Bühlmann EK-CAL calprotectin ELISA test ELISA – quantitative Range: 10–600 micrograms/g Bühlmann EK-CAL calprotectin ELISA test ELISA – quantitative Range: 30–1800 micrograms/g Bühlmann LF-CAL25 Quantum Blue calprotectin test Rapid test – Immunoassay designed for the quantitative determination of faecal calprotectin in combination with the BÜHLMANN Quantum Blue reader Range: 30–300 micrograms/g Bühlmann LF-CHR 25 Quantum Blue calprotectin test Rapid test – Immunoassay designed for the quantitative determination of faecal calprotectin in combination with the BÜHLMANN Quantum Blue reader Range: 100–1800 micrograms/g Calpro CALPRO CALPROTECTIN ELISA TEST (ALP) – formerly known as the Phical test CAL0100 ELISA – quantitative Range: up to 1250 mg/kg Calpro CALPROLAB CALPROTECTIN ELISA (ALP) – formerly known as the Phical test CALP0170 ELISA – quantitative Range: up to 2500 mg/kg Eurospital Calprest ELISA – quantitative Eurospital CalFast Rapid test – Quantitative determination of faecal calprotectin in combination with a dedicated reader Immundiagnostik ELISA (K6927) ELISA – quantitative Phadia AB, part of Thermo Fisher Scientific EliA Calprotectin EliA – quantitative Quantitative fluorescence enzyme immunoassay (FEIA) test Range 15–3000 mg/kg Preventis (sister company to Immundiagnostik) KST11005 CalDetect Calprotectin Rapid test (version 1 – Caldetect) POCT – immunochromatographic rapid test A semi-quantitative test with 3 lines corresponding to: Calprotectin 'negative', Calprotectin≤15 micrograms/g, Calprotectin 16–60 micrograms/g and Calprotectin>60 micrograms/g stool Preventis (sister company to Immundiagnostik) CalDetect Calprotectin Rapid test (version 3 – CalScreen) POCT – immunochromatographic rapid test A yes/no test with only 1 test‑line corresponding to the cut‑off value of 50 micrograms/g stool (no inflammation=<50 micrograms/g and inflammation present=≥50 micrograms/g) Abbreviations: ELISA, enzyme-linked immunosorbent assay; POCT, point-of-care test. Immundiagnostik tests K6967 and K6937 were included in the scope but were not included in the assessment conducted by the External Assessment Group because one is a variant (K6967) and the other (K6937) was superseded by the Immundiagnostik test K6927, which was included in the assessment. In total, 12 tests were included in the assessment conducted by the External Assessment Group. The reference standard was histology after endoscopy. Because faecal calprotectin correlates with the level of bowel inflammation, test results need to be interpreted in the context of a cut‑off value, below which the test is deemed negative and above which is deemed positive. In the context of distinguishing between irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), this would mean a negative result would support a diagnosis of IBS (a disease not characterised by inflammation) and a positive result would support a diagnosis of IBD (a disease characterised by inflammation). For a quantitative test, the output is often a single number representing micrograms of calprotectin per gram of stool sample (for example, 15 micrograms/g). If the cut‑off value is selected as 50 micrograms/g for distinguishing between IBS and IBD, then a person with a faecal calprotectin level of 15 micrograms/g would be classified as negative (indicating the person is likely to have IBS). The cut‑off value selected influences the diagnostic accuracy of the tests under consideration and different cut‑off values can be selected for different purposes. Cut‑off values can include a middle range in which results are considered indeterminate, below which are deemed negative and above which are deemed positive. Although a cut‑off value needs to be selected for interpreting results of a quantitative test, the cut‑offs for a POCT might be pre‑specified in the design of the test. For example, CalDetect reports 1 of 4 results when the test runs correctly: negative – faecal calprotectin is not detectable; negative – faecal calprotectin level is equal to or less than 15 micrograms/g; positive – faecal calprotectin level is 16–60 micrograms/g; and positive – faecal calprotectin level is more than 60 micrograms/g. Users might apply local cut‑offs for interpreting the results of POCTs; for example, a cut‑off of 60 micrograms/g might be applied, test results below which are deemed negative and above which are deemed positive. The most common cut‑off recommended by manufacturers is 50 micrograms/g. It should be noted that, in some cases, people with IBS can have raised levels of faecal calprotectin above the selected cut‑off value and the opposite is true for people with IBD (faecal calprotectin levels can be below the selected cut‑off). # The comparator The comparator is standard clinical practice in England. The main tests currently used to measure inflammation are erythrocyte sedimentation rate and C‑reactive protein, which can indicate inflammation but not localise it.# Outcomes The Diagnostics Advisory Committee (section 11) considered evidence from a number of sources (section 12). # How outcomes were assessed The assessment consisted of a systematic review of the evidence on test performance and clinical-effectiveness data for faecal calprotectin testing. The outcome measures included in the assessment were: referral rates numbers of colonoscopies with or without faecal calprotectin testing proportion of colonoscopies with no abnormal findings duration from onset of symptoms to definite diagnosis of inflammatory bowel disease (IBD) – late diagnosis of Crohn's disease costs adverse events such as complications of colonoscopy quality of life and hence quality‑adjusted life years (QALYs). The External Assessment Group did a systematic review of the evidence on cost effectiveness for faecal calprotectin testing and constructed a de novo economic model. The outcomes of interest for the economic evaluation were the morbidity and mortality associated with inflammatory and non‑inflammatory diseases of the bowel and their treatment, and particularly of people with IBD incorrectly diagnosed as irritable bowel syndrome (IBS). Given the chronic nature of the conditions and their potential impact on a person's quality of life, the main outcome of interest was health-related quality of life, including the impact of adverse effects associated with colonoscopy. The de novo economic model followed a linked evidence approach in which intermediate outcomes (results of faecal calprotectin testing) were linked to treatment outcomes and hence QALY gains. Costs and QALYs were assigned to each of the strategies assessed in the model. Although the scope allowed for the assessment of faecal calprotectin testing for both adults and children in both primary and secondary care, the External Assessment Group modelled 2 specific scenarios: faecal calprotectin testing for distinguishing between IBD and IBS in an adult population in primary care; and faecal calprotectin testing for distinguishing between IBD and non‑IBD in a paediatric population in secondary care. The External Assessment Group believed these scenarios reflect the most likely use of faecal calprotectin testing in clinical practice. # Clinical effectiveness ## Previous systematic reviews Five previously conducted systematic reviews of faecal calprotectin testing were quality assessed and summarised by the External Assessment Group. In summary, reviews conducted recently (published in 2010 or later) and judged to be medium or high quality by the External Assessment Group concluded that faecal calprotectin testing is a useful tool. For example, the Centre for Evidence‑based Purchasing (2010) review focusing on faecal calprotectin for distinguishing between IBS and IBD concluded that faecal calprotectin performs well in distinguishing organic bowel disease from functional bowel disease (organic disease includes IBD and functional disease includes IBS). Sensitivity and specificity were over 80% in most of these studies (at a 50 micrograms/g cut‑off) and, when calculated, most positive and negative predictive values were 70–90%. ## Diagnostic accuracy of faecal calprotectin – the comparisons The External Assessment Group summarised the ability of faecal calprotectin testing in 4 sets of comparisons: -rganic compared with non‑organic IBS compared with IBD (most appropriate comparison for adults) -rganic compared with IBS IBD compared with non‑IBD (most appropriate comparison for paediatrics). Organic disease includes inflammatory diseases. 'Organic' disease is formally defined as a condition in which there is an observable and measurable disease process (for example, inflammation). The External Assessment Group suggested that comparisons 2 and 4 represent the most likely use of faecal calprotectin testing in clinical practice and therefore that the economic analysis should focus on the cost effectiveness of faecal calprotectin testing within these applications of the test. Diagnostic accuracy data for comparisons 2 and 4 are summarised below. Faecal calprotectin testing is used in symptomatic patients to distinguish between 2 different types of disease. Diagnostic sensitivity refers to the proportion of patients whose test is positive in the presence of an inflammatory disease of the bowel (such as IBD); diagnostic specificity refers to the proportion of patients whose test is negative in the absence of inflammatory disease of the bowel. Patients whose test is negative may be found to have IBS. Nearly all of the evidence came from studies in secondary care, with few data from primary care. Data from a pilot project supported by the NHS Technology Adoption Centre were available to the External Assessment Group and were used in the economic analysis. These data are also summarised below. Seven studies gave results that compared IBS and IBD, at 8 cut‑off levels ranging from 8–150 micrograms/g, all in adults in secondary care. All studies assessed enzyme‑linked immunosorbent assay (ELISA) tests, and one also assessed the performance of the point‑of‑care test (POCT) CalDetect. As expected, low cut‑offs gave high sensitivity for IBD but poor specificity. Sensitivity was consistently high (usually 100% at levels under 50 micrograms/g; ranging from 83–100% at a cut‑off of 50 micrograms/g), but specificity was more varied (51–100%). Many of the studies had a small sample size. The largest study was by Li et al. (2006), which employed a sample of 240 people. Studies were of mixed quality. Schroder et al. (2007) and Schoepfer et al. (2008) were assessed as having the least risk of bias. Five studies reported data for faecal calprotectin testing with ELISA with a cut‑off of 50 micrograms/g. This allowed for the meta‑analysis of the studies to provide an overall combined estimate of sensitivity and specificity. The combined estimates for ELISA tests, at a 50 micrograms/g cut‑off, were a sensitivity of 93% and a specificity of 94%. The meta‑analysis estimates were informed by a pool of 596 people, of which 40% were from the Li et al. (2006) study. The mean age of people in these studies, when reported, ranged from 40–52 years in people with IBS and 34–45 years in people with IBD. However, the age of people in the Schoepfer et al. (2008) study went as high as 78 years. The only study using a POCT was Otten et al. (2008), which assessed the CalDetect test in a sample of 114 people. Otten et al. showed that the test performed well at a cut‑off of 15 micrograms/g, with a sensitivity of 100% and a specificity of 95%. At a cut‑off of 60 micrograms/g, although specificity improved slightly to 98%, sensitivity was only 61%, which the External Assessment Group considered to be unlikely to be acceptable in clinical practice given the importance of not missing people with IBD. The average age of people in the Otten et al. study was 52 years in people with IBS and 45 years in people with IBD. The cost effectiveness of faecal calprotectin testing for distinguishing between IBD and IBS in an adult population in primary care was assessed in the economic evaluation conducted by the External Assessment Group. Eleven studies reported IBD compared with non‑IBD, at 8 cut‑off levels. Eight studies were conducted in paediatrics and 3 in adults. All used ELISA tests, and one (Damms and Bischoff 2008) also assessed the Prevista POCT (not identified in the scope for the assessment). The studies showed consistently high sensitivity at lower cut‑offs, nearly all over 90%, with most at the 50 micrograms/g cut‑off having sensitivities of 100%. Specificity was more varied, ranging from 44–93% at a 50 micrograms/g cut‑off. Most of these results were in paediatric groups. Most studies reported results at only 1 cut‑off, but 1 study reported 5 cut‑offs and another 4, both in paediatric populations. Studies were of mixed quality with Canini et al. (2006), Diamanti et al. (2010), Fagerberg et al. (2005), Henderson et al. (2012) and van de Vijver et al. (2012) assessed as having the least risk of bias compared with the other studies. Six separate estimates of sensitivity and specificity were available at a cut‑off of 50 micrograms/g and another 6 estimates at 100 micrograms/g, which allowed the individual estimates to be meta‑analysed into combined overall estimates of sensitivity and specificity for ELISA tests. The overall pooled results for IBD compared with non‑IBD showed very high sensitivity of 99% but moderate specificity of 74% at a cut‑off of 50 micrograms/g. These estimates were informed by a pool of 531 people with most of these studies including people up to the age of 18 years. At a cut‑off of 100 micrograms/g, sensitivity was found to fall to 94% but specificity to improve to 82%. These estimates were informed by a pool of 656 people; however, the upper age limit varied in these studies. Two studies recruited people up to the age of approximately 15 years, 2 studies up to the age of 18 years and 1 study up to an age of 20 years. The age limit was not reported in the sixth study. The cost effectiveness of faecal calprotectin testing for distinguishing between IBD and non‑IBD in a paediatric population in secondary care was assessed in the economic evaluation conducted by the External Assessment Group. ## Primary care pilot data on faecal calprotectin testing Implementation projects for faecal calprotectin testing in 2 North East Clinical Commissioning Groups in Northumberland and Durham Dales during 2011/12 were undertaken by the NHS Technology Adoption Centre. The Durham Dales data were available to the External Assessment Group and were used to inform the economic analysis, which also allowed exploration of what might happen if faecal calprotectin testing is introduced in primary care. The Durham Dales project provided data on GP referrals following the introduction of faecal calprotectin testing in primary care. GPs made diagnostic decisions based on clinical assessment and knowledge of the faecal calprotectin test result. They referred patients who they thought might have IBD, and managed those who they thought had IBS in primary care. A final consultant diagnosis was made, based on faecal calprotectin test results and clinical data including colonoscopy. The clinical data came from GP and outpatient data, when patients were referred, or just from GP data, when patients were not referred. Patients diagnosed as having IBS and not referred for specialist investigation did not have colonoscopy, so it was not possible to completely exclude patients with false negative results (partial verification bias). The Durham Dales data could not be used to inform the estimates of test accuracy for the CalDetect test (used in the implementation project) in the main economic analysis in primary care because of the partial verification bias. Using the Durham Dales data of 111 patients who were followed up, the External Assessment Group used a prevalence of IBD of 6.3% in primary care and, in the absence of faecal calprotectin testing, a sensitivity of GP current practice of 100%, and 79% specificity in the model. The data also showed that GPs referred about 25% (29/111) of patients who presented with symptoms. The External Assessment Group created a scenario analysis that arbitrarily assumed that, if faecal calprotectin testing becomes available, GPs will test twice as many patients (50%) than they would have referred in the absence of faecal calprotectin testing. Using the North-European data from Shivananda et al. (2006), a ratio of ulcerative colitis to Crohn's disease of 3:2 (incidence of ulcerative colitis 12.9 in 15–44 age group, based on 539 cases, and of Crohn's disease 8.7, based on 365 cases) would be expected in this adult population. ## Ranges of faecal calprotectin values and choice of test The distribution of faecal calprotectin values is highly skewed and a wide range can be observed. Low levels may be seen in people with IBD and raised levels may be seen in people with IBS/non‑IBD (for example, people with infectious gastroenteritis or food poisoning). In some studies, the ranges did not overlap, but in others they did. For example, in El‑Badry et al. (2010), the value of faecal calprotectin in people with IBD ranged from 98–637 micrograms/g, which did not overlap with the value of faecal calprotectin in people with IBS (14–65 micrograms/g). In all other studies, the range of faecal calprotectin in patients with IBD overlapped with the range of faecal calprotectin in patients with IBS. In some studies, such as Li et al. (2006) and Schroder et al. (2007), the range of faecal calprotectin levels in people with IBD was wide, with the lowest value being 15 micrograms/g and the highest being 2574 micrograms/g. The range of results in studies comparing IBD and non‑IBD in children was similar to that found in studies comparing IBD and IBS in adults. In some studies (Canini et al. 2006; Diamanti et al. 2010; Sidler and Leach 2008), the ranges of faecal calprotectin levels overlapped in children and faecal calprotectin levels were high. The External Assessment Group noted that faecal calprotectin levels were often raised in conditions other than IBD, such as larger colorectal adenomas and some colorectal cancers. The accuracy of faecal calprotectin testing is lower in these other conditions when compared with IBD. The External Assessment Group summarised several studies that evaluated the comparative performance of faecal calprotectin tests in particular situations. For example, some studies assessed the performance of the tests for distinguishing IBS from IBD and others assessed the tests in distinguishing organic from non‑organic disease. Overall, the External Assessment Group concluded that there are limited data comparing the performance of different faecal calprotectin tests. Of the studies conducted, they concluded that none suggested any considerable differences between the various faecal calprotectin tests. ## Clinical outcomes Modelling was used to estimate clinical outcomes and QALYs. Please refer to the economic analysis below. # Economic analysis ## Review of existing economic analyses Seven references were identified in the systematic review of economic analyses. Although previous economic analyses have typically concluded that faecal calprotectin testing is cost saving compared with diagnostic pathway costs without it, several issues were highlighted in the critique of the literature, which need further consideration. These included: the use of a small sample size to inform the analysis (Hornung and Anwar 2011); assumptions about test accuracy and no consideration of false negative results (Mindemark and Larsson 2012); the analysis considering colonoscopy but not faecal calprotectin testing (Goldfarb et al. 2004 and Dubinsky et al. 2002 – also, this analysis was conducted in the US context); studies that were conducted in England but in primary care only (York Health Economics Consortium economic report for the Centre for Evidence‑based Purchasing review, 2010); and some studies that were available only in abstract/poster format, which did not allow for a full critique of the analysis (Mascialino et al. 2012 and 2013). The External Assessment Group constructed a de novo economic model to address the decision problem for this evaluation. ## Cost-effectiveness model constructed by the External Assessment Group The External Assessment Group constructed a full cost‑effectiveness model. The External Assessment Group model was informed by the model used in the NICE guideline on Crohn's disease, the modelling for the NICE guideline on ulcerative colitis, the modelling for the NICE guideline on irritable bowel syndrome in adults, and the YHEC model. In particular, these models were used to inform induction therapy and remission patterns in people with IBD and IBS. The model uses a linked-evidence approach to combine the outcomes of diagnostic strategies with the management (induction therapy and remission patterns) of patients' conditions, to allow the estimation of clinical outcomes and QALYs. The model assesses multiple diagnostic strategies and allows for multiple test sequences to be considered (for example, an initial ELISA test followed by colonoscopy). The outcomes from the diagnostic pathway are linked to the care pathway following diagnosis. Patients with true positive results for Crohn's disease and ulcerative colitis are considered separately from one another because patients in these groups follow different and complicated induction and remission pathways post diagnosis. Both patients with true negative and with false negative results follow the care pathway for IBS, with those patients whose disease does not respond to dietary changes after advice and subsequent medical treatment for IBS being retested for IBD. Patients with false positive results (incorrectly diagnosed as having IBD) are eventually correctly diagnosed as having IBS, given that it is assumed all patients with false positive results are referred for specialist investigation and undergo a colonoscopy (assumed 100% specificity). The model employs a weekly cycle and adopts a 10‑year time horizon. Although the scope allowed for the assessment of faecal calprotectin testing for both adults and children in both primary and secondary care, the External Assessment Group modelled 2 specific populations: an adult population in primary care, with faecal calprotectin test accuracies for IBD compared with IBS, and a paediatric population in secondary care, with faecal calprotectin test accuracies for IBD compared with non‑IBD. The External Assessment Group believed these populations reflect the most likely use of faecal calprotectin testing in clinical practice. The main aim of the model was to assess the impact of faecal calprotectin testing when added to current clinical practice compared with current practice alone on the differentiation of IBD and IBS in primary care. This model was then adjusted to reflect the differing test performances and costs in the paediatric population to provide an approximation of the cost effectiveness of faecal calprotectin testing for distinguishing between IBD and non‑IBD. However, the External Assessment Group highlighted the limitation of this approach because the main model structure does not fully account for the non‑IBD case mix in the paediatric population (prevalence of IBS in the non‑IBD group is lower than that seen in adults). The use of an ELISA faecal calprotectin testing service was evaluated in the base case for both of the primary and secondary care scenarios. The POCT CalDetect was evaluated in the base case primary care scenario. The base case applied the quality‑of‑life decrements from remission to active disease of 0.280 for Crohn's disease and 0.200 for ulcerative colitis from Stark et al. (2010). But sensitivity analyses applying the quality‑of‑life decrements from mild‑to‑moderate disease of 0.075 for Crohn's disease, as drawn from Gregor et al. (1997), and of 0.165 for ulcerative colitis, as drawn from Poole et al. (2010), were also explored. The utility decrements for IBS were less important for modelling purposes, given that the 100% specificity assumed for colonoscopy meant that there were no patients with false positive results by the end of the test sequence. For the base case, the 0.071 increment for response to treatment estimated in the NICE guideline on irritable bowel syndrome in adults was applied. The 0.662 baseline HRQoL that this increment was applied to was taken from Brazier et al. (2004). A sensitivity analysis using values from Spiegel et al. (2009) was also considered: 0.780 for response to treatment and 0.730 for no response to treatment, but the algorithm used to construct the EQ‑5D utilities was not clear. The baseline HRQoL value for IBS has an impact because of the small mortality rate associated with colonoscopy, with this impact enduring for the 10‑year time horizon of the model. Because of data constraints, the cost impacts were limited to modelling the relatively rare (less than 0.5%) serious adverse events of bleeds and perforations. The quality‑of‑life impacts were limited to the mortality associated with perforations. While perforations are rare, resulting in a very low mortality rate, the QALY impact of this persisted for the duration of the model. There is evidence from the literature that colonoscopies result in minor adverse events among a reasonable proportion of patients; for example, de Jonge et al. (2012) suggested that around 40% of those investigated with colonoscopy have some effects persisting for 30 days after the colonoscopy. In common with the NICE guideline on colonoscopic surveillance for the prevention of colorectal cancer, these minor adverse events were not taken into account in the modelling principally because of a lack of quality‑of‑life data. The costs included in the model were the costs of the different tests, treatment costs (including induction therapy and maintenance therapy costs for people in remission), NHS resource costs (for example, staff time) and costs of adverse effects associated with colonoscopy. The per person costs of an ELISA test and POCT CalDetect were estimated to be £22.79 (based on an assumption of 40 patient samples per 96 well‑plate, costed at the list price, plus an average 11–12 minutes of staff time at grade 6/7) and £24.03 (test list price plus cost of 15 minutes of GP practice‑nurse time) respectively. Colonoscopy was estimated to cost £741.68 per person. This estimate was based on a weighted average of the NHS reference cost for outpatient and day cases without biopsy (procedures payment by results code FZ51Z/FZ54Z), or with biopsy (procedures payment by results code FZ52Z/FZ55Z) for colonoscopy or, when used, sigmoidoscopy. The cost included an outpatient gastroenterology appointment (£164) and costs of adverse effects (an average of £12 per colonoscopy). ## Primary care analysis (IBS compared with IBD in adults) – key model characteristics and results The base case considered the cost effectiveness of GP testing compared with GP testing plus faecal calprotectin testing in the adult population for distinguishing IBS from IBD. For the primary care adult population, the model adopted a baseline age of 25 years for those presenting with symptoms, as used in the NICE guideline on Crohn's disease. Consistent with the modelling in this guideline, the proportion of females was taken to be 50% for both Crohn's disease and ulcerative colitis. It appears that a higher proportion of people with IBS are female; in the Brazier et al. (2004) sample, 86% were female, although the External Assessment Group suggested this estimate may be towards the upper end. For IBS, the base case adopted a proportion of females of 75%. These estimates only affect the all‑population mortality risks. Because these risks are low during mid-adulthood, for both women and men, the average age and proportion of model inputs for women will have had a minimal impact on the results. The base-case prevalence of IBD (6.3%) was drawn from the Durham Dales data, while the prevalence of ulcerative colitis among patients with IBD (a ratio of ulcerative colitis to Crohn's disease of 3:2) was drawn from Shivananda et al. (1996). The strategies assessed were: GP current practice (clinical assessment with no faecal calprotectin testing) GP current practice plus the POCT CalDetect using a cut‑off of 15 micrograms/g GP current practice plus ELISA testing using a cut‑off of 50 micrograms/g.The External Assessment Group opted to use the lower 15 micrograms/g cut‑off from Otten et al. (2008) because the data for the 60 micrograms/g cut‑off suggested only a slight gain in terms of a better specificity, 97.8% compared with 94.5%, but considerable loss in terms of a worse sensitivity, 60.9% compared with 100.0%. Test accuracy data used in the model are summarised in table 2. The External Assessment Group assumed, given lack of evidence to the contrary, that the accuracy of ELISA testing is the same as would be obtained from ELISA testing in conjunction with GP current practice. The delay between referral and colonoscopy was assumed to be 4 weeks and the time to retesting among those with negative tests but not responding to IBS therapy was assumed to be 12 weeks, both estimates being based on expert opinion. The latter estimate may have been optimistic because a sequence of unsuccessful treatments might be tried for people with IBS. This was explored in sensitivity analyses. The modelling assumed that all people who test positive or have an indeterminate result are referred to secondary care and all of these people receive a colonoscopy (indeterminate results are treated as if the results are determinate). Because of a lack of data, the External Assessment Group was not able to incorporate the impact of a gastroenterologist's assessment on the number of people who will go on to receive a colonoscopy (which may also include the use of faecal calprotectin testing) in the base case; however, this is explored in sensitivity analysis. Test GP current practice CalDetect (POCT) ELISA Colonoscopy Cut-off micrograms/g micrograms/g Sensitivity (95% CI 85–100%) (95% CI 85–98%) Specificity (95% CI 88–98%) (95% CI 76–100%) Test accuracy data source Primary care data from the NHS Technology Adoption Centre project Secondary care data from Otten et al. (2008) External Assessment Group meta-analysis of secondary care data Expert opinion Abbreviations: CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; POCT, point-of-care test. Without faecal calprotectin testing, GP current practice is highly sensitive in terms of referring people with IBD and is as good as, if not better, than faecal calprotectin testing. Of the 6.3% of people with IBD in the total population, all were identified by the GP current practice strategy and the POCT CalDetect strategy. Colonoscopy would correctly identify 6.0% of the 6.3% referred as patients with true positive results (because of its 95% sensitivity), resulting in a total of 0.3% of patients with false negative results. ELISA testing is slightly worse, identifying 5.9% of the 6.3% (because of its lower sensitivity when compared with current practice and the POCT), with 0.4% of patients being classified as having false negative results. Of the 5.9% referred for colonoscopy, 5.6% of patients would be identified as having true positive results, with 0.3% being classified as having false negative results, resulting in a total of 0.7% of patients with false negative results. Therefore, a slightly larger number of people will have IBD but will be incorrectly diagnosed as having IBS when using an ELISA testing strategy when compared with current practice strategy and a POCT CalDetect strategy (0.7% compared with 0.3%). Within the total patient population, GP current practice incorrectly identified 19.8% of patients as having false positive results (people thought to have IBD but who actually have IBS) and requiring referral for colonoscopy. The rates of patients with false positive results incorrectly referred for colonoscopy for POCT CalDetect and ELISA were much lower, at 5.1% and 5.6% respectively. Therefore, without faecal calprotectin testing, many of the patients with false positive results would go on to have a colonoscopy, which has a risk (although low) of serious complications such as perforation. Such events are too rare to significantly affect costs, but they do have some QALY impact. This is also true for the more common minor adverse effects of colonoscopy (which were not explicitly considered in the model because of a lack of data). Taking the diagnostic performance of the different testing strategies summarised above into account, the resulting total per patient costs and QALYs are provided in tables 3 to 5. Condition QALYs Test costs Other costs Total costs Crohn's disease Ulcerative colitis IBS Total Condition QALYs Test costs Other costs Total costs Crohn's disease Ulcerative colitis IBS Total Condition QALYs Test costs Other costs Total costs Crohn's disease Ulcerative colitis IBS Total Abbreviations: IBS, irritable bowel syndrome; QALY, quality-adjusted life year. The faecal calprotectin tests were estimated to result in similar average cost savings compared with GP current practice: £83 for the POCT CalDetect and £82 for ELISA per patient. This was mainly because of the lower number of referrals and colonoscopies for false positive results. Average QALY gains of around 0.0007 QALYs were also accrued, although these were limited because the low prevalence of IBD and the similar high sensitivities of the tests resulted in relatively few false negative results. Therefore, the faecal calprotectin testing strategies dominated current practice (provided greater benefit at reduced cost). Some of the QALY differences accrued were from the very slightly lower mortality associated with the lower number of colonoscopies. The POCT CalDetect and ELISA strategies were estimated to be broadly equivalent in terms of costs and QALYs, with only minor differences between them. A range of sensitivity analyses were conducted to explore the impact of varying the main model parameters. These included: varying the prevalence of IBD between 5–25% (6.3% used in the base case); changing the source of utility values; adjusting the costs of colonoscopy (no outpatient appointment cost) and removing any associated mortality; varying the number of patients whose condition did not respond to IBS medication; varying the time it takes for patients with false negative results to re‑present to the clinician (8, 16 and 24 weeks; 12 weeks was used in the base case); and exploring the impact of varying the specificity of the consultant's diagnosis at an outpatient clinic assessment in people referred with a false positive diagnosis. Scenario analyses were also undertaken using different sources of test accuracy for faecal calprotectin and alternative assumptions surrounding the uptake of faecal calprotectin testing (assuming 50% of patients are tested as opposed to the 25% used in the base case) in primary care. The sensitivity and scenario analyses appeared to broadly affect the 3 strategies in a similar way and suggested that the results of the base case were reasonably robust. The most notable impact was from assuming 50% of patients are tested in primary care, as opposed to 25%, which reduced the cost savings with faecal calprotectin testing. ## Secondary care (IBD compared with non‑IBD in children) – key model characteristics and results The base case considered the cost effectiveness of faecal calprotectin testing before colonoscopy compared with direct referral for colonoscopy in the secondary care paediatric population for distinguishing IBD from non‑IBD. For the secondary care paediatric population, the proportions of females included were 38% (35/91) for patients with IBD and 44% (44/99) for patients without IBD; these were drawn from Henderson et al. (2012). An average age of 16 years was assumed because, for the adult modelling, this had minimal impact on results. In the base case, a 48% (91/190) prevalence of IBD and a 75% (62/83) prevalence of Crohn's disease among patients with IBD were drawn from Henderson et al. (2012). The strategies assessed were: direct referral for colonoscopy ELISA testing when used at the 50 micrograms/g cut‑off followed by colonoscopy ELISA testing when used at the 100 micrograms/g cut‑off followed by colonoscopy. Test accuracy data used in the model are summarised in table 6. Test ELISA ELISA Colonoscopy Cut-off micrograms/g micrograms/g Sensitivity (95% CI: 95–100%) (95% CI: 87–99%) Specificity (95% CI: 59–85%) (95% CI: 68–92%) Test accuracy data source External Assessment Group meta-analysis of secondary care data External Assessment Group meta-analysis of secondary care data) Expert opinion Abbreviations: CI, confidence interval; ELISA, enzyme-linked immunosorbent assay. The base-case prevalence of IBD of 47.9% increased the importance of test sensitivities compared with the primary care setting, and so the effect of false negative results on the modelling outputs. Within the total patient population, ELISA with the 50 micrograms/g cut‑off led to 47.4% of patients with true positive results being referred for colonoscopy, while ELISA with the 100 micrograms/g cut‑off led to 45.0% of patients with true positive results being referred for colonoscopy. Colonoscopy was assumed to have a sensitivity of 95%. So, if all (47.9%) patients were referred immediately for colonoscopy, 45.5% would be diagnosed with IBD. With ELISA with the 50 micrograms/g cut‑off, 45.0% of the 47.4% of patients referred for colonoscopy were diagnosed as having IBD, while 42.8% of the 45.0% of patients referred for colonoscopy after ELISA with the 100 micrograms/g cut‑off were diagnosed as having IBD; a net difference between the cut‑offs of 2.2%. Despite the higher IBD prevalence in the secondary care population, the main test differences still lay in the number of unnecessary colonoscopies. Without faecal calprotectin testing, all 52.1% of patients without IBD received a colonoscopy, compared with 13.5% for ELISA with the 50 micrograms/g cut‑off and only 9.4% for ELISA with the 100 micrograms/g cut‑off. Taking the diagnostic performance of the different testing strategies summarised above into account, the resulting total per patient costs and QALYs are provided in tables 7 to 9. Condition QALYs Tests Other Total Crohn's disease Ulcerative colitis Non-IBD Total Condition QALYs Tests Other Total Crohn's disease Ulcerative colitis Non-IBD Total Condition QALYs Tests Other Total Crohn's disease Ulcerative colitis Non-IBD Total Abbreviations: IBD, inflammatory bowel disease; QALY, quality-adjusted life year. Prior testing using ELISA was estimated to dominate (provided greater benefit at reduced cost) the strategy of sending all patients directly for colonoscopy. Compared with referring all patients directly for colonoscopy, ELISA used at the 50 micrograms/g cut‑off was estimated to save £205 per patient, while ELISA used at the 100 micrograms/g cut‑off was estimated to save £240 per patient. QALY gains of around 0.001 QALYs were estimated for ELISA compared with direct referral for colonoscopy, these being slightly larger for ELISA with the 50 micrograms/g cut‑off because of its better sensitivity. The additional average cost of £35 and additional average QALYs of 0.0001 for ELISA with the 50 micrograms/g cut‑off compared with ELISA with the 100 micrograms/g cut‑off resulted in an incremental cost‑effectiveness ratio (ICER) of £35,000 per QALY gained. A range of sensitivity analyses were conducted to explore the impact of varying the main model parameters. These included: varying the prevalence of IBD to 40% and 60% (48% used in the base case); changing the source of utility values; removing any associated mortality of colonoscopy; varying the time it takes for patients with false negative results to re‑present to the clinician (8, 16 and 24 weeks; 12 weeks was used in the base case); and changing the annualised net cost of false negative results to £376 (£188 was used in the base case). As for primary care, most of the changes appeared to broadly affect the 3 strategies in a similar manner. The main difference arose from varying the prevalence of IBD, which tended to reduce the cost savings from faecal calprotectin testing because of the rise in prevalence, as would be anticipated. The source of utilities also had an impact on the anticipated net gain from ELISA with the 50 micrograms/g cut‑off compared with ELISA with the 100 micrograms/g cut‑off, the ICER for which increased to £117,000 per QALY gained. However, the External Assessment Group thought that this may have overstated the effect, given the prevalence of Crohn's disease within the presenting population and the perhaps rather small quality‑of‑life decrement sourced from Gregor et al. (1997).# Considerations The Diagnostics Advisory Committee discussed the focus of the evaluation and the evidence available for faecal calprotectin testing. It noted that evidence existed on faecal calprotectin testing in differing populations with differing conditions. For example, some study populations included large numbers of adults with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) (for example, Li et al. 2006), while others included children with a much wider range of organic and non‑organic conditions (for example, Tomas et al. 2007). It also noted that, while the evaluation was concerned with the role of faecal calprotectin testing for distinguishing between inflammatory and non‑inflammatory conditions of the bowel, the External Assessment Group suggested that the role of faecal calprotectin in 2 specific scenarios is likely to be the most important in clinical practice. These are IBD and IBS in the adult population presenting in primary care and IBD and non‑IBD in children who are referred for specialist investigation. Furthermore, the Committee noted that, although the use of faecal calprotectin testing is most relevant for helping to distinguish between inflammatory and non‑inflammatory conditions of the bowel, the number of conditions involved placed a prohibitively large burden on the data requirements for a cost‑effectiveness analysis. Therefore, the scenarios above represent a reasonable proxy for the likely clinical use of faecal calprotectin testing, balanced against the demands of the economic analysis. The Committee agreed with the External Assessment Group that it was appropriate for the evaluation to focus on the clinical and cost effectiveness of faecal calprotectin testing in these 2 scenarios. Faecal calprotectin testing is used in symptomatic patients to distinguish between 2 different types of disease. Diagnostic sensitivity refers to the proportion of patients whose test is positive in the presence of an inflammatory disease of the bowel (such as IBD); diagnostic specificity refers to the proportion of patients whose test is negative in the absence of inflammatory disease of the bowel. Patients whose test is negative may be found to have IBS. The Committee also noted that, although there is a growing focus on faecal calprotectin testing in primary care, there were limited data on faecal calprotectin testing in this environment. The Committee understood that several different types of faecal calprotectin tests are available to the NHS in England and that such tests are continually improving. The Committee noted that there were limited data on the comparative effectiveness of different faecal calprotectin tests and agreed with the External Assessment Group that sufficiently robust data suggesting considerable differences in clinical reliability and performance between the tests were not available. The Committee recommended research on the comparative performance of different faecal calprotectin tests. The Committee discussed pre‑analytical factors that may affect the results of faecal calprotectin testing. The Committee heard from specialists that several factors can affect the result of faecal calprotectin testing, including: sample storage, stool consistency, stool sampling, extraction and extract dilution. The Committee also heard that a UK National External Quality Assessment Service scheme (UK NEQAS scheme) has been set up for faecal calprotectin testing. The Committee encouraged participation in the UK NEQAS scheme and, when possible, standardisation of sample preparation methodology. The Committee discussed the evidence on the clinical effectiveness of faecal calprotectin testing in IBD and IBS in adults. It noted that multiple studies of diagnostic accuracy were identified, which assessed faecal calprotectin testing when interpreted using different thresholds. The Committee noted that the evidence mainly concerned the use of quantitative ELISA tests in a secondary care adult population. The most commonly used threshold value in these studies was 50 micrograms/g, which allowed the results of 5 studies to be meta‑analysed. The Committee noted that the results of the meta‑analysis showed that faecal calprotectin testing performed well, with a sensitivity of 93% and a specificity of 94%. The Committee was aware that a study was also published on the performance of a point‑of‑care test (POCT), CalDetect, when used in secondary care (Otten et al. 2008), which showed that the test performed well, with a sensitivity of 100% and a specificity of 95%. However, the Committee noted that the Otten et al. study included relatively few patients. The Committee concluded that, on the whole, faecal calprotectin was a reliable marker for distinguishing between IBD and IBS in a secondary care adult population, but that further data are needed on point‑of‑care testing, to verify the results seen in the Otten et al. study. The Committee recommended further research on the use and clinical utility of faecal calprotectin testing for the diagnosis and long‑term management of these conditions in the community. The Committee also recommended that support pathways be developed for faecal calprotectin testing to support consistent and appropriate use. The Committee discussed the de novo model constructed by the External Assessment Group. The Committee understood that limitations in the available data and/or variability in clinical practice meant that the model did not account for: (1) the way in which people with indeterminate results would be followed up before receiving a colonoscopy (all are assumed to be determinate and, therefore, receive a colonoscopy) and (2) the costs associated with the more common but relatively minor adverse events associated with colonoscopy (the costs of relatively rare but serious adverse effects are accounted for in the model). The Committee noted that, despite these limitations, the outcomes of the External Assessment Group's model were similar to those observed in previously conducted economic analyses. The Committee thought that, although the analysis may have benefitted from further sensitivity analysis, the results of the model are likely to be reasonably robust. The Committee concluded that the model was acceptable for decision‑making. The Committee went on to discuss the economic analysis that assessed the cost effectiveness of faecal calprotectin for distinguishing between IBD and IBS in a primary care adult population. It noted that data from the Durham Dales implementation project were used to inform the sensitivity and specificity estimates of GP current practice (see section 5.47). The Committee noted from the data that GPs were currently very good at identifying those patients with IBD who needed to be referred for specialist investigation (near‑perfect sensitivity); however, a lower specificity of GP assessment meant that a significant proportion of people with IBS are being referred for specialist investigation, which may be avoided. The cost‑effectiveness analysis compared GP current practice plus quantitative ELISA testing, GP current practice plus point‑of‑care testing with CalDetect and GP current practice without faecal calprotectin testing as separate diagnostic strategies in adults presenting in primary care with lower gastrointestinal symptoms of abdominal pain or discomfort, bloating or change in bowel habit for at least 6 weeks. The Committee noted that the main goal of faecal calprotectin testing in primary care is to help reduce the number of unnecessary referrals of people with IBS (given the relatively high prevalence compared with IBD) and so reduce the number of unnecessary colonoscopies. The Committee noted that the model demonstrated that the differing diagnostic accuracies of the different strategies resulted in 19.8% (GP current practice), 5.6% (ELISA strategy) and 5.1% (CalDetect strategy) of the total modelled population being classified as having a false positive result and referred for colonoscopy. Furthermore, the Committee noted that the lower number of referrals after faecal calprotectin testing meant that both ELISA and CalDetect strategies dominated current practice (produced greater health benefits at reduced cost); however, the Committee agreed that the greatest benefit of faecal calprotectin testing is in reduced costs. Both ELISA and CalDetect strategies led to cost savings of £82 and £83 per patient respectively. The Committee concluded that faecal calprotectin testing is a cost‑effective use of NHS resources for distinguishing between IBD and IBS in adults in primary care and that sensitivity analysis showed these results to be robust. The Committee discussed the use of faecal calprotectin testing of adults in secondary care. The Committee heard from clinical specialists that most of the faecal calprotectin testing in adults is expected to take place in primary care rather than secondary care. The Committee also recognised that there is a trend towards reducing the number of referrals to secondary care. It noted, however, that testing may also be appropriate for adults who have been referred for specialist assessment if testing has not already been done in primary care, in order to inform the decision on whether to do further investigations such as colonoscopy. Furthermore, the Committee concluded that cost savings from reduced numbers of colonoscopies are likely in this situation. Therefore, the Committee recommended faecal calprotectin testing as an option to aid differential diagnosis in adults with recent onset of lower gastrointestinal symptoms for distinguishing between IBD and IBS. The Committee discussed the use of faecal calprotectin testing for clinical decision‑making. It agreed with the clinical specialists that faecal calprotectin should be used with other clinical information to support a physician's assessment and that physicians should be aware that inflammatory and non‑inflammatory diseases other than IBD and IBS respectively may affect levels of faecal calprotectin. The Committee emphasised that faecal calprotectin testing has the potential to falsely reassure GPs when used in people suspected of having bowel cancer, and so these people should be excluded from the recommendations. The Committee strongly emphasised that, when uncertainty remains in primary care around whether to refer a patient for specialist assessment based on faecal calprotectin testing, the clinician will benefit from further specialist input (clinical or laboratory) before making a decision. The Committee also considered that a repeat testing strategy may be considered as part of patient follow‑up (see section 6.14). The Committee was aware that there are limited data on the use of faecal calprotectin testing in primary care. However, the Committee concluded that the assessment had demonstrated the benefit of using faecal calprotectin testing in adults who meet the specific criteria set out in section 1.1 and the benefits were, on balance, generalisable to testing in primary care. The Committee discussed the evidence on the clinical effectiveness of faecal calprotectin testing for distinguishing between IBD and non‑IBD in children. It noted that multiple studies of diagnostic accuracy were identified that assessed faecal calprotectin testing using different thresholds. The Committee noted that the evidence mainly concerned the use of quantitative ELISA tests in a secondary care paediatric population. The most commonly used threshold values in these studies were 50 micrograms/g and 100 micrograms/g, which allowed the results of 6 studies for each threshold to be meta‑analysed. The Committee noted that the results of the meta‑analysis showed that faecal calprotectin testing performed reasonably well at both thresholds (50 micrograms/g with a sensitivity of 99% and a specificity of 74%, and 100 micrograms/g with a sensitivity of 94% and a specificity of 82%). The Committee concluded that, on the whole, faecal calprotectin was a reliable marker for distinguishing between IBD and non‑IBD in a secondary care paediatric population. The Committee went on to discuss the economic analysis that assessed the cost effectiveness of faecal calprotectin for distinguishing between IBD and non‑IBD in a secondary care paediatric population. It noted that this model was an adaptation of the primary care model for IBD and IBS in a primary care adult population. The Committee agreed with the External Assessment Group that the secondary care paediatric model was limited because it did not fully account for the non‑IBD case mix in the paediatric population (the prevalence of IBS in the non‑IBD group is lower than that seen in adults). The Committee concluded that, despite this and other limitations in the model (see section 6.5), this analysis would provide a reasonable proxy for the expected costs and benefits of faecal calprotectin testing in a secondary care paediatric population. The cost‑effectiveness analysis compared quantitative ELISA testing interpreted using a threshold of 50 micrograms/g followed by colonoscopy; quantitative ELISA testing interpreted using a threshold of 100 micrograms/g followed by colonoscopy; and direct referral for colonoscopy as separate diagnostic strategies in children with lower gastrointestinal symptoms of abdominal pain or discomfort, bloating or change in bowel habit, for at least 6 weeks, who had been referred for specialist investigation. The Committee noted that the main goal of faecal calprotectin testing in people who have been referred for specialist investigation is to help identify those who are likely to have IBD and will need further diagnostic tests (because the prevalence of IBD in this population is much greater than that seen in primary care), for example, colonoscopy. The Committee noted that the model demonstrated the different strategies resulted in 100% (direct referral for colonoscopy), 61.5% (ELISA with a 50 micrograms/g threshold) and 54.4% (ELISA with a 100 micrograms/g threshold) of the total modelled population receiving a colonoscopy. These estimates include 13.5% of people with false positive results being referred to colonoscopy with the 50 micrograms/g cut‑off strategy, and 9.4% of people with false positive results being referred to colonoscopy with the 100 micrograms/g cut‑off strategy. Furthermore, the Committee noted that the lower number of people expected to receive colonoscopies with the faecal calprotectin strategies meant that ELISA testing at both thresholds dominated current practice (produced greater health benefits at reduced cost); however, the Committee agreed that the greatest benefit of faecal calprotectin testing is in reduced per‑patient costs. Both ELISA interpreted at a threshold of 50 micrograms/g and ELISA interpreted at a threshold of 100 micrograms/g led to cost savings, of £205 and £240 per patient respectively. The Committee concluded that faecal calprotectin testing is a cost‑effective use of NHS resources for distinguishing between IBD and non‑IBD in a secondary care paediatric population and that sensitivity analysis showed these results to be robust. Therefore, the Committee recommended faecal calprotectin testing as an option in children with suspected IBD who have been referred for specialist assessment. The Committee discussed the clinical interpretation of test results in children. The Committee heard from, and agreed with, the clinical specialists that faecal calprotectin should be used with other clinical information to support a specialist's assessment and that the specialist should be aware that inflammatory and non‑inflammatory diseases, other than IBD and IBS respectively, may affect levels of faecal calprotectin. The Committee was aware that most of the data on faecal calprotectin identified for this assessment came from studies of ELISA testing in a secondary care population. Therefore, in the absence of robust primary care data (in particular, robust primary care data for POCTs), the Committee recommended that faecal calprotectin testing is performed in accordance with appropriate quality assurance processes and locally agreed care pathways to ensure results are reliable and replicable, and to increase the likelihood that the benefits and cost savings estimated by the model are delivered in the NHS. In addition, the Committee recommended that additional expertise should be sought when the faecal calprotectin tests are used in general practice, as outlined in section 6.8. Given the lack of robust evidence comparing different tests, the Committee thought it appropriate that preferred faecal calprotectin tests might be selected locally in the NHS but that people should be aware that differences between tests may exist. The Committee noted that POCTs currently have a smaller evidence base and are not yet widely used in routine practice. The Committee therefore concluded that robust evidence is needed on the comparative performance of different faecal calprotectin tests, including the performance of POCTs compared with laboratory-based tests. The Committee discussed the different thresholds for interpreting faecal calprotectin results. The Committee heard from clinical specialists that, while faecal calprotectin has been studied when interpreted using different thresholds (and investigated in the economic analysis), further research is needed on the impact of testing on clinical decision‑making when added to current practice before a recommendation on a particular cut‑off can be made. The Committee was aware of emerging evidence from a study of faecal calprotectin in primary care by Pavlidis et al. (publication in press, provided to the Committee as academic in confidence). However, the Committee concluded that it was too early to make judgements on these data. The Committee was aware that the assessment did not account for people with minimally elevated (intermediate) levels of faecal calprotectin who, as suggested by clinical specialists, may have low‑grade IBD and might be better off following a repeat testing strategy with faecal calprotectin to monitor levels of bowel inflammation through time as opposed to being subjected to invasive colonoscopies. The Committee heard from clinical specialists that faecal calprotectin levels can vary markedly between the time a person is tested in primary care and then subsequently retested (likely to be after several weeks) either by their GP or a specialist. The Committee noted that differences in tests may exist in the intermediate range of faecal calprotectin levels but may not have been measured in studies to date because of selective sampling of study populations. Therefore, the Committee recommended further research on the impact of faecal calprotectin testing on clinical decision‑making when added to current practice in both primary and secondary care. The Committee also recommended research into optimal cut‑off values for tests and the investigation of repeat testing strategies in people with intermediate levels of faecal calprotectin. Development of a consistent definition for the 'intermediate range' is encouraged by the Committee. The Committee further recommended that test result cut‑offs should be discussed and agreed locally as part of the implementation process for this testing pathway. The Committee noted some general points: (1) the clinical-effectiveness estimates for faecal calprotectin testing summarised in this evaluation have been corroborated by faecal calprotectin databases around the country (for example, the Edinburgh Faecal Calprotectin Registry and the database maintained by King's Health Partners); (2) the Durham Dales project data may represent a best‑case scenario for GP current practice and, if this is the case, faecal calprotectin may have an even greater benefit in primary care (this additional benefit may be offset by losses in benefit if more than 50% of people with lower gastrointestinal symptoms are tested); (3) a significant proportion of people with IBD (particularly children with Crohn's disease), largely because of the similarity in symptoms to those in people with non‑IBD conditions, face delays in their diagnosis of up to several years, and the introduction of faecal calprotectin may help to reduce such delays. The Committee was encouraged by the results of the assessment because it is likely that the use of faecal calprotectin testing will result in significant capacity being generated in colonoscopy departments to allow them to focus on people with greater need for a colonoscopy (for example, those suspected of having bowel cancer). Furthermore, the Committee noted that the good diagnostic performance of faecal calprotectin has the ability to provide reassurance to both physicians and patients alike given the heterogeneous and overlapping symptoms in lower gastrointestinal disease. The Committee considered the impact of this guidance on groups of people with characteristics protected by UK equality legislation. During scoping, it was noted that IBS is most common in people in the 20–40 years age range, and is twice as common in women as men. Additionally, IBD is more common in white people than in African‑Caribbean people or those of Asian origin. The condition is most prevalent among Jewish people of European origin. The Committee considered that the guidance did not present any restrictions in access to diagnosis or treatment in the above groups.# Recommendations for further research Further research is needed on the use and clinical utility of faecal calprotectin testing, and support pathways for the long‑term management of these conditions in the community should be developed. Further research is needed on the impact of faecal calprotectin testing on clinical decision‑making when added to current practice. This includes research into optimal cut‑off values for tests and the investigation of repeat testing strategies in people with intermediate levels of faecal calprotectin. Development of a consistent definition for the 'intermediate range' is encouraged. Robust evidence is needed on the comparative performance of different faecal calprotectin tests, including the performance of POCTs compared with laboratory-based tests.# Related NICE guidance Ulcerative colitis: management in adults, children and young people. NICE clinical guideline 166 (2013). Crohn's disease: management in adults, children and young people. NICE clinical guideline 152 (2012). Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn's disease or adenomas. NICE clinical guideline 118 (2011). Infliximab (review) and adalimumab for the treatment of Crohn's disease. NICE technology appraisal 187 (2010). Irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care. NICE clinical guideline 61 (2008). Infliximab for acute exacerbations of ulcerative colitis. NICE technology appraisal 163 (2008). Infliximab for subacute manifestations of ulcerative colitis. NICE technology appraisal 140 (2008).# Review NICE updates the literature search at least every 3 years to ensure that relevant new evidence is identified. NICE will contact product sponsors and other stakeholders about issues that may affect the value of the diagnostic technologies. NICE may review and update diagnostics guidance at any time if significant new evidence becomes available. Andrew DillonChief ExecutiveOctober 2013	{'Recommendations': 'Faecal calprotectin testing is recommended as an option to support clinicians with the differential diagnosis of inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) in adults with recent onset lower gastrointestinal symptoms for whom specialist assessment is being considered, if:\n\ncancer is not suspected, having considered the risk factors (for example, age) described in the NICE guideline on suspected cancer and\n\nappropriate quality assurance processes and locally agreed care pathways are in place for the testing.\n\nFaecal calprotectin testing is recommended as an option to support clinicians with the differential diagnosis of IBD or non‑IBD (including IBS) in children with suspected IBD who have been referred for specialist assessment, if:\n\nappropriate quality assurance processes and locally agreed care pathways are in place for the testing.', 'The technologies': 'Several technologies that measure the level of calprotectin in stool samples (faecal calprotectin) were evaluated, including fully quantitative laboratory-based tests, fully quantitative rapid tests and semi-quantitative point‑of‑care tests. Faecal calprotectin is excreted in excess into the intestinal lumen during the inflammatory process and so can act as a marker for inflammatory diseases of the lower gastrointestinal tract. The tests are intended to help distinguish between inflammatory bowel diseases and non‑inflammatory bowel diseases. Additional details are provided in section\xa04.', 'Clinical need and practice': "# The problem addressed\n\nThe aim of this evaluation was to examine the clinical and cost effectiveness of faecal calprotectin tests to help differentiate between non‑inflammatory disorders such as irritable bowel syndrome (IBS) and inflammatory disorders such as inflammatory bowel disease (IBD) in people presenting with any of the following lower gastrointestinal symptoms for at least 6\xa0weeks: abdominal pain or discomfort, bloating, or change in bowel habit. Patients with IBD need to be referred to specialist care (most likely, gastroenterology) for further investigation.\n\nThe External Assessment Group suggested that, in adults, the distinction between IBD and IBS is likely to be most clinically useful. It was also suggested that children presenting with these symptoms can have a different range of conditions than adults, and the most clinically useful distinction in children was thought to be between IBD and non‑IBD.\n\n# The conditions\n\n## Background, epidemiology and incidence\n\nChronic abdominal pain or discomfort, with diarrhoea or constipation, are common. The symptoms can be caused by several different conditions, including IBD, of which ulcerative colitis and Crohn's disease are the most common, and IBS.\n\nLower bowel symptoms are very common in general practice. They are most often associated with IBS. However, the symptoms can be caused by IBD, which can lead to serious complications. For example, over 50% of people with Crohn's disease need surgery within 10\xa0years of diagnosis. It is important to distinguish IBD from non‑IBD, such as IBS, so that the conditions can be appropriately managed and monitored. IBD is characterised by inflammation of the bowel, which is not seen in most patients with IBS.\n\nIBS is a functional bowel disorder characterised by frequent bouts of bowel disturbance, abdominal pain and discomfort, and bloating. There is no clear cause, no distinctive pathology and treatment is symptomatic. Exacerbations may be triggered by diet or stress. Physiological studies often show an increase in bowel sensitivity, and the condition may be associated with abnormal muscle activity in the wall of the bowel. It is troublesome and can interfere with activities of daily life, although it does not usually cause serious morbidity.\n\nThe NICE guideline on irritable bowel syndrome in adults suggests a prevalence of between 10% and 20% in the general population. Prevalence figures can vary depending on the diagnostic criteria used, which may account for the range of reported values. The true prevalence of IBS may be higher than estimated because many people with IBS symptoms do not seek medical advice; the NICE guideline cites NHS Direct online data that suggest 75% of people using this service rely on self-care. IBS most commonly affects people between the ages of 20 and 30\xa0years and is twice as common in women as in men. Recent evidence shows that there is also a significant prevalence of IBS in older people. In terms of non‑IBD conditions, the percentage of people with IBS is greater in adults than children.\n\nIBD is the term normally given to a group of conditions that involves inflammation of the gastrointestinal tract, such as Crohn's disease and ulcerative colitis. These conditions can sometimes have serious complications, including a high risk of surgery and an increased risk of colorectal cancer. In both ulcerative colitis and Crohn's disease, some people have active disease but no symptoms.\n\nUlcerative colitis and Crohn's disease are the 2\xa0most common forms of IBD. The incidence of ulcerative colitis is approximately 10–20\xa0per 100,000\xa0per year, with a reported prevalence of 100–200\xa0per\xa0100,000 people. The incidence of Crohn's disease is around 5–10\xa0per 100,000\xa0per year (and thought to be increasing), with a prevalence of 50–100\xa0per 100,000\xa0people. There is little gender difference in the prevalence of IBD, but it is more common in white people than in African‑Caribbean people or those of Asian origin. The condition is most prevalent in Jewish people of European origin. The ratio of Crohn's disease to ulcerative colitis varies between adults and children. In adults, the ratio of Crohn's disease to ulcerative colitis is 2:3, while the ratio in children is much higher (2.3:1).\n\nUlcerative colitis: is a relapsing and remitting disease characterised by inflammation of the colon, sometimes intense, with bloody diarrhoea, but more often milder. The cause is not known, but some people seem to be more genetically susceptible than others; around 10% of people with ulcerative colitis have a first‑degree relative with the condition. There may be an abnormal immune response to the natural bacteria that live in the gut. Sometimes, ulcerative colitis occurs after an episode of gastroenteritis caused by organisms such as Salmonella, Shigella and Campylobacter. However, in this case, the condition is more commonly triggered by resulting changes in the natural gut flora than by the direct effects of these organisms.\n\nCrohn's disease: can present in different ways, depending on which part of the intestinal tract is affected. Like ulcerative colitis, it is a relapsing and remitting inflammatory disease. However, it can be a much more extensive disease and can affect any part of the gastrointestinal tract. The cause is unknown, but there is a genetic susceptibility. Like ulcerative colitis, it can occur after infectious gastroenteritis and is associated with disturbances in the natural gut flora. The highest incidence of Crohn's disease is in the 15–30\xa0year age range, but 20–30% of people with the condition are younger than 20\xa0years and onset occurs in people younger than 17\xa0years about 25% of the time. The incidence of Crohn's disease in the general population has been increasing both within the UK and internationally.\n\nThe pattern of symptoms in children is different from that in adults. The largest prospective survey in the UK and Ireland was carried out by the British Paediatric Surveillance Unit, the British Society of Gastroenterology Research Unit and the Paediatric Register of IBD. The commonest presenting symptoms of Crohn's disease are abdominal pain, weight loss and diarrhoea, but 44% of children in the survey did not report diarrhoea, and only 25% reported all 3\xa0together. Other symptoms at presentation included lethargy and anorexia. Paediatric IBD is often more extensive at diagnosis than in adults.\n\n## Prognosis\n\nIBS is not associated with the development of serious comorbidities, and there is no indication that it is linked with a worse prognosis compared with the general population.\n\nHowever, IBS can be painful, disrupt normal activities and reduce quality of life. For example, Spiegel et al. (2009) reported that quality of life in people with IBS is reduced by 26% on average and by 30% if the condition is severe when compared with a person at full health. Quality of life is reduced because of disturbed work and sleep, and anxiety. People with IBS can have symptoms for many years.\n\nIBD can be painful, disrupt normal activities and reduce quality of life, particularly during periods of active disease. For example, Stark et al. (2010) reported that quality of life is reduced by an average of 16% (by 9% for those in remission and by 29% for those with active disease) in people with ulcerative colitis, and reduced by an average of 23% (by 11% for those in remission and by 39% for those with active disease) in people with Crohn's disease when compared with a person at full health.\n\nUlcerative colitis: at first presentation, most patients have mild disease and only 10% have severe disease. About 50% will continue to have mild disease or be in remission but, in about 20% of patients, ulcerative colitis will be chronic and continuous, and be more likely to become extensive throughout the colon. Ordas et al. (2012) noted that, 10\xa0years after onset, 20–30% of patients will have needed removal of the colon (colectomy). Ford and Talley (2013) estimated a lower colectomy rate of around 10%. The risk of mortality does not seem to be raised in people with ulcerative colitis compared with the general population.\n\nCrohn's disease: the outlook in Crohn's disease is worse than in ulcerative colitis. Only 10% of people with this condition have prolonged remission. Ford and Talley (2013) estimated that approximately 20% need hospital admission each year, and 50% will need surgery within 10\xa0years of diagnosis. Life expectancy is slightly decreased in people with Crohn's disease compared with the general population (Baumgart and Sandborn 2012).\n\nThere are 3\xa0main serious intestinal complications in Crohn's disease. One is stricture (narrowing) of the bowel, which can lead to intestinal obstruction, so Crohn's disease can present as an 'acute abdomen' needing surgery, sometimes mimicking appendicitis. Another is fistulas, which are abnormal connections between sections of the bowel, or between the bowel and bladder. The third is colorectal cancer, and surveillance for this is needed.\n\n# The diagnostic and care pathways\n\n## Diagnosis of IBS and IBD\n\nThe symptoms of lower gastrointestinal disorders (including IBD and IBS) can be sufficiently similar to sometimes make diagnosis difficult. Tests are often carried out to exclude conditions rather than to diagnose them, leading to repeat visits and investigations.\n\nIn most cases the diagnosis of IBS can be made on the basis of clinical history alone. The NICE guideline on irritable bowel syndrome in adults recommends that people presenting with abdominal pain or discomfort, bloating or a change in bowel habit for at least 6\xa0months should be asked if they have any red flag indicators such as unexplained weight loss. They should also be clinically tested for red flag indicators, including anaemia, rectal masses, inflammatory biomarkers for IBD (faecal calprotectin is not specifically mentioned) and late onset (older than 60\xa0years) change in bowel habits. Presence of any of these indicators should result in a referral to secondary care for further investigation. Therefore, patients presenting with symptoms or test results indicative of IBD are referred to secondary care for specialist investigation (most likely to a gastroenterology clinic).\n\nIf there are no red flag indicators to cause concern, the NICE guideline on irritable bowel syndrome in adults states that patients who meet the IBS diagnostic criteria should receive the following laboratory tests to exclude other diagnoses:\n\nfull blood count\n\nerythrocyte sedimentation rate or plasma viscosity\n\nC-reactive protein\n\nantibody testing for coeliac disease (endomysial antibodies or tissue transglutaminase antibody).\n\nOf these, the 2\xa0main tests for inflammation are erythrocyte sedimentation rate and C‑reactive protein. However, these tests can be influenced by non‑intestinal diseases and can lack diagnostic accuracy. Therefore, while both tests can identify inflammation, they cannot localise it to the bowel. As a result, many patients are referred for further investigation involving endoscopy, which may not be needed. The NICE guideline on irritable bowel syndrome in adults states that an endoscopy (and a range of other tests) is not needed to confirm the diagnosis of IBS.\n\nMost people diagnosed with IBS at this stage are managed in primary care.\n\nPeople with lower bowel symptoms are likely to be referred to secondary care when there is uncertainty about the diagnosis, or a high clinical suspicion of IBD that needs further investigation.\n\nBritish Society of Gastroenterology guidelines on IBS (2007) suggest that tests conducted in secondary care are largely based on the likely differential diagnosis. Initial laboratory tests in secondary care include full blood count, erythrocyte sedimentation rate, C‑reactive protein, endomysial antibodies and tissue transglutaminase antibody. These tests may already have been done at the request of primary care. The next level of investigation involves endoscopy and imaging.\n\nBritish Society of Gastroenterology guidelines on IBD (2011) state that 'the diagnosis of IBD is confirmed by clinical evaluation and a combination of biochemical, endoscopic, radiological, histological, or nuclear medicine based investigations'. Initial laboratory investigations in common practice include full blood count, erythrocyte sedimentation rate, C‑reactive protein and other tests such as kidney function tests. The guidelines state: 'faecal calprotectin is accurate in detecting colonic inflammation and can help identify functional diarrhoea'. The next level of investigation involves endoscopy (with or without a biopsy), histology and imaging.\n\nEndoscopy can be colonoscopy, involving inspection of the whole colon; sigmoidoscopy, inspecting only the distal part of the bowel (the sigmoid colon); or gastroscopy, visualising the oesophagus, stomach and upper part of the small bowel. There are some sections of the small bowel that cannot currently be reached by widely available forms of endoscopy. Options then include capsule camera endoscopy (the 'camera pill'), and imaging methods including ultrasound and MRI.\n\nTherefore, the British Society of Gastroenterology guidelines suggest that patients with symptoms indicative of IBD or IBS presenting in secondary care follow a similar diagnostic pathway of initial investigations before receiving endoscopy (second level of testing). As in primary care, erythrocyte sedimentation rate and C‑reactive protein are the main markers used to measure intestinal inflammation.\n\nA UK and Ireland survey found that delays in diagnosis of Crohn's disease in children were common; 18% had had a pre‑diagnosis symptom for 1 to 3\xa0years, and 9% had had one for more than 3\xa0years. Only 9% had isolated small bowel disease.\n\n## Differential diagnosis\n\nIBS is often diagnosed on the basis of signs and symptoms, without a need for further investigations, but distinction from IBD on clinical grounds is not always possible. Blood tests that show the presence of inflammation (erythrocyte sedimentation rate and C‑reactive protein) have been used as an aid to diagnosis, but may be abnormal because of other, non-gastrointestinal conditions, and can be normal in people with IBD. Until recently, colonoscopy in specialist care has often been needed to distinguish between IBD and IBS. This is an invasive and unpleasant investigation needing sedation, and is usually carried out on a day‑case basis. In younger patients, over 60% of colonoscopies are normal.\n\n## Management\n\nThe aetiology of IBS has not yet been established and, as a result, management focuses on the relief of symptoms. The symptom profile can vary and can need a combination of different interventions to achieve effective relief. These include watchful waiting, diet and lifestyle interventions, patient education and self‑help, drugs, behavioural and psychological therapies, and complementary and alternative therapies. Drugs include antispasmodic agents, laxatives, antimotility agents and, as second‑line treatment, antidepressants. The treatment of IBS often requires trials of different therapies because some do not improve symptoms. The process of trying different therapies may take several months; the significance of this is that the patient may have IBD and there may be a delay before the correct diagnosis is suspected and the patient is referred for specialist investigation.\n\nThe treatments and the aims of management for IBD have changed in recent years. Schoepfer et al. (2012) comment that the aims have evolved from relieving symptoms towards mucosal healing. They consider that this shift has been driven by the arrival of new medications such as the anti‑tumour necrosis factor (anti‑TNF) drugs, which can induce and maintain mucosal healing.\n\nThe aim of treatment in active disease is to secure and maintain remission. Management involves diet and lifestyle interventions, drugs and surgery to induce and maintain remission. Drugs include aminosalicylates, corticosteroids, thiopurines, disease-modifying anti-rheumatic drugs (such as methotrexate), immunosuppressants (such as ciclosporin) and anti‑TNF drugs (such as infliximab). There is an increased risk of colorectal cancer, so surveillance is part of patient care.", 'The diagnostic tests': "# The interventions\n\nSeveral faecal calprotectin tests are available to the NHS in England, including fully quantitative laboratory-based technologies (many of which use an enzyme‑linked immunosorbent assay [ELISA] platform), fully quantitative rapid tests and semi-quantitative point‑of‑care tests (POCTs). Rapid tests have not been characterised as POCTs in this assessment because they need a dedicated reader to process the tests but with appropriate training and quality assurance processes they may be appropriate for use in point‑of‑care settings. In principle, all technologies can be used to provide a faecal calprotectin testing service to either primary or secondary care.\n\nManufacturer\n\nTest\n\nPlatform\n\nBühlmann\n\nEK-CAL calprotectin ELISA test\n\nELISA – quantitative\n\nRange: 10–600\xa0micrograms/g\n\nBühlmann\n\nEK-CAL calprotectin ELISA test\n\nELISA – quantitative\n\nRange: 30–1800\xa0micrograms/g\n\nBühlmann\n\nLF-CAL25 Quantum Blue calprotectin test\n\nRapid test – Immunoassay designed for the quantitative determination of faecal calprotectin in combination with the BÜHLMANN Quantum Blue reader\n\nRange: 30–300\xa0micrograms/g\n\nBühlmann\n\nLF-CHR 25 Quantum Blue calprotectin test\n\nRapid test – Immunoassay designed for the quantitative determination of faecal calprotectin in combination with the BÜHLMANN Quantum Blue reader\n\nRange: 100–1800\xa0micrograms/g\n\nCalpro\n\nCALPRO CALPROTECTIN ELISA TEST (ALP) – formerly known as the Phical test\n\nCAL0100\n\nELISA – quantitative\n\nRange: up to 1250\xa0mg/kg\n\nCalpro\n\nCALPROLAB CALPROTECTIN ELISA (ALP) – formerly known as the Phical test\n\nCALP0170\n\nELISA – quantitative\n\nRange: up to 2500\xa0mg/kg\n\nEurospital\n\nCalprest\n\nELISA – quantitative\n\nEurospital\n\nCalFast\n\nRapid test – Quantitative determination of faecal calprotectin in combination with a dedicated reader\n\nImmundiagnostik\n\nELISA (K6927)\n\nELISA – quantitative\n\nPhadia AB, part of Thermo Fisher Scientific\n\nEliA Calprotectin\n\nEliA – quantitative\n\nQuantitative fluorescence enzyme immunoassay (FEIA) test\n\nRange 15–3000\xa0mg/kg\n\nPreventis (sister company to Immundiagnostik)\n\nKST11005 CalDetect Calprotectin Rapid test (version 1 – Caldetect)\n\nPOCT – immunochromatographic rapid test\n\nA semi-quantitative test with 3\xa0lines corresponding to: Calprotectin 'negative', Calprotectin≤15\xa0micrograms/g, Calprotectin 16–60\xa0micrograms/g and Calprotectin>60\xa0micrograms/g stool\n\nPreventis (sister company to Immundiagnostik)\n\nCalDetect Calprotectin Rapid test (version\xa03 – CalScreen)\n\nPOCT – immunochromatographic rapid test\n\nA yes/no test with only 1\xa0test‑line corresponding to the cut‑off value of 50\xa0micrograms/g stool (no inflammation=<50\xa0micrograms/g and inflammation present=≥50\xa0micrograms/g)\n\nAbbreviations: ELISA, enzyme-linked immunosorbent assay; POCT, point-of-care test.\n\nImmundiagnostik tests K6967 and K6937 were included in the scope but were not included in the assessment conducted by the External Assessment Group because one is a variant (K6967) and the other (K6937) was superseded by the Immundiagnostik test K6927, which was included in the assessment.\n\nIn total, 12\xa0tests were included in the assessment conducted by the External Assessment Group. The reference standard was histology after endoscopy.\n\nBecause faecal calprotectin correlates with the level of bowel inflammation, test results need to be interpreted in the context of a cut‑off value, below which the test is deemed negative and above which is deemed positive. In the context of distinguishing between irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), this would mean a negative result would support a diagnosis of IBS (a disease not characterised by inflammation) and a positive result would support a diagnosis of IBD (a disease characterised by inflammation). For a quantitative test, the output is often a single number representing micrograms of calprotectin per gram of stool sample (for example, 15\xa0micrograms/g). If the cut‑off value is selected as 50\xa0micrograms/g for distinguishing between IBS and IBD, then a person with a faecal calprotectin level of 15\xa0micrograms/g would be classified as negative (indicating the person is likely to have IBS). The cut‑off value selected influences the diagnostic accuracy of the tests under consideration and different cut‑off values can be selected for different purposes. Cut‑off values can include a middle range in which results are considered indeterminate, below which are deemed negative and above which are deemed positive. Although a cut‑off value needs to be selected for interpreting results of a quantitative test, the cut‑offs for a POCT might be pre‑specified in the design of the test. For example, CalDetect reports 1 of 4\xa0results when the test runs correctly: negative – faecal calprotectin is not detectable; negative – faecal calprotectin level is equal to or less than 15\xa0micrograms/g; positive – faecal calprotectin level is 16–60\xa0micrograms/g; and positive – faecal calprotectin level is more than 60\xa0micrograms/g. Users might apply local cut‑offs for interpreting the results of POCTs; for example, a cut‑off of 60\xa0micrograms/g might be applied, test results below which are deemed negative and above which are deemed positive. The most common cut‑off recommended by manufacturers is 50\xa0micrograms/g. It should be noted that, in some cases, people with IBS can have raised levels of faecal calprotectin above the selected cut‑off value and the opposite is true for people with IBD (faecal calprotectin levels can be below the selected cut‑off).\n\n# The comparator\n\nThe comparator is standard clinical practice in England. The main tests currently used to measure inflammation are erythrocyte sedimentation rate and C‑reactive protein, which can indicate inflammation but not localise it.", 'Outcomes': "The Diagnostics Advisory Committee (section\xa011) considered evidence from a number of sources (section\xa012).\n\n# How outcomes were assessed\n\nThe assessment consisted of a systematic review of the evidence on test performance and clinical-effectiveness data for faecal calprotectin testing. The outcome measures included in the assessment were:\n\nreferral rates\n\nnumbers of colonoscopies with or without faecal calprotectin testing\n\nproportion of colonoscopies with no abnormal findings\n\nduration from onset of symptoms to definite diagnosis of inflammatory bowel disease (IBD) – late diagnosis of Crohn's disease\n\ncosts\n\nadverse events such as complications of colonoscopy\n\nquality of life and hence quality‑adjusted life years (QALYs).\n\nThe External Assessment Group did a systematic review of the evidence on cost effectiveness for faecal calprotectin testing and constructed a de novo economic model. The outcomes of interest for the economic evaluation were the morbidity and mortality associated with inflammatory and non‑inflammatory diseases of the bowel and their treatment, and particularly of people with IBD incorrectly diagnosed as irritable bowel syndrome (IBS). Given the chronic nature of the conditions and their potential impact on a person's quality of life, the main outcome of interest was health-related quality of life, including the impact of adverse effects associated with colonoscopy. The de novo economic model followed a linked evidence approach in which intermediate outcomes (results of faecal calprotectin testing) were linked to treatment outcomes and hence QALY gains. Costs and QALYs were assigned to each of the strategies assessed in the model.\n\nAlthough the scope allowed for the assessment of faecal calprotectin testing for both adults and children in both primary and secondary care, the External Assessment Group modelled 2\xa0specific scenarios: faecal calprotectin testing for distinguishing between IBD and IBS in an adult population in primary care; and faecal calprotectin testing for distinguishing between IBD and non‑IBD in a paediatric population in secondary care. The External Assessment Group believed these scenarios reflect the most likely use of faecal calprotectin testing in clinical practice.\n\n# Clinical effectiveness\n\n## Previous systematic reviews\n\nFive previously conducted systematic reviews of faecal calprotectin testing were quality assessed and summarised by the External Assessment Group.\n\nIn summary, reviews conducted recently (published in 2010 or later) and judged to be medium or high quality by the External Assessment Group concluded that faecal calprotectin testing is a useful tool. For example, the Centre for Evidence‑based Purchasing (2010) review focusing on faecal calprotectin for distinguishing between IBS and IBD concluded that faecal calprotectin performs well in distinguishing organic bowel disease from functional bowel disease (organic disease includes IBD and functional disease includes IBS). Sensitivity and specificity were over 80% in most of these studies (at a 50\xa0micrograms/g cut‑off) and, when calculated, most positive and negative predictive values were 70–90%.\n\n## Diagnostic accuracy of faecal calprotectin – the comparisons\n\nThe External Assessment Group summarised the ability of faecal calprotectin testing in 4\xa0sets of comparisons:\n\norganic compared with non‑organic\n\nIBS compared with IBD (most appropriate comparison for adults)\n\norganic compared with IBS\n\nIBD compared with non‑IBD (most appropriate comparison for paediatrics).\n\nOrganic disease includes inflammatory diseases. 'Organic' disease is formally defined as a condition in which there is an observable and measurable disease process (for example, inflammation).\n\nThe External Assessment Group suggested that comparisons\xa02 and\xa04 represent the most likely use of faecal calprotectin testing in clinical practice and therefore that the economic analysis should focus on the cost effectiveness of faecal calprotectin testing within these applications of the test. Diagnostic accuracy data for comparisons\xa02 and\xa04 are summarised below. Faecal calprotectin testing is used in symptomatic patients to distinguish between 2 different types of disease. Diagnostic sensitivity refers to the proportion of patients whose test is positive in the presence of an inflammatory disease of the bowel (such as IBD); diagnostic specificity refers to the proportion of patients whose test is negative in the absence of inflammatory disease of the bowel. Patients whose test is negative may be found to have IBS.\n\nNearly all of the evidence came from studies in secondary care, with few data from primary care. Data from a pilot project supported by the NHS Technology Adoption Centre were available to the External Assessment Group and were used in the economic analysis. These data are also summarised below.\n\nSeven studies gave results that compared IBS and IBD, at 8\xa0cut‑off levels ranging from 8–150\xa0micrograms/g, all in adults in secondary care. All studies assessed enzyme‑linked immunosorbent assay (ELISA) tests, and one also assessed the performance of the point‑of‑care test (POCT) CalDetect. As expected, low cut‑offs gave high sensitivity for IBD but poor specificity. Sensitivity was consistently high (usually 100% at levels under 50\xa0micrograms/g; ranging from 83–100% at a cut‑off of 50\xa0micrograms/g), but specificity was more varied (51–100%).\n\nMany of the studies had a small sample size. The largest study was by Li et al. (2006), which employed a sample of 240\xa0people. Studies were of mixed quality. Schroder et al. (2007) and Schoepfer et al. (2008) were assessed as having the least risk of bias.\n\nFive studies reported data for faecal calprotectin testing with ELISA with a cut‑off of 50\xa0micrograms/g. This allowed for the meta‑analysis of the studies to provide an overall combined estimate of sensitivity and specificity. The combined estimates for ELISA tests, at a 50\xa0micrograms/g cut‑off, were a sensitivity of 93% and a specificity of 94%. The meta‑analysis estimates were informed by a pool of 596\xa0people, of which 40% were from the Li et al. (2006) study. The mean age of people in these studies, when reported, ranged from 40–52\xa0years in people with IBS and 34–45\xa0years in people with IBD. However, the age of people in the Schoepfer et al. (2008) study went as high as 78\xa0years.\n\nThe only study using a POCT was Otten et al. (2008), which assessed the CalDetect test in a sample of 114\xa0people. Otten et al. showed that the test performed well at a cut‑off of 15\xa0micrograms/g, with a sensitivity of 100% and a specificity of 95%. At a cut‑off of 60\xa0micrograms/g, although specificity improved slightly to 98%, sensitivity was only 61%, which the External Assessment Group considered to be unlikely to be acceptable in clinical practice given the importance of not missing people with IBD. The average age of people in the Otten et al. study was 52\xa0years in people with IBS and 45\xa0years in people with IBD.\n\nThe cost effectiveness of faecal calprotectin testing for distinguishing between IBD and IBS in an adult population in primary care was assessed in the economic evaluation conducted by the External Assessment Group.\n\nEleven studies reported IBD compared with non‑IBD, at 8\xa0cut‑off levels. Eight studies were conducted in paediatrics and 3\xa0in adults. All used ELISA tests, and one (Damms and Bischoff 2008) also assessed the Prevista POCT (not identified in the scope for the assessment).\n\nThe studies showed consistently high sensitivity at lower cut‑offs, nearly all over 90%, with most at the 50\xa0micrograms/g cut‑off having sensitivities of 100%. Specificity was more varied, ranging from 44–93% at a 50\xa0micrograms/g cut‑off. Most of these results were in paediatric groups. Most studies reported results at only 1\xa0cut‑off, but 1\xa0study reported 5\xa0cut‑offs and another\xa04, both in paediatric populations. Studies were of mixed quality with Canini et al. (2006), Diamanti et al. (2010), Fagerberg et al. (2005), Henderson et al. (2012) and van de Vijver et al. (2012) assessed as having the least risk of bias compared with the other studies.\n\nSix separate estimates of sensitivity and specificity were available at a cut‑off of 50\xa0micrograms/g and another 6\xa0estimates at 100\xa0micrograms/g, which allowed the individual estimates to be meta‑analysed into combined overall estimates of sensitivity and specificity for ELISA tests. The overall pooled results for IBD compared with non‑IBD showed very high sensitivity of 99% but moderate specificity of 74% at a cut‑off of 50\xa0micrograms/g. These estimates were informed by a pool of 531\xa0people with most of these studies including people up to the age of 18\xa0years. At a cut‑off of 100\xa0micrograms/g, sensitivity was found to fall to 94% but specificity to improve to 82%. These estimates were informed by a pool of 656\xa0people; however, the upper age limit varied in these studies. Two studies recruited people up to the age of approximately 15\xa0years, 2\xa0studies up to the age of 18\xa0years and 1\xa0study up to an age of 20\xa0years. The age limit was not reported in the sixth study.\n\nThe cost effectiveness of faecal calprotectin testing for distinguishing between IBD and non‑IBD in a paediatric population in secondary care was assessed in the economic evaluation conducted by the External Assessment Group.\n\n## Primary care pilot data on faecal calprotectin testing\n\nImplementation projects for faecal calprotectin testing in 2\xa0North East Clinical Commissioning Groups in Northumberland and Durham Dales during 2011/12 were undertaken by the NHS Technology Adoption Centre. The Durham Dales data were available to the External Assessment Group and were used to inform the economic analysis, which also allowed exploration of what might happen if faecal calprotectin testing is introduced in primary care.\n\nThe Durham Dales project provided data on GP referrals following the introduction of faecal calprotectin testing in primary care. GPs made diagnostic decisions based on clinical assessment and knowledge of the faecal calprotectin test result. They referred patients who they thought might have IBD, and managed those who they thought had IBS in primary care.\n\nA final consultant diagnosis was made, based on faecal calprotectin test results and clinical data including colonoscopy. The clinical data came from GP and outpatient data, when patients were referred, or just from GP data, when patients were not referred. Patients diagnosed as having IBS and not referred for specialist investigation did not have colonoscopy, so it was not possible to completely exclude patients with false negative results (partial verification bias). The Durham Dales data could not be used to inform the estimates of test accuracy for the CalDetect test (used in the implementation project) in the main economic analysis in primary care because of the partial verification bias.\n\nUsing the Durham Dales data of 111\xa0patients who were followed up, the External Assessment Group used a prevalence of IBD of 6.3% in primary care and, in the absence of faecal calprotectin testing, a sensitivity of GP current practice of 100%, and 79% specificity in the model. The data also showed that GPs referred about 25% (29/111) of patients who presented with symptoms. The External Assessment Group created a scenario analysis that arbitrarily assumed that, if faecal calprotectin testing becomes available, GPs will test twice as many patients (50%) than they would have referred in the absence of faecal calprotectin testing.\n\nUsing the North-European data from Shivananda et al. (2006), a ratio of ulcerative colitis to Crohn's disease of 3:2 (incidence of ulcerative colitis 12.9 in 15–44\xa0age group, based on 539\xa0cases, and of Crohn's disease 8.7, based on 365\xa0cases) would be expected in this adult population.\n\n## Ranges of faecal calprotectin values and choice of test\n\nThe distribution of faecal calprotectin values is highly skewed and a wide range can be observed. Low levels may be seen in people with IBD and raised levels may be seen in people with IBS/non‑IBD (for example, people with infectious gastroenteritis or food poisoning).\n\nIn some studies, the ranges did not overlap, but in others they did. For example, in El‑Badry et al. (2010), the value of faecal calprotectin in people with IBD ranged from 98–637\xa0micrograms/g, which did not overlap with the value of faecal calprotectin in people with IBS (14–65\xa0micrograms/g). In all other studies, the range of faecal calprotectin in patients with IBD overlapped with the range of faecal calprotectin in patients with IBS. In some studies, such as Li et al. (2006) and Schroder et al. (2007), the range of faecal calprotectin levels in people with IBD was wide, with the lowest value being 15\xa0micrograms/g and the highest being 2574\xa0micrograms/g.\n\nThe range of results in studies comparing IBD and non‑IBD in children was similar to that found in studies comparing IBD and IBS in adults. In some studies (Canini et al. 2006; Diamanti et al. 2010; Sidler and Leach 2008), the ranges of faecal calprotectin levels overlapped in children and faecal calprotectin levels were high.\n\nThe External Assessment Group noted that faecal calprotectin levels were often raised in conditions other than IBD, such as larger colorectal adenomas and some colorectal cancers. The accuracy of faecal calprotectin testing is lower in these other conditions when compared with IBD.\n\nThe External Assessment Group summarised several studies that evaluated the comparative performance of faecal calprotectin tests in particular situations. For example, some studies assessed the performance of the tests for distinguishing IBS from IBD and others assessed the tests in distinguishing organic from non‑organic disease.\n\nOverall, the External Assessment Group concluded that there are limited data comparing the performance of different faecal calprotectin tests. Of the studies conducted, they concluded that none suggested any considerable differences between the various faecal calprotectin tests.\n\n## Clinical outcomes\n\nModelling was used to estimate clinical outcomes and QALYs. Please refer to the economic analysis below.\n\n# Economic analysis\n\n## Review of existing economic analyses\n\nSeven references were identified in the systematic review of economic analyses. Although previous economic analyses have typically concluded that faecal calprotectin testing is cost saving compared with diagnostic pathway costs without it, several issues were highlighted in the critique of the literature, which need further consideration. These included: the use of a small sample size to inform the analysis (Hornung and Anwar 2011); assumptions about test accuracy and no consideration of false negative results (Mindemark and Larsson 2012); the analysis considering colonoscopy but not faecal calprotectin testing (Goldfarb et al. 2004 and Dubinsky et al. 2002 – also, this analysis was conducted in the US context); studies that were conducted in England but in primary care only (York Health Economics Consortium [YHEC] economic report for the Centre for Evidence‑based Purchasing review, 2010); and some studies that were available only in abstract/poster format, which did not allow for a full critique of the analysis (Mascialino et al. 2012 and 2013).\n\nThe External Assessment Group constructed a de novo economic model to address the decision problem for this evaluation.\n\n## Cost-effectiveness model constructed by the External Assessment Group\n\nThe External Assessment Group constructed a full cost‑effectiveness model. The External Assessment Group model was informed by the model used in the NICE guideline on Crohn's disease, the modelling for the NICE guideline\xa0on ulcerative colitis, the modelling for the NICE guideline on irritable bowel syndrome in adults, and the YHEC model. In particular, these models were used to inform induction therapy and remission patterns in people with IBD and IBS.\n\nThe model uses a linked-evidence approach to combine the outcomes of diagnostic strategies with the management (induction therapy and remission patterns) of patients' conditions, to allow the estimation of clinical outcomes and QALYs. The model assesses multiple diagnostic strategies and allows for multiple test sequences to be considered (for example, an initial ELISA test followed by colonoscopy). The outcomes from the diagnostic pathway are linked to the care pathway following diagnosis. Patients with true positive results for Crohn's disease and ulcerative colitis are considered separately from one another because patients in these groups follow different and complicated induction and remission pathways post diagnosis. Both patients with true negative and with false negative results follow the care pathway for IBS, with those patients whose disease does not respond to dietary changes after advice and subsequent medical treatment for IBS being retested for IBD. Patients with false positive results (incorrectly diagnosed as having IBD) are eventually correctly diagnosed as having IBS, given that it is assumed all patients with false positive results are referred for specialist investigation and undergo a colonoscopy (assumed 100% specificity). The model employs a weekly cycle and adopts a 10‑year time horizon.\n\nAlthough the scope allowed for the assessment of faecal calprotectin testing for both adults and children in both primary and secondary care, the External Assessment Group modelled 2\xa0specific populations: an adult population in primary care, with faecal calprotectin test accuracies for IBD compared with IBS, and a paediatric population in secondary care, with faecal calprotectin test accuracies for IBD compared with non‑IBD. The External Assessment Group believed these populations reflect the most likely use of faecal calprotectin testing in clinical practice.\n\nThe main aim of the model was to assess the impact of faecal calprotectin testing when added to current clinical practice compared with current practice alone on the differentiation of IBD and IBS in primary care. This model was then adjusted to reflect the differing test performances and costs in the paediatric population to provide an approximation of the cost effectiveness of faecal calprotectin testing for distinguishing between IBD and non‑IBD. However, the External Assessment Group highlighted the limitation of this approach because the main model structure does not fully account for the non‑IBD case mix in the paediatric population (prevalence of IBS in the non‑IBD group is lower than that seen in adults).\n\nThe use of an ELISA faecal calprotectin testing service was evaluated in the base case for both of the primary and secondary care scenarios. The POCT CalDetect was evaluated in the base case primary care scenario.\n\nThe base case applied the quality‑of‑life decrements from remission to active disease of 0.280 for Crohn's disease and 0.200 for ulcerative colitis from Stark et al. (2010). But sensitivity analyses applying the quality‑of‑life decrements from mild‑to‑moderate disease of 0.075 for Crohn's disease, as drawn from Gregor et al. (1997), and of 0.165 for ulcerative colitis, as drawn from Poole et al. (2010), were also explored. The utility decrements for IBS were less important for modelling purposes, given that the 100% specificity assumed for colonoscopy meant that there were no patients with false positive results by the end of the test sequence. For the base case, the 0.071 increment for response to treatment estimated in the NICE guideline on irritable bowel syndrome in adults was applied. The 0.662 baseline HRQoL that this increment was applied to was taken from Brazier et al. (2004). A sensitivity analysis using values from Spiegel et al. (2009) was also considered: 0.780 for response to treatment and 0.730 for no response to treatment, but the algorithm used to construct the EQ‑5D utilities was not clear. The baseline HRQoL value for IBS has an impact because of the small mortality rate associated with colonoscopy, with this impact enduring for the 10‑year time horizon of the model.\n\nBecause of data constraints, the cost impacts were limited to modelling the relatively rare (less than 0.5%) serious adverse events of bleeds and perforations. The quality‑of‑life impacts were limited to the mortality associated with perforations. While perforations are rare, resulting in a very low mortality rate, the QALY impact of this persisted for the duration of the model.\n\nThere is evidence from the literature that colonoscopies result in minor adverse events among a reasonable proportion of patients; for example, de Jonge et al. (2012) suggested that around 40% of those investigated with colonoscopy have some effects persisting for 30\xa0days after the colonoscopy. In common with the NICE guideline on colonoscopic surveillance for the prevention of colorectal cancer, these minor adverse events were not taken into account in the modelling principally because of a lack of quality‑of‑life data.\n\nThe costs included in the model were the costs of the different tests, treatment costs (including induction therapy and maintenance therapy costs for people in remission), NHS resource costs (for example, staff time) and costs of adverse effects associated with colonoscopy.\n\nThe per person costs of an ELISA test and POCT CalDetect were estimated to be £22.79 (based on an assumption of 40\xa0patient samples per 96\xa0well‑plate, costed at the list price, plus an average 11–12\xa0minutes of staff time at grade\xa06/7) and £24.03 (test list price plus cost of 15\xa0minutes of GP practice‑nurse time) respectively.\n\nColonoscopy was estimated to cost £741.68 per person. This estimate was based on a weighted average of the NHS reference cost for outpatient and day cases without biopsy (procedures payment by results code FZ51Z/FZ54Z), or with biopsy (procedures payment by results code FZ52Z/FZ55Z) for colonoscopy or, when used, sigmoidoscopy. The cost included an outpatient gastroenterology appointment (£164) and costs of adverse effects (an average of £12 per colonoscopy).\n\n## Primary care analysis (IBS compared with IBD in adults) – key model characteristics and results\n\nThe base case considered the cost effectiveness of GP testing compared with GP testing plus faecal calprotectin testing in the adult population for distinguishing IBS from IBD.\n\nFor the primary care adult population, the model adopted a baseline age of 25\xa0years for those presenting with symptoms, as used in the NICE guideline\xa0on Crohn's disease. Consistent with the modelling in this guideline, the proportion of females was taken to be 50% for both Crohn's disease and ulcerative colitis. It appears that a higher proportion of people with IBS are female; in the Brazier et al. (2004) sample, 86% were female, although the External Assessment Group suggested this estimate may be towards the upper end. For IBS, the base case adopted a proportion of females of 75%. These estimates only affect the all‑population mortality risks. Because these risks are low during mid-adulthood, for both women and men, the average age and proportion of model inputs for women will have had a minimal impact on the results.\n\nThe base-case prevalence of IBD (6.3%) was drawn from the Durham Dales data, while the prevalence of ulcerative colitis among patients with IBD (a ratio of ulcerative colitis to Crohn's disease of 3:2) was drawn from Shivananda et al. (1996).\n\nThe strategies assessed were:\n\nGP current practice (clinical assessment with no faecal calprotectin testing)\n\nGP current practice plus the POCT CalDetect using a cut‑off of 15\xa0micrograms/g\n\nGP current practice plus ELISA testing using a cut‑off of 50\xa0micrograms/g.The External Assessment Group opted to use the lower 15\xa0micrograms/g cut‑off from Otten et al. (2008) because the data for the 60\xa0micrograms/g cut‑off suggested only a slight gain in terms of a better specificity, 97.8% compared with 94.5%, but considerable loss in terms of a worse sensitivity, 60.9% compared with 100.0%. Test accuracy data used in the model are summarised in table\xa02.\n\nThe External Assessment Group assumed, given lack of evidence to the contrary, that the accuracy of ELISA testing is the same as would be obtained from ELISA testing in conjunction with GP current practice.\n\nThe delay between referral and colonoscopy was assumed to be 4\xa0weeks and the time to retesting among those with negative tests but not responding to IBS therapy was assumed to be 12\xa0weeks, both estimates being based on expert opinion. The latter estimate may have been optimistic because a sequence of unsuccessful treatments might be tried for people with IBS. This was explored in sensitivity analyses.\n\nThe modelling assumed that all people who test positive or have an indeterminate result are referred to secondary care and all of these people receive a colonoscopy (indeterminate results are treated as if the results are determinate). Because of a lack of data, the External Assessment Group was not able to incorporate the impact of a gastroenterologist's assessment on the number of people who will go on to receive a colonoscopy (which may also include the use of faecal calprotectin testing) in the base case; however, this is explored in sensitivity analysis.\n\nTest\n\nGP current practice\n\nCalDetect (POCT)\n\nELISA\n\nColonoscopy\n\nCut-off\n\n–\n\nmicrograms/g\n\nmicrograms/g\n\n–\n\nSensitivity\n\n%\n\n%\n\n(95%\xa0CI 85–100%)\n\n%\n\n(95%\xa0CI 85–98%)\n\n%\n\nSpecificity\n\n%\n\n%\n\n(95%\xa0CI 88–98%)\n\n%\n\n(95%\xa0CI 76–100%)\n\n%\n\nTest accuracy data source\n\nPrimary care data from the NHS Technology Adoption Centre project\n\nSecondary care data from Otten et al. (2008)\n\nExternal Assessment Group meta-analysis of secondary care data\n\nExpert opinion\n\nAbbreviations: CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; POCT, point-of-care test.\n\nWithout faecal calprotectin testing, GP current practice is highly sensitive in terms of referring people with IBD and is as good as, if not better, than faecal calprotectin testing. Of the 6.3% of people with IBD in the total population, all were identified by the GP current practice strategy and the POCT CalDetect strategy. Colonoscopy would correctly identify 6.0% of the 6.3% referred as patients with true positive results (because of its 95% sensitivity), resulting in a total of 0.3% of patients with false negative results. ELISA testing is slightly worse, identifying 5.9% of the 6.3% (because of its lower sensitivity when compared with current practice and the POCT), with 0.4% of patients being classified as having false negative results. Of the 5.9% referred for colonoscopy, 5.6% of patients would be identified as having true positive results, with 0.3% being classified as having false negative results, resulting in a total of 0.7% of patients with false negative results. Therefore, a slightly larger number of people will have IBD but will be incorrectly diagnosed as having IBS when using an ELISA testing strategy when compared with current practice strategy and a POCT CalDetect strategy (0.7% compared with 0.3%).\n\nWithin the total patient population, GP current practice incorrectly identified 19.8% of patients as having false positive results (people thought to have IBD but who actually have IBS) and requiring referral for colonoscopy. The rates of patients with false positive results incorrectly referred for colonoscopy for POCT CalDetect and ELISA were much lower, at 5.1% and 5.6% respectively. Therefore, without faecal calprotectin testing, many of the patients with false positive results would go on to have a colonoscopy, which has a risk (although low) of serious complications such as perforation. Such events are too rare to significantly affect costs, but they do have some QALY impact. This is also true for the more common minor adverse effects of colonoscopy (which were not explicitly considered in the model because of a lack of data).\n\nTaking the diagnostic performance of the different testing strategies summarised above into account, the resulting total per patient costs and QALYs are provided in tables\xa03 to 5.\n\nCondition\n\nQALYs\n\nTest costs\n\nOther costs\n\nTotal costs\n\nCrohn's disease\n\n\n\n£22\n\n£493\n\n£515\n\nUlcerative colitis\n\n\n\n£32\n\n£144\n\n£176\n\nIBS\n\n\n\n£202\n\n£2404\n\n£2606\n\nTotal\n\n\n\n£257\n\n£3041\n\n£3297\n\nCondition\n\nQALYs\n\nTest costs\n\nOther costs\n\nTotal costs\n\nCrohn's disease\n\n\n\n£23\n\n£493\n\n£516\n\nUlcerative colitis\n\n\n\n£33\n\n£144\n\n£177\n\nIBS\n\n\n\n£114\n\n£2408\n\n£2522\n\nTotal\n\n\n\n£170\n\n£3044\n\n£3214\n\nCondition\n\nQALYs\n\nTest costs\n\nOther costs\n\nTotal costs\n\nCrohn's disease\n\n\n\n£23\n\n£492\n\n£515\n\nUlcerative colitis\n\n\n\n£34\n\n£143\n\n£177\n\nIBS\n\n\n\n£116\n\n£2407\n\n£2524\n\nTotal\n\n\n\n£173\n\n£3042\n\n£3215\n\nAbbreviations: IBS, irritable bowel syndrome; QALY, quality-adjusted life year.\n\nThe faecal calprotectin tests were estimated to result in similar average cost savings compared with GP current practice: £83 for the POCT CalDetect and £82 for ELISA per patient. This was mainly because of the lower number of referrals and colonoscopies for false positive results. Average QALY gains of around 0.0007\xa0QALYs were also accrued, although these were limited because the low prevalence of IBD and the similar high sensitivities of the tests resulted in relatively few false negative results. Therefore, the faecal calprotectin testing strategies dominated current practice (provided greater benefit at reduced cost). Some of the QALY differences accrued were from the very slightly lower mortality associated with the lower number of colonoscopies. The POCT CalDetect and ELISA strategies were estimated to be broadly equivalent in terms of costs and QALYs, with only minor differences between them.\n\nA range of sensitivity analyses were conducted to explore the impact of varying the main model parameters. These included: varying the prevalence of IBD between 5–25% (6.3% used in the base case); changing the source of utility values; adjusting the costs of colonoscopy (no outpatient appointment cost) and removing any associated mortality; varying the number of patients whose condition did not respond to IBS medication; varying the time it takes for patients with false negative results to re‑present to the clinician (8, 16 and 24\xa0weeks; 12\xa0weeks was used in the base case); and exploring the impact of varying the specificity of the consultant's diagnosis at an outpatient clinic assessment in people referred with a false positive diagnosis. Scenario analyses were also undertaken using different sources of test accuracy for faecal calprotectin and alternative assumptions surrounding the uptake of faecal calprotectin testing (assuming 50% of patients are tested as opposed to the 25% used in the base case) in primary care.\n\nThe sensitivity and scenario analyses appeared to broadly affect the 3\xa0strategies in a similar way and suggested that the results of the base case were reasonably robust. The most notable impact was from assuming 50% of patients are tested in primary care, as opposed to 25%, which reduced the cost savings with faecal calprotectin testing.\n\n## Secondary care (IBD compared with non‑IBD in children) – key model characteristics and results\n\nThe base case considered the cost effectiveness of faecal calprotectin testing before colonoscopy compared with direct referral for colonoscopy in the secondary care paediatric population for distinguishing IBD from non‑IBD.\n\nFor the secondary care paediatric population, the proportions of females included were 38% (35/91) for patients with IBD and 44% (44/99) for patients without IBD; these were drawn from Henderson et al. (2012). An average age of 16\xa0years was assumed because, for the adult modelling, this had minimal impact on results.\n\nIn the base case, a 48% (91/190) prevalence of IBD and a 75% (62/83) prevalence of Crohn's disease among patients with IBD were drawn from Henderson et al. (2012).\n\nThe strategies assessed were:\n\ndirect referral for colonoscopy\n\nELISA testing when used at the 50\xa0micrograms/g cut‑off followed by colonoscopy\n\nELISA testing when used at the 100\xa0micrograms/g cut‑off followed by colonoscopy. Test accuracy data used in the model are summarised in table\xa06.\n\nTest\n\nELISA\n\nELISA\n\nColonoscopy\n\nCut-off\n\nmicrograms/g\n\nmicrograms/g\n\n-\n\nSensitivity\n\n%\n\n(95%\xa0CI: 95–100%)\n\n%\n\n(95%\xa0CI: 87–99%)\n\n%\n\nSpecificity\n\n%\n\n(95%\xa0CI: 59–85%)\n\n%\n\n(95%\xa0CI: 68–92%)\n\n%\n\nTest accuracy data source\n\nExternal Assessment Group meta-analysis of secondary care data\n\nExternal Assessment Group meta-analysis of secondary care data)\n\nExpert opinion\n\nAbbreviations: CI, confidence interval; ELISA, enzyme-linked immunosorbent assay.\n\nThe base-case prevalence of IBD of 47.9% increased the importance of test sensitivities compared with the primary care setting, and so the effect of false negative results on the modelling outputs. Within the total patient population, ELISA with the 50\xa0micrograms/g cut‑off led to 47.4% of patients with true positive results being referred for colonoscopy, while ELISA with the 100\xa0micrograms/g cut‑off led to 45.0% of patients with true positive results being referred for colonoscopy. Colonoscopy was assumed to have a sensitivity of 95%. So, if all (47.9%) patients were referred immediately for colonoscopy, 45.5% would be diagnosed with IBD. With ELISA with the 50\xa0micrograms/g cut‑off, 45.0% of the 47.4% of patients referred for colonoscopy were diagnosed as having IBD, while 42.8% of the 45.0% of patients referred for colonoscopy after ELISA with the 100\xa0micrograms/g cut‑off were diagnosed as having IBD; a net difference between the cut‑offs of 2.2%.\n\nDespite the higher IBD prevalence in the secondary care population, the main test differences still lay in the number of unnecessary colonoscopies. Without faecal calprotectin testing, all 52.1% of patients without IBD received a colonoscopy, compared with 13.5% for ELISA with the 50\xa0micrograms/g cut‑off and only 9.4% for ELISA with the 100\xa0micrograms/g cut‑off.\n\nTaking the diagnostic performance of the different testing strategies summarised above into account, the resulting total per patient costs and QALYs are provided in tables\xa07 to 9.\n\nCondition\n\nQALYs\n\nTests\n\nOther\n\nTotal\n\nCrohn's disease\n\n\n\n£244\n\n£6938\n\n£7183\n\nUlcerative colitis\n\n\n\n£83\n\n£463\n\n£546\n\nNon-IBD\n\n\n\n£338\n\n£629\n\n£967\n\nTotal\n\n\n\n£665\n\n£8031\n\n£8696\n\nCondition\n\nQALYs\n\nTests\n\nOther\n\nTotal\n\nCrohn's disease\n\n\n\n£254\n\n£6934\n\n£7188\n\nUlcerative colitis\n\n\n\n£86\n\n£463\n\n£549\n\nNon-IBD\n\n\n\n£120\n\n£634\n\n£754\n\nTotal\n\n\n\n£460\n\n£8031\n\n£8491\n\nCondition\n\nQALYs\n\nTests\n\nOther\n\nTotal\n\nCrohn's disease\n\n\n\n£256\n\n£6921\n\n£7177\n\nUlcerative colitis\n\n\n\n£87\n\n£462\n\n£549\n\nNon-IBD\n\n\n\n£95\n\n£634\n\n£729\n\nTotal\n\n\n\n£438\n\n£8018\n\n£8456\n\nAbbreviations: IBD, inflammatory bowel disease; QALY, quality-adjusted life year.\n\nPrior testing using ELISA was estimated to dominate (provided greater benefit at reduced cost) the strategy of sending all patients directly for colonoscopy. Compared with referring all patients directly for colonoscopy, ELISA used at the 50\xa0micrograms/g cut‑off was estimated to save £205 per patient, while ELISA used at the 100\xa0micrograms/g cut‑off was estimated to save £240 per patient. QALY gains of around 0.001\xa0QALYs were estimated for ELISA compared with direct referral for colonoscopy, these being slightly larger for ELISA with the 50\xa0micrograms/g cut‑off because of its better sensitivity. The additional average cost of £35 and additional average QALYs of 0.0001 for ELISA with the 50\xa0micrograms/g cut‑off compared with ELISA with the 100\xa0micrograms/g cut‑off resulted in an incremental cost‑effectiveness ratio (ICER) of £35,000 per QALY gained.\n\nA range of sensitivity analyses were conducted to explore the impact of varying the main model parameters. These included: varying the prevalence of IBD to 40% and 60% (48% used in the base case); changing the source of utility values; removing any associated mortality of colonoscopy; varying the time it takes for patients with false negative results to re‑present to the clinician (8, 16 and 24\xa0weeks; 12\xa0weeks was used in the base case); and changing the annualised net cost of false negative results to £376 (£188 was used in the base case).\n\nAs for primary care, most of the changes appeared to broadly affect the 3\xa0strategies in a similar manner. The main difference arose from varying the prevalence of IBD, which tended to reduce the cost savings from faecal calprotectin testing because of the rise in prevalence, as would be anticipated. The source of utilities also had an impact on the anticipated net gain from ELISA with the 50\xa0micrograms/g cut‑off compared with ELISA with the 100\xa0micrograms/g cut‑off, the ICER for which increased to £117,000 per QALY gained. However, the External Assessment Group thought that this may have overstated the effect, given the prevalence of Crohn's disease within the presenting population and the perhaps rather small quality‑of‑life decrement sourced from Gregor et al. (1997).", 'Considerations': "The Diagnostics Advisory Committee discussed the focus of the evaluation and the evidence available for faecal calprotectin testing. It noted that evidence existed on faecal calprotectin testing in differing populations with differing conditions. For example, some study populations included large numbers of adults with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) (for example, Li et al. 2006), while others included children with a much wider range of organic and non‑organic conditions (for example, Tomas et al. 2007). It also noted that, while the evaluation was concerned with the role of faecal calprotectin testing for distinguishing between inflammatory and non‑inflammatory conditions of the bowel, the External Assessment Group suggested that the role of faecal calprotectin in 2\xa0specific scenarios is likely to be the most important in clinical practice. These are IBD and IBS in the adult population presenting in primary care and IBD and non‑IBD in children who are referred for specialist investigation. Furthermore, the Committee noted that, although the use of faecal calprotectin testing is most relevant for helping to distinguish between inflammatory and non‑inflammatory conditions of the bowel, the number of conditions involved placed a prohibitively large burden on the data requirements for a cost‑effectiveness analysis. Therefore, the scenarios above represent a reasonable proxy for the likely clinical use of faecal calprotectin testing, balanced against the demands of the economic analysis. The Committee agreed with the External Assessment Group that it was appropriate for the evaluation to focus on the clinical and cost effectiveness of faecal calprotectin testing in these 2\xa0scenarios. Faecal calprotectin testing is used in symptomatic patients to distinguish between 2 different types of disease. Diagnostic sensitivity refers to the proportion of patients whose test is positive in the presence of an inflammatory disease of the bowel (such as IBD); diagnostic specificity refers to the proportion of patients whose test is negative in the absence of inflammatory disease of the bowel. Patients whose test is negative may be found to have IBS. The Committee also noted that, although there is a growing focus on faecal calprotectin testing in primary care, there were limited data on faecal calprotectin testing in this environment.\n\nThe Committee understood that several different types of faecal calprotectin tests are available to the NHS in England and that such tests are continually improving. The Committee noted that there were limited data on the comparative effectiveness of different faecal calprotectin tests and agreed with the External Assessment Group that sufficiently robust data suggesting considerable differences in clinical reliability and performance between the tests were not available. The Committee recommended research on the comparative performance of different faecal calprotectin tests.\n\nThe Committee discussed pre‑analytical factors that may affect the results of faecal calprotectin testing. The Committee heard from specialists that several factors can affect the result of faecal calprotectin testing, including: sample storage, stool consistency, stool sampling, extraction and extract dilution. The Committee also heard that a UK National External Quality Assessment Service scheme (UK NEQAS scheme) has been set up for faecal calprotectin testing. The Committee encouraged participation in the UK NEQAS scheme and, when possible, standardisation of sample preparation methodology.\n\nThe Committee discussed the evidence on the clinical effectiveness of faecal calprotectin testing in IBD and IBS in adults. It noted that multiple studies of diagnostic accuracy were identified, which assessed faecal calprotectin testing when interpreted using different thresholds. The Committee noted that the evidence mainly concerned the use of quantitative ELISA tests in a secondary care adult population. The most commonly used threshold value in these studies was 50\xa0micrograms/g, which allowed the results of 5\xa0studies to be meta‑analysed. The Committee noted that the results of the meta‑analysis showed that faecal calprotectin testing performed well, with a sensitivity of 93% and a specificity of 94%. The Committee was aware that a study was also published on the performance of a point‑of‑care test (POCT), CalDetect, when used in secondary care (Otten et al. 2008), which showed that the test performed well, with a sensitivity of 100% and a specificity of 95%. However, the Committee noted that the Otten et al. study included relatively few patients. The Committee concluded that, on the whole, faecal calprotectin was a reliable marker for distinguishing between IBD and IBS in a secondary care adult population, but that further data are needed on point‑of‑care testing, to verify the results seen in the Otten et al. study. The Committee recommended further research on the use and clinical utility of faecal calprotectin testing for the diagnosis and long‑term management of these conditions in the community. The Committee also recommended that support pathways be developed for faecal calprotectin testing to support consistent and appropriate use.\n\nThe Committee discussed the de novo model constructed by the External Assessment Group. The Committee understood that limitations in the available data and/or variability in clinical practice meant that the model did not account for: (1) the way in which people with indeterminate results would be followed up before receiving a colonoscopy (all are assumed to be determinate and, therefore, receive a colonoscopy) and (2) the costs associated with the more common but relatively minor adverse events associated with colonoscopy (the costs of relatively rare but serious adverse effects are accounted for in the model). The Committee noted that, despite these limitations, the outcomes of the External Assessment Group's model were similar to those observed in previously conducted economic analyses. The Committee thought that, although the analysis may have benefitted from further sensitivity analysis, the results of the model are likely to be reasonably robust. The Committee concluded that the model was acceptable for decision‑making.\n\nThe Committee went on to discuss the economic analysis that assessed the cost effectiveness of faecal calprotectin for distinguishing between IBD and IBS in a primary care adult population. It noted that data from the Durham Dales implementation project were used to inform the sensitivity and specificity estimates of GP current practice (see section 5.47). The Committee noted from the data that GPs were currently very good at identifying those patients with IBD who needed to be referred for specialist investigation (near‑perfect sensitivity); however, a lower specificity of GP assessment meant that a significant proportion of people with IBS are being referred for specialist investigation, which may be avoided. The cost‑effectiveness analysis compared GP current practice plus quantitative ELISA testing, GP current practice plus point‑of‑care testing with CalDetect and GP current practice without faecal calprotectin testing as separate diagnostic strategies in adults presenting in primary care with lower gastrointestinal symptoms of abdominal pain or discomfort, bloating or change in bowel habit for at least 6\xa0weeks. The Committee noted that the main goal of faecal calprotectin testing in primary care is to help reduce the number of unnecessary referrals of people with IBS (given the relatively high prevalence compared with IBD) and so reduce the number of unnecessary colonoscopies. The Committee noted that the model demonstrated that the differing diagnostic accuracies of the different strategies resulted in 19.8% (GP current practice), 5.6% (ELISA strategy) and 5.1% (CalDetect strategy) of the total modelled population being classified as having a false positive result and referred for colonoscopy. Furthermore, the Committee noted that the lower number of referrals after faecal calprotectin testing meant that both ELISA and CalDetect strategies dominated current practice (produced greater health benefits at reduced cost); however, the Committee agreed that the greatest benefit of faecal calprotectin testing is in reduced costs. Both ELISA and CalDetect strategies led to cost savings of £82 and £83 per patient respectively. The Committee concluded that faecal calprotectin testing is a cost‑effective use of NHS resources for distinguishing between IBD and IBS in adults in primary care and that sensitivity analysis showed these results to be robust.\n\nThe Committee discussed the use of faecal calprotectin testing of adults in secondary care. The Committee heard from clinical specialists that most of the faecal calprotectin testing in adults is expected to take place in primary care rather than secondary care. The Committee also recognised that there is a trend towards reducing the number of referrals to secondary care. It noted, however, that testing may also be appropriate for adults who have been referred for specialist assessment if testing has not already been done in primary care, in order to inform the decision on whether to do further investigations such as colonoscopy. Furthermore, the Committee concluded that cost savings from reduced numbers of colonoscopies are likely in this situation. Therefore, the Committee recommended faecal calprotectin testing as an option to aid differential diagnosis in adults with recent onset of lower gastrointestinal symptoms for distinguishing between IBD and IBS.\n\nThe Committee discussed the use of faecal calprotectin testing for clinical decision‑making. It agreed with the clinical specialists that faecal calprotectin should be used with other clinical information to support a physician's assessment and that physicians should be aware that inflammatory and non‑inflammatory diseases other than IBD and IBS respectively may affect levels of faecal calprotectin. The Committee emphasised that faecal calprotectin testing has the potential to falsely reassure GPs when used in people suspected of having bowel cancer, and so these people should be excluded from the recommendations. The Committee strongly emphasised that, when uncertainty remains in primary care around whether to refer a patient for specialist assessment based on faecal calprotectin testing, the clinician will benefit from further specialist input (clinical or laboratory) before making a decision. The Committee also considered that a repeat testing strategy may be considered as part of patient follow‑up (see section\xa06.14). The Committee was aware that there are limited data on the use of faecal calprotectin testing in primary care. However, the Committee concluded that the assessment had demonstrated the benefit of using faecal calprotectin testing in adults who meet the specific criteria set out in section\xa01.1 and the benefits were, on balance, generalisable to testing in primary care.\n\nThe Committee discussed the evidence on the clinical effectiveness of faecal calprotectin testing for distinguishing between IBD and non‑IBD in children. It noted that multiple studies of diagnostic accuracy were identified that assessed faecal calprotectin testing using different thresholds. The Committee noted that the evidence mainly concerned the use of quantitative ELISA tests in a secondary care paediatric population. The most commonly used threshold values in these studies were 50\xa0micrograms/g and 100\xa0micrograms/g, which allowed the results of 6\xa0studies for each threshold to be meta‑analysed. The Committee noted that the results of the meta‑analysis showed that faecal calprotectin testing performed reasonably well at both thresholds (50\xa0micrograms/g with a sensitivity of 99% and a specificity of 74%, and 100\xa0micrograms/g with a sensitivity of 94% and a specificity of 82%). The Committee concluded that, on the whole, faecal calprotectin was a reliable marker for distinguishing between IBD and non‑IBD in a secondary care paediatric population.\n\nThe Committee went on to discuss the economic analysis that assessed the cost effectiveness of faecal calprotectin for distinguishing between IBD and non‑IBD in a secondary care paediatric population. It noted that this model was an adaptation of the primary care model for IBD and IBS in a primary care adult population. The Committee agreed with the External Assessment Group that the secondary care paediatric model was limited because it did not fully account for the non‑IBD case mix in the paediatric population (the prevalence of IBS in the non‑IBD group is lower than that seen in adults). The Committee concluded that, despite this and other limitations in the model (see section\xa06.5), this analysis would provide a reasonable proxy for the expected costs and benefits of faecal calprotectin testing in a secondary care paediatric population. The cost‑effectiveness analysis compared quantitative ELISA testing interpreted using a threshold of 50\xa0micrograms/g followed by colonoscopy; quantitative ELISA testing interpreted using a threshold of 100\xa0micrograms/g followed by colonoscopy; and direct referral for colonoscopy as separate diagnostic strategies in children with lower gastrointestinal symptoms of abdominal pain or discomfort, bloating or change in bowel habit, for at least 6\xa0weeks, who had been referred for specialist investigation. The Committee noted that the main goal of faecal calprotectin testing in people who have been referred for specialist investigation is to help identify those who are likely to have IBD and will need further diagnostic tests (because the prevalence of IBD in this population is much greater than that seen in primary care), for example, colonoscopy. The Committee noted that the model demonstrated the different strategies resulted in 100% (direct referral for colonoscopy), 61.5% (ELISA with a 50\xa0micrograms/g threshold) and 54.4% (ELISA with a 100\xa0micrograms/g threshold) of the total modelled population receiving a colonoscopy. These estimates include 13.5% of people with false positive results being referred to colonoscopy with the 50\xa0micrograms/g cut‑off strategy, and 9.4% of people with false positive results being referred to colonoscopy with the 100\xa0micrograms/g cut‑off strategy. Furthermore, the Committee noted that the lower number of people expected to receive colonoscopies with the faecal calprotectin strategies meant that ELISA testing at both thresholds dominated current practice (produced greater health benefits at reduced cost); however, the Committee agreed that the greatest benefit of faecal calprotectin testing is in reduced per‑patient costs. Both ELISA interpreted at a threshold of 50\xa0micrograms/g and ELISA interpreted at a threshold of 100\xa0micrograms/g led to cost savings, of £205 and £240 per patient respectively. The Committee concluded that faecal calprotectin testing is a cost‑effective use of NHS resources for distinguishing between IBD and non‑IBD in a secondary care paediatric population and that sensitivity analysis showed these results to be robust. Therefore, the Committee recommended faecal calprotectin testing as an option in children with suspected IBD who have been referred for specialist assessment.\n\nThe Committee discussed the clinical interpretation of test results in children. The Committee heard from, and agreed with, the clinical specialists that faecal calprotectin should be used with other clinical information to support a specialist's assessment and that the specialist should be aware that inflammatory and non‑inflammatory diseases, other than IBD and IBS respectively, may affect levels of faecal calprotectin.\n\nThe Committee was aware that most of the data on faecal calprotectin identified for this assessment came from studies of ELISA testing in a secondary care population. Therefore, in the absence of robust primary care data (in particular, robust primary care data for POCTs), the Committee recommended that faecal calprotectin testing is performed in accordance with appropriate quality assurance processes and locally agreed care pathways to ensure results are reliable and replicable, and to increase the likelihood that the benefits and cost savings estimated by the model are delivered in the NHS. In addition, the Committee recommended that additional expertise should be sought when the faecal calprotectin tests are used in general practice, as outlined in section\xa06.8.\n\nGiven the lack of robust evidence comparing different tests, the Committee thought it appropriate that preferred faecal calprotectin tests might be selected locally in the NHS but that people should be aware that differences between tests may exist. The Committee noted that POCTs currently have a smaller evidence base and are not yet widely used in routine practice. The Committee therefore concluded that robust evidence is needed on the comparative performance of different faecal calprotectin tests, including the performance of POCTs compared with laboratory-based tests.\n\nThe Committee discussed the different thresholds for interpreting faecal calprotectin results. The Committee heard from clinical specialists that, while faecal calprotectin has been studied when interpreted using different thresholds (and investigated in the economic analysis), further research is needed on the impact of testing on clinical decision‑making when added to current practice before a recommendation on a particular cut‑off can be made. The Committee was aware of emerging evidence from a study of faecal calprotectin in primary care by Pavlidis et al. (publication in press, provided to the Committee as academic in confidence). However, the Committee concluded that it was too early to make judgements on these data. The Committee was aware that the assessment did not account for people with minimally elevated (intermediate) levels of faecal calprotectin who, as suggested by clinical specialists, may have low‑grade IBD and might be better off following a repeat testing strategy with faecal calprotectin to monitor levels of bowel inflammation through time as opposed to being subjected to invasive colonoscopies. The Committee heard from clinical specialists that faecal calprotectin levels can vary markedly between the time a person is tested in primary care and then subsequently retested (likely to be after several weeks) either by their GP or a specialist. The Committee noted that differences in tests may exist in the intermediate range of faecal calprotectin levels but may not have been measured in studies to date because of selective sampling of study populations. Therefore, the Committee recommended further research on the impact of faecal calprotectin testing on clinical decision‑making when added to current practice in both primary and secondary care. The Committee also recommended research into optimal cut‑off values for tests and the investigation of repeat testing strategies in people with intermediate levels of faecal calprotectin. Development of a consistent definition for the 'intermediate range' is encouraged by the Committee. The Committee further recommended that test result cut‑offs should be discussed and agreed locally as part of the implementation process for this testing pathway.\n\nThe Committee noted some general points: (1) the clinical-effectiveness estimates for faecal calprotectin testing summarised in this evaluation have been corroborated by faecal calprotectin databases around the country (for example, the Edinburgh Faecal Calprotectin Registry and the database maintained by King's Health Partners); (2) the Durham Dales project data may represent a best‑case scenario for GP current practice and, if this is the case, faecal calprotectin may have an even greater benefit in primary care (this additional benefit may be offset by losses in benefit if more than 50% of people with lower gastrointestinal symptoms are tested); (3) a significant proportion of people with IBD (particularly children with Crohn's disease), largely because of the similarity in symptoms to those in people with non‑IBD conditions, face delays in their diagnosis of up to several years, and the introduction of faecal calprotectin may help to reduce such delays.\n\nThe Committee was encouraged by the results of the assessment because it is likely that the use of faecal calprotectin testing will result in significant capacity being generated in colonoscopy departments to allow them to focus on people with greater need for a colonoscopy (for example, those suspected of having bowel cancer). Furthermore, the Committee noted that the good diagnostic performance of faecal calprotectin has the ability to provide reassurance to both physicians and patients alike given the heterogeneous and overlapping symptoms in lower gastrointestinal disease.\n\nThe Committee considered the impact of this guidance on groups of people with characteristics protected by UK equality legislation. During scoping, it was noted that IBS is most common in people in the 20–40\xa0years age range, and is twice as common in women as men. Additionally, IBD is more common in white people than in African‑Caribbean people or those of Asian origin. The condition is most prevalent among Jewish people of European origin. The Committee considered that the guidance did not present any restrictions in access to diagnosis or treatment in the above groups.", 'Recommendations for further research': "Further research is needed on the use and clinical utility of faecal calprotectin testing, and support pathways for the long‑term management of these conditions in the community should be developed.\n\nFurther research is needed on the impact of faecal calprotectin testing on clinical decision‑making when added to current practice. This includes research into optimal cut‑off values for tests and the investigation of repeat testing strategies in people with intermediate levels of faecal calprotectin. Development of a consistent definition for the 'intermediate range' is encouraged.\n\nRobust evidence is needed on the comparative performance of different faecal calprotectin tests, including the performance of POCTs compared with laboratory-based tests.", 'Related NICE guidance': "Ulcerative colitis: management in adults, children and young people. NICE clinical guideline\xa0166 (2013).\n\nCrohn's disease: management in adults, children and young people. NICE clinical guideline\xa0152 (2012).\n\nColonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn's disease or adenomas. NICE clinical guideline\xa0118 (2011).\n\nInfliximab (review) and adalimumab for the treatment of Crohn's disease. NICE technology appraisal\xa0187 (2010).\n\nIrritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care. NICE clinical guideline\xa061 (2008).\n\nInfliximab for acute exacerbations of ulcerative colitis. NICE technology appraisal\xa0163 (2008).\n\nInfliximab for subacute manifestations of ulcerative colitis. NICE technology appraisal\xa0140 (2008).", 'Review': 'NICE updates the literature search at least every 3\xa0years to ensure that relevant new evidence is identified. NICE will contact product sponsors and other stakeholders about issues that may affect the value of the diagnostic technologies. NICE may review and update diagnostics guidance at any time if significant new evidence becomes available.\n\nAndrew DillonChief ExecutiveOctober 2013'}	https://www.nice.org.uk/guidance/dg11	Evidence-based recommendations on faecal calprotectin tests for distinguishing between inflammatory bowel diseases (such as Crohn’s disease and ulcerative colitis) and non-inflammatory bowel diseases (such as irritable bowel syndrome).
5a7fa901f67786d210129f2c80154006502ddfc3	nice	Photochemical corneal collagen cross‑linkage using riboflavin and ultraviolet A for keratoconus and keratectasia	Photochemical corneal collagen cross‑linkage using riboflavin and ultraviolet A for keratoconus and keratectasia # Recommendations This document replaces previous guidance on photochemical corneal collagen cross‑linkage using riboflavin and ultraviolet A for keratoconus (interventional procedure guidance 320). Most of the published evidence on photochemical corneal collagen cross‑linkage (CXL) using riboflavin and ultraviolet A (UVA) for keratoconus and keratectasia relates to the technique known as 'epithelium‑off' CXL'. 'Epithelium‑on (transepithelial) CXL' is a more recent technique and less evidence is available on its safety and efficacy. Either procedure (epithelium‑off or epithelium‑on CXL) can be combined with other interventions, and the evidence base for these combination procedures (known as 'CXL‑plus') is also limited. Therefore, different recommendations apply to the variants of this procedure, as follows. Current evidence on the safety and efficacy of epithelium‑off CXL for keratoconus and keratectasia is adequate in quality and quantity. Therefore, this procedure can be used provided that normal arrangements are in place for clinical governance, consent and audit. Current evidence on the safety and efficacy of epithelium‑on (transepithelial) CXL, and the combination (CXL‑plus) procedures for keratoconus and keratectasia is inadequate in quantity and quality. Therefore, these procedures should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake epithelium‑on (transepithelial) CXL, or the combination (CXL‑plus) procedures should take the following actions: Inform the clinical governance leads in their NHS trusts. Ensure that patients and their parents or carers understand the uncertainty about the efficacy and safety of the procedures in the long term and provide them with clear information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having these procedures for keratoconus and keratectasia. Patient selection for these procedures should include assessment of corneal thickness and consideration of the likelihood of disease progression. The procedures should only be carried out by ophthalmologists with expertise in managing corneal disease and specific training in the use of ultraviolet light or by appropriately trained staff under their supervision. NICE encourages further research into CXL using riboflavin and UVA for keratoconus and keratectasia, especially epithelium‑on (transepithelial) CXL and the combination (CXL‑plus) procedures. Details of the techniques used should be clearly described. Reported outcomes should include visual acuity, corneal topography and quality of life. Data on long-term outcomes for all types of CXL using riboflavin and UVA for keratoconus and keratectasia would be useful – specifically data about prevention of progression to corneal transplantation and about repeat procedures and their efficacy.# Indications and current treatments Keratoconus is a degeneration of the structure of the cornea in which the corneal surface thins and begins to bulge into a cone shape. This causes refractive error, which is usually a myopic shift and is often associated with astigmatism, leading to visual impairment. It commonly affects children and young adults and may be progressive. Iatrogenic keratoconus (for example, as a result of laser-assisted in situ keratomileusis surgery) is called keratectasia. In mild to moderate keratoconus, visual acuity can be corrected using spectacles, contact lenses and in some cases intracorneal ring segment (ICRS) implantation. Keratectasia can be managed by using contact lenses or ICRS implantation. In advanced disease corneal surgery, including deep lamellar keratoplasty or penetrating keratoplasty, may be needed.# The procedures The CXL procedures are normally done as outpatient procedures using topical anaesthesia, and typically take 60–90 minutes. In epithelium‑off CXL, the epithelium is first abraded with a blunt spatula to allow penetration of riboflavin into the corneal tissue. Riboflavin eye drops are applied to the corneal surface before the procedure and intermittently during the procedure. The corneal surface is exposed to UVA radiation: precise timings and treatment protocols vary. Postoperatively, topical antibiotics and anti-inflammatory drops are normally prescribed, with topical steroids if necessary. In some cases, a bandage contact lens may also be used for a few days. The procedure is done on 1 eye at a time and may also be repeated if needed. In epithelium‑on (transepithelial) CXL, the corneal epithelial surface is left intact (or may be partially disrupted) and a longer riboflavin loading time is needed. Sometimes the procedure is used in combination with other interventions such as ICRS implantation, photorefractive keratectomy (PRK) or phakic intraocular lens (PIOL) implantation to improve visual acuity. These combination procedures are referred to as 'CXL‑plus'. The mechanism of action of the CXL procedures is not fully understood: they may increase the number of 'anchors' that bond collagen fibres together and strengthen the cornea. This is expected to stop the progression of the disease but the duration of benefit is uncertain.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about these procedures. For more detailed information on the evidence, see the systematic review and the addendum to the systematic review. A systematic review of the published evidence on these procedures was commissioned by NICE. # Epithelium‑off CXL In the studies included in the systematic review for epithelium‑off CXL, meta‑analysis of the change between preoperative and postoperative data for topography reported significant improvements in maximum keratometric values (max K) at 6, 12 and 24 months (−0.8 dioptres at 6 months and −1.0 D at 12 and 24 months), and mean and minimum keratometric values (mean K and min K) at 12 months only (−1.0 D and −0.7 D for mean K and min K respectively). Meta‑analysis results for visual acuity reported significant improvement in corrected visual acuity (CVA) (−0.20 LogMAR) but not uncorrected visual acuity (UCVA) between intervention and control eyes on the LogMAR scale at 12 months follow‑up. Meta‑analysis of the change between preoperative and postoperative data showed significant improvements in UCVA postoperatively at 6, 12 and 24 months. Improvements on the LogMAR scale were in the order of −0.15 for UCVA and −0.10 for CVA at various time points. Meta‑analysis results for astigmatism reported no significant differences between the treatment and control groups at 12 months (–1.42 D). Differences between preoperative and postoperative data showed significant improvements at 6, 12 and 24 months (−0.4 D at 6 months, −0.7 D at 12 months and −0.5 D at 24 months). Change in spherical equivalence (SE) was only significant at 12 months (there was a reduction of between 0.3 and 0.5 D). Meta‑analysis of the change between preoperative and postoperative data showed a significant decrease (−14.4 micrometres) in central corneal thickness and no significant difference in intraocular pressure at 12 months follow-up. # Epithelium‑off CXL in combination with other interventions (CXL‑plus) A randomised controlled trial in 48 eyes with progressive keratoconus (43 patients) compared 2 sequences of combined CXL and intracorneal ring segment (ICRS) implantation with a mean interval between treatments of 7 months. Group 1 had epithelium‑off CXL followed by ICRS implantation and group 2 were treated by ICRS implantation followed by epithelium‑off CXL. The mean UCVA and corrected distance visual acuity (CDVA) had improved significantly in both groups 6 months after the procedures (each group gained 1 Snellen line in UCVA, and group 1 gained 1 line in CDVA but group 2 gained only half a line). The same study reported statistically significant improvements in the mean SE, cylinder and mean K values in both groups but there was more improvement in CDVA, SE (2.76 D versus 0.93 D), and mean K (3.3 D versus 1.1 D) in group 2 than in group 1. A randomised comparative case series of 42 eyes (21 patients) with bilateral keratoconus and 50 micrometres of epithelium removed by photorefractive keratectomy (PRK) compared 2 levels of exposure to UVA (both eyes were treated with CXL). In both groups mean uncorrected distance visual acuity improved, from 20/60 to 20/38 and from 20/62 to 20/40 Snellen lines respectively; CVA improved from 20/30 to 20/25 Snellen lines; mean SE was reduced by 2.5 D and 2.1 D; mean refractive cylinder was reduced by 2.9 D and 2.5 D; max K was reduced by 3.4 D and 2.9 D at 24 months. A case series of 11 eyes (11 patients with progressive keratoconus) treated with CXL 6 months before phakic intraocular lens (PIOL) implantation and followed up 6 months after the PIOL implantation reported statistically significant improvement in mean UCVA (by 0.24 LogMAR 6 months after CXL, and by 1.24 LogMAR 6 months after PIOL) and CVA (by 0.02 LogMAR and 0.1 LogMAR at the 2 time points), reduction in mean K values (by 1.26 D and 2.14 D at the 2 time points), SE (by 0.45 D and 5.43 D at the 2 time points) and cylinder values (by 0.16 D and 0.55 D at the 2 time points). # Epithelium-on (transepithelial) CXL with or without additional interventions (CXL‑plus) A comparative case series of 51 eyes (51 patients with progressive keratoconus) treated with epithelium‑on (transepithelial) CXL reported improvements in mean CDVA (by 0.036 LogMAR for CXL versus 0.039 LogMAR for control, p0.05) and SE (0.35 D after CXL versus 0.83 D for control, p<0.05) at 12 months follow-up. A case series of 14 eyes (10 patients with mild to moderate keratoconus) treated with epithelium‑on (transepithelial) CXL and combined same-day corneal implants reported improvements in mean best corrected visual acuity (BCVA) (from 0.24 LogMAR to 0.16 LogMAR, p=0.34), and mean K values (45.83 D to 44.03 D, p=0.0023) at 3 years follow‑up. A case series of 21 eyes (13 patients) treated with ICRS implantation followed by CXL after a mean of 4 months reported improvements in mean UCVA and BCVA 6 months after CXL (UCVA from 0.05 to 0.23 LogMAR, p=0.951; BCVA from 0.18 to 0.41 LogMAR, p=0.08). The study also reported reductions in SE and cylindrical and mean keratometric values after ICRS implantation (2.8 D, p<0.05; 2.1 D, p<0.05; and 2.5 D, p<0.05 respectively) which were maintained 6 months after CXL. The specialist advisers listed efficacy outcomes as arrest of progression of keratoconus and stabilisation of the corneal shape measured by topography, refraction and keratometry, refractive astigmatism, change in corneal thickness, cone apex power, quality of life and contact lens independence.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about these procedures. This safety evidence is not subdivided by procedure variant because similar adverse events were reported for each. For more detailed information on the evidence, see the systematic review and the addendum to the systematic review. Infections were reported in 8 single case reports. In 4 of these patients there was no major long-term adverse impact, visual acuity was reduced in 1 patient and no further details were reported in 3 patients. Sterile keratitis associated with scarring or loss of vision or needing keratoplasty was reported in 3% (4/117) of patients in a case series of 117 patients. This was treated with high-dose topical or subconjunctival corticosteroids and 2 patients had a persistent decrease in BCVA. Deep stromal infiltrates with scarring at 2 months despite treatment with antibiotics was reported in a single case report. Stromal scar developed in 4 patients (3 cases in 1 study); in 3 patients, the UCVA increased significantly despite scars, and in the other patient visual acuity was corrected with a lens. Corneal oedema within 24 hours after CXL and inflammation for 2–3 weeks, iris atrophy and pigment dispersion were reported in a case series of 10 patients. These resolved in 1 patient and improved in 4 patients after treatment. Corneal oedema that developed in a single case report resolved after 6 months' treatment but scarring and poor visual acuity remained. Corneal melting was reported in 1 single case report. This patient was initially treated with tissue glue and bandage contact lens application but needed penetrating keratoplasty on day 12. Perforation due to corneal melting was reported in 2 single case reports. These patients were treated by penetrating keratoplasty and antibiotics with no long-term adverse impact. Corneal burn and ulcer were reported in 3 single case reports; 1 patient was treated by phototherapeutic keratectomy (CVA improved from 20/69 to 20/20 at 28 months) and treatment details were not reported for the other 2 patients. Corneal haze with diffuse subepithelial opacification and paracentral corneal thinning associated with scarring was reported in a single case report. This disappeared only gradually despite intensive therapy. Stromal haze was reported in all eyes in a randomised controlled trial of 10 patients comparing same-day ICRS and CXL with ICRS and CXL 6 months later. This resolved eventually in both groups (the time period was not reported). Mild posterior linear stromal haze at 1 month after CXL with PRK was reported in 46% of eyes (13/28) in a case series of 28 eyes (23 patients). At 12 months follow-up, this had decreased in density but had not completely disappeared. The specialist advisers listed anecdotal adverse events as delayed epithelial healing, bilateral corneal infection and transient recurrent erosion syndrome. In addition, a specialist provided information about a single occurrence of corneal perforation after the procedure.# Further information This guidance requires that clinicians undertaking the epithelium‑on (transepithelial) CXL and combination (CXL‑plus) procedures make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). # Information for patients NICE has produced information on these procedures for patients and carers (Information for the public). It explains the nature of the procedures and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. It updates and replaces NICE interventional procedure guidance 320. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0288-0	{'Recommendations': "This document replaces previous guidance on photochemical corneal collagen cross‑linkage using riboflavin and ultraviolet A for keratoconus (interventional procedure guidance\xa0320).\n\nMost of the published evidence on photochemical corneal collagen cross‑linkage (CXL) using riboflavin and ultraviolet\xa0A (UVA) for keratoconus and keratectasia relates to the technique known as 'epithelium‑off' CXL'. 'Epithelium‑on (transepithelial) CXL' is a more recent technique and less evidence is available on its safety and efficacy. Either procedure (epithelium‑off or epithelium‑on CXL) can be combined with other interventions, and the evidence base for these combination procedures (known as 'CXL‑plus') is also limited. Therefore, different recommendations apply to the variants of this procedure, as follows.\n\nCurrent evidence on the safety and efficacy of epithelium‑off CXL for keratoconus and keratectasia is adequate in quality and quantity. Therefore, this procedure can be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nCurrent evidence on the safety and efficacy of epithelium‑on (transepithelial) CXL, and the combination (CXL‑plus) procedures for keratoconus and keratectasia is inadequate in quantity and quality. Therefore, these procedures should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake epithelium‑on (transepithelial) CXL, or the combination (CXL‑plus) procedures should take the following actions:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients and their parents or carers understand the uncertainty about the efficacy and safety of the procedures in the long term and provide them with clear information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having these procedures for keratoconus and keratectasia.\n\nPatient selection for these procedures should include assessment of corneal thickness and consideration of the likelihood of disease progression.\n\nThe procedures should only be carried out by ophthalmologists with expertise in managing corneal disease and specific training in the use of ultraviolet light or by appropriately trained staff under their supervision.\n\nNICE encourages further research into CXL using riboflavin and UVA for keratoconus and keratectasia, especially epithelium‑on (transepithelial) CXL and the combination (CXL‑plus) procedures. Details of the techniques used should be clearly described. Reported outcomes should include visual acuity, corneal topography and quality of life. Data on long-term outcomes for all types of CXL using riboflavin and UVA for keratoconus and keratectasia would be useful – specifically data about prevention of progression to corneal transplantation and about repeat procedures and their efficacy.", 'Indications and current treatments': 'Keratoconus is a degeneration of the structure of the cornea in which the corneal surface thins and begins to bulge into a cone shape. This causes refractive error, which is usually a myopic shift and is often associated with astigmatism, leading to visual impairment. It commonly affects children and young adults and may be progressive. Iatrogenic keratoconus (for example, as a result of laser-assisted in situ keratomileusis [LASIK] surgery) is called keratectasia.\n\nIn mild to moderate keratoconus, visual acuity can be corrected using spectacles, contact lenses and in some cases intracorneal ring segment (ICRS) implantation. Keratectasia can be managed by using contact lenses or ICRS implantation. In advanced disease corneal surgery, including deep lamellar keratoplasty or penetrating keratoplasty, may be needed.', 'The procedures': "The CXL procedures are normally done as outpatient procedures using topical anaesthesia, and typically take 60–90\xa0minutes.\n\nIn epithelium‑off CXL, the epithelium is first abraded with a blunt spatula to allow penetration of riboflavin into the corneal tissue. Riboflavin eye drops are applied to the corneal surface before the procedure and intermittently during the procedure. The corneal surface is exposed to UVA radiation: precise timings and treatment protocols vary. Postoperatively, topical antibiotics and anti-inflammatory drops are normally prescribed, with topical steroids if necessary. In some cases, a bandage contact lens may also be used for a few days. The procedure is done on 1\xa0eye at a time and may also be repeated if needed.\n\nIn epithelium‑on (transepithelial) CXL, the corneal epithelial surface is left intact (or may be partially disrupted) and a longer riboflavin loading time is needed.\n\nSometimes the procedure is used in combination with other interventions such as ICRS implantation, photorefractive keratectomy (PRK) or phakic intraocular lens (PIOL) implantation to improve visual acuity. These combination procedures are referred to as 'CXL‑plus'.\n\nThe mechanism of action of the CXL procedures is not fully understood: they may increase the number of 'anchors' that bond collagen fibres together and strengthen the cornea. This is expected to stop the progression of the disease but the duration of benefit is uncertain.", 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about these procedures. For more detailed information on the evidence, see the systematic review and the addendum to the systematic review.\n\nA systematic review of the published evidence on these procedures was commissioned by NICE.\n\n# Epithelium‑off CXL\n\nIn the studies included in the systematic review for epithelium‑off CXL, meta‑analysis of the change between preoperative and postoperative data for topography reported significant improvements in maximum keratometric values (max\xa0K) at\xa06, 12\xa0and 24\xa0months (−0.8\xa0dioptres [D] at 6\xa0months and −1.0\xa0D at 12\xa0and 24\xa0months), and mean and minimum keratometric values (mean\xa0K and min\xa0K) at 12\xa0months only (−1.0\xa0D and −0.7\xa0D for mean\xa0K and min\xa0K respectively).\n\nMeta‑analysis results for visual acuity reported significant improvement in corrected visual acuity (CVA) (−0.20\xa0LogMAR) but not uncorrected visual acuity (UCVA) between intervention and control eyes on the LogMAR scale at 12\xa0months follow‑up. Meta‑analysis of the change between preoperative and postoperative data showed significant improvements in UCVA postoperatively at\xa06, 12\xa0and 24\xa0months. Improvements on the LogMAR scale were in the order of −0.15\xa0for UCVA and −0.10\xa0for CVA at various time points.\n\nMeta‑analysis results for astigmatism reported no significant differences between the treatment and control groups at 12\xa0months (–1.42\xa0D). Differences between preoperative and postoperative data showed significant improvements at\xa06, 12\xa0and 24\xa0months (−0.4\xa0D at 6\xa0months, −0.7\xa0D at 12\xa0months and −0.5\xa0D at 24\xa0months). Change in spherical equivalence (SE) was only significant at 12\xa0months (there was a reduction of between 0.3\xa0and 0.5\xa0D).\n\nMeta‑analysis of the change between preoperative and postoperative data showed a significant decrease (−14.4\xa0micrometres) in central corneal thickness and no significant difference in intraocular pressure at 12\xa0months follow-up.\n\n# Epithelium‑off CXL in combination with other interventions (CXL‑plus)\n\nA randomised controlled trial in 48\xa0eyes with progressive keratoconus (43\xa0patients) compared 2\xa0sequences of combined CXL and intracorneal ring segment (ICRS) implantation with a mean interval between treatments of 7\xa0months. Group\xa01 had epithelium‑off CXL followed by ICRS implantation and group\xa02 were treated by ICRS implantation followed by epithelium‑off CXL. The mean UCVA and corrected distance visual acuity (CDVA) had improved significantly in both groups 6\xa0months after the procedures (each group gained 1\xa0Snellen line in UCVA, and group\xa01 gained 1\xa0line in CDVA but group\xa02 gained only half a line). The same study reported statistically significant improvements in the mean SE, cylinder and mean\xa0K values in both groups but there was more improvement in CDVA, SE (2.76\xa0D versus 0.93\xa0D), and mean\xa0K (3.3\xa0D versus 1.1\xa0D) in group\xa02 than in group\xa01.\n\nA randomised comparative case series of 42\xa0eyes (21\xa0patients) with bilateral keratoconus and 50\xa0micrometres of epithelium removed by photorefractive keratectomy (PRK) compared 2\xa0levels of exposure to UVA (both eyes were treated with CXL). In both groups mean uncorrected distance visual acuity improved, from 20/60 to 20/38 and from 20/62 to 20/40 Snellen lines respectively; CVA improved from 20/30 to 20/25 Snellen lines; mean SE was reduced by 2.5\xa0D and 2.1\xa0D; mean refractive cylinder was reduced by 2.9\xa0D and 2.5\xa0D; max\xa0K was reduced by 3.4\xa0D and 2.9\xa0D at 24\xa0months.\n\nA case series of 11\xa0eyes (11\xa0patients with progressive keratoconus) treated with CXL 6\xa0months before phakic intraocular lens (PIOL) implantation and followed up 6\xa0months after the PIOL implantation reported statistically significant improvement in mean UCVA (by 0.24\xa0LogMAR 6\xa0months after CXL, and by 1.24\xa0LogMAR 6\xa0months after PIOL) and CVA (by 0.02\xa0LogMAR and 0.1\xa0LogMAR at the 2\xa0time points), reduction in mean\xa0K values (by 1.26\xa0D and 2.14\xa0D at the 2\xa0time points), SE (by 0.45\xa0D and 5.43\xa0D at the 2\xa0time points) and cylinder values (by 0.16\xa0D and 0.55\xa0D at the 2\xa0time points).\n\n# Epithelium-on (transepithelial) CXL with or without additional interventions (CXL‑plus)\n\nA comparative case series of 51\xa0eyes (51\xa0patients with progressive keratoconus) treated with epithelium‑on (transepithelial) CXL reported improvements in mean CDVA (by 0.036\xa0LogMAR for CXL versus 0.039\xa0LogMAR for control, p<0.05), and reduction in mean\xa0K values (by 0.51\xa0D after CXL versus 1.61\xa0D for control, p>0.05) and SE (0.35\xa0D after CXL versus 0.83\xa0D for control, p<0.05) at 12\xa0months follow-up.\n\nA case series of 14\xa0eyes (10\xa0patients with mild to moderate keratoconus) treated with epithelium‑on (transepithelial) CXL and combined same-day corneal implants reported improvements in mean best corrected visual acuity (BCVA) (from 0.24\xa0LogMAR to 0.16\xa0LogMAR, p=0.34), and mean\xa0K values (45.83\xa0D to 44.03\xa0D, p=0.0023) at 3\xa0years follow‑up.\n\nA case series of 21\xa0eyes (13\xa0patients) treated with ICRS implantation followed by CXL after a mean of 4\xa0months reported improvements in mean UCVA and BCVA 6\xa0months after CXL (UCVA from 0.05 to 0.23\xa0LogMAR, p=0.951; BCVA from 0.18 to 0.41\xa0LogMAR, p=0.08). The study also reported reductions in SE and cylindrical and mean keratometric values after ICRS implantation (2.8\xa0D, p<0.05; 2.1\xa0D, p<0.05; and 2.5\xa0D, p<0.05 respectively) which were maintained 6\xa0months after CXL.\n\nThe specialist advisers listed efficacy outcomes as arrest of progression of keratoconus and stabilisation of the corneal shape measured by topography, refraction and keratometry, refractive astigmatism, change in corneal thickness, cone apex power, quality of life and contact lens independence.', 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about these procedures. This safety evidence is not subdivided by procedure variant because similar adverse events were reported for each. For more detailed information on the evidence, see the systematic review and the addendum to the systematic review.\n\nInfections were reported in 8\xa0single case reports. In 4\xa0of these patients there was no major long-term adverse impact, visual acuity was reduced in 1\xa0patient and no further details were reported in 3\xa0patients.\n\nSterile keratitis associated with scarring or loss of vision or needing keratoplasty was reported in 3% (4/117) of patients in a case series of 117\xa0patients. This was treated with high-dose topical or subconjunctival corticosteroids and 2\xa0patients had a persistent decrease in BCVA. Deep stromal infiltrates with scarring at 2\xa0months despite treatment with antibiotics was reported in a single case report.\n\nStromal scar developed in 4\xa0patients (3\xa0cases in 1\xa0study); in 3\xa0patients, the UCVA increased significantly despite scars, and in the other patient visual acuity was corrected with a lens.\n\nCorneal oedema within 24\xa0hours after CXL and inflammation for 2–3\xa0weeks, iris atrophy and pigment dispersion were reported in a case series of 10\xa0patients. These resolved in 1\xa0patient and improved in 4\xa0patients after treatment. Corneal oedema that developed in a single case report resolved after 6\xa0months' treatment but scarring and poor visual acuity remained.\n\nCorneal melting was reported in 1\xa0single case report. This patient was initially treated with tissue glue and bandage contact lens application but needed penetrating keratoplasty on day\xa012. Perforation due to corneal melting was reported in 2\xa0single case reports. These patients were treated by penetrating keratoplasty and antibiotics with no long-term adverse impact.\n\nCorneal burn and ulcer were reported in 3\xa0single case reports; 1\xa0patient was treated by phototherapeutic keratectomy (CVA improved from 20/69 to 20/20 at 28\xa0months) and treatment details were not reported for the other 2\xa0patients.\n\nCorneal haze with diffuse subepithelial opacification and paracentral corneal thinning associated with scarring was reported in a single case report. This disappeared only gradually despite intensive therapy.\n\nStromal haze was reported in all eyes in a randomised controlled trial of 10\xa0patients comparing same-day ICRS and CXL with ICRS and CXL 6\xa0months later. This resolved eventually in both groups (the time period was not reported). Mild posterior linear stromal haze at 1\xa0month after CXL with PRK was reported in 46% of eyes (13/28) in a case series of 28\xa0eyes (23\xa0patients). At 12\xa0months follow-up, this had decreased in density but had not completely disappeared.\n\nThe specialist advisers listed anecdotal adverse events as delayed epithelial healing, bilateral corneal infection and transient recurrent erosion syndrome. In addition, a specialist provided information about a single occurrence of corneal perforation after the procedure.", 'Further information': 'This guidance requires that clinicians undertaking the epithelium‑on (transepithelial) CXL and combination (CXL‑plus) procedures make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\n# Information for patients\n\nNICE has produced information on these procedures for patients and carers (Information for the public). It explains the nature of the procedures and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance\xa0320.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0288-0'}	https://www.nice.org.uk/guidance/ipg466
8a1bf7a36f9088bd81223f1dc28d5117453216f1	nice	Endoscopic radiofrequency ablation for gastro-oesophageal reflux disease	Endoscopic radiofrequency ablation for gastro-oesophageal reflux disease # Recommendations This document replaces previous guidance on endoscopic radiofrequency ablation for gastro-oesophageal reflux disease (interventional procedure guidance 292). The evidence on the safety of endoscopic radiofrequency ablation for gastro-oesophageal reflux disease (GORD) is adequate in the short and medium term but there is uncertainty about longer‑term outcomes. With regard to efficacy, there is evidence of symptomatic relief but objective evidence on reduction of reflux is inconclusive. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake endoscopic radiofrequency ablation for GORD should take the following actions. Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having endoscopic radiofrequency ablation for GORD (see section 7.1). Future review of the guidance might consider evidence from research that includes objective outcome measures such as oesophageal pH, long‑term follow‑up data, comparison with Nissen fundoplication, information about patient selection and further insight into the mechanism of action of the procedure.# Indications and current treatments Gastro-oesophageal reflux disease is a common problem caused by disturbance of sphincter function at the lower end of the oesophagus. Symptoms include heartburn, regurgitation, chest pain, nausea, respiratory difficulties and dysphagia. If untreated, complications such as Barrett's oesophagus or oesophageal stricture can develop. Lifestyle modification and gastric acidity‑lowering medication can help to improve symptoms. Patients who have refractory symptoms, who develop complications despite medication or who develop intolerance to medication may be considered for anti‑reflux surgery. Most commonly this is laparoscopic fundoplication but alternative endoscopic techniques have also been used.# The procedure The aim of endoscopic radiofrequency ablation for gastro-oesophageal reflux disease is to reduce symptoms. The mechanism of action is unclear. The procedure is usually performed with the patient under sedation. The distance to the gastro-oesophageal junction is measured endoscopically and a guidewire with a flexible tip is passed through the endoscope and left in the stomach; the endoscope is removed. A specially designed radiofrequency balloon catheter, consisting of an inflatable balloon-basket with 4 electrode needle sheaths, is inserted through the mouth over the guidewire and advanced to the gastro-oesophageal junction. The balloon is inflated to the diameter of the oesophagus and the electrodes are deployed to penetrate through the mucosa and deliver radiofrequency energy to the musculature of the lower oesophageal sphincter and the gastric cardia. Several cycles of approximately 1 minute of radiofrequency energy are delivered. These cause changes in the tissues of the lower oesophagus, but the precise mechanism of action of radiofrequency energy on the oesophagogastric junction remains a subject of debate (see section 6.1).# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. A systematic review of 20 studies including 1441 patients reported oesophageal acid exposure from 11 studies (364 patients). The mean percentage of time that the pH was less than 4 decreased from 10% at baseline to 7% (p=0.0003) at mean 12‑month follow‑up. A crossover randomised controlled trial (RCT) of 22 patients comparing endoscopic radiofrequency ablation against sham reported that there were no significant changes in oesophageal acid exposure at 3‑ or 6‑month follow‑up. An RCT of 43 patients reported abnormal oesophageal acid exposure in 94% (17/18) of patients treated by radiofrequency ablation and in 75% (9/12) of patients treated with proton pump inhibitors (PPIs) alone at 6‑month follow‑up (p=0.27). A non-randomised comparative study of 126 patients treated by radiofrequency ablation or endoluminal full-thickness plication reported that the percentage of time the pH was less than 4 reduced from 11% at baseline to 9% at mean 5‑month follow‑up (not significant) and from 10% at baseline to 6% at mean 8‑month follow-up (p=0.05), respectively. The RCT of 43 patients reported oesophagitis (diagnosed by endoscopy) in 53% (10/19) of patients treated by radiofrequency ablation and 54% (7/13) of patients treated with PPIs alone at 6‑month follow‑up (p=0.97). The systematic review of 20 studies including 1441 patients reported the mean gastro-oesophageal reflux disease health-related quality of life score in 9 studies (433 patients), which improved from 26.1 at baseline to 9.3 after treatment (p=0.0001, mean follow‑up 20 months). In the same review, 6 studies with 299 patients reported that the mean SF‑36 (physical) score improved from 36 to 46 points at mean 10‑month follow‑up (p=0.0001). Five studies (264 patients) reported that the mean SF‑36 (mental) score improved from 47 to 55 at mean 10‑month follow‑up (p=0.0015). The systematic review of 20 studies reported a pooled heartburn score from 9 studies (525 patients) of 3.6 at baseline and 1.2 at mean 24‑month follow‑up (p=0.0001; lower scores indicate less severe symptoms). The crossover RCT of 22 patients comparing radiofrequency ablation against sham reported a significant improvement in symptom score at 3 months compared with baseline in the active treatment group (from 14.7 to 8.3; p<0.005) but not in the sham group (from 16.1 to 15.6; not significant). When patients in the sham group were subsequently treated by radiofrequency ablation, the symptom score significantly improved to 7.2 (p<0.05) at 3‑month follow‑up. The RCT of 43 patients treated by endoscopic radiofrequency ablation or PPIs alone reported symptoms fewer than 3 times a week in 80% (16/20) and 40% (6/15) of patients respectively at 6‑month follow‑up (p=0.01). At 12‑month follow‑up, 69% (11/20) of patients in the radiofrequency ablation group had symptoms fewer than 3 times a week compared with 62% (8/14) of patients in the control group (p=0.71). There were no statistically significant differences in the individual symptom scores. The crossover RCT of 22 patients reported no significant change in medication use from baseline in either group at 6‑month follow‑up. The RCT of 43 patients reported that 13% (3/23) and 17% (4/23) of patients in the radiofrequency ablation group at 6 and 12 months respectively were able to stop PPIs completely compared with none of the control patients. The specialist advisers listed key efficacy outcomes as long‑term objective evidence (pH studies), long‑term symptomatic control, quality of life and decreasing or stopping PPIs.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. One case series reported 3 deaths and 22 complications overall (not otherwise defined) in patients treated by radiofrequency ablation for gastro-oesophageal reflux disease (number of procedures to which these events relate not known). Mucosal bleeding was reported in 3% (3/90) of patients in a case series of 90 patients. Superficial mucosal injury was reported in 2% (2/90) of patients in the same study. All these complications resolved within 1 week of the procedure. Prolonged gastroparesis was reported in 1 patient in a case series of 56 patients: this resolved within 8 weeks. The specialist advisers stated that oesophageal perforation is an adverse event which, although rare, is generally acknowledged. The specialist advisers advised of a theoretical risk of developing oesophageal cancer which they considered might be a consequence of long-term unrecognised reflux.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. It updates and replaces NICE interventional procedure guidance 292. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes after publication August 2013: Minor maintenance Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0250-7	{'Recommendations': "This document replaces previous guidance on endoscopic radiofrequency ablation for gastro-oesophageal reflux disease (interventional procedure guidance 292).\n\nThe evidence on the safety of endoscopic radiofrequency ablation for gastro-oesophageal reflux disease (GORD) is adequate in the short and medium term but there is uncertainty about longer‑term outcomes. With regard to efficacy, there is evidence of symptomatic relief but objective evidence on reduction of reflux is inconclusive. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake endoscopic radiofrequency ablation for GORD should take the following actions.\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having endoscopic radiofrequency ablation for GORD (see section 7.1).\n\nFuture review of the guidance might consider evidence from research that includes objective outcome measures such as oesophageal pH, long‑term follow‑up data, comparison with Nissen fundoplication, information about patient selection and further insight into the mechanism of action of the procedure.", 'Indications and current treatments': "Gastro-oesophageal reflux disease is a common problem caused by disturbance of sphincter function at the lower end of the oesophagus. Symptoms include heartburn, regurgitation, chest pain, nausea, respiratory difficulties and dysphagia. If untreated, complications such as Barrett's oesophagus or oesophageal stricture can develop.\n\nLifestyle modification and gastric acidity‑lowering medication can help to improve symptoms. Patients who have refractory symptoms, who develop complications despite medication or who develop intolerance to medication may be considered for anti‑reflux surgery. Most commonly this is laparoscopic fundoplication but alternative endoscopic techniques have also been used.", 'The procedure': 'The aim of endoscopic radiofrequency ablation for gastro-oesophageal reflux disease is to reduce symptoms. The mechanism of action is unclear.\n\nThe procedure is usually performed with the patient under sedation. The distance to the gastro-oesophageal junction is measured endoscopically and a guidewire with a flexible tip is passed through the endoscope and left in the stomach; the endoscope is removed. A specially designed radiofrequency balloon catheter, consisting of an inflatable balloon-basket with 4\xa0electrode needle sheaths, is inserted through the mouth over the guidewire and advanced to the gastro-oesophageal junction. The balloon is inflated to the diameter of the oesophagus and the electrodes are deployed to penetrate through the mucosa and deliver radiofrequency energy to the musculature of the lower oesophageal sphincter and the gastric cardia. Several cycles of approximately 1\xa0minute of radiofrequency energy are delivered. These cause changes in the tissues of the lower oesophagus, but the precise mechanism of action of radiofrequency energy on the oesophagogastric junction remains a subject of debate (see section 6.1).', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nA systematic review of 20\xa0studies including 1441\xa0patients reported oesophageal acid exposure from 11\xa0studies (364\xa0patients). The mean percentage of time that the pH was less than 4 decreased from 10% at baseline to 7% (p=0.0003) at mean 12‑month follow‑up. A crossover randomised controlled trial (RCT) of 22\xa0patients comparing endoscopic radiofrequency ablation against sham reported that there were no significant changes in oesophageal acid exposure at 3‑ or 6‑month follow‑up. An RCT of 43\xa0patients reported abnormal oesophageal acid exposure in 94% (17/18) of patients treated by radiofrequency ablation and in 75% (9/12) of patients treated with proton pump inhibitors (PPIs) alone at 6‑month follow‑up (p=0.27).\n\nA non-randomised comparative study of 126\xa0patients treated by radiofrequency ablation or endoluminal full-thickness plication reported that the percentage of time the pH was less than 4 reduced from 11% at baseline to 9% at mean 5‑month follow‑up (not significant) and from 10% at baseline to 6% at mean 8‑month follow-up (p=0.05), respectively.\n\nThe RCT of 43\xa0patients reported oesophagitis (diagnosed by endoscopy) in 53% (10/19) of patients treated by radiofrequency ablation and 54% (7/13) of patients treated with PPIs alone at 6‑month follow‑up (p=0.97).\n\nThe systematic review of 20\xa0studies including 1441\xa0patients reported the mean gastro-oesophageal reflux disease health-related quality of life score in 9\xa0studies (433\xa0patients), which improved from 26.1 at baseline to 9.3 after treatment (p=0.0001, mean follow‑up 20\xa0months). In the same review, 6\xa0studies with 299\xa0patients reported that the mean SF‑36 (physical) score improved from 36 to 46\xa0points at mean 10‑month follow‑up (p=0.0001). Five studies (264\xa0patients) reported that the mean SF‑36 (mental) score improved from 47 to 55 at mean 10‑month follow‑up (p=0.0015).\n\nThe systematic review of 20\xa0studies reported a pooled heartburn score from 9\xa0studies (525\xa0patients) of 3.6 at baseline and 1.2 at mean 24‑month follow‑up (p=0.0001; lower scores indicate less severe symptoms). The crossover RCT of 22\xa0patients comparing radiofrequency ablation against sham reported a significant improvement in symptom score at 3\xa0months compared with baseline in the active treatment group (from 14.7 to 8.3; p<0.005) but not in the sham group (from 16.1 to 15.6; not significant). When patients in the sham group were subsequently treated by radiofrequency ablation, the symptom score significantly improved to 7.2 (p<0.05) at 3‑month follow‑up. The RCT of 43\xa0patients treated by endoscopic radiofrequency ablation or PPIs alone reported symptoms fewer than 3\xa0times a week in 80% (16/20) and 40% (6/15) of patients respectively at 6‑month follow‑up (p=0.01). At 12‑month follow‑up, 69% (11/20) of patients in the radiofrequency ablation group had symptoms fewer than 3\xa0times a week compared with 62% (8/14) of patients in the control group (p=0.71). There were no statistically significant differences in the individual symptom scores.\n\nThe crossover RCT of 22\xa0patients reported no significant change in medication use from baseline in either group at 6‑month follow‑up. The RCT of 43\xa0patients reported that 13% (3/23) and 17% (4/23) of patients in the radiofrequency ablation group at 6 and 12\xa0months respectively were able to stop PPIs completely compared with none of the control patients.\n\nThe specialist advisers listed key efficacy outcomes as long‑term objective evidence (pH studies), long‑term symptomatic control, quality of life and decreasing or stopping PPIs.', 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nOne case series reported 3\xa0deaths and 22\xa0complications overall (not otherwise defined) in patients treated by radiofrequency ablation for gastro-oesophageal reflux disease (number of procedures to which these events relate not known).\n\nMucosal bleeding was reported in 3% (3/90) of patients in a case series of 90\xa0patients. Superficial mucosal injury was reported in 2% (2/90) of patients in the same study. All these complications resolved within 1\xa0week of the procedure.\n\nProlonged gastroparesis was reported in 1\xa0patient in a case series of 56\xa0patients: this resolved within 8\xa0weeks.\n\nThe specialist advisers stated that oesophageal perforation is an adverse event which, although rare, is generally acknowledged. The specialist advisers advised of a theoretical risk of developing oesophageal cancer which they considered might be a consequence of long-term unrecognised reflux.', 'Further information': 'This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 292.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges after publication\n \n August 2013: Minor maintenance\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0250-7'}	https://www.nice.org.uk/guidance/ipg461
90eea3b3c08eb3e5e243ccd462b18034eb0282cb	nice	Translaryngeal tracheostomy	Translaryngeal tracheostomy # Recommendations The evidence on the efficacy and safety of translaryngeal tracheostomy is adequate for use with normal arrangements for clinical governance, consent and audit. Clinicians wishing to undertake translaryngeal tracheostomy should receive specific training and should be experienced in using the procedure because carrying it out safely requires different skills to other methods of percutaneous tracheostomy insertion.# Indications and current treatments Tracheostomy is commonly carried out for patients in intensive care to maintain their airway, to remove excessive airway secretions and to enable mechanical ventilation to be gradually withdrawn. This may be performed surgically but anaesthetists and intensive care physicians usually perform the procedure using a percutaneous technique, inserting a tube from the outside of the neck into the trachea, using various devices and commonly under endoscopic guidance. The translaryngeal tracheostomy technique may lead to lower rates of bleeding, trauma and infection to the tissues surrounding the insertion area, compared with surgical and other percutaneous techniques. It may also avoid the risk of damage to the posterior wall of the trachea and tracheal rings because of a lack of external compression during insertion.# The procedure Translaryngeal tracheostomy is a method for inserting a tracheostomy tube using direct endoscopic visualisation. It is usually carried out with the patient under general anaesthesia with muscle relaxation. The patient lies supine with the head extended, and the endotracheal tube is partially withdrawn to allow an endoscope to be passed into the trachea. A small introducer needle is inserted percutaneously between the second and third tracheal rings and visualised endoscopically as it enters the trachea. A metal guide wire is then passed through this needle into the trachea and pulled upwards and out through the mouth. The existing tubes are then temporarily replaced with a narrower ventilation tube for the remainder of the procedure. There are variations in this part of the technique: for example the guide wire may be fed through the distal end of the endotracheal tube or a rigid tracheoscope and recovered at the tube connector. The guide wire is attached to a special tracheostomy device consisting of a flexible plastic cone with a pointed metal tip, joined to an armoured tracheal cannula. The tracheostomy device is then drawn back through, in turn, the oral cavity, the oropharynx, the larynx, the trachea and finally out to the surface of the neck, through the small stoma created by the introducer needle. Traction is applied to the guide wire with one hand, and counter pressure to the neck with the other hand. The cone is then separated from the tracheostomy tube, which is rotated 180° so the open end of the tube faces down towards the carina and bronchi. Correct placement of the tracheostomy tube is confirmed by auscultation of the lungs and endoscopy.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. A case series of 245 patients undergoing translaryngeal tracheostomy reported successful insertion in 99.2% (243 of 245) of patients. A randomised controlled trial of 139 patients comparing translaryngeal tracheostomy (n=67) against surgical tracheostomy (n=72) reported no significant differences in quality of life between the groups (assessed in 31 patients using the SF‑12 Health Survey questionnaire) at 1‑year follow‑up. The specialist advisers listed key efficacy outcomes as reduced trauma, bleeding and infection, good cosmetic outcome, and technical suitability in patients with coagulopathy or those with neck masses or altered tracheal anatomy, compared with surgical or other methods of percutaneous tracheostomy.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. Massive haemorrhage due to an erosive lesion in the dorsal wall of the brachiocephalic artery was reported in a single case report 6 days after translaryngeal tracheostomy. After bleeding had been controlled a 'conventional' tracheostomy was performed. A 4 cm perforation of the posterior tracheal wall with severe damage to the second and third tracheal rings and massive subcutaneous emphysema occurred during 180° rotation of the tube in 1 patient in the translaryngeal tracheostomy group in a comparative study of 100 patients comparing translaryngeal tracheostomy (n=50) against guide wire dilating forceps tracheostomy (n=50). An emergency surgical tracheostomy was performed. Lateral tracheal wall lesions caused during the 180° rotation of the cannula were reported in 3 patients in a case series of 470 patients; 1 needed thoracotomy to suture the defect, the other 2 patients were treated with laser therapy. Loss of the airway causing hypoxia was reported in 6% (3/47) of patients in the translaryngeal tracheostomy group in a randomised controlled trial (RCT) of 100 patients comparing translaryngeal tracheostomy against forceps dilatation tracheostomy because of difficulties re‑intubating patients with the narrower type of endotracheal tube. Stomal infection was reported in 3% (2/67) of patients in the translaryngeal tracheostomy group in the RCT of 139 patients. The tube was accidentally pulled completely out of the neck during insertion in 9 patients in a case series of 145. The RCT of 100 patients reported problems with tube placement in 23% (11/47) of patients. These included the guide wire breaking in 3 patients and difficult retrograde passage of the guide wire in 3 patients. The RCT of 100 patients reported a significant decrease in post‑procedural partial pressure of oxygen in blood in the translaryngeal tracheostomy group (from 311 to 261 mmHg; p=0.0069) but not in the forceps dilatation tracheostomy group (from 289 to 284 mmHg; not significant). The specialist advisers listed anecdotal adverse events as directional misplacement of tube, dislocation of the tube, difficulty in delivering the tube through the larynx, pneumothorax and airway obstruction by the device. Theoretical adverse events reported by the specialist advisers were: damage to the recurrent laryngeal nerve, and thyroid injury.# Further information # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0252-1	{'Recommendations': 'The evidence on the efficacy and safety of translaryngeal tracheostomy is adequate for use with normal arrangements for clinical governance, consent and audit.\n\nClinicians wishing to undertake translaryngeal tracheostomy should receive specific training and should be experienced in using the procedure because carrying it out safely requires different skills to other methods of percutaneous tracheostomy insertion.', 'Indications and current treatments': 'Tracheostomy is commonly carried out for patients in intensive care to maintain their airway, to remove excessive airway secretions and to enable mechanical ventilation to be gradually withdrawn. This may be performed surgically but anaesthetists and intensive care physicians usually perform the procedure using a percutaneous technique, inserting a tube from the outside of the neck into the trachea, using various devices and commonly under endoscopic guidance.\n\nThe translaryngeal tracheostomy technique may lead to lower rates of bleeding, trauma and infection to the tissues surrounding the insertion area, compared with surgical and other percutaneous techniques. It may also avoid the risk of damage to the posterior wall of the trachea and tracheal rings because of a lack of external compression during insertion.', 'The procedure': 'Translaryngeal tracheostomy is a method for inserting a tracheostomy tube using direct endoscopic visualisation. It is usually carried out with the patient under general anaesthesia with muscle relaxation. The patient lies supine with the head extended, and the endotracheal tube is partially withdrawn to allow an endoscope to be passed into the trachea. A small introducer needle is inserted percutaneously between the second and third tracheal rings and visualised endoscopically as it enters the trachea. A metal guide wire is then passed through this needle into the trachea and pulled upwards and out through the mouth. The existing tubes are then temporarily replaced with a narrower ventilation tube for the remainder of the procedure. There are variations in this part of the technique: for example the guide wire may be fed through the distal end of the endotracheal tube or a rigid tracheoscope and recovered at the tube connector.\n\nThe guide wire is attached to a special tracheostomy device consisting of a flexible plastic cone with a pointed metal tip, joined to an armoured tracheal cannula. The tracheostomy device is then drawn back through, in turn, the oral cavity, the oropharynx, the larynx, the trachea and finally out to the surface of the neck, through the small stoma created by the introducer needle. Traction is applied to the guide wire with one\xa0hand, and counter pressure to the neck with the other hand. The cone is then separated from the tracheostomy tube, which is rotated 180° so the open end of the tube faces down towards the carina and bronchi. Correct placement of the tracheostomy tube is confirmed by auscultation of the lungs and endoscopy.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nA case series of 245\xa0patients undergoing translaryngeal tracheostomy reported successful insertion in 99.2% (243 of 245) of patients.\n\nA randomised controlled trial of 139\xa0patients comparing translaryngeal tracheostomy (n=67) against surgical tracheostomy (n=72) reported no significant differences in quality of life between the groups (assessed in 31\xa0patients using the SF‑12 Health Survey questionnaire) at 1‑year follow‑up.\n\nThe specialist advisers listed key efficacy outcomes as reduced trauma, bleeding and infection, good cosmetic outcome, and technical suitability in patients with coagulopathy or those with neck masses or altered tracheal anatomy, compared with surgical or other methods of percutaneous tracheostomy.', 'Safety': "This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nMassive haemorrhage due to an erosive lesion in the dorsal wall of the brachiocephalic artery was reported in a single case report 6\xa0days after translaryngeal tracheostomy. After bleeding had been controlled a 'conventional' tracheostomy was performed.\n\nA 4\xa0cm perforation of the posterior tracheal wall with severe damage to the second and third tracheal rings and massive subcutaneous emphysema occurred during 180°\xa0rotation of the tube in 1\xa0patient in the translaryngeal tracheostomy group in a comparative study of 100\xa0patients comparing translaryngeal tracheostomy (n=50) against guide wire dilating forceps tracheostomy (n=50). An emergency surgical tracheostomy was performed. Lateral tracheal wall lesions caused during the 180°\xa0rotation of the cannula were reported in 3\xa0patients in a case series of 470\xa0patients; 1\xa0needed thoracotomy to suture the defect, the other 2\xa0patients were treated with laser therapy.\n\nLoss of the airway causing hypoxia was reported in 6% (3/47) of patients in the translaryngeal tracheostomy group in a randomised controlled trial (RCT) of 100\xa0patients comparing translaryngeal tracheostomy against forceps dilatation tracheostomy because of difficulties re‑intubating patients with the narrower type of endotracheal tube.\n\nStomal infection was reported in 3% (2/67) of patients in the translaryngeal tracheostomy group in the RCT of 139\xa0patients.\n\nThe tube was accidentally pulled completely out of the neck during insertion in 9\xa0patients in a case series of 145. The RCT of 100\xa0patients reported problems with tube placement in 23% (11/47) of patients. These included the guide wire breaking in 3\xa0patients and difficult retrograde passage of the guide wire in 3\xa0patients.\n\nThe RCT of 100\xa0patients reported a significant decrease in post‑procedural partial pressure of oxygen in blood in the translaryngeal tracheostomy group (from 311 to 261\xa0mmHg; p=0.0069) but not in the forceps dilatation tracheostomy group (from 289 to 284\xa0mmHg; not significant).\n\nThe specialist advisers listed anecdotal adverse events as directional misplacement of tube, dislocation of the tube, difficulty in delivering the tube through the larynx, pneumothorax and airway obstruction by the device. Theoretical adverse events reported by the specialist advisers were: damage to the recurrent laryngeal nerve, and thyroid injury.", 'Further information': '# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0252-1'}	https://www.nice.org.uk/guidance/ipg462
b9a2ba1562e000ea2bed86445dd316bd06ac3c3f	nice	EGFR‑TK mutation testing in adults with locally advanced or metastatic non-small-cell lung cancer	EGFR‑TK mutation testing in adults with locally advanced or metastatic non-small-cell lung cancer Evidence-based recommendations on testing for epidermal growth factor receptor tyrosine kinase (EGFR–TK) mutations in untreated, locally advanced or metastatic non-small-cell-lung cancer. # Recommendations The tests and test strategies listed below are recommended as options for detecting epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutations in the tumours of adults with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC), when used in accredited laboratories participating in an external quality assurance scheme. The laboratory-developed tests should be designed to detect the mutations that can be detected by one of the CE‑marked tests as a minimum. therascreen EGFR RGQ PCR Kit (CE‑marked, Qiagen) cobas EGFR Mutation Test (CE‑marked, Roche Molecular Systems) Sanger sequencing of samples with more than 30% tumour cells and therascreen EGFR RGQ PCR Kit for samples with lower tumour cell contents Sanger sequencing of samples with more than 30% tumour cells and cobas EGFR Mutation Test for samples with lower tumour cell contents Sanger sequencing followed by fragment length analysis and polymerase chain reaction (PCR) of negative samples. There was insufficient evidence for the Committee to make recommendations on the following methods: high-resolution melt analysis pyrosequencing combined with fragment length analysis single-strand conformation polymorphism analysis next-generation sequencing therascreen EGFR Pyro Kit (CE‑marked, Qiagen).# The technologies Ten epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutation methods for identifying adults with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC) who may benefit from first-line treatment with EGFR‑TK inhibitors were evaluated. Three are CE‑marked tests; 5 are laboratory-developed tests; and 2 are test strategies combining a CE‑marked test and a laboratory-developed test. Additional details of the tests are provided in section 4. Other tests and methods for detecting EGFR‑TK mutations are available, such as MALDI‑TOF. NICE is aware that the tests and methods are evolving, so new ones are likely to appear in the future.# Clinical need and practice # The problem addressed Epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutation testing is indicated in adults with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC). Clinical trials have shown that patients with EGFR‑TK mutation-positive tumours gain more benefit from treatment with EGFR‑TK inhibitors than from standard chemotherapy treatment. Conversely, patients with EGFR‑TK mutation-negative tumours gain more benefit from standard chemotherapy than from EGFR‑TK inhibitors. Multiple tests and test strategies for EGFR‑TK mutation testing are currently used in NHS laboratories in England. The aim of this evaluation was to identify which tests and test strategies for EGFR‑TK mutation testing in adults with previously untreated, locally advanced or metastatic NSCLC are clinically and cost effective for informing first-line treatment decisions as currently recommended by NICE. # The condition NSCLC is the most common type of lung cancer in England and Wales, accounting for around 72% of all lung cancer cases. It can be further categorised by histological subtype; the 3 main types being squamous cell carcinoma, adenocarcinoma and large-cell carcinoma. The prevalence of EGFR‑TK mutations in NSCLC varies widely with population ethnicity, with reported prevalence of EGFR‑TK mutations in adenocarcinoma ranging from 10.4% in a study of Italian patients (Marchetti et al. 2005) to 50% in a study of Japanese patients (Kosaka et al. 2004). The estimated proportion of EGFR‑TK mutations in NSCLC in England and Wales is 16.6% (Rosell et al. 2009). # The diagnostic and care pathways NICE clinical guideline 121 (Lung cancer: the diagnosis and treatment of lung cancer) recommends that patients with suspected lung cancer should be urgently referred for a chest X‑ray. If the results suggest lung cancer, a contrast-enhanced CT scan of the chest, upper abdomen and lower neck is performed. Further investigations to confirm a diagnosis and to provide information on the stage of the disease are then carried out. These investigations generally include a biopsy for histological confirmation and subtyping, but may also include positron emission tomography-computed tomography, endobronchial ultrasound-guided transbronchial needle aspiration, endoscopic ultrasound-guided fine needle aspiration or non-ultrasound-guided transbronchial needle aspiration. When biopsy is successful, DNA extraction and mutation analysis can be carried out on the biopsy tissue (which is generally stored as formalin-fixed paraffin-embedded tissue) to determine whether the tumour is EGFR‑TK mutation-positive or -negative. If biopsy tissue is not available, DNA extracted from cytology samples can be used for mutation analysis. Other molecular tests may be performed as clinically indicated. Participants at a European multidisciplinary workshop 'EGFR testing in NSCLC: from biology to clinical practice' (2009) emphasised the importance of standardisation and validation of EGFR‑TK mutation tests and recommended that testing should only be undertaken in a quality-assured, accredited setting. However, there was no consensus on which laboratory test should be used for clinical decision-making. Participants agreed that the decision to request EGFR‑TK mutation testing should be made by the treating physician and that results should be reported within 7 working days of request. Conversely, guidelines from the Royal College of Pathologists recommend that, to minimise turnaround time, molecular diagnostic tests should be ordered by the pathologist reporting on the histology of the tumour. Treatment options for NSCLC include gefitinib and erlotinib, which are EGFR‑TK inhibitors indicated for patients with EGFR‑TK mutation-positive tumours. NICE's technology appraisal guidance 192 (Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer) and technology appraisal guidance 258 (Erlotinib for the first-line treatment of locally advanced or metastatic EGFR‑TK mutation-positive non-small-cell lung cancer) recommend gefitinib and erlotinib respectively as options for the first-line treatment of locally advanced or metastatic NSCLC in people whose tumour tests positive for an EGFR‑TK mutation. Other treatment options for NSCLC include chemotherapy regimens. NICE clinical guideline 121 recommends that chemotherapy should be offered to people with stage III or IV NSCLC and a good performance status (WHO 0, 1 or Karnofsky score 80–100) with the aim of improving survival, disease control and quality of life. Treatment with curative intent is not possible for these people. First-line chemotherapy should be a combination of a single third-generation drug (docetaxel, gemcitabine, paclitaxel or vinorelbine) and a platinum drug (carboplatin or cisplatin). People who are unable to tolerate a platinum combination may be offered single-agent chemotherapy with a third-generation drug. NICE technology appraisal guidance 181 (Pemetrexed for the first-line treatment of non-small-cell lung cancer) recommends pemetrexed plus cisplatin as a first-line treatment for locally advanced or metastatic NSCLC, if the histology of the tumour has been confirmed as adenocarcinoma or large-cell tumour.# The diagnostic tests # The interventions ## Therascreen EGFR RGQ PCR Kit The therascreen EGFR RGQ PCR Kit (Qiagen) is a CE‑marked real-time polymerase chain reaction (PCR) assay for the targeted detection of 29 mutations in exons 18 to 21 of the epidermal growth factor receptor tyrosine kinase (EGFR‑TK) gene: G719X (G719S/G719A/G719C) in exon 18 deletions in exon 19 T790M in exon 20 S768I in exon 20 insertions in exon 20 L858R in exon 21 L861Q in exon 21. To ensure it complies with the CE marking, the DNA is first isolated from a specimen of formalin-fixed paraffin-embedded tissue using the QIAamp DNA FFPE Tissue Kit. The total amount of DNA in the sample is assessed by a control assay. The therascreen EGFR RGQ PCR Kit then uses 2 technologies for detecting mutations: ARMS (amplification-refractory mutation system) for mutation-specific DNA amplification; and Scorpions for detecting amplified regions. Scorpions are bi-functional molecules containing a PCR primer covalently linked to a fluorescently labelled probe. A real-time PCR instrument (Rotor‑Gene Q 5‑Plex HRM Platform for consistency with CE marking) is used to perform the amplification and to measure fluorescence. The limits of detection (the per cent mutant DNA present in a background of wild-type DNA, at which 95% or more replicates were determined positive) reported by the manufacturer for the different mutations ranged from 0.5% to 7.0%. An older version of the test exists (the therascreen EGFR PCR Kit), which was inherited by Qiagen when they acquired DxS Ltd. This older version uses the same methods as the newer therascreen EGFR RGQ PCR Kit, and detects 28 of the same mutations, but is not designed to detect the resistance mutation T790M. The limit of detection claimed by the manufacturer for the therascreen EGFR PCR Kit is 1% mutant DNA in a background of wild-type DNA. This version is no longer being actively marketed by Qiagen, was not used in any of the studies included in this review and has been superseded by the therascreen EGFR RGQ PCR Kit. Further, an earlier version of the therascreen EGFR PCR Kit, which did include an assay for T790M, was used to analyse all samples in the IPASS trial. This version is no longer available, but is considered equivalent to the therascreen EGFR RGQ PCR Kit for the purpose of this assessment. ## Cobas EGFR Mutation Test The cobas EGFR Mutation Test (Roche Molecular Systems) is a CE‑marked real-time PCR test for the targeted detection of 41 mutations in exons 18 to 21 of the EGFR‑TK gene: G719X (G719S/G719A/G719C) in exon 18 deletions and complex mutations in exon 19 T790M in exon 20 S768I in exon 20 insertions in exon 20 L858R in exon 21 (2 variants). The tumour tissue is first processed using the cobas DNA Sample Preparation Kit. The second step is PCR amplification and detection of EGFR‑TK mutations using complementary primer pairs and fluorescently labelled probes. The PCR is run using the cobas z 480 Analyzer, which automates amplification and detection. Cobas 4800 software provides automated test result reporting. The limits of detection (lowest amount of DNA per reaction well to achieve a 95% or higher 'mutation detected' rate), as reported by the manufacturer for the different mutations, ranged from 0.78 nanograms to 3.13 nanograms of DNA per well. ## Sanger sequencing of samples with more than 30% tumour cells and therascreen EGFR RGQ PCR Kit for samples with lower tumour cell contents In this test strategy, Sanger sequencing of exons 18 to 21 (described in section 4.19) is used to detect EGFR‑TK mutations in test samples with more than 30% tumour cells, and the therascreen EGFR RGQ PCR Kit (described in sections 4.1 to 4.4) is used to detect EGFR‑TK mutations in samples with less than 30% tumour cells. ## Sanger sequencing of samples with more than 30% tumour cells and cobas EGFR Mutation Test for samples with lower tumour cell content In this test strategy, Sanger sequencing of exons 18 to 21 (described in section 4.19) is used to detect EGFR‑TK mutations in test samples with more than 30% tumour cells, and the cobas EGFR Mutation Test (described in sections 4.5 to 4.7) is used to detect EGFR‑TK mutations in samples with less than 30% tumour cells. ## Sanger sequencing followed by fragment length analysis and PCR of negative samples Sanger sequencing of exons 18 to 21 is used as an initial test to screen for mutations. Fragment length analysis to detect exon 19 deletions and real-time PCR to detect the exon 21 mutation L858R are then used on samples that produce a negative result using Sanger sequencing. ## Pyrosequencing and fragment length analysis This test strategy combines in-house methods of pyrosequencing (to detect point mutations) with in-house methods of fragment length analysis (to detect deletions and insertions) for EGFR‑TK mutation detection. Pyrosequencing involves extracting DNA from the sample and amplifying it using PCR. Nucleotides are added sequentially to the amplified PCR product. A series of enzymes incorporates nucleotides into the complementary DNA strand, generates light proportional to the number of nucleotides added and degrades unincorporated nucleotides. The DNA sequence is determined from the resulting pyrogram trace. In fragment length analysis, DNA is extracted from the sample, and then amplified and labelled with fluorescent dye using PCR. Amplified DNA is mixed with size standards and analysed using capillary electrophoresis. The fluorescence intensity is monitored as a function of time, and analysis software can determine the size of the fragments. The presence or absence of deletions and insertions can then be reported. ## Therascreen EGFR Pyro Kit The therascreen EGFR Pyro Kit (Qiagen) is a CE‑marked pyrosequencing kit. It is a targeted method of mutation detection designed to detect and distinguish between: G719S, G719A and G719C in exon 18 the 20 most common deletions in exon 19 S768I and T790M in exon 20 L858R and L861Q in exon 21. The kit provides all primers, controls, buffers and reagents necessary to perform the assay. Samples are analysed on the PyroMark Q24 System and a plug-in report tool that simplifies analysis of the pyrogram trace is available. ## Single-strand conformation polymorphism analysis Single-strand conformation polymorphism analysis is a screening method of mutation detection. The DNA is first extracted from the sample and amplified using PCR. The PCR product is then prepared for analysis by heat denature and analysed using capillary electrophoresis under non-denaturing conditions. Sequence variations (single-point mutations and other small changes) are detected through electrophoretic mobility differences. ## High-resolution melt analysis High-resolution melt analysis is a screening method of mutation detection. The DNA is first extracted from the sample and amplified using PCR. The PCR product is then precisely warmed so that the 2 strands of DNA 'melt' apart. Fluorescent dye, which only binds to double-stranded DNA, is used to monitor the process. A region of DNA with a mutation will 'melt' at a different temperature from the same region of DNA without a mutation. These changes are documented as melt curves and the presence or absence of a mutation can be reported. ## Next-generation sequencing Next-generation sequencing is a screening method of mutation detection. The concept is similar to Sanger sequencing (described in section 4.19), but the sample DNA is first fragmented into a library of small segments that can be sequenced in parallel reactions. # The comparator ## Sanger sequencing Sanger sequencing (also called direct sequencing) is a screening method of mutation detection. Sanger sequencing is a commonly used method, but there is a lot of variation in how it is carried out. In general, after DNA is extracted from the sample, it is amplified using PCR. The PCR product is then cleaned up and sequenced in both forward and reverse directions. The sequencing reaction uses dideoxynucleotides labelled with coloured dyes, which randomly terminate DNA synthesis, creating DNA fragments of various lengths. The sequencing reaction product is then cleaned up and analysed using capillary electrophoresis. The raw data are analysed using software to generate the DNA sequence. All steps are performed at least in duplicate to increase confidence that an identified mutation is real. It should be noted that sequencing only works well when viable tumour cells constitute 25% or more of the sample.# Outcomes The Diagnostics Advisory Committee (section 11) considered evidence from several sources (section 12). # How outcomes were assessed The assessment was performed by an External Assessment Group and consisted of a systematic review, a web-based survey and the development of a decision analytic model. The systematic review was carried out to identify evidence on the technical performance and clinical effectiveness of the different options available to detect epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutations in previously untreated locally advanced or metastatic non-small-cell lung cancer (NSCLC), and so adults who may benefit from first-line treatment with EGFR‑TK inhibitors. The web-based survey was conducted to gather data on the technical performance characteristics and costs of EGFR‑TK mutation tests in use in NHS laboratories. A decision analytic model was developed to assess the cost effectiveness of different methods of EGFR‑TK mutation testing in helping to decide between treatment with standard chemotherapy and EGFR‑TK inhibitors for patients with locally advanced or metastatic NSCLC. Three different analytic approaches, described below, were used to calculate cost effectiveness, each involving different levels of evidence. 'Comparative effectiveness' analysis: This analysis used data on the comparative effectiveness (progression-free survival and overall survival) of EGFR‑TK inhibitors and standard chemotherapy in patients with EGFR‑TK mutation-positive, EGFR‑TK mutation-negative and EGFR‑TK mutation-unknown tumours. The tests included in this analysis were the therascreen EGFR PCR Kit and Sanger sequencing of exons 19 to 21. 'Linked evidence' analysis: This is the same as the 'comparative effectiveness' analysis, except that it allowed the inclusion of EGFR‑TK mutation tests that have data on the accuracy of the test for predicting response to EGFR‑TK inhibitors but no data on comparative effectiveness (progression-free survival and overall survival in patients with EGFR‑TK mutation-positive, EGFR‑TK mutation-negative and EGFR‑TK mutation-unknown tumours). Tests included in this analysis were the therascreen EGFR PCR Kit, Sanger sequencing of exons 18 to 21 and Sanger sequencing of exons 19 to 21. 'Assumption of equal prognostic value' analysis: For the remaining EGFR‑TK mutation tests in the scope, no data were available on either the comparative effectiveness or the accuracy of the test for predicting response to EGFR‑TK inhibitors. Therefore, for these tests, it was only possible to make a comparison based on differences in technical performance and test costs retrieved from the web-based survey, while assuming equal prognostic value across tests. # Technical performance One study identified from the systematic review evaluated the technical performance of EGFR‑TK mutation tests. The study was conducted in the Department of Molecular Diagnostics at the Royal Marsden Hospital and the Institute of Cancer Research. The study reported data for 2 years of EGFR‑TK mutation testing from January 2009 to January 2011. During year 1 of the testing, the therascreen EGFR PCR Kit was used. During year 2, a combination of the therascreen EGFR PCR Kit, fragment analysis (for exon 19 deletions and exon 20 insertions) and Sanger sequencing (for the rarer exon 19 or exon 21 mutations) was used. A total of 121 patients were tested during year 1 and 755 during year 2. The mean turnaround time for the therascreen EGFR PCR test alone during year 1 was 4.9 business days (95% confidence interval 4.5 days to 5.5 days). However, the actual time from the test request to the result was 17.8 days (95% CI 16.4 days to 19.4 days). The total test failure rate for the first year of the study was 19% of all samples assessed, but this improved over time from a failure rate of 33% over the first 3 months to 13% during the last 3 months of year 1 testing. The total failure rate was lower in the second year of the study at only 5% of all samples assessed. There were 24 UK laboratories participating in the 2012–2013 UK National External Quality Assessment Service (NEQAS) pilot scheme for EGFR‑TK mutation testing. Of these, 14 provided information to NICE during the scoping phase of the assessment and were invited to participate in the survey. Thirteen of the 14 laboratories completed the web-based survey. The therascreen EGFR PCR Kit was the most commonly used EGFR‑TK mutation test, with 6 laboratories using it. A combination of fragment length analysis and pyrosequencing was used in 2 laboratories. Sanger sequencing was used in 2 laboratories. However, one of these laboratories also uses the cobas EGFR Mutation Test for verifying mutations or when the sample contains insufficient tumour cells for Sanger sequencing (less than 30%). The second of these laboratories also uses fragment length analysis and real-time PCR to follow up samples found to be negative with Sanger sequencing. Single-strand conformation analysis, high-resolution melt analysis and pyrosequencing were used in single laboratories. One laboratory also provided information on a next-generation sequencing method that is being developed and validated. The survey results showed that there were no clear differences between tests. The number of samples screened for EGFR‑TK mutations in a typical week varied by laboratory from less than 5 (6 laboratories) to more than 20 (3 laboratories). The frequency at which the laboratories ran the tests ranged from daily to every other week. Batch sizes ranged from less than 3 samples to 10 samples but most laboratories stated that they would match demand rather than waiting for a minimum batch size. Most laboratories had a turnaround time from receiving the sample to reporting the result to the clinician of 3–5 days or 6–7 days, with 1 laboratory reporting a turnaround of 24–28 hours (therascreen EGFR PCR Kit) and 1 laboratory reporting a turnaround of 8–10 days (therascreen EGFR PCR Kit). The estimated total number of failed samples ranged from 0% to 10%, with the number of failed samples because of insufficient tumour cells ranging from 0–5%. The most common reasons for failed tests were insufficient tumour cell count and poor-quality DNA or DNA degradation. The cost of the EGFR‑TK mutation tests ranged from £110 to £190 and the price that the laboratories charged for the tests ranged from £120 to £200. When there was a difference between the test cost and the price charged, this ranged from £10 to £37.50 per test. No single test appeared to be more or less expensive than any of the other tests. It was noted by UK NEQAS that error rates seen in the quality assurance scheme for EGFR‑TK mutation testing are not always method related, and may be because of processing and reporting problems. In addition, UK NEQAS noted that there had been no correlation between any method used for EGFR‑TK mutation testing and errors since the scheme was started in 2010. # Accuracy Two randomised controlled trials and 4 cohort studies provided data on the accuracy of EGFR‑TK mutation testing for predicting the response to treatment with EGFR‑TK inhibitors in patients with advanced or metastatic NSCLC. Three studies included patients treated with gefitinib and 3 included patients treated with erlotinib. Patient characteristics varied across studies. One study included mainly white patients and 1 study included mainly East Asian patients (4 studies did not report the ethnicity of patients). All studies reported that a high proportion of patients had metastatic disease. Most patients had a histological diagnosis of adenocarcinoma (45–100%), but 2 studies included some patients with squamous cell carcinoma (9–15%). Four studies mainly, or only, included patients who had never smoked, whereas 2 studies mainly included patients who were current or former smokers. Five studies evaluated Sanger sequencing methods for identifying any EGFR‑TK mutation; 3 assessed exons 18 to 21, 1 assessed exons 19 to 21, and 1 assessed exons 18 to 24 (Sanger sequencing or WAVE-HS for inadequate samples ). One study assessed the therascreen EGFR PCR Kit (the version designed to detect 29 mutations, including T790M). The therascreen EGFR PCR Kit appears to have the best overall performance for discriminating between patients who are likely to benefit from EGFR‑TK inhibitor treatment and patients who are not. The sensitivity and specificity estimates using objective response as the reference standard were 99% (95% CI 94% to 100%) and 69% (95% CI 60% to 77%) respectively. Of the 5 studies that used Sanger sequencing methods to identify EGFR‑TK mutations, 4 reported high estimates of specificity (more than 80%) and sensitivities ranged from 60% to 80% when objective response was used as the reference standard. The remaining Sanger sequencing study reported low specificity (61%) with high sensitivity (84%) for objective response as the reference standard. # Clinical effectiveness Five randomised controlled trials provided data on the clinical effectiveness of EGFR‑TK inhibitors compared with standard chemotherapy in patients with advanced or metastatic NSCLC whose tumours tested positive for EGFR‑TK mutations. One additional study reported data for a subgroup of patients from the EURTAC trial whose samples had been re-analysed using a different EGFR‑TK mutation testing method. Three of the trials included only patients with EGFR‑TK mutation-positive tumours, and the remaining 2 trials (IPASS and First-SIGNAL) included all patients regardless of EGFR‑TK mutation status, but also reported a subgroup analysis for patients whose tumours tested positive for EGFR‑TK mutations. The trials compared the EGFR‑TK inhibitors gefitinib or erlotinib with various single-agent or combination standard chemotherapy regimens. Patient characteristics varied across studies. Four studies were conducted in East Asia and 1 was conducted in Western Europe. One study included patients who had never smoked, 1 study included mainly patients who had never smoked (94%) and the rest included between 62% and 71% of patients who had never smoked. One study included only patients with a diagnosis of adenocarcinoma, whereas in the remaining studies approximately 90% had a diagnosis of adenocarcinoma. Most patients (more than 75%) in all studies had metastatic disease. Two studies used Sanger sequencing methods to assess EGFR‑TK mutation status, but both limited the definition of positive EGFR‑TK mutation status to the presence of an 'activating mutation' (exon 19 deletions or exon 21 mutation L858R). The remaining studies used EGFR‑TK mutation tests that targeted a wider range of mutations. One study reported the results of a re-analysis of samples from the EURTAC trial using the cobas EGFR Mutation Test. The other study (IPASS) used the therascreen EGFR PCR Kit (the version designed to detect 29 mutations, including T790M). The North East Japan Study Group (NEJSG) trial used fragment length analysis, targeting exon 19 deletions, exon 21 point mutations (L858R, L861Q), exon 18 point mutations (G719A, G719C, G719S), and exon 20 point mutation (T790M). The First-SIGNAL trial used Sanger sequencing of exons 19 to 21. All studies reported improvements in objective response, measured as relative risk. Objective response ranged from a relative risk of 1.51 (95% CI 1.23 to 1.88) to 3.89 (95% CI 2.34 to 6.68) for patients with EGFR‑TK mutation-positive tumours who were given EGFR‑TK inhibitors compared with patients given standard chemotherapy. All studies also reported statistically significant improvements or trends towards improvement in progression-free survival, with hazard ratios ranging from 0.16 (95% CI 0.10 to 0.26) to 0.54 (95% CI 0.27 to 1.10) for patients with EGFR‑TK mutation-positive tumours who were given EGFR‑TK inhibitors compared with patients given standard chemotherapy. Four studies reported overall survival but none found a statistically significant difference between patients given EGFR‑TK inhibitors and patients given standard chemotherapy, with hazard ratios ranging from 0.89 (95% CI 0.63 to 1.24) to 1.04 (95% CI 0.65 to 1.68). The results from the IPASS trial showed that progression-free survival in patients with EGFR‑TK mutation-negative tumours was statistically significantly shorter when patients were treated with EGFR‑TK inhibitors than with standard chemotherapy (hazard ratio 2.85, 95% CI 2.05 to 3.98). A similar trend for patients with EGFR‑TK mutation-negative tumours, although not statistically significant, was observed in the First-SIGNAL trial (HR 1.42, 95% CI 0.82 to 2.47). # Cost effectiveness The External Assessment Group received the health economic model submitted by AstraZeneca for NICE technology appraisal guidance 192 (Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer). The External Assessment Group also took into account amendments and corrections to the model that were accepted by the appraisal committee for NICE technology appraisal guidance 192. This model calculates the expected cost effectiveness of gefitinib compared with standard chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC in patients with a positive EGFR‑TK mutation test based on the therascreen EGFR PCR Kit. The External Assessment Group used the AstraZeneca model to develop a de novo model that included patients with a positive, negative or unknown EGFR‑TK mutation test result. The External Assessment Group developed a decision tree and a Markov model to analyse the long-term consequences of technical performance and accuracy of the different EGFR‑TK mutation tests and test combinations followed by treatment with either standard chemotherapy or an EGFR‑TK inhibitor in patients with NSCLC. The decision tree was used to model the test result (positive, unknown or negative) and the treatment decision. Patients with a positive test result receive an EGFR‑TK inhibitor. Patients with a negative test result or an unknown EGFR‑TK mutation status receive standard chemotherapy (pemetrexed and cisplatin). The Markov model was used to estimate the long-term consequences in terms of costs and quality-adjusted life years (QALYs). The model has a cycle time of 21 days (resembling the duration of 1 cycle of chemotherapy), and a time horizon of 6 years. In the model, after a treatment decision is made, patients can either have progression-free disease (subdivided into 'response' and 'stable disease' based on objective response rate), experience disease progression or die. The proportions of positive and negative EGFR‑TK mutation test results were based on: the estimated proportions of patients with NSCLC and EGFR‑TK mutation-positive tumours in England and Wales (16.6%, standard error 0.8%); the test accuracy (sensitivity and specificity with objective response to EGFR‑TK inhibitor as reference standard); and the proportion of patients with an unknown test result, based on data from published studies (IPASS and Jackman et al. 2007). The proportions of positive, negative and unknown EGFR‑TK mutation test results for the therascreen EGFR PCR Kit were 32.8%, 44.6% and 22.7% respectively. The proportions of positive, negative and unknown EGFR‑TK mutation test results for Sanger sequencing of exons 18 to 21 were 29.0%, 33.4% and 37.7% respectively. In the 'assumption of equal prognostic value' analysis, the proportions of positive, negative and unknown EGFR‑TK mutation test results were assumed equal to the therascreen EGFR PCR Kit for all tests and test strategies. The objective response rates were based on data from published studies (IPASS, First-SIGNAL and Yang et al. 2008). For EGFR‑TK mutation-negative or -unknown tumours (treated with standard chemotherapy), objective response rates were adjusted to correspond to treatment with pemetrexed and cisplatin. Objective response rates for EGFR‑TK mutation-positive, -negative and ‑unknown tumours identified using the therascreen EGFR PCR Kit were 0.712, 0.335 and 0.403 respectively. Objective response rates for EGFR‑TK mutation-positive, -negative and -unknown tumours identified using Sanger sequencing of exons 18 to 21 were 0.731, 0.604 and 0.403 respectively. In the 'assumption of equal prognostic value' analysis, the objective response rates for EGFR‑TK mutation-positive, -negative and -unknown tumours were assumed equal to the therascreen EGFR PCR Kit for all tests and test strategies. Progression-free survival and overall survival after testing with the therascreen EGFR PCR Kit were modelled using Weibull regression models based on the IPASS trial and a hazard ratio favouring treatment with an EGFR‑TK inhibitor (HR 0.43, 95% CI 0.34 to 0.53). For testing using Sanger sequencing of exons 19 to 21, progression-free survival and overall survival for patients with EGFR‑TK mutation-positive or -negative tumours were modelled using Kaplan-Meier curves extracted from the First-SIGNAL trial. Progression-free survival and overall survival for patients with tumours of unknown EGFR‑TK mutation status were based on the IPASS Weibull model for unknown mutations. For testing using Sanger sequencing of exons 18 to 21, progression-free survival and overall survival were assumed equal to testing using Sanger sequencing of exons 19 to 21. The test costs were based on the prices charged by the NHS laboratories in England and Wales involved in the web-based survey (see table 1). In the case of an unknown EGFR‑TK mutation status, no test costs were taken into account if there was a pre-laboratory clinical failure, but full test costs were taken into account if there was a technical failure in the laboratory. Table 1 EGFR‑TK mutation test costs Test Price charged Standard error therascreen EGFR PCR Kit Sanger sequencing of exons 19 to 21 Sanger sequencing of exons 18 to 21 Sanger sequencing or therascreen EGFR PCR Kit for samples with insufficient tumour cells Sanger sequencing or cobas EGFR Mutation Test for samples with insufficient tumour cells Pyrosequencing combined with fragment length analysis Sanger sequencing followed by fragment length analysis/real-time PCR High-resolution melt analysis cobas EGFR Mutation Test Single-strand conformation analysis Abbreviations: EGFR, epidermal growth factor receptor; PCR, polymerase chain reaction. Results from the 'comparative effectiveness' analysis showed the therascreen EGFR PCR Kit to be both less effective and less costly compared with Sanger sequencing of exons 19 to 21, with an incremental cost-effectiveness ratio (ICER) of £32,167 saved per QALY lost. Adjustments to costs and the proportions of patients with unknown mutation status in sensitivity analyses had little effect on the results. When treatment costs and adverse event costs were updated to 2012 costs, the ICER was £32,196 saved per QALY lost for the therascreen EGFR PCR Kit compared with Sanger sequencing. When the proportions of patients with unknown mutation status were based on the results from the web-based survey rather than information from published trials, the ICER was £34,555 saved per QALY lost for the therascreen EGFR PCR Kit compared with Sanger sequencing. The External Assessment Group explained that the lower costs and QALYs for the therascreen EGFR PCR Kit were because patients with EGFR‑TK mutation-negative tumours had shorter overall survival in the IPASS trial (therascreen EGFR PCR Kit) than in the First-SIGNAL trial (Sanger sequencing of exons 19 to 21), whereas the outcome was comparable for patients whose tumours were EGFR‑TK mutation positive. For patients whose tumours were EGFR‑TK mutation unknown, overall survival was the same by assumption. Therefore, on average, with the therascreen EGFR PCR Kit patients had shorter overall survival, resulting in fewer QALYs and reduced costs compared with Sanger sequencing of exons 19 to 21. The External Assessment Group noted that this analysis is particularly problematic because of the assumption that the differences in relative treatment response, progression-free survival and overall survival between the results of the First-SIGNAL trial (Sanger sequencing of exons 19 to 21) and the results of the IPASS trial (therascreen EGFR PCR Kit) were solely because of the different EGFR‑TK mutation tests used to distinguish between patients whose tumours were EGFR‑TK mutation positive (and receive EGFR‑TK inhibitor treatment) and patients whose tumours were EGFR‑TK mutation negative (and receive standard chemotherapy). Results from the 'linked evidence' analysis also showed the therascreen EGFR PCR Kit to be both less effective and less costly than Sanger sequencing of exons 18 to 21 at an ICER of £31,849 saved per QALY lost. Sensitivity analyses had little effect on the results. When the treatment costs and adverse event costs were updated to 2012 costs, the ICER was £34,169 saved per QALY lost for the therascreen EGFR PCR Kit compared with Sanger sequencing of exons 18 to 21. When the proportions of patients with unknown mutation status were based on the results from the web-based survey rather than information from published trials, the ICER was £31,880 saved per QALY lost for the therascreen EGFR PCR Kit compared with Sanger sequencing of exons 18 to 21. The reason for the lower costs and QALYs for the therascreen EGFR PCR Kit were the same as for the 'comparative effectiveness' analysis, as described in section 5.28. In addition to the assumption described in section 5.30, the 'linked evidence' analysis also assumed that the relative progression-free survival and overall survival for Sanger sequencing of exons 18 to 21 correlated perfectly with the relative progression-free survival and overall survival for Sanger sequencing of exons 19 to 21. In the 'assumption of equal prognostic value' analysis, the comparative effectiveness, test accuracy and proportion of patients with unknown mutation status for each test strategy were assumed equal to those of the therascreen EGFR PCR Kit. Therefore, the test strategies only differed with respect to costs. Results showed that the test strategy of Sanger sequencing or the cobas EGFR Mutation Test for samples with insufficient tumour cells was the least expensive (£15 cheaper than Sanger sequencing of exons 18 to 21 alone), and fragment length analysis combined with pyrosequencing was the most expensive strategy (£33 more expensive than Sanger sequencing of exons 18 to 21 alone). The External Assessment Group did not include next-generation sequencing and the therascreen EGFR Pyro Kit in any of the cost-effectiveness analyses because of a lack of data. No published studies were identified for either of these methods and neither method is currently in routine clinical use in any NHS laboratories in England and Wales.# Considerations The Diagnostics Advisory Committee reviewed the evidence available on the clinical and cost effectiveness of epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutation testing to inform first-line treatment decisions in adults with locally advanced or metastatic non-small-cell lung cancer (NSCLC). The Committee considered the report produced by the External Assessment Group and statements from patient experts on the Committee and from clinical specialists who acted as specialist Committee members on this assessment. The Committee discussed the External Assessment Group's report on the clinical and cost effectiveness of EGFR‑TK mutation tests. It noted that, during scoping, 10 interventions had been identified as suitable for review in this assessment. However, during systematic review of the evidence, the External Assessment Group found limited data for many of the tests and no data on the clinical and cost effectiveness of next-generation sequencing and the therascreen EGFR Pyro Kit. # Technical performance and clinical validity The Committee considered the technical performance of the different tests. It heard from clinical specialists on the Committee that, in their experience, the different tests generally have a similar level of accuracy in detecting the mutations that they are designed to detect. The Committee also noted the statement from the UK National External Quality Assessment Service (NEQAS) that errors seen in the EGFR quality assurance scheme are not always method related, and that variations in how tests are processed and implemented can lead to variations in the failure rates (see section 5.11). The Committee also considered the failure rates reported for the different tests in the web-based survey. The Committee considered that, although the survey was limited by its small sample size, it seemed to suggest that failure rates are generally not test-dependent. Furthermore, the Committee heard that it is standard practice for the quality of tissue samples to be initially assessed by a pathologist. Therefore, the decision made by the pathologist about whether to send a sample for EGFR‑TK mutation testing could impact on the number of patients with an unknown EGFR‑TK mutation status. The Committee concluded that the technical performance of the tests is not solely influenced by test accuracy, and that processing of samples and testing practices is likely to influence technical performance. It further concluded that, in UK practice, the technical performance of the tests under assessment is likely to be very similar. The Committee discussed the lack of a gold standard test for assessing test accuracy, the difficulties relating to the different mutation coverage of the various tests, and the uncertainty about the clinical significance of some mutations. The Committee acknowledged that the approach taken by the External Assessment Group, in which accuracy for predicting response to treatment was calculated using objective response and disease control as reference standards, was a valid approach in this situation. It was advised by clinical specialists on the Committee, however, that deriving accuracy from response to treatment with an EGFR‑TK inhibitor is problematic. For instance, the definition of false positives was 'patients identified as having tumours with an EGFR‑TK mutation that do not respond to treatment with an EGFR‑TK inhibitor'. It noted that there may be other reasons why a tumour does not respond to treatment, such as concomitant medications, patient characteristics and other clinical factors. The Committee considered the accuracy of EGFR‑TK mutation tests for predicting response to treatment. It noted that the External Assessment Group had only been able to obtain sensitivity and specificity estimates for therascreen EGFR PCR Kit and Sanger sequencing of exons 18 to 21 and exons 19 to 21. The Committee also noted that, when accuracy estimates were available, the accuracy of different tests was calculated from different studies with different patient populations and different ways of classifying resistance mutations. The Committee heard from the External Assessment Group that, ideally, sensitivity and specificity values should be generated for all tests from a single set of samples, therefore limiting the influence of sampling and population differences on the accuracy estimates. The Committee acknowledged that this assessment did not present such a scenario and that it was plausible that differences in patient populations could have impacted on relative accuracy estimates for individual tests. The Committee therefore concluded that the relative predictive accuracy for the different tests could not be reliably established. The Committee considered the effect of tissue quality on the accuracy of EGFR‑TK mutation testing. It heard from clinical specialists on the Committee that the quality of tissue samples available for testing often varies, and this may impact on both the test failure rates and test accuracy. The Committee noted that, in addition to obtaining good-quality tumour samples, it is important to use a sensitive test to enable detection of EGFR‑TK mutations, especially to ensure correct results in lower-quality tumour samples. It discussed the consequences of assigning the wrong EGFR‑TK mutation status to a patient and noted that both the IPASS and the Signal-FIRST trials (see section 5.21) had demonstrated that progression-free survival was shorter for patients receiving an EGFR‑TK inhibitor than for patients receiving standard chemotherapy in the EGFR‑TK mutation-negative subgroup. For this reason, the Committee concluded that it is important to ensure high accuracy of testing, particularly to minimise the chances of incorrect treatment. The Committee then discussed the generalisability of the clinical evidence to UK clinical practice and the UK patient population. It noted that 4 out of the 5 randomised controlled trials identified by the External Assessment Group were conducted in East Asia (see sections 5.18 and 5.19). The Committee acknowledged that the patients included in the trials had characteristics different from patients usually seen in UK practice, most notably that the studies included a high proportion of patients who had never smoked and a high proportion of patients of East Asian origin. The Committee noted that all evidence for the therascreen EGFR RGQ PCR Kit came from the IPASS trial, which looked almost exclusively at patients from East Asia. It also noted that, although most of the evidence came from patients with adenocarcinoma, patients with squamous cell carcinoma would also be tested for EGFR‑TK mutations and these patients may have different clinical characteristics. The Committee concluded that, although there were some substantial differences between the trial populations and the population of patients presenting with advanced NSCLC in the UK, the effect on test accuracy was likely to be minimal and therefore the trial evidence could be used to support the effectiveness of testing in patients with adenocarcinoma and in patients with squamous cell carcinoma in a UK setting. The Committee considered the value of tests that identify rare EGFR‑TK mutations. It acknowledged that screening tests are designed to detect more mutations than the targeted tests. In addition, the targeted tests (therascreen EGFR PCR Kit and the cobas EGFR Mutation Test) are designed to detect different sets of mutations, which vary in the number of rare forms of mutations included. The Committee heard from clinical specialists on the Committee that the clinical significance of rare mutations is generally unknown, and that treatment decisions for patients with a rare EGFR‑TK mutation would be made by the oncologist based on the availability of evidence, such as case studies. The Committee acknowledged that evidence on the clinical effect of rare mutations is being generated. However, it concluded that currently there is little additional value of tests designed to detect rare mutations, except for the purpose of collecting clinical outcome data for research. The Committee discussed whether there are any benefits of using CE‑marked tests over laboratory-developed tests for detecting EGFR‑TK mutations. It heard that the CE‑marked EGFR‑TK mutation tests (therascreen EGFR RGQ PCR Kit and cobas EGFR Mutation Test) and the simpler laboratory-developed tests such as polymerase chain reaction (PCR) may be easier to implement than tests based on Sanger sequencing for laboratories with little molecular diagnostics experience (for example, pathology laboratories). The Committee therefore concluded that, although there was no distinguishable difference in the technical performance of the tests, the ease of use of the CE‑marked tests may be an advantage in some clinical settings, particularly when limited molecular diagnostics technical support is available. The Committee considered the turnaround time of EGFR‑TK mutation testing. It noted that turnaround time was assumed not to be test-dependent and was therefore not included in the economic modelling. The Committee heard from clinical specialists on the Committee that turnaround time was impacted by factors such as transporting samples between different locations for testing and the set-up of the laboratory. It also heard from patient experts that waiting for test results causes additional anxiety to patients and that the rapid turnaround of test results is a priority for patients. The Committee acknowledged that, although the survey conducted by the External Assessment Group showed, on average, that similar turnaround times were achieved for all tests in the UK laboratories surveyed, the only test achieving a turnaround time shorter than 3 days was the therascreen EGFR PCR Kit. However, the Committee concluded that, although it is possible that the CE‑marked tests could achieve quicker turnaround times, the frequency of batch testing would have a considerable impact on turnaround time in practice, and therefore it is likely that standard turnaround times could be met, irrespective of which test method is used. The Committee considered next-generation sequencing and noted that research is currently being done on this method to look at panels of lung cancer genes. It noted that current turnaround time and cost are a hindrance to implementation, but that these practicalities are likely to be resolved in the future. The Committee concluded that next-generation sequencing is likely to be an important method for identifying EGFR‑TK mutations in the future. # Cost effectiveness The Committee noted that the price a laboratory charged for an EGFR‑TK mutation test was used in the cost-effectiveness analyses and that this price is not necessarily a true reflection of the actual cost to a laboratory. The Committee noted that the mean test costs reported in the survey of laboratories in England and Wales ranged from £130 to £188 (see section 5.27). It heard from clinical specialists on the Committee that the true cost to a laboratory may vary depending on their individual set-up, and that costs can change over time as experience and throughput changes. The Committee accepted that the reference case states that costs to the NHS should be used, and therefore that the approach taken by the External Assessment Group in their cost-effectiveness modelling was appropriate. The Committee concluded that the true costs of the tests are likely to be very similar for all the tests included in this assessment and that they are appropriately incorporated in the cost-effectiveness models. The Committee noted that the overall survival estimates used in the 'comparative effectiveness' and the 'linked evidence' cost-effectiveness analyses came from the IPASS trial for the therascreen EGFR PCR Kit and from the First-SIGNAL trial for Sanger sequencing. The Committee heard from the External Assessment Group that the reason for this was the need to use the same assumptions as in NICE technology appraisal guidance 192 (Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer). It also heard from the External Assessment Group that, if the IPASS survival estimates were used for both tests, Sanger sequencing was more costly and more effective than the therascreen EGFR PCR Kit. However, if the survival estimates from the First-SIGNAL trial were used for both tests, the therascreen EGFR PCR Kit became more costly and more effective than Sanger sequencing. The Committee noted that that 'comparative effectiveness' and the 'linked evidence' cost-effectiveness models appeared sensitive to the difference in quality-adjusted life year (QALY) gains from the 2 trials, and that these results could be because of relatively small differences in QALYs. The Committee considered the assumptions used in the cost-effectiveness analyses. It noted that, in the 'comparative effectiveness' and the 'linked evidence' analyses, a key assumption was that the difference in comparative effectiveness between the studies was solely because of the use of different tests. However, the Committee acknowledged that the differences in comparative effectiveness between the tests may be caused by a variety of factors, such as differences in the patient populations. The Committee therefore concluded that the assumption on comparative effectiveness used in these models is unlikely to hold true. The Committee considered the face validity of the 'comparative effectiveness' and the 'linked evidence' analyses. It noted that, although the External Assessment Group had made a good attempt to model the cost effectiveness of EGFR‑TK mutation testing, the analyses were severely hampered by lack of evidence and therefore the greater level of assumptions needed. The Committee was especially concerned about the uncertainties in input parameters, such as cost and overall survival (see sections 6.12 and 6.13). The Committee concluded that, given these problems, the results of the cost-effectiveness analyses were not robust. The Committee considered the validity of the results of the 'equal prognostic value' analysis. It acknowledged that the assumption of equal prognostic value across the tests was not an unreasonable approach given the lack of evidence and the similarity in technical performance of the tests. The Committee noted that, in the base case, the difference in total costs between the most expensive and least expensive test strategy was small. It also noted that, in the sensitivity analysis, although the difference in total costs between the different test strategies increased, it still remained relatively small and that the difference in total QALYs was also low. The Committee concluded that, on balance, the cost effectiveness of the different tests and test strategies for EGFR‑TK mutation testing are likely to be similar. The Committee noted that, for some of the tests (high-resolution melt analysis, pyrosequencing combined with fragment length analysis and single-strand conformation polymorphism analysis), the 'equal prognostic value' analysis was the only economic modelling performed, and that test accuracy and clinical effectiveness were not assessed by the External Assessment Group because data were not available. The Committee acknowledged that this represented a weaker evidence base than that for the therascreen EGFR PCR Kit, the cobas EGFR Mutation Test and Sanger sequencing tests. It noted further that 2 tests (therascreen EGFR Pyro Kit and next-generation sequencing) were not included in the assessment because no information on failure rates in clinical practice in the UK was available. The Committee acknowledged that, although the cost effectiveness of the different tests and test strategies for EGFR‑TK mutation testing are likely to be similar, there is insufficient evidence to support this conclusion. The Committee noted that the analysis in NICE technology appraisal guidance 192 (Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer) was primarily based on data from the IPASS trial, which used the therascreen EGFR PCR Kit to classify tumours of patients as EGFR‑TK mutation positive or negative. The Committee acknowledged that the recommendation of gefitinib for the first-line treatment of locally advanced or metastatic NSCLC in patients whose tumours test positive for the EGFR‑TK mutation (NICE technology appraisal guidance 192) implies that the therascreen EGFR PCR Kit is recommended and cost effective as part of the test-treat strategy. The Committee concluded that, for the cobas EGFR Mutation Test and for Sanger sequencing-based methods, an equivalent evidence base exists, and therefore these tests and the therascreen EGFR PCR Kit can be considered clinically effective and cost effective for informing first-line treatment decisions in patients with previously untreated, locally advanced or metastatic NSCLC in the NHS. The Committee further concluded that, for the non-Sanger sequencing-based tests (high-resolution melt analysis, pyrosequencing combined with fragment length analysis and single-strand conformation polymorphism analysis) and for tests not included in the External Assessment Group's assessment (the therascreen EGFR Pyro Kit and next-generation sequencing), the evidence was insufficient to allow any recommendations to be made on their use.# Recommendations for further research NICE recommends that studies directly comparing different epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutation test methods are performed. These studies should include the re-testing of stored non-small-cell lung cancer (NSCLC) tumour samples using different EGFR‑TK mutation test methods and should link to patient outcomes. NICE recommends that a multivariate prediction model is developed with the aim of predicting the response of previously untreated, advanced or metastatic non-small-cell lung cancer NSCLC to treatment with an EGFR‑TK inhibitor.# Related NICE guidance # Published Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer. NICE technology appraisal guidance 258 (2012). Lung cancer for adults. NICE quality standard 17 (2012). Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 227 (2011). Lung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline 121 (2011). Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010). Pemetrexed for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 190 (2010). Pemetrexed for the first-line treatment of non-small-cell lung cancer. NICE technology appraisal guidance 181(2009). Erlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008). Endobronchial ultrasound-guided transbronchial needle aspiration for mediastinal masses. NICE interventional procedure guidance 254 (2008). Pemetrexed for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 124 (2007). # Under development NICE is developing the following guidance: Crizotinib for the treatment of previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. NICE technology appraisal. Publication expected September 2013. Afatinib for the treatment of EGFR mutation-positive non-small-cell lung cancer. NICE technology appraisal. Publication expected June 2014. Erlotinib and gefitinib for the treatment of non-small-cell lung cancer following prior chemotherapy (Review of TA162 and TA175). NICE technology appraisal. Publication expected June 2014. Pemetrexed for maintenance treatment following induction therapy with pemetrexed and cisplatin for non-squamous non-small-cell lung cancer. NICE technology appraisal. Publication date to be confirmed.# Review NICE will update the literature search at least every 3 years to ensure that relevant new evidence is identified. NICE will contact product sponsors and other stakeholders about issues that may affect the value of the diagnostic technology. NICE may review and update the guidance at any time if significant new evidence becomes available. Andrew DillonChief ExecutiveAugust 2013# About this guidance NICE diagnostics technologies guidance is designed to help the NHS adopt efficient and cost-effective medical diagnostic technologies more rapidly and consistently. The programme concentrates on pathological tests, imaging, endoscopy and physiological measurement, since these represent most of the investigations performed on patients. The types of products that might be included are medical diagnostic technologies that give greater independence to patients, and diagnostic devices or tests used to detect or monitor medical conditions. Diagnostic technologies may be used for various purposes: diagnosis, clinical monitoring, screening, treatment triage, assessing stages of disease progression, and risk stratification. This guidance was developed using the NICE diagnostic technologies guidance process. We have produced a summary for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the view of NICE, which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity, and foster good relations. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0264-4	{'Recommendations': 'The tests and test strategies listed below are recommended as options for detecting epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutations in the tumours of adults with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC), when used in accredited laboratories participating in an external quality assurance scheme. The laboratory-developed tests should be designed to detect the mutations that can be detected by one of the CE‑marked tests as a minimum.\n\ntherascreen EGFR RGQ PCR Kit (CE‑marked, Qiagen)\n\ncobas EGFR Mutation Test (CE‑marked, Roche Molecular Systems)\n\nSanger sequencing of samples with more than 30% tumour cells and therascreen EGFR RGQ PCR Kit for samples with lower tumour cell contents\n\nSanger sequencing of samples with more than 30% tumour cells and cobas EGFR Mutation Test for samples with lower tumour cell contents\n\nSanger sequencing followed by fragment length analysis and polymerase chain reaction (PCR) of negative samples.\n\nThere was insufficient evidence for the Committee to make recommendations on the following methods:\n\nhigh-resolution melt analysis\n\npyrosequencing combined with fragment length analysis\n\nsingle-strand conformation polymorphism analysis\n\nnext-generation sequencing\n\ntherascreen EGFR Pyro Kit (CE‑marked, Qiagen).', 'The technologies': 'Ten epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutation methods for identifying adults with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC) who may benefit from first-line treatment with EGFR‑TK inhibitors were evaluated. Three are CE‑marked tests; 5\xa0are laboratory-developed tests; and 2\xa0are test strategies combining a CE‑marked test and a laboratory-developed test. Additional details of the tests are provided in section\xa04.\n\nOther tests and methods for detecting EGFR‑TK mutations are available, such as MALDI‑TOF. NICE is aware that the tests and methods are evolving, so new ones are likely to appear in the future.', 'Clinical need and practice': "# The problem addressed\n\nEpidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutation testing is indicated in adults with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC). Clinical trials have shown that patients with EGFR‑TK mutation-positive tumours gain more benefit from treatment with EGFR‑TK inhibitors than from standard chemotherapy treatment. Conversely, patients with EGFR‑TK mutation-negative tumours gain more benefit from standard chemotherapy than from EGFR‑TK inhibitors.\n\nMultiple tests and test strategies for EGFR‑TK mutation testing are currently used in NHS laboratories in England. The aim of this evaluation was to identify which tests and test strategies for EGFR‑TK mutation testing in adults with previously untreated, locally advanced or metastatic NSCLC are clinically and cost effective for informing first-line treatment decisions as currently recommended by NICE.\n\n# The condition\n\nNSCLC is the most common type of lung cancer in England and Wales, accounting for around 72% of all lung cancer cases. It can be further categorised by histological subtype; the 3\xa0main types being squamous cell carcinoma, adenocarcinoma and large-cell carcinoma.\n\nThe prevalence of EGFR‑TK mutations in NSCLC varies widely with population ethnicity, with reported prevalence of EGFR‑TK mutations in adenocarcinoma ranging from 10.4% in a study of Italian patients (Marchetti et al. 2005) to 50% in a study of Japanese patients (Kosaka et al. 2004). The estimated proportion of EGFR‑TK mutations in NSCLC in England and Wales is 16.6% (Rosell et al. 2009).\n\n# The diagnostic and care pathways\n\nNICE clinical guideline\xa0121 (Lung cancer: the diagnosis and treatment of lung cancer) recommends that patients with suspected lung cancer should be urgently referred for a chest X‑ray. If the results suggest lung cancer, a contrast-enhanced CT scan of the chest, upper abdomen and lower neck is performed. Further investigations to confirm a diagnosis and to provide information on the stage of the disease are then carried out. These investigations generally include a biopsy for histological confirmation and subtyping, but may also include positron emission tomography-computed tomography, endobronchial ultrasound-guided transbronchial needle aspiration, endoscopic ultrasound-guided fine needle aspiration or non-ultrasound-guided transbronchial needle aspiration.\n\nWhen biopsy is successful, DNA extraction and mutation analysis can be carried out on the biopsy tissue (which is generally stored as formalin-fixed paraffin-embedded tissue) to determine whether the tumour is EGFR‑TK mutation-positive or -negative. If biopsy tissue is not available, DNA extracted from cytology samples can be used for mutation analysis. Other molecular tests may be performed as clinically indicated.\n\nParticipants at a European multidisciplinary workshop 'EGFR testing in NSCLC: from biology to clinical practice' (2009) emphasised the importance of standardisation and validation of EGFR‑TK mutation tests and recommended that testing should only be undertaken in a quality-assured, accredited setting. However, there was no consensus on which laboratory test should be used for clinical decision-making. Participants agreed that the decision to request EGFR‑TK mutation testing should be made by the treating physician and that results should be reported within 7\xa0working days of request. Conversely, guidelines from the Royal College of Pathologists recommend that, to minimise turnaround time, molecular diagnostic tests should be ordered by the pathologist reporting on the histology of the tumour.\n\nTreatment options for NSCLC include gefitinib and erlotinib, which are EGFR‑TK inhibitors indicated for patients with EGFR‑TK mutation-positive tumours. NICE's technology appraisal guidance\xa0192 (Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer) and technology appraisal guidance\xa0258 (Erlotinib for the first-line treatment of locally advanced or metastatic EGFR‑TK mutation-positive non-small-cell lung cancer) recommend gefitinib and erlotinib respectively as options for the first-line treatment of locally advanced or metastatic NSCLC in people whose tumour tests positive for an EGFR‑TK mutation. Other treatment options for NSCLC include chemotherapy regimens. NICE clinical guideline\xa0121 recommends that chemotherapy should be offered to people with stage\xa0III or\xa0IV NSCLC and a good performance status (WHO 0, 1 or Karnofsky score 80–100) with the aim of improving survival, disease control and quality of life. Treatment with curative intent is not possible for these people. First-line chemotherapy should be a combination of a single third-generation drug (docetaxel, gemcitabine, paclitaxel or vinorelbine) and a platinum drug (carboplatin or cisplatin). People who are unable to tolerate a platinum combination may be offered single-agent chemotherapy with a third-generation drug. NICE technology appraisal guidance\xa0181 (Pemetrexed for the first-line treatment of non-small-cell lung cancer) recommends pemetrexed plus cisplatin as a first-line treatment for locally advanced or metastatic NSCLC, if the histology of the tumour has been confirmed as adenocarcinoma or large-cell tumour.", 'The diagnostic tests': "# The interventions\n\n## Therascreen EGFR RGQ PCR Kit\n\nThe therascreen EGFR RGQ PCR Kit (Qiagen) is a CE‑marked real-time polymerase chain reaction (PCR) assay for the targeted detection of 29\xa0mutations in exons\xa018 to\xa021 of the epidermal growth factor receptor tyrosine kinase (EGFR‑TK) gene:\n\nG719X (G719S/G719A/G719C) in exon\xa018\n\ndeletions in exon\xa019\n\nT790M in exon\xa020\n\nS768I in exon\xa020\n\ninsertions in exon\xa020\n\nL858R in exon\xa021\n\nL861Q in exon\xa021.\n\nTo ensure it complies with the CE marking, the DNA is first isolated from a specimen of formalin-fixed paraffin-embedded tissue using the QIAamp DNA FFPE Tissue Kit. The total amount of DNA in the sample is assessed by a control assay. The therascreen EGFR RGQ PCR Kit then uses 2\xa0technologies for detecting mutations: ARMS (amplification-refractory mutation system) for mutation-specific DNA amplification; and Scorpions for detecting amplified regions. Scorpions are bi-functional molecules containing a PCR primer covalently linked to a fluorescently labelled probe. A real-time PCR instrument (Rotor‑Gene Q 5‑Plex HRM Platform for consistency with CE marking) is used to perform the amplification and to measure fluorescence.\n\nThe limits of detection (the per cent mutant DNA present in a background of wild-type DNA, at which 95% or more replicates were determined positive) reported by the manufacturer for the different mutations ranged from 0.5% to 7.0%.\n\nAn older version of the test exists (the therascreen EGFR PCR Kit), which was inherited by Qiagen when they acquired DxS Ltd. This older version uses the same methods as the newer therascreen EGFR RGQ PCR Kit, and detects 28 of the same mutations, but is not designed to detect the resistance mutation T790M. The limit of detection claimed by the manufacturer for the therascreen EGFR PCR Kit is 1% mutant DNA in a background of wild-type DNA. This version is no longer being actively marketed by Qiagen, was not used in any of the studies included in this review and has been superseded by the therascreen EGFR RGQ PCR Kit. Further, an earlier version of the therascreen EGFR PCR Kit, which did include an assay for T790M, was used to analyse all samples in the IPASS trial. This version is no longer available, but is considered equivalent to the therascreen EGFR RGQ PCR Kit for the purpose of this assessment.\n\n## Cobas EGFR Mutation Test\n\nThe cobas EGFR Mutation Test (Roche Molecular Systems) is a CE‑marked real-time PCR test for the targeted detection of 41\xa0mutations in exons\xa018 to\xa021 of the EGFR‑TK gene:\n\nG719X (G719S/G719A/G719C) in exon\xa018\n\ndeletions and complex mutations in exon\xa019\n\nT790M in exon\xa020\n\nS768I in exon\xa020\n\ninsertions in exon\xa020\n\nL858R in exon\xa021 (2 variants).\n\nThe tumour tissue is first processed using the cobas DNA Sample Preparation Kit. The second step is PCR amplification and detection of EGFR‑TK mutations using complementary primer pairs and fluorescently labelled probes. The PCR is run using the cobas z\xa0480\xa0Analyzer, which automates amplification and detection. Cobas\xa04800 software provides automated test result reporting.\n\nThe limits of detection (lowest amount of DNA [nanogram] per reaction well to achieve a 95% or higher 'mutation detected' rate), as reported by the manufacturer for the different mutations, ranged from 0.78\xa0nanograms to 3.13\xa0nanograms of DNA per well.\n\n## Sanger sequencing of samples with more than 30% tumour cells and therascreen EGFR RGQ PCR Kit for samples with lower tumour cell contents\n\nIn this test strategy, Sanger sequencing of exons\xa018 to\xa021 (described in section\xa04.19) is used to detect EGFR‑TK mutations in test samples with more than 30% tumour cells, and the therascreen EGFR RGQ PCR Kit (described in sections\xa04.1 to\xa04.4) is used to detect EGFR‑TK mutations in samples with less than 30% tumour cells.\n\n## Sanger sequencing of samples with more than 30% tumour cells and cobas EGFR Mutation Test for samples with lower tumour cell content\n\nIn this test strategy, Sanger sequencing of exons\xa018 to\xa021 (described in section\xa04.19) is used to detect EGFR‑TK mutations in test samples with more than 30% tumour cells, and the cobas EGFR Mutation Test (described in sections\xa04.5 to\xa04.7) is used to detect EGFR‑TK mutations in samples with less than 30% tumour cells.\n\n## Sanger sequencing followed by fragment length analysis and PCR of negative samples\n\nSanger sequencing of exons\xa018 to\xa021 is used as an initial test to screen for mutations. Fragment length analysis to detect exon\xa019 deletions and real-time PCR to detect the exon\xa021 mutation L858R are then used on samples that produce a negative result using Sanger sequencing.\n\n## Pyrosequencing and fragment length analysis\n\nThis test strategy combines in-house methods of pyrosequencing (to detect point mutations) with in-house methods of fragment length analysis (to detect deletions and insertions) for EGFR‑TK mutation detection.\n\nPyrosequencing involves extracting DNA from the sample and amplifying it using PCR. Nucleotides are added sequentially to the amplified PCR product. A series of enzymes incorporates nucleotides into the complementary DNA strand, generates light proportional to the number of nucleotides added and degrades unincorporated nucleotides. The DNA sequence is determined from the resulting pyrogram trace.\n\nIn fragment length analysis, DNA is extracted from the sample, and then amplified and labelled with fluorescent dye using PCR. Amplified DNA is mixed with size standards and analysed using capillary electrophoresis. The fluorescence intensity is monitored as a function of time, and analysis software can determine the size of the fragments. The presence or absence of deletions and insertions can then be reported.\n\n## Therascreen EGFR Pyro Kit\n\nThe therascreen EGFR Pyro Kit (Qiagen) is a CE‑marked pyrosequencing kit. It is a targeted method of mutation detection designed to detect and distinguish between:\n\nG719S, G719A and G719C in exon\xa018\n\nthe 20\xa0most common deletions in exon\xa019\n\nS768I and T790M in exon\xa020\n\nL858R and L861Q in exon\xa021.\n\nThe kit provides all primers, controls, buffers and reagents necessary to perform the assay. Samples are analysed on the PyroMark Q24 System and a plug-in report tool that simplifies analysis of the pyrogram trace is available.\n\n## Single-strand conformation polymorphism analysis\n\nSingle-strand conformation polymorphism analysis is a screening method of mutation detection. The DNA is first extracted from the sample and amplified using PCR. The PCR product is then prepared for analysis by heat denature and analysed using capillary electrophoresis under non-denaturing conditions. Sequence variations (single-point mutations and other small changes) are detected through electrophoretic mobility differences.\n\n## High-resolution melt analysis\n\nHigh-resolution melt analysis is a screening method of mutation detection. The DNA is first extracted from the sample and amplified using PCR. The PCR product is then precisely warmed so that the 2\xa0strands of DNA 'melt' apart. Fluorescent dye, which only binds to double-stranded DNA, is used to monitor the process. A region of DNA with a mutation will 'melt' at a different temperature from the same region of DNA without a mutation. These changes are documented as melt curves and the presence or absence of a mutation can be reported.\n\n## Next-generation sequencing\n\nNext-generation sequencing is a screening method of mutation detection. The concept is similar to Sanger sequencing (described in section\xa04.19), but the sample DNA is first fragmented into a library of small segments that can be sequenced in parallel reactions.\n\n# The comparator\n\n## Sanger sequencing\n\nSanger sequencing (also called direct sequencing) is a screening method of mutation detection. Sanger sequencing is a commonly used method, but there is a lot of variation in how it is carried out. In general, after DNA is extracted from the sample, it is amplified using PCR. The PCR product is then cleaned up and sequenced in both forward and reverse directions. The sequencing reaction uses dideoxynucleotides labelled with coloured dyes, which randomly terminate DNA synthesis, creating DNA fragments of various lengths. The sequencing reaction product is then cleaned up and analysed using capillary electrophoresis. The raw data are analysed using software to generate the DNA sequence. All steps are performed at least in duplicate to increase confidence that an identified mutation is real. It should be noted that sequencing only works well when viable tumour cells constitute 25% or more of the sample.", 'Outcomes': "The Diagnostics Advisory Committee (section\xa011) considered evidence from several sources (section\xa012).\n\n# How outcomes were assessed\n\nThe assessment was performed by an External Assessment Group and consisted of a systematic review, a web-based survey and the development of a decision analytic model.\n\nThe systematic review was carried out to identify evidence on the technical performance and clinical effectiveness of the different options available to detect epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutations in previously untreated locally advanced or metastatic non-small-cell lung cancer (NSCLC), and so adults who may benefit from first-line treatment with EGFR‑TK inhibitors.\n\nThe web-based survey was conducted to gather data on the technical performance characteristics and costs of EGFR‑TK mutation tests in use in NHS laboratories.\n\nA decision analytic model was developed to assess the cost effectiveness of different methods of EGFR‑TK mutation testing in helping to decide between treatment with standard chemotherapy and EGFR‑TK inhibitors for patients with locally advanced or metastatic NSCLC. Three different analytic approaches, described below, were used to calculate cost effectiveness, each involving different levels of evidence.\n\n'Comparative effectiveness' analysis: This analysis used data on the comparative effectiveness (progression-free survival and overall survival) of EGFR‑TK inhibitors and standard chemotherapy in patients with EGFR‑TK mutation-positive, EGFR‑TK mutation-negative and EGFR‑TK mutation-unknown tumours. The tests included in this analysis were the therascreen EGFR PCR Kit and Sanger sequencing of exons\xa019 to\xa021.\n\n'Linked evidence' analysis: This is the same as the 'comparative effectiveness' analysis, except that it allowed the inclusion of EGFR‑TK mutation tests that have data on the accuracy of the test for predicting response to EGFR‑TK inhibitors but no data on comparative effectiveness (progression-free survival and overall survival in patients with EGFR‑TK mutation-positive, EGFR‑TK mutation-negative and EGFR‑TK mutation-unknown tumours). Tests included in this analysis were the therascreen EGFR PCR Kit, Sanger sequencing of exons\xa018 to\xa021 and Sanger sequencing of exons\xa019 to\xa021.\n\n'Assumption of equal prognostic value' analysis: For the remaining EGFR‑TK mutation tests in the scope, no data were available on either the comparative effectiveness or the accuracy of the test for predicting response to EGFR‑TK inhibitors. Therefore, for these tests, it was only possible to make a comparison based on differences in technical performance and test costs retrieved from the web-based survey, while assuming equal prognostic value across tests.\n\n# Technical performance\n\nOne study identified from the systematic review evaluated the technical performance of EGFR‑TK mutation tests. The study was conducted in the Department of Molecular Diagnostics at the Royal Marsden Hospital and the Institute of Cancer Research. The study reported data for 2\xa0years of EGFR‑TK mutation testing from January\xa02009 to January\xa02011. During year\xa01 of the testing, the therascreen EGFR PCR Kit was used. During year\xa02, a combination of the therascreen EGFR PCR Kit, fragment analysis (for exon\xa019 deletions and exon\xa020 insertions) and Sanger sequencing (for the rarer exon\xa019 or exon\xa021 mutations) was used. A total of 121\xa0patients were tested during year\xa01 and 755 during year\xa02. The mean turnaround time for the therascreen EGFR PCR test alone during year\xa01 was 4.9\xa0business days (95% confidence interval [CI] 4.5\xa0days to 5.5\xa0days). However, the actual time from the test request to the result was 17.8\xa0days (95%\xa0CI 16.4\xa0days to 19.4\xa0days). The total test failure rate for the first year of the study was 19% of all samples assessed, but this improved over time from a failure rate of 33% over the first 3\xa0months to 13% during the last 3\xa0months of year\xa01 testing. The total failure rate was lower in the second year of the study at only 5% of all samples assessed.\n\nThere were 24\xa0UK laboratories participating in the 2012–2013 UK National External Quality Assessment Service (NEQAS) pilot scheme for EGFR‑TK mutation testing. Of these, 14 provided information to NICE during the scoping phase of the assessment and were invited to participate in the survey. Thirteen of the 14\xa0laboratories completed the web-based survey.\n\nThe therascreen EGFR PCR Kit was the most commonly used EGFR‑TK mutation test, with 6\xa0laboratories using it. A combination of fragment length analysis and pyrosequencing was used in 2\xa0laboratories. Sanger sequencing was used in 2\xa0laboratories. However, one of these laboratories also uses the cobas EGFR Mutation Test for verifying mutations or when the sample contains insufficient tumour cells for Sanger sequencing (less than 30%). The second of these laboratories also uses fragment length analysis and real-time PCR to follow up samples found to be negative with Sanger sequencing. Single-strand conformation analysis, high-resolution melt analysis and pyrosequencing were used in single laboratories. One laboratory also provided information on a next-generation sequencing method that is being developed and validated.\n\nThe survey results showed that there were no clear differences between tests. The number of samples screened for EGFR‑TK mutations in a typical week varied by laboratory from less than 5 (6\xa0laboratories) to more than 20 (3\xa0laboratories). The frequency at which the laboratories ran the tests ranged from daily to every other week. Batch sizes ranged from less than 3\xa0samples to 10\xa0samples but most laboratories stated that they would match demand rather than waiting for a minimum batch size.\n\nMost laboratories had a turnaround time from receiving the sample to reporting the result to the clinician of 3–5\xa0days or 6–7\xa0days, with 1\xa0laboratory reporting a turnaround of 24–28\xa0hours (therascreen EGFR PCR Kit) and 1\xa0laboratory reporting a turnaround of 8–10\xa0days (therascreen EGFR PCR Kit). The estimated total number of failed samples ranged from 0% to 10%, with the number of failed samples because of insufficient tumour cells ranging from 0–5%. The most common reasons for failed tests were insufficient tumour cell count and poor-quality DNA or DNA degradation.\n\nThe cost of the EGFR‑TK mutation tests ranged from £110 to £190 and the price that the laboratories charged for the tests ranged from £120 to £200. When there was a difference between the test cost and the price charged, this ranged from £10 to £37.50 per test. No single test appeared to be more or less expensive than any of the other tests.\n\nIt was noted by UK NEQAS that error rates seen in the quality assurance scheme for EGFR‑TK mutation testing are not always method related, and may be because of processing and reporting problems. In addition, UK NEQAS noted that there had been no correlation between any method used for EGFR‑TK mutation testing and errors since the scheme was started in 2010.\n\n# Accuracy\n\nTwo randomised controlled trials and 4\xa0cohort studies provided data on the accuracy of EGFR‑TK mutation testing for predicting the response to treatment with EGFR‑TK inhibitors in patients with advanced or metastatic NSCLC. Three studies included patients treated with gefitinib and 3\xa0included patients treated with erlotinib.\n\nPatient characteristics varied across studies. One study included mainly white patients and 1\xa0study included mainly East Asian patients (4\xa0studies did not report the ethnicity of patients). All studies reported that a high proportion of patients had metastatic disease. Most patients had a histological diagnosis of adenocarcinoma (45–100%), but 2\xa0studies included some patients with squamous cell carcinoma (9–15%). Four studies mainly, or only, included patients who had never smoked, whereas 2\xa0studies mainly included patients who were current or former smokers.\n\nFive studies evaluated Sanger sequencing methods for identifying any EGFR‑TK mutation; 3\xa0assessed exons\xa018 to\xa021, 1\xa0assessed exons\xa019 to\xa021, and 1\xa0assessed exons\xa018 to\xa024 (Sanger sequencing or WAVE-HS for inadequate samples [less than 50% tumour cells]). One study assessed the therascreen EGFR PCR Kit (the version designed to detect 29\xa0mutations, including T790M).\n\nThe therascreen EGFR PCR Kit appears to have the best overall performance for discriminating between patients who are likely to benefit from EGFR‑TK inhibitor treatment and patients who are not. The sensitivity and specificity estimates using objective response as the reference standard were 99% (95%\xa0CI 94% to 100%) and 69% (95%\xa0CI 60% to 77%) respectively.\n\nOf the 5\xa0studies that used Sanger sequencing methods to identify EGFR‑TK mutations, 4\xa0reported high estimates of specificity (more than 80%) and sensitivities ranged from 60% to 80% when objective response was used as the reference standard. The remaining Sanger sequencing study reported low specificity (61%) with high sensitivity (84%) for objective response as the reference standard.\n\n# Clinical effectiveness\n\nFive randomised controlled trials provided data on the clinical effectiveness of EGFR‑TK inhibitors compared with standard chemotherapy in patients with advanced or metastatic NSCLC whose tumours tested positive for EGFR‑TK mutations. One additional study reported data for a subgroup of patients from the EURTAC trial whose samples had been re-analysed using a different EGFR‑TK mutation testing method. Three of the trials included only patients with EGFR‑TK mutation-positive tumours, and the remaining 2\xa0trials (IPASS and First-SIGNAL) included all patients regardless of EGFR‑TK mutation status, but also reported a subgroup analysis for patients whose tumours tested positive for EGFR‑TK mutations. The trials compared the EGFR‑TK inhibitors gefitinib or erlotinib with various single-agent or combination standard chemotherapy regimens.\n\nPatient characteristics varied across studies. Four studies were conducted in East Asia and 1\xa0was conducted in Western Europe. One study included patients who had never smoked, 1\xa0study included mainly patients who had never smoked (94%) and the rest included between 62% and 71% of patients who had never smoked. One study included only patients with a diagnosis of adenocarcinoma, whereas in the remaining studies approximately 90% had a diagnosis of adenocarcinoma. Most patients (more than 75%) in all studies had metastatic disease.\n\nTwo studies used Sanger sequencing methods to assess EGFR‑TK mutation status, but both limited the definition of positive EGFR‑TK mutation status to the presence of an 'activating mutation' (exon\xa019 deletions or exon\xa021 mutation L858R). The remaining studies used EGFR‑TK mutation tests that targeted a wider range of mutations. One study reported the results of a re-analysis of samples from the EURTAC trial using the cobas EGFR Mutation Test. The other study (IPASS) used the therascreen EGFR PCR Kit (the version designed to detect 29\xa0mutations, including T790M). The North East Japan Study Group (NEJSG) trial used fragment length analysis, targeting exon\xa019 deletions, exon\xa021 point mutations (L858R, L861Q), exon\xa018 point mutations (G719A, G719C, G719S), and exon\xa020 point mutation (T790M). The First-SIGNAL trial used Sanger sequencing of exons\xa019 to\xa021.\n\nAll studies reported improvements in objective response, measured as relative risk. Objective response ranged from a relative risk of 1.51 (95%\xa0CI 1.23 to 1.88) to 3.89 (95%\xa0CI 2.34 to 6.68) for patients with EGFR‑TK mutation-positive tumours who were given EGFR‑TK inhibitors compared with patients given standard chemotherapy. All studies also reported statistically significant improvements or trends towards improvement in progression-free survival, with hazard ratios ranging from 0.16 (95%\xa0CI 0.10 to 0.26) to 0.54 (95%\xa0CI\xa00.27 to 1.10) for patients with EGFR‑TK mutation-positive tumours who were given EGFR‑TK inhibitors compared with patients given standard chemotherapy. Four studies reported overall survival but none found a statistically significant difference between patients given EGFR‑TK inhibitors and patients given standard chemotherapy, with hazard ratios ranging from 0.89 (95%\xa0CI 0.63 to 1.24) to 1.04 (95%\xa0CI\xa00.65 to 1.68).\n\nThe results from the IPASS trial showed that progression-free survival in patients with EGFR‑TK mutation-negative tumours was statistically significantly shorter when patients were treated with EGFR‑TK inhibitors than with standard chemotherapy (hazard ratio [HR] 2.85, 95%\xa0CI 2.05 to 3.98). A similar trend for patients with EGFR‑TK mutation-negative tumours, although not statistically significant, was observed in the First-SIGNAL trial (HR\xa01.42, 95%\xa0CI 0.82 to 2.47).\n\n# Cost effectiveness\n\nThe External Assessment Group received the health economic model submitted by AstraZeneca for NICE technology appraisal guidance\xa0192 (Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer). The External Assessment Group also took into account amendments and corrections to the model that were accepted by the appraisal committee for NICE technology appraisal guidance 192. This model calculates the expected cost effectiveness of gefitinib compared with standard chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC in patients with a positive EGFR‑TK mutation test based on the therascreen EGFR PCR Kit. The External Assessment Group used the AstraZeneca model to develop a de\xa0novo model that included patients with a positive, negative or unknown EGFR‑TK mutation test result.\n\nThe External Assessment Group developed a decision tree and a Markov model to analyse the long-term consequences of technical performance and accuracy of the different EGFR‑TK mutation tests and test combinations followed by treatment with either standard chemotherapy or an EGFR‑TK inhibitor in patients with NSCLC. The decision tree was used to model the test result (positive, unknown or negative) and the treatment decision. Patients with a positive test result receive an EGFR‑TK inhibitor. Patients with a negative test result or an unknown EGFR‑TK mutation status receive standard chemotherapy (pemetrexed and cisplatin). The Markov model was used to estimate the long-term consequences in terms of costs and quality-adjusted life years (QALYs). The model has a cycle time of 21\xa0days (resembling the duration of 1\xa0cycle of chemotherapy), and a time horizon of 6\xa0years. In the model, after a treatment decision is made, patients can either have progression-free disease (subdivided into 'response' and 'stable disease' based on objective response rate), experience disease progression or die.\n\nThe proportions of positive and negative EGFR‑TK mutation test results were based on: the estimated proportions of patients with NSCLC and EGFR‑TK mutation-positive tumours in England and Wales (16.6%, standard error 0.8%); the test accuracy (sensitivity and specificity with objective response to EGFR‑TK inhibitor as reference standard); and the proportion of patients with an unknown test result, based on data from published studies (IPASS and Jackman et\xa0al. 2007). The proportions of positive, negative and unknown EGFR‑TK mutation test results for the therascreen EGFR PCR Kit were 32.8%, 44.6% and 22.7% respectively. The proportions of positive, negative and unknown EGFR‑TK mutation test results for Sanger sequencing of exons\xa018 to\xa021 were 29.0%, 33.4% and 37.7% respectively. In the 'assumption of equal prognostic value' analysis, the proportions of positive, negative and unknown EGFR‑TK mutation test results were assumed equal to the therascreen EGFR PCR Kit for all tests and test strategies.\n\nThe objective response rates were based on data from published studies (IPASS, First-SIGNAL and Yang et al. 2008). For EGFR‑TK mutation-negative or -unknown tumours (treated with standard chemotherapy), objective response rates were adjusted to correspond to treatment with pemetrexed and cisplatin. Objective response rates for EGFR‑TK mutation-positive, -negative and ‑unknown tumours identified using the therascreen EGFR PCR Kit were 0.712, 0.335 and 0.403 respectively. Objective response rates for EGFR‑TK mutation-positive, -negative and -unknown tumours identified using Sanger sequencing of exons\xa018 to\xa021 were 0.731, 0.604 and 0.403 respectively. In the 'assumption of equal prognostic value' analysis, the objective response rates for EGFR‑TK mutation-positive, -negative and -unknown tumours were assumed equal to the therascreen EGFR PCR Kit for all tests and test strategies.\n\nProgression-free survival and overall survival after testing with the therascreen EGFR PCR Kit were modelled using Weibull regression models based on the IPASS trial and a hazard ratio favouring treatment with an EGFR‑TK inhibitor (HR\xa00.43, 95%\xa0CI\xa00.34 to 0.53). For testing using Sanger sequencing of exons\xa019 to\xa021, progression-free survival and overall survival for patients with EGFR‑TK mutation-positive or -negative tumours were modelled using Kaplan-Meier curves extracted from the First-SIGNAL trial. Progression-free survival and overall survival for patients with tumours of unknown EGFR‑TK mutation status were based on the IPASS Weibull model for unknown mutations. For testing using Sanger sequencing of exons\xa018 to\xa021, progression-free survival and overall survival were assumed equal to testing using Sanger sequencing of exons\xa019 to\xa021.\n\nThe test costs were based on the prices charged by the NHS laboratories in England and Wales involved in the web-based survey (see table\xa01). In the case of an unknown EGFR‑TK mutation status, no test costs were taken into account if there was a pre-laboratory clinical failure, but full test costs were taken into account if there was a technical failure in the laboratory.\n\nTable 1 EGFR‑TK mutation test costs\n\nTest\n\nPrice charged\n\nStandard error\n\ntherascreen EGFR PCR Kit\n\n£154.58\n\n£12.01\n\nSanger sequencing of exons\xa019 to\xa021\n\n£147.50\n\n£27.50\n\nSanger sequencing of exons\xa018 to\xa021\n\n£147.50\n\n£27.50\n\nSanger sequencing or therascreen EGFR PCR Kit for samples with insufficient tumour cells\n\n£137.30\n\n£14.88\n\nSanger sequencing or cobas EGFR Mutation Test for samples with insufficient tumour cells\n\n£130.00\n\n£19.34\n\nPyrosequencing combined with fragment length analysis\n\n£187.50\n\n£12.50\n\nSanger sequencing followed by fragment length analysis/real-time PCR\n\n£140.00\n\n£27.50\n\nHigh-resolution melt analysis\n\n£150.00\n\n£27.50\n\ncobas EGFR Mutation Test\n\n£140.00\n\n£27.50\n\nSingle-strand conformation analysis\n\n£140.00\n\n£27.50\n\nAbbreviations: EGFR, epidermal growth factor receptor; PCR, polymerase chain reaction.\n\nResults from the 'comparative effectiveness' analysis showed the therascreen EGFR PCR Kit to be both less effective and less costly compared with Sanger sequencing of exons\xa019 to\xa021, with an incremental cost-effectiveness ratio (ICER) of £32,167 saved per QALY lost. Adjustments to costs and the proportions of patients with unknown mutation status in sensitivity analyses had little effect on the results. When treatment costs and adverse event costs were updated to 2012 costs, the ICER was £32,196 saved per QALY lost for the therascreen EGFR PCR Kit compared with Sanger sequencing. When the proportions of patients with unknown mutation status were based on the results from the web-based survey rather than information from published trials, the ICER was £34,555 saved per QALY lost for the therascreen EGFR PCR Kit compared with Sanger sequencing.\n\nThe External Assessment Group explained that the lower costs and QALYs for the therascreen EGFR PCR Kit were because patients with EGFR‑TK mutation-negative tumours had shorter overall survival in the IPASS trial (therascreen EGFR PCR Kit) than in the First-SIGNAL trial (Sanger sequencing of exons\xa019 to\xa021), whereas the outcome was comparable for patients whose tumours were EGFR‑TK mutation positive. For patients whose tumours were EGFR‑TK mutation unknown, overall survival was the same by assumption. Therefore, on average, with the therascreen EGFR PCR Kit patients had shorter overall survival, resulting in fewer QALYs and reduced costs compared with Sanger sequencing of exons\xa019 to\xa021.\n\nThe External Assessment Group noted that this analysis is particularly problematic because of the assumption that the differences in relative treatment response, progression-free survival and overall survival between the results of the First-SIGNAL trial (Sanger sequencing of exons\xa019 to\xa021) and the results of the IPASS trial (therascreen EGFR PCR Kit) were solely because of the different EGFR‑TK mutation tests used to distinguish between patients whose tumours were EGFR‑TK mutation positive (and receive EGFR‑TK inhibitor treatment) and patients whose tumours were EGFR‑TK mutation negative (and receive standard chemotherapy).\n\nResults from the 'linked evidence' analysis also showed the therascreen EGFR PCR Kit to be both less effective and less costly than Sanger sequencing of exons\xa018 to\xa021 at an ICER of £31,849 saved per QALY lost. Sensitivity analyses had little effect on the results. When the treatment costs and adverse event costs were updated to 2012 costs, the ICER was £34,169 saved per QALY lost for the therascreen EGFR PCR Kit compared with Sanger sequencing of exons\xa018 to\xa021. When the proportions of patients with unknown mutation status were based on the results from the web-based survey rather than information from published trials, the ICER was £31,880 saved per QALY lost for the therascreen EGFR PCR Kit compared with Sanger sequencing of exons 18\xa0to\xa021.\n\nThe reason for the lower costs and QALYs for the therascreen EGFR PCR Kit were the same as for the 'comparative effectiveness' analysis, as described in section\xa05.28.\n\nIn addition to the assumption described in section\xa05.30, the 'linked evidence' analysis also assumed that the relative progression-free survival and overall survival for Sanger sequencing of exons\xa018 to\xa021 correlated perfectly with the relative progression-free survival and overall survival for Sanger sequencing of exons\xa019 to\xa021.\n\nIn the 'assumption of equal prognostic value' analysis, the comparative effectiveness, test accuracy and proportion of patients with unknown mutation status for each test strategy were assumed equal to those of the therascreen EGFR PCR Kit. Therefore, the test strategies only differed with respect to costs. Results showed that the test strategy of Sanger sequencing or the cobas EGFR Mutation Test for samples with insufficient tumour cells was the least expensive (£15 [0.06%] cheaper than Sanger sequencing of exons\xa018 to\xa021 alone), and fragment length analysis combined with pyrosequencing was the most expensive strategy (£33 [0.13%] more expensive than Sanger sequencing of exons\xa018 to\xa021 alone).\n\nThe External Assessment Group did not include next-generation sequencing and the therascreen EGFR Pyro Kit in any of the cost-effectiveness analyses because of a lack of data. No published studies were identified for either of these methods and neither method is currently in routine clinical use in any NHS laboratories in England and Wales.", 'Considerations': "The Diagnostics Advisory Committee reviewed the evidence available on the clinical and cost effectiveness of epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutation testing to inform first-line treatment decisions in adults with locally advanced or metastatic non-small-cell lung cancer (NSCLC). The Committee considered the report produced by the External Assessment Group and statements from patient experts on the Committee and from clinical specialists who acted as specialist Committee members on this assessment.\n\nThe Committee discussed the External Assessment Group's report on the clinical and cost effectiveness of EGFR‑TK mutation tests. It noted that, during scoping, 10\xa0interventions had been identified as suitable for review in this assessment. However, during systematic review of the evidence, the External Assessment Group found limited data for many of the tests and no data on the clinical and cost effectiveness of next-generation sequencing and the therascreen EGFR Pyro Kit.\n\n# Technical performance and clinical validity\n\nThe Committee considered the technical performance of the different tests. It heard from clinical specialists on the Committee that, in their experience, the different tests generally have a similar level of accuracy in detecting the mutations that they are designed to detect. The Committee also noted the statement from the UK National External Quality Assessment Service (NEQAS) that errors seen in the EGFR quality assurance scheme are not always method related, and that variations in how tests are processed and implemented can lead to variations in the failure rates (see section\xa05.11). The Committee also considered the failure rates reported for the different tests in the web-based survey. The Committee considered that, although the survey was limited by its small sample size, it seemed to suggest that failure rates are generally not test-dependent. Furthermore, the Committee heard that it is standard practice for the quality of tissue samples to be initially assessed by a pathologist. Therefore, the decision made by the pathologist about whether to send a sample for EGFR‑TK mutation testing could impact on the number of patients with an unknown EGFR‑TK mutation status. The Committee concluded that the technical performance of the tests is not solely influenced by test accuracy, and that processing of samples and testing practices is likely to influence technical performance. It further concluded that, in UK practice, the technical performance of the tests under assessment is likely to be very similar.\n\nThe Committee discussed the lack of a gold standard test for assessing test accuracy, the difficulties relating to the different mutation coverage of the various tests, and the uncertainty about the clinical significance of some mutations. The Committee acknowledged that the approach taken by the External Assessment Group, in which accuracy for predicting response to treatment was calculated using objective response and disease control as reference standards, was a valid approach in this situation. It was advised by clinical specialists on the Committee, however, that deriving accuracy from response to treatment with an EGFR‑TK inhibitor is problematic. For instance, the definition of false positives was 'patients identified as having tumours with an EGFR‑TK mutation that do not respond to treatment with an EGFR‑TK inhibitor'. It noted that there may be other reasons why a tumour does not respond to treatment, such as concomitant medications, patient characteristics and other clinical factors.\n\nThe Committee considered the accuracy of EGFR‑TK mutation tests for predicting response to treatment. It noted that the External Assessment Group had only been able to obtain sensitivity and specificity estimates for therascreen EGFR PCR Kit and Sanger sequencing of exons\xa018 to\xa021 and exons 19\xa0to\xa021. The Committee also noted that, when accuracy estimates were available, the accuracy of different tests was calculated from different studies with different patient populations and different ways of classifying resistance mutations. The Committee heard from the External Assessment Group that, ideally, sensitivity and specificity values should be generated for all tests from a single set of samples, therefore limiting the influence of sampling and population differences on the accuracy estimates. The Committee acknowledged that this assessment did not present such a scenario and that it was plausible that differences in patient populations could have impacted on relative accuracy estimates for individual tests. The Committee therefore concluded that the relative predictive accuracy for the different tests could not be reliably established.\n\nThe Committee considered the effect of tissue quality on the accuracy of EGFR‑TK mutation testing. It heard from clinical specialists on the Committee that the quality of tissue samples available for testing often varies, and this may impact on both the test failure rates and test accuracy. The Committee noted that, in addition to obtaining good-quality tumour samples, it is important to use a sensitive test to enable detection of EGFR‑TK mutations, especially to ensure correct results in lower-quality tumour samples. It discussed the consequences of assigning the wrong EGFR‑TK mutation status to a patient and noted that both the IPASS and the Signal-FIRST trials (see section\xa05.21) had demonstrated that progression-free survival was shorter for patients receiving an EGFR‑TK inhibitor than for patients receiving standard chemotherapy in the EGFR‑TK mutation-negative subgroup. For this reason, the Committee concluded that it is important to ensure high accuracy of testing, particularly to minimise the chances of incorrect treatment.\n\nThe Committee then discussed the generalisability of the clinical evidence to UK clinical practice and the UK patient population. It noted that 4\xa0out of the 5\xa0randomised controlled trials identified by the External Assessment Group were conducted in East Asia (see sections\xa05.18 and\xa05.19). The Committee acknowledged that the patients included in the trials had characteristics different from patients usually seen in UK practice, most notably that the studies included a high proportion of patients who had never smoked and a high proportion of patients of East Asian origin. The Committee noted that all evidence for the therascreen EGFR RGQ PCR Kit came from the IPASS trial, which looked almost exclusively at patients from East Asia. It also noted that, although most of the evidence came from patients with adenocarcinoma, patients with squamous cell carcinoma would also be tested for EGFR‑TK mutations and these patients may have different clinical characteristics. The Committee concluded that, although there were some substantial differences between the trial populations and the population of patients presenting with advanced NSCLC in the UK, the effect on test accuracy was likely to be minimal and therefore the trial evidence could be used to support the effectiveness of testing in patients with adenocarcinoma and in patients with squamous cell carcinoma in a UK setting.\n\nThe Committee considered the value of tests that identify rare EGFR‑TK mutations. It acknowledged that screening tests are designed to detect more mutations than the targeted tests. In addition, the targeted tests (therascreen EGFR PCR Kit and the cobas EGFR Mutation Test) are designed to detect different sets of mutations, which vary in the number of rare forms of mutations included. The Committee heard from clinical specialists on the Committee that the clinical significance of rare mutations is generally unknown, and that treatment decisions for patients with a rare EGFR‑TK mutation would be made by the oncologist based on the availability of evidence, such as case studies. The Committee acknowledged that evidence on the clinical effect of rare mutations is being generated. However, it concluded that currently there is little additional value of tests designed to detect rare mutations, except for the purpose of collecting clinical outcome data for research.\n\nThe Committee discussed whether there are any benefits of using CE‑marked tests over laboratory-developed tests for detecting EGFR‑TK mutations. It heard that the CE‑marked EGFR‑TK mutation tests (therascreen EGFR RGQ PCR Kit and cobas EGFR Mutation Test) and the simpler laboratory-developed tests such as polymerase chain reaction (PCR) may be easier to implement than tests based on Sanger sequencing for laboratories with little molecular diagnostics experience (for example, pathology laboratories). The Committee therefore concluded that, although there was no distinguishable difference in the technical performance of the tests, the ease of use of the CE‑marked tests may be an advantage in some clinical settings, particularly when limited molecular diagnostics technical support is available.\n\nThe Committee considered the turnaround time of EGFR‑TK mutation testing. It noted that turnaround time was assumed not to be test-dependent and was therefore not included in the economic modelling. The Committee heard from clinical specialists on the Committee that turnaround time was impacted by factors such as transporting samples between different locations for testing and the set-up of the laboratory. It also heard from patient experts that waiting for test results causes additional anxiety to patients and that the rapid turnaround of test results is a priority for patients. The Committee acknowledged that, although the survey conducted by the External Assessment Group showed, on average, that similar turnaround times were achieved for all tests in the UK laboratories surveyed, the only test achieving a turnaround time shorter than 3\xa0days was the therascreen EGFR PCR Kit. However, the Committee concluded that, although it is possible that the CE‑marked tests could achieve quicker turnaround times, the frequency of batch testing would have a considerable impact on turnaround time in practice, and therefore it is likely that standard turnaround times could be met, irrespective of which test method is used.\n\nThe Committee considered next-generation sequencing and noted that research is currently being done on this method to look at panels of lung cancer genes. It noted that current turnaround time and cost are a hindrance to implementation, but that these practicalities are likely to be resolved in the future. The Committee concluded that next-generation sequencing is likely to be an important method for identifying EGFR‑TK mutations in the future.\n\n# Cost effectiveness\n\nThe Committee noted that the price a laboratory charged for an EGFR‑TK mutation test was used in the cost-effectiveness analyses and that this price is not necessarily a true reflection of the actual cost to a laboratory. The Committee noted that the mean test costs reported in the survey of laboratories in England and Wales ranged from £130 to £188 (see section\xa05.27). It heard from clinical specialists on the Committee that the true cost to a laboratory may vary depending on their individual set-up, and that costs can change over time as experience and throughput changes. The Committee accepted that the reference case states that costs to the NHS should be used, and therefore that the approach taken by the External Assessment Group in their cost-effectiveness modelling was appropriate. The Committee concluded that the true costs of the tests are likely to be very similar for all the tests included in this assessment and that they are appropriately incorporated in the cost-effectiveness models.\n\nThe Committee noted that the overall survival estimates used in the 'comparative effectiveness' and the 'linked evidence' cost-effectiveness analyses came from the IPASS trial for the therascreen EGFR PCR Kit and from the First-SIGNAL trial for Sanger sequencing. The Committee heard from the External Assessment Group that the reason for this was the need to use the same assumptions as in NICE technology appraisal guidance\xa0192 (Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer). It also heard from the External Assessment Group that, if the IPASS survival estimates were used for both tests, Sanger sequencing was more costly and more effective than the therascreen EGFR PCR Kit. However, if the survival estimates from the First-SIGNAL trial were used for both tests, the therascreen EGFR PCR Kit became more costly and more effective than Sanger sequencing. The Committee noted that that 'comparative effectiveness' and the 'linked evidence' cost-effectiveness models appeared sensitive to the difference in quality-adjusted life year (QALY) gains from the 2\xa0trials, and that these results could be because of relatively small differences in QALYs.\n\nThe Committee considered the assumptions used in the cost-effectiveness analyses. It noted that, in the 'comparative effectiveness' and the 'linked evidence' analyses, a key assumption was that the difference in comparative effectiveness between the studies was solely because of the use of different tests. However, the Committee acknowledged that the differences in comparative effectiveness between the tests may be caused by a variety of factors, such as differences in the patient populations. The Committee therefore concluded that the assumption on comparative effectiveness used in these models is unlikely to hold true.\n\nThe Committee considered the face validity of the 'comparative effectiveness' and the 'linked evidence' analyses. It noted that, although the External Assessment Group had made a good attempt to model the cost effectiveness of EGFR‑TK mutation testing, the analyses were severely hampered by lack of evidence and therefore the greater level of assumptions needed. The Committee was especially concerned about the uncertainties in input parameters, such as cost and overall survival (see sections\xa06.12 and\xa06.13). The Committee concluded that, given these problems, the results of the cost-effectiveness analyses were not robust.\n\nThe Committee considered the validity of the results of the 'equal prognostic value' analysis. It acknowledged that the assumption of equal prognostic value across the tests was not an unreasonable approach given the lack of evidence and the similarity in technical performance of the tests. The Committee noted that, in the base case, the difference in total costs between the most expensive and least expensive test strategy was small. It also noted that, in the sensitivity analysis, although the difference in total costs between the different test strategies increased, it still remained relatively small and that the difference in total QALYs was also low. The Committee concluded that, on balance, the cost effectiveness of the different tests and test strategies for EGFR‑TK mutation testing are likely to be similar.\n\nThe Committee noted that, for some of the tests (high-resolution melt analysis, pyrosequencing combined with fragment length analysis and single-strand conformation polymorphism analysis), the 'equal prognostic value' analysis was the only economic modelling performed, and that test accuracy and clinical effectiveness were not assessed by the External Assessment Group because data were not available. The Committee acknowledged that this represented a weaker evidence base than that for the therascreen EGFR PCR Kit, the cobas EGFR Mutation Test and Sanger sequencing tests. It noted further that 2\xa0tests (therascreen EGFR Pyro Kit and next-generation sequencing) were not included in the assessment because no information on failure rates in clinical practice in the UK was available. The Committee acknowledged that, although the cost effectiveness of the different tests and test strategies for EGFR‑TK mutation testing are likely to be similar, there is insufficient evidence to support this conclusion.\n\nThe Committee noted that the analysis in NICE technology appraisal guidance\xa0192 (Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer) was primarily based on data from the IPASS trial, which used the therascreen EGFR PCR Kit to classify tumours of patients as EGFR‑TK mutation positive or negative. The Committee acknowledged that the recommendation of gefitinib for the first-line treatment of locally advanced or metastatic NSCLC in patients whose tumours test positive for the EGFR‑TK mutation (NICE technology appraisal guidance\xa0192) implies that the therascreen EGFR PCR Kit is recommended and cost effective as part of the test-treat strategy. The Committee concluded that, for the cobas EGFR Mutation Test and for Sanger sequencing-based methods, an equivalent evidence base exists, and therefore these tests and the therascreen EGFR PCR Kit can be considered clinically effective and cost effective for informing first-line treatment decisions in patients with previously untreated, locally advanced or metastatic NSCLC in the NHS. The Committee further concluded that, for the non-Sanger sequencing-based tests (high-resolution melt analysis, pyrosequencing combined with fragment length analysis and single-strand conformation polymorphism analysis) and for tests not included in the External Assessment Group's assessment (the therascreen EGFR Pyro Kit and next-generation sequencing), the evidence was insufficient to allow any recommendations to be made on their use.", 'Recommendations for further research': 'NICE recommends that studies directly comparing different epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutation test methods are performed. These studies should include the re-testing of stored non-small-cell lung cancer (NSCLC) tumour samples using different EGFR‑TK mutation test methods and should link to patient outcomes.\n\nNICE recommends that a multivariate prediction model is developed with the aim of predicting the response of previously untreated, advanced or metastatic non-small-cell lung cancer NSCLC to treatment with an EGFR‑TK inhibitor.', 'Related NICE guidance': '# Published\n\nErlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer. NICE technology appraisal guidance 258 (2012).\n\nLung cancer for adults. NICE quality standard 17 (2012).\n\nErlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 227 (2011).\n\nLung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline 121 (2011).\n\nGefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010).\n\nPemetrexed for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 190 (2010).\n\nPemetrexed for the first-line treatment of non-small-cell lung cancer. NICE technology appraisal guidance 181(2009).\n\nErlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008).\n\nEndobronchial ultrasound-guided transbronchial needle aspiration for mediastinal masses. NICE interventional procedure guidance 254 (2008).\n\nPemetrexed for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 124 (2007).\n\n# Under development\n\nNICE is developing the following guidance:\n\nCrizotinib for the treatment of previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. NICE technology appraisal. Publication expected September 2013.\n\nAfatinib for the treatment of EGFR mutation-positive non-small-cell lung cancer. NICE technology appraisal. Publication expected June 2014.\n\nErlotinib and gefitinib for the treatment of non-small-cell lung cancer following prior chemotherapy (Review of TA162 and TA175). NICE technology appraisal. Publication expected June 2014.\n\nPemetrexed for maintenance treatment following induction therapy with pemetrexed and cisplatin for non-squamous non-small-cell lung cancer. NICE technology appraisal. Publication date to be confirmed.', 'Review': 'NICE will update the literature search at least every 3\xa0years to ensure that relevant new evidence is identified. NICE will contact product sponsors and other stakeholders about issues that may affect the value of the diagnostic technology. NICE may review and update the guidance at any time if significant new evidence becomes available.\n\nAndrew DillonChief ExecutiveAugust 2013', 'About this guidance': 'NICE diagnostics technologies guidance is designed to help the NHS adopt efficient and cost-effective medical diagnostic technologies more rapidly and consistently.\n\nThe programme concentrates on pathological tests, imaging, endoscopy and physiological measurement, since these represent most of the investigations performed on patients. The types of products that might be included are medical diagnostic technologies that give greater independence to patients, and diagnostic devices or tests used to detect or monitor medical conditions. Diagnostic technologies may be used for various purposes: diagnosis, clinical monitoring, screening, treatment triage, assessing stages of disease progression, and risk stratification.\n\nThis guidance was developed using the NICE diagnostic technologies guidance process.\n\nWe have produced a summary for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n This guidance represents the view of NICE, which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity, and foster good relations. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0264-4'}	https://www.nice.org.uk/guidance/dg9	Evidence-based recommendations on testing for epidermal growth factor receptor tyrosine kinase (EGFR–TK) mutations in untreated, locally advanced or metastatic non-small-cell-lung cancer.
c063671c9a5d5f2d2ea57b8ddb7f9db2c5b0c833	nice	Intraoperative tests (RD‑100i OSNA system and Metasin test) for detecting sentinel lymph node metastases in breast cancer	Intraoperative tests (RD‑100i OSNA system and Metasin test) for detecting sentinel lymph node metastases in breast cancer Evidence-based recommendations on the RD-100i OSNA system and Metasin test for detecting sentinel lymph node metastases in people having breast cancer surgery. # Recommendations Whole lymph node analysis using the RD‑100i OSNA system is recommended as an option for detecting sentinel lymph node metastases during breast surgery in people with early invasive breast cancer who have a sentinel lymph node biopsy and in whom axillary lymph node dissection will be considered. Details of the development of a national registry are included in section 7 of this guidance. The Metasin test is not recommended for detecting sentinel lymph node metastases in people with early invasive breast cancer in routine clinical NHS practice. The Metasin test shows promise and the development of robust evidence is recommended to demonstrate its utility in clinical practice.# The technologies The RD‑100i OSNA system (Sysmex UK) and the Metasin test (TIB MOLBIOL) are intraoperative molecular tests that are designed to indicate if cancer has spread to the lymph nodes in people diagnosed with invasive breast cancer. The Metasin test was developed within the NHS at the Princess Alexandra Hospital in Harlow, Essex. It was CE marked by TIB MOLBIOL in December 2012.# Clinical need and practice # The problem addressed The intraoperative molecular tests (RD‑100i OSNA system and Metasin test) are used during breast cancer surgery to detect the presence of 1 or 2 biological markers that are associated with metastatic spread in sentinel lymph node samples. The intention is that the test results are available during surgery and may be used to determine if other axillary lymph nodes should be removed at the same time as the initial tumour. This could avoid the need for a second operation and allow subsequent treatments such as chemotherapy to begin earlier. The aim of this evaluation is to determine the clinical and cost effectiveness of using the RD‑100i OSNA system and the Metasin test to detect metastases in the sentinel lymph nodes of patients having breast cancer surgery. # The condition Breast cancer is one of the most common cancers in women in England and Wales; there are about 46,000 new cases diagnosed and 10,900 deaths recorded each year. Around 1 in 9 women develop breast cancer at some stage in their life. Most breast cancers develop in women over 50 years, but they can also occur in younger women and, in rare cases, in men. There are around 260 cases of breast cancer diagnosed and 68 deaths recorded in men in England and Wales each year. Around 11,000 women with newly diagnosed breast cancer need additional surgery to manage the spread of breast cancer to the lymph nodes every year. In a few people, the tumour has spread significantly within the breast or to other organs of the body at initial diagnosis. Also, some people who have been treated with curative intent subsequently develop either a local recurrence or metastases. Breast cancer mainly spreads by local spread to nearby tissues, or by regional or distant spread through the circulatory or lymphatic system. Spread through the lymphatic system is of relevance for this evaluation. It occurs when cancer cells become detached from the main breast tumour. These are then usually carried in the lymph to the axillary (armpit) lymph nodes, most likely the sentinel lymph nodes. The cancer cells can grow in the lymph nodes and cause swelling, although not all metastatic lymph nodes are morphologically abnormal. Lymph nodes are often used to stage cancer (measure the extent of the disease) because their function is to monitor lymph and trigger an immune response if a foreign substance is detected, and so they are one of the earliest sites at which the spread of cancer can be detected. The treatment of breast cancer can cause many side effects including pain, fatigue, reduced fertility and osteoporosis. A diagnosis of breast cancer and subsequent treatment can cause long-term anxiety, depression and isolation in both the patient and their relatives. Cancer chemotherapy and radiotherapy can cause hair loss, and people with cancer can experience changes to the body that arise from the disease itself or from treatments such as mastectomy. These are associated with social stigma, and can have a significant impact on quality of life and reduce self-esteem. One side effect of lymph node surgery is lymphoedema, which is more likely after axillary lymph node dissection than after sentinel lymph node biopsy. The most common symptom is swelling of the arm, hands and fingers on the side of the body that has been operated on, which can persist for months or years. Swelling can also affect the breast, chest and shoulder. Lymphoedema does not affect all people who have lymph node surgery but, in some people, it can develop soon after treatment or years later because of inflammation, infection and scarring. Axillary lymph node dissections result in major and minor complications for 80% of women. Major complications include a 22% incidence of seromas (pockets of fluid under the skin), a 21% incidence of arm lymphoedema (general swelling) and a 14% infection rate. Other complications include pain, limited mobility, numbness and sensory loss. Sentinel lymph node biopsy is associated with a 7% incidence of lymphoedema, a 7% incidence of seroma and a 2% infection rate. # The diagnostic and care pathways The current breast cancer care pathway is outlined in the NICE guideline on early and locally advanced breast cancer. This guideline recommends that ultrasound evaluation of the axilla (armpit) is done in all patients being investigated for early invasive breast cancer. If morphologically abnormal lymph nodes are identified, ultrasound-guided needle sampling is offered preoperatively. For patients who have no evidence of abnormal lymph nodes on ultrasound images or aspiration cytodiagnosis, minimal surgery is performed to stage the axilla during breast surgery to confirm that the cancer has not spread. Sentinel lymph node biopsy, in which the first lymph nodes are removed to see if the cancer has spread from the original site, is the preferred technique. A radioactive solution and a blue dye are injected into the breast before surgery to help identify the sentinel lymph nodes during surgery. However, identifying the nodes during surgery can be difficult and there is a widely recognised learning curve for performing sentinel lymph node biopsy. The Royal College of Surgeons of England, Cardiff University and the Department of Health established a surgical training programme (NEW START) for performing the biopsy and set standards for surgeons to achieve a greater than 90% localisation rate (ability to locate sentinel nodes) and a less than 10% false negative rate. One study reported that the localisation rate achieved for sentinel lymph node biopsy was around 98% (Mansel et al. 2006). The fresh biopsy tissue from sentinel lymph node biopsy is currently analysed using postoperative histopathology. This involves slicing the lymph node into very thin sections. These tissue sections are then stained and viewed by a consultant histopathologist to identify any abnormalities in the tissue. There is a small risk that histopathological analysis may miss a metastasis because only a few sections of the lymph node are examined, and metastatic foci are not evenly distributed through a lymph node so may not be present in sections that are examined. It is not clear how many sections from a lymph node are currently analysed in routine NHS practice. Results from histopathology usually take between 5 and 15 working days to be reported in the NHS. If the results are positive, the patient will have a second operation to remove the remaining lymph nodes (axillary dissection). This can be more technically challenging than performing the axillary dissection as part of the initial surgery. Two pathological methods that can be used intraoperatively are frozen section and touch imprint cytology. Frozen section involves a section of the lymph node being snap-frozen, stained and sliced before being viewed by a consultant histopathologist. Touch imprint cytology involves the lymph node being sliced and the cut surface of the node imprinted on to a slide, which is then stained and viewed by a consultant histopathologist or cytopathologist. Both intraoperative pathological methods can be used to help determine if axillary lymph node dissection should be done at the same time as the first operation. Postoperative histopathology analysis is usually carried out on the remaining tissue to reduce the risk of a false negative result. However, in practice these intraoperative methods are rarely used because they have low accuracy and pathology resources are limited within the NHS. The RD‑100i OSNA system and the Metasin test can be used to analyse either the whole lymph node or half of the lymph node with follow-up histopathology on the remaining half to confirm the results. The decision on whether to analyse the whole lymph node is based on clinical judgement. People who have macrometastases or micrometastases detected in their sentinel lymph node are regarded as lymph node-positive, and usually receive axillary lymph node dissection. People who have isolated tumour cells in their sentinel lymph node are regarded as lymph node-negative and will not receive axillary lymph node dissection. All information on the sentinel nodes, axillary nodes and primary breast tumour is typically discussed at a multidisciplinary team meeting to determine the appropriate systemic adjuvant therapy. The NICE guideline on early and locally advanced breast cancer recommends that adjuvant chemotherapy and radiotherapy should be started as soon as clinically possible within 31 days of completion of surgery in patients with early breast cancer having these treatments. The use of intraoperative molecular tests and a potential consequent reduction in the number of second operations performed may result in patients starting adjuvant therapy earlier.# The diagnostic tests # The interventions ## RD‑100i OSNA system The RD‑100i OSNA system analyses and amplifies mRNA from solubilised biopsy samples of sentinel lymph node tissue. It detects the level of expression of the cytokeratin‑19 (CK19) gene, an epithelial marker associated with breast cancer. CK19 is normally not present in healthy lymph node tissue. The OSNA technology involves the homogenisation of sentinel lymph node tissue followed by analysis of the CK19 mRNA using reverse transcription loop mediated isothermal amplification (RT-LAMP) on the automated analyser within the RD‑100i OSNA system. The system does not need the mRNA to be extracted from the tissue and purified before analysis. The expression level of CK19 mRNA correlates with the size of the metastatic foci. Since the metastatic foci may not be evenly distributed throughout the node, the system provides more accurate results if more of the node is analysed because there is less risk of tissue allocation bias (sample bias). Tissue allocation bias can occur when half of the lymph node is analysed using an intraoperative test and the other half using histopathology, if the metastasis is only contained in the tissue slices used for one of the methods. The RD‑100i OSNA system can be used with half of the lymph node (1 piece or alternate slices), allowing for the possibility of follow-up histopathology but potentially decreasing the accuracy of the results because of the increased risk of tissue allocation bias. The time to results depends on the number of lymph nodes analysed, but the test takes approximately 30 to 45 minutes. The RD‑100i OSNA system result is expressed both quantitatively and qualitatively: − for lymph node-negative test results; + for lymph nodes with a micro-metastatic tumour burden (that is, greater than 250 copies of CK19 mRNA/microlitre); and ++ for lymph nodes with a macro-metastatic tumour burden (that is, greater than 5000 copies of CK19 mRNA/microlitre). The analyser amplifies and detects the CK19 mRNA by using 6 different primers that have been designed to avoid the amplification of CK19 pseudogenes or their transcripts because amplification of these would lead to false positive results. The manufacturer estimates that 1% of breast tumours do not express CK19 mRNA and so, if cancer spreads to the lymph nodes from these tumours, CK19 mRNA will not be detected even though the lymph nodes are metastatic. Pre-screening of tumour biopsies for CK19 expression could be carried out before using the RD‑100i OSNA system to reduce the small risk of false negative results for metastatic sentinel lymph nodes. ## Metasin test The Metasin test is an intraoperative molecular test developed within the NHS at the Princess Alexandra Hospital in Harlow, Essex. The test has similarities to a discontinued commercial test (Veridex GeneSearch breast lymph node assay) and uses quantitative reverse transcription polymerase chain reaction (qRT‑PCR) to detect 2 predictive markers of metastases, CK19 and mammaglobin. Mammaglobin is expressed mainly by breast epithelial cells and high levels of mammaglobin are associated with breast cancer. A reference gene (porphobilinogen deaminase; PBGD) is used to confirm the validity of the mRNA used in the test and 2 other controls (positive and negative) are also included. The test uses reagents that can be purchased from commercial suppliers and can be used on the Cepheid Smartcycler platform. The Metasin test uses different primer-probe combinations to detect the CK19 and mammaglobin genes from the discontinued commercial test. It takes approximately 32 minutes to extract and purify mRNA from the tissue and then to produce results. The Metasin test is currently used in the NHS as an in-house test to analyse half of the lymph node. The results are confirmed by follow-up histopathology. The Metasin test could also be used as a replacement test for postoperative histopathology. Pre-screening of tumour biopsies for CK19 mRNA and mammaglobin mRNA expression may be carried out before using the Metasin test because, like the CK19 biomarker, mammaglobin is not expressed in all breast tumours. The proportion of breast cancer tumours that do not express mammaglobin mRNA is not known. # The comparator: postoperative histopathology Postoperative histopathology is the usual approach used in the NHS, in which the sentinel lymph nodes are fixed in paraffin blocks, sliced very thinly to produce sections that are mounted on slides, stained and then examined under a microscope by a consultant histopathologist. The time to receive results from histopathology is usually between 5 and 15 working days in the NHS. People who have macrometastases (defined as tumour deposits in which at least 1 dimension is above 2 mm) or micrometastases (tumour deposits that are only discernible microscopically and measure greater than 0.2 mm but have no dimension greater than 2 mm) detected in their sentinel lymph node are regarded as lymph node-positive, and will usually receive axillary lymph node dissection. People who have isolated tumour cells in their sentinel lymph node are regarded as lymph node-negative and will not receive axillary lymph node dissection. The wait for histopathology test results can cause anxiety for patients and can also lead to the patient having a second operation to remove all of the relevant axillary lymph nodes if the test result is positive. This second operation can be more difficult and result in a higher risk of complications because it will involve operating on the same area of the breast and armpit as the first operation. There are several levels of histopathology that can be performed. In one-level histopathology, 1 section of the lymph node is examined, in three-level, 3 sections and, in five-level, 5 sections. The level of histopathology used may affect the accuracy of histopathology because of the risk of tissue allocation bias. There is also uncertainty about the accuracy of histopathology associated with the different staining techniques used, the thickness of the section examined and the experience of the pathologist reading the section slides.# Outcomes The Diagnostics Advisory Committee (section 9) considered evidence from a number of sources (section 10). # How outcomes were assessed The assessment was performed by an external assessment group and consisted of a systematic review of the evidence on test performance and clinical effectiveness data for the RD‑100i OSNA system and the Metasin test compared with postoperative histopathology. The outcome measures relevant to test performance included diagnostic test accuracy, test failure rate, discordant test results, and time to test result. The outcome measures relevant to clinical effectiveness included: patient anxiety associated with the waiting time for results and with not knowing what the extent of surgery would be before the operation; number of repeat operations (excluding those for re-excision of positive margins); time to start and nature of adjuvant therapy; morbidity and mortality from biopsies, axillary dissections, first and second operations and treatment of cancer; and adverse events from false test results, including patient distress and sequelae. No study was excluded on the basis of intervention, population, comparator or outcome, provided it appeared relevant to the scope of the evaluation. # Clinical effectiveness ## RD‑100i OSNA system The external assessment group included 16 studies in the systematic review that investigated the performance of the RD‑100i OSNA system in detecting metastases in the sentinel or axillary lymph nodes, although 2 of these studies reported the same trial. Fourteen of these 16 studies reported test accuracy as an outcome and of these 14 studies, 2 also reported time to analysis. An additional observational study reported time to analysis as an outcome alone. One other study reported time in operating theatre, days in hospital, costs and postoperative complications. No data were found for the clinical outcomes of patient anxiety and number of repeat operations. Eleven of the 16 studies were single-gate studies in which people with unknown disease status were assessed using both the intraoperative test and the reference standard (histopathology) to compare the results of the 2 tests and confirm diagnosis. The remaining studies comprised 4 cohort studies and 1 observational study. In the cohort studies, different patient samples were used for each test, which enabled whole-node analysis with the RD‑100i OSNA system. There was heterogeneity across studies in their definitions of histopathology. Three studies reported using five-level histopathological analysis to detect metastases in the node. Two other studies used five-level histopathological analysis during the validation phase of the study and one-level histopathological analysis during routine use. Five studies reported using three-level histopathological analysis and 1 other study reported using one-level histopathological analysis. The level of histopathological analysis used in the remaining studies is unclear. These varying levels of histopathological analyses may impact on the accuracy of histopathology because five-level analysis may be more likely to detect micrometastases than one-level analysis. In addition, depending on the level of analysis used some studies did not reflect current NHS practice for histopathological analysis. The external assessment group found that, in all of the studies, there was a lack of detail on patient recruitment and patient characteristics so the risk of bias in the studies is unclear. Spectrum bias may arise if the severity of the cancer is greater in one study population than another because it is more likely that a test will detect metastases in people with severe disease and it will therefore appear to have a higher sensitivity. In addition, study populations may vary depending on the upstream diagnostic pathway because some clinics may be better at detecting metastases with fine needle aspiration cytology so sentinel lymph node biopsy would not be needed in some cases. This could result in a patient population with higher levels of micrometastases than macrometastases receiving sentinel lymph node biopsy and so the sensitivity of the intraoperative test or histopathology may appear lower in this population. There was also a lack of information on sampling methods, so there was no evidence of sample replicates and reproducibility for molecular analysis. The assessment of test accuracy for the RD‑100i OSNA system was hindered by tissue allocation bias and by comparison with an inconsistent reference standard (different levels of histopathology). In some studies, discordant samples were further analysed (by extensive histopathology, molecular analysis or Western blotting) and attributed to tissue allocation bias. In these cases, the test accuracy analyses could be adjusted by excluding the data from the discordant samples. No adjustment could be made for the varying levels of histopathology used across the studies. The range of estimates for sensitivity and specificity by patient before adjustment for tissue allocation bias from the studies were 77.8–80.0% and 88.0–97.2% respectively. The range of estimates for sensitivity and specificity by patient after adjustment for tissue allocation bias from the studies were 89.8–100% and 93.3–97.2% respectively. The external assessment group performed a meta-analysis (bivariate method) of diagnostic test accuracy from studies that reported the numbers of true positives, true negatives, false negatives and false positives in the text (or sufficient data for these test statistics to be calculated). Five studies were included that did not adjust for tissue allocation bias and 3 studies were included that did adjust for tissue allocation bias. The sensitivity and specificity by patient without adjustment for tissue allocation bias were 84.5% (95% confidence interval 74.7% to 91.0%) and 91.8% (95% CI 87.8% to 94.6%) respectively. The sensitivity and specificity by patient with adjustment for tissue allocation bias were 91.3% (95% CI 83.6% to 95.6%) and 94.2% (95% CI 91.2% to 96.2%) respectively. Four studies reported the time to analysis by the RD‑100i OSNA system. The estimates for time to analysis from the studies ranged from less than 30 minutes to 39.6 minutes for 1 node and increased by 5–10 minutes per additional node analysed. One study reported that the longest and most variable time period corresponded to transporting the node from the operating room to the pathology department. The least variable time period corresponded to the homogenisation of tissue, preparation of the diluted sample and gene amplification by RT‑LAMP. One other study compared the number of postoperative complications between the use of histopathology and the use of RD‑100i OSNA to analyse lymph node samples. The aim of this study was to analyse the economic costs of intraoperative testing with the RD‑100i OSNA system compared with postoperative histopathology. Overall, the patients having intraoperative lymph node testing using the RD‑100i OSNA system experienced fewer postoperative complications than patients having postoperative histopathology analysis, although the only major complication reported occurred in the OSNA group (no further details of the major complication were reported). This study was conducted in Spain and the assessment group stated that it was uncertain to what extent the study findings might be generalisable to the UK owing to possible differences in clinical practice. ## Metasin test Two draft unpublished non-peer reviewed studies that investigated the performance of the Metasin test in detecting metastases in the lymph nodes of patients with breast cancer were included in the systematic review. The results of one of the studies are considered academic in confidence. The other study, by Sundaresan et al. (unpublished), was designed as a single-gate study comparing the Metasin test with histopathology, in which people were assessed by both methods. It reported test accuracy and time to analysis as outcomes. It used three-level histopathological analysis to detect metastases in the nodes but did not report details of patient recruitment or patient characteristics, so the risk of bias is unclear. There was also a lack of information about sample replicates and reproducibility for molecular analysis, and the external assessment group did not consider the study to meet the STAndards for the Reporting of Diagnostic accuracy studies (STARD) criteria. As with the studies assessing the RD‑100i OSNA system, one of the main issues with assessing the accuracy of the Metasin test was tissue allocation bias. No discordant analyses were performed in the study but discordant results were observed in 56 out of 1265 patients (4.4%): 36 patients had a positive Metasin test and negative histopathology, and 20 patients had a negative Metasin test and positive histopathology. The authors considered that tissue allocation bias was responsible for the discordant results, although no evidence or analysis was presented in the study to support this. The estimates for test accuracy by patient without adjustment for tissue allocation bias in Sundaresan et al. were 92% sensitivity (95% CI 89% to 95%) and 97% specificity (95% CI 95% to 97%). No meta-analysis was performed by the external assessment group for the 2 studies assessing the Metasin test because at least 4 studies are needed to use the bivariate method of meta-analysis. The accuracy values from Sundaresan et al. were used in the cost-effectiveness analyses. # Cost effectiveness The external assessment group identified 2 studies that were considered relevant for the systematic review on the cost effectiveness of intraoperative tests for the detection of sentinel lymph node metastases. Both studies were single-centre observational studies that compared an intraoperative test with histopathology for assessing sentinel lymph node biopsy. One study was based in the UK and assessed the GeneSearch BLN assay and the other study was conducted in Spain and evaluated the RD‑100i OSNA system. Both studies found their respective intraoperative tests to be cost effective compared with histopathology, with both assays being cost saving while reducing theatre time and length of hospital stay. Neither study considered outcomes beyond the diagnostic phase. The UK study provided evidence on resource use and costs of intraoperative testing in the UK but evaluated the GeneSearch BLN assay, which has been withdrawn from the market. The Metasin test uses the same markers as the GeneSearch BLN assay, CK19 and Mammaglobin, but different primer-probe combinations, so it is expected to perform differently from the GeneSearch BLN assay. Therefore, this UK study is not directly relevant to this evaluation. The study conducted in Spain also provided evidence on resource use and costs but was limited in the extent to which it was generalisable to the UK. Therefore, the external assessment group did not consider the study directly relevant to this evaluation. The external assessment group performed an economic analysis to assess the cost effectiveness of using intraoperative tests to detect sentinel node metastases compared with using histopathology. The economic model was divided into 2 separate sections (diagnostic and management) to encompass both the short-term and long-term outcomes of intraoperative testing. The costs were evaluated from the perspective of the NHS and personal social services. Outcomes were expressed as quality-adjusted life years (QALYs). Both costs and outcomes were discounted using a 3.5% annual discount rate. The external assessment group developed a decision tree to model the short-term diagnostic outcomes outlined in the decision problem. People enter the model as patients who have sentinel lymph node biopsy performed during their initial tumour removal. The model then splits into 3 different diagnostic strategies: postoperative histopathology (current practice) alone, intraoperative testing alone and intraoperative testing combined with postoperative histopathology confirmation. In the model, patients who are diagnosed with sentinel lymph node metastases receive axillary lymph node dissection, either during the same operation as their sentinel lymph node biopsy if intraoperative testing is used or during a second operation if postoperative histopathology is used. Once the diagnostic subgroups have been identified (true positive sentinel lymph node, false positive sentinel lymph node, true negative sentinel lymph node and false negative sentinel lymph node), the model moves into the management pathway and the subgroups are separated based on whether or not patients receive an axillary lymph node dissection. This section of the model calculates the long-term outcomes for each subgroup and at this point, a discrete event simulation model, previously developed at the University of Sheffield (ScHARR-TAG), was used to model the natural disease history of the patients once their outcome from the diagnostic decision tree had been determined. In the model, after surgery, patients receive adjuvant therapy comprising chemotherapy and hormonal therapy (where appropriate) for patients diagnosed with metastases and hormonal therapy alone (where appropriate) for patients diagnosed without. After adjuvant therapy, patients can move into a disease-free state, or experience locoregional or metastatic relapse. Patients can also move between these states. The meta-analysed accuracy values without adjustment for tissue allocation bias for the RD‑100i OSNA system and the accuracy values from one of the unpublished papers for the Metasin test were used in the base case. The node-positive prevalence was set at 20% in the base case, in line with the studies in the clinical systematic review. Unit costs for the intraoperative tests were taken from the sponsors of the technologies and the cost of histopathology was based on data provided by the NHS Technology Adoption Centre. The unit cost of the RD‑100i OSNA system was £350 and the unit cost of histopathology was £472. The surgery costs were mainly based on NHS reference costs and the costs of short-term adverse events were taken from Jeruss et al. (2006). The costs associated with lymphoedema were obtained from the Sheffield Lymphoedema Service and the length of additional hospital stay was calculated from a study by the York Health Economics Consortium. The costs of additional time in surgery were estimated from a study by Ng et al. (2011) and from the report by York Health Economics Consortium. All costs were updated to 2010 levels. The QALY decrement associated with a 2‑week wait for histopathology results was calculated by the external assessment group to be 0.019 (undiscounted). For patients having a separate second operation, the disutility was estimated as 0.03. The external assessment group considered the results of the cost-effectiveness analyses for the Metasin test to be illustrative because of the high levels of uncertainty associated with the unpublished evidence base relating to the diagnostic accuracy of the test. The cost-effectiveness analyses of the short-term outcomes examined the diagnostic accuracy of the intraoperative tests compared with postoperative histopathology, and the disutility of waiting for histopathology results and having a second operation. For strategies that did not involve histopathology, the utility was 1 because there was no wait for test results or any second operations directly resulting from the intraoperative test. Only short-term QALY gains were included in these analyses. Using the NHS reference costs in the short-term model, whole-node OSNA analysis and half-node OSNA analysis dominated histopathology analysis because they were less costly and more effective. Whole-node OSNA analysis also dominated half-node OSNA analysis. It was estimated that 4.1% of the 76.5% of patients who received a negative test result from half-node OSNA analysis would end up with a positive result while waiting for confirmation by histopathology analysis, compared with 20% of patients who would receive a positive result using postoperative histopathology analysis alone. In the short-term model, whole-node and half-node Metasin analyses dominated histopathology analysis because they were less costly and more effective. Whole-node Metasin also dominated half-node Metasin analysis. It was estimated that, of the 78.5% of patients who received a negative result by half-node Metasin analysis, 1.9% would receive a positive result while waiting for confirmation by histopathology analysis, compared with 20% of patients who would receive a positive result using postoperative histopathology analysis alone. The cost-effectiveness analyses of the long-term outcomes examined all the costs and benefits from accurate diagnosis through to improved patient management. In these analyses, the diagnostic strategies were ordered by the number of QALYs associated with them, with whole-node OSNA analysis producing the least QALYs (9.22) and postoperative histopathology producing the most QALYs (9.32). The QALY difference is equal to 0.1 (that is, equivalent to 5 weeks of full-health life) and this difference occurs because the higher accuracy of histopathology assumed in the model leads to more correct diagnoses and appropriate subsequent treatment. Using the NHS reference costs in the long-term model, the incremental cost-effectiveness ratio (ICER) was £4324 saved per QALY lost for whole-node OSNA analysis compared with histopathology analysis and £24,863 saved per QALY lost for whole-node Metasin analysis compared with histopathology analysis. The ICERs for whole-node analysis compared with histopathology analysis suggest that the intraoperative testing strategies save money but that there is a loss of approximately 0.1 QALY, compared with histopathology analysis. In the modelling, histopathology analysis was assumed to be the 'gold standard' and was given an accuracy of 100% sensitivity and 100% specificity. The level of uncertainty in this assumption is unclear and the estimated ICERs may change depending on the assumed absolute accuracy of histopathology. The sensitivity and specificity of OSNA analysis were changed to use values from studies that had been adjusted for tissue allocation bias (Frere Belda et al. 2012, Snook et al. 2011 and Khaddage et al. 2011). Using NHS reference costs, the ICER was £9493 saved per QALY lost for whole-node OSNA analysis compared with histopathology analysis using accuracy values from the Frere Belda et al. study (91.4% sensitivity and 93.3% specificity) and £8840 saved per QALY lost for whole-node OSNA analysis compared with histopathology analysis using values from the Snook et al. study (89.8% sensitivity and 94.5% specificity). However, using the higher accuracy values from the Khaddage et al. study (100% sensitivity and 97.2% specificity) resulted in ICERs for whole-node OSNA analysis that dominated both half-node OSNA analysis and histopathology analysis. The change in ICERs when accuracy values adjusted for tissue allocation bias were used showed that test accuracy has a direct impact on the cost effectiveness of the tests. Threshold analysis was used to investigate sensitivity by increasing sensitivity over a range of 70–100% while specificity was held constant. The opposite was also performed to investigate specificity. These analyses were conducted on the results for the whole-node OSNA analysis. Short-term utility results were not reported as the utility of OSNA was not affected by the accuracy of the test. The results of the threshold analysis for the long-term results showed that, when the sensitivity of OSNA increased (and specificity was kept at the 91.8% base-case value), the saving per QALY lost increased when comparing whole-node OSNA with histopathology. When comparing OSNA with histopathology, the ICERs for OSNA ranged from £2119 saved per QALY lost when OSNA had a sensitivity of 70% to £14,193 saved per QALY lost when OSNA had 95% sensitivity. At 100% sensitivity, OSNA dominated histopathology, having more QALYs gained and lower costs. For specificity, the long-term cost of OSNA decreased and the QALY gain increased as the specificity increased. At a specificity of 70%, whole-node OSNA analysis was dominated by histopathology analysis because it was more expensive and had fewer QALYs. The largest ICER for OSNA was £8430 saved per QALY lost compared with histopathology when whole-node OSNA analysis had 100% specificity (and sensitivity was kept at the base-case value of 94.5%). Overall, the threshold analyses suggested that, if the true values of sensitivity and specificity for whole-node OSNA analysis lie within the range of 90–100%, the cost effectiveness of whole-node OSNA analysis may increase. The results also imply that changes to specificity may have more of an impact in the short-term than the long-term, but that changes to sensitivity may have a much greater impact on the long-term cost effectiveness. Sensitivity analysis was also conducted on the effect of prevalence of sentinel lymph node metastases in the patient population. When the prevalence was reduced to 10%, histopathology analysis dominated half-node OSNA analysis and had an ICER of £2626 per QALY gained compared with whole-node OSNA analysis. When the prevalence was increased to 40%, half-node OSNA analysis dominated histopathology analysis and had an ICER of £2208 per QALY gained compared with whole-node OSNA analysis. Changing individual costs and utility parameter values in the short-term or long-term sections of the model had very little impact on the overall cost-effectiveness results. This highlighted the importance of the diagnostic accuracy of the tests because this was the most influential parameter.# Considerations The Committee considered the heterogeneity and uncertainty in the studies. The Committee heard from the clinical specialists on the Committee that histopathology practices can vary between hospitals in the UK. It also heard that, in routine clinical practice, the standard of histopathology may be different to that in the studies. It concluded that the extensive research-standard histopathology described in the studies may not be representative of the histopathology conducted in routine clinical NHS practice because it is very time consuming. The Committee also concluded that there is variation in how histopathology is performed across the NHS. The Committee discussed the use of the intraoperative tests in clinical practice. The Committee noted that RNA extraction is needed for the Metasin test but not for the RD‑100i OSNA system. It raised concerns about quality assurance when performing RNA extraction in the operating theatre and noted that there were advantages in not having to perform this step with the RD‑100i OSNA system. The Committee also discussed the support available for users of the intraoperative tests from the manufacturers and considered that there was more uncertainty about the support for the Metasin test than for the RD‑100i OSNA system. The Committee concluded that further evidence was needed to show that the Metasin test could be used effectively in hospitals that had not been involved in the development of the test. The Committee considered that biomedical scientists can carry out testing using the RD‑100i OSNA system or the Metasin test, although a higher level of molecular biology expertise appears to be needed for the Metasin test. This expertise may not be available in all hospitals performing breast surgery, particularly once laboratory services are centralised. The Committee noted that a biomedical scientist may need to travel to the surgery site to perform the intraoperative test, which would result in a loss of resources from the laboratory during that time. The Committee also considered that there is a shortage of pathologists in the NHS and that using these intraoperative molecular tests may free pathology resources for other uses in the NHS. The Committee considered the unpublished non-peer reviewed evidence for the Metasin test. The Committee acknowledged the findings of the 2 draft unpublished studies, but noted that the studies had not been peer reviewed and therefore the results should be interpreted with caution. The Committee concluded that the test appeared promising but that there was too much uncertainty associated with the evidence to recommend use of the test in routine NHS practice. The Committee was encouraging of further research on this test. The Committee considered the 20% prevalence of sentinel lymph node metastases in the patient population used in the base case for the cost-effectiveness analyses. It heard from the clinical specialists that the prevalence was likely to be higher than 20%, and possibly around 30%. The Committee noted the sensitivity analysis, which showed that an increase in the prevalence of sentinel lymph node metastases increased the cost effectiveness of the RD‑100i OSNA system (see section 5.37). Therefore, the Committee concluded that using the RD‑100i OSNA system was likely to be more cost effective than the base-case incremental cost-effectiveness ratios (ICERs) suggested. The Committee considered the accuracy of histopathology. The Committee heard from a specialist committee member that the sensitivity of histopathology in routine UK practice was likely to be lower than 100%, which was what was assumed in the cost-effectiveness analysis. The committee heard that the main source of inaccuracy in histopathology is tissue allocation bias, but that other sources of inaccuracy are possible, including user variability. The Committee noted that it was unlikely that a macrometastasis would be missed if the current histopathology guidelines were followed but that it was possible that micrometastases could be missed. However, the clinical significance of this is not known. The Committee concluded that it was very difficult to determine the absolute accuracy of histopathology because of the nature of the technique and the inherent variation from qualitative judgement of different pathologists. However, it was likely to be lower than 100% in routine clinical practice. The Committee also considered the assumption in the modelling that histopathology was 100% accurate following discussions about the accuracy of histopathology in clinical practice. The Committee concluded that the accuracy of histopathology in any setting could not be 100% because time and resources did not allow every slice of a node to be analysed for metastases. The Committee therefore concluded that use of the RD‑100i OSNA system was likely to be more cost effective than the base-case ICERs suggested. The Committee discussed the option to use the RD‑100i OSNA system to analyse either a whole node, or half a node, with the remaining half used to confirm the results by follow-up histopathology. Clinical specialists on the Committee said that whole-node analysis had more benefit than half-node analysis followed by histopathology because there was no risk of tissue allocation bias when the whole node was analysed. The Committee heard from the manufacturer of the RD‑100i OSNA system that there is a small risk of test failure and the Committee considered the impact of this when all of the node tissue is used in whole-node analysis. The manufacturer stated that tissue lysate samples can be stored for up to 1 month and can be re-tested in the event of test failure. The Committee concluded that it was acceptable for half-node analysis with postoperative histopathology confirmation to be used while the RD‑100i OSNA system is being validated locally but recommended that, after validation, whole-node OSNA analysis should be fully implemented in local clinical practice to reduce the risk of tissue allocation bias. The Committee considered the possibility of pre-screening tumours for the expression of CK19 and mammaglobin to reduce the small risk of a false negative result. The Committee heard from clinical specialists that pre-screening would use pathology resources that are already limited and that it may not be possible to deliver results during surgery. The Committee also heard that the interpretation of pre-screening results is complicated by tumour tissue heterogeneity, which means that this information has limited clinical value. Furthermore, the Committee heard that the mammaglobin antibody is difficult to work with and that immunohistochemistry staining for mammaglobin is not routinely available in the NHS. The Committee concluded that pre-screening for expression of CK19 and mammaglobin was not likely to take place in routine clinical practice because of the resource restraints on pathology services. The Committee considered the difference in the clinical information obtained from intraoperative whole-node analysis compared with histopathological analysis. The Committee discussed whether the absence of sentinel lymph node tissue for histopathological analysis following whole-node analysis with the RD‑100i OSNA system posed any risk to clinical decision-making when deciding on the strategy for systemic adjuvant therapy. The Committee also considered the risk of a false positive result, such as the detection of CK19 expression from high-grade lymphoma rather than lymph node metastases from breast cancer. The Committee concluded that these risks were very low. The Committee discussed the scenario in which intraoperative analysis of sentinel lymph nodes is not performed and when a second operation is needed following identification of lymph node metastases with histopathology. The Committee noted that the value in the economic model for the disutility arising from a second operation was 0.03. The Committee heard from the clinical specialists that a second breast operation is technically more difficult because of disrupted tissue structure. It also heard that a second operation had an increased risk of complications compared with breast surgery being done for the first time. Furthermore, the Committee heard from a patient expert that patients generally found the prospect of having a second operation very worrying and that the option of not having to have a second operation was an important consideration for patients. The Committee therefore considered that the disutility from the second operation was likely to be larger than that assumed in the economic model and the cost effectiveness of intraoperative testing was, as a consequence, likely to be underestimated in the base case. The Committee concluded that intraoperative analysis of sentinel lymph nodes had considerable advantages over traditional histopathology testing and had the potential to reduce both clinical complications, and patient anxiety and distress. The Committee considered the impact on patients of not knowing what the extent of their surgery would be before the operation. The Committee heard from a patient expert the importance of patients being informed before surgery about the different types of surgery they may have, depending on the results of the intraoperative test. The Committee noted that there was strong patient preference for all procedures to be done in a single operation and noted that, in routine clinical practice, the uncertainty about the extent of surgery would be explained to the patient. The Committee considered the cost-effectiveness analyses of the RD‑100i OSNA system. The Committee acknowledged that the model contained several assumptions that could potentially increase the uncertainty of the cost-effectiveness analysis. However, the Committee considered that it was appropriate to assume a higher prevalence than that used in the base case (see section 6.5), an accuracy value of less than 100% for histopathology (see sections 6.6 and 6.7), and that the technical difficulty and complications associated with a second operation may have been underestimated (see section 6.11). The Committee concluded that, taking these considerations together, the RD‑100i OSNA system was likely to be more cost effective than the base-case ICERs suggested and that it was likely that the RD‑100i OSNA system was equally or more cost effective than postoperative histopathology. The Committee also concluded that the substantial patient benefits associated with using the RD‑100i OSNA system and the strong patient preference for all procedures to be done in a single operation were not fully captured in the cost-effectiveness analyses. The Committee therefore concluded that the RD‑100i OSNA system would represent a cost-effective use of NHS resources if used as an option for detecting sentinel lymph node metastases in people with early invasive breast cancer who have a sentinel lymph node biopsy and in whom axillary lymph node dissection is being considered. The Committee considered the cost of histopathology used in the cost-effectiveness analyses and acknowledged it was higher than it is likely to be current practice. The Committee was of the view that, if the economic model used a more realistic cost for histopathology, it would indicate that the RD‑100i OSNA system was less cost effective than the base-case ICERs presented in the diagnostics assessment report. However, given all of the uncertainty in the cost-effectiveness analyses (see section 6.13), the Committee concluded that the RD‑100i OSNA system was still likely to be a cost-effective use of NHS resources. The Committee heard from clinical specialists about the recent publication of the Z0011 trial, which reported no improvement in survival after axillary lymph node dissection in women who received a positive result for lymph node metastases. The Committee heard from the clinical specialists that there was concern that the Z00011 trial was not definitive and possibly under-powered, and that there was no radiotherapy quality assurance programme to monitor the dose of radiation given. The Committee concluded that using intraoperative tests for detecting sentinel lymph node metastases offered substantial benefits to patients in current clinical practice and that these benefits were likely to be useful while the uncertainty in the effectiveness of performing axillary lymph node dissection remains. The Committee considered that a quality assurance scheme for the use of the RD‑100i OSNA system and any other relevant intraoperative tests is needed. The Committee considered that, for the efficient use of intraoperative testing, surgical theatre lists may need to be carefully scheduled and multiple analysers may be needed for sentinel lymph node testing if breast operations occur in parallel. The Committee heard from clinical specialists that the sentinel lymph node biopsy can be performed first so that the lymph nodes can be analysed using the RD‑100i OSNA system while the primary tumour is being removed. This prevents the time in surgery being significantly increased by use of an intraoperative test. Clinical specialists on the Committee also informed the Committee that fewer sentinel lymph node biopsies may be performed during an operating theatre list to allow time to perform axillary lymph node dissections when the intraoperative test results are positive. However, theatre time is made available in the subsequent weeks because the patients are not returning for a second operation, which would occur if patients had to wait for postoperative histopathology results. The Committee concluded that any disruption to theatre lists can be overcome with careful planning and scheduling.# Recommendations for further research NICE recommends that a national registry is developed to collect data on the use of the RD‑100i OSNA system in detecting sentinel lymph node metastases during breast cancer surgery. It also recommends that data on all patients having whole lymph node analysis by the RD‑100i OSNA system should be submitted to this registry. These data should be integrated with data from other registries for breast cancer where appropriate.	{'Recommendations': 'Whole lymph node analysis using the RD‑100i OSNA system is recommended as an option for detecting sentinel lymph node metastases during breast surgery in people with early invasive breast cancer who have a sentinel lymph node biopsy and in whom axillary lymph node dissection will be considered. Details of the development of a national registry are included in section\xa07 of this guidance.\n\nThe Metasin test is not recommended for detecting sentinel lymph node metastases in people with early invasive breast cancer in routine clinical NHS practice. The Metasin test shows promise and the development of robust evidence is recommended to demonstrate its utility in clinical practice.', 'The technologies': 'The RD‑100i OSNA system (Sysmex UK) and the Metasin test (TIB MOLBIOL) are intraoperative molecular tests that are designed to indicate if cancer has spread to the lymph nodes in people diagnosed with invasive breast cancer.\n\nThe Metasin test was developed within the NHS at the Princess Alexandra Hospital in Harlow, Essex. It was CE marked by TIB MOLBIOL in December 2012.', 'Clinical need and practice': '# The problem addressed\n\nThe intraoperative molecular tests (RD‑100i OSNA system and Metasin test) are used during breast cancer surgery to detect the presence of 1\xa0or 2\xa0biological markers that are associated with metastatic spread in sentinel lymph node samples. The intention is that the test results are available during surgery and may be used to determine if other axillary lymph nodes should be removed at the same time as the initial tumour. This could avoid the need for a second operation and allow subsequent treatments such as chemotherapy to begin earlier.\n\nThe aim of this evaluation is to determine the clinical and cost effectiveness of using the RD‑100i OSNA system and the Metasin test to detect metastases in the sentinel lymph nodes of patients having breast cancer surgery.\n\n# The condition\n\nBreast cancer is one of the most common cancers in women in England and Wales; there are about 46,000\xa0new cases diagnosed and 10,900\xa0deaths recorded each year. Around 1\xa0in 9\xa0women develop breast cancer at some stage in their life. Most breast cancers develop in women over 50\xa0years, but they can also occur in younger women and, in rare cases, in men. There are around 260\xa0cases of breast cancer diagnosed and 68\xa0deaths recorded in men in England and Wales each year. Around 11,000\xa0women with newly diagnosed breast cancer need additional surgery to manage the spread of breast cancer to the lymph nodes every year. In a few people, the tumour has spread significantly within the breast or to other organs of the body at initial diagnosis. Also, some people who have been treated with curative intent subsequently develop either a local recurrence or metastases.\n\nBreast cancer mainly spreads by local spread to nearby tissues, or by regional or distant spread through the circulatory or lymphatic system. Spread through the lymphatic system is of relevance for this evaluation. It occurs when cancer cells become detached from the main breast tumour. These are then usually carried in the lymph to the axillary (armpit) lymph nodes, most likely the sentinel lymph nodes. The cancer cells can grow in the lymph nodes and cause swelling, although not all metastatic lymph nodes are morphologically abnormal. Lymph nodes are often used to stage cancer (measure the extent of the disease) because their function is to monitor lymph and trigger an immune response if a foreign substance is detected, and so they are one of the earliest sites at which the spread of cancer can be detected.\n\nThe treatment of breast cancer can cause many side effects including pain, fatigue, reduced fertility and osteoporosis. A diagnosis of breast cancer and subsequent treatment can cause long-term anxiety, depression and isolation in both the patient and their relatives. Cancer chemotherapy and radiotherapy can cause hair loss, and people with cancer can experience changes to the body that arise from the disease itself or from treatments such as mastectomy. These are associated with social stigma, and can have a significant impact on quality of life and reduce self-esteem.\n\nOne side effect of lymph node surgery is lymphoedema, which is more likely after axillary lymph node dissection than after sentinel lymph node biopsy. The most common symptom is swelling of the arm, hands and fingers on the side of the body that has been operated on, which can persist for months or years. Swelling can also affect the breast, chest and shoulder. Lymphoedema does not affect all people who have lymph node surgery but, in some people, it can develop soon after treatment or years later because of inflammation, infection and scarring.\n\nAxillary lymph node dissections result in major and minor complications for 80% of women. Major complications include a 22% incidence of seromas (pockets of fluid under the skin), a 21% incidence of arm lymphoedema (general swelling) and a 14% infection rate. Other complications include pain, limited mobility, numbness and sensory loss. Sentinel lymph node biopsy is associated with a 7% incidence of lymphoedema, a 7% incidence of seroma and a 2% infection rate.\n\n# The diagnostic and care pathways\n\nThe current breast cancer care pathway is outlined in the NICE guideline on early and locally advanced breast cancer. This guideline recommends that ultrasound evaluation of the axilla (armpit) is done in all patients being investigated for early invasive breast cancer. If morphologically abnormal lymph nodes are identified, ultrasound-guided needle sampling is offered preoperatively.\n\nFor patients who have no evidence of abnormal lymph nodes on ultrasound images or aspiration cytodiagnosis, minimal surgery is performed to stage the axilla during breast surgery to confirm that the cancer has not spread. Sentinel lymph node biopsy, in which the first lymph nodes are removed to see if the cancer has spread from the original site, is the preferred technique. A radioactive solution and a blue dye are injected into the breast before surgery to help identify the sentinel lymph nodes during surgery. However, identifying the nodes during surgery can be difficult and there is a widely recognised learning curve for performing sentinel lymph node biopsy. The Royal College of Surgeons of England, Cardiff University and the Department of Health established a surgical training programme (NEW START) for performing the biopsy and set standards for surgeons to achieve a greater than 90% localisation rate (ability to locate sentinel nodes) and a less than 10% false negative rate. One study reported that the localisation rate achieved for sentinel lymph node biopsy was around 98% (Mansel et al. 2006).\n\nThe fresh biopsy tissue from sentinel lymph node biopsy is currently analysed using postoperative histopathology. This involves slicing the lymph node into very thin sections. These tissue sections are then stained and viewed by a consultant histopathologist to identify any abnormalities in the tissue. There is a small risk that histopathological analysis may miss a metastasis because only a few sections of the lymph node are examined, and metastatic foci are not evenly distributed through a lymph node so may not be present in sections that are examined. It is not clear how many sections from a lymph node are currently analysed in routine NHS practice. Results from histopathology usually take between 5\xa0and 15\xa0working days to be reported in the NHS. If the results are positive, the patient will have a second operation to remove the remaining lymph nodes (axillary dissection). This can be more technically challenging than performing the axillary dissection as part of the initial surgery.\n\nTwo pathological methods that can be used intraoperatively are frozen section and touch imprint cytology. Frozen section involves a section of the lymph node being snap-frozen, stained and sliced before being viewed by a consultant histopathologist. Touch imprint cytology involves the lymph node being sliced and the cut surface of the node imprinted on to a slide, which is then stained and viewed by a consultant histopathologist or cytopathologist. Both intraoperative pathological methods can be used to help determine if axillary lymph node dissection should be done at the same time as the first operation. Postoperative histopathology analysis is usually carried out on the remaining tissue to reduce the risk of a false negative result. However, in practice these intraoperative methods are rarely used because they have low accuracy and pathology resources are limited within the NHS.\n\nThe RD‑100i OSNA system and the Metasin test can be used to analyse either the whole lymph node or half of the lymph node with follow-up histopathology on the remaining half to confirm the results. The decision on whether to analyse the whole lymph node is based on clinical judgement.\n\nPeople who have macrometastases or micrometastases detected in their sentinel lymph node are regarded as lymph node-positive, and usually receive axillary lymph node dissection. People who have isolated tumour cells in their sentinel lymph node are regarded as lymph node-negative and will not receive axillary lymph node dissection.\n\nAll information on the sentinel nodes, axillary nodes and primary breast tumour is typically discussed at a multidisciplinary team meeting to determine the appropriate systemic adjuvant therapy. The NICE guideline on early and locally advanced breast cancer recommends that adjuvant chemotherapy and radiotherapy should be started as soon as clinically possible within 31\xa0days of completion of surgery in patients with early breast cancer having these treatments. The use of intraoperative molecular tests and a potential consequent reduction in the number of second operations performed may result in patients starting adjuvant therapy earlier.', 'The diagnostic tests': '# The interventions\n\n## RD‑100i OSNA system\n\nThe RD‑100i OSNA system analyses and amplifies mRNA from solubilised biopsy samples of sentinel lymph node tissue. It detects the level of expression of the cytokeratin‑19 (CK19) gene, an epithelial marker associated with breast cancer. CK19 is normally not present in healthy lymph node tissue. The OSNA technology involves the homogenisation of sentinel lymph node tissue followed by analysis of the CK19 mRNA using reverse transcription loop mediated isothermal amplification (RT-LAMP) on the automated analyser within the RD‑100i OSNA system. The system does not need the mRNA to be extracted from the tissue and purified before analysis. The expression level of CK19 mRNA correlates with the size of the metastatic foci. Since the metastatic foci may not be evenly distributed throughout the node, the system provides more accurate results if more of the node is analysed because there is less risk of tissue allocation bias (sample bias). Tissue allocation bias can occur when half of the lymph node is analysed using an intraoperative test and the other half using histopathology, if the metastasis is only contained in the tissue slices used for one of the methods. The RD‑100i OSNA system can be used with half of the lymph node (1\xa0piece or alternate slices), allowing for the possibility of follow-up histopathology but potentially decreasing the accuracy of the results because of the increased risk of tissue allocation bias. The time to results depends on the number of lymph nodes analysed, but the test takes approximately 30\xa0to 45\xa0minutes. The RD‑100i OSNA system result is expressed both quantitatively and qualitatively: −\xa0for lymph node-negative test results; +\xa0for lymph nodes with a micro-metastatic tumour burden (that is, greater than 250\xa0copies of CK19 mRNA/microlitre); and ++\xa0for lymph nodes with a macro-metastatic tumour burden (that is, greater than 5000 copies of CK19 mRNA/microlitre). The analyser amplifies and detects the CK19 mRNA by using 6\xa0different primers that have been designed to avoid the amplification of CK19 pseudogenes or their transcripts because amplification of these would lead to false positive results.\n\nThe manufacturer estimates that 1% of breast tumours do not express CK19 mRNA and so, if cancer spreads to the lymph nodes from these tumours, CK19 mRNA will not be detected even though the lymph nodes are metastatic. Pre-screening of tumour biopsies for CK19 expression could be carried out before using the RD‑100i OSNA system to reduce the small risk of false negative results for metastatic sentinel lymph nodes.\n\n## Metasin test\n\nThe Metasin test is an intraoperative molecular test developed within the NHS at the Princess Alexandra Hospital in Harlow, Essex. The test has similarities to a discontinued commercial test (Veridex GeneSearch breast lymph node [BLN] assay) and uses quantitative reverse transcription polymerase chain reaction (qRT‑PCR) to detect 2\xa0predictive markers of metastases, CK19 and mammaglobin. Mammaglobin is expressed mainly by breast epithelial cells and high levels of mammaglobin are associated with breast cancer. A reference gene (porphobilinogen deaminase; PBGD) is used to confirm the validity of the mRNA used in the test and 2\xa0other controls (positive and negative) are also included. The test uses reagents that can be purchased from commercial suppliers and can be used on the Cepheid Smartcycler platform. The Metasin test uses different primer-probe combinations to detect the CK19 and mammaglobin genes from the discontinued commercial test. It takes approximately 32\xa0minutes to extract and purify mRNA from the tissue and then to produce results. The Metasin test is currently used in the NHS as an in-house test to analyse half of the lymph node. The results are confirmed by follow-up histopathology. The Metasin test could also be used as a replacement test for postoperative histopathology.\n\nPre-screening of tumour biopsies for CK19 mRNA and mammaglobin mRNA expression may be carried out before using the Metasin test because, like the CK19 biomarker, mammaglobin is not expressed in all breast tumours. The proportion of breast cancer tumours that do not express mammaglobin mRNA is not known.\n\n# The comparator: postoperative histopathology\n\nPostoperative histopathology is the usual approach used in the NHS, in which the sentinel lymph nodes are fixed in paraffin blocks, sliced very thinly to produce sections that are mounted on slides, stained and then examined under a microscope by a consultant histopathologist. The time to receive results from histopathology is usually between 5\xa0and 15\xa0working days in the NHS. People who have macrometastases (defined as tumour deposits in which at least 1\xa0dimension is above 2\xa0mm) or micrometastases (tumour deposits that are only discernible microscopically and measure greater than 0.2\xa0mm but have no dimension greater than 2\xa0mm) detected in their sentinel lymph node are regarded as lymph node-positive, and will usually receive axillary lymph node dissection. People who have isolated tumour cells in their sentinel lymph node are regarded as lymph node-negative and will not receive axillary lymph node dissection.\n\nThe wait for histopathology test results can cause anxiety for patients and can also lead to the patient having a second operation to remove all of the relevant axillary lymph nodes if the test result is positive. This second operation can be more difficult and result in a higher risk of complications because it will involve operating on the same area of the breast and armpit as the first operation.\n\nThere are several levels of histopathology that can be performed. In one-level histopathology, 1\xa0section of the lymph node is examined, in three-level, 3\xa0sections and, in five-level, 5\xa0sections. The level of histopathology used may affect the accuracy of histopathology because of the risk of tissue allocation bias. There is also uncertainty about the accuracy of histopathology associated with the different staining techniques used, the thickness of the section examined and the experience of the pathologist reading the section slides.', 'Outcomes': "The Diagnostics Advisory Committee (section\xa09) considered evidence from a number of sources (section\xa010).\n\n# How outcomes were assessed\n\nThe assessment was performed by an external assessment group and consisted of a systematic review of the evidence on test performance and clinical effectiveness data for the RD‑100i OSNA system and the Metasin test compared with postoperative histopathology.\n\nThe outcome measures relevant to test performance included diagnostic test accuracy, test failure rate, discordant test results, and time to test result.\n\nThe outcome measures relevant to clinical effectiveness included: patient anxiety associated with the waiting time for results and with not knowing what the extent of surgery would be before the operation; number of repeat operations (excluding those for re-excision of positive margins); time to start and nature of adjuvant therapy; morbidity and mortality from biopsies, axillary dissections, first and second operations and treatment of cancer; and adverse events from false test results, including patient distress and sequelae.\n\nNo study was excluded on the basis of intervention, population, comparator or outcome, provided it appeared relevant to the scope of the evaluation.\n\n# Clinical effectiveness\n\n## RD‑100i OSNA system\n\nThe external assessment group included 16\xa0studies in the systematic review that investigated the performance of the RD‑100i OSNA system in detecting metastases in the sentinel or axillary lymph nodes, although 2\xa0of these studies reported the same trial. Fourteen of these 16\xa0studies reported test accuracy as an outcome and of these 14\xa0studies, 2\xa0also reported time to analysis. An additional observational study reported time to analysis as an outcome alone. One other study reported time in operating theatre, days in hospital, costs and postoperative complications. No data were found for the clinical outcomes of patient anxiety and number of repeat operations.\n\nEleven of the 16\xa0studies were single-gate studies in which people with unknown disease status were assessed using both the intraoperative test and the reference standard (histopathology) to compare the results of the 2\xa0tests and confirm diagnosis. The remaining studies comprised 4\xa0cohort studies and 1\xa0observational study. In the cohort studies, different patient samples were used for each test, which enabled whole-node analysis with the RD‑100i OSNA system.\n\nThere was heterogeneity across studies in their definitions of histopathology. Three studies reported using five-level histopathological analysis to detect metastases in the node. Two other studies used five-level histopathological analysis during the validation phase of the study and one-level histopathological analysis during routine use. Five studies reported using three-level histopathological analysis and 1\xa0other study reported using one-level histopathological analysis. The level of histopathological analysis used in the remaining studies is unclear. These varying levels of histopathological analyses may impact on the accuracy of histopathology because five-level analysis may be more likely to detect micrometastases than one-level analysis. In addition, depending on the level of analysis used some studies did not reflect current NHS practice for histopathological analysis.\n\nThe external assessment group found that, in all of the studies, there was a lack of detail on patient recruitment and patient characteristics so the risk of bias in the studies is unclear. Spectrum bias may arise if the severity of the cancer is greater in one\xa0study population than another because it is more likely that a test will detect metastases in people with severe disease and it will therefore appear to have a higher sensitivity. In addition, study populations may vary depending on the upstream diagnostic pathway because some clinics may be better at detecting metastases with fine needle aspiration cytology so sentinel lymph node biopsy would not be needed in some cases. This could result in a patient population with higher levels of micrometastases than macrometastases receiving sentinel lymph node biopsy and so the sensitivity of the intraoperative test or histopathology may appear lower in this population. There was also a lack of information on sampling methods, so there was no evidence of sample replicates and reproducibility for molecular analysis.\n\nThe assessment of test accuracy for the RD‑100i OSNA system was hindered by tissue allocation bias and by comparison with an inconsistent reference standard (different levels of histopathology). In some studies, discordant samples were further analysed (by extensive histopathology, molecular analysis or Western blotting) and attributed to tissue allocation bias. In these cases, the test accuracy analyses could be adjusted by excluding the data from the discordant samples. No adjustment could be made for the varying levels of histopathology used across the studies.\n\nThe range of estimates for sensitivity and specificity by patient before adjustment for tissue allocation bias from the studies were 77.8–80.0% and 88.0–97.2% respectively. The range of estimates for sensitivity and specificity by patient after adjustment for tissue allocation bias from the studies were 89.8–100% and 93.3–97.2% respectively.\n\nThe external assessment group performed a meta-analysis (bivariate method) of diagnostic test accuracy from studies that reported the numbers of true positives, true negatives, false negatives and false positives in the text (or sufficient data for these test statistics to be calculated). Five studies were included that did not adjust for tissue allocation bias and 3\xa0studies were included that did adjust for tissue allocation bias. The sensitivity and specificity by patient without adjustment for tissue allocation bias were 84.5% (95% confidence interval [CI] 74.7% to 91.0%) and 91.8% (95%\xa0CI 87.8% to 94.6%) respectively. The sensitivity and specificity by patient with adjustment for tissue allocation bias were 91.3% (95%\xa0CI 83.6% to 95.6%) and 94.2% (95%\xa0CI 91.2% to 96.2%) respectively.\n\nFour studies reported the time to analysis by the RD‑100i OSNA system. The estimates for time to analysis from the studies ranged from less than 30\xa0minutes to 39.6\xa0minutes for 1\xa0node and increased by 5–10\xa0minutes per additional node analysed. One study reported that the longest and most variable time period corresponded to transporting the node from the operating room to the pathology department. The least variable time period corresponded to the homogenisation of tissue, preparation of the diluted sample and gene amplification by RT‑LAMP.\n\nOne other study compared the number of postoperative complications between the use of histopathology and the use of RD‑100i OSNA to analyse lymph node samples. The aim of this study was to analyse the economic costs of intraoperative testing with the RD‑100i OSNA system compared with postoperative histopathology. Overall, the patients having intraoperative lymph node testing using the RD‑100i OSNA system experienced fewer postoperative complications than patients having postoperative histopathology analysis, although the only major complication reported occurred in the OSNA group (no further details of the major complication were reported). This study was conducted in Spain and the assessment group stated that it was uncertain to what extent the study findings might be generalisable to the UK owing to possible differences in clinical practice.\n\n## Metasin test\n\nTwo draft unpublished non-peer reviewed studies that investigated the performance of the Metasin test in detecting metastases in the lymph nodes of patients with breast cancer were included in the systematic review. The results of one of the studies are considered academic in confidence.\n\nThe other study, by Sundaresan et al. (unpublished), was designed as a single-gate study comparing the Metasin test with histopathology, in which people were assessed by both methods. It reported test accuracy and time to analysis as outcomes. It used three-level histopathological analysis to detect metastases in the nodes but did not report details of patient recruitment or patient characteristics, so the risk of bias is unclear. There was also a lack of information about sample replicates and reproducibility for molecular analysis, and the external assessment group did not consider the study to meet the STAndards for the Reporting of Diagnostic accuracy studies (STARD) criteria.\n\nAs with the studies assessing the RD‑100i OSNA system, one of the main issues with assessing the accuracy of the Metasin test was tissue allocation bias. No discordant analyses were performed in the study but discordant results were observed in 56 out of 1265 patients (4.4%): 36\xa0patients had a positive Metasin test and negative histopathology, and 20\xa0patients had a negative Metasin test and positive histopathology. The authors considered that tissue allocation bias was responsible for the discordant results, although no evidence or analysis was presented in the study to support this.\n\nThe estimates for test accuracy by patient without adjustment for tissue allocation bias in Sundaresan et al. were 92% sensitivity (95%\xa0CI 89% to 95%) and 97% specificity (95%\xa0CI 95% to 97%). No meta-analysis was performed by the external assessment group for the 2\xa0studies assessing the Metasin test because at least 4\xa0studies are needed to use the bivariate method of meta-analysis. The accuracy values from Sundaresan et al. were used in the cost-effectiveness analyses.\n\n# Cost effectiveness\n\nThe external assessment group identified 2\xa0studies that were considered relevant for the systematic review on the cost effectiveness of intraoperative tests for the detection of sentinel lymph node metastases. Both studies were single-centre observational studies that compared an intraoperative test with histopathology for assessing sentinel lymph node biopsy. One study was based in the UK and assessed the GeneSearch BLN assay and the other study was conducted in Spain and evaluated the RD‑100i OSNA system. Both studies found their respective intraoperative tests to be cost effective compared with histopathology, with both assays being cost saving while reducing theatre time and length of hospital stay. Neither study considered outcomes beyond the diagnostic phase. The UK study provided evidence on resource use and costs of intraoperative testing in the UK but evaluated the GeneSearch BLN assay, which has been withdrawn from the market. The Metasin test uses the same markers as the GeneSearch BLN assay, CK19 and Mammaglobin, but different primer-probe combinations, so it is expected to perform differently from the GeneSearch BLN assay. Therefore, this UK study is not directly relevant to this evaluation. The study conducted in Spain also provided evidence on resource use and costs but was limited in the extent to which it was generalisable to the UK. Therefore, the external assessment group did not consider the study directly relevant to this evaluation.\n\nThe external assessment group performed an economic analysis to assess the cost effectiveness of using intraoperative tests to detect sentinel node metastases compared with using histopathology. The economic model was divided into 2\xa0separate sections (diagnostic and management) to encompass both the short-term and long-term outcomes of intraoperative testing. The costs were evaluated from the perspective of the NHS and personal social services. Outcomes were expressed as quality-adjusted life years (QALYs). Both costs and outcomes were discounted using a 3.5% annual discount rate.\n\nThe external assessment group developed a decision tree to model the short-term diagnostic outcomes outlined in the decision problem. People enter the model as patients who have sentinel lymph node biopsy performed during their initial tumour removal. The model then splits into 3\xa0different diagnostic strategies: postoperative histopathology (current practice) alone, intraoperative testing alone and intraoperative testing combined with postoperative histopathology confirmation. In the model, patients who are diagnosed with sentinel lymph node metastases receive axillary lymph node dissection, either during the same operation as their sentinel lymph node biopsy if intraoperative testing is used or during a second operation if postoperative histopathology is used.\n\nOnce the diagnostic subgroups have been identified (true positive sentinel lymph node, false positive sentinel lymph node, true negative sentinel lymph node and false negative sentinel lymph node), the model moves into the management pathway and the subgroups are separated based on whether or not patients receive an axillary lymph node dissection. This section of the model calculates the long-term outcomes for each subgroup and at this point, a discrete event simulation model, previously developed at the University of Sheffield (ScHARR-TAG), was used to model the natural disease history of the patients once their outcome from the diagnostic decision tree had been determined. In the model, after surgery, patients receive adjuvant therapy comprising chemotherapy and hormonal therapy (where appropriate) for patients diagnosed with metastases and hormonal therapy alone (where appropriate) for patients diagnosed without. After adjuvant therapy, patients can move into a disease-free state, or experience locoregional or metastatic relapse. Patients can also move between these states.\n\nThe meta-analysed accuracy values without adjustment for tissue allocation bias for the RD‑100i OSNA system and the accuracy values from one of the unpublished papers for the Metasin test were used in the base case. The node-positive prevalence was set at 20% in the base case, in line with the studies in the clinical systematic review.\n\nUnit costs for the intraoperative tests were taken from the sponsors of the technologies and the cost of histopathology was based on data provided by the NHS Technology Adoption Centre. The unit cost of the RD‑100i OSNA system was £350 and the unit cost of histopathology was £472. The surgery costs were mainly based on NHS reference costs and the costs of short-term adverse events were taken from Jeruss et al. (2006). The costs associated with lymphoedema were obtained from the Sheffield Lymphoedema Service and the length of additional hospital stay was calculated from a study by the York Health Economics Consortium. The costs of additional time in surgery were estimated from a study by Ng et al. (2011) and from the report by York Health Economics Consortium. All costs were updated to 2010 levels.\n\nThe QALY decrement associated with a 2‑week wait for histopathology results was calculated by the external assessment group to be 0.019 (undiscounted). For patients having a separate second operation, the disutility was estimated as 0.03.\n\nThe external assessment group considered the results of the cost-effectiveness analyses for the Metasin test to be illustrative because of the high levels of uncertainty associated with the unpublished evidence base relating to the diagnostic accuracy of the test.\n\nThe cost-effectiveness analyses of the short-term outcomes examined the diagnostic accuracy of the intraoperative tests compared with postoperative histopathology, and the disutility of waiting for histopathology results and having a second operation. For strategies that did not involve histopathology, the utility was\xa01 because there was no wait for test results or any second operations directly resulting from the intraoperative test. Only short-term QALY gains were included in these analyses.\n\nUsing the NHS reference costs in the short-term model, whole-node OSNA analysis and half-node OSNA analysis dominated histopathology analysis because they were less costly and more effective. Whole-node OSNA analysis also dominated half-node OSNA analysis. It was estimated that 4.1% of the 76.5% of patients who received a negative test result from half-node OSNA analysis would end up with a positive result while waiting for confirmation by histopathology analysis, compared with 20% of patients who would receive a positive result using postoperative histopathology analysis alone.\n\nIn the short-term model, whole-node and half-node Metasin analyses dominated histopathology analysis because they were less costly and more effective. Whole-node Metasin also dominated half-node Metasin analysis. It was estimated that, of the 78.5% of patients who received a negative result by half-node Metasin analysis, 1.9% would receive a positive result while waiting for confirmation by histopathology analysis, compared with 20% of patients who would receive a positive result using postoperative histopathology analysis alone.\n\nThe cost-effectiveness analyses of the long-term outcomes examined all the costs and benefits from accurate diagnosis through to improved patient management. In these analyses, the diagnostic strategies were ordered by the number of QALYs associated with them, with whole-node OSNA analysis producing the least QALYs (9.22) and postoperative histopathology producing the most QALYs (9.32). The QALY difference is equal to\xa00.1 (that is, equivalent to 5\xa0weeks of full-health life) and this difference occurs because the higher accuracy of histopathology assumed in the model leads to more correct diagnoses and appropriate subsequent treatment.\n\nUsing the NHS reference costs in the long-term model, the incremental cost-effectiveness ratio (ICER) was £4324 saved per QALY lost for whole-node OSNA analysis compared with histopathology analysis and £24,863 saved per QALY lost for whole-node Metasin analysis compared with histopathology analysis. The ICERs for whole-node analysis compared with histopathology analysis suggest that the intraoperative testing strategies save money but that there is a loss of approximately 0.1\xa0QALY, compared with histopathology analysis.\n\nIn the modelling, histopathology analysis was assumed to be the 'gold standard' and was given an accuracy of 100% sensitivity and 100% specificity. The level of uncertainty in this assumption is unclear and the estimated ICERs may change depending on the assumed absolute accuracy of histopathology.\n\nThe sensitivity and specificity of OSNA analysis were changed to use values from studies that had been adjusted for tissue allocation bias (Frere Belda et al. 2012, Snook et al. 2011 and Khaddage et al. 2011). Using NHS reference costs, the ICER was £9493 saved per QALY lost for whole-node OSNA analysis compared with histopathology analysis using accuracy values from the Frere Belda et al. study (91.4% sensitivity and 93.3% specificity) and £8840 saved per QALY lost for whole-node OSNA analysis compared with histopathology analysis using values from the Snook et al. study (89.8% sensitivity and 94.5% specificity). However, using the higher accuracy values from the Khaddage et al. study (100% sensitivity and 97.2% specificity) resulted in ICERs for whole-node OSNA analysis that dominated both half-node OSNA analysis and histopathology analysis.\n\nThe change in ICERs when accuracy values adjusted for tissue allocation bias were used showed that test accuracy has a direct impact on the cost effectiveness of the tests. Threshold analysis was used to investigate sensitivity by increasing sensitivity over a range of 70–100% while specificity was held constant. The opposite was also performed to investigate specificity. These analyses were conducted on the results for the whole-node OSNA analysis. Short-term utility results were not reported as the utility of OSNA was not affected by the accuracy of the test.\n\nThe results of the threshold analysis for the long-term results showed that, when the sensitivity of OSNA increased (and specificity was kept at the 91.8% base-case value), the saving per QALY lost increased when comparing whole-node OSNA with histopathology. When comparing OSNA with histopathology, the ICERs for OSNA ranged from £2119 saved per QALY lost when OSNA had a sensitivity of 70% to £14,193 saved per QALY lost when OSNA had 95% sensitivity. At 100% sensitivity, OSNA dominated histopathology, having more QALYs gained and lower costs.\n\nFor specificity, the long-term cost of OSNA decreased and the QALY gain increased as the specificity increased. At a specificity of 70%, whole-node OSNA analysis was dominated by histopathology analysis because it was more expensive and had fewer QALYs. The largest ICER for OSNA was £8430 saved per QALY lost compared with histopathology when whole-node OSNA analysis had 100% specificity (and sensitivity was kept at the base-case value of 94.5%).\n\nOverall, the threshold analyses suggested that, if the true values of sensitivity and specificity for whole-node OSNA analysis lie within the range of 90–100%, the cost effectiveness of whole-node OSNA analysis may increase. The results also imply that changes to specificity may have more of an impact in the short-term than the long-term, but that changes to sensitivity may have a much greater impact on the long-term cost effectiveness.\n\nSensitivity analysis was also conducted on the effect of prevalence of sentinel lymph node metastases in the patient population. When the prevalence was reduced to 10%, histopathology analysis dominated half-node OSNA analysis and had an ICER of £2626 per QALY gained compared with whole-node OSNA analysis. When the prevalence was increased to 40%, half-node OSNA analysis dominated histopathology analysis and had an ICER of £2208 per QALY gained compared with whole-node OSNA analysis.\n\nChanging individual costs and utility parameter values in the short-term or long-term sections of the model had very little impact on the overall cost-effectiveness results. This highlighted the importance of the diagnostic accuracy of the tests because this was the most influential parameter.", 'Considerations': 'The Committee considered the heterogeneity and uncertainty in the studies. The Committee heard from the clinical specialists on the Committee that histopathology practices can vary between hospitals in the UK. It also heard that, in routine clinical practice, the standard of histopathology may be different to that in the studies. It concluded that the extensive research-standard histopathology described in the studies may not be representative of the histopathology conducted in routine clinical NHS practice because it is very time consuming. The Committee also concluded that there is variation in how histopathology is performed across the NHS.\n\nThe Committee discussed the use of the intraoperative tests in clinical practice. The Committee noted that RNA extraction is needed for the Metasin test but not for the RD‑100i OSNA system. It raised concerns about quality assurance when performing RNA extraction in the operating theatre and noted that there were advantages in not having to perform this step with the RD‑100i OSNA system. The Committee also discussed the support available for users of the intraoperative tests from the manufacturers and considered that there was more uncertainty about the support for the Metasin test than for the RD‑100i OSNA system. The Committee concluded that further evidence was needed to show that the Metasin test could be used effectively in hospitals that had not been involved in the development of the test.\n\nThe Committee considered that biomedical scientists can carry out testing using the RD‑100i OSNA system or the Metasin test, although a higher level of molecular biology expertise appears to be needed for the Metasin test. This expertise may not be available in all hospitals performing breast surgery, particularly once laboratory services are centralised. The Committee noted that a biomedical scientist may need to travel to the surgery site to perform the intraoperative test, which would result in a loss of resources from the laboratory during that time. The Committee also considered that there is a shortage of pathologists in the NHS and that using these intraoperative molecular tests may free pathology resources for other uses in the NHS.\n\nThe Committee considered the unpublished non-peer reviewed evidence for the Metasin test. The Committee acknowledged the findings of the 2\xa0draft unpublished studies, but noted that the studies had not been peer reviewed and therefore the results should be interpreted with caution. The Committee concluded that the test appeared promising but that there was too much uncertainty associated with the evidence to recommend use of the test in routine NHS practice. The Committee was encouraging of further research on this test.\n\nThe Committee considered the 20% prevalence of sentinel lymph node metastases in the patient population used in the base case for the cost-effectiveness analyses. It heard from the clinical specialists that the prevalence was likely to be higher than 20%, and possibly around 30%. The Committee noted the sensitivity analysis, which showed that an increase in the prevalence of sentinel lymph node metastases increased the cost effectiveness of the RD‑100i OSNA system (see section\xa05.37). Therefore, the Committee concluded that using the RD‑100i OSNA system was likely to be more cost effective than the base-case incremental cost-effectiveness ratios (ICERs) suggested.\n\nThe Committee considered the accuracy of histopathology. The Committee heard from a specialist committee member that the sensitivity of histopathology in routine UK practice was likely to be lower than 100%, which was what was assumed in the cost-effectiveness analysis. The committee heard that the main source of inaccuracy in histopathology is tissue allocation bias, but that other sources of inaccuracy are possible, including user variability. The Committee noted that it was unlikely that a macrometastasis would be missed if the current histopathology guidelines were followed but that it was possible that micrometastases could be missed. However, the clinical significance of this is not known. The Committee concluded that it was very difficult to determine the absolute accuracy of histopathology because of the nature of the technique and the inherent variation from qualitative judgement of different pathologists. However, it was likely to be lower than 100% in routine clinical practice.\n\nThe Committee also considered the assumption in the modelling that histopathology was 100% accurate following discussions about the accuracy of histopathology in clinical practice. The Committee concluded that the accuracy of histopathology in any setting could not be 100% because time and resources did not allow every slice of a node to be analysed for metastases. The Committee therefore concluded that use of the RD‑100i OSNA system was likely to be more cost effective than the base-case ICERs suggested.\n\nThe Committee discussed the option to use the RD‑100i OSNA system to analyse either a whole node, or half a node, with the remaining half used to confirm the results by follow-up histopathology. Clinical specialists on the Committee said that whole-node analysis had more benefit than half-node analysis followed by histopathology because there was no risk of tissue allocation bias when the whole node was analysed. The Committee heard from the manufacturer of the RD‑100i OSNA system that there is a small risk of test failure and the Committee considered the impact of this when all of the node tissue is used in whole-node analysis. The manufacturer stated that tissue lysate samples can be stored for up to 1\xa0month and can be re-tested in the event of test failure. The Committee concluded that it was acceptable for half-node analysis with postoperative histopathology confirmation to be used while the RD‑100i OSNA system is being validated locally but recommended that, after validation, whole-node OSNA analysis should be fully implemented in local clinical practice to reduce the risk of tissue allocation bias.\n\nThe Committee considered the possibility of pre-screening tumours for the expression of CK19 and mammaglobin to reduce the small risk of a false negative result. The Committee heard from clinical specialists that pre-screening would use pathology resources that are already limited and that it may not be possible to deliver results during surgery. The Committee also heard that the interpretation of pre-screening results is complicated by tumour tissue heterogeneity, which means that this information has limited clinical value. Furthermore, the Committee heard that the mammaglobin antibody is difficult to work with and that immunohistochemistry staining for mammaglobin is not routinely available in the NHS. The Committee concluded that pre-screening for expression of CK19 and mammaglobin was not likely to take place in routine clinical practice because of the resource restraints on pathology services.\n\nThe Committee considered the difference in the clinical information obtained from intraoperative whole-node analysis compared with histopathological analysis. The Committee discussed whether the absence of sentinel lymph node tissue for histopathological analysis following whole-node analysis with the RD‑100i OSNA system posed any risk to clinical decision-making when deciding on the strategy for systemic adjuvant therapy. The Committee also considered the risk of a false positive result, such as the detection of CK19 expression from high-grade lymphoma rather than lymph node metastases from breast cancer. The Committee concluded that these risks were very low.\n\nThe Committee discussed the scenario in which intraoperative analysis of sentinel lymph nodes is not performed and when a second operation is needed following identification of lymph node metastases with histopathology. The Committee noted that the value in the economic model for the disutility arising from a second operation was\xa00.03. The Committee heard from the clinical specialists that a second breast operation is technically more difficult because of disrupted tissue structure. It also heard that a second operation had an increased risk of complications compared with breast surgery being done for the first time. Furthermore, the Committee heard from a patient expert that patients generally found the prospect of having a second operation very worrying and that the option of not having to have a second operation was an important consideration for patients. The Committee therefore considered that the disutility from the second operation was likely to be larger than that assumed in the economic model and the cost effectiveness of intraoperative testing was, as a consequence, likely to be underestimated in the base case. The Committee concluded that intraoperative analysis of sentinel lymph nodes had considerable advantages over traditional histopathology testing and had the potential to reduce both clinical complications, and patient anxiety and distress.\n\nThe Committee considered the impact on patients of not knowing what the extent of their surgery would be before the operation. The Committee heard from a patient expert the importance of patients being informed before surgery about the different types of surgery they may have, depending on the results of the intraoperative test. The Committee noted that there was strong patient preference for all procedures to be done in a single\xa0operation and noted that, in routine clinical practice, the uncertainty about the extent of surgery would be explained to the patient.\n\nThe Committee considered the cost-effectiveness analyses of the RD‑100i OSNA system. The Committee acknowledged that the model contained several assumptions that could potentially increase the uncertainty of the cost-effectiveness analysis. However, the Committee considered that it was appropriate to assume a higher prevalence than that used in the base case (see section\xa06.5), an accuracy value of less than 100% for histopathology (see sections\xa06.6 and\xa06.7), and that the technical difficulty and complications associated with a second operation may have been underestimated (see section\xa06.11). The Committee concluded that, taking these considerations together, the RD‑100i OSNA system was likely to be more cost effective than the base-case ICERs suggested and that it was likely that the RD‑100i OSNA system was equally or more cost effective than postoperative histopathology. The Committee also concluded that the substantial patient benefits associated with using the RD‑100i OSNA system and the strong patient preference for all procedures to be done in a single\xa0operation were not fully captured in the cost-effectiveness analyses. The Committee therefore concluded that the RD‑100i OSNA system would represent a cost-effective use of NHS resources if used as an option for detecting sentinel lymph node metastases in people with early invasive breast cancer who have a sentinel lymph node biopsy and in whom axillary lymph node dissection is being considered.\n\nThe Committee considered the cost of histopathology used in the cost-effectiveness analyses and acknowledged it was higher than it is likely to be current practice. The Committee was of the view that, if the economic model used a more realistic cost for histopathology, it would indicate that the RD‑100i OSNA system was less cost effective than the base-case ICERs presented in the diagnostics assessment report. However, given all of the uncertainty in the cost-effectiveness analyses (see section\xa06.13), the Committee concluded that the RD‑100i OSNA system was still likely to be a cost-effective use of NHS resources.\n\nThe Committee heard from clinical specialists about the recent publication of the Z0011 trial, which reported no improvement in survival after axillary lymph node dissection in women who received a positive result for lymph node metastases. The Committee heard from the clinical specialists that there was concern that the Z00011 trial was not definitive and possibly under-powered, and that there was no radiotherapy quality assurance programme to monitor the dose of radiation given. The Committee concluded that using intraoperative tests for detecting sentinel lymph node metastases offered substantial benefits to patients in current clinical practice and that these benefits were likely to be useful while the uncertainty in the effectiveness of performing axillary lymph node dissection remains.\n\nThe Committee considered that a quality assurance scheme for the use of the RD‑100i OSNA system and any other relevant intraoperative tests is needed.\n\nThe Committee considered that, for the efficient use of intraoperative testing, surgical theatre lists may need to be carefully scheduled and multiple analysers may be needed for sentinel lymph node testing if breast operations occur in parallel. The Committee heard from clinical specialists that the sentinel lymph node biopsy can be performed first so that the lymph nodes can be analysed using the RD‑100i OSNA system while the primary tumour is being removed. This prevents the time in surgery being significantly increased by use of an intraoperative test.\n\nClinical specialists on the Committee also informed the Committee that fewer sentinel lymph node biopsies may be performed during an operating theatre list to allow time to perform axillary lymph node dissections when the intraoperative test results are positive. However, theatre time is made available in the subsequent weeks because the patients are not returning for a second operation, which would occur if patients had to wait for postoperative histopathology results. The Committee concluded that any disruption to theatre lists can be overcome with careful planning and scheduling.', 'Recommendations for further research': 'NICE recommends that a national registry is developed to collect data on the use of the RD‑100i OSNA system in detecting sentinel lymph node metastases during breast cancer surgery. It also recommends that data on all patients having whole lymph node analysis by the RD‑100i OSNA system should be submitted to this registry. These data should be integrated with data from other registries for breast cancer where appropriate.'}	https://www.nice.org.uk/guidance/dg8	Evidence-based recommendations on the RD-100i OSNA system and Metasin test for detecting sentinel lymph node metastases in people having breast cancer surgery.
485b7020b82b59e79059d545126af67b546f95e7	nice	Pazopanib for the first-line treatment of advanced renal cell carcinoma	Pazopanib for the first-line treatment of advanced renal cell carcinoma Evidence-based recommendations on pazopanib (Votrient) for previously untreated advanced renal cell carcinoma in adults. # Guidance This guidance has been re-issued after a change to the patient access scheme (August 2013). Part B of the patient access scheme will not be activated. Reference to part B of the patient access scheme has been removed from the recommendations. Reference to it elsewhere in the document should be considered obsolete. Pazopanib is recommended as a first-line treatment option for people with advanced renal cell carcinoma who have not received prior cytokine therapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and if the manufacturer provides pazopanib with a 12.5% discount on the list price as agreed in the patient access scheme. When using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate. People who are currently being treated with pazopanib for advanced metastatic renal cell carcinoma but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.# The technology Pazopanib (Votrient, GlaxoSmithKline) is an orally administered tyrosine kinase inhibitor. It inhibits vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors on cancer cells, vascular endothelial cells and pericytes, stopping the proliferation of tumour cells and the development of tumour blood vessels. Pazopanib has a conditional marketing authorisation for 'the first-line treatment of advanced renal cell carcinoma and for patients who have received prior cytokine therapy for advanced disease'. The conditional marketing authorisation is linked to the provision of further data including the outcome of the ongoing head-to-head non-inferiority trial of pazopanib versus sunitinib in patients with advanced renal cell carcinoma (COMPARZ). Only the indication for pazopanib for the first-line treatment of advanced renal cell carcinoma is within the remit of the appraisal. Pazopanib is contraindicated in people who have hypersensitivity to the active substance or to any of the excipients, and people with severe hepatic impairment. The summary of product characteristics lists the adverse events that may be associated with pazopanib treatment, the most common being diarrhoea, hair colour changes, hypertension, nausea, anorexia, vomiting, fatigue, taste disturbance or loss of taste, and abnormal liver function. For full details of side effects and contraindications, see the summary of product characteristics. Pazopanib is administered orally. The recommended dosage is 800 mg once daily. The dose may be adjusted in steps of 200 mg according to tolerability in order to manage adverse reactions but should not exceed 800 mg. The price for a pack of 400 mg tablets (30 tablets per pack) is £1121.00 (MIMS, November 2010). The daily cost of pazopanib is £74.73 as stated by the manufacturer. The manufacturer of pazopanib has agreed a two-part patient access scheme with the Department of Health. Part A of the patient access scheme provides a 12.5% discount from the list price. Therefore the daily acquisition cost of pazopanib is £65.39. Part B of the patient access scheme, the details of which are 'commercial in confidence', offers a future rebate linked to the outcome of the head-to-head COMPARZ trial. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pazopanib and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer presented evidence on the clinical effectiveness of pazopanib used in line with the conditional marketing authorisation and the appraisal scope. The main clinical-effectiveness evidence came from patients in the treatment-naive subgroup of a phase III randomised controlled trial (RCT). The RCT, VEG105192, compared the effect of a once-daily dose of pazopanib plus best supportive care (155 patients) with placebo plus best supportive care (78 patients). Best supportive care was defined as the monitoring of progression, symptom control and palliative care without active treatment. The trial was conducted in patients with advanced renal cell carcinoma with predominantly clear cell histology. All patients had a good performance status (ECOG performance status 0 or 1) at the start of the trial. Baseline characteristics of the patients in the two treatment arms were equally balanced. The primary outcome in the study was progression-free survival, which was defined as time from randomisation to disease progression or death. Tumour assessments were performed using RECIST (Response Evaluation Criteria in Solid Tumours) and were confirmed by an independent review committee. Once disease progression was confirmed, patients who previously received placebo plus best supportive care could be offered open-label pazopanib plus best supportive care in the open-label extension study (VEG107769) if the treating clinician thought this was in the best interests of the patient. At disease progression, only patients with an ECOG performance status of less than or equal to 2 were permitted to cross over to receive pazopanib. The median progression-free survival was statistically significantly longer in patients receiving pazopanib (p < 0.001). The median progression-free survival was 11.1 months (95% confidence interval 7.4 to 14.8) for patients receiving pazopanib plus best supportive care and 2.8 months (95% CI 1.9 to 5.6) for patients receiving placebo plus best supportive care (hazard ratio 0.40, 95% CI 0.27 to 0.60) based on blinded imaging assessment by the Independent Review Committee. This meant there was a 60% reduction in risk of disease progression for patients receiving pazopanib plus best supportive care compared with those receiving placebo plus best supportive care at the final analysis. The manufacturer performed sensitivity analyses of progression-free survival based on actual scan dates and investigators' assessment to confirm the robustness of the findings. The median progression-free survival based on actual scan dates was 10.8 months (95% CI 7.4 to 14.8) for patients receiving pazopanib plus best supportive care and 2.9 months (95% CI 1.9 to 5.4) for patients receiving placebo plus best supportive care (HR 0.36, 95% CI 0.24 to 0.55). These latter estimates were used in the indirect comparison. At the time of the interim overall survival analysis (23 May 2008), 31 of 78 (40%) treatment-naive patients randomised to receive placebo in the VEG105192 trial had crossed over to receive pazopanib. At the final analysis (15 March 2010), a total of 40 (51%) treatment-naive patients randomised to placebo had crossed over to receive pazopanib. Overall survival for the treatment-naive, intention-to-treat population, unadjusted for crossover, was 22.9 months (95% CI 17.6 to 25.4 months) for patients randomised to pazopanib plus best supportive care and 23.5 months (95% CI 12.0 to 34.3 months) for patients randomised to placebo plus best supportive care. The hazard ratio for overall survival was 1.01 (95% CI 0.72 to 1.42, p = 0.525). The manufacturer presented a variety of methods to adjust for crossover when estimating median overall survival, including the inverse probability censoring weighted (IPCW) and rank preserved structural failure time (RPSFT) methods. The manufacturer considered the RPSFT weighted method to be the most appropriate because it was considered an acceptable approach for NICE technology appraisal guidance 179 ('Sunitinib for the treatment of gastrointestinal stromal tumours') and the ongoing technology appraisal 'Everolimus for the second-line treatment of advanced renal cell carcinoma'. The RPSFT weighted method estimated the overall survival of patients randomised to receive placebo assuming that they had not crossed over, that is, as if they had remained on placebo for the duration of the trial. The method proportionally 'shrunk' the estimated amount of additional survival given to patients who crossed over to receive pazopanib. The RPSFT analysis suggested that treatment with pazopanib was consistently associated with survival benefit compared with placebo (HR 0.501, 95% CI 0.136 to 2.348). The manufacturer also noted that the 0.501 hazard ratio lies within the range of estimates obtained from the different methods used to adjust for crossover. This hazard ratio was subsequently used for the indirect comparison. No head-to-head trials analysing the efficacy of pazopanib compared with other active treatment options were available. Therefore, the manufacturer undertook a search for trials of comparator interventions and carried out an indirect comparison to estimate the relative effect of pazopanib versus the comparators (sunitinib, interferon-α and best supportive care). Seven studies were included in the indirect comparison, including one study of pazopanib compared with placebo (VEG105192), one study of sunitinib compared with interferon-α (Motzer et al. 2009) and five studies that directly compared interferon-α with a non-interferon control therapy (medroxyprogesterone acetate and vinblastine). The populations in the pazopanib (VEG105192) and sunitinib (Motzer et al. 2009) studies were comparable, but with the exception that a higher proportion of patients with a baseline ECOG performance status of 0 were recruited to the sunitinib study than to the VEG105192 trial (approximately 60% versus 40%). Both studies restricted entry to patients with renal cell carcinoma with either clear cell or predominantly clear cell histology. The average age of patients in both studies was 60 years and 83–91% of patients had prior nephrectomy. The patient populations in the five interferon-α studies were generally similar. All patients had renal cell carcinoma, the age range was 60–66 years and 57–100% of patients had prior nephrectomy. Three of the interferon-α studies included some patients with a baseline ECOG performance status of 2. Hazard ratios for progression free survival and overall survival from all seven studies were used in the indirect comparison to obtain hazard ratios for pazopanib versus interferon-α and pazopanib versus sunitinib. The hazard ratios for progression-free survival used in the indirect comparison for pazopanib versus placebo plus best supportive care, sunitinib versus interferon-α and interferon-α versus best supportive care were 0.36 (95% CI 0.24 to 0.55), 0.539 (95% CI 0.451 to 0.643) and 0.704 (95% CI 0.0.580 to 0.854). Median progression-free survival estimates derived from the indirect comparison for pazopanib, sunitinib, interferon-α and placebo plus best supportive care were 11.3 months (95% CI 5.1 to 17.5), 10.7 months (95% CI 7.9 to 13.4), 5.4 months (95% CI 5.4 to 5.4) and 5.6 months (95% CI 4.0 to 7.3) respectively. The pazopanib overall survival value was estimated using the RPSFT weighted method. The manufacturer used hazard ratios derived from all seven studies in a Weibull survival model to estimate the median overall survival values for pazopanib versus interferon-α and pazopanib versus sunitinib. In the base-case scenario, derived using the RPSFT weighted method, the median overall survival estimates for pazopanib, sunitinib, interferon-α and placebo plus best supportive care were 27.8, 26.8, 15.8 and 12.1 months, respectively. These results indicated that pazopanib was associated with a decreased risk of death (37% reduction) compared with interferon-α, and that pazopanib appeared to have comparable efficacy with sunitinib in terms of overall survival. The manufacturer highlighted that the 95% confidence intervals around the hazard ratios were wide, indicating a level of uncertainty with the estimates. Sensitivity analyses were performed that included varying the hazard ratio for overall survival in the VEG105192 trial by using different methods for adjusting for crossover and varying the interferon-α studies included. The manufacturer concluded that the results of these sensitivity analyses of the indirect comparison were similar to those of the base-case analysis. Only the VEG105192 trial, which compared pazopanib and placebo, and the study by Motzer et al. (2009), which compared sunitinib with interferon-α, reported health-related quality of life data. For the VEG105192 trial, there were no statistically significant differences between pazopanib and placebo for any of the instruments used (European Organisation for Research and Treatment of Cancer quality of life questionnaire – Core 30, EQ-5D, EQ-5D-VAS). For the comparison of sunitinib with interferon-α, patients receiving sunitinib had a statistically significantly better quality of life than patients receiving interferon-α, as measured by the EQ-5D, EQ-5D-VAS and the Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index Disease-related Symptom (FKSI-DRS) Index, FACT-Kidney Symptom Index – 15-item scale (FKSI-15 Index) and the FACT-General Scale (FACT-G). No indirect comparison was made for this outcome. In the VEG105192 trial, 91% of patients receiving pazopanib experienced an adverse event. In 87% of patients the adverse events were related to study medication. In the placebo group 74% of patients experienced an adverse event and in 37% of patients these were related to study medication. The most frequent adverse events related to pazopanib treatment were diarrhoea, hair colour change, hypertension, nausea, anorexia and increased liver enzymes. The manufacturer conducted an indirect comparison using one of the interferon-α studies to estimate the adverse event rates of pazopanib compared with sunitinb. The adverse event rates for pazopanib were generally lower than for sunitinib, in particular for dyspepsia, mucositis/stomatitis, fatigue, hand-foot syndrome, skin discolouration, hypophosphataemia, anaemia and altered taste. However, only the difference in fatigue was statistically significant (HR 0.21, 95% CI 0.06 to 0.77). The manufacturer submitted an economic model to assess the cost effectiveness of pazopanib in treatment-naive patients. The model compared pazopanib with interferon-α, sunitinib and best supportive care. The manufacturer described the model as a 'partitioned survival' model, characterised by three mutually exclusive health states: alive pre-progression, alive post-progression and dead. Unlike a Markov model, which models transitions between health states explicitly using transition probabilities, the partitioned survival model calculated the proportion of patients in each treatment arm at any time after starting treatment, using parametric survival curves fitted to empirical data on overall survival and progression-free survival over time. The proportion of patients in the 'alive post-progression' health state at any given time was calculated as the difference between overall survival and progression-free survival. In the model, pazopanib was assumed to be given until disease progression or death (if occurring before progression). After starting treatment, patients were assumed to be in an 'alive pre-progression' health state, and to be at risk of disease progression and/or death over time. Patients who experienced disease progression were assumed to discontinue treatment with pazopanib (and receive only best supportive care) and to transition to an 'alive post-progression' health state and to stay in that state until death. For the model, a utility value of 0.70 was assumed for patients who had no disease progression and no adverse events, based on the mean EQ-5D utility value among patients without adverse events in the VEG105192 trial. Disease progression was assumed to be associated with a decrement in utility of 15% (that is, a post-progression utility value of 0.59). These values were used for all the interventions in the model. Utility decrements for adverse events were also obtained from the VEG105192 trial. As a result of the lack of published utility data in this patient population, the manufacturer commissioned a health state preference study to generate utility values for progression-free survival and post-progression survival and disutilities for treatment-related adverse events such as anaemia, diarrhoea, fatigue, hand-foot syndrome, nausea, mucositis and hypertension. The utility decrements for adverse events were used in a sensitivity analysis. The manufacturer agreed a two-part patient access scheme with the Department of Health. Part A of the patient access scheme provides a 12.5% discount to the list price of pazopanib. Part B of the patient access scheme, the details of which are 'commercial-in-confidence', offers a future rebate linked to the outcome of the head-to-head COMPARZ trial. The manufacturer assumed that there would be no additional costs to the NHS associated with administering the patient access scheme. The costs considered in the economic model included acquisition costs for study medications, drug administration costs for infusions, costs of treating grade 3 or higher adverse events, routine follow-up costs, costs of progression and supportive care costs. In order to account for dose reductions and dose interruptions, the manufacturer adjusted the cost of study medication by using relative dose intensities reported in RCTs of the study treatments. In the model, the manufacturer used a dose intensity for pazopanib of 86%, equivalent to 688 mg per patient per day. Similar dose intensities were used for sunitinib (86%) and interferon-α (84%). Only the costs of treating adverse events that were grade 3 or higher with an incidence of at least 5% were considered for any treatment based on the indirect comparison. The cost per event was assumed to be independent of treatment. For part A of the patient access scheme, which provides a 12.5% discount to the pazopanib list price, sunitinib was extendedly dominated by a combination of pazopanib and interferon-α. An option is 'extendedly dominated' when its ICER is higher than that of the next, more effective, option when compared with a common baseline (that is, it is dominated by a combination of two other alternatives). As a result, using the RPSFT weighted method of adjusting for crossover, the ICERs for pazopanib versus sunitinib, interferon-α and best supportive care were £1790, £38,925 and £32,898 per QALY gained respectively. These ICERs were derived from incremental costs of £122, £27,921 and £32,216, and incremental QALYs of 0.068, 0.717 and 0.979 respectively. The manufacturer provided additional cost-effectiveness analyses using alternative methods of adjusting for crossover. The ICERs for pazopanib versus sunitinib, interferon-α and best supportive care ranged from £1790 to £5327, £21,625 to £72,274 and £20,824 to £48,877 per QALY gained respectively. One-way sensitivity analyses showed that the ICER was most sensitive to the efficacy estimates for pazopanib versus interferon-α, which contribute to the relative efficacy of pazopanib and sunitinib. Specifically, the model is sensitive to the method used for adjusting for crossover for overall survival data from the VEG105192 trial. The manufacturer also provided cost-effectiveness estimates based on part B of the patient access scheme. However, these data are 'commercial-in-confidence' and therefore no details can be reported. The ERG stated that the evidence base was not ideal for this appraisal as there were no data available from head-to-head comparisons of pazopanib with sunitinib or interferon-α. However, the ERG commented on the substantial amount of evidence on the efficacy and safety of pazopanib and on the considerable effort that had gone into providing these data, and the methods were generally well reported. The ERG commented that the choice of model appeared to be appropriate given the decision problem and the data available. The time horizon appeared to be appropriate, although there were concerns that it may overestimate survival because the median age of diagnosis is 60–65 years and constant all-cause mortality was assumed, rather than taking data from life tables, which would have the impact of mortality increasing over time. The ERG stated that the results appeared valid with the methods used. Most of the model analyses performed could be replicated, although this was not true for all sensitivity analyses. The ERG noted that in the manufacturer's original submission the base-case analysis was based on estimates from the model using the unweighted unadjusted RPSFT method to adjust for crossover and pooled interferon-α studies. In the updated analysis, provided as an addendum to the original submission, the method used for adjusting for crossover was the RPSFT weighted method, unadjusted. The ERG acknowledged that the manufacturer had presented a set of analyses that comprehensively covered the range of methods available for crossover. The ERG stated that the RPSFT weighted method advocated by the manufacturer was weakened by the lack of an adequately developed method to analyse relatively immature data robustly. The RPSFT weighted method provided a higher hazard ratio than the unweighted method, and although this did affect the results, the change in method had not necessarily been favourable to pazopanib. The ERG also highlighted a concern about the manufacturer's assumption that as soon as a patient's disease progressed they stopped treatment. The ERG considered that, in practice, it is unlikely this will happen immediately because patients will only know the status of their disease when they have their next review, which may not be at the exact time the disease progresses. This assumption may create a small bias in favour of the more costly treatments such as pazopanib. The ERG also stated that there was some uncertainty around the utility value estimate used. The manufacturer used an estimate that was based on the EQ-5D utility value among all patients without adverse events in the VEG105192 trial. The manufacturer also assumed this value to be similar for all interventions. The ERG noted, however, that given the minimal impact adverse events had on the model (in terms of QALYs and costs) this was not likely to be a major issue. The ERG conducted an exploratory analysis to address concerns about the weighted unadjusted RPSFT results for overall survival being used for the base-case analysis. It assessed the potential impact of a robust weighted analysis on the results, particularly with a model adjusted for baseline covariates, for which methods are still in development. The ERG considered the impact of weighting by comparing the unweighted analyses with the weighted analyses when the models were unadjusted for baseline. The ERG concluded that, overall, weighting does have an impact on the hazard ratio, but it is difficult to establish the direction and magnitude of this effect. The ERG performed multivariate sensitivity analyses around utility value estimates for progression-free survival, utility decrement for progression and duration of utility with adverse events. The results of these analyses indicated that they are sensitive to some combinations of changes and that the ICER associated with pazopanib could increase to more than £50,000 per QALY gained. However, the confidence interval around the hazard ratio for overall survival was very wide. The ERG noted that the manufacturer only reported pair-wise probabilistic sensitivity analysis, therefore the ERG used the base case to compare all four treatment options. The ERG concluded that pazopanib is most likely to be the most cost effective option at willingness to pay thresholds between £35,000 and £50,000. However, the ERG stated that such analyses take the base case at face value and that it was not possible to explore the uncertainty of the various methods used to adjust for crossover or the point estimates used in the economic model due to limited data available for some parameters. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pazopanib, having considered evidence on the nature of advanced renal cell carcinoma and the value placed on the benefits of pazopanib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Committee heard from the patient experts and clinical specialists that advanced renal cell carcinoma is a relatively rare cancer and noted the views of patient experts and clinical specialists on the severity of the disease. The Committee noted that there are limited treatment options for patients with advanced renal cell carcinoma and that currently sunitinib is the only first-line treatment recommended by NICE (Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 169). The Committee heard from the patient experts that, while sunitinib is considered an effective treatment, it is associated with a number of side effects as a result of its toxicity. These include hypertension, fatigue, diarrhoea and hand-foot syndrome. The patient experts highlighted that hand-foot syndrome is frequently intolerable. The clinical specialists stated that patients receiving treatment with sunitinib require a 2-week rest period as part of the treatment cycle, because patients are not able to tolerate sunitinib after 4 weeks. In addition, for a number of patients the dose of sunitinib has to be adjusted to maintain tolerability. The clinical specialists considered that the 2-week rest period and dose adjustment may reduce the benefits gained from sunitinib. The clinical specialists and patient experts were of the opinion that pazopanib is a useful option because it has a more favourable toxicity profile than sunitinib. The Committee considered the evidence on the clinical effectiveness of pazopanib presented in the manufacturer's submission and the ERG report. The Committee noted that the VEG105192 trial compared pazopanib with placebo and the trial was generally of acceptable quality. It was aware of the ERG's concerns that the trial included only a small number of patients from the UK. The Committee accepted advice from clinical specialists that the data were relevant to clinical practice in England and Wales. The Committee considered the evidence from the VEG105192 trial. It noted that pazopanib, when compared with placebo, produced a statistically significant improvement in median progression-free survival of approximately 8 months (10.8 versus 2.9 months ). The Committee then discussed the estimates of overall survival gain obtained from the VEG105192 trial. The Committee acknowledged that the estimates of overall survival for pazopanib versus placebo according to the intention-to-treat analysis (22.9 versus 23.5 months; HR 1.01, 95% CI 0.72 to 1.42) had been confounded by crossover and that 51% of patients who had received placebo crossed over to receive pazopanib after disease progression. The Committee heard from the clinical specialists that an increase in progression-free survival would be expected to result in an increase in overall survival, and agreed that it was appropriate to adjust the results to control for the crossover using statistical modelling techniques. The Committee discussed the manufacturer's approach to estimating overall survival, adjusting for crossover. It acknowledged that the manufacturer had presented a set of analyses that comprehensively covered the range of methods available to adjust for crossover, including an analysis of survival in patients who did not receive post-study cancer therapy. The Committee noted the hazard ratios for overall survival varied from 0.30, based on patients who did not receive post-study cancer therapy, to 0.642, based on the IPCW method, and that these had wide confidence intervals. The Committee acknowledged that the hazard ratio chosen by the manufacturer for the indirect comparison (HR 0.501, 95% CI 0.136 to 2.348) was estimated by the RPSFT weighted method. Although subject to uncertainty, the hazard ratio was in the middle of the range of estimates generated by the manufacturer. The Committee noted the ERG's comments suggesting that this approach was reasonable and it accepted the use of this hazard ratio in the indirect comparison. The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain. The Committee noted that the pazopanib trial was only conducted with patients who had a good ECOG performance status of 0 or 1. Therefore the Committee concluded that pazopanib is a clinically effective first-line treatment for advanced renal cell carcinoma for patients with an ECOG performance status of 0 or 1 when compared with placebo or best supportive care. The Committee then discussed the manufacturer's indirect comparison, used to estimate progression-free survival and overall survival for pazopanib compared with sunitinib, interferon-α and best supportive care. It noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon-α (11.3 versus 5.4 months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009) (11.0 versus 5.1 months; HR 0.539, 95% CI 0.451 to 0.643). The Committee noted the results of the indirect comparison that suggested pazopanib was associated with considerably improved overall survival compared with either interferon-α or best supportive care, and was comparable with sunitinib, although the confidence intervals around the hazard ratios were wide. The Committee heard from the clinical specialists that, in their opinion, the estimates obtained for progression-free survival (with no need for adjustment for crossover) supported the overall survival estimates. The Committee noted that the results of a direct comparison would be available in 2012 when an ongoing head-to-head study of pazopanib versus sunitinib (the COMPARZ trial) was complete, but until then it was reasonable to consider that pazopanib was as clinically effective as sunitinib. The Committee concluded that pazopanib is likely to be more clinically effective than interferon-α and is probably comparable in its effectiveness to sunitinib. The Committee heard from the clinical specialists that the evidence presented by the manufacturer suggested that pazopanib has a more favourable toxicity profile than sunitinib, especially in relation to hand-foot syndrome. It noted that in the VEG105192 trial, 1.9% of patients receiving pazopanib had hand-foot syndrome (all grades) compared with 0% receiving placebo, while in the study by Motzer et al. (2009), 29% of patients receiving sunitinib) experienced hand-foot syndrome (all grades) compared with 3% of patients receiving interferon-α. The Committee noted that grade 3 or 4 hand-foot syndrome occurred in 0% of patients receiving either pazopanib or placebo in the VEG105192 study, while 9% of patients receiving sunitinib in the study by Motzer et al. (2009) had grade 3 or 4 hand-foot syndrome compared with 1% of patients receiving interferon-α. The Committee discussed the evidence provided by the manufacturer on the adverse events associated with pazopanib. The Committee noted that the numbers of grade 3 and 4 adverse events were similar between the pazopanib and placebo groups in the VEG105192 trial. The Committee noted that the evidence from the indirect comparison indicated that the number of adverse events was generally lower for pazopanib than for sunitinib, although only statistically significant for fatigue. The Committee noted that the results of the indirect comparison were not presented for hand-foot syndrome. The Committee was aware of the evidence from the patient experts about the debilitating adverse effects of treatment with sunitinib and the importance of an alternative treatment being available for patients experiencing such adverse effects. The Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma. # Cost effectiveness The Committee considered the manufacturer's economic model and the critique and exploratory sensitivity analyses performed by the ERG. It broadly accepted the model structure, but was aware of the points raised by the ERG about the uncertainties around the parameter values used in the economic model. The Committee discussed the cost-effectiveness data submitted by the manufacturer for pazopanib compared with sunitinib, interferon-α and best supportive care. The Committee discussed the key parameters used in the model. It agreed that the cost-effectiveness estimates derived from the hazard ratio estimate for overall survival for pazopanib versus placebo, obtained using the unadjusted weighted RPSFT analysis (hazard ratio 0.501), were reasonable (see section 4.6). The Committee then considered the utility values used in the model (0.70 for patients who had no disease progression and no adverse events and 0.59 for post progression). It was aware of the issues raised by the ERG about the methods used by the manufacturer to derive the values but also noted that these issues were not considered to be major. The Committee noted that these utility values were lower than those used in NICE technology appraisal 169 but that the difference of 0.11 between these values was greater. The Committee agreed that this difference in utility values between the health states was reasonable and therefore accepted the utility values modelled by the manufacturer. The Committee was aware that a two-part patient access scheme has been agreed by the Department of Health (see section 2.3). The Committee agreed that when considering the cost effectiveness of pazopanib it was appropriate to consider both parts of the patient access scheme. The Committee noted that when the manufacturer had presented cost-effectiveness estimates for part A of the patient access scheme, it had also provided additional cost-effectiveness results that used alternative methods of adjusting for crossover in the VEG105192 trial. It acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from £21,600 to £72,300 per QALY gained for pazopanib versus interferon-α, and from £1790 to £5330 per QALY gained for pazopanib versus sunitinib. Given that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained (based on incremental costs of £32,200, £27,900, £122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates. The Committee then discussed how to apply these ICERs given that a treatment such as sunitinib, recommended using the supplementary advice on appraising life extending, end-of-life treatments, should not, in view of the same supplementary advice, automatically be considered a standard comparator when a new treatment for the same indication is appraised. The Committee agreed that for this reason, and because sunitinib and pazopanib were developed at the same time, it was appropriate that pazopanib also be considered against interferon-α when applying the supplementary advice on appraising life extending, end of life treatments. The Committee was aware that only the ICERs for pazopanib compared with best supportive care and interferon-α in relation to part A of the patient access scheme were higher than the range normally considered a cost-effective use of NHS resources. The Committee next considered whether pazopanib fulfilled the criteria for an end of life treatment in the context of the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations.When taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The Committee was aware from discussion with the clinical specialists that in England and Wales the total number of people that would be eligible for treatment with pazopanib was less than 4000. The Committee heard from the clinical specialist that the life expectancy for people with advanced renal cell carcinoma receiving best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 5 months. The Committee also noted that the evidence from the RPSFT analysis suggested that pazopanib increased overall survival by more than 3 months compared with placebo, and from the indirect comparison by more than 3 months compared with interferon-α. In summary, the Committee was satisfied that pazopanib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust. The Committee considered the central estimate of the ICER (£38,900 per QALY gained) and the robustness and uncertainty of the ICER. The Committee was aware of exploratory net benefit analyses carried out by the ERG which indicated that pazopanib would be considered cost effective at willingness to pay thresholds between £35,000 and £50,000 per QALY gained. The Committee considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group was within the range considered acceptable for an end of life treatment. Therefore, the Committee concluded that pazopanib should be recommended as a first-line treatment option for patients with advanced renal cell carcinoma who have not received prior cytokine therapy and have an ECOG performance status of 0 or 1, and if the manufacturer provides pazopanib with a 12.5% discount on the list price. The Committee considered part B of the patient access scheme which linked a specific future rebate to the outcome of the COMPARZ trial. The Committee accepted that the approach taken in part B of the patient access scheme, the details of which are provided 'commercially in confidence', was reasonable and that the ICERs were acceptable. The Committee concluded that pazopanib should be recommended as indicated above (see section 4.14) and if the manufacturer provides a future rebate linked to the outcome of the COMPARZ trial, as agreed under the terms of the patient access scheme and to be confirmed when the COMPARZ trial data are made available. The Committee considered whether its recommendation was associated with any potential issues related to equality. The Committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate. # Summary of Appraisal Committee's key conclusions TA215 Appraisal title: Pazopanib for the first-line treatment of advanced renal cell carcinoma Section Key conclusion Pazopanib is recommended as a first-line treatment option for people with advanced renal cell carcinoma who have not received prior cytokine therapy and have an ECOG performance status of 0 or 1 and if the manufacturer provides pazopanib with a 12.5% discount on the list price as agreed in the patient access scheme. When using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate. People who are currently being treated with pazopanib for advanced metastatic renal cell carcinoma but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop. Current practice Clinical need of patients, including the availability of alternative treatments The Committee noted that there are limited treatment options for patients with advanced renal cell carcinoma and that currently sunitinib is the only first-line treatment recommended by NICE. The Committee heard from the patient experts that, while sunitinib is considered an effective treatment, it is associated with a number of side effects as a result of its toxicity, including hypertension, fatigue, diarrhoea and hand-foot syndrome. The clinical specialists and patient experts were of the opinion that pazopanib is a useful option because it has a more favourable toxicity profile than sunitinib and is expected to be as effective. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee heard from the clinical specialists that the evidence from the indirect comparison suggested that pazopanib has a more favourable toxicity profile than sunitinib, especially in relation to hand-foot syndrome, and is expected to be as effective. The Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma. What is the position of the treatment in the pathway of care for the condition? Pazopanib has a conditional marketing authorisation for 'the first-line treatment of advanced renal cell carcinoma and for patients who have received prior cytokine therapy for advanced disease'. Only the indication for pazopanib for the first-line treatment of advanced renal cell carcinoma is within the remit of the appraisal. Adverse effects The most frequent adverse events related to pazopanib treatment were diarrhoea, hair colour change, hypertension, nausea, anorexia and increased liver enzymes. The Committee noted that the evidence from the indirect comparison indicated that the number of adverse events was generally lower for pazopanib than for sunitinib, although only statistically significant for fatigue. The Committee noted that the results of the indirect comparison were not presented for hand-foot syndrome. The Committee was aware of the evidence from the patient experts about the debilitating adverse effects of treatment with sunitinib and the importance of an alternative treatment being available for patients experiencing such adverse effects. The Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee considered the evidence from the VEG105192 trial. It noted that pazopanib, when compared with placebo, produced a statistically significant improvement in median progression-free survival of approximately 8 months (10.8 versus 2.9 months ). The Committee noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon-α (11.3 versus 5.4 months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009) (11.0 versus 5.1 months; HR 0.539, 95% CI 0.451 to 0.643). The Committee heard from the clinical specialists that an increase in progression-free survival would be expected to result in an increase in overall survival, and agreed that it was appropriate to adjust the results to control for the crossover using statistical modelling techniques. The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain. Therefore the Committee concluded that pazopanib is a clinically effective first-line treatment for advanced renal cell carcinoma for patients with an ECOG performance status of 0 or 1 when compared with placebo or best supportive care. Relevance to general clinical practice in the NHS The Committee was aware of the ERG's concerns that the VEG105192 trial included only a small number of patients from the UK. The Committee accepted advice from clinical specialists that the data were relevant to clinical practice in England and Wales. Uncertainties generated by the evidence The Committee acknowledged that the hazard ratio chosen by the manufacturer for the indirect comparison (HR 0.501, 95% CI 0.136 to 2.348) was estimated by the RPSFT weighted method. Although subject to uncertainty, the hazard ratio was in the middle of the range of estimates generated by the manufacturer. The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain. The Committee noted the results of the indirect comparison that suggested pazopanib was associated with considerably improved overall survival compared with either interferon-α or best supportive care, and was comparable with sunitinib, although the confidence intervals around the hazard ratios were wide. The Committee concluded that pazopanib was more clinically effective than interferon-α and was probably comparable in its effectiveness to sunitinib. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? None Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon-α (11.3 versus 5.4 months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009) (11.0 versus 5.1 months; HR 0.539, 95% CI 0.451 to 0.643). The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the manufacturer's economic model and the critique and exploratory sensitivity analyses performed by the ERG. It broadly accepted the model structure, but was aware of the points raised by the ERG about the uncertainties around the parameter values used in the economic model. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from £21,600 to £72,300 per QALY gained for pazopanib versus interferon-α, and from £1790 to £5330 per QALY gained for pazopanib versus sunitinib. Given that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained (based on incremental costs of £32,200, £27,900, £122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates. Incorporation of health-related quality-of-life benefits and utility values The Committee considered the utility values used in the model (0.70 for patients who had no disease progression and no adverse events and 0.59 for post progression). It was aware of the issues raised by the ERG about the methods used by the manufacturer to derive the values but also noted that these issues were not considered to be major. The Committee agreed that the difference in utility values between the health states was reasonable and therefore accepted the utility values modelled by the manufacturer. Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? No potential health-related benefits have been identified that were not included in the model. Are there specific groups of people for whom the technology is particularly cost effective? The Committee did not identify any specific groups of people for whom the technology was considered particularly cost effective. What are the key drivers of cost effectiveness? The Committee acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from £21,600 to £72,300 per QALY gained for pazopanib versus interferon-α, and from £1790 to £5330 per QALY gained for pazopanib versus sunitinib. The Committee agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained (based on incremental costs of £32,200, £27,900, £122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates. Most likely cost-effectiveness estimate (given as an ICER) Given that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained were reasonable. Additional factors taken into account Patient access schemes (PPRS) The Committee was aware that a two-part patient access scheme has been agreed by the Department of Health (see section 2.3). The Committee agreed that when considering the cost effectiveness of pazopanib it was appropriate to consider both parts of the patient access scheme. It agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained (based on incremental costs of £32,200, £27,900, £122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates. The Committee accepted that the approach taken in part B of the patient access scheme, the details of which were provided 'commercially in confidence', was reasonable and that the ICERs were acceptable. End-of-life considerations The Committee then discussed how to apply these ICERs given that a treatment such as sunitinib, recommended using the supplementary advice on appraising life extending, end-of-life treatments, should not, in view of the same supplementary advice, automatically be considered a standard comparator when a new treatment for the same indication is appraised. The Committee agreed that for this reason, and because sunitinib and pazopanib were developed at the same time, it was appropriate that pazopanib also be considered against interferon-α when applying the supplementary advice on appraising life extending, end of life treatments. The Committee also noted that the evidence from the RPSFT analysis suggested that pazopanib increased survival by more than 3 months compared with placebo, and from the indirect comparison by more than 3 months compared with interferon-α. In summary, the Committee was satisfied that pazopanib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust. Equalities considerations and social value judgements The Committee considered whether its recommendations were associated with any potential issues related to equality. The Committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate. # Recommendations for further research An ongoing head-to-head study of pazopanib versus sunitinib (COMPARZ) is due to report in June 2012.# Related NICE guidance Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 169 (2009). Bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 178 (2009). Everolimus for the second-line treatment of advanced renal cell carcinoma.NICE technology appraisal guidance 219 (2011).# Review of guidance The guidance on this technology will be considered for review when the COMPARZ data will be made available and at the latest in December 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveFebruary 2011# Changes after publication March 2012: Minor maintenance. August 2013: Part B of the patient access scheme removed. April 2017: The company changed from GlaxoSmithKline to Novartis. Contact details for the patient access scheme updated.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. ISBN: 978-1-4731-2483-7	{'Guidance': 'This guidance has been re-issued after a change to the patient access scheme (August 2013). Part B of the patient access scheme will not be activated. Reference to part B of the patient access scheme has been removed from the recommendations. Reference to it elsewhere in the document should be considered obsolete.\n\nPazopanib is recommended as a first-line treatment option for people with advanced renal cell carcinoma\n\nwho have not received prior cytokine therapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and\n\nif the manufacturer provides pazopanib with a 12.5% discount on the list price as agreed in the patient access scheme.\n\nWhen using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\nPeople who are currently being treated with pazopanib for advanced metastatic renal cell carcinoma but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.', 'The technology ': "Pazopanib (Votrient, GlaxoSmithKline) is an orally administered tyrosine kinase inhibitor. It inhibits vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors on cancer cells, vascular endothelial cells and pericytes, stopping the proliferation of tumour cells and the development of tumour blood vessels. Pazopanib has a conditional marketing authorisation for 'the first-line treatment of advanced renal cell carcinoma and for patients who have received prior cytokine therapy for advanced disease'. The conditional marketing authorisation is linked to the provision of further data including the outcome of the ongoing head-to-head non-inferiority trial of pazopanib versus sunitinib in patients with advanced renal cell carcinoma (COMPARZ). Only the indication for pazopanib for the first-line treatment of advanced renal cell carcinoma is within the remit of the appraisal.\n\nPazopanib is contraindicated in people who have hypersensitivity to the active substance or to any of the excipients, and people with severe hepatic impairment. The summary of product characteristics lists the adverse events that may be associated with pazopanib treatment, the most common being diarrhoea, hair colour changes, hypertension, nausea, anorexia, vomiting, fatigue, taste disturbance or loss of taste, and abnormal liver function. For full details of side effects and contraindications, see the summary of product characteristics.\n\nPazopanib is administered orally. The recommended dosage is 800\xa0mg once daily. The dose may be adjusted in steps of 200\xa0mg according to tolerability in order to manage adverse reactions but should not exceed 800\xa0mg. The price for a pack of 400\xa0mg tablets (30 tablets per pack) is £1121.00 (MIMS, November 2010). The daily cost of pazopanib is £74.73 as stated by the manufacturer. The manufacturer of pazopanib has agreed a two-part patient access scheme with the Department of Health. Part A of the patient access scheme provides a 12.5% discount from the list price. Therefore the daily acquisition cost of pazopanib is £65.39. Part B of the patient access scheme, the details of which are 'commercial in confidence', offers a future rebate linked to the outcome of the head-to-head COMPARZ trial. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pazopanib and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer presented evidence on the clinical effectiveness of pazopanib used in line with the conditional marketing authorisation and the appraisal scope. The main clinical-effectiveness evidence came from patients in the treatment-naive subgroup of a phase III randomised controlled trial (RCT). The RCT, VEG105192, compared the effect of a once-daily dose of pazopanib plus best supportive care (155 patients) with placebo plus best supportive care (78 patients). Best supportive care was defined as the monitoring of progression, symptom control and palliative care without active treatment. The trial was conducted in patients with advanced renal cell carcinoma with predominantly clear cell histology. All patients had a good performance status (ECOG performance status 0 or 1) at the start of the trial. Baseline characteristics of the patients in the two treatment arms were equally balanced.\n\nThe primary outcome in the study was progression-free survival, which was defined as time from randomisation to disease progression or death. Tumour assessments were performed using RECIST (Response Evaluation Criteria in Solid Tumours) and were confirmed by an independent review committee. Once disease progression was confirmed, patients who previously received placebo plus best supportive care could be offered open-label pazopanib plus best supportive care in the open-label extension study (VEG107769) if the treating clinician thought this was in the best interests of the patient. At disease progression, only patients with an ECOG performance status of less than or equal to\xa02 were permitted to cross over to receive pazopanib. The median progression-free survival was statistically significantly longer in patients receiving pazopanib (p\xa0<\xa00.001). The median progression-free survival was 11.1\xa0months (95% confidence interval [CI] 7.4 to 14.8) for patients receiving pazopanib plus best supportive care and 2.8\xa0months (95% CI 1.9 to 5.6) for patients receiving placebo plus best supportive care (hazard ratio [HR] 0.40, 95% CI 0.27 to 0.60) based on blinded imaging assessment by the Independent Review Committee. This meant there was a 60% reduction in risk of disease progression for patients receiving pazopanib plus best supportive care compared with those receiving placebo plus best supportive care at the final analysis. The manufacturer performed sensitivity analyses of progression-free survival based on actual scan dates and investigators' assessment to confirm the robustness of the findings. The median progression-free survival based on actual scan dates was 10.8\xa0months (95% CI 7.4 to 14.8) for patients receiving pazopanib plus best supportive care and 2.9\xa0months (95% CI 1.9 to 5.4) for patients receiving placebo plus best supportive care (HR 0.36, 95% CI 0.24 to 0.55). These latter estimates were used in the indirect comparison.\n\nAt the time of the interim overall survival analysis (23 May 2008), 31 of 78 (40%) treatment-naive patients randomised to receive placebo in the VEG105192 trial had crossed over to receive pazopanib. At the final analysis (15 March 2010), a total of 40 (51%) treatment-naive patients randomised to placebo had crossed over to receive pazopanib. Overall survival for the treatment-naive, intention-to-treat population, unadjusted for crossover, was 22.9\xa0months (95% CI 17.6 to 25.4 months) for patients randomised to pazopanib plus best supportive care and 23.5 months (95% CI 12.0 to 34.3\xa0months) for patients randomised to placebo plus best supportive care. The hazard ratio for overall survival was 1.01 (95%\xa0CI 0.72 to 1.42, p\xa0=\xa00.525). The manufacturer presented a variety of methods to adjust for crossover when estimating median overall survival, including the inverse probability censoring weighted (IPCW) and rank preserved structural failure time (RPSFT) methods. The manufacturer considered the RPSFT weighted method to be the most appropriate because it was considered an acceptable approach for NICE technology appraisal guidance 179 ('Sunitinib for the treatment of gastrointestinal stromal tumours') and the ongoing technology appraisal 'Everolimus for the second-line treatment of advanced renal cell carcinoma'. The RPSFT weighted method estimated the overall survival of patients randomised to receive placebo assuming that they had not crossed over, that is, as if they had remained on placebo for the duration of the trial. The method proportionally 'shrunk' the estimated amount of additional survival given to patients who crossed over to receive pazopanib. The RPSFT analysis suggested that treatment with pazopanib was consistently associated with survival benefit compared with placebo (HR 0.501, 95% CI 0.136 to 2.348). The manufacturer also noted that the 0.501 hazard ratio lies within the range of estimates obtained from the different methods used to adjust for crossover. This hazard ratio was subsequently used for the indirect comparison.\n\nNo head-to-head trials analysing the efficacy of pazopanib compared with other active treatment options were available. Therefore, the manufacturer undertook a search for trials of comparator interventions and carried out an indirect comparison to estimate the relative effect of pazopanib versus the comparators (sunitinib, interferon-α and best supportive care). Seven studies were included in the indirect comparison, including one study of pazopanib compared with placebo (VEG105192), one study of sunitinib compared with interferon-α (Motzer et al. 2009) and five studies that directly compared interferon-α with a non-interferon control therapy (medroxyprogesterone acetate and vinblastine). The populations in the pazopanib (VEG105192) and sunitinib (Motzer et al. 2009) studies were comparable, but with the exception that a higher proportion of patients with a baseline ECOG performance status of 0 were recruited to the sunitinib study than to the VEG105192 trial (approximately 60% versus 40%). Both studies restricted entry to patients with renal cell carcinoma with either clear cell or predominantly clear cell histology. The average age of patients in both studies was 60\xa0years and 83–91% of patients had prior nephrectomy. The patient populations in the five interferon-α studies were generally similar. All patients had renal cell carcinoma, the age range was 60–66\xa0years and 57–100% of patients had prior nephrectomy. Three of the interferon-α studies included some patients with a baseline ECOG performance status of 2.\n\nHazard ratios for progression free survival and overall survival from all seven studies were used in the indirect comparison to obtain hazard ratios for pazopanib versus interferon-α and pazopanib versus sunitinib. The hazard ratios for progression-free survival used in the indirect comparison for pazopanib versus placebo plus best supportive care, sunitinib versus interferon-α and interferon-α versus best supportive care were 0.36 (95% CI 0.24 to 0.55), 0.539 (95% CI 0.451 to 0.643) and 0.704 (95% CI 0.0.580 to 0.854). Median progression-free survival estimates derived from the indirect comparison for pazopanib, sunitinib, interferon-α and placebo plus best supportive care were 11.3\xa0months (95% CI 5.1 to 17.5), 10.7\xa0months (95% CI 7.9 to 13.4), 5.4\xa0months (95% CI 5.4 to 5.4) and 5.6 months (95% CI 4.0 to 7.3) respectively.\n\nThe pazopanib overall survival value was estimated using the RPSFT weighted method. The manufacturer used hazard ratios derived from all seven studies in a Weibull survival model to estimate the median overall survival values for pazopanib versus interferon-α and pazopanib versus sunitinib. In the base-case scenario, derived using the RPSFT weighted method, the median overall survival estimates for pazopanib, sunitinib, interferon-α and placebo plus best supportive care were 27.8, 26.8, 15.8\xa0and 12.1 months, respectively. These results indicated that pazopanib was associated with a decreased risk of death (37% reduction) compared with interferon-α, and that pazopanib appeared to have comparable efficacy with sunitinib in terms of overall survival. The manufacturer highlighted that the 95% confidence intervals around the hazard ratios were wide, indicating a level of uncertainty with the estimates. Sensitivity analyses were performed that included varying the hazard ratio for overall survival in the VEG105192 trial by using different methods for adjusting for crossover and varying the interferon-α studies included. The manufacturer concluded that the results of these sensitivity analyses of the indirect comparison were similar to those of the base-case analysis.\n\nOnly the VEG105192 trial, which compared pazopanib and placebo, and the study by Motzer et al. (2009), which compared sunitinib with interferon-α, reported health-related quality of life data. For the VEG105192 trial, there were no statistically significant differences between pazopanib and placebo for any of the instruments used (European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaire – Core 30, EQ-5D, EQ-5D-VAS). For the comparison of sunitinib with interferon-α, patients receiving sunitinib had a statistically significantly better quality of life than patients receiving interferon-α, as measured by the EQ-5D, EQ-5D-VAS and the Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index Disease-related Symptom (FKSI-DRS) Index, FACT-Kidney Symptom Index – 15-item scale (FKSI-15 Index) and the FACT-General Scale (FACT-G). No indirect comparison was made for this outcome.\n\nIn the VEG105192 trial, 91% of patients receiving pazopanib experienced an adverse event. In 87% of patients the adverse events were related to study medication. In the placebo group 74% of patients experienced an adverse event and in 37% of patients these were related to study medication. The most frequent adverse events related to pazopanib treatment were diarrhoea, hair colour change, hypertension, nausea, anorexia and increased liver enzymes. The manufacturer conducted an indirect comparison using one of the interferon-α studies to estimate the adverse event rates of pazopanib compared with sunitinb. The adverse event rates for pazopanib were generally lower than for sunitinib, in particular for dyspepsia, mucositis/stomatitis, fatigue, hand-foot syndrome, skin discolouration, hypophosphataemia, anaemia and altered taste. However, only the difference in fatigue was statistically significant (HR 0.21, 95% CI 0.06 to 0.77).\n\nThe manufacturer submitted an economic model to assess the cost effectiveness of pazopanib in treatment-naive patients. The model compared pazopanib with interferon-α, sunitinib and best supportive care. The manufacturer described the model as a 'partitioned survival' model, characterised by three mutually exclusive health states: alive pre-progression, alive post-progression and dead. Unlike a Markov model, which models transitions between health states explicitly using transition probabilities, the partitioned survival model calculated the proportion of patients in each treatment arm at any time after starting treatment, using parametric survival curves fitted to empirical data on overall survival and progression-free survival over time. The proportion of patients in the 'alive post-progression' health state at any given time was calculated as the difference between overall survival and progression-free survival. In the model, pazopanib was assumed to be given until disease progression or death (if occurring before progression). After starting treatment, patients were assumed to be in an 'alive pre-progression' health state, and to be at risk of disease progression and/or death over time. Patients who experienced disease progression were assumed to discontinue treatment with pazopanib (and receive only best supportive care) and to transition to an 'alive post-progression' health state and to stay in that state until death.\n\nFor the model, a utility value of 0.70 was assumed for patients who had no disease progression and no adverse events, based on the mean EQ-5D utility value among patients without adverse events in the VEG105192 trial. Disease progression was assumed to be associated with a decrement in utility of 15% (that is, a post-progression utility value of 0.59). These values were used for all the interventions in the model. Utility decrements for adverse events were also obtained from the VEG105192 trial. As a result of the lack of published utility data in this patient population, the manufacturer commissioned a health state preference study to generate utility values for progression-free survival and post-progression survival and disutilities for treatment-related adverse events such as anaemia, diarrhoea, fatigue, hand-foot syndrome, nausea, mucositis and hypertension. The utility decrements for adverse events were used in a sensitivity analysis.\n\nThe manufacturer agreed a two-part patient access scheme with the Department of Health. Part A of the patient access scheme provides a 12.5% discount to the list price of pazopanib. Part B of the patient access scheme, the details of which are 'commercial-in-confidence', offers a future rebate linked to the outcome of the head-to-head COMPARZ trial. The manufacturer assumed that there would be no additional costs to the NHS associated with administering the patient access scheme. The costs considered in the economic model included acquisition costs for study medications, drug administration costs for infusions, costs of treating grade 3 or higher adverse events, routine follow-up costs, costs of progression and supportive care costs. In order to account for dose reductions and dose interruptions, the manufacturer adjusted the cost of study medication by using relative dose intensities reported in RCTs of the study treatments. In the model, the manufacturer used a dose intensity for pazopanib of 86%, equivalent to 688\xa0mg per patient per day. Similar dose intensities were used for sunitinib (86%) and interferon-α (84%). Only the costs of treating adverse events that were grade 3 or higher with an incidence of at least 5% were considered for any treatment based on the indirect comparison. The cost per event was assumed to be independent of treatment.\n\nFor part A of the patient access scheme, which provides a 12.5% discount to the pazopanib list price, sunitinib was extendedly dominated by a combination of pazopanib and interferon-α. An option is 'extendedly dominated' when its ICER is higher than that of the next, more effective, option when compared with a common baseline (that is, it is dominated by a combination of two other alternatives). As a result, using the RPSFT weighted method of adjusting for crossover, the ICERs for pazopanib versus sunitinib, interferon-α and best supportive care were £1790, £38,925 and £32,898 per QALY gained respectively. These ICERs were derived from incremental costs of £122, £27,921 and £32,216, and incremental QALYs of 0.068, 0.717 and 0.979 respectively. The manufacturer provided additional cost-effectiveness analyses using alternative methods of adjusting for crossover. The ICERs for pazopanib versus sunitinib, interferon-α and best supportive care ranged from £1790 to £5327, £21,625 to £72,274 and £20,824 to £48,877 per QALY gained respectively. One-way sensitivity analyses showed that the ICER was most sensitive to the efficacy estimates for pazopanib versus interferon-α, which contribute to the relative efficacy of pazopanib and sunitinib. Specifically, the model is sensitive to the method used for adjusting for crossover for overall survival data from the VEG105192 trial. The manufacturer also provided cost-effectiveness estimates based on part B of the patient access scheme. However, these data are 'commercial-in-confidence' and therefore no details can be reported.\n\nThe ERG stated that the evidence base was not ideal for this appraisal as there were no data available from head-to-head comparisons of pazopanib with sunitinib or interferon-α. However, the ERG commented on the substantial amount of evidence on the efficacy and safety of pazopanib and on the considerable effort that had gone into providing these data, and the methods were generally well reported.\n\nThe ERG commented that the choice of model appeared to be appropriate given the decision problem and the data available. The time horizon appeared to be appropriate, although there were concerns that it may overestimate survival because the median age of diagnosis is 60–65\xa0years and constant all-cause mortality was assumed, rather than taking data from life tables, which would have the impact of mortality increasing over time. The ERG stated that the results appeared valid with the methods used. Most of the model analyses performed could be replicated, although this was not true for all sensitivity analyses.\n\nThe ERG noted that in the manufacturer's original submission the base-case analysis was based on estimates from the model using the unweighted unadjusted RPSFT method to adjust for crossover and pooled interferon-α studies. In the updated analysis, provided as an addendum to the original submission, the method used for adjusting for crossover was the RPSFT weighted method, unadjusted. The ERG acknowledged that the manufacturer had presented a set of analyses that comprehensively covered the range of methods available for crossover. The ERG stated that the RPSFT weighted method advocated by the manufacturer was weakened by the lack of an adequately developed method to analyse relatively immature data robustly. The RPSFT weighted method provided a higher hazard ratio than the unweighted method, and although this did affect the results, the change in method had not necessarily been favourable to pazopanib.\n\nThe ERG also highlighted a concern about the manufacturer's assumption that as soon as a patient's disease progressed they stopped treatment. The ERG considered that, in practice, it is unlikely this will happen immediately because patients will only know the status of their disease when they have their next review, which may not be at the exact time the disease progresses. This assumption may create a small bias in favour of the more costly treatments such as pazopanib.\n\nThe ERG also stated that there was some uncertainty around the utility value estimate used. The manufacturer used an estimate that was based on the EQ-5D utility value among all patients without adverse events in the VEG105192 trial. The manufacturer also assumed this value to be similar for all interventions. The ERG noted, however, that given the minimal impact adverse events had on the model (in terms of QALYs and costs) this was not likely to be a major issue.\n\nThe ERG conducted an exploratory analysis to address concerns about the weighted unadjusted RPSFT results for overall survival being used for the base-case analysis. It assessed the potential impact of a robust weighted analysis on the results, particularly with a model adjusted for baseline covariates, for which methods are still in development. The ERG considered the impact of weighting by comparing the unweighted analyses with the weighted analyses when the models were unadjusted for baseline. The ERG concluded that, overall, weighting does have an impact on the hazard ratio, but it is difficult to establish the direction and magnitude of this effect. The ERG performed multivariate sensitivity analyses around utility value estimates for progression-free survival, utility decrement for progression and duration of utility with adverse events. The results of these analyses indicated that they are sensitive to some combinations of changes and that the ICER associated with pazopanib could increase to more than £50,000 per QALY gained. However, the confidence interval around the hazard ratio for overall survival was very wide. The ERG noted that the manufacturer only reported pair-wise probabilistic sensitivity analysis, therefore the ERG used the base case to compare all four treatment options. The ERG concluded that pazopanib is most likely to be the most cost effective option at willingness to pay thresholds between £35,000 and £50,000. However, the ERG stated that such analyses take the base case at face value and that it was not possible to explore the uncertainty of the various methods used to adjust for crossover or the point estimates used in the economic model due to limited data available for some parameters.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pazopanib, having considered evidence on the nature of advanced renal cell carcinoma and the value placed on the benefits of pazopanib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee heard from the patient experts and clinical specialists that advanced renal cell carcinoma is a relatively rare cancer and noted the views of patient experts and clinical specialists on the severity of the disease. The Committee noted that there are limited treatment options for patients with advanced renal cell carcinoma and that currently sunitinib is the only first-line treatment recommended by NICE (Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 169). The Committee heard from the patient experts that, while sunitinib is considered an effective treatment, it is associated with a number of side effects as a result of its toxicity. These include hypertension, fatigue, diarrhoea and hand-foot syndrome. The patient experts highlighted that hand-foot syndrome is frequently intolerable. The clinical specialists stated that patients receiving treatment with sunitinib require a 2-week rest period as part of the treatment cycle, because patients are not able to tolerate sunitinib after 4\xa0weeks. In addition, for a number of patients the dose of sunitinib has to be adjusted to maintain tolerability. The clinical specialists considered that the 2-week rest period and dose adjustment may reduce the benefits gained from sunitinib. The clinical specialists and patient experts were of the opinion that pazopanib is a useful option because it has a more favourable toxicity profile than sunitinib.\n\nThe Committee considered the evidence on the clinical effectiveness of pazopanib presented in the manufacturer's submission and the ERG report. The Committee noted that the VEG105192 trial compared pazopanib with placebo and the trial was generally of acceptable quality. It was aware of the ERG's concerns that the trial included only a small number of patients from the UK. The Committee accepted advice from clinical specialists that the data were relevant to clinical practice in England and Wales. The Committee considered the evidence from the VEG105192 trial. It noted that pazopanib, when compared with placebo, produced a statistically significant improvement in median progression-free survival of approximately 8\xa0months (10.8 versus 2.9\xa0months [Independent Review Committee assessment, HR 0.36, 95% CI 0.24 to 0.55]).\n\nThe Committee then discussed the estimates of overall survival gain obtained from the VEG105192 trial. The Committee acknowledged that the estimates of overall survival for pazopanib versus placebo according to the intention-to-treat analysis (22.9 versus 23.5\xa0months; HR 1.01, 95% CI 0.72 to 1.42) had been confounded by crossover and that 51% of patients who had received placebo crossed over to receive pazopanib after disease progression. The Committee heard from the clinical specialists that an increase in progression-free survival would be expected to result in an increase in overall survival, and agreed that it was appropriate to adjust the results to control for the crossover using statistical modelling techniques.\n\nThe Committee discussed the manufacturer's approach to estimating overall survival, adjusting for crossover. It acknowledged that the manufacturer had presented a set of analyses that comprehensively covered the range of methods available to adjust for crossover, including an analysis of survival in patients who did not receive post-study cancer therapy. The Committee noted the hazard ratios for overall survival varied from 0.30, based on patients who did not receive post-study cancer therapy, to 0.642, based on the IPCW method, and that these had wide confidence intervals. The Committee acknowledged that the hazard ratio chosen by the manufacturer for the indirect comparison (HR 0.501, 95% CI 0.136 to 2.348) was estimated by the RPSFT weighted method. Although subject to uncertainty, the hazard ratio was in the middle of the range of estimates generated by the manufacturer. The Committee noted the ERG's comments suggesting that this approach was reasonable and it accepted the use of this hazard ratio in the indirect comparison. The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain. The Committee noted that the pazopanib trial was only conducted with patients who had a good ECOG performance status of 0 or 1. Therefore the Committee concluded that pazopanib is a clinically effective first-line treatment for advanced renal cell carcinoma for patients with an ECOG performance status of 0 or 1 when compared with placebo or best supportive care.\n\nThe Committee then discussed the manufacturer's indirect comparison, used to estimate progression-free survival and overall survival for pazopanib compared with sunitinib, interferon-α and best supportive care. It noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon-α (11.3 versus 5.4\xa0months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009) (11.0 versus 5.1\xa0months; HR 0.539, 95% CI 0.451 to 0.643). The Committee noted the results of the indirect comparison that suggested pazopanib was associated with considerably improved overall survival compared with either interferon-α or best supportive care, and was comparable with sunitinib, although the confidence intervals around the hazard ratios were wide. The Committee heard from the clinical specialists that, in their opinion, the estimates obtained for progression-free survival (with no need for adjustment for crossover) supported the overall survival estimates. The Committee noted that the results of a direct comparison would be available in 2012 when an ongoing head-to-head study of pazopanib versus sunitinib (the COMPARZ trial) was complete, but until then it was reasonable to consider that pazopanib was as clinically effective as sunitinib. The Committee concluded that pazopanib is likely to be more clinically effective than interferon-α and is probably comparable in its effectiveness to sunitinib.\n\nThe Committee heard from the clinical specialists that the evidence presented by the manufacturer suggested that pazopanib has a more favourable toxicity profile than sunitinib, especially in relation to hand-foot syndrome. It noted that in the VEG105192 trial, 1.9% of patients receiving pazopanib had hand-foot syndrome (all grades) compared with 0% receiving placebo, while in the study by Motzer et al. (2009), 29% of patients receiving sunitinib) experienced hand-foot syndrome (all grades) compared with 3% of patients receiving interferon-α. The Committee noted that grade 3 or 4 hand-foot syndrome occurred in 0% of patients receiving either pazopanib or placebo in the VEG105192 study, while 9% of patients receiving sunitinib in the study by Motzer et al. (2009) had grade 3 or 4 hand-foot syndrome compared with 1% of patients receiving interferon-α. The Committee discussed the evidence provided by the manufacturer on the adverse events associated with pazopanib. The Committee noted that the numbers of grade 3 and 4 adverse events were similar between the pazopanib and placebo groups in the VEG105192 trial. The Committee noted that the evidence from the indirect comparison indicated that the number of adverse events was generally lower for pazopanib than for sunitinib, although only statistically significant for fatigue. The Committee noted that the results of the indirect comparison were not presented for hand-foot syndrome. The Committee was aware of the evidence from the patient experts about the debilitating adverse effects of treatment with sunitinib and the importance of an alternative treatment being available for patients experiencing such adverse effects. The Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model and the critique and exploratory sensitivity analyses performed by the ERG. It broadly accepted the model structure, but was aware of the points raised by the ERG about the uncertainties around the parameter values used in the economic model.\n\nThe Committee discussed the cost-effectiveness data submitted by the manufacturer for pazopanib compared with sunitinib, interferon-α and best supportive care. The Committee discussed the key parameters used in the model. It agreed that the cost-effectiveness estimates derived from the hazard ratio estimate for overall survival for pazopanib versus placebo, obtained using the unadjusted weighted RPSFT analysis (hazard ratio 0.501), were reasonable (see section 4.6). The Committee then considered the utility values used in the model (0.70 for patients who had no disease progression and no adverse events and 0.59 for post progression). It was aware of the issues raised by the ERG about the methods used by the manufacturer to derive the values but also noted that these issues were not considered to be major. The Committee noted that these utility values were lower than those used in NICE technology appraisal 169 but that the difference of 0.11 between these values was greater. The Committee agreed that this difference in utility values between the health states was reasonable and therefore accepted the utility values modelled by the manufacturer.\n\nThe Committee was aware that a two-part patient access scheme has been agreed by the Department of Health (see section 2.3). The Committee agreed that when considering the cost effectiveness of pazopanib it was appropriate to consider both parts of the patient access scheme. The Committee noted that when the manufacturer had presented cost-effectiveness estimates for part A of the patient access scheme, it had also provided additional cost-effectiveness results that used alternative methods of adjusting for crossover in the VEG105192 trial. It acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from £21,600 to £72,300 per QALY gained for pazopanib versus interferon-α, and from £1790 to £5330 per QALY gained for pazopanib versus sunitinib. Given that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained (based on incremental costs of £32,200, £27,900, £122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates.\n\nThe Committee then discussed how to apply these ICERs given that a treatment such as sunitinib, recommended using the supplementary advice on appraising life extending, end-of-life treatments, should not, in view of the same supplementary advice, automatically be considered a standard comparator when a new treatment for the same indication is appraised. The Committee agreed that for this reason, and because sunitinib and pazopanib were developed at the same time, it was appropriate that pazopanib also be considered against interferon-α when applying the supplementary advice on appraising life extending, end of life treatments. The Committee was aware that only the ICERs for pazopanib compared with best supportive care and interferon-α in relation to part A of the patient access scheme were higher than the range normally considered a cost-effective use of NHS resources.\n\nThe Committee next considered whether pazopanib fulfilled the criteria for an end of life treatment in the context of the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.When taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee was aware from discussion with the clinical specialists that in England and Wales the total number of people that would be eligible for treatment with pazopanib was less than 4000. The Committee heard from the clinical specialist that the life expectancy for people with advanced renal cell carcinoma receiving best supportive care alone was unlikely to be greater than 24\xa0months and was potentially as low as 5\xa0months. The Committee also noted that the evidence from the RPSFT analysis suggested that pazopanib increased overall survival by more than 3\xa0months compared with placebo, and from the indirect comparison by more than 3 months compared with interferon-α. In summary, the Committee was satisfied that pazopanib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.\n\nThe Committee considered the central estimate of the ICER (£38,900 per QALY gained) and the robustness and uncertainty of the ICER. The Committee was aware of exploratory net benefit analyses carried out by the ERG which indicated that pazopanib would be considered cost effective at willingness to pay thresholds between £35,000 and £50,000 per QALY gained. The Committee considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group was within the range considered acceptable for an end of life treatment. Therefore, the Committee concluded that pazopanib should be recommended as a first-line treatment option for patients with advanced renal cell carcinoma who have not received prior cytokine therapy and have an ECOG performance status of 0 or 1, and if the manufacturer provides pazopanib with a 12.5% discount on the list price.\n\nThe Committee considered part B of the patient access scheme which linked a specific future rebate to the outcome of the COMPARZ trial. The Committee accepted that the approach taken in part B of the patient access scheme, the details of which are provided 'commercially in confidence', was reasonable and that the ICERs were acceptable. The Committee concluded that pazopanib should be recommended as indicated above (see section 4.14) and if the manufacturer provides a future rebate linked to the outcome of the COMPARZ trial, as agreed under the terms of the patient access scheme and to be confirmed when the COMPARZ trial data are made available.\n\nThe Committee considered whether its recommendation was associated with any potential issues related to equality. The Committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA215\n\nAppraisal title: Pazopanib for the first-line treatment of advanced renal cell carcinoma\n\nSection\n\nKey conclusion\n\nPazopanib is recommended as a first-line treatment option for people with advanced renal cell carcinoma\n\nwho have not received prior cytokine therapy and have an ECOG performance status of 0 or 1\n\nand\n\nif the manufacturer provides pazopanib with a 12.5% discount on the list price as agreed in the patient access scheme.\n\nWhen using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\n\n\n, 1.2, 4.15\n\nPeople who are currently being treated with pazopanib for advanced metastatic renal cell carcinoma but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee noted that there are limited treatment options for patients with advanced renal cell carcinoma and that currently sunitinib is the only first-line treatment recommended by NICE.\n\nThe Committee heard from the patient experts that, while sunitinib is considered an effective treatment, it is associated with a number of side effects as a result of its toxicity, including hypertension, fatigue, diarrhoea and hand-foot syndrome.\n\nThe clinical specialists and patient experts were of the opinion that pazopanib is a useful option because it has a more favourable toxicity profile than sunitinib and is expected to be as effective.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee heard from the clinical specialists that the evidence from the indirect comparison suggested that pazopanib has a more favourable toxicity profile than sunitinib, especially in relation to hand-foot syndrome, and is expected to be as effective.\n\nThe Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nPazopanib has a conditional marketing authorisation for 'the first-line treatment of advanced renal cell carcinoma and for patients who have received prior cytokine therapy for advanced disease'. Only the indication for pazopanib for the first-line treatment of advanced renal cell carcinoma is within the remit of the appraisal.\n\n\n\nAdverse effects\n\nThe most frequent adverse events related to pazopanib treatment were diarrhoea, hair colour change, hypertension, nausea, anorexia and increased liver enzymes.\n\n\n\n\n\n\n\nThe Committee noted that the evidence from the indirect comparison indicated that the number of adverse events was generally lower for pazopanib than for sunitinib, although only statistically significant for fatigue. The Committee noted that the results of the indirect comparison were not presented for hand-foot syndrome. The Committee was aware of the evidence from the patient experts about the debilitating adverse effects of treatment with sunitinib and the importance of an alternative treatment being available for patients experiencing such adverse effects.\n\nThe Committee agreed that pazopanib would be a useful treatment option for patients with advanced renal cell carcinoma.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee considered the evidence from the VEG105192 trial. It noted that pazopanib, when compared with placebo, produced a statistically significant improvement in median progression-free survival of approximately 8\xa0months (10.8 versus 2.9\xa0months [Independent Review Committee assessment, HR 0.36, 95% CI 0.24 to 0.55]).\n\n\n\nThe Committee noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon-α (11.3 versus 5.4\xa0months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009) (11.0 versus 5.1\xa0months; HR 0.539, 95% CI 0.451 to 0.643).\n\n\n\nThe Committee heard from the clinical specialists that an increase in progression-free survival would be expected to result in an increase in overall survival, and agreed that it was appropriate to adjust the results to control for the crossover using statistical modelling techniques.\n\n\n\nThe Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain.\n\nTherefore the Committee concluded that pazopanib is a clinically effective first-line treatment for advanced renal cell carcinoma for patients with an ECOG performance status of 0 or 1 when compared with placebo or best supportive care.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee was aware of the ERG's concerns that the VEG105192 trial included only a small number of patients from the UK. The Committee accepted advice from clinical specialists that the data were relevant to clinical practice in England and Wales.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee acknowledged that the hazard ratio chosen by the manufacturer for the indirect comparison (HR 0.501, 95% CI 0.136 to 2.348) was estimated by the RPSFT weighted method. Although subject to uncertainty, the hazard ratio was in the middle of the range of estimates generated by the manufacturer. The Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain.\n\n\n\nThe Committee noted the results of the indirect comparison that suggested pazopanib was associated with considerably improved overall survival compared with either interferon-α or best supportive care, and was comparable with sunitinib, although the confidence intervals around the hazard ratios were wide.\n\n\n\nThe Committee concluded that pazopanib was more clinically effective than interferon-α and was probably comparable in its effectiveness to sunitinib.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone\n\n-\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that the results of the indirect comparison for median progression-free survival for pazopanib versus interferon-α (11.3 versus 5.4\xa0months; HR 0.512, 95% CI 0.326 to 0.802) were comparable with the corresponding results from the sunitinib study by Motzer et al. (2009) (11.0 versus 5.1\xa0months; HR 0.539, 95% CI 0.451 to 0.643).\n\n\n\n\n\nThe Committee concluded that there was sufficient evidence that pazopanib increased progression-free and overall survival compared with placebo, although there was uncertainty about the precise magnitude of the overall survival gain.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the manufacturer's economic model and the critique and exploratory sensitivity analyses performed by the ERG. It broadly accepted the model structure, but was aware of the points raised by the ERG about the uncertainties around the parameter values used in the economic model.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from £21,600 to £72,300 per QALY gained for pazopanib versus interferon-α, and from £1790 to £5330 per QALY gained for pazopanib versus sunitinib.\n\nGiven that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained (based on incremental costs of £32,200, £27,900, £122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\n\n\nThe Committee considered the utility values used in the model (0.70 for patients who had no disease progression and no adverse events and 0.59 for post progression). It was aware of the issues raised by the ERG about the methods used by the manufacturer to derive the values but also noted that these issues were not considered to be major. The Committee agreed that the difference in utility values between the health states was reasonable and therefore accepted the utility values modelled by the manufacturer.\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNo potential health-related benefits have been identified that were not included in the model.\n\n–\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee did not identify any specific groups of people for whom the technology was considered particularly cost effective.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee acknowledged that the ICERs were highly sensitive to the method used for adjusting for crossover, with ICERs ranging from £21,600 to £72,300 per QALY gained for pazopanib versus interferon-α, and from £1790 to £5330 per QALY gained for pazopanib versus sunitinib.\n\n\n\nThe Committee agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained (based on incremental costs of £32,200, £27,900, £122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nGiven that the Committee accepted the RPSFT-derived hazard ratio of 0.501 used for the indirect comparison, it agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained were reasonable.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe Committee was aware that a two-part patient access scheme has been agreed by the Department of Health (see section 2.3).\n\nThe Committee agreed that when considering the cost effectiveness of pazopanib it was appropriate to consider both parts of the patient access scheme.\n\nIt agreed that the base-case ICERs for pazopanib (including a 12.5% discount on the list price) compared with best supportive care, interferon-α and sunitinib of £33,000, £38,900 and £1790 per QALY gained (based on incremental costs of £32,200, £27,900, £122 and incremental QALYs of 0.979, 0.717 and 0.068 respectively) were reasonable estimates.\n\n\n\nThe Committee accepted that the approach taken in part B of the patient access scheme, the details of which were provided 'commercially in confidence', was reasonable and that the ICERs were acceptable.\n\n\n\nEnd-of-life considerations\n\nThe Committee then discussed how to apply these ICERs given that a treatment such as sunitinib, recommended using the supplementary advice on appraising life extending, end-of-life treatments, should not, in view of the same supplementary advice, automatically be considered a standard comparator when a new treatment for the same indication is appraised. The Committee agreed that for this reason, and because sunitinib and pazopanib were developed at the same time, it was appropriate that pazopanib also be considered against interferon-α when applying the supplementary advice on appraising life extending, end of life treatments.\n\n\n\nThe Committee also noted that the evidence from the RPSFT analysis suggested that pazopanib increased survival by more than 3\xa0months compared with placebo, and from the indirect comparison by more than 3 months compared with interferon-α. In summary, the Committee was satisfied that pazopanib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee considered whether its recommendations were associated with any potential issues related to equality. The Committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\n", 'Recommendations for further research ': 'An ongoing head-to-head study of pazopanib versus sunitinib (COMPARZ) is due to report in June 2012.', 'Related NICE guidance': 'Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 169 (2009).\n\nBevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 178 (2009).\n\nEverolimus for the second-line treatment of advanced renal cell carcinoma.NICE technology appraisal guidance 219 (2011).', 'Review of guidance': 'The guidance on this technology will be considered for review when the COMPARZ data will be made available and at the latest in December 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveFebruary 2011', 'Changes after publication': 'March 2012: Minor maintenance.\n\nAugust 2013: Part B of the patient access scheme removed.\n\nApril 2017: The company changed from GlaxoSmithKline to Novartis. Contact details for the patient access scheme updated.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nISBN: 978-1-4731-2483-7'}	https://www.nice.org.uk/guidance/ta215	Evidence-based recommendations on pazopanib (Votrient) for previously untreated advanced renal cell carcinoma in adults.
691683037bc8d14e80c8e00421e246e366a2405f	nice	Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar I disorder	Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar I disorder Evidence-based recommendations on aripiprazole for treating moderate to severe manic episodes in young people with bipolar I disorder. # Guidance Aripiprazole is recommended as an option for treating moderate to severe manic episodes in adolescents with bipolar I disorder, within its marketing authorisation (that is, up to 12 weeks of treatment for moderate to severe manic episodes in bipolar I disorder in adolescents aged 13 and older).# The technology Aripiprazole (Abilify, Otsuka Pharmaceuticals Europe) is an antipsychotic with partial dopamine D2 and D3 agonistic properties. It has a UK marketing authorisation 'for the treatment up to 12 weeks of moderate to severe manic episodes in bipolar I disorder in adolescents aged 13 and older'. It also has a UK marketing authorisation for the treatment of moderate to severe manic episodes in bipolar I disorder in adults, and for the prevention of a new manic episode in adults who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment. Aripiprazole is administered orally. The summary of product characteristics states that the recommended dosage for aripiprazole is 10 mg per day administered once daily without regard to meals. It also states that treatment should be initiated at 2 mg (using aripiprazole oral solution 1 mg/ml) for 2 days, and titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The summary of product characteristics notes that enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated and that a daily dose of 30 mg is associated with a substantially higher incidence of significant undesirable effects. It states that doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring. The summary of product characteristics lists the following adverse reactions specific to adolescents treated with aripiprazole: very common reactions (10% or more) were somnolence (23.0%), extrapyramidal disorder (18.4%), akathisia (16.0%) and fatigue (11.8%); and common reactions (between 1% and 10%) were upper abdominal pain, increased heart rate, increased weight, increased appetite, muscle twitching and dyskinesia. The following undesirable effects had a possible dose–response relationship: extrapyramidal disorder (incidences were: 10 mg dose 9.1%, 30 mg dose 28.8%, placebo 1.7%) and akathisia (incidences were: 10 mg dose 12.1%, 30 mg dose 20.3%, placebo 1.7%). For full details of adverse reactions and contraindications, see the summary of product characteristics. Aripiprazole is available in 5 mg, 10 mg, 15 mg and 30 mg tablets, as 10 mg and 15 mg orodispersible tablets, and as an oral solution (1 mg/ml). The acquisition cost of aripiprazole 5 mg, 10 mg and 15 mg is £95.74 for 28 tablets. For 30 mg it is £191.47 for 28 tablets, and for oral solution it is £102.57 for 150 ml. Costs exclude VAT and are from the 'British national formulary' (BNF, edition 63). For people whose condition responds to aripiprazole, the expected length of a course of treatment is 12 weeks. For a course of 12 weeks (84 days), the 10 mg dose would cost £287.22. This cost would be the same for a 15 mg dose. A course of the 30 mg dose would cost £574.41. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of aripiprazole and a review of this submission by the Evidence Review Group (ERG; section 9). The manufacturer presented direct clinical-effectiveness evidence from 2 randomised controlled trials comparing aripiprazole with placebo and performed a meta-analysis of these trials. The manufacturer also presented a network meta-analysis based on a network containing aripiprazole, olanzapine, risperidone, quetiapine and placebo. The manufacturer undertook a systematic review to identify published evidence for aripiprazole for the treatment and prevention of acute manic and mixed episodes in children and adolescents with bipolar disorder. The review identified 3 randomised controlled trials (NCT00110461, NCT00194077 and NCT00116259) that investigated aripiprazole in children and adolescents with bipolar disorder. The NCT00194077 trial was excluded because it only included children under the age of 10, a group outside the licensed indication. The manufacturer considered NCT00110461 to be the main evidence for the use of aripiprazole in children and adolescents. The NCT00116259 trial was not discussed in detail because the manufacturer considered it to be a small trial in a specific population of children and adolescents with bipolar disorder (both types I and II) and attention-deficit hyperactive disorder (ADHD). No relevant non-randomised controlled trial evidence for aripiprazole was identified from the systematic review. NCT00110461 was a multicentre, double-blind, randomised, placebo-controlled clinical trial undertaken across 59 sites in the USA between March 2005 and February 2007. The study was designed to test the safety and efficacy of 2 doses of aripiprazole in children and adolescents with bipolar I disorder who experienced manic or mixed episodes with or without psychotic features. There were 296 participants randomised to receive aripiprazole 10 mg/day (n=98), aripiprazole 30 mg/day (n=99) or placebo (n=99). The study duration was 30 weeks with a 4-week acute phase followed by an extension phase of 26 weeks. Participants in NCT00110461 were aged between 10 and 17 years with a DSM-IV diagnosis of bipolar I disorder who were experiencing manic or mixed episodes, with or without psychotic features. Comorbid diagnoses were permitted including ADHD, conduct disorder, oppositional defiant disorder and anxiety disorders. All participants had a baseline Young Mania Rating Scale (YMRS) score of more than 20. Exclusion criteria included bipolar II disorder, unspecified bipolar disorder and psychosis caused by other medical conditions or concomitant mediations. Participants with learning disabilities and those who were determined by the investigator to be at risk of suicide were also excluded. In the NCT00110461 trial, 72% (296/413) of participants screened were enrolled in the study. Participant characteristics at baseline were comparable between the 3 groups in the trial. Approximately 63% of participants were aged 13 or over and fell within the licensed population. In response to a clarification request, the manufacturer provided post-hoc data on the proportion of participants in mixed and manic states at baseline and on the proportion of 'rapid cyclers' (participants who experienced 4 or more manic, hypomanic or mixed episodes in the previous year). In both cases the proportions were relatively similar between the groups. The primary outcome in NCT00110461 was the change from baseline to week 4 on the YMRS total score. Secondary outcomes were changes from baseline scores in the Children's Global Assessment Scale (CGAS), Clinical Global Impressions Scale-Bipolar Version (CGI-BP) severity scores for mania, depression and overall bipolar illness, Children's Depression Rating Scale - Revised (CDRS-R) score, General Behaviour Inventory Scale (GBI) score and Attention-Deficit Hyperactivity Disorders Rating Scale (ADHD-RS-IV) score. A YMRS response rate was based on a responder definition of a 50% or more reduction from the YMRS total score at baseline. In the NCT00110461 trial, both aripiprazole doses demonstrated statistically significant improvements over placebo in the YMRS total score at week 4, with treatment differences from placebo of −5.99 (95% confidence interval −8.49 to −3.50; p<0.0001) for the aripiprazole 10 mg group, and −8.26 (95% CI −10.7 to −5.77; p<0.0001) for the aripiprazole 30 mg group. Statistically significant improvements in YMRS total score were demonstrated at week 1 for both aripiprazole doses, and were maintained until week 30. At week 30, the treatment difference in YMRS total score from placebo for the aripiprazole 10 mg dose was −5.89 (95% CI −8.70 to −3.08), and for the aripiprazole 30 mg dose it was −6.73 (95% CI −9.53 to −3.94). The YMRS responder rates were also significantly higher in the aripiprazole arms than in the placebo arm at week 4 and week 30. Both aripiprazole doses demonstrated significant improvements at week 4 compared with baseline in the secondary end points: CGAS core, CGI-BP severity scores for mania, depression and overall bipolar illness, GBI – parent/guardian version and subject version mania total score, and the ADHD-RS-IV total score. Significant differences were not observed at week 4 in the CGI-BP severity scores for depression, GBI – patient depression total scores or the CDRS-R score. A significant difference was observed in the 10 mg aripiprazole arm for the GBI-parent/guardian version for depression (p= 0.0430) but not in the 30 mg arm. The manufacturer presented results from a post-hoc subgroup analysis based on the change in YMRS score from baseline calculated using both the observed case dataset and the last observation carried forward dataset for age subgroups (10–12, and 13–17 years). Results from the last observation carried forward data showed that participants receiving aripiprazole in both age groups had a statistically significant change in YMRS score from baseline at both weeks 4 and 12 compared with those receiving placebo. Using the observed case dataset, there was a statistically significant change in YMRS score in participants receiving aripiprazole in both age groups at week 4; however by week 12, although the change in YRMS score was still greater in participants receiving aripiprazole compared with those receiving placebo, this was not statistically significant. At the end of the acute phase of the trial (4 weeks) the proportion of participants not completing the trial was 14.3% in the aripiprazole 10 mg group, 22.2% in the aripiprazole 30 mg group and 23.2% in the placebo group. At 30 weeks the drop-out rates were 65.3% in the aripiprazole 10 mg group, 77.7% in the aripiprazole 30 mg group and 87.9% in the placebo group. The manufacturer noted the statement in the Committee for Medicinal Products for Human Use (CHMP) assessment report that results based on the observed case analysis dataset failed to show statistical significance for aripiprazole compared with placebo for both doses on all analysed efficacy end points at week 12. The manufacturer stated that the lack of statistically significant differences between aripiprazole and placebo at week 12 along with the high discontinuation rate resulted in the CHMP restricting the treatment length with aripiprazole to 12 weeks. The manufacturer also carried out a post-hoc subgroup analysis to investigate if the efficacy of aripiprazole was influenced by the presence or absence of ADHD symptoms. Results presented in 3 age subgroups (10–12, 13–14, and 15–17 years) suggested no change in the treatment effect. In NCT00110461, health-related quality of life was measured by the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q). The manufacturer reported that although the results did not reach statistical significance, both aripiprazole arms demonstrated a trend for improvement relative to placebo. The manufacturer presented adverse events occurring in more than 5% of any group in NCT00110461 over the acute phase and over the full trial duration. There were no deaths or suicides in the study. The manufacturer acknowledged that somnolence and extrapyramidal symptoms occurred more frequently in the aripiprazole arms than in the placebo group. In the acute phase (up to 4 weeks) extrapyramidal disorder occurred in 12.2% (12/98) of the aripiprazole 10 mg group, 27.3% (27/99) of the aripiprazole 30 mg group and 3.1% (3/97) of the placebo group. In the acute phase (up to 4 weeks) somnolence occurred in 19.4% (19/98) of the aripiprazole 10 mg group, 26.3% (26/99) of the aripiprazole 30 mg group and 3.1% (3/97) of the placebo group. In the acute phase (up to 4 weeks) akathisia occurred in 8.2% (8/98) of the aripiprazole 10 mg group, 11.1% (11/99) of the aripiprazole 30 mg group and 2.1% (2/97) of the placebo group. The manufacturer concluded that most of the adverse events occurred in the acute phase of the study and were mild to moderate in severity, and therefore were expected to be manageable. The manufacturer presented changes in baseline metabolic parameters at 4 and 30 weeks. Differences in the treatment groups between the incidence of clinically significant weight gain (7% or more weight gain compared with baseline) and change from baseline body mass index (BMI) were not statistically significant at week 4. Data on the incidence of clinically significant weight gain at 30 weeks was considered to be academic in confidence by the manufacturer and therefore cannot be reported in this document. There were no differences between the treatment groups in the proportion of participants with a BMI on or above the 95th percentile for age and sex at week 4. Data on the proportion of participants with a BMI on or above the 95th percentile at week 30 was considered to be academic in confidence. The manufacturer noted that the CHMP limited the indication for aripiprazole to adolescents aged 13 and over as a result of safety concerns in younger people. The manufacturer reported results from a post-hoc subgroup analysis to assess the safety profile across age subgroups (10–12 years, and 13–17 years). In the 10–12 years subgroup there were statistically significant increases in mean weight and BMI changes from baseline in the aripiprazole 30 mg treatment arm at weeks 4 and 12. There were also statistically significant increases in weight and BMI measurements in the aripiprazole 10 mg treatment arm at week 12 using the last observation carried forward analysis for the 10–12 years subgroup. The NCT00116259 trial was a double-blind randomised placebo-controlled clinical trial undertaken in Brazil. There were 43 participants who were randomised to receive aripiprazole 20 mg per day (n=18) or placebo (n=25). The study duration was 6 weeks. Participants were aged between 8 and 17 years with a DSM-IV diagnosis of bipolar I or II disorder, comorbid with DSM-IV ADHD. All participants were in an acutely manic or mixed state defined as a YMRS score of more than 20 at the baseline visit. Exclusion criteria included learning disabilities and severe risk of suicide. Results from NCT00116259 showed that participants receiving aripiprazole had a statistically significantly larger reduction in YMRS total scores from baseline to week 6 than participants receiving placebo (−27.22 versus −19.52, p=0.02). A greater proportion of participants on aripiprazole compared with placebo experienced a response (88.9% versus 52%, p=0.02; number needed to treat =2.70) and experienced remission (72% versus 32%, p=0.01; NNT=2.50). The manufacturer presented a meta-analysis of NCT00110461 (pooled 10 mg per day and 30 mg per day) and NCT00116259 (20 mg per day). Results from the meta-analysis indicated that aripiprazole was statistically significantly superior to placebo in inducing symptomatic response (as measured as a 50% or more change in YMRS score) at weeks 1, 2 and 4, but not at week 3. Also, results from the meta-analysis showed aripiprazole to be associated with a statistically significant higher rate of extrapyramidal symptoms than placebo, but not of somnolence. The manufacturer commented that the meta-analysis was performed to be transparent rather than to provide meaningful results. The manufacturer stated that the results should be treated with caution because the information from the NCT00116259 trial is limited by the small trial size and the different population compared with NCT00110461 (that is, it included people with bipolar II disorder and was restricted to participants with comorbid ADHD). As there are no head-to-head trials comparing aripiprazole with the comparators specified in the final scope issued by NICE, the manufacturer presented a network meta-analysis to determine the relative efficacy of the treatments using placebo as the common comparator. Five randomised controlled trials were identified in addition to the 2 studies including aripiprazole (NCT00110461 and NCT00116259). The 5 studies were as follows: 3 studies for risperidone (risperidone compared with placebo, risperidone compared with divalproex sodium and risperidone compared with divalproex sodium and lithium), 1 study for quetiapine (quetiapine compared with placebo), and 1 study for olanzapine (olanzapine compared with placebo). The network meta-analysis included NCT00110461, one of the studies for risperidone (risperidone compared with placebo), and the studies for quetiapine and olanzapine (both compared with placebo). The manufacturer undertook a sensitivity analysis in which the NCT00116259 trial and the remaining 2 studies for risperidone (risperidone compared with lithium and divalproex sodium) were also included. The network analysis used a fixed-effects Bayesian model, because the manufacturer considered there was not enough evidence to support the estimation of a random-effects model. Results from studies that included treatment groups with different intervention doses were pooled to provide an average treatment dose effect. Efficacy outcomes considered in the network meta-analysis were the YMRS response rates at weeks 1, 2 and 3, and discontinuation at week 3. Analyses were also conducted for the following safety outcomes: extrapyramidal symptoms, clinically significant weight gain, clinically significant increase in prolactin and somnolence. The manufacturer presented results from the network meta-analysis as relative risks using placebo and aripiprazole (pooled dose) as references. These results indicated that all the antipsychotics considered (aripiprazole, risperidone, quetiapine and olanzapine) were statistically more effective than placebo at achieving YMRS response at weeks 1–3. The results also indicated that there were no statistically significant differences in YMRS response rates at weeks 1–3 between the antipsychotics. No statistically significant differences were found for discontinuation of treatment at week 3 between the interventions considered in the network. Participants receiving aripiprazole were found to be statistically significantly more likely to experience extrapyramidal symptoms than those receiving placebo. They were also more likely to experience them than participants receiving risperidone and quetiapine, but these differences were not statistically significant. There was no statistically significant difference between aripiprazole and placebo in the risk of experiencing a clinically significant increase in weight. Aripiprazole (pooled dose) was statistically significantly less likely to cause clinically significant weight gain than olanzapine and quetiapine. Participants receiving aripiprazole were less likely to experience a clinically significant increase in prolactin than those on olanzapine, risperidone or quetiapine. Participants receiving aripiprazole were found to be statistically significantly more likely to experience somnolence than those receiving placebo. They were also more likely to experience somnolence than participants receiving risperidone and quetiapine, but this was not statistically significant. # Cost effectiveness The manufacturer undertook a systematic review to identify relevant cost-effectiveness or cost–utility studies. No economic evaluations were identified for the treatment of bipolar I disorder in children and adolescents. The manufacturer developed a de novo economic model to assess the cost effectiveness of aripiprazole compared with the other antipsychotics. The population in the economic evaluation was adolescents with manic episodes of bipolar I disorder between 13 and 17 years as specified in the marketing authorisation. The age of onset used in the model was 15 years and the time horizon was until the person reached adulthood at 18 years. The cost-effectiveness model presented by the manufacturer was a Markov cohort model with a weekly cycle length. The treatment pathway in the model was based on a sequence of up to 4 treatment lines. The first 3 related to treatment with an antipsychotic drug and the fourth included lithium treatment for participants whose condition was resistant to previous therapy. The antipsychotic treatment lines were identical in structure and each contained an acute phase of 3 weeks of inpatient treatment, a sub-acute phase of up to 5 weeks of inpatient treatment for participants who experienced a response, a maintenance phase of outpatient treatment for an average of 4 weeks, and then withdrawal of treatment. The 'therapy resistance' phase contained up to 5 weeks inpatient lithium treatment, followed by outpatient lithium treatment and a maintenance phase similar to that in the antipsychotic lines for participants who experienced a response. Participants entered the model at the start of the first treatment line. They moved to the next treatment line if they discontinued treatment before response during the acute phase, if they did not respond to current treatment by the end of week 3, or if they relapsed before discharge from hospital. If participants relapsed within the maintenance phase they remained on the same treatment line to which they had responded. If participants did not respond to 3 lines of antipsychotic treatment they entered the 'therapy resistance' treatment line. If participants relapsed on 'therapy resistance' treatment they returned to the inpatient lithium treatment (that is the 'therapy resistance' hospitalised state). The modelling of adverse events was included in the treatment-related health states. Participants could also die in any health state in the model. Based on clinical opinion, the manufacturer specified the treatment sequence of risperidone, quetiapine and olanzapine to represent usual care (labelled strategy 1 in the model). The manufacturer considered either quetiapine or olanzapine could be replaced by aripiprazole. For the base-case analyses, olanzapine was replaced with aripiprazole and the position of aripiprazole in the treatment sequences was varied, giving 4 different strategies: Strategy 1: risperidone, quetiapine, olanzapine. Strategy 2: risperidone, aripiprazole, quetiapine. Strategy 3: aripiprazole, risperidone, quetiapine. Strategy 4: risperidone, quetiapine, aripiprazole. Clinical data for the effectiveness for each antipsychotic in the 3‑week acute phase were taken from the results of the network meta-analysis based on pooled dose levels. It was assumed the effectiveness of each antipsychotic intervention was not influenced by its position in the treatment pathway and that the treatment was at a constant dose. Beyond the acute phase, it was assumed that all antipsychotics were equally effective and the common weekly relapse value was based on expert opinion. The manufacturer also assumed an identical mortality rate for all the antipsychotic interventions, based on UK life tables adjusted to reflect the higher rates of mortality observed among participants with bipolar disorder. The model included 3 adverse events: extrapyramidal symptoms, somnolence and weight gain. Data for the incidence of these events were based on the results of the network meta-analysis. There were no available data for the incidence of extrapyramidal symptoms or somnolence associated with olanzapine treatment, and so these values were set equal to the lowest incidence of the other antipsychotics. The health-related quality of life data collected in NCT00110461 were not based on a preference-based measure. As a result of a lack of available data, for preference-based utility values from bipolar disorder in adolescents, the manufacturer based the utilities in the model on published data from adult populations with bipolar disorder. For the main analysis, the utility values for the bipolar health states were based on EQ-5D data from a study of an adult UK population with bipolar I disorder. A multiplicative model for the utility values was used to take into account the demographic (age and sex) of the population from which the utility was calculated. The calculated multipliers were then applied to an appropriate general population utility value for the adolescent population in the model. The utility values were also further adjusted according to hospitalisation status, adverse events and the ageing of the cohort. The utility value for weight gain was taken from a cohort of children who are overweight or obese and the utility values for somnolence and extrapyramidal symptoms came from participants with schizophrenia. In the economic model in-hospital costs were based on NHS reference costs 2010/1155 (code MHIPC1; NHS Trusts Mental Health Inpatients – Children). This cost was assumed to include costs relating to adverse events, but not the cost of antipsychotic treatments. Outpatient resource use was based on expert opinion, with costs taken from the Personal Social Services Research Unit. Non-propriety costs were used for each of the antipsychotics apart from aripiprazole. The base case was based on the pooled dose efficacy and safety results and so an average dose cost was used. In the base case, the cost-effectiveness results were similar for the 4 strategies. The use of aripiprazole at any point in the treatment pathway dominated usual care (that is, was more effective and less costly), which had the highest total cost (£75,066) and the lowest total quality-adjusted life years (QALYs) (2.516). Aripiprazole used as second-line therapy after risperidone had the lowest total cost (£74,133) and the highest total QALYs (2.525) and dominated the other base-case strategies. The manufacturer undertook a wide range of univariate sensitivity analyses and identified the rates of response applied during the acute treatment phase as the main parameters that influenced the cost-effectiveness estimates of the strategies. The manufacturer noted that this was expected because the response rates were varied by ±30%, and the differences in the base-case response rates between the 4 antipsychotic treatments considered were not substantial. Scatterplots from probabilistic sensitivity analysis were also presented in the submission. From these results the manufacturer noted that there was some uncertainty surrounding the cost-effectiveness results, but that for all 3 strategies containing aripiprazole, the majority of probabilistic sensitivity analysis iterations indicated cost effectiveness or dominance. The manufacturer presented various scenario analyses in its submission and in response to a clarification request. These included: Using 10 mg aripiprazole rather than a pooled dose. Using results from the network meta-analysis sensitivity analysis based on all trials identified in the manufacturer's review. Swapping the position of quetiapine and olanzapine in the base-case treatment strategy. Using utility values from a different source. Changing the starting age of participants to 13 years and 17 years. Reducing treatment efficacy between lines 1 and 2 and between lines 2 and 3. Including the cost of drug-related adverse events in the model. Extending the acute and euthymic treated phases of the model. None of these scenarios produced results that differed greatly from the base case, and use of aripiprazole in the treatment pathway always dominated usual care. # Evidence Review Group comments The ERG noted that the searches in the manufacturer's submission were limited to January 2012 and requested that the manufacturer update them. As a result of time constraints the manufacturer provided results from a non-systematic approach and identified 3 further trials. The ERG repeated and updated the searches until January 2013. The ERG found 3 studies not identified by the manufacturer, but none of them were phase III randomised controlled trials. The ERG considered that the NCT0011461 trial was of reasonable methodological quality, and measured a range of outcomes that are relevant to the decision problem. However, the ERG expressed concern that the trial population described in the manufacturer's submission is not likely to represent the UK clinical population: Clinical advisers to the ERG considered that the age of the population in the trial was much younger than that seen in UK clinical practice. Clinical advisers also raised concerns about the high proportion of participants in the trial with comorbid ADHD. The ERG considered it likely that many of the participants in the trials were treated as outpatients, which does not reflect current UK practice for this population. The ERG commented that excluding from the trial participants who were at risk of suicide may have resulted in the trial population having less severe disease than those presenting in UK clinical practice. The ERG noted the manufacturer's acknowledgement that the inclusion and exclusion criteria for NCT0011461 could have reduced the external validity of the trial population. It also noted that no information was presented on the duration or maintenance of effect after 12 weeks of treatment with aripiprazole. The ERG noted the advice in the European Medicines Agency (EMA) guidance for clinical investigation of bipolar disorder, that the occurrence of switching to depression should be investigated. In response to a clarification request, the manufacturer provided depression outcomes at weeks 4 and 30 using the CGI-BP severity depression score, the CDRS-R score, the GBI total score – parent/guardian (depression), and the GBI total scores – patient (depression) score. The ERG considered that although the data presented did not raise concerns about the occurrence of depression associated with aripiprazole treatment, the effect of aripiprazole on depression was not explored in depth in the submission. The ERG stated that the key clinical evidence for this appraisal came from the network meta-analysis. The ERG noted that relevant placebo-controlled trials of the antipsychotic comparators were used for the indirect comparison. The ERG agreed with the manufacturer that the NCT00116259 trial should be excluded from the base case because of the different participant population. The ERG also agreed that excluding the study comparing risperidone with lithium and divalproex sodium was appropriate. The ERG did not consider it appropriate for the study comparing risperidone with divalproex sodium to be excluded but acknowledged that including this study would have little impact on the conclusions from the network meta-analysis. The ERG questioned the pooling of doses from treatment arms with multiple doses in the network meta-analysis because it considered that different doses are associated with different efficacies and side effects. The manufacturer was requested to conduct a network meta-analysis with doses from multiple treatment arms separated, but was unable to do so in the time available. The ERG considered that caution should be used when interpreting the results from the network meta-analysis based on pooled interventions from multiple treatment arms. The ERG considered that a random-effects model was more appropriate for the network meta-analysis than the fixed-effects model used by the manufacturer because of the heterogeneity between the trials. The ERG undertook the network meta-analysis using a random-effects model, and obtained similar results to those from the fixed-effects model; although in all cases the 95% credible intervals were wider, reflecting the increased uncertainty. In general the ERG was satisfied that the economic evidence submitted by the manufacturer does not represent a biased assessment of the cost effectiveness of aripiprazole. The ERG considered the manufacturer's model to be robust and transparent and well structured, allowing for analysis of uncertainty in the model inputs. The ERG explored the manufacturer's probabilistic sensitivity analysis. The ERG noted that all changes in the total costs and QALYS between the deterministic and mean probabilistic sensitivity analysis results were less than 0.1% of the deterministic value. Although second-line aripiprazole (strategy 2) dominated all the other strategies in the deterministic analysis and mean probabilistic sensitivity analysis results, the probabilistic 95% confidence intervals included the possibility of each strategy dominating this strategy. The ERG summarised the results to show that the strategy that excludes aripiprazole (strategy 1) was dominated by each of the other strategies in over half of the probabilistic sensitivity analysis results: strategy 2 dominated strategy 1 in 72.1% of iterations, strategy 3 dominated strategy 1 in 54.4% of iterations, and strategy 4 dominated strategy 1 in 57.2% of iterations. The cost-effectiveness acceptability curve indicated that the probability that strategy 1 is cost effective is roughly half that of the probabilities for strategy 2 or strategy 3 for all the thresholds explored. The ERG highlighted that its clinical advisers and those of the manufacturer stressed the importance of tailoring the treatment sequence to reflect an individual's needs (based on factors such as severity of symptoms, side-effect profile and comorbidities). As there are limited data available to model treatment within subgroups, the ERG conducted an exploratory scenario analysis to assess the possible implications of treatment sequences tailored to reflect an individual's needs. The results showed that only small changes in the modelled results for each treatment sequence were needed for the incremental cost-effectiveness ratio (ICER) for that strategy to be £20,000 or £30,000 per QALY gained. The ERG stated that these results suggest that the actual place of aripiprazole within a treatment sequence is likely to depend on individual circumstances. The ERG explored the potential implications of 2 different treatment durations for aripiprazole: 1 use reflected its licensed duration of a maximum of 12 weeks, the other reflected clinical opinion of its real-life use based on an average of 12 months. The ERG amended the manufacturer's model to have maximum treatment duration (for all antipsychotics) of 12 weeks. Responding to a request, the manufacturer provided an amended version of its model to have an average of 12 months of antipsychotic treatment. The ERG considered that although total costs and total QALYs showed a reduction in both of the 2 new models, the substantive conclusions of the manufacturer's base case analysis remained unchanged. The ERG considered that a treatment sequence containing all 4 antipsychotics was appropriate. Clinical advisers to the ERG stated that if a person's condition had not responded to the first 3 antipsychotic interventions, clinicians would generally try the remaining antipsychotic rather than conclude that a person's condition was treatment resistant. It was not possible to evaluate this scenario within the time frame of the clarification process. The ERG stated that there is no evidence to suggest that a 4-line treatment sequence would substantially alter the conclusions. The ERG made the following changes to the model to explore the plausibility of the manufacturer's results: it used network meta-analysis results from a random-effects model it included a half-cycle correction it adjusted the discounting formula used it amended the mortality rate calculations it included a 10% reduction in efficacy between lines 1 and 2, and 15% between lines 2 and 3 it included a logical constraint on the probabilistic sensitivity analysis inputs so that week 3 probability of discontinuing or responding did not exceed 100%. These amendments were incorporated into a 'licensed duration' model, which reflected the maximum 12 week duration specified in the marketing authorisation, and into a 'real-world' model, which assumed 4 weeks of acute treatment and 12 months of euthymic treatment. The deterministic and probabilistic cost-effectiveness results from both models were similar to those obtained in the manufacturer's base-case model: The probabilistic sensitivity analysis results from the 'licensed duration' model indicated that the use of aripiprazole at any point in the treatment pathway dominated usual care, which had the highest total cost (£72,157) and the lowest total QALYs (2.458). Aripiprazole used as second-line therapy after risperidone had the lowest total cost (£70,707) and the highest total QALYs (2.471). The probabilistic sensitivity analysis results from the 'real-world' model indicated that aripiprazole used as first-line therapy had the highest total cost (£63,384) and the lowest total QALYs (2.428). Aripiprazole used as second-line therapy had the lowest total cost (£62,138) and the highest total QALYs (2.429). The ERG also explored the impact on the cost effectiveness of the amendments (described in section 3.45) separately, and concluded that the key drivers to changes in the cost-effectiveness results were the extension of treatment duration either to 4 weeks acute treatment or 12 months of euthymic treatment. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aripiprazole, having considered evidence on the nature of acute manic episodes in bipolar I disorder in adolescents and the value placed on the benefits of aripiprazole by people with the condition, and clinical specialists. It also took into account the effective use of NHS resources. The Committee discussed the nature of acute manic episodes in bipolar I disorder. The clinical specialists explained that acute manic episodes can have a large impact on adolescents and their families. Symptoms of mania may include poor concentration, little need for sleep, poor temper control, irritability, reckless behaviour and lack of self-control. For adolescents, the symptoms may impact on schooling, work and social life. The impact on families may include sleep deprivation, financial pressures and family wellbeing. The Committee heard that there is often a need to resolve the manic episode quickly so that adolescents can return to normal functioning in terms of schooling, work and family life. The Committee discussed current standard clinical management of manic episodes in bipolar I disorder in adolescents. The clinical specialists highlighted that the main aim of treatment is to maximise control of the mania and minimise the adverse reactions to treatment that are most troublesome for each individual. The Committee heard from the clinical specialists that drug treatment options for adolescents who develop acute mania include antipsychotic drugs such as aripiprazole, risperidone, olanzapine or quetiapine. The clinical specialists explained that lithium is associated with a range of practical limitations, including the need for pre- and post-treatment blood tests, a narrow therapeutic range, and significant adverse effects. The clinical specialists further explained that although lithium can be prescribed as a monotherapy, it is usually prescribed in combination with antipsychotics. They also highlighted that valproate is rarely used as a monotherapy and is usually not given to women of childbearing age because of fetal malformation risks during pregnancy and risk of polycystic ovary syndrome. The clinical specialists confirmed that in UK clinical practice, the routinely prescribed antipsychotics for this indication are olanzapine, aripiprazole, risperidone and quetiapine, and they acknowledged that all are prescribed off-label for the adolescent population (except aripiprazole, which received its marketing authorisation for this indication in January 2013). The Committee was aware that NICE clinical guideline 38 on bipolar disorder recommends following the recommendations for adults with bipolar disorder when prescribing medication for adolescents with acute manic episodes, except that drugs should be started at lower doses. The Committee understood from the clinical specialists that no single antipsychotic drug is considered to be more clinically effective than the others, but that tolerability and adverse reactions vary between the treatments. The Committee heard from the clinical specialists that there is substantial variation between the antipsychotics in the adverse reactions associated with each treatment including weight gain, hyperprolactinaemia and sexual dysfunction, aggression, and akathisia or extrapyramidal symptoms. The clinical specialists explained that it is important for adolescents with moderate to severe manic episodes to have a range of treatment options available. This is in order to individualise treatment and to minimise adverse treatment effects, as adolescents are often less tolerant of adverse reactions than adults, leading to problems with adherence to medication. The Committee discussed the manufacturer's decision problem, noting that the manufacturer had excluded lithium and valproate as comparators even though they were specified in the final scope issued by NICE. The Committee noted the comments from the manufacturer, ERG and the clinical specialists highlighting that lithium and valproate monotherapy are rarely used in UK clinical practice. The Committee accepted that these 2 treatments are rarely used as monotherapy and agreed that it was appropriate to consider only risperidone, olanzapine and quetiapine as the comparators, as listed in the manufacturer's decision problem. # Clinical effectiveness The Committee considered the relevance of the USA-based NCT00110461 trial to UK clinical practice. It discussed whether the population in the trial reflected that seen in UK clinical practice. The Committee noted that the trial recruited people who were aged between 10 and 17 years and that approximately 63% of the trial participants were aged 13 or older, and so were within the UK marketing authorisation. The Committee heard from the clinical specialists that the diagnosis criteria for bipolar I disorder in children and adolescents in the UK differed from those used in the USA and it is likely that some of the participants with bipolar I disorder comorbid with ADHD in the trial would not have been diagnosed with bipolar I disorder in the UK. The clinical specialists also confirmed that it was usual in clinical trials involving children and adolescents with bipolar I disorder to exclude people with learning disabilities and those at risk of suicide. The Committee discussed the concerns raised by the ERG that most of the participants recruited to the trial were treated as outpatients, whereas in UK clinical practice, they would be usually treated as inpatients. The Committee heard from the clinical specialists that a significant proportion of people in the NHS are managed as outpatients, especially outside the major cities where there is often limited availability of inpatient facilities for this age group. The Committee concluded that the results from the NCT00110461 trial were generalisable to UK clinical practice. The Committee then considered the clinical-effectiveness results of the NCT00110461 trial, which showed that aripiprazole was associated with a statistically significant reduction in total YMRS score when compared with placebo throughout the 30-week study duration based on the last observation carried forward dataset. The Committee understood that the marketing authorisation is restricted to 12 weeks' treatment because of high discontinuation rates and the lack of a statistically significant difference in efficacy outcomes beyond 12 weeks when the analysis was based on the observed case dataset. The Committee discussed the usefulness of the YMRS score as the primary outcome and heard from the clinical specialists that this score is a well-recognised tool used in clinical trials for assessing symptoms of mania but that the tool is not routinely used by all clinicians in the UK. The clinical specialists explained that any changes in the YMRS are clearly evident in the change in severity of the symptoms of the individual. The Committee accepted that the YMRS is a valid tool for measuring the severity of symptoms of mania. It concluded that evidence from the trial demonstrated a reduction in manic symptoms in those receiving aripiprazole for 12 weeks compared with those receiving placebo. The Committee considered the adverse event data from the NCT00110461 trial. Extrapyramidal disorder and somnolence were statistically significantly more common in those receiving either 10 mg or 30 mg aripiprazole compared with those receiving placebo. Akathisia was statistically significantly more common, but only in those receiving the 30 mg dose of aripiprazole compared with those receiving placebo. It noted there were no statistically significant increases in weight gain or BMI in those receiving aripiprazole compared with those receiving placebo at 4 weeks. The Committee heard from the clinical specialists that the patterns of adverse events seen in the trial were consistent with the use of aripiprazole in other indications. The clinical specialists also stated that for this group, in the short term, somnolence may help in the management of acute mania. The Committee noted the lack of long-term safety data for aripiprazole, but was aware that the risk management plan agreed with the EMA included a long-term (up to 2 years) study to evaluate the safety and tolerability of aripiprazole as maintenance treatment in adolescents with schizophrenia, and children and adolescents with bipolar disorder. The Committee concluded that current evidence suggests that the tolerability and range of adverse reactions associated with aripiprazole are acceptable. The Committee was aware that the population in the NCT00110461 trial was broader than that in the UK marketing authorisation, because the trial included children aged younger than 13 years and those with mixed episodes. The Committee understood that the EMA had restricted the licence for aripiprazole to adolescents aged 13 or older because of safety concerns in younger people. The Committee noted that the manufacturer had presented clinical efficacy and safety results in its submission by age group, that is, for ages 10–12 years and 13–17 years. The Committee noted that the subgroup analysis by age group suggested that there was no change in treatment effect between the age subgroups, but that the younger age group experienced a greater increase in mean weight and BMI changes from baseline at week 12. The Committee noted that the manufacturer provided baseline data on the current episode type (manic or mixed) but a subgroup analysis by age group and episode type was not presented. The Committee understood that these subgroups were post hoc subgroups. It was also aware that the subgroup analyses were based on small numbers of people in the groups, which increased the uncertainty in the results. The Committee therefore concluded that evidence of treatment effect should be based on the whole trial population of NCT00110461. The Committee noted that there were no head-to-head comparisons of aripiprazole with the other comparator antipsychotics. The Committee considered the manufacturer's approach to conducting a network meta-analysis to determine the relative efficacy and tolerability of aripiprazole, risperidone, olanzapine and quetiapine. The Committee noted and accepted the ERG's concerns about the network meta-analysis (see sections 3.37–3.39). The Committee was aware that using a random-effects model in the network meta-analysis as suggested by the ERG produced results similar to those obtained by the manufacturer. The Committee therefore accepted the results of the network meta-analysis as a reasonable basis for the economic model given the evidence available. The Committee considered the clinical effectiveness evidence of aripiprazole compared with risperidone, olanzapine and quetiapine obtained from the network meta-analysis. It noted that the results suggested that aripiprazole and the other antipsychotics showed greater efficacy than placebo but that no statistically significant differences in efficacy were found between aripiprazole and the other antipsychotics. It then considered the adverse-event profile of aripiprazole compared with risperidone, olanzapine and quetiapine. It was aware that the results suggested that the extrapyramidal symptoms and somnolence occurred more frequently with aripiprazole than with risperidone or quetiapine but that these results were not statistically significant. The Committee also noted that the results suggested that clinically significant weight gain was statistically significantly less likely with aripiprazole than with olanzapine or quetiapine. The Committee was aware of the testimony from the clinical specialists about the importance of having a range of treatments available in order to individualise treatment, minimise adverse treatment effects and therefore increase adherence to medication. The Committee heard from the clinical specialists that avoiding weight gain may be of considerable importance to adolescents. The Committee concluded that based on the evidence available, aripiprazole was as effective as other antipsychotics for treating acute mania and had a comparable and acceptable adverse reaction profile. # Cost effectiveness The Committee considered the manufacturer's economic model and the ERG's critique and exploratory analysis. It noted that the ERG considered the manufacturer's model to be transparent, robust, and well structured. The Committee agreed that the model structure was appropriate. The Committee considered the manufacturer's base case in which strategies with aripiprazole used at any stage of the treatment pathway (that is, strategies 2 to 4) were compared with a treatment strategy without aripiprazole (strategy 1). The Committee noted that the manufacturer had undertaken a number of deterministic sensitivity analyses (see section 3.32). The Committee was aware that the main parameters that could make the strategies including aripiprazole become less cost effective were the rates of response applied during the treatment phase. The Committee noted that a higher response rate during the treatment phase resulted in people leaving hospital earlier, which had both cost and health-related quality-of-life benefits. The Committee was also aware that the manufacturer's probabilistic sensitivity analyses suggested that there was uncertainty surrounding the ICERs and it understood that this may be a result of the lack of statistically significant differences in response rates obtained from the network meta-analysis for the 4 antipsychotics. The Committee noted that the results from the manufacturer's probabilistic sensitivity analyses indicated that for the 3 strategies that include aripiprazole, the majority of the probabilistic sensitivity iterations indicated cost effectiveness or dominance. The Committee therefore agreed that the base-case results suggested that a treatment strategy that includes aripiprazole is a cost-effective option when compared with a treatment strategy without it. The Committee then considered the impact of the position of aripiprazole within the treatment pathway on the cost effectiveness results. The Committee discussed the results of the manufacturer's base case as presented in the incremental analysis. The Committee noted that the pathway in which aripiprazole was positioned second, that is strategy 2, dominated all of the other strategies. The Committee also noted that a comparison of the ranges of costs and QALYs (in the base case, costs ranged from £74,133 to £75,066, and QALYs ranged from 2.516 to 2.525) across the strategies showed that they were similar. The Committee noted that the treatment pathway without aripiprazole (strategy 1) was dominated by each of the other treatment pathways including aripiprazole in over half of the probabilistic sensitivity analysis iterations, and that the probability of strategy 1 being the most cost-effective strategy was half the probabilities for strategy 2 and strategy 3 for all of the thresholds explored by the ERG (see section 3.41). Given that each of the strategies was dominated by every other strategy in at least some of the probabilistic iterations, the Committee agreed that the results were not sufficiently robust to make a recommendation on the position of aripiprazole in the treatment pathway. The Committee concluded that aripiprazole should be recommended as an option for the treatment of moderate to severe manic episodes in bipolar I disorder in adolescents. # Summary of Appraisal Committee's key conclusions TA292 Appraisal title: Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar I disorder Section Key conclusion Aripiprazole is recommended as an option for treating moderate to severe manic episodes in adolescents with bipolar I disorder, within its marketing authorisation (that is, up to 12 weeks of treatment for moderate to severe manic episodes in bipolar I disorder in adolescents aged 13 and older). The Committee concluded that based on the evidence available, aripiprazole was as effective as other antipsychotics for treating acute mania and had a comparable and acceptable adverse reaction profile. The Committee agreed that the base-case results suggested that a treatment strategy that includes aripiprazole is a cost-effective option when compared with a treatment strategy without aripiprazole. Given that each of the strategies was dominated by every other strategy in at least some of the probabilistic iterations, the Committee agreed that the results were not sufficiently robust to make a recommendation on the position of aripiprazole in the treatment pathway. The Committee concluded that aripiprazole should be recommended as an option for the treatment of moderate to severe manic episodes in bipolar I disorder in adolescents. Current practice Clinical need of participants, including the availability of alternative treatments The Committee heard that the symptoms of mania in adolescents may impact on their schooling, work and family life and there is often a need to resolve the manic episode quickly. The Committee discussed the drug treatments available for adolescents and understood antipsychotics such as olanzapine, risperidone and quetiapine are routinely used off-label. Clinical specialists explained that it is important for adolescents with acute manic episodes to have a range of treatment options available. This is in order to individualise treatment and to minimise adverse treatment effects, as adolescents are often less tolerant of adverse reactions than adults, leading to problems with adherence to medication. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee understood from the clinical specialists that no single antipsychotic drug is considered to be more clinically effective than the others, but that tolerability and adverse reactions vary between the treatments. What is the position of the treatment in the pathway of care for the condition? The Committee heard from the clinical specialists that the treatment options for adolescents who develop acute mania include an antipsychotic drugs (such as aripiprazole, risperidone, olanzapine or quetiapine), lithium or valproate. The clinical specialists explained that lithium and valproate are not routinely used as monotherapy for this patient population. Adverse reactions The Committee was aware that extrapyramidal symptoms, somnolence and akathisia were all statistically significantly more common in those receiving aripiprazole compared with those receiving placebo in NCT0010461. It noted there were no statistically significant increases in weight gain or BMI in those receiving aripiprazole compared with those receiving placebo at 4 weeks. The Committee understood that the ERG did not consider that the frequency or nature of adverse events reported in NCT0010461 raised safety concerns about aripiprazole treatment above other antipsychotics. The Committee concluded that current evidence suggests that aripiprazole has an acceptable safety profile compared with placebo for treatment in adolescents aged 13 or older. Evidence for clinical effectiveness Availability, nature and quality of evidence The main clinical-effectiveness evidence came from the NCT00110461 trial with supporting evidence from the NCT00116259. The manufacturer also presented a network meta-analysis based on a network containing aripiprazole, olanzapine, risperidone, quetiapine and placebo. The Committee accepted the results of the network meta-analysis as a reasonable basis for the economic model given the evidence available. Relevance to general clinical practice in the NHS The Committee considered the relevance of the USA-based NCT00110461 trial to UK clinical practice. It discussed whether the population in the trial reflected that seen in UK clinical practice. The Committee concluded that overall the results from the NCT00110461 trial were generalisable to UK clinical practice. Uncertainties generated by the evidence The Committee understood that the EMA had restricted the licence for aripiprazole to adolescents aged 13 or older because of safety concerns in younger people. The Committee noted that the subgroup analysis by age group suggested that there was no change in treatment effect between the age subgroups, but that the younger age group experienced a greater increase in mean weight and BMI changes from baseline at week 12. The Committee was also aware that the subgroup analyses were based on small numbers of people in the groups, which increased the uncertainty in the results. The Committee concluded that evidence of treatment effect should be based on the whole trial population of NCT00110461. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee noted that the subgroup analysis by age group suggested that there was no change in treatment effect between the age subgroups. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that evidence from the NCT00110461 trial demonstrated a reduction in manic symptoms in those receiving aripiprazole for 12 weeks compared with those receiving placebo. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the manufacturer's economic model and the ERG's critique and exploratory analysis. It noted that the ERG considered the manufacturer's model to be transparent, robust, and well structured. The Committee agreed that the model structure was appropriate. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee was aware that the manufacturer's probabilistic sensitivity analyses suggested that there was uncertainty surrounding the ICERs and it understood that this may be a result of the lack of statistically significant differences in response rates obtained from the network meta-analysis for the 4 antipsychotics. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? Not applicable as the Committee had no concerns about the health-related quality-of-life data used in the manufacturer's economic model. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable to this appraisal. What are the key drivers of cost effectiveness? The Committee was aware that the main parameters that influenced the results were the rates of response applied during the treatment phase. The Committee noted that a higher response rate during the treatment phase resulted in people leaving hospital earlier, which had both cost and health-related quality-of-life benefits. Most likely cost-effectiveness estimate (given as an ICER) The Committee noted that the pathway in which aripiprazole was positioned second dominated all of the other strategies. The Committee also noted that the ranges of costs and QALYs (in the base case, costs ranged from £74,133 to £75,066, and QALYs ranged from 2.516 to 2.525) across the strategies were similar. Results from the sensitivity analyses demonstrated that each of the strategies was dominated by every other strategy in at least some of the probabilistic iterations. Additional factors taken into account Patient access schemes (PPRS) Not applicable to this appraisal. End-of-life considerations Not applicable to this appraisal. Equalities considerations and social value judgements No equality issues relevant to the Committee recommendation were raised. # Related NICE guidance Details are correct at the time of publication. Further information is available on the NICE website. Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years. NICE technology appraisal guidance 213 (2011). Bipolar disorder. NICE clinical guideline 38 (2006). Depression in children and young people. NICE clinical guideline 28 (2005). The clinical effectiveness and cost effectiveness of electroconvulsive therapy (ECT) for depressive illness, schizophrenia, catatonia and mania. NICE technology appraisal guidance 59 (2003).# Review of guidance The guidance on this technology will be considered for review in July 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveJuly 2013# Changes after publication January 2014: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0230-9	{'Guidance': 'Aripiprazole is recommended as an option for treating moderate to severe manic episodes in adolescents with bipolar I disorder, within its marketing authorisation (that is, up to 12\xa0weeks of treatment for moderate to severe manic episodes in bipolar I disorder in adolescents aged 13\xa0and older).', 'The technology ': "Aripiprazole (Abilify, Otsuka Pharmaceuticals Europe) is an antipsychotic with partial dopamine D2\xa0and D3\xa0agonistic properties. It has a UK marketing authorisation 'for the treatment up to 12\xa0weeks of moderate to severe manic episodes in bipolar I disorder in adolescents aged 13\xa0and older'. It also has a UK marketing authorisation for the treatment of moderate to severe manic episodes in bipolar\xa0I disorder in adults, and for the prevention of a new manic episode in adults who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment.\n\nAripiprazole is administered orally. The summary of product characteristics states that the recommended dosage for aripiprazole is 10\xa0mg per day administered once daily without regard to meals. It also states that treatment should be initiated at 2\xa0mg (using aripiprazole oral solution 1\xa0mg/ml) for 2\xa0days, and titrated to 5\xa0mg for 2\xa0additional days to reach the recommended daily dose of 10\xa0mg. The summary of product characteristics notes that enhanced efficacy at doses higher than a daily dose of 10\xa0mg has not been demonstrated and that a daily dose of 30\xa0mg is associated with a substantially higher incidence of significant undesirable effects. It states that doses higher than 10\xa0mg/day should therefore only be used in exceptional cases and with close clinical monitoring.\n\nThe summary of product characteristics lists the following adverse reactions specific to adolescents treated with aripiprazole: very common reactions (10% or more) were somnolence (23.0%), extrapyramidal disorder (18.4%), akathisia (16.0%) and fatigue (11.8%); and common reactions (between 1% and 10%) were upper abdominal pain, increased heart rate, increased weight, increased appetite, muscle twitching and dyskinesia. The following undesirable effects had a possible dose–response relationship: extrapyramidal disorder (incidences were: 10\xa0mg dose 9.1%, 30\xa0mg dose 28.8%, placebo 1.7%) and akathisia (incidences were: 10\xa0mg dose 12.1%, 30\xa0mg dose 20.3%, placebo 1.7%). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nAripiprazole is available in 5\xa0mg, 10\xa0mg, 15\xa0mg and 30\xa0mg tablets, as 10\xa0mg and 15\xa0mg orodispersible tablets, and as an oral solution (1\xa0mg/ml). The acquisition cost of aripiprazole 5\xa0mg, 10\xa0mg and 15\xa0mg is £95.74 for 28\xa0tablets. For 30\xa0mg it is £191.47 for 28\xa0tablets, and for oral solution it is £102.57 for 150\xa0ml. Costs exclude VAT and are from the 'British national formulary' (BNF, edition\xa063). For people whose condition responds to aripiprazole, the expected length of a course of treatment is 12\xa0weeks. For a course of 12\xa0weeks (84\xa0days), the 10\xa0mg dose would cost £287.22. This cost would be the same for a 15\xa0mg dose. A course of the 30\xa0mg dose would cost £574.41. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (section\xa08) considered evidence submitted by the manufacturer of aripiprazole and a review of this submission by the Evidence Review Group (ERG; section\xa09).\n\nThe manufacturer presented direct clinical-effectiveness evidence from 2\xa0randomised controlled trials comparing aripiprazole with placebo and performed a meta-analysis of these trials. The manufacturer also presented a network meta-analysis based on a network containing aripiprazole, olanzapine, risperidone, quetiapine and placebo.\n\nThe manufacturer undertook a systematic review to identify published evidence for aripiprazole for the treatment and prevention of acute manic and mixed episodes in children and adolescents with bipolar disorder. The review identified 3\xa0randomised controlled trials (NCT00110461, NCT00194077\xa0and NCT00116259) that investigated aripiprazole in children and adolescents with bipolar disorder. The NCT00194077\xa0trial was excluded because it only included children under the age of 10, a group outside the licensed indication. The manufacturer considered NCT00110461\xa0to be the main evidence for the use of aripiprazole in children and adolescents. The NCT00116259\xa0trial was not discussed in detail because the manufacturer considered it to be a small trial in a specific population of children and adolescents with bipolar disorder (both types I and II) and attention-deficit hyperactive disorder (ADHD). No relevant non-randomised controlled trial evidence for aripiprazole was identified from the systematic review.\n\nNCT00110461\xa0was a multicentre, double-blind, randomised, placebo-controlled clinical trial undertaken across 59\xa0sites in the USA between March\xa02005\xa0and February\xa02007. The study was designed to test the safety and efficacy of 2\xa0doses of aripiprazole in children and adolescents with bipolar\xa0I disorder who experienced manic or mixed episodes with or without psychotic features. There were 296\xa0participants randomised to receive aripiprazole 10\xa0mg/day (n=98), aripiprazole 30\xa0mg/day (n=99) or placebo (n=99). The study duration was 30\xa0weeks with a 4-week acute phase followed by an extension phase of 26\xa0weeks.\n\nParticipants in NCT00110461\xa0were aged between 10\xa0and 17\xa0years with a DSM-IV diagnosis of bipolar\xa0I disorder who were experiencing manic or mixed episodes, with or without psychotic features. Comorbid diagnoses were permitted including ADHD, conduct disorder, oppositional defiant disorder and anxiety disorders. All participants had a baseline Young Mania Rating Scale (YMRS) score of more than 20. Exclusion criteria included bipolar\xa0II disorder, unspecified bipolar disorder and psychosis caused by other medical conditions or concomitant mediations. Participants with learning disabilities and those who were determined by the investigator to be at risk of suicide were also excluded.\n\nIn the NCT00110461\xa0trial, 72% (296/413) of participants screened were enrolled in the study. Participant characteristics at baseline were comparable between the 3\xa0groups in the trial. Approximately 63% of participants were aged 13\xa0or over and fell within the licensed population. In response to a clarification request, the manufacturer provided post-hoc data on the proportion of participants in mixed and manic states at baseline and on the proportion of 'rapid cyclers' (participants who experienced 4\xa0or more manic, hypomanic or mixed episodes in the previous year). In both cases the proportions were relatively similar between the groups.\n\nThe primary outcome in NCT00110461\xa0was the change from baseline to week\xa04\xa0on the YMRS total score. Secondary outcomes were changes from baseline scores in the Children's Global Assessment Scale (CGAS), Clinical Global Impressions Scale-Bipolar Version (CGI-BP) severity scores for mania, depression and overall bipolar illness, Children's Depression Rating Scale - Revised (CDRS-R) score, General Behaviour Inventory Scale (GBI) score and Attention-Deficit Hyperactivity Disorders Rating Scale (ADHD-RS-IV) score. A YMRS response rate was based on a responder definition of a 50% or more reduction from the YMRS total score at baseline.\n\nIn the NCT00110461\xa0trial, both aripiprazole doses demonstrated statistically significant improvements over placebo in the YMRS total score at week\xa04, with treatment differences from placebo of −5.99\xa0(95%\xa0confidence interval −8.49\xa0to −3.50; p<0.0001) for the aripiprazole 10\xa0mg group, and −8.26\xa0(95%\xa0CI −10.7\xa0to −5.77; p<0.0001) for the aripiprazole 30\xa0mg group. Statistically significant improvements in YMRS total score were demonstrated at week\xa01\xa0for both aripiprazole doses, and were maintained until week\xa030. At week\xa030, the treatment difference in YMRS total score from placebo for the aripiprazole 10\xa0mg dose was −5.89\xa0(95%\xa0CI −8.70\xa0to −3.08), and for the aripiprazole 30\xa0mg dose it was −6.73\xa0(95%\xa0CI −9.53\xa0to −3.94). The YMRS responder rates were also significantly higher in the aripiprazole arms than in the placebo arm at week\xa04\xa0and week\xa030.\n\nBoth aripiprazole doses demonstrated significant improvements at week\xa04\xa0compared with baseline in the secondary end points: CGAS core, CGI-BP severity scores for mania, depression and overall bipolar illness, GBI – parent/guardian version and subject version mania total score, and the ADHD-RS-IV total score. Significant differences were not observed at week\xa04\xa0in the CGI-BP severity scores for depression, GBI – patient depression total scores or the CDRS-R score. A significant difference was observed in the 10\xa0mg aripiprazole arm for the GBI-parent/guardian version for depression (p=\xa00.0430) but not in the 30\xa0mg arm.\n\nThe manufacturer presented results from a post-hoc subgroup analysis based on the change in YMRS score from baseline calculated using both the observed case dataset and the last observation carried forward dataset for age subgroups (10–12, and 13–17\xa0years). Results from the last observation carried forward data showed that participants receiving aripiprazole in both age groups had a statistically significant change in YMRS score from baseline at both weeks 4\xa0and 12\xa0compared with those receiving placebo. Using the observed case dataset, there was a statistically significant change in YMRS score in participants receiving aripiprazole in both age groups at week\xa04; however by week\xa012,\xa0although the change in YRMS score was still greater in participants receiving aripiprazole compared with those receiving placebo, this was not statistically significant.\n\nAt the end of the acute phase of the trial (4\xa0weeks) the proportion of participants not completing the trial was 14.3% in the aripiprazole 10\xa0mg group, 22.2% in the aripiprazole 30\xa0mg group and 23.2% in the placebo group. At 30\xa0weeks the drop-out rates were 65.3% in the aripiprazole 10\xa0mg group, 77.7% in the aripiprazole 30\xa0mg group and 87.9% in the placebo group. The manufacturer noted the statement in the Committee for Medicinal Products for Human Use (CHMP) assessment report that results based on the observed case analysis dataset failed to show statistical significance for aripiprazole compared with placebo for both doses on all analysed efficacy end points at week\xa012. The manufacturer stated that the lack of statistically significant differences between aripiprazole and placebo at week\xa012\xa0along with the high discontinuation rate resulted in the CHMP restricting the treatment length with aripiprazole to 12\xa0weeks.\n\nThe manufacturer also carried out a post-hoc subgroup analysis to investigate if the efficacy of aripiprazole was influenced by the presence or absence of ADHD symptoms. Results presented in 3\xa0age subgroups (10–12, 13–14, and 15–17\xa0years) suggested no change in the treatment effect.\n\nIn NCT00110461, health-related quality of life was measured by the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q). The manufacturer reported that although the results did not reach statistical significance, both aripiprazole arms demonstrated a trend for improvement relative to placebo.\n\nThe manufacturer presented adverse events occurring in more than 5% of any group in NCT00110461\xa0over the acute phase and over the full trial duration. There were no deaths or suicides in the study. The manufacturer acknowledged that somnolence and extrapyramidal symptoms occurred more frequently in the aripiprazole arms than in the placebo group. In the acute phase (up to 4\xa0weeks) extrapyramidal disorder occurred in 12.2% (12/98) of the aripiprazole 10\xa0mg group, 27.3% (27/99) of the aripiprazole 30\xa0mg group and 3.1% (3/97) of the placebo group. In the acute phase (up to 4\xa0weeks) somnolence occurred in 19.4% (19/98) of the aripiprazole 10\xa0mg group, 26.3% (26/99) of the aripiprazole 30\xa0mg group and 3.1% (3/97) of the placebo group. In the acute phase (up to 4\xa0weeks) akathisia occurred in 8.2% (8/98) of the aripiprazole 10\xa0mg group, 11.1% (11/99) of the aripiprazole 30\xa0mg group and 2.1% (2/97) of the placebo group. The manufacturer concluded that most of the adverse events occurred in the acute phase of the study and were mild to moderate in severity, and therefore were expected to be manageable.\n\nThe manufacturer presented changes in baseline metabolic parameters at 4\xa0and 30\xa0weeks. Differences in the treatment groups between the incidence of clinically significant weight gain (7% or more weight gain compared with baseline) and change from baseline body mass index (BMI) were not statistically significant at week\xa04. Data on the incidence of clinically significant weight gain at 30\xa0weeks was considered to be academic in confidence by the manufacturer and therefore cannot be reported in this document. There were no differences between the treatment groups in the proportion of participants with a BMI on or above the 95th percentile for age and sex at week\xa04. Data on the proportion of participants with a BMI on or above the 95th percentile at week\xa030\xa0was considered to be academic in confidence.\n\nThe manufacturer noted that the CHMP limited the indication for aripiprazole to adolescents aged 13\xa0and over as a result of safety concerns in younger people. The manufacturer reported results from a post-hoc subgroup analysis to assess the safety profile across age subgroups (10–12\xa0years, and 13–17\xa0years). In the 10–12\xa0years subgroup there were statistically significant increases in mean weight and BMI changes from baseline in the aripiprazole 30\xa0mg treatment arm at weeks 4\xa0and 12. There were also statistically significant increases in weight and BMI measurements in the aripiprazole 10\xa0mg treatment arm at week\xa012\xa0using the last observation carried forward analysis for the 10–12\xa0years subgroup.\n\nThe NCT00116259\xa0trial was a double-blind randomised placebo-controlled clinical trial undertaken in Brazil. There were 43\xa0participants who were randomised to receive aripiprazole 20\xa0mg per day (n=18) or placebo (n=25). The study duration was 6\xa0weeks. Participants were aged between 8\xa0and 17\xa0years with a DSM-IV diagnosis of bipolar\xa0I or II disorder, comorbid with DSM-IV ADHD. All participants were in an acutely manic or mixed state defined as a YMRS score of more than 20\xa0at the baseline visit. Exclusion criteria included learning disabilities and severe risk of suicide.\n\nResults from NCT00116259\xa0showed that participants receiving aripiprazole had a statistically significantly larger reduction in YMRS total scores from baseline to week\xa06\xa0than participants receiving placebo (−27.22\xa0versus −19.52, p=0.02). A greater proportion of participants on aripiprazole compared with placebo experienced a response (88.9% versus 52%, p=0.02; number needed to treat [NNT] =2.70) and experienced remission (72% versus 32%, p=0.01; NNT=2.50).\n\nThe manufacturer presented a meta-analysis of NCT00110461\xa0(pooled 10\xa0mg per day and 30\xa0mg per day) and NCT00116259\xa0(20\xa0mg per day). Results from the meta-analysis indicated that aripiprazole was statistically significantly superior to placebo in inducing symptomatic response (as measured as a 50% or more change in YMRS score) at weeks 1, 2\xa0and 4, but not at week\xa03. Also, results from the meta-analysis showed aripiprazole to be associated with a statistically significant higher rate of extrapyramidal symptoms than placebo, but not of somnolence. The manufacturer commented that the meta-analysis was performed to be transparent rather than to provide meaningful results. The manufacturer stated that the results should be treated with caution because the information from the NCT00116259\xa0trial is limited by the small trial size and the different population compared with NCT00110461\xa0(that is, it included people with bipolar\xa0II disorder and was restricted to participants with comorbid ADHD).\n\nAs there are no head-to-head trials comparing aripiprazole with the comparators specified in the final scope issued by NICE, the manufacturer presented a network meta-analysis to determine the relative efficacy of the treatments using placebo as the common comparator. Five randomised controlled trials were identified in addition to the 2\xa0studies including aripiprazole (NCT00110461\xa0and NCT00116259). The 5\xa0studies were as follows: 3\xa0studies for risperidone (risperidone compared with placebo, risperidone compared with divalproex sodium [valproate semisodium] and risperidone compared with divalproex sodium and lithium), 1\xa0study for quetiapine (quetiapine compared with placebo), and 1\xa0study for olanzapine (olanzapine compared with placebo). The network meta-analysis included NCT00110461, one\xa0of the studies for risperidone (risperidone compared with placebo), and the studies for quetiapine and olanzapine (both compared with placebo). The manufacturer undertook a sensitivity analysis in which the NCT00116259\xa0trial and the remaining 2\xa0studies for risperidone (risperidone compared with lithium and divalproex sodium) were also included.\n\nThe network analysis used a fixed-effects Bayesian model, because the manufacturer considered there was not enough evidence to support the estimation of a random-effects model. Results from studies that included treatment groups with different intervention doses were pooled to provide an average treatment dose effect. Efficacy outcomes considered in the network meta-analysis were the YMRS response rates at weeks 1, 2\xa0and 3, and discontinuation at week\xa03. Analyses were also conducted for the following safety outcomes: extrapyramidal symptoms, clinically significant weight gain, clinically significant increase in prolactin and somnolence.\n\nThe manufacturer presented results from the network meta-analysis as relative risks using placebo and aripiprazole (pooled dose) as references. These results indicated that all the antipsychotics considered (aripiprazole, risperidone, quetiapine and olanzapine) were statistically more effective than placebo at achieving YMRS response at weeks 1–3. The results also indicated that there were no statistically significant differences in YMRS response rates at weeks 1–3\xa0between the antipsychotics. No statistically significant differences were found for discontinuation of treatment at week\xa03\xa0between the interventions considered in the network.\n\nParticipants receiving aripiprazole were found to be statistically significantly more likely to experience extrapyramidal symptoms than those receiving placebo. They were also more likely to experience them than participants receiving risperidone and quetiapine, but these differences were not statistically significant. There was no statistically significant difference between aripiprazole and placebo in the risk of experiencing a clinically significant increase in weight. Aripiprazole (pooled dose) was statistically significantly less likely to cause clinically significant weight gain than olanzapine and quetiapine. Participants receiving aripiprazole were less likely to experience a clinically significant increase in prolactin than those on olanzapine, risperidone or quetiapine. Participants receiving aripiprazole were found to be statistically significantly more likely to experience somnolence than those receiving placebo. They were also more likely to experience somnolence than participants receiving risperidone and quetiapine, but this was not statistically significant.\n\n# Cost effectiveness\n\nThe manufacturer undertook a systematic review to identify relevant cost-effectiveness or cost–utility studies. No economic evaluations were identified for the treatment of bipolar I disorder in children and adolescents. The manufacturer developed a de novo economic model to assess the cost effectiveness of aripiprazole compared with the other antipsychotics. The population in the economic evaluation was adolescents with manic episodes of bipolar\xa0I disorder between 13\xa0and 17\xa0years as specified in the marketing authorisation. The age of onset used in the model was 15\xa0years and the time horizon was until the person reached adulthood at 18\xa0years.\n\nThe cost-effectiveness model presented by the manufacturer was a Markov cohort model with a weekly cycle length. The treatment pathway in the model was based on a sequence of up to 4\xa0treatment lines. The first 3\xa0related to treatment with an antipsychotic drug and the fourth included lithium treatment for participants whose condition was resistant to previous therapy. The antipsychotic treatment lines were identical in structure and each contained an acute phase of 3\xa0weeks of inpatient treatment, a sub-acute phase of up to 5\xa0weeks of inpatient treatment for participants who experienced a response, a maintenance phase of outpatient treatment for an average of 4\xa0weeks, and then withdrawal of treatment. The 'therapy resistance' phase contained up to 5\xa0weeks inpatient lithium treatment, followed by outpatient lithium treatment and a maintenance phase similar to that in the antipsychotic lines for participants who experienced a response.\n\nParticipants entered the model at the start of the first treatment line. They moved to the next treatment line if they discontinued treatment before response during the acute phase, if they did not respond to current treatment by the end of week 3, or if they relapsed before discharge from hospital. If participants relapsed within the maintenance phase they remained on the same treatment line to which they had responded. If participants did not respond to 3\xa0lines of antipsychotic treatment they entered the 'therapy resistance' treatment line. If participants relapsed on 'therapy resistance' treatment they returned to the inpatient lithium treatment (that is the 'therapy resistance' hospitalised state). The modelling of adverse events was included in the treatment-related health states. Participants could also die in any health state in the model.\n\nBased on clinical opinion, the manufacturer specified the treatment sequence of risperidone, quetiapine and olanzapine to represent usual care (labelled strategy\xa01\xa0in the model). The manufacturer considered either quetiapine or olanzapine could be replaced by aripiprazole. For the base-case analyses, olanzapine was replaced with aripiprazole and the position of aripiprazole in the treatment sequences was varied, giving 4\xa0different strategies:\n\nStrategy 1: risperidone, quetiapine, olanzapine.\n\nStrategy 2: risperidone, aripiprazole, quetiapine.\n\nStrategy 3: aripiprazole, risperidone, quetiapine.\n\nStrategy 4: risperidone, quetiapine, aripiprazole.\n\nClinical data for the effectiveness for each antipsychotic in the 3‑week acute phase were taken from the results of the network meta-analysis based on pooled dose levels. It was assumed the effectiveness of each antipsychotic intervention was not influenced by its position in the treatment pathway and that the treatment was at a constant dose. Beyond the acute phase, it was assumed that all antipsychotics were equally effective and the common weekly relapse value was based on expert opinion. The manufacturer also assumed an identical mortality rate for all the antipsychotic interventions, based on UK life tables adjusted to reflect the higher rates of mortality observed among participants with bipolar disorder.\n\nThe model included 3\xa0adverse events: extrapyramidal symptoms, somnolence and weight gain. Data for the incidence of these events were based on the results of the network meta-analysis. There were no available data for the incidence of extrapyramidal symptoms or somnolence associated with olanzapine treatment, and so these values were set equal to the lowest incidence of the other antipsychotics.\n\nThe health-related quality of life data collected in NCT00110461\xa0were not based on a preference-based measure. As a result of a lack of available data, for preference-based utility values from bipolar disorder in adolescents, the manufacturer based the utilities in the model on published data from adult populations with bipolar disorder. For the main analysis, the utility values for the bipolar health states were based on EQ-5D data from a study of an adult UK population with bipolar\xa0I disorder. A multiplicative model for the utility values was used to take into account the demographic (age and sex) of the population from which the utility was calculated. The calculated multipliers were then applied to an appropriate general population utility value for the adolescent population in the model. The utility values were also further adjusted according to hospitalisation status, adverse events and the ageing of the cohort. The utility value for weight gain was taken from a cohort of children who are overweight or obese and the utility values for somnolence and extrapyramidal symptoms came from participants with schizophrenia.\n\nIn the economic model in-hospital costs were based on NHS reference costs 2010/1155\xa0(code MHIPC1; NHS Trusts Mental Health Inpatients – Children). This cost was assumed to include costs relating to adverse events, but not the cost of antipsychotic treatments. Outpatient resource use was based on expert opinion, with costs taken from the Personal Social Services Research Unit. Non-propriety costs were used for each of the antipsychotics apart from aripiprazole. The base case was based on the pooled dose efficacy and safety results and so an average dose cost was used.\n\nIn the base case, the cost-effectiveness results were similar for the 4\xa0strategies. The use of aripiprazole at any point in the treatment pathway dominated usual care (that is, was more effective and less costly), which had the highest total cost (£75,066) and the lowest total quality-adjusted life years (QALYs) (2.516). Aripiprazole used as second-line therapy after risperidone had the lowest total cost (£74,133) and the highest total QALYs (2.525) and dominated the other base-case strategies.\n\nThe manufacturer undertook a wide range of univariate sensitivity analyses and identified the rates of response applied during the acute treatment phase as the main parameters that influenced the cost-effectiveness estimates of the strategies. The manufacturer noted that this was expected because the response rates were varied by ±30%, and the differences in the base-case response rates between the 4\xa0antipsychotic treatments considered were not substantial. Scatterplots from probabilistic sensitivity analysis were also presented in the submission. From these results the manufacturer noted that there was some uncertainty surrounding the cost-effectiveness results, but that for all 3\xa0strategies containing aripiprazole, the majority of probabilistic sensitivity analysis iterations indicated cost effectiveness or dominance.\n\nThe manufacturer presented various\xa0scenario analyses in its submission and in response to a clarification request. These included:\n\nUsing 10\xa0mg aripiprazole rather than a pooled dose.\n\nUsing results from the network meta-analysis sensitivity analysis based on all trials identified in the manufacturer's review.\n\nSwapping the position of quetiapine and olanzapine in the base-case treatment strategy.\n\nUsing utility values from a different source.\n\nChanging the starting age of participants to 13\xa0years and 17\xa0years.\n\nReducing treatment efficacy between lines 1\xa0and 2\xa0and between lines 2\xa0and 3.\n\nIncluding the cost of drug-related adverse events in the model.\n\nExtending the acute and euthymic treated phases of the model. None of these scenarios produced results that differed greatly from the base case, and use of aripiprazole in the treatment pathway always dominated usual care.\n\n# Evidence Review Group comments\n\nThe ERG noted that the searches in the manufacturer's submission were limited to January\xa02012\xa0and requested that the manufacturer update them. As a result of time constraints the manufacturer provided results from a non-systematic approach and identified 3\xa0further trials. The ERG repeated and updated the searches until January\xa02013. The ERG found 3\xa0studies not identified by the manufacturer, but none of them were phase\xa0III randomised controlled trials.\n\nThe ERG considered that the NCT0011461\xa0trial was of reasonable methodological quality, and measured a range of outcomes that are relevant to the decision problem. However, the ERG expressed concern that the trial population described in the manufacturer's submission is not likely to represent the UK clinical population:\n\nClinical advisers to the ERG considered that the age of the population in the trial was much younger than that seen in UK clinical practice.\n\nClinical advisers also raised concerns about the high proportion of participants in the trial with comorbid ADHD.\n\nThe ERG considered it likely that many of the participants in the trials were treated as outpatients, which does not reflect current UK practice for this population.\n\nThe ERG commented that excluding from the trial participants who were at risk of suicide may have resulted in the trial population having less severe disease than those presenting in UK clinical practice. The ERG noted the manufacturer's acknowledgement that the inclusion and exclusion criteria for NCT0011461\xa0could have reduced the external validity of the trial population. It also noted that no information was presented on the duration or maintenance of effect after 12\xa0weeks of treatment with aripiprazole.\n\nThe ERG noted the advice in the European Medicines Agency (EMA) guidance for clinical investigation of bipolar disorder, that the occurrence of switching to depression should be investigated. In response to a clarification request, the manufacturer provided depression outcomes at weeks 4\xa0and 30\xa0using the CGI-BP severity depression score, the CDRS-R score, the GBI total score – parent/guardian (depression), and the GBI total scores – patient (depression) score. The ERG considered that although the data presented did not raise concerns about the occurrence of depression associated with aripiprazole treatment, the effect of aripiprazole on depression was not explored in depth in the submission.\n\nThe ERG stated that the key clinical evidence for this appraisal came from the network meta-analysis. The ERG noted that relevant placebo-controlled trials of the antipsychotic comparators were used for the indirect comparison. The ERG agreed with the manufacturer that the NCT00116259\xa0trial should be excluded from the base case because of the different participant population. The ERG also agreed that excluding the study comparing risperidone with lithium and divalproex sodium was appropriate. The ERG did not consider it appropriate for the study comparing risperidone with divalproex sodium to be excluded but acknowledged that including this study would have little impact on the conclusions from the network meta-analysis.\n\nThe ERG questioned the pooling of doses from treatment arms with multiple doses in the network meta-analysis because it considered that different doses are associated with different efficacies and side effects. The manufacturer was requested to conduct a network meta-analysis with doses from multiple treatment arms separated, but was unable to do so in the time available. The ERG considered that caution should be used when interpreting the results from the network meta-analysis based on pooled interventions from multiple treatment arms.\n\nThe ERG considered that a random-effects model was more appropriate for the network meta-analysis than the fixed-effects model used by the manufacturer because of the heterogeneity between the trials. The ERG undertook the network meta-analysis using a random-effects model, and obtained similar results to those from the fixed-effects model; although in all cases the 95% credible intervals were wider, reflecting the increased uncertainty.\n\nIn general the ERG was satisfied that the economic evidence submitted by the manufacturer does not represent a biased assessment of the cost effectiveness of aripiprazole. The ERG considered the manufacturer's model to be robust and transparent and well structured, allowing for analysis of uncertainty in the model inputs.\n\nThe ERG explored the manufacturer's probabilistic sensitivity analysis. The ERG noted that all changes in the total costs and QALYS between the deterministic and mean probabilistic sensitivity analysis results were less than 0.1% of the deterministic value. Although second-line aripiprazole (strategy 2) dominated all the other strategies in the deterministic analysis and mean probabilistic sensitivity analysis results, the probabilistic 95% confidence intervals included the possibility of each strategy dominating this strategy. The ERG summarised the results to show that the strategy that excludes aripiprazole (strategy 1) was dominated by each of the other strategies in over half of the probabilistic sensitivity analysis results: strategy 2\xa0dominated strategy 1\xa0in 72.1% of iterations, strategy 3\xa0dominated strategy 1\xa0in 54.4% of iterations, and strategy 4\xa0dominated strategy 1\xa0in 57.2% of iterations. The cost-effectiveness acceptability curve indicated that the probability that strategy 1\xa0is cost effective is roughly half that of the probabilities for strategy 2\xa0or strategy 3\xa0for all the thresholds explored.\n\nThe ERG highlighted that its clinical advisers and those of the manufacturer stressed the importance of tailoring the treatment sequence to reflect an individual's needs (based on factors such as severity of symptoms, side-effect profile and comorbidities). As there are limited data available to model treatment within subgroups, the ERG conducted an exploratory scenario analysis to assess the possible implications of treatment sequences tailored to reflect an individual's needs. The results showed that only small changes in the modelled results for each treatment sequence were needed for the incremental cost-effectiveness ratio (ICER) for that strategy to be £20,000\xa0or £30,000\xa0per QALY gained. The ERG stated that these results suggest that the actual place of aripiprazole within a treatment sequence is likely to depend on individual circumstances.\n\nThe ERG explored the potential implications of 2\xa0different treatment durations for aripiprazole: 1\xa0use reflected its licensed duration of a maximum of 12\xa0weeks, the other reflected clinical opinion of its real-life use based on an average of 12\xa0months. The ERG amended the manufacturer's model to have maximum treatment duration (for all antipsychotics) of 12\xa0weeks. Responding to a request, the manufacturer provided an amended version of its model to have an average of 12\xa0months of antipsychotic treatment. The ERG considered that although total costs and total QALYs showed a reduction in both of the 2\xa0new models, the substantive conclusions of the manufacturer's base case analysis remained unchanged.\n\nThe ERG considered that a treatment sequence containing all 4\xa0antipsychotics was appropriate. Clinical advisers to the ERG stated that if a person's condition had not responded to the first 3\xa0antipsychotic interventions, clinicians would generally try the remaining antipsychotic rather than conclude that a person's condition was treatment resistant. It was not possible to evaluate this scenario within the time frame of the clarification process. The ERG stated that there is no evidence to suggest that a 4-line treatment sequence would substantially alter the conclusions.\n\nThe ERG made the following changes to the model to explore the plausibility of the manufacturer's results:\n\nit used network meta-analysis results from a random-effects model\n\nit included a half-cycle correction\n\nit adjusted the discounting formula used\n\nit amended the mortality rate calculations\n\nit included a 10% reduction in efficacy between lines 1\xa0and 2, and 15% between lines 2\xa0and 3\n\nit included a logical constraint on the probabilistic sensitivity analysis inputs so that week\xa03\xa0probability of discontinuing or responding did not exceed 100%. These amendments were incorporated into a 'licensed duration' model, which reflected the maximum 12\xa0week duration specified in the marketing authorisation, and into a 'real-world' model, which assumed 4\xa0weeks of acute treatment and 12\xa0months of euthymic treatment.\n\nThe deterministic and probabilistic cost-effectiveness results from both models were similar to those obtained in the manufacturer's base-case model:\n\nThe probabilistic sensitivity analysis results from the 'licensed duration' model indicated that the use of aripiprazole at any point in the treatment pathway dominated usual care, which had the highest total cost (£72,157) and the lowest total QALYs (2.458). Aripiprazole used as second-line therapy after risperidone had the lowest total cost (£70,707) and the highest total QALYs (2.471).\n\nThe probabilistic sensitivity analysis results from the 'real-world' model indicated that aripiprazole used as first-line therapy had the highest total cost (£63,384) and the lowest total QALYs (2.428). Aripiprazole used as second-line therapy had the lowest total cost (£62,138) and the highest total QALYs (2.429).\n\nThe ERG also explored the impact on the cost effectiveness of the amendments (described in section 3.45) separately, and concluded that the key drivers to changes in the cost-effectiveness results were the extension of treatment duration either to 4\xa0weeks acute treatment or 12\xa0months of euthymic treatment.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aripiprazole, having considered evidence on the nature of acute manic episodes in bipolar\xa0I disorder in adolescents and the value placed on the benefits of aripiprazole by people with the condition, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the nature of acute manic episodes in bipolar\xa0I disorder. The clinical specialists explained that acute manic episodes can have a large impact on adolescents and their families. Symptoms of mania may include poor concentration, little need for sleep, poor temper control, irritability, reckless behaviour and lack of self-control. For adolescents, the symptoms may impact on schooling, work and social life. The impact on families may include sleep deprivation, financial pressures and family wellbeing. The Committee heard that there is often a need to resolve the manic episode quickly so that adolescents can return to normal functioning in terms of schooling, work and family life.\n\nThe Committee discussed current standard clinical management of manic episodes in bipolar\xa0I disorder in adolescents. The clinical specialists highlighted that the main aim of treatment is to maximise control of the mania and minimise the adverse reactions to treatment that are most troublesome for each individual. The Committee heard from the clinical specialists that drug treatment options for adolescents who develop acute mania include antipsychotic drugs such as aripiprazole, risperidone, olanzapine or quetiapine. The clinical specialists explained that lithium is associated with a range of practical limitations, including the need for pre- and post-treatment blood tests, a narrow therapeutic range, and significant adverse effects. The clinical specialists further explained that although lithium can be prescribed as a monotherapy, it is usually prescribed in combination with antipsychotics. They also highlighted that valproate is rarely used as a monotherapy and is usually not given to women of childbearing age because of fetal malformation risks during pregnancy and risk of polycystic ovary syndrome.\n\nThe clinical specialists confirmed that in UK clinical practice, the routinely prescribed antipsychotics for this indication are olanzapine, aripiprazole, risperidone and quetiapine, and they acknowledged that all are prescribed off-label for the adolescent population (except aripiprazole, which received its marketing authorisation for this indication in January 2013). The Committee was aware that NICE clinical guideline\xa038 on bipolar disorder recommends following the recommendations for adults with bipolar disorder when prescribing medication for adolescents with acute manic episodes, except that drugs should be started at lower doses. The Committee understood from the clinical specialists that no single antipsychotic drug is considered to be more clinically effective than the others, but that tolerability and adverse reactions vary between the treatments. The Committee heard from the clinical specialists that there is substantial variation between the antipsychotics in the adverse reactions associated with each treatment including weight gain, hyperprolactinaemia and sexual dysfunction, aggression, and akathisia or extrapyramidal symptoms. The clinical specialists explained that it is important for adolescents with moderate to severe manic episodes to have a range of treatment options available. This is in order to individualise treatment and to minimise adverse treatment effects, as adolescents are often less tolerant of adverse reactions than adults, leading to problems with adherence to medication.\n\nThe Committee discussed the manufacturer's decision problem, noting that the manufacturer had excluded lithium and valproate as comparators even though they were specified in the final scope issued by NICE. The Committee noted the comments from the manufacturer, ERG and the clinical specialists highlighting that lithium and valproate monotherapy are rarely used in UK clinical practice. The Committee accepted that these 2\xa0treatments are rarely used as monotherapy and agreed that it was appropriate to consider only risperidone, olanzapine and quetiapine as the comparators, as listed in the manufacturer's decision problem.\n\n# Clinical effectiveness\n\nThe Committee considered the relevance of the USA-based NCT00110461\xa0trial to UK clinical practice. It discussed whether the population in the trial reflected that seen in UK clinical practice. The Committee noted that the trial recruited people who were aged between 10\xa0and 17\xa0years and that approximately 63% of the trial participants were aged 13\xa0or older, and so were within the UK marketing authorisation. The Committee heard from the clinical specialists that the diagnosis criteria for bipolar\xa0I disorder in children and adolescents in the UK differed from those used in the USA and it is likely that some of the participants with bipolar\xa0I disorder comorbid with ADHD in the trial would not have been diagnosed with bipolar\xa0I disorder in the UK. The clinical specialists also confirmed that it was usual in clinical trials involving children and adolescents with bipolar\xa0I disorder to exclude people with learning disabilities and those at risk of suicide. The Committee discussed the concerns raised by the ERG that most of the participants recruited to the trial were treated as outpatients, whereas in UK clinical practice, they would be usually treated as inpatients. The Committee heard from the clinical specialists that a significant proportion of people in the NHS are managed as outpatients, especially outside the major cities where there is often limited availability of inpatient facilities for this age group. The Committee concluded that the results from the NCT00110461\xa0trial were generalisable to UK clinical practice.\n\nThe Committee then considered the clinical-effectiveness results of the NCT00110461\xa0trial, which showed that aripiprazole was associated with a statistically significant reduction in total YMRS score when compared with placebo throughout the 30-week study duration based on the last observation carried forward dataset. The Committee understood that the marketing authorisation is restricted to 12\xa0weeks' treatment because of high discontinuation rates and the lack of a statistically significant difference in efficacy outcomes beyond 12\xa0weeks when the analysis was based on the observed case dataset. The Committee discussed the usefulness of the YMRS score as the primary outcome and heard from the clinical specialists that this score is a well-recognised tool used in clinical trials for assessing symptoms of mania but that the tool is not routinely used by all clinicians in the UK. The clinical specialists explained that any changes in the YMRS are clearly evident in the change in severity of the symptoms of the individual. The Committee accepted that the YMRS is a valid tool for measuring the severity of symptoms of mania. It concluded that evidence from the trial demonstrated a reduction in manic symptoms in those receiving aripiprazole for 12\xa0weeks compared with those receiving placebo.\n\nThe Committee considered the adverse event data from the NCT00110461\xa0trial. Extrapyramidal disorder and somnolence were statistically significantly more common in those receiving either 10\xa0mg or 30\xa0mg aripiprazole compared with those receiving placebo. Akathisia was statistically significantly more common, but only in those receiving the 30\xa0mg dose of aripiprazole compared with those receiving placebo. It noted there were no statistically significant increases in weight gain or BMI in those receiving aripiprazole compared with those receiving placebo at 4\xa0weeks. The Committee heard from the clinical specialists that the patterns of adverse events seen in the trial were consistent with the use of aripiprazole in other indications. The clinical specialists also stated that for this group, in the short term, somnolence may help in the management of acute mania. The Committee noted the lack of long-term safety data for aripiprazole, but was aware that the risk management plan agreed with the EMA included a long-term (up to 2\xa0years) study to evaluate the safety and tolerability of aripiprazole as maintenance treatment in adolescents with schizophrenia, and children and adolescents with bipolar disorder. The Committee concluded that current evidence suggests that the tolerability and range of adverse reactions associated with aripiprazole are acceptable. The Committee was aware that the population in the NCT00110461\xa0trial was broader than that in the UK marketing authorisation, because the trial included children aged younger than 13\xa0years and those with mixed episodes. The Committee understood that the EMA had restricted the licence for aripiprazole to adolescents aged 13\xa0or older because of safety concerns in younger people. The Committee noted that the manufacturer had presented clinical efficacy and safety results in its submission by age group, that is, for ages 10–12\xa0years and 13–17\xa0years. The Committee noted that the subgroup analysis by age group suggested that there was no change in treatment effect between the age subgroups, but that the younger age group experienced a greater increase in mean weight and BMI changes from baseline at week\xa012. The Committee noted that the manufacturer provided baseline data on the current episode type (manic or mixed) but a subgroup analysis by age group and episode type was not presented. The Committee understood that these subgroups were post hoc subgroups. It was also aware that the subgroup analyses were based on small numbers of people in the groups, which increased the uncertainty in the results. The Committee therefore concluded that evidence of treatment effect should be based on the whole trial population of NCT00110461.\n\nThe Committee noted that there were no head-to-head comparisons of aripiprazole with the other comparator antipsychotics. The Committee considered the manufacturer's approach to conducting a network meta-analysis to determine the relative efficacy and tolerability of aripiprazole, risperidone, olanzapine and quetiapine. The Committee noted and accepted the ERG's concerns about the network meta-analysis (see sections\xa03.37–3.39). The Committee was aware that using a random-effects model in the network meta-analysis as suggested by the ERG produced results similar to those obtained by the manufacturer. The Committee therefore accepted the results of the network meta-analysis as a reasonable basis for the economic model given the evidence available.\n\nThe Committee considered the clinical effectiveness evidence of aripiprazole compared with risperidone, olanzapine and quetiapine obtained from the network meta-analysis. It noted that the results suggested that aripiprazole and the other antipsychotics showed greater efficacy than placebo but that no statistically significant differences in efficacy were found between aripiprazole and the other antipsychotics. It then considered the adverse-event profile of aripiprazole compared with risperidone, olanzapine and quetiapine. It was aware that the results suggested that the extrapyramidal symptoms and somnolence occurred more frequently with aripiprazole than with risperidone or quetiapine but that these results were not statistically significant. The Committee also noted that the results suggested that clinically significant weight gain was statistically significantly less likely with aripiprazole than with olanzapine or quetiapine. The Committee was aware of the testimony from the clinical specialists about the importance of having a range of treatments available in order to individualise treatment, minimise adverse treatment effects and therefore increase adherence to medication. The Committee heard from the clinical specialists that avoiding weight gain may be of considerable importance to adolescents. The Committee concluded that based on the evidence available, aripiprazole was as effective as other antipsychotics for treating acute mania and had a comparable and acceptable adverse reaction profile.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model and the ERG's critique and exploratory analysis. It noted that the ERG considered the manufacturer's model to be transparent, robust, and well structured. The Committee agreed that the model structure was appropriate.\n\nThe Committee considered the manufacturer's base case in which strategies with aripiprazole used at any stage of the treatment pathway (that is, strategies 2\xa0to 4) were compared with a treatment strategy without aripiprazole (strategy\xa01). The Committee noted that the manufacturer had undertaken a number of deterministic sensitivity analyses (see section\xa03.32). The Committee was aware that the main parameters that could make the strategies including aripiprazole become less cost effective were the rates of response applied during the treatment phase. The Committee noted that a higher response rate during the treatment phase resulted in people leaving hospital earlier, which had both cost and health-related quality-of-life benefits. The Committee was also aware that the manufacturer's probabilistic sensitivity analyses suggested that there was uncertainty surrounding the ICERs and it understood that this may be a result of the lack of statistically significant differences in response rates obtained from the network meta-analysis for the 4\xa0antipsychotics. The Committee noted that the results from the manufacturer's probabilistic sensitivity analyses indicated that for the 3\xa0strategies that include aripiprazole, the majority of the probabilistic sensitivity iterations indicated cost effectiveness or dominance. The Committee therefore agreed that the base-case results suggested that a treatment strategy that includes aripiprazole is a cost-effective option when compared with a treatment strategy without it.\n\nThe Committee then considered the impact of the position of aripiprazole within the treatment pathway on the cost effectiveness results. The Committee discussed the results of the manufacturer's base case as presented in the incremental analysis. The Committee noted that the pathway in which aripiprazole was positioned second, that is strategy\xa02, dominated all of the other strategies. The Committee also noted that a comparison of the ranges of costs and QALYs (in the base case, costs ranged from £74,133 to £75,066, and QALYs ranged from 2.516 to 2.525) across the strategies showed that they were similar. The Committee noted that the treatment pathway without aripiprazole (strategy\xa01) was dominated by each of the other treatment pathways including aripiprazole in over half of the probabilistic sensitivity analysis iterations, and that the probability of strategy\xa01\xa0being the most cost-effective strategy was half the probabilities for strategy\xa02\xa0and strategy\xa03\xa0for all of the thresholds explored by the ERG (see section\xa03.41). Given that each of the strategies was dominated by every other strategy in at least some of the probabilistic iterations, the Committee agreed that the results were not sufficiently robust to make a recommendation on the position of aripiprazole in the treatment pathway. The Committee concluded that aripiprazole should be recommended as an option for the treatment of moderate to severe manic episodes in bipolar I disorder in adolescents.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA292\n\nAppraisal title: Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar I disorder\n\nSection\n\nKey conclusion\n\nAripiprazole is recommended as an option for treating moderate to severe manic episodes in adolescents with bipolar I disorder, within its marketing authorisation (that is, up to 12\xa0weeks of treatment for moderate to severe manic episodes in bipolar I disorder in adolescents aged 13\xa0and older).\n\n\n\nThe Committee concluded that based on the evidence available, aripiprazole was as effective as other antipsychotics for treating acute mania and had a comparable and acceptable adverse reaction profile.\n\n\n\nThe Committee agreed that the base-case results suggested that a treatment strategy that includes aripiprazole is a cost-effective option when compared with a treatment strategy without aripiprazole. Given that each of the strategies was dominated by every other strategy in at least some of the probabilistic iterations, the Committee agreed that the results were not sufficiently robust to make a recommendation on the position of aripiprazole in the treatment pathway. The Committee concluded that aripiprazole should be recommended as an option for the treatment of moderate to severe manic episodes in bipolar I disorder in adolescents.\n\n\n\n\n\nCurrent practice\n\nClinical need of participants, including the availability of alternative treatments\n\nThe Committee heard that the symptoms of mania in adolescents may impact on their schooling, work and family life and there is often a need to resolve the manic episode quickly.\n\nThe Committee discussed the drug treatments available for adolescents and understood antipsychotics such as olanzapine, risperidone and quetiapine are routinely used off-label. Clinical specialists explained that it is important for adolescents with acute manic episodes to have a range of treatment options available. This is in order to individualise treatment and to minimise adverse treatment effects, as adolescents are often less tolerant of adverse reactions than adults, leading to problems with adherence to medication.\n\n–4.3\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee understood from the clinical specialists that no single antipsychotic drug is considered to be more clinically effective than the others, but that tolerability and adverse reactions vary between the treatments.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from the clinical specialists that the treatment options for adolescents who develop acute mania include an antipsychotic drugs (such as aripiprazole, risperidone, olanzapine or quetiapine), lithium or valproate. The clinical specialists explained that lithium and valproate are not routinely used as monotherapy for this patient population.\n\n\n\nAdverse reactions\n\nThe Committee was aware that extrapyramidal symptoms, somnolence and akathisia were all statistically significantly more common in those receiving aripiprazole compared with those receiving placebo in NCT0010461. It noted there were no statistically significant increases in weight gain or BMI in those receiving aripiprazole compared with those receiving placebo at 4\xa0weeks. The Committee understood that the ERG did not consider that the frequency or nature of adverse events reported in NCT0010461\xa0raised safety concerns about aripiprazole treatment above other antipsychotics. The Committee concluded that current evidence suggests that aripiprazole has an acceptable safety profile compared with placebo for treatment in adolescents aged 13\xa0or older.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe main clinical-effectiveness evidence came from the NCT00110461\xa0trial with supporting evidence from the NCT00116259. The manufacturer also presented a network meta-analysis based on a network containing aripiprazole, olanzapine, risperidone, quetiapine and placebo.\n\n\n\nThe Committee accepted the results of the network meta-analysis as a reasonable basis for the economic model given the evidence available.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee considered the relevance of the USA-based NCT00110461\xa0trial to UK clinical practice. It discussed whether the population in the trial reflected that seen in UK clinical practice. The Committee concluded that overall the results from the NCT00110461\xa0trial were generalisable to UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee understood that the EMA had restricted the licence for aripiprazole to adolescents aged 13\xa0or older because of safety concerns in younger people. The Committee noted that the subgroup analysis by age group suggested that there was no change in treatment effect between the age subgroups, but that the younger age group experienced a greater increase in mean weight and BMI changes from baseline at week 12. The Committee was also aware that the subgroup analyses were based on small numbers of people in the groups, which increased the uncertainty in the results. The Committee concluded that evidence of treatment effect should be based on the whole trial population of NCT00110461.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee noted that the subgroup analysis by age group suggested that there was no change in treatment effect between the age subgroups.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that evidence from the NCT00110461\xa0trial demonstrated a reduction in manic symptoms in those receiving aripiprazole for 12\xa0weeks compared with those receiving placebo.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the manufacturer's economic model and the ERG's critique and exploratory analysis. It noted that the ERG considered the manufacturer's model to be transparent, robust, and well structured. The Committee agreed that the model structure was appropriate.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee was aware that the manufacturer's probabilistic sensitivity analyses suggested that there was uncertainty surrounding the ICERs and it understood that this may be a result of the lack of statistically significant differences in response rates obtained from the network meta-analysis for the 4\xa0antipsychotics.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNot applicable as the Committee had no concerns about the health-related quality-of-life data used in the manufacturer's economic model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable to this appraisal.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee was aware that the main parameters that influenced the results were the rates of response applied during the treatment phase. The Committee noted that a higher response rate during the treatment phase resulted in people leaving hospital earlier, which had both cost and health-related quality-of-life benefits.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that the pathway in which aripiprazole was positioned second dominated all of the other strategies. The Committee also noted that the ranges of costs and QALYs (in the base case, costs ranged from £74,133\xa0to £75,066, and QALYs ranged from 2.516\xa0to 2.525) across the strategies were similar. Results from the sensitivity analyses demonstrated that each of the strategies was dominated by every other strategy in at least some of the probabilistic iterations.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable to this appraisal.\n\n\n\nEnd-of-life considerations\n\nNot applicable to this appraisal.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues relevant to the Committee recommendation were raised.\n\n", 'Related NICE guidance': 'Details are correct at the time of publication. Further information is available on the NICE website.\n\nAripiprazole for the treatment of schizophrenia in people aged 15 to 17 years. NICE technology appraisal guidance 213 (2011).\n\nBipolar disorder. NICE clinical guideline 38 (2006).\n\nDepression in children and young people. NICE clinical guideline 28 (2005).\n\nThe clinical effectiveness and cost effectiveness of electroconvulsive therapy (ECT) for depressive illness, schizophrenia, catatonia and mania. NICE technology appraisal guidance 59 (2003).', 'Review of guidance': 'The guidance on this technology will be considered for review in July 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJuly 2013', 'Changes after publication': 'January 2014: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0230-9'}	https://www.nice.org.uk/guidance/ta292	Evidence-based recommendations on aripiprazole for treating moderate to severe manic episodes in young people with bipolar I disorder.
41bca9deda1a5c1b6175649aa7e58cbe960b1b98	nice	Aflibercept solution for injection for treating wet age‑related macular degeneration	Aflibercept solution for injection for treating wet age‑related macular degeneration Evidence-based recommendations on aflibercept solution for injection (Eylea) for treating wet age‑related macular degeneration in adults. # Guidance Aflibercept solution for injection is recommended as an option for treating wet age‑related macular degeneration only if: it is used in accordance with the recommendations for ranibizumab in NICE technology appraisal guidance 155 (re‑issued in May 2012) and the manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme. People currently receiving aflibercept solution for injection whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology Aflibercept solution for injection (Eylea, Bayer Pharma) is a soluble vascular endothelial growth factor (VEGF) receptor fusion protein which binds to all forms of VEGF‑A, VEGF‑B, and the placental growth factor. Aflibercept solution for injection prevents these factors from stimulating the growth of the fragile and permeable new blood vessels associated with wet age‑related macular degeneration. Aflibercept solution for injection has a UK marketing authorisation 'for adults for the treatment of neovascular (wet) age‑related macular degeneration (AMD)'. The summary of product characteristics states that the recommended dose for aflibercept is 2 mg and that treatment should be given monthly for 3 consecutive doses, followed by 1 injection every 2 months. Each 100‑microlitre vial contains 4 mg of aflibercept. Aflibercept solution for injection must only be administered by a qualified doctor experienced in administering intravitreal injections. The summary of product characteristics also states that there is no need for monitoring between injections. After the first 12 months of treatment, the treatment interval may be extended based on visual and anatomic outcomes. In this case the schedule for monitoring should be determined by the treating doctor. The summary of product characteristics lists the following most common adverse reactions for aflibercept solution for injection: conjunctival haemorrhage, eye pain, vitreous detachment, cataract, vitreous floaters and increased intraocular pressure. For full details of adverse reactions and contraindications, see the summary of product characteristics. The list price of aflibercept 40 mg/ml solution for injection is £816 per 100‑microlitre vial (excluding VAT; 'British national formulary' edition 52). The manufacturer of aflibercept solution for injection has agreed a patient access scheme with the Department of Health. This involves a confidential discount applied to the list price of aflibercept solution for injection. The level of the discount is commercial in confidence (see section 5.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.# The manufacturer's submission The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of aflibercept solution for injection and a review of this submission by the Evidence Review Group (ERG; section 9). # Clinical effectiveness The manufacturer performed a systematic literature review of the evidence on the clinical effectiveness of aflibercept. The review identified 2 studies that directly compared aflibercept with ranibizumab in people with wet age‑related macular degeneration: VIEW 1 (n=1217) and VIEW 2 (n=1240). Both studies were multicentre (VIEW 1: 154 centres in USA and Canada; VIEW 2: 172 centres in 26 countries, including the UK), active‑controlled, double‑blind, randomised trials that compared aflibercept with ranibizumab. Both studies were identical in design (except for location) so that data could be pooled. Only one eye per patient was included in both studies. If a patient needed treatment in the second eye during the study, the second eye was allowed to receive any approved treatment although it was not included in the study. In both studies patients were randomised on a 1:1:1:1 basis to receive either (i) aflibercept 2 mg every 8 weeks after 3 initial monthly loading doses, (ii) aflibercept 2 mg every 4 weeks, (iii) aflibercept 0.5 mg every 4 weeks, or (iv) ranibizumab 0.5 mg every 4 weeks. The manufacturer stated that both studies were designed primarily to test whether aflibercept at its recommended dose (2 mg every 8 weeks) was non‑inferior to ranibizumab (0.5 mg every 4 weeks). Therefore, the results reported here are limited to the treatment arms of both studies. The manufacturer stated that non‑inferiority margins and definitions were established in discussion with the US Food and Drugs Administration, European Medicines Agency and other regulatory agencies to be consistent with key trials of ranibizumab, including the MARINA study (2006), for treating wet age‑related macular degeneration. Both studies had 2 phases, including a primary phase (from randomisation to week 48) during which patients received treatment according to randomisation arm, with patients in the aflibercept 2 mg every 8 weeks arm receiving sham injections when no active treatment was due. In the follow‑up extension phase (up to 92 weeks), patients in all 4 treatment arms continued to be evaluated every 4 weeks and remained in their allocated treatment groups. The total duration of both studies was 96 weeks consisting of up to 92 weeks of treatment plus a screening period and a 4‑week safety follow‑up period. For both studies, the manufacturer defined 3 populations for analysis. The full analysis set included all randomised patients who received any study drug and had a baseline and at least 1 post‑baseline assessment. The per protocol set included all patients in the full analysis set who received at least 9 injections of study drug or sham and attended at least 9 scheduled visits during the first 52 weeks, except for those who were excluded because of major protocol violations. The safety analysis set included all patients who received any study drug. The manufacturer stated that the per protocol set was used for primary analysis (statistical evaluation of non‑inferiority). A patient who withdrew from the study before week 36 because of treatment failure was considered a 'non‑responder'. The last observation carried forward approach was used to calculate missing data except for baseline values. Patients withdrawing before week 36 were not included in the primary analysis but were included in the secondary analysis (in the full analysis set). The baseline demographics and disease characteristics were similar between the aflibercept 2 mg every 8 weeks and ranibizumab treatment arms in the VIEW 1 and 2 studies. In VIEW 1, the mean age was 78 years, 41% of patients were male, and 97% of patients were white. In VIEW 2, the mean age was 73–75 years, 45% of patients were male, and 73% of patients were white. The total mean baseline best‑corrected visual acuity score (defined by Early Treatment Diabetic Retinopathy Study scale) ranged from 54 to 56 letters in VIEW 1 and from 52 to 54 letters in VIEW 2. In both studies, the distribution of occult, minimally classic and predominantly classic lesion types in the study eye was similar across both treatment arms. The primary outcome of VIEW 1 and 2 was the proportion of patients who maintained vision at week 52, defined as losing fewer than 15 letters on the ETDRS scale compared with baseline. This outcome was also measured at week 96. In a pooled analysis of both studies, the proportion of patients treated with aflibercept who maintained vision at week 52 was 95.3% compared with 94.4% of patients treated with ranibizumab (difference −0.9%, 95% confidence interval −3.5 to 1.7). At week 96, the proportion of patients treated with aflibercept who maintained vision was 92.4% compared with 91.6% of patients treated with ranibizumab (difference −0.8%, 95% CI −3.8 to 2.3). The manufacturer stated that aflibercept showed non‑inferiority to ranibizumab at weeks 52 and 96 because the upper limits of the confidence intervals for the differences in proportions were consistently below the pre‑specified boundary of 10%. The manufacturer also evaluated the primary outcome for pre‑planned subgroup analyses in both studies by age, sex, race, renal function, hepatic impairment, baseline visual acuity, lesion size and type. The manufacturer stated that the results for all subgroups in both studies and in pooled analyses were consistent with the results in the whole study populations. However, the results of these subgroup analyses were not presented by the manufacturer. Secondary outcomes in VIEW 1 and 2 included changes from baseline to week 52 for: best‑corrected visual acuity as measured by ETDRS letter score, proportion of patients gaining at least 15 letters, and choroidal neovascularisation area. For the outcome of best‑corrected visual acuity at week 52, mean ETDRS letter scores increased by approximately 7−11 letters in both treatment arms in VIEW 1 and by approximately 8–10 letters in VIEW 2. No statistically significant differences in change in best‑corrected visual acuity from baseline to week 52 were reported between aflibercept and ranibizumab in a pooled analysis of both studies (mean difference −0.32 letters, 95% CI −1.87 to 1.23). In VIEW 1 and 2, improvements in visual acuity observed at week 52 were largely maintained at week 96 in both treatment arms. No statistically significant differences in the proportion of patients who gained at least 15 ETDRS letters were reported between aflibercept and ranibizumab treatment arms at week 52 in a pooled analysis of both studies (30.97% and 32.44% respectively, p‑value not reported). Similar results were reported at week 96. In VIEW 1, the ranibizumab arm had a statistically significantly greater mean reduction in choroidal neovascularisation area at week 52 than the aflibercept arm (−4.2 mm2 and −3.4 mm2 respectively, p=0.017). No statistically significant differences in choroidal neovascularisation area at week 52 were reported between ranibizumab and aflibercept 2 mg every 8 weeks in VIEW 2 (−4.16 mm2 and −5.16 mm2 respectively, p=0.073). Similar results were also reported at week 96 in both studies. Vision‑related quality of life was measured in VIEW 1 and 2 using the National Eye Institute Visual Function Questionnaire‑25 (NEI VFQ‑25), which includes 25 questions designed to measure the effect of visual impairment on daily functioning and quality of life. Improvements in the mean NEI VFQ‑25 total score from baseline to week 52 were similar in both the aflibercept and the ranibizumab treatment arms in a pooled analysis of both studies (5.0 points and 5.6 points respectively, p‑value not reported). These improvements in vision‑related quality of life were maintained at week 96 in both treatment arms. The VIEW 2 study also measured changes in health‑related quality of life using the EQ‑5D questionnaire, which were incorporated in the manufacturer's cost‑effectiveness analysis. The manufacturer did not present a formal meta‑analysis of the VIEW 1 and 2 studies on the basis that both studies were similarly designed so that their data could be pooled directly. The manufacturer commented that, although the VIEW 1 and 2 studies used a fixed dosing regimen for ranibizumab (0.5 mg every 4 weeks), in clinical practice a 'treatment as needed' approach is used which involves monthly ranibizumab treatment until the patient's visual acuity is stable for 3 consecutive months, with re‑treatment in a similar way upon loss of visual acuity (with a minimum of 2 injections). Therefore, the manufacturer conducted a systematic literature review and mixed treatment comparison (network meta‑analysis) to compare aflibercept 2 mg every 8 weeks with ranibizumab 0.5 mg in a 'treatment as needed' regimen. The manufacturer produced 3 networks at 6, 12 and 24 months. Because no data were available for aflibercept at 6 months, only networks for outcomes at 12 and 24 months were considered further by the manufacturer. The manufacturer assumed that 52‑week and 96‑week data from VIEW 1 and 2 corresponded with outcomes at 12 and 24 months respectively. Results were presented for 3 outcomes: maintained vision (defined as the proportion of patients losing 15 or fewer ETDRS letters), improved vision (defined as the proportion of patients gaining more than 15 ETDRS letters) and mean change from baseline in best‑corrected visual acuity. The network meta‑analysis of outcomes at 12 months incorporated up to 10 studies, depending on the outcome, and included the VIEW 1 and 2 studies. For the outcome of mean change from baseline in best‑corrected visual acuity, the manufacturer repeated the analysis after excluding one study (DETAIL study; London et al. 2009) because patients in the study responded differently to ranibizumab in a 'treatment as needed' regimen compared with other studies. The manufacturer presented separate network meta‑analyses for outcomes at 12 months, using both frequentist methods, based on traditional statistical methods applied in making comparisons, and Bayesian methods, which combine the probability of the data as a function of the parameters with prior beliefs about possible values of those parameters. These analyses showed no statistically significant differences between aflibercept 2 mg every 8 weeks and ranibizumab 0.5 mg treatment as needed in the proportion of patients who maintained vision (frequentist method: odds ratio 1.44, 95% CI 0.68 to 3.09; Bayesian method: OR 1.51, 95% CI 0.42 to 5.94) or gained vision (frequentist method: OR 1.29, 95% CI 0.91 to 1.83; Bayesian method: OR 1.28, 95% CI 0.45 to 3.68). No statistically significant differences in mean change in best‑corrected visual acuity at 12 months were shown between aflibercept 2 mg every 8 weeks and ranibizumab 0.5 mg treatment as needed (frequentist method: mean difference 0.83, 95% CI −1.57 to 3.23; Bayesian method: mean difference −2.87, 95% CI −10.02 to 4.30). When the manufacturer repeated the analysis after excluding the DETAIL study, the results for the outcome of mean change in best‑corrected visual acuity at 12 months were similar (frequentist method: mean difference 1.35, 95% CI −1.08 to 3.77; Bayesian method: mean difference 1.15, 95% CI −3.92 to 6.09). The manufacturer did not present a network meta‑analysis of outcomes at 24 months because VIEW 1 and 2 both allowed treatment switching after 12 months from a fixed dosing regimen of aflibercept 2 mg every 8 weeks to a treatment as needed regimen (aflibercept fixed 2 mg every 8 weeks/treatment as needed). Therefore, two‑step indirect comparisons, based on the Bucher method, were used to compare aflibercept fixed 2 mg every 8 weeks/treatment as needed with ranibizumab 0.5 mg treatment as needed. The indirect comparisons included data from 3 studies: VIEW 1 and 2, and CATT, a 2‑year study that compared ranibizumab 0.5 mg with bevacizumab for treating patients with wet age‑related macular degeneration (CATT Research Group, 2012). The CATT study presented data for ranibizumab as an identical switch trial and as fixed dose or treatment as needed only. Both sets of data from the CATT study were analysed for the indirect comparison. The results of the manufacturer's indirect comparison for the outcomes at 24 months also showed no statistically significant differences between aflibercept fixed 2 mg every 8 weeks/treatment as needed and ranibizumab 0.5 mg treatment as needed in the proportion of patients who maintained vision (relative risk 0.99, 95% CI 0.93 to 1.07) or gained vision (relative risk 0.88, 95% CI 0.61 to 1.28). No statistically significant differences in mean change in best‑corrected visual acuity at 24 months were shown between aflibercept 2 mg every 8 weeks and ranibizumab 0.5 mg treatment as needed (mean difference 0.31, 95% CI −4.33 to 3.71). The manufacturer highlighted concerns about the validity of the network meta‑analyses and indirect comparisons because of the heterogeneity between the included studies. On the basis of a quality assessment checklist, the manufacturer found that 3 of the included studies had a high risk of bias. The manufacturer also noted that several of the studies had different baseline characteristics in terms of ETDRS letter score, treatment as needed re‑treatment criteria, proportion of men, central retinal thickness and numbers of injections. The manufacturer commented that sensitivity analyses were performed with regard to the heterogeneity but that the results were unchanged. The manufacturer stated that the safety and tolerability of aflibercept compared with ranibizumab for up to 96 weeks was included as a secondary objective in the VIEW 1 and 2 studies. On the basis of the safety analysis dataset, no clinically meaningful differences were reported between aflibercept and ranibizumab for treatment‑emergent adverse events, with similar incidences of reported events between treatment arms. The most common treatment‑emergent adverse events (reported in at least 5% of patients treated with aflibercept in VIEW 1 and 2) were: conjunctival haemorrhage (26.7%), eye pain (10.3%), vitreous detachment (8.4%), cataract (7.9%), vitreous floaters (7.6%), and increased intraocular pressure (7.2%). The incidence of arterial thromboembolic events (including non‑fatal myocardial infarction, non‑fatal stroke or vascular stroke), which are potentially related to anti‑VEGF treatment, was also similar between the aflibercept (3.3%) and ranibizumab (3.2%) treatment groups in VIEW 1 and 2. # Cost effectiveness The economic evidence provided by the manufacturer included a literature review, which identified one published cost‑effectiveness analysis of aflibercept in US patients with wet age‑related macular degeneration, and a de novo cost–utility analysis. The manufacturer developed a Markov state‑transition cohort model simulating cohorts of people with wet age‑related macular degeneration receiving aflibercept 2 mg every 8 weeks or ranibizumab 0.5 mg treatment as needed. The model assumed a cycle length of 1 month based on the level of monitoring associated with ranibizumab treatment, and used a lifetime horizon (25 years based on a starting age of 74 years). An NHS and personal social services perspective was taken and costs and benefits were discounted at 3.5%. The economic model included a total of 30 health states defined by a combination of different levels of visual acuity in both eyes (the treated eye and the second eye) in addition to the absorbing health state of death. For each health state, visual acuity in the treated eye or second eye was defined according to 5 possible levels on the ETDRS scale, ranging from no visual impairment (ETDRS more than 80 letters) to blindness (ETDRS fewer than 36 letters) with 3 intermediate levels (ETDRS 66–80 letters; 51–65 letters and 36–50 letters). In each model cycle, people were assumed to have the median visual acuity of each ETDRS range and moved to the median value of either the adjacent state or the state 2 levels higher or lower, based on the number of letters gained or lost. For each health state, the patient could either be on or off active treatment. The economic model included a 5‑year treatment period on the basis of clinical opinion which suggested that patients are likely to continue treatment beyond 24 months. For the first 2 years, clinical-effectiveness data at baseline, 52 and 96 weeks from the last observation carried forward population in the VIEW 2 study were used to estimate the visual acuity of people receiving aflibercept. The probabilities of gaining and losing visual acuity in year 1 were applied to the VIEW 2 patient distribution at baseline and the probabilities of gaining and losing visual acuity in year 2 were applied to the modelled year 1 distribution. The visual acuity of people receiving ranibizumab for the first 2 years of the model was estimated from the relative risks of improving and maintaining vision for aflibercept compared with ranibizumab taken from the manufacturer's network meta‑analysis and indirect comparison of aflibercept 2 mg every 8 weeks with ranibizumab 0.5 mg treatment as needed. During this period, people who were defined as being in the blind health state received treatment with ranibizumab or aflibercept. However, this did not continue in years 3 to 5 on the basis of clinical opinion which suggested that the blind eye is unlikely to benefit from treatment. Simple linear interpolation was used to populate the monthly model cycles for year 1 (cycles 1–12) and year 2 (cycles 13–24). The annual rates of treatment discontinuation in year 1 (2.7%) and year 2 (3.5%) were assumed to be identical between both treatment groups and were based on an average of the discontinuation rates reported in the VIEW 2 and CATT studies. For years 3 to 5 in the model, it was assumed that people on active treatment would remain in the same health state that they were in after 2 years. Because no statistically significant differences in clinical effectiveness were identified in the indirect comparison of aflibercept with ranibizumab, identical assumptions were made for both treatment groups during this period. In the absence of available trial data, clinical opinion was used to estimate the annual probability of treatment discontinuation in years 3 to 5 (18.7%), which were also assumed to be identical between treatment groups. From year 6 it was assumed that all people in both treatment groups discontinued active treatment and started best supportive care. The manufacturer assumed that clinical effectiveness in the treated eye was independent of effectiveness in the second eye. Clinical‑effectiveness data for the second eye while on treatment was calculated using the same methodology applied to the treated eye. The manufacturer assumed that wet age‑related macular degeneration involvement in both eyes was 0% at the start of the model and that people developed wet age‑related macular degeneration in the second eye from year 3. The manufacturer also assumed that all people in the model who developed wet age‑related macular degeneration in the second eye from year 3 were treated. On the basis of a meta‑analysis by Wong et al. (2008) of patients with wet age‑related macular degeneration receiving no active treatment, the manufacturer estimated a 0.65% monthly probability of developing wet age‑related macular degeneration in the second eye. For people who were not receiving active treatment, clinical‑effectiveness data from Wong et al. were used to estimate the monthly probability of losing either 15 letters (0.56%) or 30 letters (1.56%) with the remaining people maintaining stable visual acuity. The manufacturer stated that there is limited evidence of a relationship between wet age‑related macular degeneration and an increased risk of mortality and that, on the basis of data from the VIEW 1 and 2 studies, it is unlikely that there is any difference in mortality between aflibercept and ranibizumab. Therefore, age‑specific all‑cause mortality from UK life tables was used for both treatment groups. For people who were blind in both eyes, an excess risk of mortality was taken from a UK study of older patients with visual impairment (Thiagarajan et al. 2005). To estimate the health‑related quality of life associated with each health state corresponding to visual acuity in both eyes, EQ‑5D data from VIEW 2 were transformed to utility values using the UK population tariff. A pooled dataset of all trial arms at baseline, 52 weeks and 96 weeks was used by the manufacturer. The manufacturer adjusted the utility values for 4 of the health states in the model to maintain the assumption that utility values decrease consistently with worsening visual acuity. This was achieved by taking the average of the utility values above and below the anomalous value. Utility values were not adjusted for age in the model. The resulting utility values applied in the model are academic in confidence and therefore not reported here. The manufacturer stated that, because of the low rates of adverse events observed in the VIEW 1 and 2 trials and the small differences observed between the aflibercept and ranibizumab treatment groups, the impact of adverse events on health‑related quality of life was not included in the base‑case analysis. However, in a scenario analysis, the manufacturer included the loss in utility associated with adverse ocular events taken from 2 separate studies identified in a systematic literature review (Brown et al. 2007; Gower et al. 2010). These utility decrements were subtracted from the utility values for the health states defined by visual acuity and included retinal haemorrhage (−0.300), vitreous haemorrhage (−0.305), endophthalmitis (−0.300), cataract (−0.142) and retinal detachment (−0.27). The manufacturer included the costs of drug treatment, including drug acquisition, administration and monitoring costs. The drug acquisition costs incorporated the confidential discount applied to the list price of aflibercept approved as part of the patient access scheme. The manufacturer of ranibizumab has also previously agreed a revised patient access scheme with the Department of Health in 2013 (as revised in the context of NICE technology appraisal guidance 274), in which it applied a revised discount to ranibizumab for all indications. At the time of submission for this appraisal, the manufacturer of aflibercept was unaware of the size of the confidential discount and therefore presented a range of scenario analyses, which applied discounts to the list price of ranibizumab ranging from 10% to 50%, in increments of 5%. The resource use and unit costs associated with treatment and monitoring visits were based on Hospital Episode Statistics (HES 2010/11) and NHS reference costs (2011/12). The manufacturer assumed that in year 1 people treated with aflibercept had their treatment administration and monitoring at the same visit (one‑stop model), and that 50% of people treated with ranibizumab followed a one‑stop model and 50% had separate visits for treatment and monitoring (two‑stop model). In years 2 to 5, the manufacturer assumed that 50% of people in both treatment groups followed a one‑stop model and 50% followed a two‑stop model. The manufacturer assumed that treatment with both aflibercept and ranibizumab occurred as a weighted average of a day‑case visit (55%) and outpatient visit (45%), resulting in a total cost of £257.45 per treatment visit. It was assumed that people in both treatment groups would need one fluorescein angiography (£117) before starting treatment. The manufacturer assumed that people receiving aflibercept had 7 injections in the first year and 4 injections in the second year based on the treatment frequency recommended in the summary of product characteristics and the VIEW 2 study. It was assumed that people receiving ranibizumab had 8 injections in the first year and 6 injections in the second year based on NICE technology appraisal guidance 155 and the European Medicines Agency assessment report for the 2011 revision of the summary of product characteristics. Based on clinical specialist opinion, the manufacturer assumed that people in both treatment groups had 4 injections in years 3 to 5. The manufacturer assumed that separate monitoring visits included the cost of an ophthalmologist outpatient visit (£80) and an optical coherence tomography (£117), resulting in a total cost of £197 per monitoring visit. The frequency of monitoring visits in the first 2 years of the model was also based on the summary of product characteristics for both treatments. People receiving aflibercept had 7 monitoring visits in year 1 and 6 monitoring visits in year 2 and people receiving ranibizumab had 12 monitoring visits in years 1 and 2. People receiving aflibercept in a one‑stop model had their treatment and monitoring at the same visit and therefore needed no separate monitoring visits in the first year and 2 separate visits in the second year. People receiving aflibercept in a two‑stop model in the second year had their treatment and monitoring at separate visits and therefore needed 6 separate monitoring visits in the second year. People receiving ranibizumab had 4 separate monitoring visits in the first year and 6 separate visits in the second year in a one‑stop model and 12 separate monitoring visits in the first 2 years in a two‑stop model. On the basis of clinical specialist opinion, people in years 3 to 5 in both treatment groups had 3 separate monitoring visits in the one‑stop model and 7 separate monitoring visits in a two‑stop model. The manufacturer estimated the costs associated with blindness for people who were defined as being blind in both eyes (ETDRS score under 36 letters). The manufacturer applied cost data taken from a published UK costing study of blindness in people with age‑related macular degeneration (Meads and Hyde 2003). This study estimated the costs associated with a range of items including low‑vision aids, rehabilitation, residential care, district nursing, community care and the cost of treating complications including depression and falls. After adjusting for inflation, the total estimated annual cost of blindness was £585. Because of the low incidence of adverse events reported in the VIEW 1 and 2 studies, the manufacturer did not apply the costs of adverse events in the base‑case analysis. The manufacturer's base‑case deterministic cost‑effectiveness results (including the patient access scheme for aflibercept but not for ranibizumab) showed that aflibercept dominated ranibizumab because it resulted in lower costs and higher quality‑adjusted life years (QALYs; 7.77 compared with 7.76). When the manufacturer applied a discount to the list price of ranibizumab, ranging from 10 to 50%, aflibercept continued to dominate ranibizumab. The manufacturer performed one‑way sensitivity analysis using a net monetary benefit approach because aflibercept dominated ranibizumab in the base‑case analysis.The deterministic and probabilistic sensitivity analyses used the discounted price for aflibercept agreed under the patient access scheme and the list price for ranibizumab. The results of the one‑way sensitivity analyses indicated that the cost effectiveness of aflibercept was most sensitive to the drug acquisition costs, frequency of injections and monitoring visits, proportion of people in one‑stop and two‑stop models, discount rates and the relative risk of gaining or losing visual acuity with ranibizumab treatment. The manufacturer stated that, in all sensitivity analyses, aflibercept continued to dominate ranibizumab. Results of the manufacturer's probabilistic sensitivity analysis showed that aflibercept had a 100% probability of being cost effective compared with ranibizumab if the maximum acceptable incremental cost‑effectiveness ratio (ICER) was £20,000 per QALY gained. The manufacturer also conducted a number of scenario analyses, which included the discounted price for aflibercept but not for ranibizumab. Two scenarios involved varying the frequency of injections and monitoring: applying the average number of injections reported in years 1 and 2 of the VIEW 2 and CATT trials for aflibercept and ranibizumab respectively, and applying monthly monitoring visits for ranibizumab and bi‑monthly monitoring visits for aflibercept in years 3 to 5. One scenario involved applying the same clinical‑effectiveness data for both treatments so that the same proportions of people gaining or losing visual acuity were applied in both treatment groups. One scenario applied alternative utility values from a study by Czoski‑Murray et al. (2009) in which members of the general public valued levels of visual impairment that were simulated by custom‑made contact lenses, using the time trade‑off method. One scenario modelled the impact of adverse ocular events in the ranibizumab treatment group, which included retinal haemorrhage, vitreous haemorrhage, endophthalmitis, cataract and retinal detachment taken from a separate trial of ranibizumab in patients with wet age‑related macular degeneration (Boyer et al. 2009). Another scenario applied clinical‑effectiveness estimates equivalent to best‑supportive care, taken from Wong et al., in years 3–5 for both treatment groups. For all scenario analyses, aflibercept either continued to dominate ranibizumab or resulted in net cost savings (when the same proportions of people gaining or losing visual acuity were applied in both treatment groups). # ERG critique of manufacturer's submission The ERG considered that the clinical‑effectiveness evidence from the VIEW 1 and 2 studies was of good quality without any obvious sources of bias. The ERG noted that the manufacturer used the last observation carried forward approach to calculate missing data for the primary outcome of the proportion of people who maintained vision at week 52 in VIEW 1 and 2. The ERG considered that this approach may have introduced bias because it can artificially stabilise disease, which may be inappropriate for a progressive disease such as wet age‑related macular degeneration. After clarification, the manufacturer provided the observed results at week 52 for the outcome of maintained vision from the per protocol and full analysis datasets, which were similar to the original results based on the last observation carried forward approach. The ERG also ran the network meta‑analysis for the outcome of maintained vision at 12 months using observed data from VIEW 1 and 2 and found that the results were similar to the original results obtained using the last observation carried forward approach. Therefore, the ERG was satisfied that the use of last observation carried forward did not substantially impact the results for the primary outcome at week 52 in VIEW 1 and 2. The ERG agreed with the manufacturer that there were concerns about the validity of the network meta‑analyses and indirect comparison because of heterogeneity between the included studies. The ERG noted that the manufacturer had conducted sensitivity analyses with regard to heterogeneity, but commented it was not clear what these sensitivity analyses were. The ERG also noted that the network meta‑analysis for the outcome of mean change from baseline in best‑corrected visual acuity at 12 months excluded a treatment arm from one of the studies included in the analysis (ranibizumab fixed dose 0.3 mg arm in the DETAIL study). The ERG was concerned about the validity of the results as a result of this omission and therefore repeated the analysis including this treatment arm. The ERG found that, although this did not significantly alter the results in terms of the mean difference in change in best‑corrected visual acuity between treatment arms, the results of the network analyses and indirect comparison should be interpreted with caution. In its critique of the manufacturer's economic model, the ERG noted that clinical‑effectiveness data for the aflibercept treatment group were derived from the VIEW 2 study rather than pooled data from VIEW 1 and 2. The ERG also noted that the proportion of people treated with aflibercept who gained or lost visual acuity at 52 weeks and 96 weeks was broadly similar between VIEW 1 and 2 and that there was no suggestion of bias arising from the choice of VIEW 2 data rather than pooled clinical‑effectiveness data. However, the ERG highlighted that there were discrepancies between the clinical‑effectiveness data from VIEW 2 and the modelled population in terms of the proportion of people who gained or maintained visual acuity at week 52. The ERG commented that it was unclear what clinical‑effectiveness data were used for the aflibercept group in the model. The ERG noted that people treated with aflibercept in VIEW 1 and 2 received an average of 7.5 and 7.7 injections in the first year of both studies. The ERG also noted that the dosing schedule suggests that people who remain on treatment would need 8 injections in year 1. Therefore, the ERG considered that it may have been more reasonable for the manufacturer to model 8 injections of aflibercept in year 1. The ERG also noted that the average number of 4 aflibercept injections in year 2 of the model, which were taken from the VIEW 2 study, had been annualised from 44 weeks to 52 weeks to account for the study duration (96 weeks) which was slightly shorter than 2 years (104 weeks).The ERG considered that, on the basis of the weighted average number of injections of ranibizumab (7.4) in a treatment as needed dosing regimen in studies included in the manufacturer's systematic review, the number of ranibizumab injections in year 1 of the model should probably have been 7 rather than 8. The ERG commented that the network meta‑analysis for visual acuity outcomes at 24 months relied largely upon data from the CATT study, in which patients treated with ranibizumab had an average of 5.7 injections in a 'treatment as needed' regimen in year 2. The ERG therefore considered that the manufacturer's assumption of 6 ranibizumab injections in the second year of the model was reasonable. The ERG noted that the manufacturer reported relative risks of maintaining and gaining visual acuity from its network meta‑analysis and indirect comparison between baseline and 12 months and between 12 months and 24 months. However, the ERG considered that the results of the manufacturer's systematic review and indirect comparison at 24 months were the relative risks of gaining or maintaining visual acuity between baseline and 24 months. The ERG also noted that applying the 24‑month relative risks to the probability of gaining or maintaining visual acuity between 12 months and 24 months resulted in more people in the aflibercept treatment group gaining or maintaining visual acuity compared with ranibizumab at 24 months. However, the ERG considered that, because the estimated relative risks of gaining and maintaining visual acuity for aflibercept compared with ranibizumab from baseline to 24 months were less than 1, fewer people in the aflibercept treatment group should have gained or maintained visual acuity compared with ranibizumab at 24 months. The ERG considered that the manufacturer's approach to modelling second‑eye involvement was incorrect. The ERG noted that the probabilities of gaining or maintaining visual acuity with aflibercept or ranibizumab during the first 2 years of treatment were not applied to the second eye and that there was no incidence of second‑eye involvement in years 1 and 2 of the model. The ERG also noted that, although the baseline prevalence of wet age‑related macular degeneration in the second eye was 19% in the pooled VIEW 1 and 2 population, the manufacturer had assumed that people in both treatment groups had no visual impairment or wet age‑related macular degeneration in their second eye at the start of the model. Furthermore, the ERG considered that the model did not allow for sensible consideration of the timing of second‑eye involvement because the effect of treatment on visual acuity in the second eye and the costs of treating any second‑eye involvement were limited to years 3 to 5. Therefore, the ERG concluded that the manufacturer's economic model in its current form is a 'one‑eye model' that should be limited to considering the cost effectiveness of aflibercept as unilateral treatment for wet age‑related macular degeneration. Because the ERG concluded that the manufacturer's model may be limited to being a one‑eye model, it suggested that further consideration should be given as to whether people received treatment in their better‑seeing eye or their worse‑seeing eye and the resulting impact on health‑related quality of life. The ERG considered that the manufacturer's assumption of no second‑eye involvement in years 1 and 2 resulted in the model being a worse‑seeing eye model, with the additional assumption of the second eye having no visual impairment. On the basis of the manufacturer's EQ‑5D utility values from VIEW 2, the ERG suggested a narrower range of utility values for the 5 health states defined by visual acuity in a worse‑seeing eye model. For a better‑seeing eye model, the ERG suggested that utility values should be taken from a study by Brown (1999) that measured vision‑related utility values using the time trade‑off method in 325 people from the USA with impaired vision (Snellen scale 20/40) in at least 1 eye. The ERG noted from the Brown study that, among people who had good vision in their better‑seeing eye, the worse‑seeing eye contributed little to health‑related quality of life. The utility values taken from the Brown study ranged from 0.920 to 0.621 for the 5 health states defined by visual acuity in the manufacturer's model, a range that the ERG noted was similar to the range of utility values from the VIEW 1 study under the assumption of the worse‑seeing eye being blind. The ERG considered that it was unclear why all patients in the aflibercept group followed a one‑stop monitoring model and 50% of patients in the ranibizumab group followed one‑stop and 50% followed a two‑stop model in the first year of the economic model. If patients in the aflibercept group followed a two‑stop model, they would therefore have 7 separate monitoring visits in year 1. The ERG also considered that the manufacturer's estimated cost per treatment visit of £257, which was based on a weighted average of outpatient and day‑case visits from 2010/11 HES data, may have been too high. On the basis of 2011/12 HES data, the ERG estimated a lower weighted average cost of £129.46 per treatment visit. The ERG also noted that, in the appraisal of ranibizumab for treating diabetic macular oedema (NICE technology appraisal guidance 274), the manufacturer estimated a total cost of £143 per treatment visit. The ERG also considered that the manufacturer's estimated cost of £117.26 for an optical coherence tomography (based on a fluorescein angiography) may have been too high and that a lower cost of £51.27 (based on a 20‑minute ultrasound scan) may have been more appropriate. The ERG also noted that the manufacturer's estimate of the annual costs of blindness was implemented as a monthly cost in the model. The ERG conducted exploratory analyses, which involved the following modifications to the manufacturer's model: second‑eye involvement after year 1 and 2 was set to zero to reflect the ERG's view that the submitted modelling of second‑eye involvement is untenable injections in year 1 were assumed for both treatment groups treatment visit costs were reduced to £129.46 and optical coherence tomography costs to £51.27 % of people in both treatment groups were monitored according to the one‑stop model in year 1 utility values for a better‑seeing eye model (see section 3.35) were drawn from the Brown study, ranging from 0.920 to 0.621; utility values for a worse‑seeing eye model were consistent with those used in the manufacturer's submission. The ERG applied the changes outlined in section 3.37 in 2 scenario analyses for the worse‑seeing eye model and 2 scenario analyses for the better‑seeing eye model. The first scenario for each model adopted the manufacturer's interpretation that its indirect comparison of aflibercept with ranibizumab at 24 months provided relative risks of maintaining and gaining visual acuity from 12 to 24 months. In this first scenario, the ERG retained the proportions of people maintaining and gaining visual acuity in the manufacturer's original model. The second scenario for each model adopted the ERG's interpretation that the manufacturer's indirect comparison at 24 months provided relative risks of gaining and maintaining visual acuity from baseline to 24 months. In this second scenario, the ERG retained the baseline distribution of visual acuity from the manufacturer's original model. The ERG incorporated the confidential discount applied to the list price of aflibercept and a range of discounts (from 0 to 50% in increments of 5%) to the list price of ranibizumab in its scenario analyses as outlined in section 3.38. In the ERG's first scenario analysis for the worse‑seeing eye model, aflibercept either dominated ranibizumab (discount 0–45%) or resulted in an ICER of £60,153 per QALY gained (discount 50%). In the ERG's first scenario analysis for the better‑seeing eye model, aflibercept either dominated ranibizumab (discount 0–45%) or resulted in an ICER of £9002 per QALY gained (discount 50%). In the ERG's second scenario analysis for the worse‑seeing eye model, aflibercept resulted in lower costs and lower QALYs compared with ranibizumab when a discount range of 0–45% was applied to the list price of ranibizumab, with ICERs ranging from £1,692,511 to £108,180 saved per QALY lost. In the ERG's second scenario analysis for the better‑seeing eye model, the ICERs for aflibercept compared with ranibizumab ranged from £261,432 to £16,710 saved per QALY lost when a discount range of 0–45% was applied to the list price ranibizumab. When the ERG applied a 50% discount to the list price of ranibizumab, aflibercept was dominated by ranibizumab for both the worse‑seeing eye and better‑seeing eye models. Full details of all the evidence are in the manufacturer's submission and the ERG report. Net monetary benefit=(£20,000×incremental QALYs)–incremental costs# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aflibercept solution for injection, having considered evidence on the nature of wet age‑related macular degeneration and the value placed on the benefits of aflibercept by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee heard from the patient experts that visual impairment has a substantial negative impact on the physical and emotional wellbeing of people with wet age‑related macular degeneration. The patient experts stated that the condition affects their ability to work and other leisure activities and in turn, can increase the risk of depression and social isolation. The patient experts also acknowledged that, despite any initial anxiety about having an injection in the eye, they are willing to receive injections in order to prevent sight loss. The Committee agreed that loss of vision caused by wet age‑related macular degeneration can substantially impair health‑related quality of life. The Committee discussed the currently available treatments and the likely place of aflibercept in treating wet age‑related macular degeneration. The Committee heard from the clinical specialists that the current standard treatment for wet age‑related macular degeneration is ranibizumab as a consequence of NICE technology appraisal guidance 155. It also heard that, in some NHS trusts and private clinical practice, both ranibizumab and bevacizumab for intravitreal use are used on the basis of economic considerations. However, the clinical specialists explained that people treated with ranibizumab and bevacizumab should have their condition monitored every 4 weeks and that very few NHS trusts were able to manage wet age‑related macular degeneration at such regular intervals. They also stated that people usually receive 6 ranibizumab injections in the first year of treatment rather than up to 12 injections seen in the clinical trials. The clinical specialists commented that data from several UK ophthalmology departments suggest that the current ranibizumab treatment regimen is inadequate and so visual acuity outcomes may be inferior to results reported in the clinical trials. However, the Committee also acknowledged that these inferior visual acuity outcomes could be attributed to the widening range of disease severity seen in clinical practice. The Committee understood from the clinical specialists that an important advantage of aflibercept is that it needs less frequent administration than ranibizumab while achieving similar clinical outcomes, as seen in the clinical trials, thus imposing less burden on NHS capacity. The Committee also understood from the patient experts that, because aflibercept is associated with fewer treatment and monitoring visits, it will reduce the burden on patients and their carers in terms of time off work and travel costs. The Committee considered the manufacturer's decision to exclude bevacizumab for intravitreal use as a comparator in its submission, despite being listed as a comparator in the scope. It was aware that bevacizumab does not have a UK marketing authorisation for treating wet age‑related macular degeneration. However, the Committee noted that a marketing authorisation is not a prerequisite for a comparator in a NICE technology appraisal. It noted that NICE's Guide to the methods of technology appraisal, in recommending comparison with technologies that are 'best practice' or in 'routine use', is not intended to be restrictive but to emphasise the need for comparison with all relevant comparators; any medicine in routine use or considered to be best practice should be considered a potential comparator. The Committee also noted advice from the NICE Board that the decision to include bevacizumab as a comparator should be based on both a careful consideration of its use in clinical practice for wet age‑related macular degeneration and a thorough assessment of its efficacy, quality and safety. The Committee was aware of recently published evidence from the IVAN and CATT trials comparing the clinical efficacy and safety of bevacizumab with ranibizumab in people with wet age‑related macular degeneration, which has addressed some of these issues. However, the Committee acknowledged that bevacizumab was not included as a comparator treatment in the appraisal of ranibizumab and pegaptanib for the treatment of age\u2011\related macular degeneration (NICE technology appraisal guidance 155), and that this appraisal was undertaken before the emergence of evidence on the clinical effectiveness of bevacizumab. Therefore, the Committee agreed that it was reasonable to defer consideration of bevacizumab as a comparator in this appraisal. In the interests of fairness, it also agreed that the proposed review of the guidance on aflibercept should coincide with the review date for NICE technology appraisal guidance 155, which should also include bevacizumab (see section 7). The Committee considered the manufacturer's decision to exclude photodynamic therapy as a comparator in its submission, despite being listed as a comparator in the scope. The Committee noted from the manufacturer that, although NICE technology appraisal guidance 68 recommended photodynamic therapy for the treatment of wet age‑related macular degeneration for individuals who have a confirmed diagnosis of classic with no occult subfoveal choroidal neovascularisation, clinical practice has subsequently changed for this group and that newer treatments, including anti‑vascular endothelial growth factor (VEGF) therapies have superseded photodynamic therapy. The Committee heard from the clinical specialists that photodynamic therapy is currently used in combination with an anti‑VEGF therapy for treating wet age‑related macular degeneration in people with polypoidal choroidal vasculopathy whose condition does not respond to initial anti‑VEGF therapy (approximately 10–15% of patients). Therefore, the Committee considered that photodynamic therapy would only be offered as a second‑line treatment option after first‑line anti‑VEGF therapy for this group of people and concluded that it was reasonable to exclude photodynamic therapy as a comparator in this appraisal. # Clinical effectiveness The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of aflibercept. The Committee noted that the main sources of evidence came from the VIEW 1 and 2 trials which compared aflibercept (2 mg every 8 weeks) with ranibizumab (0.5 mg every 4 weeks) in people with wet age‑related macular degeneration and that both studies were considered to be of high quality by the Evidence Review Group (ERG). It also noted that aflibercept at its licensed dose was shown to be clinically non‑inferior to ranibizumab in terms of visual acuity outcomes at 96 weeks. The Committee concluded that aflibercept is a clinically effective treatment option for visual impairment caused by wet age‑related macular degeneration. The Committee considered the network meta‑analyses and indirect comparisons submitted by the manufacturer, which estimated the clinical effectiveness of aflibercept at its licensed dose compared with ranibizumab in a 'treatment as needed' regimen at 12 and 24 months. The Committee accepted the concerns highlighted by the manufacturer and the ERG about the validity of these analyses because of the heterogeneity of the included studies. It was also aware that, although the point estimates for visual acuity outcomes favoured aflibercept, no statistically significant differences compared with ranibizumab were reported. The Committee concluded that, in the absence of stronger evidence, the results could be used to inform decisions about the clinical effectiveness of aflibercept compared with ranibizumab in a 'treatment as needed' regimen. The Committee considered the evidence for adverse events associated with aflibercept. The Committee noted that the frequency of adverse events in both treatment groups in the VIEW 1 and 2 trials was low. The Committee noted that the manufacturer had not provided a formal statistical analysis comparing adverse events between the 2 treatment groups. However, it also noted that no clinically meaningful differences in adverse events were reported by the manufacturer or the ERG. The Committee concluded that aflibercept was safe and well tolerated in patients with wet age‑related macular degeneration. # Cost effectiveness The Committee considered the manufacturer's economic model and the ERG's critique and exploratory analyses. The Committee noted that the model structure accounted for different levels of visual acuity in both eyes rather than the first eye to come to clinical attention. The Committee also noted the ERG's concerns about the manufacturer's approach to modelling second‑eye involvement. The Committee agreed with the ERG that it was unrealistic to assume no second‑eye involvement in the first 2 years of the model because a large proportion of patients in the VIEW 1 and 2 trials had visual impairment in their second eye at the start of treatment. It also agreed that the manufacturer did not give appropriate consideration to the timing of second‑eye involvement because the effect of treatment on visual acuity in the second eye and any associated costs were limited to years 3 to 5 in the model. The Committee concluded that the ERG's exploratory approach, which involved separate analyses depending on whether the study eye was a better‑seeing eye or worse‑seeing eye, was more reasonable. The Committee discussed the clinical‑effectiveness data that were used in the economic model. The Committee noted that clinical‑effectiveness data for aflibercept were derived from the VIEW 2 study only rather than from a pooled analysis of the VIEW 1 and 2 studies. The Committee heard from the manufacturer that this was because VIEW 2 was conducted across multiple centres including the UK and therefore was more relevant to UK clinical practice than the VIEW 1 study, and also because the EQ‑5D utility values used in the model were collected in the VIEW 2 study. The Committee agreed that using clinical-effectiveness data from VIEW 1 only was unlikely to introduce any additional bias because results were similar between VIEW 1 and 2 and a pooled analysis of both studies. The Committee also noted the ERG's comments that the manufacturer had applied comparative clinical‑effectiveness data in terms of visual acuity from its network meta‑analyses and indirect comparisons between baseline and 12 months and between 12 months and 24 months rather than between baseline and 12 months and between baseline and 24 months. It noted that this resulted in aflibercept having better visual acuity than ranibizumab at 24 months in the model although the point estimates from the indirect comparison showed that aflibercept resulted in slightly worse outcomes. The Committee agreed with the ERG that the results of the manufacturer's indirect comparison at 24 months provided comparative clinical‑effectiveness data between baseline and 24 months, and it concluded that the ERG's exploratory analysis that incorporated this data was the preferred approach. The Committee discussed the manufacturer's assumptions about the number of treatment and monitoring visits people in both treatment groups needed in the model. The Committee considered that, in the absence of any longer‑term data, it was reasonable for the manufacturer to assume that both treatment groups would have the same number of treatment and monitoring visits in years 3 to 5 of the model. The Committee noted that the manufacturer assumed that people receiving aflibercept had 7 treatment visits in the first year based on the summary of product characteristics. However, the Committee agreed with the ERG that it was more likely that people treated with aflibercept would need 8 treatment visits in the first year of the model on the basis of the average number of injections that patients received in the VIEW 2 study. It also noted that the ERG had corrected for this in its exploratory analyses. The Committee was aware that there are data from UK clinical practice on the treatment and monitoring frequency of ranibizumab but that no such data on the use of aflibercept currently exist. For this reason, the Committee considered that it would be fairer to use the same data that were used to estimate the relative clinical effectiveness of aflibercept and ranibizumab to inform assumptions about the number of treatment and monitoring visits in the model. Therefore, the Committee concluded that it was reasonable to assume that people in both treatment groups would need 8 treatment visits in the first year of the model in line with the approach taken by the ERG in its exploratory analyses. The Committee discussed the manufacturer's assumptions about whether treatment administration and monitoring occurred at the same visit. The Committee noted that the manufacturer had assumed that, in the first year of the model, people in the aflibercept group had their treatment administration and monitoring at the same visit in a one‑stop model but 50% of people in the ranibizumab group had separate monitoring visits in a two‑stop model. The Committee heard from the clinical specialists that, in future clinical practice, it is expected that fewer people treated with anti‑VEGF therapies would need separate treatment and monitoring visits. The Committee noted that, if a higher proportion of people in both treatment groups had their treatment administration and monitoring at the same visit, this would reduce the total incremental costs of ranibizumab compared with aflibercept because of the higher number of monitoring visits needed by people treated with ranibizumab in the first 2 years of the manufacturer's model. However, the Committee agreed that, for people who had their treatment and monitoring at the same visit in a one-stop model, the aflibercept group had no separate monitoring visits in the first year and 2 separate visits in the second year and the ranibizumab group had 4 separate monitoring visits in the first year and 6 separate visits in the second year. The Committee also agreed that, for people who had their treatment and monitoring at separate visits in a two-stop model, the aflibercept group had 7 separate monitoring visits in the first year and 6 separate monitoring visits in the second year and the ranibizumab group had 12 separate monitoring visits in the first 2 years. The Committee concluded that, based on current clinical practice, it was reasonable to assume that 50% of people in both treatment groups would need separate monitoring visits in line with the approach taken by the ERG in its exploratory analyses. The Committee discussed the manufacturer's assumptions about the costs of treatment and monitoring visits. The Committee noted that the manufacturer's estimated cost per treatment visit was higher than the cost used in the appraisal of ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance 274) and that the ERG also estimated a lower average cost per treatment visit of £129. However, the Committee heard from the clinical specialists that the ERG's lower estimate was likely to be an underestimate of the true costs of a treatment visit. The Committee also heard from the clinical specialists that the ERG's estimated cost for optical coherence tomography of £51 as part of a monitoring visit was probably too low. Overall, the Committee concluded that although some uncertainty remained about the true costs involved in treatment and monitoring visits for people with wet age‑related macular degeneration, the estimates used in the ERG's exploratory analyses were a fair reflection of the costs involved. The Committee considered the incremental cost‑effectiveness ratios (ICERs) estimated by the manufacturer and the ERG, which incorporated the confidential discounts applied to the list prices of aflibercept and ranibizumab agreed under the respective patient access schemes. The Committee noted that, in the manufacturer's base‑case analysis, aflibercept dominated (that is, was less expensive and more effective than) ranibizumab. The Committee also considered its preferred analyses based on the ERG's exploratory approach, which incorporated separate analyses depending on whether the study eye was a better‑seeing eye or a worse‑seeing eye, and its preferred assumptions about the frequency of injections, monitoring visits and clinical‑effectiveness data (see sections 4.8 to 4.11). It noted that these exploratory analyses incorporated the confidential discount to the list price of aflibercept and a range of discounts (from 0 to 50%) to the list price of ranibizumab. The Committee also noted that, when discounts to the list price of ranibizumab ranged from 0 to 45%, aflibercept had lower costs and quality-adjusted life years (QALYs) than ranibizumab, which resulted in ICERs for aflibercept compared with ranibizumab ranging from £1,690,000 to £16,700 saved per QALY lost and that, when a 50% discount was applied to the list price of ranibizumab, aflibercept was dominated by ranibizumab in both the worse-seeing eye and better-seeing eye models (see section 3.39). However, the Committee was aware that, in both the manufacturer's and the ERG's analyses, the differences in total costs and QALYs were very small. The Committee therefore concluded that aflibercept could be recommended as a cost‑effective use of NHS resources if ranibizumab would otherwise be the treatment used. The Committee discussed whether aflibercept solution for injection should be recommended within the terms of its UK marketing authorisation, that is, for the treatment of neovascular (wet) age‑related macular degeneration, or whether a more restrictive set of criteria was necessary. The Committee noted that guidance on the use of ranibizumab outlined in NICE technology appraisal guidance 155 was based on a more restrictive set of criteria than described in the terms of its UK marketing authorisation and that these criteria were set out in the clinical trials for ranibizumab for treating wet age‑related macular degeneration. It also noted that these criteria were very similar to those set out in the VIEW 1 and 2 studies. The Committee also heard from the clinical specialists that they would prefer that the use of aflibercept should not be restricted to people with a best‑corrected visual acuity between 6/12 and 6/96, as is the case with ranibizumab in NICE technology appraisal guidance 155. However, the Committee concluded that it would be appropriate to recommend aflibercept as a treatment option for people with wet age‑related macular degeneration if it is used according to the same criteria as described for the use of ranibizumab in NICE technology appraisal guidance 155 until both technologies could be appraised simultaneously in the context of a multiple technology appraisal. The Committee discussed how innovative aflibercept is in its potential to make a significant and substantial impact on health‑related benefits. It agreed that anti‑VEGF treatments were a substantial improvement over previous treatments, but considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was in the development of anti‑VEGF treatments, not the act of licensing. In addition the Committee was not aware of any substantial benefits of aflibercept compared with ranibizumab that had not already been captured in the manufacturer's economic model. The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal in the guidance. # Summary of Appraisal Committee's key conclusions TA294 Appraisal title: Aflibercept solution for injection for treating wet age‑related macular degeneration Section Key conclusion Aflibercept solution for injection is recommended as an option for treating wet age‑related macular degeneration only if it is used in accordance with the recommendations for ranibizumab in NICE technology appraisal guidance 155 (re‑issued in May 2012) and the manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme. The Committee noted that its preferred analyses incorporated the confidential discount to the list price of aflibercept and a range of discounts (from 0 to 50%) to the list price of ranibizumab. It also noted that, when discounts to the list price of ranibizumab ranged from 0 to 45%, aflibercept had lower costs and quality-adjusted life years (QALYs) than ranibizumab, which resulted in ICERs for aflibercept compared with ranibizumab ranging from £1,690,000 to £16,700 saved per QALY lost and that, when a 50% discount was applied to the list price of ranibizumab, aflibercept was dominated by ranibizumab in both the worse-seeing eye and better-seeing eye models. However, the Committee was aware that, in both the manufacturer's and the ERG's analyses, the differences in total costs and QALYs were very small. The Committee therefore concluded that aflibercept could be recommended as a cost‑effective use of NHS resources if ranibizumab would otherwise be the treatment used. Current practice Clinical need of patients, including the availability of alternative treatments The Committee agreed that loss of vision caused by wet age‑related macular degeneration can substantially impair health‑related quality of life. The Committee heard from the clinical specialists that the current standard treatment for wet age‑related macular degeneration is ranibizumab as a consequence of NICE technology appraisal guidance 155. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits? The Committee understood from the clinical specialists that an important advantage of aflibercept is that it needs less frequent administration than ranibizumab while achieving similar clinical outcomes, as seen in the clinical trials, thus imposing less burden on NHS capacity. The Committee was not aware of any substantial benefits of aflibercept compared with ranibizumab that had not already been captured in the manufacturer's economic model. What is the position of the treatment in the pathway of care for the condition? Aflibercept solution for injection has a UK marketing authorisation 'for adults for the treatment of neovascular (wet) age‑related macular degeneration (AMD)'. Adverse reactions The Committee concluded that aflibercept was safe and well tolerated in patients with wet age‑related macular degeneration. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee noted that the main sources of evidence came from the VIEW 1 and 2 trials which compared aflibercept (2 mg every 8 weeks) with ranibizumab (0.5 mg every 4 weeks) in people with wet age‑related macular degeneration and that both studies were considered to be of high quality by the Evidence Review Group (ERG). For the comparison of aflibercept at its licensed dose with ranibizumab in a 'treatment as needed' regimen at 12 and 24 months, the Committee accepted the concerns highlighted by the manufacturer and the ERG about the validity of the manufacturer's network meta‑analyses and indirect comparisons because of the heterogeneity of the included studies. The Committee concluded that, in the absence of stronger evidence, the results could be used to inform decisions about the clinical effectiveness of aflibercept compared with ranibizumab in a 'treatment as needed' regimen. Relevance to general clinical practice in the NHS The clinical specialists explained that people treated with ranibizumab and bevacizumab should have their condition monitored every 4 weeks and that very few NHS trusts were able to manage wet age-related macular degeneration at such regular intervals. They also stated that patients usually receive 6 ranibizumab injections in the first year of treatment rather than up to 12 injections seen in the clinical trials. The clinical specialists commented that data from several UK ophthalmology departments suggest that the current ranibizumab treatment regimen is inadequate and so visual acuity outcomes may be inferior to results reported in the clinical trials. However, the Committee also acknowledged that these inferior visual acuity outcomes could be attributed to the widening range of disease severity seen in clinical practice. Uncertainties generated by the evidence The Committee acknowledged that bevacizumab was not included as a comparator treatment in the appraisal of ranibizumab and pegaptanib for the treatment of age\u2011\related macular degeneration (NICE technology appraisal guidance 155), although this was undertaken before the emergence of evidence on the clinical effectiveness of bevacizumab. Therefore, the Committee agreed that it was reasonable to defer consideration of bevacizumab as a comparator in this appraisal. In the interests of fairness, it also agreed that the proposed review of the guidance on aflibercept should coincide with the review date for NICE technology appraisal guidance 155, which should also include bevacizumab. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? None was identified. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that aflibercept at its licensed dose was shown to be clinically non‑inferior to ranibizumab in terms of visual acuity outcomes at 96 weeks. The Committee concluded that aflibercept is a clinically effective treatment option for visual impairment caused by wet age‑related macular degeneration. For the network meta‑analyses and indirect comparisons submitted by the manufacturer, the Committee was aware that, although the point estimates for visual acuity outcomes favoured aflibercept, no statistically significant differences with ranibizumab were reported. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the manufacturer's economic model and the ERG's critique and exploratory analyses. The Committee agreed with the ERG that it was unrealistic to assume no second‑eye involvement in the first 2 years of the model because a large proportion of patients in the VIEW 1 and 2 trials had visual impairment in their second eye at the start of treatment. The Committee concluded that the ERG's exploratory approach, which involved separate analyses depending on whether the study eye was a better‑seeing eye or worse‑seeing eye, was more reasonable. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee noted the ERG's comments that the manufacturer had applied comparative clinical-effectiveness data in terms of visual acuity from its network meta‑analyses and indirect comparisons between baseline and 12 months and between 12 months and 24 months rather than between baseline and 12 months and between baseline and 24 months. The Committee agreed with the ERG that the results of the manufacturer's indirect comparison at 24 months provided comparative clinical-effectiveness data between baseline and 24 months, and it concluded that the ERG's exploratory analysis that incorporated this data was the preferred approach. The Committee concluded that it was reasonable to assume that people in both treatment groups would need 8 treatment visits in the first year of the model in line with the approach taken by the ERG in its exploratory analyses. The Committee concluded that, based on current clinical practice, it was reasonable to assume that 50% of people in both treatment groups would need separate monitoring visits in line with the approach taken by the ERG in its exploratory analyses. The Committee concluded that although some uncertainty remained about the true costs involved in treatment and monitoring visits for people with wet age‑related macular degeneration, the estimates used in the ERG's exploratory analyses were a fair reflection of the costs involved. Incorporation of health‑related quality‑of‑life benefits and utility values Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered? No specific conclusions were made by the Committee about health‑related quality‑of‑life benefits and utility values. Are there specific groups of people for whom the technology is particularly cost effective? None was identified. What are the key drivers of cost effectiveness? The results of the manufacturer's one‑way sensitivity analyses indicated that the cost effectiveness of aflibercept was most sensitive to the drug acquisition costs, frequency of injections and monitoring visits, proportion of people in one‑stop and two‑stop models, discount rates and the relative risk of gaining or losing visual acuity with ranibizumab treatment. Most likely cost‑effectiveness estimate (given as an ICER) The Committee noted that its preferred analyses incorporated the confidential discount to the list price of aflibercept and a range of discounts (from 0 to 50%) to the list price of ranibizumab. It also noted that, when discounts to the list price of ranibizumab ranged from 0 to 45%, aflibercept had lower costs and quality-adjusted life years (QALYs) than ranibizumab, which resulted in ICERs for aflibercept compared with ranibizumab ranging from £1,690,000 to £16,700 saved per QALY lost and that, when a 50% discount was applied to the list price of ranibizumab, aflibercept was dominated by ranibizumab in both the worse-seeing eye and better-seeing eye models. However, the Committee was aware that, in both the manufacturer's and the ERG's analyses, the differences in total costs and QALYs were very small. Additional factors taken into account Patient access schemes (PPRS) The manufacturer of aflibercept solution for injection has agreed a patient access scheme with the Department of Health. This involves a confidential discount applied to the list price of aflibercept solution for injection. The level of the discount is commercial in confidence. End‑of‑life considerations Not applicable. Equalities considerations and social value judgements The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal in the guidance. # Related NICE guidance Epiretinal brachytherapy for wet age related macular degeneration. NICE interventional procedure guidance 415 (2011). Macular translocation with 360° retinotomy for wet age\u2011\related macular degeneration. NICE interventional procedure guidance 340 (2010). Limited macular translocation for wet age\u2011\related macular degeneration. NICE interventional procedure guidance 339 (2010). Implantation of miniature lens systems for advanced age\u2011\related macular degeneration. NICE interventional procedure guidance 272 (2008). Ranibizumab and pegaptanib for the treatment of age\u2011\related macular degeneration. NICE technology appraisal guidance 155 (2008). Transpupilary thermotherapy for age\u2011\related macular degeneration. NICE interventional procedure guidance 58 (2004). Radiotherapy for age\u2011\related macular degeneration. NICE interventional procedure guidance 49 (2004). Guidance on the use of photodynamic therapy for age\u2011\related macular degeneration. NICE technology appraisal guidance 68 (2003).# Review of guidance The guidance on this technology will be considered for review in February 2014. This is to coincide with the review date proposed for NICE technology appraisal guidance 155 (ranibizumab and pegaptanib for the treatment of age‑related macular degeneration). The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew Dillon Chief ExecutiveJuly 2013# Changes after publication January 2014: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0234-7	{'Guidance': 'Aflibercept solution for injection is recommended as an option for treating wet age‑related macular degeneration only if:\n\nit is used in accordance with the recommendations for ranibizumab in NICE technology appraisal guidance\xa0155 (re‑issued in May 2012) and\n\nthe manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme.\n\nPeople currently receiving aflibercept solution for injection whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology': "Aflibercept solution for injection (Eylea, Bayer Pharma) is a soluble vascular endothelial growth factor (VEGF) receptor fusion protein which binds to all forms of VEGF‑A, VEGF‑B, and the placental growth factor. Aflibercept solution for injection prevents these factors from stimulating the growth of the fragile and permeable new blood vessels associated with wet age‑related macular degeneration. Aflibercept solution for injection has a UK marketing authorisation 'for adults for the treatment of neovascular (wet) age‑related macular degeneration (AMD)'.\n\nThe summary of product characteristics states that the recommended dose for aflibercept is 2\xa0mg and that treatment should be given monthly for 3\xa0consecutive doses, followed by 1\xa0injection every 2\xa0months. Each 100‑microlitre vial contains 4\xa0mg of aflibercept. Aflibercept solution for injection must only be administered by a qualified doctor experienced in administering intravitreal injections. The summary of product characteristics also states that there is no need for monitoring between injections. After the first 12\xa0months of treatment, the treatment interval may be extended based on visual and anatomic outcomes. In this case the schedule for monitoring should be determined by the treating doctor.\n\nThe summary of product characteristics lists the following most common adverse reactions for aflibercept solution for injection: conjunctival haemorrhage, eye pain, vitreous detachment, cataract, vitreous floaters and increased intraocular pressure. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe list price of aflibercept 40\xa0mg/ml solution for injection is £816 per 100‑microlitre vial (excluding VAT; 'British national formulary' [BNF] edition\xa052). The manufacturer of aflibercept solution for injection has agreed a patient access scheme with the Department of Health. This involves a confidential discount applied to the list price of aflibercept solution for injection. The level of the discount is commercial in confidence (see section\xa05.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.", "The manufacturer's submission": "The Appraisal Committee (section\xa08) considered evidence submitted by the manufacturer of aflibercept solution for injection and a review of this submission by the Evidence Review Group (ERG; section\xa09).\n\n# Clinical effectiveness\n\nThe manufacturer performed a systematic literature review of the evidence on the clinical effectiveness of aflibercept. The review identified 2\xa0studies that directly compared aflibercept with ranibizumab in people with wet age‑related macular degeneration: VIEW\xa01 (n=1217) and VIEW\xa02 (n=1240). Both studies were multicentre (VIEW\xa01: 154\xa0centres in USA and Canada; VIEW\xa02: 172\xa0centres in 26\xa0countries, including the UK), active‑controlled, double‑blind, randomised trials that compared aflibercept with ranibizumab. Both studies were identical in design (except for location) so that data could be pooled. Only one eye per patient was included in both studies. If a patient needed treatment in the second eye during the study, the second eye was allowed to receive any approved treatment although it was not included in the study. In both studies patients were randomised on a 1:1:1:1 basis to receive either (i) aflibercept 2\xa0mg every 8\xa0weeks after 3\xa0initial monthly loading doses, (ii) aflibercept 2\xa0mg every 4\xa0weeks, (iii) aflibercept 0.5\xa0mg every 4\xa0weeks, or (iv) ranibizumab 0.5\xa0mg every 4\xa0weeks. The manufacturer stated that both studies were designed primarily to test whether aflibercept at its recommended dose (2\xa0mg every 8\xa0weeks) was non‑inferior to ranibizumab (0.5\xa0mg every 4\xa0weeks). Therefore, the results reported here are limited to the treatment arms of both studies. The manufacturer stated that non‑inferiority margins and definitions were established in discussion with the US Food and Drugs Administration, European Medicines Agency and other regulatory agencies to be consistent with key trials of ranibizumab, including the MARINA study (2006), for treating wet age‑related macular degeneration. Both studies had 2\xa0phases, including a primary phase (from randomisation to week\xa048) during which patients received treatment according to randomisation arm, with patients in the aflibercept 2\xa0mg every 8\xa0weeks arm receiving sham injections when no active treatment was due. In the follow‑up extension phase (up to 92\xa0weeks), patients in all 4\xa0treatment arms continued to be evaluated every 4\xa0weeks and remained in their allocated treatment groups. The total duration of both studies was 96\xa0weeks consisting of up to 92\xa0weeks of treatment plus a screening period and a 4‑week safety follow‑up period.\n\nFor both studies, the manufacturer defined 3\xa0populations for analysis. The full analysis set included all randomised patients who received any study drug and had a baseline and at least 1\xa0post‑baseline assessment. The per protocol set included all patients in the full analysis set who received at least 9\xa0injections of study drug or sham and attended at least 9\xa0scheduled visits during the first 52\xa0weeks, except for those who were excluded because of major protocol violations. The safety analysis set included all patients who received any study drug. The manufacturer stated that the per protocol set was used for primary analysis (statistical evaluation of non‑inferiority). A patient who withdrew from the study before week\xa036 because of treatment failure was considered a 'non‑responder'. The last observation carried forward approach was used to calculate missing data except for baseline values. Patients withdrawing before week\xa036 were not included in the primary analysis but were included in the secondary analysis (in the full analysis set).\n\nThe baseline demographics and disease characteristics were similar between the aflibercept 2\xa0mg every 8\xa0weeks and ranibizumab treatment arms in the VIEW\xa01 and 2\xa0studies. In VIEW\xa01, the mean age was 78\xa0years, 41% of patients were male, and 97% of patients were white. In VIEW\xa02, the mean age was 73–75\xa0years, 45% of patients were male, and 73% of patients were white. The total mean baseline best‑corrected visual acuity score (defined by Early Treatment Diabetic Retinopathy Study [ETDRS] scale) ranged from 54 to 56\xa0letters in VIEW\xa01 and from 52 to 54\xa0letters in VIEW\xa02. In both studies, the distribution of occult, minimally classic and predominantly classic lesion types in the study eye was similar across both treatment arms.\n\nThe primary outcome of VIEW\xa01 and 2 was the proportion of patients who maintained vision at week\xa052, defined as losing fewer than 15\xa0letters on the ETDRS scale compared with baseline. This outcome was also measured at week\xa096. In a pooled analysis of both studies, the proportion of patients treated with aflibercept who maintained vision at week\xa052 was 95.3% compared with 94.4% of patients treated with ranibizumab (difference −0.9%, 95%\xa0confidence interval [CI] −3.5 to 1.7). At week\xa096, the proportion of patients treated with aflibercept who maintained vision was 92.4% compared with 91.6% of patients treated with ranibizumab (difference −0.8%, 95%\xa0CI −3.8 to 2.3). The manufacturer stated that aflibercept showed non‑inferiority to ranibizumab at weeks\xa052 and 96 because the upper limits of the confidence intervals for the differences in proportions were consistently below the pre‑specified boundary of 10%. The manufacturer also evaluated the primary outcome for pre‑planned subgroup analyses in both studies by age, sex, race, renal function, hepatic impairment, baseline visual acuity, lesion size and type. The manufacturer stated that the results for all subgroups in both studies and in pooled analyses were consistent with the results in the whole study populations. However, the results of these subgroup analyses were not presented by the manufacturer.\n\nSecondary outcomes in VIEW\xa01 and 2 included changes from baseline to week\xa052 for: best‑corrected visual acuity as measured by ETDRS letter score, proportion of patients gaining at least 15\xa0letters, and choroidal neovascularisation area. For the outcome of best‑corrected visual acuity at week\xa052, mean ETDRS letter scores increased by approximately 7−11\xa0letters in both treatment arms in VIEW\xa01 and by approximately 8–10\xa0letters in VIEW\xa02. No statistically significant differences in change in best‑corrected visual acuity from baseline to week\xa052 were reported between aflibercept and ranibizumab in a pooled analysis of both studies (mean difference −0.32\xa0letters, 95%\xa0CI\xa0−1.87 to 1.23). In VIEW\xa01 and 2, improvements in visual acuity observed at week\xa052 were largely maintained at week\xa096 in both treatment arms. No statistically significant differences in the proportion of patients who gained at least 15\xa0ETDRS letters were reported between aflibercept and ranibizumab treatment arms at week\xa052 in a pooled analysis of both studies (30.97% and 32.44% respectively, p‑value not reported). Similar results were reported at week\xa096. In VIEW\xa01, the ranibizumab arm had a statistically significantly greater mean reduction in choroidal neovascularisation area at week\xa052 than the aflibercept arm (−4.2\xa0mm2 and −3.4\xa0mm2 respectively, p=0.017). No statistically significant differences in choroidal neovascularisation area at week\xa052 were reported between ranibizumab and aflibercept 2\xa0mg every 8\xa0weeks in VIEW\xa02 (−4.16\xa0mm2 and −5.16\xa0mm2 respectively, p=0.073). Similar results were also reported at week\xa096 in both studies.\n\nVision‑related quality of life was measured in VIEW\xa01 and 2 using the National Eye Institute Visual Function Questionnaire‑25 (NEI\xa0VFQ‑25), which includes 25\xa0questions designed to measure the effect of visual impairment on daily functioning and quality of life. Improvements in the mean NEI\xa0VFQ‑25 total score from baseline to week\xa052 were similar in both the aflibercept and the ranibizumab treatment arms in a pooled analysis of both studies (5.0\xa0points and 5.6\xa0points respectively, p‑value not reported). These improvements in vision‑related quality of life were maintained at week\xa096 in both treatment arms. The VIEW\xa02 study also measured changes in health‑related quality of life using the EQ‑5D questionnaire, which were incorporated in the manufacturer's cost‑effectiveness analysis.\n\nThe manufacturer did not present a formal meta‑analysis of the VIEW\xa01 and 2 studies on the basis that both studies were similarly designed so that their data could be pooled directly. The manufacturer commented that, although the VIEW\xa01 and 2 studies used a fixed dosing regimen for ranibizumab (0.5\xa0mg every 4\xa0weeks), in clinical practice a 'treatment as needed' approach is used which involves monthly ranibizumab treatment until the patient's visual acuity is stable for 3\xa0consecutive months, with re‑treatment in a similar way upon loss of visual acuity (with a minimum of 2\xa0injections). Therefore, the manufacturer conducted a systematic literature review and mixed treatment comparison (network meta‑analysis) to compare aflibercept 2\xa0mg every 8\xa0weeks with ranibizumab 0.5\xa0mg in a 'treatment as needed' regimen.\n\nThe manufacturer produced 3\xa0networks at 6, 12 and 24\xa0months. Because no data were available for aflibercept at 6\xa0months, only networks for outcomes at 12 and 24\xa0months were considered further by the manufacturer. The manufacturer assumed that 52‑week and 96‑week data from VIEW\xa01 and 2 corresponded with outcomes at 12 and 24\xa0months respectively. Results were presented for 3\xa0outcomes: maintained vision (defined as the proportion of patients losing 15\xa0or fewer ETDRS letters), improved vision (defined as the proportion of patients gaining more than 15\xa0ETDRS letters) and mean change from baseline in best‑corrected visual acuity. The network meta‑analysis of outcomes at 12\xa0months incorporated up to 10\xa0studies, depending on the outcome, and included the VIEW\xa01 and 2\xa0studies. For the outcome of mean change from baseline in best‑corrected visual acuity, the manufacturer repeated the analysis after excluding one study (DETAIL study; London et al. 2009) because patients in the study responded differently to ranibizumab in a 'treatment as needed' regimen compared with other studies.\n\nThe manufacturer presented separate network meta‑analyses for outcomes at 12\xa0months, using both frequentist methods, based on traditional statistical methods applied in making comparisons, and Bayesian methods, which combine the probability of the data as a function of the parameters with prior beliefs about possible values of those parameters. These analyses showed no statistically significant differences between aflibercept 2\xa0mg every 8\xa0weeks and ranibizumab 0.5\xa0mg treatment as needed in the proportion of patients who maintained vision (frequentist method: odds ratio [OR] 1.44, 95%\xa0CI 0.68 to 3.09; Bayesian method: OR 1.51, 95% CI 0.42 to 5.94) or gained vision (frequentist method: OR 1.29, 95%\xa0CI 0.91 to 1.83; Bayesian method: OR 1.28, 95%\xa0CI 0.45 to 3.68). No statistically significant differences in mean change in best‑corrected visual acuity at 12\xa0months were shown between aflibercept 2\xa0mg every 8\xa0weeks and ranibizumab 0.5\xa0mg treatment as needed (frequentist method: mean difference 0.83, 95%\xa0CI −1.57 to 3.23; Bayesian method: mean difference −2.87, 95%\xa0CI −10.02 to 4.30). When the manufacturer repeated the analysis after excluding the DETAIL study, the results for the outcome of mean change in best‑corrected visual acuity at 12\xa0months were similar (frequentist method: mean difference 1.35, 95%\xa0CI −1.08 to 3.77; Bayesian method: mean difference 1.15, 95%\xa0CI −3.92 to 6.09).\n\nThe manufacturer did not present a network meta‑analysis of outcomes at 24\xa0months because VIEW\xa01 and 2 both allowed treatment switching after 12\xa0months from a fixed dosing regimen of aflibercept 2\xa0mg every 8\xa0weeks to a treatment as needed regimen (aflibercept fixed 2\xa0mg every 8\xa0weeks/treatment as needed). Therefore, two‑step indirect comparisons, based on the Bucher method, were used to compare aflibercept fixed 2\xa0mg every 8\xa0weeks/treatment as needed with ranibizumab 0.5\xa0mg treatment as needed. The indirect comparisons included data from 3\xa0studies: VIEW\xa01 and 2, and CATT, a 2‑year study that compared ranibizumab 0.5\xa0mg with bevacizumab for treating patients with wet age‑related macular degeneration (CATT Research Group, 2012). The CATT study presented data for ranibizumab as an identical switch trial and as fixed dose or treatment as needed only. Both sets of data from the CATT study were analysed for the indirect comparison.\n\nThe results of the manufacturer's indirect comparison for the outcomes at 24\xa0months also showed no statistically significant differences between aflibercept fixed 2\xa0mg every 8\xa0weeks/treatment as needed and ranibizumab 0.5\xa0mg treatment as needed in the proportion of patients who maintained vision (relative risk 0.99, 95%\xa0CI 0.93 to 1.07) or gained vision (relative risk 0.88, 95%\xa0CI 0.61 to 1.28). No statistically significant differences in mean change in best‑corrected visual acuity at 24\xa0months were shown between aflibercept 2\xa0mg every 8\xa0weeks and ranibizumab 0.5\xa0mg treatment as needed (mean difference 0.31, 95%\xa0CI −4.33 to 3.71).\n\nThe manufacturer highlighted concerns about the validity of the network meta‑analyses and indirect comparisons because of the heterogeneity between the included studies. On the basis of a quality assessment checklist, the manufacturer found that 3\xa0of the included studies had a high risk of bias. The manufacturer also noted that several of the studies had different baseline characteristics in terms of ETDRS letter score, treatment as needed re‑treatment criteria, proportion of men, central retinal thickness and numbers of injections. The manufacturer commented that sensitivity analyses were performed with regard to the heterogeneity but that the results were unchanged.\n\nThe manufacturer stated that the safety and tolerability of aflibercept compared with ranibizumab for up to 96\xa0weeks was included as a secondary objective in the VIEW\xa01 and 2 studies. On the basis of the safety analysis dataset, no clinically meaningful differences were reported between aflibercept and ranibizumab for treatment‑emergent adverse events, with similar incidences of reported events between treatment arms. The most common treatment‑emergent adverse events (reported in at least 5% of patients treated with aflibercept in VIEW\xa01 and 2) were: conjunctival haemorrhage (26.7%), eye pain (10.3%), vitreous detachment (8.4%), cataract (7.9%), vitreous floaters (7.6%), and increased intraocular pressure (7.2%). The incidence of arterial thromboembolic events (including non‑fatal myocardial infarction, non‑fatal stroke or vascular stroke), which are potentially related to anti‑VEGF treatment, was also similar between the aflibercept (3.3%) and ranibizumab (3.2%) treatment groups in VIEW\xa01 and 2.\n\n# Cost effectiveness\n\nThe economic evidence provided by the manufacturer included a literature review, which identified one published cost‑effectiveness analysis of aflibercept in US patients with wet age‑related macular degeneration, and a de novo cost–utility analysis. The manufacturer developed a Markov state‑transition cohort model simulating cohorts of people with wet age‑related macular degeneration receiving aflibercept 2\xa0mg every 8\xa0weeks or ranibizumab 0.5\xa0mg treatment as needed. The model assumed a cycle length of 1\xa0month based on the level of monitoring associated with ranibizumab treatment, and used a lifetime horizon (25\xa0years based on a starting age of 74\xa0years). An NHS and personal social services perspective was taken and costs and benefits were discounted at 3.5%.\n\nThe economic model included a total of 30\xa0health states defined by a combination of different levels of visual acuity in both eyes (the treated eye and the second eye) in addition to the absorbing health state of death. For each health state, visual acuity in the treated eye or second eye was defined according to 5\xa0possible levels on the ETDRS scale, ranging from no visual impairment (ETDRS more than 80\xa0letters) to blindness (ETDRS fewer than 36\xa0letters) with 3\xa0intermediate levels (ETDRS 66–80\xa0letters; 51–65\xa0letters and 36–50\xa0letters). In each model cycle, people were assumed to have the median visual acuity of each ETDRS range and moved to the median value of either the adjacent state or the state 2\xa0levels higher or lower, based on the number of letters gained or lost. For each health state, the patient could either be on or off active treatment.\n\nThe economic model included a 5‑year treatment period on the basis of clinical opinion which suggested that patients are likely to continue treatment beyond 24\xa0months. For the first 2\xa0years, clinical-effectiveness data at baseline, 52 and 96\xa0weeks from the last observation carried forward population in the VIEW\xa02 study were used to estimate the visual acuity of people receiving aflibercept. The probabilities of gaining and losing visual acuity in year\xa01 were applied to the VIEW\xa02 patient distribution at baseline and the probabilities of gaining and losing visual acuity in year\xa02 were applied to the modelled year\xa01 distribution. The visual acuity of people receiving ranibizumab for the first 2\xa0years of the model was estimated from the relative risks of improving and maintaining vision for aflibercept compared with ranibizumab taken from the manufacturer's network meta‑analysis and indirect comparison of aflibercept 2\xa0mg every 8\xa0weeks with ranibizumab 0.5\xa0mg treatment as needed. During this period, people who were defined as being in the blind health state received treatment with ranibizumab or aflibercept. However, this did not continue in years\xa03 to 5 on the basis of clinical opinion which suggested that the blind eye is unlikely to benefit from treatment. Simple linear interpolation was used to populate the monthly model cycles for year\xa01 (cycles\xa01–12) and year\xa02 (cycles\xa013–24). The annual rates of treatment discontinuation in year\xa01 (2.7%) and year\xa02 (3.5%) were assumed to be identical between both treatment groups and were based on an average of the discontinuation rates reported in the VIEW\xa02 and CATT studies.\n\nFor\xa0years\xa03 to 5 in the model, it was assumed that people on active treatment would remain in the same health state that they were in after 2\xa0years. Because no statistically significant differences in clinical effectiveness were identified in the indirect comparison of aflibercept with ranibizumab, identical assumptions were made for both treatment groups during this period. In the absence of available trial data, clinical opinion was used to estimate the annual probability of treatment discontinuation in\xa0years\xa03 to 5 (18.7%), which were also assumed to be identical between treatment groups. From year\xa06 it was assumed that all people in both treatment groups discontinued active treatment and started best supportive care.\n\nThe manufacturer assumed that clinical effectiveness in the treated eye was independent of effectiveness in the second eye. Clinical‑effectiveness data for the second eye while on treatment was calculated using the same methodology applied to the treated eye. The manufacturer assumed that wet age‑related macular degeneration involvement in both eyes was 0% at the start of the model and that people developed wet age‑related macular degeneration in the second eye from year\xa03. The manufacturer also assumed that all people in the model who developed wet age‑related macular degeneration in the second eye from year\xa03 were treated. On the basis of a meta‑analysis by Wong et al. (2008) of patients with wet age‑related macular degeneration receiving no active treatment, the manufacturer estimated a 0.65% monthly probability of developing wet age‑related macular degeneration in the second eye. For people who were not receiving active treatment, clinical‑effectiveness data from Wong et al. were used to estimate the monthly probability of losing either 15\xa0letters (0.56%) or 30\xa0letters (1.56%) with the remaining people maintaining stable visual acuity.\n\nThe manufacturer stated that there is limited evidence of a relationship between wet age‑related macular degeneration and an increased risk of mortality and that, on the basis of data from the VIEW\xa01 and 2 studies, it is unlikely that there is any difference in mortality between aflibercept and ranibizumab. Therefore, age‑specific all‑cause mortality from UK life tables was used for both treatment groups. For people who were blind in both eyes, an excess risk of mortality was taken from a UK study of older patients with visual impairment (Thiagarajan et al. 2005).\n\nTo estimate the health‑related quality of life associated with each health state corresponding to visual acuity in both eyes, EQ‑5D data from VIEW\xa02 were transformed to utility values using the UK population tariff. A pooled dataset of all trial arms at baseline, 52\xa0weeks and 96\xa0weeks was used by the manufacturer. The manufacturer adjusted the utility values for 4\xa0of the health states in the model to maintain the assumption that utility values decrease consistently with worsening visual acuity. This was achieved by taking the average of the utility values above and below the anomalous value. Utility values were not adjusted for age in the model. The resulting utility values applied in the model are academic in confidence and therefore not reported here. The manufacturer stated that, because of the low rates of adverse events observed in the VIEW\xa01 and 2 trials and the small differences observed between the aflibercept and ranibizumab treatment groups, the impact of adverse events on health‑related quality of life was not included in the base‑case analysis. However, in a scenario analysis, the manufacturer included the loss in utility associated with adverse ocular events taken from 2\xa0separate studies identified in a systematic literature review (Brown et al. 2007; Gower et al. 2010). These utility decrements were subtracted from the utility values for the health states defined by visual acuity and included retinal haemorrhage (−0.300), vitreous haemorrhage (−0.305), endophthalmitis (−0.300), cataract (−0.142) and retinal detachment (−0.27).\n\nThe manufacturer included the costs of drug treatment, including drug acquisition, administration and monitoring costs. The drug acquisition costs incorporated the confidential discount applied to the list price of aflibercept approved as part of the patient access scheme. The manufacturer of ranibizumab has also previously agreed a revised patient access scheme with the Department of Health in 2013 (as revised in the context of NICE technology appraisal guidance\xa0274), in which it applied a revised discount to ranibizumab for all indications. At the time of submission for this appraisal, the manufacturer of aflibercept was unaware of the size of the confidential discount and therefore presented a range of scenario analyses, which applied discounts to the list price of ranibizumab ranging from 10% to 50%, in increments of 5%.\n\nThe resource use and unit costs associated with treatment and monitoring visits were based on Hospital Episode Statistics (HES 2010/11) and NHS reference costs (2011/12). The manufacturer assumed that in year\xa01 people treated with aflibercept had their treatment administration and monitoring at the same visit (one‑stop model), and that 50% of people treated with ranibizumab followed a one‑stop model and 50% had separate visits for treatment and monitoring (two‑stop model). In years\xa02 to 5, the manufacturer assumed that 50% of people in both treatment groups followed a one‑stop model and 50% followed a two‑stop model. The manufacturer assumed that treatment with both aflibercept and ranibizumab occurred as a weighted average of a day‑case visit (55%) and outpatient visit (45%), resulting in a total cost of £257.45 per treatment visit. It was assumed that people in both treatment groups would need one fluorescein angiography (£117) before starting treatment.\n\nThe manufacturer assumed that people receiving aflibercept had 7\xa0injections in the first year and 4\xa0injections in the second year based on the treatment frequency recommended in the summary of product characteristics and the VIEW\xa02 study. It was assumed that people receiving ranibizumab had 8\xa0injections in the first year and 6\xa0injections in the second year based on NICE technology appraisal guidance\xa0155 and the European Medicines Agency assessment report for the 2011 revision of the summary of product characteristics. Based on clinical specialist opinion, the manufacturer assumed that people in both treatment groups had 4\xa0injections in years\xa03 to 5.\n\nThe manufacturer assumed that separate monitoring visits included the cost of an ophthalmologist outpatient visit (£80) and an optical coherence tomography (£117), resulting in a total cost of £197 per monitoring visit. The frequency of monitoring visits in the first 2\xa0years of the model was also based on the summary of product characteristics for both treatments. People receiving aflibercept had 7\xa0monitoring visits in year\xa01 and 6\xa0monitoring visits in year\xa02 and people receiving ranibizumab had 12\xa0monitoring visits in years\xa01 and 2. People receiving aflibercept in a one‑stop model had their treatment and monitoring at the same visit and therefore needed no separate monitoring visits in the first year and 2\xa0separate visits in the second year. People receiving aflibercept in a two‑stop model in the second year had their treatment and monitoring at separate visits and therefore needed 6\xa0separate monitoring visits in the second year. People receiving ranibizumab had 4\xa0separate monitoring visits in the first year and 6\xa0separate visits in the second year in a one‑stop model and 12\xa0separate monitoring visits in the first 2\xa0years in a two‑stop model. On the basis of clinical specialist opinion, people in years\xa03 to 5 in both treatment groups had 3\xa0separate monitoring visits in the one‑stop model and 7\xa0separate monitoring visits in a two‑stop model.\n\nThe manufacturer estimated the costs associated with blindness for people who were defined as being blind in both eyes (ETDRS score under 36\xa0letters). The manufacturer applied cost data taken from a published UK costing study of blindness in people with age‑related macular degeneration (Meads and Hyde 2003). This study estimated the costs associated with a range of items including low‑vision aids, rehabilitation, residential care, district nursing, community care and the cost of treating complications including depression and falls. After adjusting for inflation, the total estimated annual cost of blindness was £585. Because of the low incidence of adverse events reported in the VIEW\xa01 and 2 studies, the manufacturer did not apply the costs of adverse events in the base‑case analysis.\n\nThe manufacturer's base‑case deterministic cost‑effectiveness results (including the patient access scheme for aflibercept but not for ranibizumab) showed that aflibercept dominated ranibizumab because it resulted in lower costs and higher quality‑adjusted life years (QALYs; 7.77 compared with 7.76). When the manufacturer applied a discount to the list price of ranibizumab, ranging from 10 to 50%, aflibercept continued to dominate ranibizumab.\n\nThe manufacturer performed one‑way sensitivity analysis using a net monetary benefit approach because aflibercept dominated ranibizumab in the base‑case analysis.The deterministic and probabilistic sensitivity analyses used the discounted price for aflibercept agreed under the patient access scheme and the list price for ranibizumab. The results of the one‑way sensitivity analyses indicated that the cost effectiveness of aflibercept was most sensitive to the drug acquisition costs, frequency of injections and monitoring visits, proportion of people in one‑stop and two‑stop models, discount rates and the relative risk of gaining or losing visual acuity with ranibizumab treatment. The manufacturer stated that, in all sensitivity analyses, aflibercept continued to dominate ranibizumab. Results of the manufacturer's probabilistic sensitivity analysis showed that aflibercept had a 100% probability of being cost effective compared with ranibizumab if the maximum acceptable incremental cost‑effectiveness ratio (ICER) was £20,000 per QALY gained.\n\nThe manufacturer also conducted a number of scenario analyses, which included the discounted price for aflibercept but not for ranibizumab. Two scenarios involved varying the frequency of injections and monitoring: applying the average number of injections reported in years\xa01 and 2 of the VIEW\xa02 and CATT trials for aflibercept and ranibizumab respectively, and applying monthly monitoring visits for ranibizumab and bi‑monthly monitoring visits for aflibercept in years\xa03 to 5. One scenario involved applying the same clinical‑effectiveness data for both treatments so that the same proportions of people gaining or losing visual acuity were applied in both treatment groups. One scenario applied alternative utility values from a study by Czoski‑Murray et al. (2009) in which members of the general public valued levels of visual impairment that were simulated by custom‑made contact lenses, using the time trade‑off method. One scenario modelled the impact of adverse ocular events in the ranibizumab treatment group, which included retinal haemorrhage, vitreous haemorrhage, endophthalmitis, cataract and retinal detachment taken from a separate trial of ranibizumab in patients with wet age‑related macular degeneration (Boyer et al. 2009). Another scenario applied clinical‑effectiveness estimates equivalent to best‑supportive care, taken from Wong et al., in years\xa03–5 for both treatment groups. For all scenario analyses, aflibercept either continued to dominate ranibizumab or resulted in net cost savings (when the same proportions of people gaining or losing visual acuity were applied in both treatment groups).\n\n# ERG critique of manufacturer's submission\n\nThe ERG considered that the clinical‑effectiveness evidence from the VIEW\xa01 and 2 studies was of good quality without any obvious sources of bias. The ERG noted that the manufacturer used the last observation carried forward approach to calculate missing data for the primary outcome of the proportion of people who maintained vision at week\xa052 in VIEW\xa01 and 2. The ERG considered that this approach may have introduced bias because it can artificially stabilise disease, which may be inappropriate for a progressive disease such as wet age‑related macular degeneration. After clarification, the manufacturer provided the observed results at week\xa052 for the outcome of maintained vision from the per protocol and full analysis datasets, which were similar to the original results based on the last observation carried forward approach. The ERG also ran the network meta‑analysis for the outcome of maintained vision at 12\xa0months using observed data from VIEW\xa01 and 2 and found that the results were similar to the original results obtained using the last observation carried forward approach. Therefore, the ERG was satisfied that the use of last observation carried forward did not substantially impact the results for the primary outcome at week\xa052 in VIEW\xa01 and 2.\n\nThe ERG agreed with the manufacturer that there were concerns about the validity of the network meta‑analyses and indirect comparison because of heterogeneity between the included studies. The ERG noted that the manufacturer had conducted sensitivity analyses with regard to heterogeneity, but commented it was not clear what these sensitivity analyses were. The ERG also noted that the network meta‑analysis for the outcome of mean change from baseline in best‑corrected visual acuity at 12\xa0months excluded a treatment arm from one of the studies included in the analysis (ranibizumab fixed dose 0.3\xa0mg arm in the DETAIL study). The ERG was concerned about the validity of the results as a result of this omission and therefore repeated the analysis including this treatment arm. The ERG found that, although this did not significantly alter the results in terms of the mean difference in change in best‑corrected visual acuity between treatment arms, the results of the network analyses and indirect comparison should be interpreted with caution.\n\nIn its critique of the manufacturer's economic model, the ERG noted that clinical‑effectiveness data for the aflibercept treatment group were derived from the VIEW\xa02 study rather than pooled data from VIEW\xa01 and 2. The ERG also noted that the proportion of people treated with aflibercept who gained or lost visual acuity at 52\xa0weeks and 96\xa0weeks was broadly similar between VIEW\xa01 and\xa02 and that there was no suggestion of bias arising from the choice of VIEW\xa02 data rather than pooled clinical‑effectiveness data. However, the ERG highlighted that there were discrepancies between the clinical‑effectiveness data from VIEW\xa02 and the modelled population in terms of the proportion of people who gained or maintained visual acuity at week\xa052. The ERG commented that it was unclear what clinical‑effectiveness data were used for the aflibercept group in the model.\n\nThe ERG noted that people treated with aflibercept in VIEW\xa01 and\xa02 received an average of 7.5 and 7.7\xa0injections in the first year of both studies. The ERG also noted that the dosing schedule suggests that people who remain on treatment would need 8\xa0injections in year\xa01. Therefore, the ERG considered that it may have been more reasonable for the manufacturer to model 8\xa0injections of aflibercept in year\xa01. The ERG also noted that the average number of 4\xa0aflibercept injections in year\xa02 of the model, which were taken from the VIEW\xa02 study, had been annualised from 44\xa0weeks to 52\xa0weeks to account for the study duration (96\xa0weeks) which was slightly shorter than 2\xa0years (104\xa0weeks).The ERG considered that, on the basis of the weighted average number of injections of ranibizumab (7.4) in a treatment as needed dosing regimen in studies included in the manufacturer's systematic review, the number of ranibizumab injections in year\xa01 of the model should probably have been 7 rather than 8. The ERG commented that the network meta‑analysis for visual acuity outcomes at 24\xa0months relied largely upon data from the CATT study, in which patients treated with ranibizumab had an average of 5.7\xa0injections in a 'treatment as needed' regimen in year\xa02. The ERG therefore considered that the manufacturer's assumption of 6\xa0ranibizumab injections in the second year of the model was reasonable.\n\nThe ERG noted that the manufacturer reported relative risks of maintaining and gaining visual acuity from its network meta‑analysis and indirect comparison between baseline and 12\xa0months and between 12\xa0months and 24\xa0months. However, the ERG considered that the results of the manufacturer's systematic review and indirect comparison at 24\xa0months were the relative risks of gaining or maintaining visual acuity between baseline and 24\xa0months. The ERG also noted that applying the 24‑month relative risks to the probability of gaining or maintaining visual acuity between 12\xa0months and 24\xa0months resulted in more people in the aflibercept treatment group gaining or maintaining visual acuity compared with ranibizumab at 24\xa0months. However, the ERG considered that, because the estimated relative risks of gaining and maintaining visual acuity for aflibercept compared with ranibizumab from baseline to 24\xa0months were less than\xa01, fewer people in the aflibercept treatment group should have gained or maintained visual acuity compared with ranibizumab at 24\xa0months.\n\nThe ERG considered that the manufacturer's approach to modelling second‑eye involvement was incorrect. The ERG noted that the probabilities of gaining or maintaining visual acuity with aflibercept or ranibizumab during the first 2\xa0years of treatment were not applied to the second eye and that there was no incidence of second‑eye involvement in\xa0years 1 and 2 of the model. The ERG also noted that, although the baseline prevalence of wet age‑related macular degeneration in the second eye was 19% in the pooled VIEW\xa01 and 2 population, the manufacturer had assumed that people in both treatment groups had no visual impairment or wet age‑related macular degeneration in their second eye at the start of the model. Furthermore, the ERG considered that the model did not allow for sensible consideration of the timing of second‑eye involvement because the effect of treatment on visual acuity in the second eye and the costs of treating any second‑eye involvement were limited to years\xa03 to 5. Therefore, the ERG concluded that the manufacturer's economic model in its current form is a 'one‑eye model' that should be limited to considering the cost effectiveness of aflibercept as unilateral treatment for wet age‑related macular degeneration.\n\nBecause the ERG concluded that the manufacturer's model may be limited to being a one‑eye model, it suggested that further consideration should be given as to whether people received treatment in their better‑seeing eye or their worse‑seeing eye and the resulting impact on health‑related quality of life. The ERG considered that the manufacturer's assumption of no second‑eye involvement in years\xa01 and 2 resulted in the model being a worse‑seeing eye model, with the additional assumption of the second eye having no visual impairment. On the basis of the manufacturer's EQ‑5D utility values from VIEW\xa02, the ERG suggested a narrower range of utility values for the 5\xa0health states defined by visual acuity in a worse‑seeing eye model. For a better‑seeing eye model, the ERG suggested that utility values should be taken from a study by Brown (1999) that measured vision‑related utility values using the time trade‑off method in 325\xa0people from the USA with impaired vision (Snellen scale 20/40) in at least 1\xa0eye. The ERG noted from the Brown study that, among people who had good vision in their better‑seeing eye, the worse‑seeing eye contributed little to health‑related quality of life. The utility values taken from the Brown study ranged from 0.920 to 0.621 for the 5\xa0health states defined by visual acuity in the manufacturer's model, a range that the ERG noted was similar to the range of utility values from the VIEW\xa01 study under the assumption of the worse‑seeing eye being blind.\n\nThe ERG considered that it was unclear why all patients in the aflibercept group followed a one‑stop monitoring model and 50% of patients in the ranibizumab group followed one‑stop and 50% followed a two‑stop model in the first year of the economic model. If patients in the aflibercept group followed a two‑stop model, they would therefore have 7\xa0separate monitoring visits in year\xa01. The ERG also considered that the manufacturer's estimated cost per treatment visit of £257, which was based on a weighted average of outpatient and day‑case visits from 2010/11 HES data, may have been too high. On the basis of 2011/12 HES data, the ERG estimated a lower weighted average cost of £129.46 per treatment visit. The ERG also noted that, in the appraisal of ranibizumab for treating diabetic macular oedema (NICE technology appraisal guidance\xa0274), the manufacturer estimated a total cost of £143 per treatment visit. The ERG also considered that the manufacturer's estimated cost of £117.26 for an optical coherence tomography (based on a fluorescein angiography) may have been too high and that a lower cost of £51.27 (based on a 20‑minute ultrasound scan) may have been more appropriate. The ERG also noted that the manufacturer's estimate of the annual costs of blindness was implemented as a monthly cost in the model.\n\nThe ERG conducted exploratory analyses, which involved the following modifications to the manufacturer's model:\n\nsecond‑eye involvement after year\xa01 and 2 was set to zero to reflect the ERG's view that the submitted modelling of second‑eye involvement is untenable\n\ninjections in year\xa01 were assumed for both treatment groups\n\ntreatment visit costs were reduced to £129.46 and optical coherence tomography costs to £51.27\n\n% of people in both treatment groups were monitored according to the one‑stop model in year\xa01\n\nutility values for a better‑seeing eye model (see section\xa03.35) were drawn from the Brown study, ranging from 0.920 to 0.621; utility values for a worse‑seeing eye model were consistent with those used in the manufacturer's submission.\n\nThe ERG applied the changes outlined in section\xa03.37 in 2\xa0scenario analyses for the worse‑seeing eye model and 2\xa0scenario analyses for the better‑seeing eye model. The first scenario for each model adopted the manufacturer's interpretation that its indirect comparison of aflibercept with ranibizumab at 24\xa0months provided relative risks of maintaining and gaining visual acuity from 12 to 24\xa0months. In this first scenario, the ERG retained the proportions of people maintaining and gaining visual acuity in the manufacturer's original model. The second scenario for each model adopted the ERG's interpretation that the manufacturer's indirect comparison at 24\xa0months provided relative risks of gaining and maintaining visual acuity from baseline to 24\xa0months. In this second scenario, the ERG retained the baseline distribution of visual acuity from the manufacturer's original model.\n\nThe ERG incorporated the confidential discount applied to the list price of aflibercept and a range of discounts (from 0 to 50% in increments of 5%) to the list price of ranibizumab in its scenario analyses as outlined in section\xa03.38. In the ERG's first scenario analysis for the worse‑seeing eye model, aflibercept either dominated ranibizumab (discount 0–45%) or resulted in an ICER of £60,153 per QALY gained (discount 50%). In the ERG's first scenario analysis for the better‑seeing eye model, aflibercept either dominated ranibizumab (discount 0–45%) or resulted in an ICER of £9002 per QALY gained (discount 50%). In the ERG's second scenario analysis for the worse‑seeing eye model, aflibercept resulted in lower costs and lower QALYs compared with ranibizumab when a discount range of 0–45% was applied to the list price of ranibizumab, with ICERs ranging from £1,692,511 to £108,180 saved per QALY lost. In the ERG's second scenario analysis for the better‑seeing eye model, the ICERs for aflibercept compared with ranibizumab ranged from £261,432 to £16,710 saved per QALY lost when a discount range of 0–45% was applied to the list price ranibizumab. When the ERG applied a 50% discount to the list price of ranibizumab, aflibercept was dominated by ranibizumab for both the worse‑seeing eye and better‑seeing eye models.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.\n\n Net monetary benefit=(£20,000×incremental QALYs)–incremental costs", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aflibercept solution for injection, having considered evidence on the nature of wet age‑related macular degeneration and the value placed on the benefits of aflibercept by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from the patient experts that visual impairment has a substantial negative impact on the physical and emotional wellbeing of people with wet age‑related macular degeneration. The patient experts stated that the condition affects their ability to work and other leisure activities and in turn, can increase the risk of depression and social isolation. The patient experts also acknowledged that, despite any initial anxiety about having an injection in the eye, they are willing to receive injections in order to prevent sight loss. The Committee agreed that loss of vision caused by wet age‑related macular degeneration can substantially impair health‑related quality of life.\n\nThe Committee discussed the currently available treatments and the likely place of aflibercept in treating wet age‑related macular degeneration. The Committee heard from the clinical specialists that the current standard treatment for wet age‑related macular degeneration is ranibizumab as a consequence of NICE technology appraisal guidance\xa0155. It also heard that, in some NHS trusts and private clinical practice, both ranibizumab and bevacizumab for intravitreal use are used on the basis of economic considerations. However, the clinical specialists explained that people treated with ranibizumab and bevacizumab should have their condition monitored every 4\xa0weeks and that very few NHS trusts were able to manage wet age‑related macular degeneration at such regular intervals. They also stated that people usually receive 6\xa0ranibizumab injections in the first year of treatment rather than up to 12\xa0injections seen in the clinical trials. The clinical specialists commented that data from several UK ophthalmology departments suggest that the current ranibizumab treatment regimen is inadequate and so visual acuity outcomes may be inferior to results reported in the clinical trials. However, the Committee also acknowledged that these inferior visual acuity outcomes could be attributed to the widening range of disease severity seen in clinical practice. The Committee understood from the clinical specialists that an important advantage of aflibercept is that it needs less frequent administration than ranibizumab while achieving similar clinical outcomes, as seen in the clinical trials, thus imposing less burden on NHS capacity. The Committee also understood from the patient experts that, because aflibercept is associated with fewer treatment and monitoring visits, it will reduce the burden on patients and their carers in terms of time off work and travel costs.\n\nThe Committee considered the manufacturer's decision to exclude bevacizumab for intravitreal use as a comparator in its submission, despite being listed as a comparator in the scope. It was aware that bevacizumab does not have a UK marketing authorisation for treating wet age‑related macular degeneration. However, the Committee noted that a marketing authorisation is not a prerequisite for a comparator in a NICE technology appraisal. It noted that NICE's Guide to the methods of technology appraisal, in recommending comparison with technologies that are 'best practice' or in 'routine use', is not intended to be restrictive but to emphasise the need for comparison with all relevant comparators; any medicine in routine use or considered to be best practice should be considered a potential comparator. The Committee also noted advice from the NICE Board that the decision to include bevacizumab as a comparator should be based on both a careful consideration of its use in clinical practice for wet age‑related macular degeneration and a thorough assessment of its efficacy, quality and safety. The Committee was aware of recently published evidence from the IVAN and CATT trials comparing the clinical efficacy and safety of bevacizumab with ranibizumab in people with wet age‑related macular degeneration, which has addressed some of these issues. However, the Committee acknowledged that bevacizumab was not included as a comparator treatment in the appraisal of ranibizumab and pegaptanib for the treatment of age\\u2011\\related macular degeneration (NICE technology appraisal guidance\xa0155), and that this appraisal was undertaken before the emergence of evidence on the clinical effectiveness of bevacizumab. Therefore, the Committee agreed that it was reasonable to defer consideration of bevacizumab as a comparator in this appraisal. In the interests of fairness, it also agreed that the proposed review of the guidance on aflibercept should coincide with the review date for NICE technology appraisal guidance\xa0155, which should also include bevacizumab (see section\xa07).\n\nThe Committee considered the manufacturer's decision to exclude photodynamic therapy as a comparator in its submission, despite being listed as a comparator in the scope. The Committee noted from the manufacturer that, although NICE technology appraisal guidance\xa068 recommended photodynamic therapy for the treatment of wet age‑related macular degeneration for individuals who have a confirmed diagnosis of classic with no occult subfoveal choroidal neovascularisation, clinical practice has subsequently changed for this group and that newer treatments, including anti‑vascular endothelial growth factor (VEGF) therapies have superseded photodynamic therapy. The Committee heard from the clinical specialists that photodynamic therapy is currently used in combination with an anti‑VEGF therapy for treating wet age‑related macular degeneration in people with polypoidal choroidal vasculopathy whose condition does not respond to initial anti‑VEGF therapy (approximately 10–15% of patients). Therefore, the Committee considered that photodynamic therapy would only be offered as a second‑line treatment option after first‑line anti‑VEGF therapy for this group of people and concluded that it was reasonable to exclude photodynamic therapy as a comparator in this appraisal.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of aflibercept. The Committee noted that the main sources of evidence came from the VIEW\xa01 and 2 trials which compared aflibercept (2\xa0mg every 8\xa0weeks) with ranibizumab (0.5\xa0mg every 4\xa0weeks) in people with wet age‑related macular degeneration and that both studies were considered to be of high quality by the Evidence Review Group (ERG). It also noted that aflibercept at its licensed dose was shown to be clinically non‑inferior to ranibizumab in terms of visual acuity outcomes at 96\xa0weeks. The Committee concluded that aflibercept is a clinically effective treatment option for visual impairment caused by wet age‑related macular degeneration.\n\nThe Committee considered the network meta‑analyses and indirect comparisons submitted by the manufacturer, which estimated the clinical effectiveness of aflibercept at its licensed dose compared with ranibizumab in a 'treatment as needed' regimen at 12 and 24\xa0months. The Committee accepted the concerns highlighted by the manufacturer and the ERG about the validity of these analyses because of the heterogeneity of the included studies. It was also aware that, although the point estimates for visual acuity outcomes favoured aflibercept, no statistically significant differences compared with ranibizumab were reported. The Committee concluded that, in the absence of stronger evidence, the results could be used to inform decisions about the clinical effectiveness of aflibercept compared with ranibizumab in a 'treatment as needed' regimen.\n\nThe Committee considered the evidence for adverse events associated with aflibercept. The Committee noted that the frequency of adverse events in both treatment groups in the VIEW\xa01 and 2 trials was low. The Committee noted that the manufacturer had not provided a formal statistical analysis comparing adverse events between the 2\xa0treatment groups. However, it also noted that no clinically meaningful differences in adverse events were reported by the manufacturer or the ERG. The Committee concluded that aflibercept was safe and well tolerated in patients with wet age‑related macular degeneration.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model and the ERG's critique and exploratory analyses. The Committee noted that the model structure accounted for different levels of visual acuity in both eyes rather than the first eye to come to clinical attention. The Committee also noted the ERG's concerns about the manufacturer's approach to modelling second‑eye involvement. The Committee agreed with the ERG that it was unrealistic to assume no second‑eye involvement in the first 2\xa0years of the model because a large proportion of patients in the VIEW\xa01 and 2 trials had visual impairment in their second eye at the start of treatment. It also agreed that the manufacturer did not give appropriate consideration to the timing of second‑eye involvement because the effect of treatment on visual acuity in the second eye and any associated costs were limited to years\xa03 to 5 in the model. The Committee concluded that the ERG's exploratory approach, which involved separate analyses depending on whether the study eye was a better‑seeing eye or worse‑seeing eye, was more reasonable.\n\nThe Committee discussed the clinical‑effectiveness data that were used in the economic model. The Committee noted that clinical‑effectiveness data for aflibercept were derived from the VIEW\xa02 study only rather than from a pooled analysis of the VIEW\xa01 and 2 studies. The Committee heard from the manufacturer that this was because VIEW\xa02 was conducted across multiple centres including the UK and therefore was more relevant to UK clinical practice than the VIEW\xa01 study, and also because the EQ‑5D utility values used in the model were collected in the VIEW\xa02 study. The Committee agreed that using clinical-effectiveness data from VIEW\xa01 only was unlikely to introduce any additional bias because results were similar between VIEW\xa01 and 2 and a pooled analysis of both studies. The Committee also noted the ERG's comments that the manufacturer had applied comparative clinical‑effectiveness data in terms of visual acuity from its network meta‑analyses and indirect comparisons between baseline and 12\xa0months and between 12\xa0months and 24\xa0months rather than between baseline and 12\xa0months and between baseline and 24\xa0months. It noted that this resulted in aflibercept having better visual acuity than ranibizumab at 24\xa0months in the model although the point estimates from the indirect comparison showed that aflibercept resulted in slightly worse outcomes. The Committee agreed with the ERG that the results of the manufacturer's indirect comparison at 24\xa0months provided comparative clinical‑effectiveness data between baseline and 24\xa0months, and it concluded that the ERG's exploratory analysis that incorporated this data was the preferred approach.\n\nThe Committee discussed the manufacturer's assumptions about the number of treatment and monitoring visits people in both treatment groups needed in the model. The Committee considered that, in the absence of any longer‑term data, it was reasonable for the manufacturer to assume that both treatment groups would have the same number of treatment and monitoring visits in years\xa03 to 5 of the model. The Committee noted that the manufacturer assumed that people receiving aflibercept had 7\xa0treatment visits in the first year based on the summary of product characteristics. However, the Committee agreed with the ERG that it was more likely that people treated with aflibercept would need 8\xa0treatment visits in the first year of the model on the basis of the average number of injections that patients received in the VIEW\xa02 study. It also noted that the ERG had corrected for this in its exploratory analyses. The Committee was aware that there are data from UK clinical practice on the treatment and monitoring frequency of ranibizumab but that no such data on the use of aflibercept currently exist. For this reason, the Committee considered that it would be fairer to use the same data that were used to estimate the relative clinical effectiveness of aflibercept and ranibizumab to inform assumptions about the number of treatment and monitoring visits in the model. Therefore, the Committee concluded that it was reasonable to assume that people in both treatment groups would need 8\xa0treatment visits in the first year of the model in line with the approach taken by the ERG in its exploratory analyses.\n\nThe Committee discussed the manufacturer's assumptions about whether treatment administration and monitoring occurred at the same visit. The Committee noted that the manufacturer had assumed that, in the first year of the model, people in the aflibercept group had their treatment administration and monitoring at the same visit in a one‑stop model but 50% of people in the ranibizumab group had separate monitoring visits in a two‑stop model. The Committee heard from the clinical specialists that, in future clinical practice, it is expected that fewer people treated with anti‑VEGF therapies would need separate treatment and monitoring visits. The Committee noted that, if a higher proportion of people in both treatment groups had their treatment administration and monitoring at the same visit, this would reduce the total incremental costs of ranibizumab compared with aflibercept because of the higher number of monitoring visits needed by people treated with ranibizumab in the first 2\xa0years of the manufacturer's model. However, the Committee agreed that, for people who had their treatment and monitoring at the same visit in a one-stop model, the aflibercept group had no separate monitoring visits in the first year and 2\xa0separate visits in the second year and the ranibizumab group had 4\xa0separate monitoring visits in the first year and 6\xa0separate visits in the second year. The Committee also agreed that, for people who had their treatment and monitoring at separate visits in a two-stop model, the aflibercept group had 7\xa0separate monitoring visits in the first year and 6\xa0separate monitoring visits in the second year and the ranibizumab group had 12\xa0separate monitoring visits in the first 2\xa0years. The Committee concluded that, based on current clinical practice, it was reasonable to assume that 50% of people in both treatment groups would need separate monitoring visits in line with the approach taken by the ERG in its exploratory analyses.\n\nThe Committee discussed the manufacturer's assumptions about the costs of treatment and monitoring visits. The Committee noted that the manufacturer's estimated cost per treatment visit was higher than the cost used in the appraisal of ranibizumab for the treatment of diabetic macular oedema (NICE technology appraisal guidance\xa0274) and that the ERG also estimated a lower average cost per treatment visit of £129. However, the Committee heard from the clinical specialists that the ERG's lower estimate was likely to be an underestimate of the true costs of a treatment visit. The Committee also heard from the clinical specialists that the ERG's estimated cost for optical coherence tomography of £51 as part of a monitoring visit was probably too low. Overall, the Committee concluded that although some uncertainty remained about the true costs involved in treatment and monitoring visits for people with wet age‑related macular degeneration, the estimates used in the ERG's exploratory analyses were a fair reflection of the costs involved.\n\nThe Committee considered the incremental cost‑effectiveness ratios (ICERs) estimated by the manufacturer and the ERG, which incorporated the confidential discounts applied to the list prices of aflibercept and ranibizumab agreed under the respective patient access schemes. The Committee noted that, in the manufacturer's base‑case analysis, aflibercept dominated (that is, was less expensive and more effective than) ranibizumab. The Committee also considered its preferred analyses based on the ERG's exploratory approach, which incorporated separate analyses depending on whether the study eye was a better‑seeing eye or a worse‑seeing eye, and its preferred assumptions about the frequency of injections, monitoring visits and clinical‑effectiveness data (see sections\xa04.8 to 4.11). It noted that these exploratory analyses incorporated the confidential discount to the list price of aflibercept and a range of discounts (from 0 to 50%) to the list price of ranibizumab. The Committee also noted that, when discounts to the list price of ranibizumab ranged from 0 to 45%, aflibercept had lower costs and quality-adjusted life years (QALYs) than ranibizumab, which resulted in ICERs for aflibercept compared with ranibizumab ranging from £1,690,000 to £16,700 saved per QALY lost and that, when a 50% discount was applied to the list price of ranibizumab, aflibercept was dominated by ranibizumab in both the worse-seeing eye and better-seeing eye models (see section\xa03.39). However, the Committee was aware that, in both the manufacturer's and the ERG's analyses, the differences in total costs and QALYs were very small. The Committee therefore concluded that aflibercept could be recommended as a cost‑effective use of NHS resources if ranibizumab would otherwise be the treatment used.\n\nThe Committee discussed whether aflibercept solution for injection should be recommended within the terms of its UK marketing authorisation, that is, for the treatment of neovascular (wet) age‑related macular degeneration, or whether a more restrictive set of criteria was necessary. The Committee noted that guidance on the use of ranibizumab outlined in NICE technology appraisal guidance\xa0155 was based on a more restrictive set of criteria than described in the terms of its UK marketing authorisation and that these criteria were set out in the clinical trials for ranibizumab for treating wet age‑related macular degeneration. It also noted that these criteria were very similar to those set out in the VIEW\xa01 and 2 studies. The Committee also heard from the clinical specialists that they would prefer that the use of aflibercept should not be restricted to people with a best‑corrected visual acuity between 6/12 and 6/96, as is the case with ranibizumab in NICE technology appraisal guidance\xa0155. However, the Committee concluded that it would be appropriate to recommend aflibercept as a treatment option for people with wet age‑related macular degeneration if it is used according to the same criteria as described for the use of ranibizumab in NICE technology appraisal guidance\xa0155 until both technologies could be appraised simultaneously in the context of a multiple technology appraisal.\n\nThe Committee discussed how innovative aflibercept is in its potential to make a significant and substantial impact on health‑related benefits. It agreed that anti‑VEGF treatments were a substantial improvement over previous treatments, but considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was in the development of anti‑VEGF treatments, not the act of licensing. In addition the Committee was not aware of any substantial benefits of aflibercept compared with ranibizumab that had not already been captured in the manufacturer's economic model.\n\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal in the guidance.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA294\n\nAppraisal title: Aflibercept solution for injection for treating wet age‑related macular degeneration\n\nSection\n\nKey conclusion\n\nAflibercept solution for injection is recommended as an option for treating wet age‑related macular degeneration only if it is used in accordance with the recommendations for ranibizumab in NICE technology appraisal guidance\xa0155 (re‑issued in May 2012) and the manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme.\n\n\n\nThe Committee noted that its preferred analyses incorporated the confidential discount to the list price of aflibercept and a range of discounts (from 0 to 50%) to the list price of ranibizumab. It also noted that, when discounts to the list price of ranibizumab ranged from 0 to 45%, aflibercept had lower costs and quality-adjusted life years (QALYs) than ranibizumab, which resulted in ICERs for aflibercept compared with ranibizumab ranging from £1,690,000 to £16,700 saved per QALY lost and that, when a 50% discount was applied to the list price of ranibizumab, aflibercept was dominated by ranibizumab in both the worse-seeing eye and better-seeing eye models. However, the Committee was aware that, in both the manufacturer's and the ERG's analyses, the differences in total costs and QALYs were very small. The Committee therefore concluded that aflibercept could be recommended as a cost‑effective use of NHS resources if ranibizumab would otherwise be the treatment used.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee agreed that loss of vision caused by wet age‑related macular degeneration can substantially impair health‑related quality of life.\n\n\n\nThe Committee heard from the clinical specialists that the current standard treatment for wet age‑related macular degeneration is ranibizumab as a consequence of NICE technology appraisal guidance\xa0155.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee understood from the clinical specialists that an important advantage of aflibercept is that it needs less frequent administration than ranibizumab while achieving similar clinical outcomes, as seen in the clinical trials, thus imposing less burden on NHS capacity.\n\n\n\nThe Committee was not aware of any substantial benefits of aflibercept compared with ranibizumab that had not already been captured in the manufacturer's economic model.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nAflibercept solution for injection has a UK marketing authorisation 'for adults for the treatment of neovascular (wet) age‑related macular degeneration (AMD)'.\n\n\n\nAdverse reactions\n\nThe Committee concluded that aflibercept was safe and well tolerated in patients with wet age‑related macular degeneration.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted that the main sources of evidence came from the VIEW\xa01 and 2 trials which compared aflibercept (2\xa0mg every 8\xa0weeks) with ranibizumab (0.5\xa0mg every 4\xa0weeks) in people with wet age‑related macular degeneration and that both studies were considered to be of high quality by the Evidence Review Group (ERG).\n\n\n\nFor the comparison of aflibercept at its licensed dose with ranibizumab in a 'treatment as needed' regimen at 12 and 24\xa0months, the Committee accepted the concerns highlighted by the manufacturer and the ERG about the validity of the manufacturer's network meta‑analyses and indirect comparisons because of the heterogeneity of the included studies. The Committee concluded that, in the absence of stronger evidence, the results could be used to inform decisions about the clinical effectiveness of aflibercept compared with ranibizumab in a 'treatment as needed' regimen.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe clinical specialists explained that people treated with ranibizumab and bevacizumab should have their condition monitored every 4\xa0weeks and that very few NHS trusts were able to manage wet age-related macular degeneration at such regular intervals. They also stated that patients usually receive 6\xa0ranibizumab injections in the first year of treatment rather than up to 12\xa0injections seen in the clinical trials. The clinical specialists commented that data from several UK ophthalmology departments suggest that the current ranibizumab treatment regimen is inadequate and so visual acuity outcomes may be inferior to results reported in the clinical trials. However, the Committee also acknowledged that these inferior visual acuity outcomes could be attributed to the widening range of disease severity seen in clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee acknowledged that bevacizumab was not included as a comparator treatment in the appraisal of ranibizumab and pegaptanib for the treatment of age\\u2011\\related macular degeneration (NICE technology appraisal guidance\xa0155), although this was undertaken before the emergence of evidence on the clinical effectiveness of bevacizumab. Therefore, the Committee agreed that it was reasonable to defer consideration of bevacizumab as a comparator in this appraisal. In the interests of fairness, it also agreed that the proposed review of the guidance on aflibercept should coincide with the review date for NICE technology appraisal guidance\xa0155, which should also include bevacizumab.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone was identified.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that aflibercept at its licensed dose was shown to be clinically non‑inferior to ranibizumab in terms of visual acuity outcomes at 96\xa0weeks. The Committee concluded that aflibercept is a clinically effective treatment option for visual impairment caused by wet age‑related macular degeneration.\n\n\n\nFor the network meta‑analyses and indirect comparisons submitted by the manufacturer, the Committee was aware that, although the point estimates for visual acuity outcomes favoured aflibercept, no statistically significant differences with ranibizumab were reported.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the manufacturer's economic model and the ERG's critique and exploratory analyses. The Committee agreed with the ERG that it was unrealistic to assume no second‑eye involvement in the first 2\xa0years of the model because a large proportion of patients in the VIEW\xa01 and 2 trials had visual impairment in their second eye at the start of treatment. The Committee concluded that the ERG's exploratory approach, which involved separate analyses depending on whether the study eye was a better‑seeing eye or worse‑seeing eye, was more reasonable.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted the ERG's comments that the manufacturer had applied comparative clinical-effectiveness data in terms of visual acuity from its network meta‑analyses and indirect comparisons between baseline and 12\xa0months and between 12\xa0months and 24\xa0months rather than between baseline and 12\xa0months and between baseline and 24\xa0months. The Committee agreed with the ERG that the results of the manufacturer's indirect comparison at 24\xa0months provided comparative clinical-effectiveness data between baseline and 24\xa0months, and it concluded that the ERG's exploratory analysis that incorporated this data was the preferred approach.\n\n\n\nThe Committee concluded that it was reasonable to assume that people in both treatment groups would need 8\xa0treatment visits in the first year of the model in line with the approach taken by the ERG in its exploratory analyses.\n\n\n\nThe Committee concluded that, based on current clinical practice, it was reasonable to assume that 50% of people in both treatment groups would need separate monitoring visits in line with the approach taken by the ERG in its exploratory analyses.\n\n\n\nThe Committee concluded that although some uncertainty remained about the true costs involved in treatment and monitoring visits for people with wet age‑related macular degeneration, the estimates used in the ERG's exploratory analyses were a fair reflection of the costs involved.\n\n\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNo specific conclusions were made by the Committee about health‑related quality‑of‑life benefits and utility values.\n\n–\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone was identified.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe results of the manufacturer's one‑way sensitivity analyses indicated that the cost effectiveness of aflibercept was most sensitive to the drug acquisition costs, frequency of injections and monitoring visits, proportion of people in one‑stop and two‑stop models, discount rates and the relative risk of gaining or losing visual acuity with ranibizumab treatment.\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe Committee noted that its preferred analyses incorporated the confidential discount to the list price of aflibercept and a range of discounts (from 0 to 50%) to the list price of ranibizumab. It also noted that, when discounts to the list price of ranibizumab ranged from 0 to 45%, aflibercept had lower costs and quality-adjusted life years (QALYs) than ranibizumab, which resulted in ICERs for aflibercept compared with ranibizumab ranging from £1,690,000 to £16,700 saved per QALY lost and that, when a 50% discount was applied to the list price of ranibizumab, aflibercept was dominated by ranibizumab in both the worse-seeing eye and better-seeing eye models. However, the Committee was aware that, in both the manufacturer's and the ERG's analyses, the differences in total costs and QALYs were very small.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer of aflibercept solution for injection has agreed a patient access scheme with the Department of Health. This involves a confidential discount applied to the list price of aflibercept solution for injection. The level of the discount is commercial in confidence.\n\n\n\nEnd‑of‑life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal in the guidance.\n\n", 'Related NICE guidance': 'Epiretinal brachytherapy for wet age related macular degeneration. NICE interventional procedure guidance\xa0415 (2011).\n\nMacular translocation with 360° retinotomy for wet age\\u2011\\related macular degeneration. NICE interventional procedure guidance\xa0340 (2010).\n\nLimited macular translocation for wet age\\u2011\\related macular degeneration. NICE interventional procedure guidance\xa0339 (2010).\n\nImplantation of miniature lens systems for advanced age\\u2011\\related macular degeneration. NICE interventional procedure guidance\xa0272 (2008).\n\nRanibizumab and pegaptanib for the treatment of age\\u2011\\related macular degeneration. NICE technology appraisal guidance\xa0155 (2008).\n\nTranspupilary thermotherapy for age\\u2011\\related macular degeneration. NICE interventional procedure guidance\xa058 (2004).\n\nRadiotherapy for age\\u2011\\related macular degeneration. NICE interventional procedure guidance\xa049 (2004).\n\nGuidance on the use of photodynamic therapy for age\\u2011\\related macular degeneration. NICE technology appraisal guidance\xa068 (2003).', 'Review of guidance': 'The guidance on this technology will be considered for review in February 2014. This is to coincide with the review date proposed for NICE technology appraisal guidance\xa0155 (ranibizumab and pegaptanib for the treatment of age‑related macular degeneration). The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon Chief ExecutiveJuly 2013', 'Changes after publication': 'January 2014: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0234-7'}	https://www.nice.org.uk/guidance/ta294	Evidence-based recommendations on aflibercept solution for injection (Eylea) for treating wet age‑related macular degeneration in adults.
1b03204061d974afe37eac7ac791703b59775c04	nice	Varicose veins: diagnosis and management	Varicose veins: diagnosis and management This guideline covers diagnosing and managing varicose veins in people aged 18 and over. It aims to ensure that people understand the options for treating varicose veins and that healthcare professionals know when to refer people for specialist assessment and treatment. # Introduction Varicose veins are dilated, often palpable subcutaneous veins with reversed blood flow. They are most commonly found in the legs. Estimates of the prevalence of varicose veins vary. Visible varicose veins in the lower limbs are estimated to affect at least a third of the population. Risk factors for developing varicose veins are unclear, although prevalence rises with age and they often develop during pregnancy. In some people varicose veins are asymptomatic or cause only mild symptoms, but in others they cause pain, aching or itching and can have a significant effect on their quality of life. Varicose veins may become more severe over time and can lead to complications such as changes in skin pigmentation, bleeding or venous ulceration. It is not known which people will develop more severe disease but it is estimated that 3–6% of people who have varicose veins in their lifetime will develop venous ulcers. There are several options for the management of varicose veins, including: advice and reassurance interventional treatments (endothermal ablation, foam sclerotherapy and surgery) compression hosiery. In 2009/10 there were 35,659 varicose veins procedures carried out in the NHS. There is no definitive system for identifying which people will benefit the most from interventional treatment and no established framework within the NHS for the diagnosis and management of varicose veins. This has resulted in wide regional variations in the management of varicose veins in the UK. This guideline was developed with the aim of giving healthcare professionals guidance on the diagnosis and management of varicose veins in the legs, in order to improve patient care and minimise disparities in care across the UK. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.# Recommendations The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Information for people with varicose veins Give people who present with varicose veins information that includes: An explanation of what varicose veins are. Possible causes of varicose veins. The likelihood of progression and possible complications, including deep vein thrombosis, skin changes, leg ulcers, bleeding and thrombophlebitis. Address any misconceptions the person may have about the risks of developing complications. Treatment options, including symptom relief, an overview of interventional treatments and the role of compression. Advice on: weight loss (for guidance on weight management see the NICE guideline on obesity prevention) light to moderate physical activity avoiding factors that are known to make their symptoms worse if possible when and where to seek further medical help. When discussing treatment for varicose veins at the vascular service tell the person: What treatment options are available. The expected benefits and risks of each treatment option. That new varicose veins may develop after treatment. That they may need more than 1 session of treatment. That the chance of recurrence after treatment for recurrent varicose veins is higher than for primary varicose veins.A vascular service is a team of healthcare professionals who have the skills to undertake a full clinical and duplex ultrasound assessment and provide a full range of treatment. # Referral to a vascular service Refer people with bleeding varicose veins to a vascular service immediately. Refer people to a vascular service if they have any of the following. Symptomatic primary or symptomatic recurrent varicose veins. Symptomatic veins are veins found in association with troublesome lower limb symptoms (typically pain, aching, discomfort, swelling, heaviness and itching). Lower‑limb skin changes, such as pigmentation or eczema, thought to be caused by chronic venous insufficiency. Superficial vein thrombosis (characterised by the appearance of hard, painful veins) and suspected venous incompetence. A venous leg ulcer (a break in the skin below the knee that has not healed within 2 weeks). A healed venous leg ulcer. # Assessment and treatment in a vascular service ## Assessment Use duplex ultrasound to confirm the diagnosis of varicose veins and the extent of truncal reflux, and to plan treatment for people with suspected primary or recurrent varicose veins. ## Interventional treatment For people with confirmed varicose veins and truncal reflux: Offer endothermal ablation (see NICE's interventional procedures guidance on radiofrequency ablation of varicose veins and endovenous laser treatment of the long saphenous vein). If endothermal ablation is unsuitable, offer ultrasound‑guided foam sclerotherapy (see NICE's interventional procedures guidance on ultrasound-guided foam sclerotherapy for varicose veins). If ultrasound‑guided foam sclerotherapy is unsuitable, offer surgery.If incompetent varicose tributaries are to be treated, consider treating them at the same time. If offering compression bandaging or hosiery for use after interventional treatment, do not use for more than 7 days. ## Non-interventional treatment Do not offer compression hosiery to treat varicose veins unless interventional treatment is unsuitable. # Management during pregnancy Give pregnant women presenting with varicose veins information on the effect of pregnancy on varicose veins. Do not carry out interventional treatment for varicose veins during pregnancy other than in exceptional circumstances. Consider compression hosiery for symptom relief of leg swelling associated with varicose veins during pregnancy.# Recommendations for research The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in appendix N of the full guideline. # Natural history of varicose veins In people with varicose veins at CEAP (Clinical, etiological, anatomical and pathophysiological) stage C2 or C3, what are the factors that influence progression of the disease to CEAP stages C5 or C6? ## Why this is important The evidence review for the guideline showed a lack of high‑quality evidence on the progression of varicose veins from CEAP stage C2 or C3 to more serious varicose veins disease. A large, observational, prospective cohort study, similar to the Framingham or Bonn veins studies, should be undertaken. The study should recruit patients with C2 and C3 disease and follow the progress of their disease for 5 years. Consideration should be given to including a genetic component in the study because genetic factors have not been studied on a large scale. The results of such a study should help to more accurately identify which patients are at risk of developing more serious disease so that interventions can be offered at an early stage to those who will benefit most. # Compression as a management option What is the clinical and cost effectiveness of compression hosiery versus no compression for the management of symptomatic varicose veins? ## Why this is important Compression hosiery is widely used as first‑line treatment for symptomatic varicose veins. In some areas of the UK a period of hosiery use is a precursor to referral to secondary care. Discomfort and difficulty in application may cause people to stop wearing compression hosiery or wear it only occasionally. The current evidence for the benefit of compression hosiery is weak. There is little evidence of an impact on symptom relief or an improvement in quality of life. It is therefore not possible to calculate the cost effectiveness of compression hosiery. A multicentre trial randomising compression hosiery versus no compression in patients with symptomatic varicose veins is needed. The trial should evaluate quality of life, including symptom reduction, and measure adherence with compression hosiery. In addition the trial should investigate the impact of compression on disease progression and the need for subsequent intervention. # Compression after interventional treatment What is the clinical and cost effectiveness of compression bandaging or hosiery after interventional treatment for varicose veins compared with no compression? If there is benefit, how long should compression bandaging or hosiery be worn for? ## Why this is important The benefit of compression after interventional treatment for varicose veins is unclear. A well‑conducted, multicentre, randomised controlled trial (RCT) of compression after interventional treatment would help determine whether compression is beneficial, and if so, what type is best and how long it should be worn for. The trial should include patients who have had 1 of the 3 main interventional treatments: endothermal ablation, ultrasound‑guided foam sclerotherapy or surgery. The patients should be divided into 3 groups based on the type of intervention they have had. There should be 6 RCT arms, 1 arm with compression and 1 arm without, in each of the 3 patient groups. Each arm should have subgroups for compression type and duration. Adherence to compression treatment and the impact of adherence on effectiveness should also be evaluated. A cost‑effectiveness analysis should be performed. If compression is beneficial, such a trial should help improve quality of life for people with varicose veins and reduce the longer‑term need for retreatment. # Truncal treatment with or without concurrent tributary treatment What is the clinical and cost effectiveness of concurrent phlebectomies or foam sclerotherapy for varicose tributaries during truncal endothermal ablation for varicose veins compared with: truncal endothermal ablation without concurrent phlebectomies or foam sclerotherapy? truncal endothermal ablation with phlebectomies or foam sclerotherapy, if needed, 6–12 weeks later? ## Why this is important Conventional truncal stripping under general anaesthetic involves synchronous phlebectomies of varicose tributaries, and in ultrasound‑guided foam sclerotherapy truncal and tributary veins are treated concurrently. In contrast, endothermal ablation may be performed alone to obliterate truncal incompetence, or synchronously with phlebectomies or foam sclerotherapy and current practice varies. Synchronous tributary treatment ensures a single treatment episode, and the removal of all symptomatic varicosities leads to a better immediate quality of life, but this takes longer and thus may be associated with increased morbidity. Deferred tributary treatment may reduce morbidity, and also mean that some patients do not need tributary treatment (or need fewer tributary treatments on smaller veins). However, it involves 2 interventions for patients who need tributary treatment. Omitting tributary treatments entirely ensures a single treatment episode, but it is unclear whether remaining varicosities will persist and impair quality of life. At present there is limited evidence from 1 small‑scale (n=50) study on the use and timing of tributary treatments after truncal endothermal ablation. There is a need for practice to be based on empirical evidence from a large and sufficiently powered RCT comparing all 3 main intervention options (no tributary treatment, concurrent tributary treatment and delayed tributary treatment). # Optimal interventional and conservative treatments at different stages of disease What is the optimal treatment (compression, surgery, endothermal ablation or foam sclerotherapy) for varicose veins at each of the CEAP stages, that is CEAP stages 2–3, CEAP stage 4 and CEAP stages 5–6? ## Why this is important Much of the research into the optimum treatment for varicose veins has involved patients with varicose veins in CEAP stages C2 and C3, so little is known of the relative efficacies of treatment at the more severe stages of disease. Furthermore, some studies have included patients with varicose veins at a range of stages without subgrouping, which may conceal important differences in efficacy between different treatments at different stages of disease. Hence current treatment recommendations, which do not differentiate between patients with varicose veins at different stages, may not be equally effective for all patients. A large‑scale RCT that compares the 4 main treatments (compression, surgery, endothermal ablation and foam sclerotherapy) in subgroups with varicose veins at different stages is needed. The use of CEAP to categorise the disease stages is not ideal because higher CEAP stages do not necessarily indicate greater severity. However, other methods of categorisation are even more problematic. Quality‑of‑life measures are unlikely to reflect severity of disease because of variations in perception of symptoms. In addition, measuring the degree of venous reflux would necessitate a method of quantifying reflux in the superficial venous system in a way that adequately reflects disease severity, and such a method does not currently exist.	{'Introduction': "Varicose veins are dilated, often palpable subcutaneous veins with reversed blood flow. They are most commonly found in the legs. Estimates of the prevalence of varicose veins vary. Visible varicose veins in the lower limbs are estimated to affect at least a third of the population. Risk factors for developing varicose veins are unclear, although prevalence rises with age and they often develop during pregnancy.\n\nIn some people varicose veins are asymptomatic or cause only mild symptoms, but in others they cause pain, aching or itching and can have a significant effect on their quality of life. Varicose veins may become more severe over time and can lead to complications such as changes in skin pigmentation, bleeding or venous ulceration. It is not known which people will develop more severe disease but it is estimated that 3–6% of people who have varicose veins in their lifetime will develop venous ulcers.\n\nThere are several options for the management of varicose veins, including:\n\nadvice and reassurance\n\ninterventional treatments (endothermal ablation, foam sclerotherapy and surgery)\n\ncompression hosiery.\n\nIn 2009/10 there were 35,659 varicose veins procedures carried out in the NHS. There is no definitive system for identifying which people will benefit the most from interventional treatment and no established framework within the NHS for the diagnosis and management of varicose veins. This has resulted in wide regional variations in the management of varicose veins in the UK. This guideline was developed with the aim of giving healthcare professionals guidance on the diagnosis and management of varicose veins in the legs, in order to improve patient care and minimise disparities in care across the UK.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information for people with varicose veins\n\nGive people who present with varicose veins information that includes:\n\nAn explanation of what varicose veins are.\n\nPossible causes of varicose veins.\n\nThe likelihood of progression and possible complications, including deep vein thrombosis, skin changes, leg ulcers, bleeding and thrombophlebitis. Address any misconceptions the person may have about the risks of developing complications.\n\nTreatment options, including symptom relief, an overview of interventional treatments and the role of compression.\n\nAdvice on:\n\n\n\nweight loss (for guidance on weight management see the NICE guideline on obesity prevention)\n\nlight to moderate physical activity\n\navoiding factors that are known to make their symptoms worse if possible\n\nwhen and where to seek further medical help.\n\n\n\nWhen discussing treatment for varicose veins at the vascular service tell the person:\n\nWhat treatment options are available.\n\nThe expected benefits and risks of each treatment option.\n\nThat new varicose veins may develop after treatment.\n\nThat they may need more than 1\xa0session of treatment.\n\nThat the chance of recurrence after treatment for recurrent varicose veins is higher than for primary varicose veins.A vascular service is a team of healthcare professionals who have the skills to undertake a full clinical and duplex ultrasound assessment and provide a full range of treatment.\n\n# Referral to a vascular service\n\nRefer people with bleeding varicose veins to a vascular service immediately.\n\nRefer people to a vascular service if they have any of the following.\n\nSymptomatic primary or symptomatic recurrent varicose veins. Symptomatic veins are veins found in association with troublesome lower limb symptoms (typically pain, aching, discomfort, swelling, heaviness and itching).\n\nLower‑limb skin changes, such as pigmentation or eczema, thought to be caused by chronic venous insufficiency.\n\nSuperficial vein thrombosis (characterised by the appearance of hard, painful veins) and suspected venous incompetence.\n\nA venous leg ulcer (a break in the skin below the knee that has not healed within 2\xa0weeks).\n\nA healed venous leg ulcer.\n\n# Assessment and treatment in a vascular service\n\n## Assessment\n\nUse duplex ultrasound to confirm the diagnosis of varicose veins and the extent of truncal reflux, and to plan treatment for people with suspected primary or recurrent varicose veins.\n\n## Interventional treatment\n\nFor people with confirmed varicose veins and truncal reflux:\n\nOffer endothermal ablation (see NICE's interventional procedures guidance on radiofrequency ablation of varicose veins and endovenous laser treatment of the long saphenous vein).\n\nIf endothermal ablation is unsuitable, offer ultrasound‑guided foam sclerotherapy (see NICE's interventional procedures guidance on ultrasound-guided foam sclerotherapy for varicose veins).\n\nIf ultrasound‑guided foam sclerotherapy is unsuitable, offer surgery.If incompetent varicose tributaries are to be treated, consider treating them at the same time.\n\nIf offering compression bandaging or hosiery for use after interventional treatment, do not use for more than 7\xa0days.\n\n## Non-interventional treatment\n\nDo not offer compression hosiery to treat varicose veins unless interventional treatment is unsuitable.\n\n# Management during pregnancy\n\nGive pregnant women presenting with varicose veins information on the effect of pregnancy on varicose veins.\n\nDo not carry out interventional treatment for varicose veins during pregnancy other than in exceptional circumstances.\n\nConsider compression hosiery for symptom relief of leg swelling associated with varicose veins during pregnancy.", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in appendix N of the full guideline.\n\n# Natural history of varicose veins\n\nIn people with varicose veins at CEAP (Clinical, etiological, anatomical and pathophysiological) stage C2 or C3, what are the factors that influence progression of the disease to CEAP stages\xa0C5 or C6?\n\n## Why this is important\n\nThe evidence review for the guideline showed a lack of high‑quality evidence on the progression of varicose veins from CEAP stage\xa0C2 or C3 to more serious varicose veins disease. A large, observational, prospective cohort study, similar to the Framingham or Bonn veins studies, should be undertaken. The study should recruit patients with C2 and C3 disease and follow the progress of their disease for 5\xa0years. Consideration should be given to including a genetic component in the study because genetic factors have not been studied on a large scale. The results of such a study should help to more accurately identify which patients are at risk of developing more serious disease so that interventions can be offered at an early stage to those who will benefit most.\n\n# Compression as a management option\n\nWhat is the clinical and cost effectiveness of compression hosiery versus no compression for the management of symptomatic varicose veins?\n\n## Why this is important\n\nCompression hosiery is widely used as first‑line treatment for symptomatic varicose veins. In some areas of the UK a period of hosiery use is a precursor to referral to secondary care.\n\nDiscomfort and difficulty in application may cause people to stop wearing compression hosiery or wear it only occasionally. The current evidence for the benefit of compression hosiery is weak. There is little evidence of an impact on symptom relief or an improvement in quality of life. It is therefore not possible to calculate the cost effectiveness of compression hosiery.\n\nA multicentre trial randomising compression hosiery versus no compression in patients with symptomatic varicose veins is needed. The trial should evaluate quality of life, including symptom reduction, and measure adherence with compression hosiery. In addition the trial should investigate the impact of compression on disease progression and the need for subsequent intervention.\n\n# Compression after interventional treatment\n\nWhat is the clinical and cost effectiveness of compression bandaging or hosiery after interventional treatment for varicose veins compared with no compression? If there is benefit, how long should compression bandaging or hosiery be worn for?\n\n## Why this is important\n\nThe benefit of compression after interventional treatment for varicose veins is unclear. A well‑conducted, multicentre, randomised controlled trial (RCT) of compression after interventional treatment would help determine whether compression is beneficial, and if so, what type is best and how long it should be worn for. The trial should include patients who have had 1\xa0of the 3\xa0main interventional treatments: endothermal ablation, ultrasound‑guided foam sclerotherapy or surgery. The patients should be divided into 3\xa0groups based on the type of intervention they have had. There should be 6\xa0RCT arms, 1\xa0arm with compression and 1\xa0arm without, in each of the 3\xa0patient groups. Each arm should have subgroups for compression type and duration. Adherence to compression treatment and the impact of adherence on effectiveness should also be evaluated. A cost‑effectiveness analysis should be performed. If compression is beneficial, such a trial should help improve quality of life for people with varicose veins and reduce the longer‑term need for retreatment.\n\n# Truncal treatment with or without concurrent tributary treatment\n\nWhat is the clinical and cost effectiveness of concurrent phlebectomies or foam sclerotherapy for varicose tributaries during truncal endothermal ablation for varicose veins compared with:\n\ntruncal endothermal ablation without concurrent phlebectomies or foam sclerotherapy?\n\ntruncal endothermal ablation with phlebectomies or foam sclerotherapy, if needed, 6–12\xa0weeks later?\n\n## Why this is important\n\nConventional truncal stripping under general anaesthetic involves synchronous phlebectomies of varicose tributaries, and in ultrasound‑guided foam sclerotherapy truncal and tributary veins are treated concurrently. In contrast, endothermal ablation may be performed alone to obliterate truncal incompetence, or synchronously with phlebectomies or foam sclerotherapy and current practice varies.\n\nSynchronous tributary treatment ensures a single treatment episode, and the removal of all symptomatic varicosities leads to a better immediate quality of life, but this takes longer and thus may be associated with increased morbidity. Deferred tributary treatment may reduce morbidity, and also mean that some patients do not need tributary treatment (or need fewer tributary treatments on smaller veins). However, it involves 2\xa0interventions for patients who need tributary treatment. Omitting tributary treatments entirely ensures a single treatment episode, but it is unclear whether remaining varicosities will persist and impair quality of life.\n\nAt present there is limited evidence from 1\xa0small‑scale (n=50) study on the use and timing of tributary treatments after truncal endothermal ablation. There is a need for practice to be based on empirical evidence from a large and sufficiently powered RCT comparing all 3\xa0main intervention options (no tributary treatment, concurrent tributary treatment and delayed tributary treatment).\n\n# Optimal interventional and conservative treatments at different stages of disease\n\nWhat is the optimal treatment (compression, surgery, endothermal ablation or foam sclerotherapy) for varicose veins at each of the CEAP stages, that is CEAP stages\xa02–3, CEAP stage\xa04 and CEAP stages\xa05–6?\n\n## Why this is important\n\nMuch of the research into the optimum treatment for varicose veins has involved patients with varicose veins in CEAP stages\xa0C2 and C3, so little is known of the relative efficacies of treatment at the more severe stages of disease. Furthermore, some studies have included patients with varicose veins at a range of stages without subgrouping, which may conceal important differences in efficacy between different treatments at different stages of disease. Hence current treatment recommendations, which do not differentiate between patients with varicose veins at different stages, may not be equally effective for all patients.\n\nA large‑scale RCT that compares the 4\xa0main treatments (compression, surgery, endothermal ablation and foam sclerotherapy) in subgroups with varicose veins at different stages is needed. The use of CEAP to categorise the disease stages is not ideal because higher CEAP stages do not necessarily indicate greater severity. However, other methods of categorisation are even more problematic. Quality‑of‑life measures are unlikely to reflect severity of disease because of variations in perception of symptoms. In addition, measuring the degree of venous reflux would necessitate a method of quantifying reflux in the superficial venous system in a way that adequately reflects disease severity, and such a method does not currently exist."}	https://www.nice.org.uk/guidance/cg168	This guideline covers diagnosing and managing varicose veins in people aged 18 and over. It aims to ensure that people understand the options for treating varicose veins and that healthcare professionals know when to refer people for specialist assessment and treatment.
e7bb5b475e223c1e0566c889b9ebc02c77d56d57	nice	Insertion of customised exposed titanium implants, without soft tissue cover, for complex orofacial reconstruction	Insertion of customised exposed titanium implants, without soft tissue cover, for complex orofacial reconstruction # Recommendations This document and Insertion of customised titanium implants, with soft tissue cover, for orofacial reconstruction (interventional procedure guidance 449) replace previous guidance on exposed customised titanium implants for orofacial reconstruction (interventional procedure guidance 28). This guidance only covers the use of titanium implants for complex orofacial reconstruction, often involving multiple surfaces, including bony and cartilaginous structures, without soft tissue cover or the expectation of substantial soft tissue cover. It does not cover the use of titanium implants for orofacial reconstruction where the implants are covered or expected to become substantially covered with soft tissue. Current evidence on the efficacy of inserting customised exposed titanium implants, without soft tissue cover, for complex orofacial reconstruction is based on very small numbers of patients. With regard to safety there is concern about the risk of recurrent infection and other complications resulting from long-term exposure of the implants. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake insertion of customised exposed titanium implants, without soft tissue cover, for complex orofacial reconstruction should take the following actions. Inform the clinical governance leads in their trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having insertion of customised exposed titanium implants, without soft tissue cover, for complex orofacial reconstruction. Patient selection is of fundamental importance. The procedure should only be offered to patients for whom there are no other options for reconstruction after consideration by head and neck surgeons and plastic surgeons.# Indications and current treatments Complex orofacial reconstruction involving multiple surfaces, including bony and cartilaginous structures, without the expectation of substantial soft tissue cover is most frequently needed after severe orofacial trauma or removal of orofacial tumours, but may also be used to treat congenital facial abnormalities. Various materials are used including autologous grafts; tissue-engineered bone; alloplastic materials such as silicone, titanium or hydroxyapatite; and composites (for example, titanium mesh embedded in porous polyethylene). The traditional method of forming titanium implants for complex orofacial reconstruction is to bend and cut titanium mesh during the operation. Positioning the implant in the appropriate site requires an accurate assessment of shape and fit, and a number of insertion attempts may be necessary before correct implant shape is achieved. In this procedure, computer-aided design and computer-aided manufacturing (CAD‑CAM) techniques are used to create a customised implant before the operation to insert the implant. The aim is to improve both functional and cosmetic outcomes.# The procedure The design and construction of custom-made implants can be achieved by a number of different techniques. In most cases, customised implants are designed and manufactured using CT scan data by CAD‑CAM and 3-dimensional printing techniques. In some cases a model is constructed on which the implant is shaped and made, either directly or indirectly. With the patient under general anaesthesia the sterilised titanium implant is fixed to adjacent bone using titanium screws. Precise details of the operation will depend on where the implant is to be used and the integrity of surrounding structures.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. A case series of 14 patients who had undergone reconstruction procedures following removal of head and neck tumours reported that the maxilla, hemimandible and nose were successfully reconstructed without needing to raise flaps for coverage. Attempts to reconstruct the subtotal mandible in 2 patients failed because of lack of soft tissue adherence. Both patients underwent further conventional procedures after the implants were removed. In the case series of 14 patients, appearance was described as excellent in 3 patients (details of appearance were not described for the remaining patients). After 2 years of follow-up, all patients remained disease-free and had an acceptable quality of life. The specialist advisers listed key efficacy outcomes as reduced operating time, reduced morbidity, long-term implant retention rates, fixation (screw) removal rates and survival rates (for patients with cancer).# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. Ulceration through the skin of titanium-coated hollow screw reconstruction plate (THORP) implants was reported in all patients with buccal placement of plates in the case series of 14 patients. Eight patients had been treated using THORP but it was not reported how many of them had buccal placement of the implant. It was noted that 1 patient was treated by fitting an acrylic cover plate over the exposed section of the THORP implant. Case reports described unintentional implant exposure in 2 patients that occurred after insertion of large titanium implants for nasal reconstruction. Both patients needed a number of additional procedures. Infection due to methicillin-resistant Staphylococcus aureus (MRSA) resulting in removal of the implant was reported in 1 patient in the case series of 14 patients. Fistulae were reported in 4 patients in the case series of 14 patients. Two of the fistulae were closed with relatively simple flap procedures, and a third was closed using adjuvant hyperbaric oxygen therapy. The fourth fistula was found after 2 years at the site of one of the rivet heads on the THORP implant. This orocervical fistula failed to close after 4 flap procedures and hyperbaric oxygen therapy; eventually titanium chain mail with a solid titanium diaphragm was used to close it. The specialist advisers listed theoretical adverse events as recurrent infection, bone infection, possible septicaemia, externalisation, bone resorption, loosening of the implant, poor aesthetics and failure of the prosthesis.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. Together with Insertion of customised titanium implants, with soft tissue cover, for orofacial reconstruction (NICE interventional procedure guidance 449) it updates and replaces NICE interventional procedure guidance 28. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Care ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk ISBN 978-1-4731-0220-0	{'Recommendations': "This document and Insertion of customised titanium implants, with soft tissue cover, for orofacial reconstruction (interventional procedure guidance\xa0449) replace previous guidance on exposed customised titanium implants for orofacial reconstruction (interventional procedure guidance\xa028).\n\nThis guidance only covers the use of titanium implants for complex orofacial reconstruction, often involving multiple surfaces, including bony and cartilaginous structures, without soft tissue cover or the expectation of substantial soft tissue cover. It does not cover the use of titanium implants for orofacial reconstruction where the implants are covered or expected to become substantially covered with soft tissue.\n\nCurrent evidence on the efficacy of inserting customised exposed titanium implants, without soft tissue cover, for complex orofacial reconstruction is based on very small numbers of patients. With regard to safety there is concern about the risk of recurrent infection and other complications resulting from long-term exposure of the implants. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake insertion of customised exposed titanium implants, without soft tissue cover, for complex orofacial reconstruction should take the following actions.\n\nInform the clinical governance leads in their trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having insertion of customised exposed titanium implants, without soft tissue cover, for complex orofacial reconstruction.\n\nPatient selection is of fundamental importance. The procedure should only be offered to patients for whom there are no other options for reconstruction after consideration by head and neck surgeons and plastic surgeons.", 'Indications and current treatments': 'Complex orofacial reconstruction involving multiple surfaces, including bony and cartilaginous structures, without the expectation of substantial soft tissue cover is most frequently needed after severe orofacial trauma or removal of orofacial tumours, but may also be used to treat congenital facial abnormalities. Various materials are used including autologous grafts; tissue-engineered bone; alloplastic materials such as silicone, titanium or hydroxyapatite; and composites (for example, titanium mesh embedded in porous polyethylene).\n\nThe traditional method of forming titanium implants for complex orofacial reconstruction is to bend and cut titanium mesh during the operation. Positioning the implant in the appropriate site requires an accurate assessment of shape and fit, and a number of insertion attempts may be necessary before correct implant shape is achieved. In this procedure, computer-aided design and computer-aided manufacturing (CAD‑CAM) techniques are used to create a customised implant before the operation to insert the implant. The aim is to improve both functional and cosmetic outcomes.', 'The procedure': 'The design and construction of custom-made implants can be achieved by a number of different techniques. In most cases, customised implants are designed and manufactured using CT scan data by CAD‑CAM and 3-dimensional printing techniques. In some cases a model is constructed on which the implant is shaped and made, either directly or indirectly.\n\nWith the patient under general anaesthesia the sterilised titanium implant is fixed to adjacent bone using titanium screws. Precise details of the operation will depend on where the implant is to be used and the integrity of surrounding structures.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nA case series of 14\xa0patients who had undergone reconstruction procedures following removal of head and neck tumours reported that the maxilla, hemimandible and nose were successfully reconstructed without needing to raise flaps for coverage. Attempts to reconstruct the subtotal mandible in 2\xa0patients failed because of lack of soft tissue adherence. Both patients underwent further conventional procedures after the implants were removed.\n\nIn the case series of 14\xa0patients, appearance was described as excellent in 3\xa0patients (details of appearance were not described for the remaining patients). After 2\xa0years of follow-up, all patients remained disease-free and had an acceptable quality of life.\n\nThe specialist advisers listed key efficacy outcomes as reduced operating time, reduced morbidity, long-term implant retention rates, fixation (screw) removal rates and survival rates (for patients with cancer).', 'Safety': 'This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nUlceration through the skin of titanium-coated hollow screw reconstruction plate (THORP) implants was reported in all patients with buccal placement of plates in the case series of 14\xa0patients. Eight patients had been treated using THORP but it was not reported how many of them had buccal placement of the implant. It was noted that 1\xa0patient was treated by fitting an acrylic cover plate over the exposed section of the THORP implant. Case reports described unintentional implant exposure in 2\xa0patients that occurred after insertion of large titanium implants for nasal reconstruction. Both patients needed a number of additional procedures.\n\nInfection due to methicillin-resistant Staphylococcus aureus (MRSA) resulting in removal of the implant was reported in 1\xa0patient in the case series of 14\xa0patients.\n\nFistulae were reported in 4\xa0patients in the case series of 14\xa0patients. Two of the fistulae were closed with relatively simple flap procedures, and a third was closed using adjuvant hyperbaric oxygen therapy. The fourth fistula was found after 2\xa0years at the site of one of the rivet heads on the THORP implant. This orocervical fistula failed to close after 4\xa0flap procedures and hyperbaric oxygen therapy; eventually titanium chain mail with a solid titanium diaphragm was used to close it.\n\nThe specialist advisers listed theoretical adverse events as recurrent infection, bone infection, possible septicaemia, externalisation, bone resorption, loosening of the implant, poor aesthetics and failure of the prosthesis.', 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nTogether with Insertion of customised titanium implants, with soft tissue cover, for orofacial reconstruction (NICE interventional procedure guidance\xa0449) it updates and replaces NICE interventional procedure guidance\xa028.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n National Institute for Health and Care ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n003 7780\n\nISBN 978-1-4731-0220-0'}	https://www.nice.org.uk/guidance/ipg457
0222cf8b9a04aa6429a83993a43b6321c97322fa	nice	Selective internal radiation therapy for primary hepatocellular carcinoma	Selective internal radiation therapy for primary hepatocellular carcinoma Evidence-based recommendations on selective internal radiation therapy (SIRT) for primary hepatocellular carcinoma. This involves infusion of microspheres loaded with yttrium‑90, which aims to deliver radiation directly into the tumour, minimising the risk of radiation damage to healthy surrounding tissues. # Guidance Current evidence on the efficacy and safety of selective internal radiation therapy (SIRT) for primary hepatocellular carcinoma is adequate for use with normal arrangements for clinical governance, consent and audit. Uncertainties remain about its comparative effectiveness, and clinicians are encouraged to enter eligible patients into trials comparing the procedure against other forms of treatment. Patients with primary hepatocellular carcinoma should be selected for treatment by SIRT or for entry into trials by a multidisciplinary hepatobiliary cancer team. SIRT should only be carried out by clinicians with specific training in its use and in techniques to minimise the risk of side effects from the procedure. Clinicians should enter details about all patients undergoing SIRT for primary hepatocellular carcinoma onto the UK SIRT register. They should audit and review clinical outcomes locally and should document them and consider their relationship to patient characteristics.# The procedure # Indications and current treatments Hepatocellular carcinoma is the most common type of primary liver cancer. The choice of treatment for primary hepatocellular carcinoma depends on a number of factors, including the exact location and stage of the cancer, and the patient's liver function. The aim of treatment is normally to slow progression with a view to improving quality of life and prolonging survival. In some patients surgical removal with curative intent may be possible: this may sometimes be achieved by downstaging the tumour using other treatment modalities first. Treatment options include chemotherapy (intravenous or by hepatic artery infusion), surgical excision, transarterial chemo-embolisation (TACE) and radiofrequency ablation. # Outline of the procedure Selective internal radiation therapy (SIRT) for primary hepatocellular carcinoma involves infusion of microspheres loaded with yttrium‑90, which aims to deliver radiation directly into the tumour, minimising the risk of radiation damage to healthy surrounding tissues. Before undertaking the treatment, a nuclear medicine liver-to-lung shunt study is carried out to assess the risk of radioactive microspheres causing lung damage. Radiographic imaging and selective coil embolisation of arteries to the stomach and duodenum are also commonly carried out. Using local anaesthesia, radioactive microspheres that are designed to lodge in the small arteries are injected into branches of the hepatic artery, usually by a percutaneous femoral approach. The procedure may be repeated depending on the response. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised comparative study of 86 patients, with 43 treated by SIRT and 43 treated by TACE, reported overall median survival of 42 months in the SIRT group compared with 19 months in the TACE group (p=0.008). A case series of 325 patients reported overall median survival was 12.8 months; this varied significantly by disease stage (Barcelona Clinic Liver Cancer stage A: 24.4 months; BCLC stage B: 16.9 months; BCLC stage C: 10 months). The non-randomised comparative study of 86 patients reported a partial response (assessed using World Health Organization criteria) in 61% (26/43) of patients treated by SIRT (median follow-up 34 months) and 37% (13/35) of patients treated by TACE (median follow-up 52 months). This difference was not significant (p=0.07). A non-randomised comparative study of 245 patients, with 123 treated by SIRT and 122 treated by TACE, reported an overall response rate (assessed using WHO criteria) in 49% (60/123) of patients treated by SIRT (median follow-up 23 months) and 36% (44/122) of patients treated by TACE (median follow-up 33 months) (p=0.05). The non-randomised comparative study of 86 patients reported downstaging from stage T3 to stage T2 in 58% (25/43) of patients in the SIRT group and 31% (11/35) of patients in the TACE group at a 'median time to downstaging was within 6 months' (p=0.02). A case series of 291 patients treated by SIRT reported that 12% (34/291) of patients underwent treatment with curative intent: 32 went on to have liver transplants and 2 had resection of their tumours (median follow-up 31 months). A case series of 35 patients treated by SIRT reported that 8 patients were downstaged and underwent liver transplantation (timing ranged from 12 days to 210 months after treatment). The non-randomised comparative study of 245 patients reported a significantly longer median time to progression of 13.3 months in patients treated by SIRT compared against 8.4 months in patients treated by TACE (p=0.05). A non-randomised comparative study of 28 patients, with 14 treated by SIRT and 14 treated by cisplatin, reported health-related quality of life measured on the Functional Assessment of Cancer Therapy – Hepatobiliary (FACT‑Hep) questionnaire (scored on a scale of 0–4; higher score indicating better quality of life or fewer symptoms). The overall health-related quality of life score was 47 for the SIRT group (n=9) and 52 for the cisplatin group (n=5) at 6-month follow-up. This difference was reported as not significant (p value not reported). The Specialist Advisers listed efficacy outcomes as tumour response, overall survival, quality of life, increased time to progression, downsizing or downstaging to potentially curative treatments, and bridging to liver transplantation. # Safety Death within 30 days was reported in 7% (2/27) of patients treated by SIRT and in 9% (4/44) of patients treated by chemo-embolisation in a non-randomised comparative study of 71 patients. Radiation pneumonitis was reported in 4 patients between 1 and 6 months after treatment by SIRT (a scan to determine lung shunting had been performed before SIRT) in a case series of 80 patients. All patients were treated by steroids. Three patients died of progressive respiratory failure and 1 from progressive cancer. Ulceration caused by radiation was reported in 11% (3/27) of patients who were treated by SIRT (after prophylactic coil embolisation of the gastroduodenal arteries) and gastritis and/or temporary ulceration was reported in 20% (9/44) of patients treated by chemo-embolisation in the non-randomised comparative study of 71 patients. Two patients in the SIRT group were treated by subtotal gastrectomy; there were no further details on the other patient (median follow-up 6 months). Cholecystitis reported as 'possibly related to treatment' occurred in 2 patients in the case series of 80 patients treated by SIRT (both treated by emergency cholecystectomy 21 and 243 days after treatment). Radiation-induced biliary stricture was described in a case report. The patient became progressively jaundiced and fatigued, with mild or moderate bilirubin toxicity (timing not reported). Bone marrow suppression resulting in transient thrombocytopenia was reported 1 month after SIRT in a case report. Post-embolisation syndrome was reported in 60% of patients in both the SIRT and TACE groups (absolute numbers not reported) in the non-randomised comparative study of 86 patients. The symptoms (fatigue and transient non-specific flu-like symptoms) lasted 7 to 10 days in the SIRT group (no further details). The Specialist Advisers listed additional anecdotal adverse events as fibrosis and skin ulceration; and additional theoretical adverse events as liver failure, portal hypertension, and radiation-induced liver disease. # Other comments The Committee noted wide variation in the published evidence about prior and adjunctive treatments that patients received. This made interpretation of the effect of SIRT difficult. The Committee noted that safety outcomes from older published studies may not reflect current practice in which prophylactic coil embolisation is used.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. ISBN: 978-1-4731-0226-2	{'Guidance': 'Current evidence on the efficacy and safety of selective internal radiation therapy (SIRT) for primary hepatocellular carcinoma is adequate for use with normal arrangements for clinical governance, consent and audit. Uncertainties remain about its comparative effectiveness, and clinicians are encouraged to enter eligible patients into trials comparing the procedure against other forms of treatment.\n\nPatients with primary hepatocellular carcinoma should be selected for treatment by SIRT or for entry into trials by a multidisciplinary hepatobiliary cancer team.\n\nSIRT should only be carried out by clinicians with specific training in its use and in techniques to minimise the risk of side effects from the procedure.\n\nClinicians should enter details about all patients undergoing SIRT for primary hepatocellular carcinoma onto the UK SIRT register. They should audit and review clinical outcomes locally and should document them and consider their relationship to patient characteristics.', 'The procedure': "# Indications and current treatments\n\nHepatocellular carcinoma is the most common type of primary liver cancer.\n\nThe choice of treatment for primary hepatocellular carcinoma depends on a number of factors, including the exact location and stage of the cancer, and the patient's liver function. The aim of treatment is normally to slow progression with a view to improving quality of life and prolonging survival. In some patients surgical removal with curative intent may be possible: this may sometimes be achieved by downstaging the tumour using other treatment modalities first. Treatment options include chemotherapy (intravenous or by hepatic artery infusion), surgical excision, transarterial chemo-embolisation (TACE) and radiofrequency ablation.\n\n# Outline of the procedure\n\nSelective internal radiation therapy (SIRT) for primary hepatocellular carcinoma involves infusion of microspheres loaded with yttrium‑90, which aims to deliver radiation directly into the tumour, minimising the risk of radiation damage to healthy surrounding tissues.\n\nBefore undertaking the treatment, a nuclear medicine liver-to-lung shunt study is carried out to assess the risk of radioactive microspheres causing lung damage. Radiographic imaging and selective coil embolisation of arteries to the stomach and duodenum are also commonly carried out.\n\nUsing local anaesthesia, radioactive microspheres that are designed to lodge in the small arteries are injected into branches of the hepatic artery, usually by a percutaneous femoral approach.\n\nThe procedure may be repeated depending on the response.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 86\xa0patients, with 43\xa0treated by SIRT and 43\xa0treated by TACE, reported overall median survival of 42\xa0months in the SIRT group compared with 19\xa0months in the TACE group (p=0.008). A case series of 325\xa0patients reported overall median survival was 12.8\xa0months; this varied significantly by disease stage (Barcelona Clinic Liver Cancer [BCLC] stage\xa0A: 24.4\xa0months; BCLC stage\xa0B: 16.9\xa0months; BCLC stage\xa0C: 10\xa0months).\n\nThe non-randomised comparative study of 86\xa0patients reported a partial response (assessed using World Health Organization [WHO] criteria) in 61% (26/43) of patients treated by SIRT (median follow-up 34\xa0months) and 37% (13/35) of patients treated by TACE (median follow-up 52\xa0months). This difference was not significant (p=0.07).\n\nA non-randomised comparative study of 245\xa0patients, with 123\xa0treated by SIRT and 122\xa0treated by TACE, reported an overall response rate (assessed using WHO criteria) in 49% (60/123) of patients treated by SIRT (median follow-up 23\xa0months) and 36% (44/122) of patients treated by TACE (median follow-up 33\xa0months) (p=0.05).\n\nThe non-randomised comparative study of 86\xa0patients reported downstaging from stage\xa0T3 to stage\xa0T2 in 58% (25/43) of patients in the SIRT group and 31% (11/35) of patients in the TACE group at a 'median time to downstaging was within 6 months' (p=0.02).\n\nA case series of 291\xa0patients treated by SIRT reported that 12% (34/291) of patients underwent treatment with curative intent: 32 went on to have liver transplants and 2 had resection of their tumours (median follow-up 31\xa0months).\n\nA case series of 35\xa0patients treated by SIRT reported that 8\xa0patients were downstaged and underwent liver transplantation (timing ranged from 12\xa0days to 210\xa0months after treatment).\n\nThe non-randomised comparative study of 245\xa0patients reported a significantly longer median time to progression of 13.3\xa0months in patients treated by SIRT compared against 8.4\xa0months in patients treated by TACE (p=0.05).\n\nA non-randomised comparative study of 28\xa0patients, with 14\xa0treated by SIRT and 14\xa0treated by cisplatin, reported health-related quality of life measured on the Functional Assessment of Cancer Therapy – Hepatobiliary (FACT‑Hep) questionnaire (scored on a scale of 0–4; higher score indicating better quality of life or fewer symptoms). The overall health-related quality of life score was 47 for the SIRT group (n=9) and 52 for the cisplatin group (n=5) at 6-month follow-up. This difference was reported as not significant (p value not reported).\n\nThe Specialist Advisers listed efficacy outcomes as tumour response, overall survival, quality of life, increased time to progression, downsizing or downstaging to potentially curative treatments, and bridging to liver transplantation.\n\n# Safety\n\nDeath within 30\xa0days was reported in 7% (2/27) of patients treated by SIRT and in 9% (4/44) of patients treated by chemo-embolisation in a non-randomised comparative study of 71\xa0patients.\n\nRadiation pneumonitis was reported in 4\xa0patients between 1 and 6\xa0months after treatment by SIRT (a scan to determine lung shunting had been performed before SIRT) in a case series of 80\xa0patients. All patients were treated by steroids. Three patients died of progressive respiratory failure and 1 from progressive cancer.\n\nUlceration caused by radiation was reported in 11% (3/27) of patients who were treated by SIRT (after prophylactic coil embolisation of the gastroduodenal arteries) and gastritis and/or temporary ulceration was reported in 20% (9/44) of patients treated by chemo-embolisation in the non-randomised comparative study of 71\xa0patients. Two patients in the SIRT group were treated by subtotal gastrectomy; there were no further details on the other patient (median follow-up 6\xa0months).\n\nCholecystitis reported as 'possibly related to treatment' occurred in 2\xa0patients in the case series of 80\xa0patients treated by SIRT (both treated by emergency cholecystectomy 21 and 243\xa0days after treatment).\n\nRadiation-induced biliary stricture was described in a case report. The patient became progressively jaundiced and fatigued, with mild or moderate bilirubin toxicity (timing not reported).\n\nBone marrow suppression resulting in transient thrombocytopenia was reported 1\xa0month after SIRT in a case report.\n\nPost-embolisation syndrome was reported in 60% of patients in both the SIRT and TACE groups (absolute numbers not reported) in the non-randomised comparative study of 86\xa0patients. The symptoms (fatigue and transient non-specific flu-like symptoms) lasted 7 to 10\xa0days in the SIRT group (no further details).\n\nThe Specialist Advisers listed additional anecdotal adverse events as fibrosis and skin ulceration; and additional theoretical adverse events as liver failure, portal hypertension, and radiation-induced liver disease.\n\n# Other comments\n\nThe Committee noted wide variation in the published evidence about prior and adjunctive treatments that patients received. This made interpretation of the effect of SIRT difficult.\n\nThe Committee noted that safety outcomes from older published studies may not reflect current practice in which prophylactic coil embolisation is used.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nISBN: 978-1-4731-0226-2'}	https://www.nice.org.uk/guidance/ipg460	Evidence-based recommendations on selective internal radiation therapy (SIRT) for primary hepatocellular carcinoma. This involves infusion of microspheres loaded with yttrium‑90, which aims to deliver radiation directly into the tumour, minimising the risk of radiation damage to healthy surrounding tissues.
f98d6967fc33c3cc123b5846e34f5a517516c5e1	nice	Insertion of customised titanium implants, with soft tissue cover, for orofacial reconstruction	Insertion of customised titanium implants, with soft tissue cover, for orofacial reconstruction # Guidance This document and Insertion of customised titanium implants, without soft tissue cover, for orofacial reconstruction (interventional procedure guidance 457) replace previous guidance on exposed customised titanium implants for orofacial reconstruction (interventional procedure guidance 28). Current evidence on the efficacy and safety of customised titanium implant insertion for orofacial reconstruction, including reconstruction of the orbital floor, where implants are covered or expected to become substantially covered with soft tissue, is adequate for this procedure to be used with normal arrangements for clinical governance, consent and audit or research. This guidance does not cover complex orofacial reconstruction involving multiple bony and cartilaginous structures, with little or no soft tissue cover.# The procedure # Indications and current treatments Orofacial reconstruction is most frequently needed after severe orofacial trauma or removal of orofacial tumours, but may also be used to treat congenital facial abnormalities. Various materials are used including autologous grafts; tissue-engineered bone; alloplastic materials such as silicone, titanium or hydroxyapatite; and composites (for example, titanium mesh embedded in porous polyethylene). In some sites in the orofacial skeleton (such as the orbital floor) such implants are initially exposed, but there is good radiological and clinical evidence that a protective soft tissue covering forms over them. The traditional method of forming titanium implants for facial reconstruction is to bend and cut titanium mesh during the operation. A number of insertion attempts may be necessary before correct implant shape is achieved. In this procedure, computer-aided design and computer-aided manufacturing (CAD‑CAM) techniques are used to create a customised implant before the operation to insert the implant. The aim is to improve both functional and cosmetic outcomes. # Outline of the procedure The first step in making a customised titanium implant for orofacial reconstruction is to create a precise anatomical model of the patient's skull or a 3-dimensional simulated computer image, using computed tomography or cone-beam computed tomography scans and CAD‑CAM techniques. The implant is then shaped using the contours of this model. The implantation procedure is performed with the patient under general anaesthesia. The sterilised titanium implant is fixed to adjacent bone using titanium screws. Precise details of the operation will depend on where the implant is to be used and the extent of surrounding damage. In most cases the implant is covered, either using existing soft tissue from the area or by transplant of a tissue flap from a donor site. However, implants abutting the paranasal sinuses are left partially exposed in the expectation of soft tissue cover developing as a result of fibrosis and epithelialisation. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised comparative study of 64 patients with facial asymmetry who had orbitozygomatic reconstruction for enophthalmos (posterior displacement of the eyeball) reported good globe projection in 76% (19/25) of patients treated by customised implants compared with 59% (23/39) of patients treated by traditional implants at 1-month follow-up; 8% (2/25) of patients treated by customised implants needed an ocular prosthesis compared with 21% (8/39) of patients treated by traditional implants (p values not reported). A case series of 29 patients reported that enophthalmos was fully corrected in 69% (20/29) of patients and improved in 31% (9/29) of patients, at a mean follow-up of 14 months. However, it was noted that overcorrection of enophthalmos occurred in 10% (3/29) of patients. A non-randomised comparative study of 24 patients reported significantly better reduction of binocular single vision loss area (p=0.015), correction of primary globe position in vertical visual disparity (p=0.012) and improvement in upgaze disparity (p=0.003) for patients treated by customised implants compared with patients treated by traditional implants at 12-month follow-up. The case series of 29 patients reported that diplopia had resolved in 21% (5/24) of patients, improved in 37% (9/24) of patients and not changed in 42% (10/24) of patients, at a mean follow-up of 14 months. The case series of 29 patients reported that restricted ocular motility resolved in 15% (4/26) of patients, improved in 35% (9/26) of patients and did not change in 50% (13/26) of patients, at a mean follow-up of 14 months. The non-randomised comparative study of 64 patients with facial asymmetry who had orbitozygomatic reconstruction reported perfect reduction of the zygoma in 92% (23/25) of patients treated by customised implants (including 11 procedures that used computer-assisted navigation) compared with 74% (29/39) of patients treated by traditional implants (p value not reported). In a case series of 22 patients with orbital defects, 1 out of 17 patients with preoperative diplopia needed ocular motor surgery after the initial procedure (follow-up 24 months). The Specialist Advisers listed key efficacy outcomes as long-term function and durability of the implant, and return to normal daily activities. # Safety Titanium mesh became unintentionally exposed in 2 patients in a case series of 20 patients who had undergone reconstruction of high maxillary defects. In 1 patient, the mesh became exposed in the oral cavity at 36 months; in the other patient, the mesh became exposed through the infraorbital skin at 4 months. Both patients had further surgery. A palpable plate rim was reported in 1 patient in the case series of 22 orbital reconstructions. The patient developed pain and irritation at the inferior orbital margin, where she was able to feel the plate flange and screw (timing not reported). The flange was trimmed and the screw removed in a further operation. Infection in the region of the implant was reported in 1 patient in the case series of 29 patients who had undergone extensive orbital reconstruction. Maxillary sinusitis was reported in 1 patient in the non-randomised comparative study of 64 patients (treatment group not reported). This resolved after debridement and drainage. Oronasal fistulae were reported in 2 patients in the case series of 20 patients who had undergone maxillary reconstruction. The fistulae were detected at the edge of palatal skin paddles 1 year after surgery and were sealed with removable partial dentures. Visual deterioration occurred in 1 patient in the case series of 22 patients. The patient developed a sudden-onset subjective decrease in visual acuity, with no perception of light after 8 hours. This resolved within a week of the implant being removed. Transient loss of visual acuity occurred in 1 patient in a case series of 15 patients who had undergone orbital reconstruction, which was attributed to the mesh plate encroaching on the optic nerve. Reoperation led to complete recovery. Intraconal soft tissue scarring, limited ocular motility and persistent diplopia were reported in 1 patient from the case series of 15 patients with orbital defects. Diplopia improved after revisional surgery. Oculomotor nerve palsy occurred in 1 patient in the non-randomised comparative study of 64 patients with a follow-up period of 1 month (treatment group not reported); surgery was carried out to correct the resulting strabismus. The Specialist Advisers listed additional theoretical adverse events as bone resorption, loosening of the implant, and loss of the integrated elements of the prosthesis.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Changes after publication July 2013: Review statement in section 1 amended on publication of Insertion of customised titanium implants, without soft tissue cover, for orofacial reconstruction (interventional procedure guidance 457), which completed the update of exposed customised titanium implants for orofacial reconstruction (interventional procedure guidance 28). Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document and Insertion of customised titanium implants, without soft tissue cover, for orofacial reconstruction (interventional procedure guidance 457) replace previous guidance on exposed customised titanium implants for orofacial reconstruction (interventional procedure guidance 28).\n\nCurrent evidence on the efficacy and safety of customised titanium implant insertion for orofacial reconstruction, including reconstruction of the orbital floor, where implants are covered or expected to become substantially covered with soft tissue, is adequate for this procedure to be used with normal arrangements for clinical governance, consent and audit or research. This guidance does not cover complex orofacial reconstruction involving multiple bony and cartilaginous structures, with little or no soft tissue cover.', 'The procedure': "# Indications and current treatments\n\nOrofacial reconstruction is most frequently needed after severe orofacial trauma or removal of orofacial tumours, but may also be used to treat congenital facial abnormalities. Various materials are used including autologous grafts; tissue-engineered bone; alloplastic materials such as silicone, titanium or hydroxyapatite; and composites (for example, titanium mesh embedded in porous polyethylene). In some sites in the orofacial skeleton (such as the orbital floor) such implants are initially exposed, but there is good radiological and clinical evidence that a protective soft tissue covering forms over them.\n\nThe traditional method of forming titanium implants for facial reconstruction is to bend and cut titanium mesh during the operation. A number of insertion attempts may be necessary before correct implant shape is achieved. In this procedure, computer-aided design and computer-aided manufacturing (CAD‑CAM) techniques are used to create a customised implant before the operation to insert the implant. The aim is to improve both functional and cosmetic outcomes.\n\n# Outline of the procedure\n\nThe first step in making a customised titanium implant for orofacial reconstruction is to create a precise anatomical model of the patient's skull or a 3-dimensional simulated computer image, using computed tomography or cone-beam computed tomography scans and CAD‑CAM techniques. The implant is then shaped using the contours of this model.\n\nThe implantation procedure is performed with the patient under general anaesthesia. The sterilised titanium implant is fixed to adjacent bone using titanium screws. Precise details of the operation will depend on where the implant is to be used and the extent of surrounding damage. In most cases the implant is covered, either using existing soft tissue from the area or by transplant of a tissue flap from a donor site. However, implants abutting the paranasal sinuses are left partially exposed in the expectation of soft tissue cover developing as a result of fibrosis and epithelialisation.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 64\xa0patients with facial asymmetry who had orbitozygomatic reconstruction for enophthalmos (posterior displacement of the eyeball) reported good globe projection in 76% (19/25) of patients treated by customised implants compared with 59% (23/39) of patients treated by traditional implants at 1-month follow-up; 8% (2/25) of patients treated by customised implants needed an ocular prosthesis compared with 21% (8/39) of patients treated by traditional implants (p values not reported). A case series of 29\xa0patients reported that enophthalmos was fully corrected in 69% (20/29) of patients and improved in 31% (9/29) of patients, at a mean follow-up of 14\xa0months. However, it was noted that overcorrection of enophthalmos occurred in 10% (3/29) of patients.\n\nA non-randomised comparative study of 24\xa0patients reported significantly better reduction of binocular single vision loss area (p=0.015), correction of primary globe position in vertical visual disparity (p=0.012) and improvement in upgaze disparity (p=0.003) for patients treated by customised implants compared with patients treated by traditional implants at 12-month follow-up. The case series of 29\xa0patients reported that diplopia had resolved in 21% (5/24) of patients, improved in 37% (9/24) of patients and not changed in 42% (10/24) of patients, at a mean follow-up of 14\xa0months.\n\nThe case series of 29\xa0patients reported that restricted ocular motility resolved in 15% (4/26) of patients, improved in 35% (9/26) of patients and did not change in 50% (13/26) of patients, at a mean follow-up of 14\xa0months.\n\nThe non-randomised comparative study of 64\xa0patients with facial asymmetry who had orbitozygomatic reconstruction reported perfect reduction of the zygoma in 92% (23/25) of patients treated by customised implants (including 11\xa0procedures that used computer-assisted navigation) compared with 74% (29/39) of patients treated by traditional implants (p value not reported).\n\nIn a case series of 22\xa0patients with orbital defects, 1\xa0out of 17\xa0patients with preoperative diplopia needed ocular motor surgery after the initial procedure (follow-up 24\xa0months).\n\nThe Specialist Advisers listed key efficacy outcomes as long-term function and durability of the implant, and return to normal daily activities.\n\n# Safety\n\nTitanium mesh became unintentionally exposed in 2\xa0patients in a case series of 20\xa0patients who had undergone reconstruction of high maxillary defects. In 1\xa0patient, the mesh became exposed in the oral cavity at 36\xa0months; in the other patient, the mesh became exposed through the infraorbital skin at 4\xa0months. Both patients had further surgery. A palpable plate rim was reported in 1\xa0patient in the case series of 22\xa0orbital reconstructions. The patient developed pain and irritation at the inferior orbital margin, where she was able to feel the plate flange and screw (timing not reported). The flange was trimmed and the screw removed in a further operation.\n\nInfection in the region of the implant was reported in 1\xa0patient in the case series of 29\xa0patients who had undergone extensive orbital reconstruction. Maxillary sinusitis was reported in 1\xa0patient in the non-randomised comparative study of 64\xa0patients (treatment group not reported). This resolved after debridement and drainage.\n\nOronasal fistulae were reported in 2\xa0patients in the case series of 20\xa0patients who had undergone maxillary reconstruction. The fistulae were detected at the edge of palatal skin paddles 1\xa0year after surgery and were sealed with removable partial dentures.\n\nVisual deterioration occurred in 1\xa0patient in the case series of 22\xa0patients. The patient developed a sudden-onset subjective decrease in visual acuity, with no perception of light after 8\xa0hours. This resolved within a week of the implant being removed. Transient loss of visual acuity occurred in 1\xa0patient in a case series of 15\xa0patients who had undergone orbital reconstruction, which was attributed to the mesh plate encroaching on the optic nerve. Reoperation led to complete recovery.\n\nIntraconal soft tissue scarring, limited ocular motility and persistent diplopia were reported in 1\xa0patient from the case series of 15\xa0patients with orbital defects. Diplopia improved after revisional surgery.\n\nOculomotor nerve palsy occurred in 1\xa0patient in the non-randomised comparative study of 64\xa0patients with a follow-up period of 1\xa0month (treatment group not reported); surgery was carried out to correct the resulting strabismus.\n\nThe Specialist Advisers listed additional theoretical adverse events as bone resorption, loosening of the implant, and loss of the integrated elements of the prosthesis.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nChanges after publication\n\nJuly 2013: Review statement in section 1 amended on publication of Insertion of customised titanium implants, without soft tissue cover, for orofacial reconstruction (interventional procedure guidance 457), which completed the update of exposed customised titanium implants for orofacial reconstruction (interventional procedure guidance 28).\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. 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fd4d6f71c206b7c789b1ddb0a13bd577e4868ebc	nice	Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism	Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism Evidence-based recommendations on rivaroxaban (Xarelto) for treating pulmonary embolism and for preventing a further deep vein thrombosis or pulmonary embolism in adults. # Guidance Rivaroxaban is recommended as an option for treating pulmonary embolism and preventing recurrent deep vein thrombosis and pulmonary embolism in adults.# The technology Rivaroxaban (Xarelto, Bayer) is indicated for the 'treatment of deep vein thrombosis and pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism in adults'. For the initial treatment of acute pulmonary embolism, the recommended dosage of rivaroxaban is 15 mg twice daily for the first 21 days followed by 20 mg once daily for continued treatment and prevention of recurrent venous thromboembolism. Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism (NICE technology appraisal guidance 261) recommends rivaroxaban as an option for treating deep vein thrombosis and preventing recurrent deep vein thrombosis and pulmonary embolism after a diagnosis of acute deep vein thrombosis in adults. The duration of treatment recommended in the summary of product characteristics depends on bleeding risk and other clinical criteria. Short-term treatment (at least 3 months) is recommended for people with transient risk factors such as recent surgery and trauma. Longer treatment is recommended for people with permanent risk factors, or idiopathic (unprovoked) deep vein thrombosis or pulmonary embolism. A reduced dosage of 15 mg twice daily for 21 days followed by 15 mg once daily should be used in people with moderate (creatinine clearance 30–49 ml/min) or severe (creatinine clearance 15–29 ml/min) renal impairment if their risk of bleeding outweighs the risk of recurrent deep vein thrombosis or pulmonary embolism. The summary of product characteristics lists the following adverse reactions for rivaroxaban: anaemia, dizziness, headache, fainting, bleeding events, tachycardia (rapid heartbeat), low blood pressure, haematoma, stomach pain, dyspepsia (heartburn), nausea, constipation, diarrhoea, vomiting, pruritus (itching), rash, bruising, pain in the extremities, fever, and swelling, especially of the ankles and feet. For full details of side effects and contraindications, see the summary of product characteristics. Rivaroxaban costs £2.10 per 15‑mg or 20‑mg tablet ('British national formulary' edition 65). The cost of treatment is estimated to be £235.86, £427.61 and £811.13 for 3, 6 and 12 months of treatment respectively. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rivaroxaban and a review of this submission by the Evidence Review Group (ERG; section 10). The key clinical evidence in the manufacturer's submission came from EINSTEIN‑PE, an international, event-driven, open-label, assessor-blind, non-inferiority study. The study included 4832 people in an intention-to-treat population. Treatment duration was 3, 6 or 12 months and this was determined by a study investigator before randomisation based on the risk profile of each person and local preferences. Patients were randomised to either rivaroxaban 15 mg twice daily for 21 days followed by 20 mg once daily for the intended treatment duration, or to enoxaparin (a low molecular weight heparin ) 1.0 mg/kg twice daily until anticoagulation was established plus a vitamin K antagonist (either warfarin or acenocoumarol), which was dose adjusted to maintain the international normalised ratio (INR) within a therapeutic range of 2.0 to 3.0 with a target of 2.5. Enoxaparin was administered for at least 5 days and was stopped when the INR was more than 2.0 on 2 consecutive measurements at least 24 hours apart. There was an advised overlap with the vitamin K antagonist of 4 to 5 days. Patients were assessed during their intended treatment duration, followed by a 30-day observation period. The manufacturer noted that there was a difference in the dose of enoxaparin used in the trial and the dose covered by the European and UK licence (that is, 1.5 mg/kg once daily for at least 5 days and until adequate oral anticoagulation is established). Out of the whole study population, 5.2% were allocated to receive 3 months of treatment, 57.4% to 6 months of treatment and 37.4% to 12 months of treatment. The median time from onset of symptoms to randomisation was 4 days. The EINSTEIN‑PE study allowed a limited amount of treatment before randomisation. A similar proportion of patients in the rivaroxaban arm (92.5%) and the LMWH/VKA arm (92.1%) received pre-randomisation anticoagulation (p=0.62, post-hoc binomial test). Among those who received pre-randomisation anticoagulation, 62.5% of patients received anticoagulation for 1 day (the maximum duration permitted was 48 hours). In the intention-to-treat population, the mean age was 58 and approximately 53% of the patients were male. Around 25% of patients in both treatment arms had a concurrent deep vein thrombosis. Pulmonary embolism was unprovoked in 65% of patients receiving rivaroxaban and 64% of patients receiving LMWH with a vitamin K antagonist (hereafter referred to as LMWH/VKA). Approximately 5% of people in both treatment arms had active cancer, and 19% and 20% of people in the rivaroxaban and LMWH/VKA treatment arms respectively had experienced a previous venous thromboembolism. EINSTEIN‑PE excluded people with a creatinine clearance of less than 30 ml/min and people for whom rivaroxaban was not suitable or who had contraindications to enoxaparin, warfarin or acenocoumarol. A total of 555 (11.5%) patients discontinued treatment; the number of people who discontinued was similar in both treatment groups (p=0.07). The primary efficacy end point for EINSTEIN‑PE was symptomatic recurrent venous thromboembolism, which was a composite end point comprising recurrent deep vein thrombosis or pulmonary embolism. This included both fatal and non-fatal pulmonary embolism, and unexplained death for which a pulmonary embolism could not be ruled out. In the intention-to-treat population (rivaroxaban n=2419; LMWH/VKA n=2413), rivaroxaban met the pre-specified non-inferiority criterion, which required the upper bound of the 95% confidence interval of the hazard ratio to be less than 2. Symptomatic recurrent venous thromboembolism events occurred in 50 (2.1%) patients in the rivaroxaban arm compared with 44 (1.8%) patients in the LMWH/VKA arm (hazard ratio 1.12; 95% confidence interval 0.75 to 1.68). The primary safety outcome for EINSTEIN‑PE was clinically relevant bleeding, that is, major bleeding and clinically relevant non-major bleeding in the safety population, which consisted of all patients who had received at least 1 dose of the study drug (rivaroxaban n=2412; LMWH/VKA n=2405). There was no difference between rivaroxaban and LMWH/VKA in clinically relevant bleeding that was experienced by 249 (10.3%) and 274 (11.4%) patients in each treatment arm respectively (HR 0.90, 95% CI 0.76 to 1.07). The proportion of patients who experienced major bleeding was statistically significantly lower with rivaroxaban (1.1%) than with LMWH/VKA (2.2%) (HR 0.49, 95% CI 0.31 to 0.79, p=0.003). In the intended treatment period, there were a similar number of deaths in the rivaroxaban arm (58 deaths) and the LMWH/VKA arm (50 deaths) (HR 1.13, 95% CI 0.77 to 1.65). Treatment-emergent adverse events (other than bleeding and recurrent venous thromboembolism) were similar between the treatment arms. Approximately 5% of patients in the rivaroxaban arm and 4% in the LMWH/VKA arm discontinued treatment because of an adverse event. The manufacturer reported a time in therapeutic range for the comparator LMWH/VKA of 62.7% across all centres. The manufacturer highlighted that guidelines from the National Patient Safety Agency and the Scottish Executive Health Department recommend a time in therapeutic range of at least 60%. It also noted there was no statistical interaction observed in EINSTEIN‑PE between time in therapeutic range and treatment effect. Health-related quality of life was not measured in EINSTEIN‑PE. The manufacturer described 2 measures of treatment satisfaction that had been measured: the Anti-Clot Treatment Scale (ACTS) and the Treatment Satisfaction Questionnaire (TSQM). Treatment satisfaction was not used to derive any of the utility values used in the economic analysis. The manufacturer presented the results for a number of subgroups considered in EINSTEIN‑PE, which included the 3 subgroups specified in the final scope issued by NICE. These were groups based on underlying risk of bleeding, provoked compared with unprovoked venous thromboembolism, and the presence or absence of cancer. The manufacturer used the intended treatment duration as a proxy for bleeding risk. The manufacturer tested for a statistically significant interaction between each subgroup and the primary efficacy and safety outcomes. The outcomes of the statistical interaction tests are academic in confidence, so the results cannot be presented in this document. The manufacturer also presented graphically the relative efficacy across subgroups, including the 3 subgroups specified in the final scope issued by NICE. The manufacturer presented similar results for the major and clinically relevant non-major bleeding outcome (with the exception of the idiopathic and non-idiopathic groups). The 95% confidence intervals surrounding the hazard ratios for all outcomes overlapped across the subgroups, suggesting a consistency of effect. The manufacturer highlighted that in the comparator arm of the trial, patients with cancer had received LMWH/VKA, whereas standard care in the UK is LMWH alone. The manufacturer did not consider it appropriate to conduct a network meta-analysis to estimate the relative effectiveness of rivaroxaban compared with LMWH in people with cancer who had experienced a pulmonary embolism. This was because of the heterogeneity of the studies assessing long-term treatment of venous thromboembolism in people with cancer, which the manufacturer had identified and presented in its submission for NICE technology appraisal guidance 261. The manufacturer constructed a Markov model to evaluate the consequences of 3-, 6- and 12-month, and lifelong, treatment with rivaroxaban for preventing recurrent venous thromboembolism in people who experience an acute pulmonary embolism. The model used a time horizon of 40 years and a cycle length of 3 months. To reflect the change in the risk patients experience over time, different risks were applied in cycle 1 (months 0–3), 2 (months 3–6), 3 and 4 (months 6–12) and 5 onwards (12 months onwards). The evaluation was undertaken from an NHS and personal social services perspective, and costs and utilities were discounted at 3.5% per year after the first year. For people initially treated for 3, 6 or 12 months, there were 13 health states including death. The lifelong treatment model contained an additional state. People entered the model after their index pulmonary embolism to an on-treatment state in which they received 3-, 6-, 12-month or lifelong treatment with rivaroxaban or LMWH/VKA. They then either stayed on treatment, experienced a recurrent venous thromboembolism (pulmonary embolism or deep vein thrombosis), experienced an adverse event (clinically relevant non-major bleed, major intracranial bleed, or major extracranial bleed), moved to an off-treatment health state, entered a long-term complication state (for example, chronic thromboembolic pulmonary hypertension), or died. The additional state in the lifelong treatment model was for people who had experienced a deep vein thrombosis in the timeframe of the model and who had not stopped treatment for other reasons. All patients who experienced a deep vein thrombosis after their index pulmonary embolism were at risk of post-thrombotic syndrome. There was not a separate health state for post-thrombotic syndrome, rather the consequences of post-thrombotic syndrome were applied as disutilities and costs to patients in both the on- and off-treatment post-deep vein thrombosis health states. The modelled cohort was adults with an acute pulmonary embolism who matched the licensed indication, the EINSTEIN‑PE trial population and the stated decision problem. Data from EINSTEIN‑PE were used to inform the clinical effectiveness of treatments and to derive the transition probabilities used in the model; this was supplemented with data from the manufacturer's systematic reviews. All drug acquisition costs and resources associated with acute treatment hospital stay, monitoring, recurrent thromboembolic events and adverse events (that is, bleeding events) were included in the model. A validated preference-based measure of quality of life was not measured in EINSTEIN‑PE; the manufacturer derived the utility values used in the model through systematic review. The manufacturer assigned a baseline utility value of 0.825 to all patients with pulmonary embolism entering the model, which was taken from a survey of the UK general population using a visual analogue scale rating and adjusted with disutility values for deep vein thrombosis, pulmonary embolism, extracranial bleed, intracranial bleed and post-thrombotic syndrome. All people who had an intracranial bleed moved to a post-intracranial bleed health state in the next cycle of the model after their bleed. The utility value assumed for an intracranial bleed was 0.33, which increased to 0.71 in the post-intracranial bleed state. A disutility due to warfarin therapy of 0.012 was applied in the LMWH/VKA arm. Base-case results were presented for the 3-, 6-, 12-month and lifelong treatment durations. For the 3-, 6- and 12-month treatment durations, rivaroxaban dominated LMWH/VKA, that is, rivaroxaban was less costly and more effective (0.027, 0.013 and 0.019 incremental quality-adjusted life years and a £395.80, £213.21 and £133.13 reduction in total costs for the 3-, 6- and 12-month treatment groups respectively). In the lifelong treatment analysis, rivaroxaban was associated with an incremental cost-effectiveness ratio (ICER) compared with LMWH/VKA of £13,252 per QALY gained (0.104 incremental QALYs for an extra £1374.73). The manufacturer performed 123 deterministic sensitivity analyses for each of the 4 durations of treatment. For the 3-, 6- and 12-month treatments, the net monetary benefit for rivaroxaban compared with LMWH/VKA was positive for all analyses if the maximum acceptable ICER was £20,000 per QALY gained. Cost effectiveness of lifelong treatment with rivaroxaban was most sensitive to changes in the frequency of INR-monitoring visits, where the ICER increased from £13,252 per QALY gained to £27,914 per QALY gained if people have 3, rather than 5, visits in each quarter after the first. The manufacturer conducted 1 scenario analysis, in which the time horizon was reduced from 40 to 5 years. With a 5-year time horizon, rivaroxaban continued to dominate LMWH/VKA for the 3-, 6- and 12-month treatment durations. For the lifelong treatment duration, reducing the time horizon to 5 years decreased the ICER of rivaroxaban compared with LMWH/VKA to £12,282 per QALY gained. Probabilistic sensitivity analysis demonstrated that there was a 99.9%, 95.9%, 93.7% and 59.1% probability that the base-case ICER for the 3-, 6-, and 12-month and lifelong treatments was lower than £20,000 per QALY gained. The ERG considered that overall, the manufacturer's submission provided an unbiased estimate of the treatment effect of rivaroxaban. The ERG stated that it was based on a well-conducted systematic review of clinical effectiveness, which identified 1 relevant randomised controlled trial. It considered the trial to be of reasonable quality with a low risk of bias. The ERG raised concerns that the patient population in the trial may not be fully representative of the treatment population in the UK. In particular, it stated that patients with severe renal impairment (a creatinine clearance of 15–29 ml/min) were excluded from the trial. The ERG noted that the summary of product characteristics specifies that rivaroxaban can be used with caution with dose reductions if needed in this group of patients. The ERG stated that as these patients are at higher risk of bleeding and were excluded from the trial, it is possible that the trial may have underestimated the rate of bleeding that may be seen in clinical practice with rivaroxaban. The ERG noted that the trial only assessed outcomes up to a 12‑month treatment period; therefore, effectiveness and safety of long-term treatment with rivaroxaban is unknown. The ERG stated that the manufacturer's Kaplan-Meier plot of cumulative venous thromboembolism rates suggested a worsening of the relative hazard of recurrent venous thromboembolism while on rivaroxaban, compared with LMWH/VKA, towards the end of the 12-month treatment period. The ERG commented that it is plausible that the hazard of recurrent venous thromboembolism might worsen further if treatments are compared in the longer term, particularly if adherence to rivaroxaban (which does not need the regular monitoring of vitamin K antagonists) declines. The ERG suggested that the long-term adherence to rivaroxaban may be lower than the 80% plus observed in most of the patients in EINSTEIN‑PE. The ERG considered the manufacturer's subgroup analyses. The ERG suggested that the outcomes may be worse in the active cancer group than those seen for other patients because of increased bleeding risk. The ERG noted that the manufacturer's presentation of subgroup data suggested consistency across the subgroups in terms of the relative safety and efficacy. It considered that because of the small numbers of people in the trial who had cancer, differences in the incidence of bleeding may not have been apparent because of the small number of events recorded in each treatment arm. The ERG also noted the 95% confidence intervals around the hazard ratio for recurrent venous thromboembolism in patients with active cancer presented by the manufacturer were wide, and suggested this indicated that there is uncertainty around where the true effect lies and that the manufacturer's analysis of efficacy in the cancer subgroup should be interpreted with caution. The ERG had concerns that the manufacturer had used intended treatment duration as a proxy for both underlying risk of bleeding and provoked or unprovoked pulmonary embolism. However, it suggested that there are no robust markers for determining length of treatment in advance, which suggests that pre-specified treatment durations may not be a good proxy for other variables. The ERG considered the structure adopted for the economic model to be reasonable, consistent with current clinical understanding of pulmonary embolism and consistent with the previous economic evaluations of treatments for venous thromboembolism, such as the submission for NICE technology appraisal guidance 261. The ERG also considered that the parameters used in the model were generally appropriate and that the population used in the model, drawn from EINSTEIN‑PE, is broadly representative of the pulmonary embolism population in the UK (with the exception that it did not include people for whom rivaroxaban is contraindicated or people with severe renal impairment who may still be eligible for rivaroxaban). The ERG noted that all transition probabilities were treatment-specific in the lifelong model but that there appeared to be an error in the model, because after 36 months, the probability of recurrent venous thromboembolism and bleeding events were the same for rivaroxaban and LMWH/VKA. The ERG stated that the probabilities of these events after 36 months were not explicitly stated in the manufacturer's submission. The ERG believed this to be an unintended error and corrected the model so that the treatment effect of rivaroxaban after 36 months was applied to the LMWH/VKA transition probabilities. After this amendment, the ICER for rivaroxaban compared with LMWH/VKA in the lifelong treatment analysis was reduced from £13,252 per QALY gained to £7072 per QALY gained. For all of the subsequent analyses, the ERG incorporated this correction and referred to this as the amended base case. The amended probabilistic base-case ICER for rivaroxaban compared with LMWH/VKA was £7019 per QALY gained. The ERG had concerns about some of the utility values used in the manufacturer's model, particularly as some of the sources of utility values identified and used by the manufacturer were small studies or did not use the EQ-5D instrument that is the preferred measure of health related quality of life in adults in NICE's reference case. The ERG considered the utility value of 0.33 for an intracranial bleed, based on a study of 129 people that had used time trade off rather than the EQ-5D to derive the utility value that the manufacturer had applied for 3 months in the intracranial bleed state model, to be low. The ERG identified a prospective, longitudinal study that suggested a utility value of 0.31 immediately after an intracranial bleed (stroke), increasing to 0.55 after 1 month and to 0.61 by 3 months. As the manufacturer had estimated that rivaroxaban was associated with fewer intracranial bleeds than LMWH/VKA, the ERG stated that a mid-value of 0.55 for the intracranial bleed health-state utility value would be a more conservative assumption. The ERG also questioned the manufacturer's choice of utility values for post-thrombotic syndrome. The manufacturer had used a study of 30 healthy volunteers that had used a standard gamble approach to derive a utility value of 0.93 for severe post-thrombotic syndrome. However, the ERG stated that the study of 129 people, which the manufacturer had used to obtain utility values for some of the health states in its model including the utility value for an intracranial bleed, gave a utility value of 0.86 for post-thrombotic syndrome. The ERG did not consider the manufacturer's choice of utility value for post-thrombotic syndrome to be a conservative assumption. The ERG was satisfied that the unit costs used in the economic model were relevant and had been obtained using suitable methods. However, it noted that the costs of reversing the effects of rivaroxaban and warfarin in the case of major bleeding or elective surgery had not been included and that these may be significant. The ERG stated that vitamin K, fresh frozen plasma and prothrombin complex concentrate (PCC) are used to reverse bleeding events on warfarin but there is no specific antidote for rivaroxaban. The ERG commented that either activated recombinant factor VIIa or PCC may be considered to manage severe and life-threatening bleeding in patients on rivaroxaban. The ERG's clinical adviser considered that the reversal of bleeding on warfarin is likely to need less PCC than rivaroxaban, and that recombinant factor VIIa may be more effective for reversing rivaroxaban than PCC. The ERG estimated that the cost of treating a patient weighing 70 kg with recombinant factor VIIa is £19,303. The ERG also estimated that the cost of treating a bleed while receiving rivaroxaban with PCC would be £1680, and the maximum cost for treating a bleed on warfarin with PCC concentrate would be £1260. The ERG conducted the following exploratory analyses: reduction in assumed frequency of INR-monitoring visits reduction in mean LMWH treatment length reduction in the efficacy of rivaroxaban after 12 months in the lifelong treatment analysis in preventing recurrent venous thromboembolism higher hazard of major bleed on rivaroxaban in the lifelong treatment analysis higher utility values for the intracranial bleed state higher mean age of model population costs of emergency anticoagulant reversal taken into account in all cases of major bleeding a multiple assumption scenario (reduction in assumed frequency of INR monitoring visits, with a greater proportion of these in secondary care and a greater proportion of the primary care monitoring visits led by nurses; reduction in mean LMWH treatment length; reduction in the efficacy of rivaroxaban after 12 months in the lifelong treatment analysis; higher hazard of major bleed). The ERG noted that the manufacturer had assumed 9 INR-monitoring visits in the first quarter for people receiving LMWH/VKA and 5 in each subsequent quarter, and that this was consistent with what the manufacturer presented for NICE technology appraisal guidance 261. The ERG highlighted that in NICE technology appraisal guidance 261, the Committee had concluded that a less intensive INR-monitoring programme of 6 visits in the first 3 months followed by 3 visits every quarter thereafter was reasonable and relevant (when a deep vein thrombosis was the index thromboembolism). The ERG reduced the frequency of INR-monitoring visits to 6 visits in the first quarter and 3 in each subsequent quarter. The ICER for rivaroxaban compared with LMWH/VKA increased from £7072 in the base case to £17,857 per QALY gained in the lifelong treatment duration analysis, and went from dominating LMWH/VKA in the 12-month treatment duration analysis to having an ICER of £3542 per QALY gained. Rivaroxaban continued to dominate LMWH/VKA in the 6-month treatment analysis. The ERG did not present the effect of a reduced INR-monitoring frequency scenario on the 3-month treatment analysis. For the lifelong treatment duration analysis, the ERG assessed a further scenario of 6 visits in the first quarter and 2 in each subsequent quarter. This assumption increased the ICER for rivaroxaban compared with LMWH/VKA from £7072 to £22,912 per QALY gained. Assuming a shorter treatment duration with LMWH from the manufacturer's estimate in the base case (derived from the academic-in-confidence average duration in EINSTEIN‑PE) of either 9, 8 or 6 days was found to have a minimal cost-saving effect in the 6-month treatment duration analysis. Rivaroxaban continued to dominate LMWH/VKA regardless of treatment duration with LMWH. The ERG did not present the effect of assuming the shorter treatment duration with LMWH on the 3-, 12-month or lifelong treatment duration analyses. As there was uncertainty surrounding the long-term efficacy and safety of rivaroxaban, the ERG performed scenario analyses that assessed varying efficacy and safety effects of rivaroxaban. The hazard ratio for recurrent venous thromboembolism for rivaroxaban compared with LMWH/VKA was 1.123 for the entirety of the lifelong treatment base case. The ERG assessed 2 scenarios in which the hazard ratio was increased to either 1.5 or 2.0 after 12 months (that is, rivaroxaban was assumed to be increasingly less effective relative to LMWH/VKA). Assuming a hazard ratio of 1.5 for venous thromboembolism after 12 months for the population in the lifelong treatment analysis increased the ICER for rivaroxaban compared with LMWH/VKA from £7072 to £9043 per QALY gained. When a hazard ratio of 2.0 was assumed, the ICER for rivaroxaban compared with LMWH/VKA increased to £14,090 per QALY gained. In the manufacturer's base-case analyses, the hazard ratio for major bleed for rivaroxaban compared with LMWH/VKA was 0.493. The ERG assessed 2 scenarios in the lifelong treatment duration analysis in which the hazard ratio for major bleeds was increased. In the first scenario, the ERG used a hazard ratio for major bleeds of 0.65. This was taken from the EINSTEIN‑DVT trial (one of the key trials supporting the clinical effectiveness of rivaroxaban in the manufacturer's submission for NICE technology appraisal guidance 261) that compared rivaroxaban with LMWH/VKA in preventing recurrent venous thromboembolism in people who had experienced a deep vein thrombosis. In this scenario, the ICER for rivaroxaban compared with LMWH/VKA increased from £7072 to £10,070 per QALY gained for the lifelong treatment duration. In the second scenario, the ERG used a hazard ratio for major bleeds of 0.79, which was the upper limit of the 95% confidence interval surrounding the hazard ratio for a major bleed seen in EINSTEIN‑PE. Applying this hazard ratio, the ICER for rivaroxaban compared with LMWH/VKA increased from £7072 to £14,177 per QALY gained for the lifelong treatment duration. Assuming an increased utility value in the intracranial bleed state from 0.33 in the base case to 0.55 (see section 3.22) did not appreciably change the total QALYs and the model outcomes were hardly altered: rivaroxaban continued to dominate LMWH/VKA for 6- and 12-month treatment durations, and in the lifelong treatment analysis the ICER increased from £7072 to £7098 per QALY gained. The ERG did not present the effect of assuming a higher utility value in the intracranial bleed state on the 3-month treatment analysis. The ERG noted that the base-case analyses used a population with a mean age of 58 years, which is lower than the mean age of some other pulmonary embolism and deep vein thrombosis patient populations described in the literature. However, assuming a higher mean age of the model population from 58 years in the base case to 65 years did not have a large effect on the cost-effectiveness estimates: rivaroxaban continued to dominate LMWH/VKA for 6- and 12-month treatment durations, and for a lifelong treatment, the ICER increased from £7072 to £7911 per QALY gained. The ERG did not present the effect of assuming a higher mean age of the model population on the 3-month treatment analysis. The ERG assessed 3 scenarios in which the costs of emergency anticoagulant reversal were taken into account. The first scenario assumed that all people received PCC in all cases of major bleeding. This scenario had a modest effect on the base-case analyses for the 12-month and lifelong treatment durations: rivaroxaban continued to dominate LMWH/VKA in the 12-month treatment analysis and the ICER decreased from £7072 to £6868 per QALY gained in the lifelong treatment analysis. The second scenario assumed that people who had a bleed while taking LMWH/VKA received PCC, whereas those taking rivaroxaban received recombinant factor VIIa. This scenario resulted in an ICER for rivaroxaban compared with LMWH/VKA of £2328 per QALY gained for the 12-month treatment duration, and increased the ICER from £7072 to £19,642 per QALY gained for the lifelong treatment duration. The third scenario assumed the same as the second scenario in terms of treatments received to reverse major bleeding but also assumed that the risk of a major bleed with rivaroxaban was more similar to the risk experienced on LMWH/VKA (HR 0.65 from EINSTEIN-DVT) and the frequency of INR monitoring for people receiving LMWH/VKA to be 6 in the first quarter and 3 in each subsequent quarter. In this scenario, the ICER increased for the 12-month treatment cohort to £23,364 per QALY gained and to £44,046 per QALY gained for lifelong treatment. The ERG's multiple assumption scenario included a reduction in the frequency of INR-monitoring visits with a greater proportion occurring in secondary care (a 50:50 split rather than the 66 primary care to 34 secondary care split as in the manufacturer's base case); a greater proportion of primary care monitoring visits led by nurses (75% rather than 50%); a reduction in LMWH treatment length; a reduction in rivaroxaban efficacy after 12 months in the lifelong treatment duration analysis; and a raised hazard of major bleed. After applying these assumptions, rivaroxaban continued to dominate LMWH/VKA for the 6-month treatment duration. For the 12-month treatment duration, the ICER for rivaroxaban compared with LMWH/VKA was £11,590 per QALY gained, and for the lifelong treatment duration the ICER was £35,909 per QALY gained. The ERG did not present the effects of these multiple assumptions on the 3-month treatment analysis. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban, having considered evidence on the nature of pulmonary embolism and recurrent thromboembolism and the value placed on the benefits of rivaroxaban by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources. The Committee discussed the clinical management of pulmonary embolism. It noted the statements received from the clinical specialists, which stated that people with suspected pulmonary embolism are generally treated with immediate parenteral anticoagulation, most commonly with a low molecular weight heparin (LMWH) delivered by subcutaneous injection, and when the diagnosis has been confirmed, an oral vitamin K antagonist such as warfarin. The LMWH is continued for at least 5 days or until the patient's international normalised ratio (INR) has been within the therapeutic range for at least 24 hours, at which point it is stopped. The Committee also heard that a minority of people receive unfractionated heparin or fondaparinux instead of LMWH. People presenting with pulmonary embolism and haemodynamic instability may receive thrombolysis (or undergo embolectomy if thrombolysis is contraindicated) before receiving a vitamin K antagonist. The Committee discussed the manufacturer's decision problem, noting that the manufacturer had excluded fondaparinux as a comparator even though it was specified in the final scope issued by NICE. The Committee noted the comments from the manufacturer and the ERG highlighting that fondaparinux is rarely used in UK clinical practice. The Committee accepted that fondaparinux is rarely used and agreed that it was appropriate to consider only LMWH and a vitamin K antagonist as the comparator as listed in the manufacturer's decision problem. The Committee considered the treatment duration with anticoagulation. The Committee was aware that the NICE clinical guideline 144 on Venous thromboembolic diseases recommends 3 months' anticoagulation with a vitamin K antagonist for people with confirmed pulmonary embolism, with treatment continued beyond 3 months for those with permanent risk factors for venous thromboembolism recurrence, taking into account individual risk factors such as bleeding. However, it noted that approximately 95% of people in EINSTEIN‑PE received anticoagulation for 6 months or more. The Committee heard from the clinical specialists that anticoagulation therapy is often started with an expected duration of therapy, but that clinical evaluation is usually carried out at 3 or 6 months, when a decision is made as to whether or not therapy should be continued long term. It also heard that pulmonary embolism is a potentially life-threatening event, and that it would be unusual for people to be treated for less than 6 months. The clinical specialists also explained that people who have had a massive pulmonary embolus, recurrent venous thromboembolism, or are considered to be at significant risk of recurrence would usually receive lifelong anticoagulation. The clinical specialists estimated that overall, as many as 50% of people with pulmonary embolism would subsequently receive lifelong anticoagulation. The Committee accepted that although NICE clinical guideline 144 recommends an initial treatment duration of 3 months, the usual duration of treatment in UK practice was 6 months or more. The Committee heard from the patient expert about the perceived benefits of rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolic events over the standard care of LMWH with a vitamin K antagonist (such as warfarin). The patient expert highlighted the disadvantages of warfarin, including the need for regular monitoring of INR, and dose adjustment. Monitoring, which needs regular visits to hospital or GP appointments, can be costly and inconvenient, and means some people may have to take time off work. The patient expert said young people of school or university age may also experience clots and INR monitoring can lead to disruption of education. The patient expert further explained that the burdens of monitoring and dose adjustments with warfarin may also affect carers of people who have had a pulmonary embolus and they may have to make adjustments to their own schedules to enable the person for whom they are caring to monitor their INR. As warfarin has many drug interactions, it may be unsuitable for people with comorbidities, and because of various food interactions, people may need to adjust and monitor their diet and lifestyle. The patient expert said that there are some people whose INR is unstable on warfarin or who are allergic to it, for whom an alternative is needed. The patient expert highlighted that rivaroxaban can be used at the onset of pulmonary embolism in primary or secondary care. Rivaroxaban has the advantage that it avoids injections, regular blood tests and the diet and lifestyle considerations necessary with the combination of heparin and warfarin. The patient expert said that patients are very interested in rivaroxaban and other newer anticoagulants, but noted that a small proportion of patients are concerned about these new agents and find regular monitoring of INR reassuring to confirm that they are adequately anticoagulated. The patient expert expressed the view that rivaroxaban should be made available as an additional treatment option. The Committee accepted the limitations of treatment with LMWH and a vitamin K antagonist and acknowledged the potential benefits of rivaroxaban. The Committee considered the clinical management of bleeding resulting from treatment with anticoagulants. The clinical specialists highlighted that there are currently no validated guidelines on how to treat bleeding experienced while taking the new anticoagulants. The clinical specialists stated that people who have a bleed while taking a vitamin K antagonist may receive vitamin K, which takes 8–12 hours to reverse the effect of the vitamin K antagonist. One clinical specialist estimated that approximately 0.1% of people receiving warfarin experience a major bleed and for major bleeds needing rapid reversal, the most effective treatment is prothrombin complex concentrate (PCC) that provides correction for 12 hours. However, PCC would only be considered appropriate for a proportion of people with a major bleed. The Committee noted that the Evidence Review Group (ERG) had suggested that recombinant factor VIIa may be used to reverse a bleed. The clinical specialists agreed that recombinant factor VIIa may be used, but as it has a very short duration of action of approximately 2 hours, and is extremely expensive, they considered that PCC would be used in preference. The Committee further noted that recombinant factor VIIa is not licensed for the reversal of bleeding experienced on the new anticoagulants. It heard from the clinical specialists and the patient expert that there is no established antidote for rivaroxaban but because of its relatively short half-life, some bleeds can be managed simply by discontinuing rivaroxaban. The Committee concluded that there are standard approaches to stop bleeding experienced while on standard vitamin K antagonists such as warfarin, but there is uncertainty about the best approach to reverse bleeding experienced while taking rivaroxaban. The Committee considered the generalisability of the EINSTEIN‑PE trial to UK clinical practice. It discussed whether the population in the trial reflects those seen in UK clinical practice. The Committee noted that the mean age of the population in the trial was 58 years. The clinical specialists highlighted that the incidence of deep vein thrombosis and pulmonary embolism increases with age, but EINSTEIN‑PE included few people over 80 years. The clinical specialists considered that the proportion of people in the trial with provoked and unprovoked pulmonary embolism was similar to that observed in clinical practice. The Committee noted the ERG's concern that EINSTEIN‑PE excluded people with severe renal impairment, even though they may be eligible for treatment with rivaroxaban with dose adjustment if needed. The clinical specialists stated that rivaroxaban would probably not be used in routine clinical practice for people with severe renal impairment. The Committee heard from the clinical specialists that in their opinion, the population in EINSTEIN‑PE generally reflected the corresponding UK patient population. The Committee concluded that the baseline characteristics of the population in EINSTEIN‑PE were generalisable to UK clinical practice. The Committee discussed the comparator used in EINSTEIN‑PE and its relevance to UK clinical practice. The clinical specialists stated the LMWH used in the trial, enoxaparin, has the largest evidence base of all the LMWHs. The clinical specialists also stated that there were no known differences in the clinical effectiveness of the different available LMWHs. The Committee considered whether the dosage of enoxaparin used in EINSTEIN‑PE is applicable to UK clinical practice. It noted that in EINSTEIN‑PE, the US licensed dose of enoxaparin was used (that is, 1.0 mg/kg twice a day), whereas the dose used in the UK is 1.5 mg/kg once a day. The Committee heard from the clinical specialists that the 2 dosages are similar in terms of efficacy, and although people in EINSTEIN‑PE received a higher overall daily dose of enoxaparin than would be seen in UK clinical practice, this is not expected to have affected the generalisability of the trial to the UK. The Committee accepted that the differences in the dosage did not appear to be clinically significant and was satisfied that the comparators used in the trial represented routine and best practice. The Committee considered the time in therapeutic range in the enoxaparin and vitamin K antagonist arm of the trial. It noted that the average time in therapeutic range for people receiving enoxaparin with a vitamin K antagonist was 62.7%. The clinical specialists stated that time in therapeutic range varies, but a range of between 60% and 70% would be expected in UK clinical practice. The Committee therefore concluded that the data from the enoxaparin with a vitamin K antagonist arm in the trial were applicable to routine clinical practice. The Committee considered the generalisability of the EINSTEIN‑PE trial to the subgroup of patients who have active cancer. The Committee noted that EINSTEIN‑PE included a small proportion of people with cancer. The clinical specialists stated that people with cancer who experience venous thromboembolism would currently receive extended treatment with a LMWH alone, as evidence has shown that LMWH is more effective than warfarin for this group of people, and has been shown to reduce mortality. The Committee noted that the manufacturer had not presented any clinical evidence for a comparison of LMWH alone with rivaroxaban. The clinical specialists suggested that, without evidence from a direct comparison, it was unlikely that clinicians would offer rivaroxaban as an alternative treatment to LMWH for people with cancer. The Committee agreed that the comparator treatment in EINSTEIN‑PE that included a vitamin K antagonist did not reflect UK clinical practice for people with cancer, and there was no evidence for the relative efficacy of rivaroxaban compared with long-term LMWH, the standard treatment for these patients. The Committee concluded that without direct evidence of the relative efficacy of rivaroxaban compared with LMWH alone, it would be inappropriate to make a recommendation for this group. The Committee considered the trial design and the clinical-effectiveness results of the EINSTEIN‑PE trial. It noted that the trial was designed to assess whether rivaroxaban was non-inferior to LMWH with a vitamin K antagonist for preventing recurrent thromboembolism after pulmonary embolism and that the manufacturers had also tested for statistical superiority for the primary efficacy outcome. The Committee noted that for the whole trial population, the rates of recurrent venous thromboembolism were not statistically significantly different in the rivaroxaban and LMWH with a vitamin K antagonist arms in the trial. The Committee concluded that rivaroxaban has acceptable clinical effectiveness compared with low molecular weight heparin and a vitamin K antagonist. The Committee discussed the safety data from EINSTEIN‑PE. It noted that there was no statistically significant difference in the composite end point of major bleeding and clinically relevant non-major bleeding between rivaroxaban and LMWH with a vitamin K antagonist, but that the incidence of major bleeds was statistically significantly lower with rivaroxaban. The Committee concluded that rivaroxaban has an acceptable safety profile compared with low molecular weight heparin and a vitamin K antagonist. The Committee considered the results from the treatment duration subgroups and noted that groups were based on clinical criteria. It discussed the level of uncertainty around the hazard ratios and noted that the confidence intervals surrounding the hazard ratio for recurrent thromboembolism overlapped. It was aware that the confidence intervals were particularly wide for the 3-month treatment duration subgroup and noted the analysis was based on a small number of people recruited to the group (around 5% of the study population) and on a small number of events in both treatment arms. In addition, the Committee heard from the clinical specialists that they were not aware of any biological reason to expect a differential effect in the 3-month treatment duration subgroup. The Committee therefore concluded that evidence of treatment effect should be based on the whole trial population of EINSTEIN‑PE. The Committee considered the issue of long-term or lifelong treatment with rivaroxaban. It noted that the maximum length of treatment in EINSTEIN‑PE was 12 months, but was mindful that it had heard from the clinical specialists that some people will need longer treatment durations in clinical practice (section 4.3). In the absence of long-term data, the Committee considered the plausibility of the effects of rivaroxaban being maintained beyond 12 months. The clinical specialists stated that there is no biological or pharmacological reason why the effects of rivaroxaban should not be maintained over time but noted that there was uncertainty about how people would adhere to treatment with rivaroxaban over the long term. The Committee accepted that there was no biological or pharmacological reason why the effects of rivaroxaban would not be maintained over the long term. The Committee noted that the manufacturer had presented 4 base-case scenarios for 3-, 6-, 12-month treatments and a lifelong treatment analysis. It noted that the economic model used clinical-effectiveness data from EINSTEIN‑PE and utility data derived through systematic review. The Committee noted that rivaroxaban dominated treatment with LMWH and a vitamin K antagonist, that is, was less costly and more effective in the manufacturer's deterministic analysis of 3-, 6- and 12-month treatment durations. It noted that for lifelong treatment, the manufacturer's base case incremental cost-effectiveness ratio (ICER) was £13,300 per quality-adjusted life year (QALY) gained but after the corrections made to the model by the ERG, the base case for lifelong treatment was reduced to £7070 per QALY gained. The Committee noted that this figure was calculated using the manufacturer's estimate of INR-monitoring costs. The Committee discussed the estimate of the cost of INR monitoring. It heard from the clinical specialists that although there is a trend towards more monitoring being performed in primary care, some people still receive monitoring in secondary care. The clinical specialists also stated that there is huge variation in the frequency of INR monitoring for people receiving a vitamin K antagonist; some people may need weekly visits, particularly at the beginning of therapy, and some people may only need INR monitoring twice a year. The clinical specialists estimated that, as a guide, on the basis of 1 audit, INR monitoring once every 5–6 weeks might be a reasonable average estimate. The patient expert also highlighted that there is interest from patients in self-monitoring of INR, but there is variation in the availability of INR-home monitoring machines. The Committee concluded that there is considerable variability and uncertainty surrounding service provision and the frequency of INR monitoring that makes determining an accurate cost of INR monitoring problematic. It noted that the ERG had assumed fewer INR-monitoring visits than the manufacturer, which the ERG confirmed resulted in lower first year monitoring costs of between £304 and £379. The application of these scenarios to lifelong treatment increased the ICER from £7070 per QALY gained in the base case to £17,900 and £22,900 per QALY gained respectively. The Committee considered how INR-monitoring costs had been estimated in previous appraisals. In Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism (NICE technology appraisal guidance 261) the Committee had considered that after deep venous thrombosis, an INR-monitoring frequency of 6 visits in the first quarter and 3 in each subsequent quarter, resulting in first-year costs of £320, to be reasonable. The Committee took into account the clinical specialists' estimates of average INR-monitoring frequency (that is, every 5–6 weeks) and also the deliberations during technology appraisal 261 and concluded that the ERG's scenarios were reasonable estimations of the impact of INR monitoring on the cost effectiveness of rivaroxaban, and that the manufacturer's estimate of frequency of monitoring visits was too high. The Committee discussed the health-related quality of life data used in the economic model. It noted that health-related quality of life had not been measured in EINSTEIN‑PE and that the manufacturer had obtained the utility values used in its model through systematic review. The Committee was aware that the ERG had considered the utility values used in the economic model to be generally appropriate; however, the Committee considered that some of the studies that the manufacturer had used to obtain the utility values were too small and did not meet the reference case outlined in NICE's Guide to the methods of technology appraisal. The Committee expressed its disappointment that the manufacturer had not followed the reference case to derive the utility values. In particular, it noted that only 1 study fully met NICE's reference case criteria (that is, the source of data for measurement of health-related quality of life was reported directly by patients or carers, the source of preference data for valuation of changes in health-related quality of life was a representative sample of the public, and the preferred measure of health-related quality of life, the EQ-5D, had been used). The Committee noted that similar utility values had been used by the manufacturer in its economic model for NICE technology appraisal guidance 261 and it also noted that in the scenario analysis carried out by the ERG in which the utility value for the intracranial bleed state was increased from 0.33 to 0.55, there was only a minimal effect on the ICER. The Committee concluded that although the health-related quality of life studies selected by the manufacturer to obtain utility values for its economic model did not meet the NICE reference case, the cost-effectiveness estimates did not appear to be sensitive to the utility values used. The Committee considered the 2 additional scenario analyses performed by the ERG for lifelong treatment that addressed the impact of an increase in the risk of a thromboembolic event or a bleeding event for rivaroxaban after 12 months. The Committee noted that the worst-case ICER for rivaroxaban compared with LMWH and a vitamin K antagonist was £14,100 per QALY gained when the hazard ratio for a recurrent venous thromboembolism was increased from 1.12 to 2, and £14,200 per QALY gained when the hazard ratio for a major bleed was increased from 0.49 to 0.79 (the upper limit of the 95% confidence interval for the major bleed hazard ratio seen in EINSTEIN‑PE). The Committee noted that the ERG had also carried out a multiple assumption scenario that resulted in an ICER of £35,900. This included the assumption that both the effectiveness of rivaroxaban in preventing venous thromboembolic events decreased and the risk of bleeds increased relative to conventional therapy after 12 months compared with the base case. The Committee heard from the clinical specialists that if an anticoagulant was less effective in preventing venous thromboembolic events, then it would be expected to have a lower rate of bleeds. The clinical specialists stated that a scenario in which both the risk of venous thromboembolism and bleeding increased was clinically implausible. The Committee concluded that the ERG's multiple assumption scenario was not plausible and the resulting ICER was not appropriate or relevant for this appraisal. The Committee considered the 3 scenario analyses undertaken by the ERG in which the costs of reversing a major bleed had been incorporated and had been assessed in the 12-month and lifelong treatment analyses. The Committee noted that in these scenarios, the ERG had assumed that all people who had a major bleed would receive either treatment with PCC or recombinant factor VIIa; however, it was mindful of the testimony from the clinical specialists that only a proportion of people who had a major bleed would receive these treatments and PCC would preferentially be used over recombinant factor VIIa (see section 4.5). The Committee noted that recombinant factor VIIa is a particularly expensive drug and that the manufacturer did not consider the costs used by the ERG for recombinant factor VIIa to be relevant to patients in the decision problem. The Committee stated that consideration of bleeding reversal costs was relevant but that the ERG had presented extreme scenarios because it assumed that all people who had a major bleed would receive PCC or recombinant factor VIIa. The Committee agreed that there was too much uncertainty surrounding the treatment of bleeds experienced while on anticoagulants to reliably estimate the impact of treatment costs for reversing bleeding on the cost-effectiveness estimates. The Committee therefore concluded that the ICERs presented by the ERG for the 12-month analysis (worst-case scenario £23,400 per QALY gained) and the lifelong analysis (worst-case scenario £44,000) were not relevant for this appraisal. The Committee considered that in all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate, or the ICER compared with LMWH and a vitamin K antagonist could be considered a cost-effective use of NHS resources. The Committee concluded that rivaroxaban was cost effective for treating pulmonary embolism for 3, 6 or 12 months. For lifelong treatment, the Committee considered the ERG's assumptions about the frequency of INR monitoring to be valid and concluded that the most plausible ICER for lifelong treatment with rivaroxaban compared with lifelong treatment with a vitamin K antagonist after initial treatment with a LMWH was between £17,900 and £22,900 per QALY gained. The Committee concluded that rivaroxaban is a cost-effective treatment option for the lifelong treatment of pulmonary embolism and prevention of recurrent thromboembolism for people in whom long-term treatment is indicated. # Summary of Appraisal Committee's key conclusions TA287 Appraisal title: Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism Section Key conclusion Rivaroxaban is recommended as an option for treating pulmonary embolism and preventing recurrent deep vein thrombosis and pulmonary embolism in adults. In all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate or the ICER compared with LMWH and a vitamin K antagonist could be considered a cost-effective use of NHS resources. The Committee concluded that rivaroxaban was cost effective for treating pulmonary embolism for 3, 6 or 12 months. For lifelong treatment, the Committee considered the ERG's assumptions about the frequency of INR monitoring to be valid and concluded that the most plausible ICER for lifelong treatment was between £17,900 and £22,900 per QALY gained. The Committee concluded that rivaroxaban is a cost-effective treatment option for the lifelong treatment of pulmonary embolism and prevention of recurrent thromboembolism for people in whom long-term treatment is indicated. Current practice Clinical need of patients, including the availability of alternative treatments People with suspected pulmonary embolism are generally treated with immediate parenteral anticoagulation, most commonly with a low molecular weight heparin (LMWH) delivered by subcutaneous injection, and when the diagnosis has been confirmed, an oral vitamin K antagonist such as warfarin. Duration of treatment is based on individual risk of recurrent venous thromboembolism and bleeding. The usual duration of treatment in UK practice is 6 months or more. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Disadvantages of long-term anticoagulation with warfarin include the need for regular monitoring of INR, dose adjustment, multiple food and drug interactions and the impact on people's lifestyle including cost and inconvenience. Rivaroxaban avoids injections, regular blood tests and the diet and lifestyle considerations necessary with the combination of heparin and warfarin. It can be used at the onset of pulmonary embolism in primary or secondary care. What is the position of the treatment in the pathway of care for the condition? Rivaroxaban is indicated for the 'treatment of deep vein thrombosis and pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism in adults'. Adverse reactions There was no statistically significant difference in the composite end point of major bleeding and clinically relevant non-major bleeding between rivaroxaban and LMWH with a vitamin K antagonist, but that the incidence of major bleeds was statistically significantly lower with rivaroxaban. The Committee concluded that rivaroxaban has an acceptable safety profile compared with LMWH and a vitamin K antagonist. Evidence for clinical effectiveness Availability, nature and quality of evidence The EINSTEIN‑PE trial was the key trial supporting the clinical effectiveness of rivaroxaban in the manufacturer's submission. Relevance to general clinical practice in the NHS The baseline characteristics of the population in EINSTEIN‑PE were generalisable to UK clinical practice. Uncertainties generated by the evidence The manufacturer had not presented any clinical evidence for a comparison of rivaroxaban with LMWH alone for people with cancer to reflect UK clinical practice for this group of patients. Therefore, the Committee concluded it would be inappropriate to make a recommendation for this group. The maximum length of treatment in EINSTEIN‑PE was 12 months, but some people will need longer treatment durations in clinical practice. The Committee accepted that there was no biological or pharmacological reason why the effects of rivaroxaban would not be maintained over the long term. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? It was noted that treatment duration was assigned based on clinical criteria. The Committee noted that the confidence intervals surrounding the hazard ratio for recurrent thromboembolism overlapped. Estimate of the size of the clinical effectiveness including strength of supporting evidence The primary efficacy outcome in EINSTEIN‑PE was symptomatic recurrent venous thromboembolism. The Committee noted that for the whole trial population, the rates of recurrent venous thromboembolism were not statistically significantly different in the rivaroxaban and LMWH with a vitamin K antagonist arms in the trial. The Committee concluded that rivaroxaban had acceptable clinical effectiveness compared with LMWH and a vitamin K antagonist. Evidence for cost effectiveness Availability and nature of evidence The manufacturer presented an economic model, which used clinical-effectiveness data from EINSTEIN‑PE and utility data derived through systematic review, and presented 4 base-case scenarios for 3-, 6-, 12-month treatments and a lifelong treatment analysis. Uncertainties around and plausibility of assumptions and inputs in the economic model There is considerable variability and uncertainty surrounding service provision and the frequency of INR monitoring that makes determining an accurate cost of INR monitoring problematic. The Committee took into account the clinical specialists' estimates, the deliberations during technology appraisal 261 and the ERG's scenarios and concluded that the manufacturer's estimate of frequency of monitoring visits was too high and the ERG's scenarios were reasonable estimates. The Committee considered that some of the studies that the manufacturer had used to obtain the utility values were too small and did not meet the reference case outlined in NICE's Guide to the methods of technology appraisal. It concluded that the cost effectiveness of rivaroxaban did not appear to be sensitive to the utility values used. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee heard from the patient expert who confirmed regular monitoring of INR, dose adjustment, multiple food and drug interactions with warfarin can impact on people's lifestyle can be costly and inconvenient. The manufacturer applied a disutility due to warfarin therapy of 0.012 in the LMWH/VKA arm. Are there specific groups of people for whom the technology is particularly cost effective? None identified What are the key drivers of cost effectiveness? INR monitoring costs. In the manufacturer's sensitivity analyses the cost effectiveness of lifelong treatment with rivaroxaban was most sensitive to changes in the frequency of INR-monitoring visits, where the ICER increased from £13,252 per QALY gained to £27,914 per QALY gained if people have 3, rather than 5, visits in each quarter after the first. For lifelong treatment, the Committee considered the ERG's assumptions about the frequency of INR monitoring to be valid resulting in the ICER for lifelong treatment with rivaroxaban compared with lifelong treatment with a vitamin K antagonist after initial treatment with a LMWH increasing from £7070 in the ERG's amended base case to between £17,900 and £22,900 per QALY gained. Most likely cost-effectiveness estimate (given as an ICER) The Committee considered that in all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate or the ICER compared with LMWH and a vitamin K antagonist could be considered a cost-effective use of NHS resources. The most plausible ICER for lifelong treatment with rivaroxaban compared with lifelong treatment with a vitamin K antagonist after initial treatment with a LMWH was between £17,900 and £22,900 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) Not applicable. End-of-life considerations Not applicable Equalities considerations and social value judgements No equalities issues were raised. # Recommendations for further research There have been no head-to-head trials of rivaroxaban compared with a low molecular weight heparin for people who have cancer and experience an acute pulmonary embolism or deep vein thrombosis. As in NICE technology appraisal guidance 261 it is recommended that further research should be carried out. Research into the long-term treatment effects of rivaroxaban is needed.# Related NICE guidance # Published Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. NICE clinical guideline 144 (2012). Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism. NICE technology appraisal guidance 261 (2012). Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. NICE technology appraisal guidance 245 (2012). Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. NICE clinical guideline 92 (2010). Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. NICE technology appraisal guidance 170 (2009). Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. NICE technology appraisal guidance 157 (2008). # NICE pathways Venous thromboembolism. NICE pathway (2011). # NICE quality standards Venous thromboembolism prevention. NICE quality standard 3 (2010). Management of venous thromboembolic diseases. NICE quality standard 29 (2013).# Review of guidance The guidance on this technology will be considered for review in May 2015 alongside the review of NICE technology appraisal guidance 261. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrews Dillon Chief ExecutiveJune 2013# Changes after publication January 2014: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It has been incorporated into the NICE pathway on venous thromboembolism along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0140-1	{'Guidance': 'Rivaroxaban is recommended as an option for treating pulmonary embolism and preventing recurrent deep vein thrombosis and pulmonary embolism in adults.', 'The technology ': "Rivaroxaban (Xarelto, Bayer) is indicated for the 'treatment of deep vein thrombosis and pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism in adults'. For the initial treatment of acute pulmonary embolism, the recommended dosage of rivaroxaban is 15\xa0mg twice daily for the first 21\xa0days followed by 20\xa0mg once daily for continued treatment and prevention of recurrent venous thromboembolism.\n\nRivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism (NICE technology appraisal guidance\xa0261) recommends rivaroxaban as an option for treating deep vein thrombosis and preventing recurrent deep vein thrombosis and pulmonary embolism after a diagnosis of acute deep vein thrombosis in adults.\n\nThe duration of treatment recommended in the summary of product characteristics depends on bleeding risk and other clinical criteria. Short-term treatment (at least 3\xa0months) is recommended for people with transient risk factors such as recent surgery and trauma. Longer treatment is recommended for people with permanent risk factors, or idiopathic (unprovoked) deep vein thrombosis or pulmonary embolism. A reduced dosage of 15\xa0mg twice daily for 21\xa0days followed by 15\xa0mg once daily should be used in people with moderate (creatinine clearance 30–49\xa0ml/min) or severe (creatinine clearance 15–29\xa0ml/min) renal impairment if their risk of bleeding outweighs the risk of recurrent deep vein thrombosis or pulmonary embolism.\n\nThe summary of product characteristics lists the following adverse reactions for rivaroxaban: anaemia, dizziness, headache, fainting, bleeding events, tachycardia (rapid heartbeat), low blood pressure, haematoma, stomach pain, dyspepsia (heartburn), nausea, constipation, diarrhoea, vomiting, pruritus (itching), rash, bruising, pain in the extremities, fever, and swelling, especially of the ankles and feet. For full details of side effects and contraindications, see the summary of product characteristics.\n\nRivaroxaban costs £2.10\xa0per 15‑mg or 20‑mg tablet ('British national formulary' edition 65). The cost of treatment is estimated to be £235.86, £427.61\xa0and £811.13\xa0for 3, 6\xa0and 12\xa0months of treatment respectively. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix\xa0A) considered evidence submitted by the manufacturer of rivaroxaban and a review of this submission by the Evidence Review Group (ERG; section 10).\n\nThe key clinical evidence in the manufacturer's submission came from EINSTEIN‑PE, an international, event-driven, open-label, assessor-blind, non-inferiority study. The study included 4832\xa0people in an intention-to-treat population. Treatment duration was 3, 6\xa0or 12\xa0months and this was determined by a study investigator before randomisation based on the risk profile of each person and local preferences. Patients were randomised to either rivaroxaban 15\xa0mg twice daily for 21\xa0days followed by 20\xa0mg once daily for the intended treatment duration, or to enoxaparin (a low molecular weight heparin [LMWH]) 1.0\xa0mg/kg twice daily until anticoagulation was established plus a vitamin\xa0K antagonist (either warfarin or acenocoumarol), which was dose adjusted to maintain the international normalised ratio (INR) within a therapeutic range of 2.0\xa0to 3.0\xa0with a target of 2.5. Enoxaparin was administered for at least 5\xa0days and was stopped when the INR was more than 2.0\xa0on 2\xa0consecutive measurements at least 24\xa0hours apart. There was an advised overlap with the vitamin\xa0K antagonist of 4\xa0to 5\xa0days. Patients were assessed during their intended treatment duration, followed by a 30-day observation period. The manufacturer noted that there was a difference in the dose of enoxaparin used in the trial and the dose covered by the European and UK licence (that is, 1.5\xa0mg/kg once daily for at least 5\xa0days and until adequate oral anticoagulation is established).\n\nOut of the whole study population, 5.2% were allocated to receive 3\xa0months of treatment, 57.4% to 6\xa0months of treatment and 37.4% to 12\xa0months of treatment. The median time from onset of symptoms to randomisation was 4\xa0days. The EINSTEIN‑PE study allowed a limited amount of treatment before randomisation. A similar proportion of patients in the rivaroxaban arm (92.5%) and the LMWH/VKA arm (92.1%) received pre-randomisation anticoagulation (p=0.62, post-hoc binomial test). Among those who received pre-randomisation anticoagulation, 62.5% of patients received anticoagulation for 1\xa0day (the maximum duration permitted was 48\xa0hours).\n\nIn the intention-to-treat population, the mean age was 58\xa0and approximately 53% of the patients were male. Around 25% of patients in both treatment arms had a concurrent deep vein thrombosis. Pulmonary embolism was unprovoked in 65% of patients receiving rivaroxaban and 64% of patients receiving LMWH with a vitamin\xa0K antagonist (hereafter referred to as LMWH/VKA). Approximately 5% of people in both treatment arms had active cancer, and 19% and 20% of people in the rivaroxaban and LMWH/VKA treatment arms respectively had experienced a previous venous thromboembolism. EINSTEIN‑PE excluded people with a creatinine clearance of less than 30\xa0ml/min and people for whom rivaroxaban was not suitable or who had contraindications to enoxaparin, warfarin or acenocoumarol. A total of 555\xa0(11.5%) patients discontinued treatment; the number of people who discontinued was similar in both treatment groups (p=0.07).\n\nThe primary efficacy end point for EINSTEIN‑PE was symptomatic recurrent venous thromboembolism, which was a composite end point comprising recurrent deep vein thrombosis or pulmonary embolism. This included both fatal and non-fatal pulmonary embolism, and unexplained death for which a pulmonary embolism could not be ruled out. In the intention-to-treat population (rivaroxaban n=2419; LMWH/VKA n=2413), rivaroxaban met the pre-specified non-inferiority criterion, which required the upper bound of the 95% confidence interval of the hazard ratio to be less than 2. Symptomatic recurrent venous thromboembolism events occurred in 50\xa0(2.1%) patients in the rivaroxaban arm compared with 44\xa0(1.8%) patients in the LMWH/VKA arm (hazard ratio [HR] 1.12; 95% confidence interval [CI] 0.75\xa0to 1.68).\n\nThe primary safety outcome for EINSTEIN‑PE was clinically relevant bleeding, that is, major bleeding and clinically relevant non-major bleeding in the safety population, which consisted of all patients who had received at least 1\xa0dose of the study drug (rivaroxaban n=2412; LMWH/VKA n=2405). There was no difference between rivaroxaban and LMWH/VKA in clinically relevant bleeding that was experienced by 249\xa0(10.3%) and 274\xa0(11.4%) patients in each treatment arm respectively (HR\xa00.90, 95%\xa0CI 0.76\xa0to 1.07). The proportion of patients who experienced major bleeding was statistically significantly lower with rivaroxaban (1.1%) than with LMWH/VKA (2.2%) (HR\xa00.49, 95%\xa0CI 0.31\xa0to 0.79, p=0.003). In the intended treatment period, there were a similar number of deaths in the rivaroxaban arm (58\xa0deaths) and the LMWH/VKA arm (50\xa0deaths) (HR\xa01.13, 95%\xa0CI 0.77\xa0to 1.65). Treatment-emergent adverse events (other than bleeding and recurrent venous thromboembolism) were similar between the treatment arms. Approximately 5% of patients in the rivaroxaban arm and 4% in the LMWH/VKA arm discontinued treatment because of an adverse event.\n\nThe manufacturer reported a time in therapeutic range for the comparator LMWH/VKA of 62.7% across all centres. The manufacturer highlighted that guidelines from the National Patient Safety Agency and the Scottish Executive Health Department recommend a time in therapeutic range of at least 60%. It also noted there was no statistical interaction observed in EINSTEIN‑PE between time in therapeutic range and treatment effect.\n\nHealth-related quality of life was not measured in EINSTEIN‑PE. The manufacturer described 2\xa0measures of treatment satisfaction that had been measured: the Anti-Clot Treatment Scale (ACTS) and the Treatment Satisfaction Questionnaire (TSQM). Treatment satisfaction was not used to derive any of the utility values used in the economic analysis.\n\nThe manufacturer presented the results for a number of subgroups considered in EINSTEIN‑PE, which included the 3\xa0subgroups specified in the final scope issued by NICE. These were groups based on underlying risk of bleeding, provoked compared with unprovoked venous thromboembolism, and the presence or absence of cancer. The manufacturer used the intended treatment duration as a proxy for bleeding risk. The manufacturer tested for a statistically significant interaction between each subgroup and the primary efficacy and safety outcomes. The outcomes of the statistical interaction tests are academic in confidence, so the results cannot be presented in this document. The manufacturer also presented graphically the relative efficacy across subgroups, including the 3\xa0subgroups specified in the final scope issued by NICE. The manufacturer presented similar results for the major and clinically relevant non-major bleeding outcome (with the exception of the idiopathic and non-idiopathic groups). The 95% confidence intervals surrounding the hazard ratios for all outcomes overlapped across the subgroups, suggesting a consistency of effect.\n\nThe manufacturer highlighted that in the comparator arm of the trial, patients with cancer had received LMWH/VKA, whereas standard care in the UK is LMWH alone. The manufacturer did not consider it appropriate to conduct a network meta-analysis to estimate the relative effectiveness of rivaroxaban compared with LMWH in people with cancer who had experienced a pulmonary embolism. This was because of the heterogeneity of the studies assessing long-term treatment of venous thromboembolism in people with cancer, which the manufacturer had identified and presented in its submission for NICE technology appraisal guidance\xa0261.\n\nThe manufacturer constructed a Markov model to evaluate the consequences of 3-, 6- and 12-month, and lifelong, treatment with rivaroxaban for preventing recurrent venous thromboembolism in people who experience an acute pulmonary embolism. The model used a time horizon of 40\xa0years and a cycle length of 3\xa0months. To reflect the change in the risk patients experience over time, different risks were applied in cycle\xa01\xa0(months 0–3), 2\xa0(months 3–6), 3\xa0and 4\xa0(months 6–12) and 5\xa0onwards (12\xa0months onwards). The evaluation was undertaken from an NHS and personal social services perspective, and costs and utilities were discounted at 3.5% per year after the first year.\n\nFor people initially treated for 3, 6\xa0or 12\xa0months, there were 13\xa0health states including death. The lifelong treatment model contained an additional state. People entered the model after their index pulmonary embolism to an on-treatment state in which they received 3-, 6-, 12-month or lifelong treatment with rivaroxaban or LMWH/VKA. They then either stayed on treatment, experienced a recurrent venous thromboembolism (pulmonary embolism or deep vein thrombosis), experienced an adverse event (clinically relevant non-major bleed, major intracranial bleed, or major extracranial bleed), moved to an off-treatment health state, entered a long-term complication state (for example, chronic thromboembolic pulmonary hypertension), or died. The additional state in the lifelong treatment model was for people who had experienced a deep vein thrombosis in the timeframe of the model and who had not stopped treatment for other reasons. All patients who experienced a deep vein thrombosis after their index pulmonary embolism were at risk of post-thrombotic syndrome. There was not a separate health state for post-thrombotic syndrome, rather the consequences of post-thrombotic syndrome were applied as disutilities and costs to patients in both the on- and off-treatment post-deep vein thrombosis health states.\n\nThe modelled cohort was adults with an acute pulmonary embolism who matched the licensed indication, the EINSTEIN‑PE trial population and the stated decision problem. Data from EINSTEIN‑PE were used to inform the clinical effectiveness of treatments and to derive the transition probabilities used in the model; this was supplemented with data from the manufacturer's systematic reviews. All drug acquisition costs and resources associated with acute treatment hospital stay, monitoring, recurrent thromboembolic events and adverse events (that is, bleeding events) were included in the model.\n\nA validated preference-based measure of quality of life was not measured in EINSTEIN‑PE; the manufacturer derived the utility values used in the model through systematic review. The manufacturer assigned a baseline utility value of 0.825\xa0to all patients with pulmonary embolism entering the model, which was taken from a survey of the UK general population using a visual analogue scale rating and adjusted with disutility values for deep vein thrombosis, pulmonary embolism, extracranial bleed, intracranial bleed and post-thrombotic syndrome. All people who had an intracranial bleed moved to a post-intracranial bleed health state in the next cycle of the model after their bleed. The utility value assumed for an intracranial bleed was 0.33, which increased to 0.71\xa0in the post-intracranial bleed state. A disutility due to warfarin therapy of 0.012\xa0was applied in the LMWH/VKA arm.\n\nBase-case results were presented for the 3-, 6-, 12-month and lifelong treatment durations. For the 3-, 6- and 12-month treatment durations, rivaroxaban dominated LMWH/VKA, that is, rivaroxaban was less costly and more effective (0.027, 0.013\xa0and 0.019\xa0incremental quality-adjusted life years [QALYs] and a £395.80, £213.21\xa0and £133.13\xa0reduction in total costs for the 3-, 6- and 12-month treatment groups respectively). In the lifelong treatment analysis, rivaroxaban was associated with an incremental cost-effectiveness ratio (ICER) compared with LMWH/VKA of £13,252\xa0per QALY gained (0.104\xa0incremental QALYs for an extra £1374.73).\n\nThe manufacturer performed 123\xa0deterministic sensitivity analyses for each of the 4\xa0durations of treatment. For the 3-, 6- and 12-month treatments, the net monetary benefit for rivaroxaban compared with LMWH/VKA was positive for all analyses if the maximum acceptable ICER was £20,000\xa0per QALY gained. Cost effectiveness of lifelong treatment with rivaroxaban was most sensitive to changes in the frequency of INR-monitoring visits, where the ICER increased from £13,252\xa0per QALY gained to £27,914\xa0per QALY gained if people have 3, rather than 5, visits in each quarter after the first. The manufacturer conducted 1\xa0scenario analysis, in which the time horizon was reduced from 40\xa0to 5\xa0years. With a 5-year time horizon, rivaroxaban continued to dominate LMWH/VKA for the 3-, 6- and 12-month treatment durations. For the lifelong treatment duration, reducing the time horizon to 5\xa0years decreased the ICER of rivaroxaban compared with LMWH/VKA to £12,282\xa0per QALY gained. Probabilistic sensitivity analysis demonstrated that there was a 99.9%, 95.9%, 93.7% and 59.1% probability that the base-case ICER for the 3-, 6-, and 12-month and lifelong treatments was lower than £20,000\xa0per QALY gained.\n\nThe ERG considered that overall, the manufacturer's submission provided an unbiased estimate of the treatment effect of rivaroxaban. The ERG stated that it was based on a well-conducted systematic review of clinical effectiveness, which identified 1\xa0relevant randomised controlled trial. It considered the trial to be of reasonable quality with a low risk of bias.\n\nThe ERG raised concerns that the patient population in the trial may not be fully representative of the treatment population in the UK. In particular, it stated that patients with severe renal impairment (a creatinine clearance of 15–29\xa0ml/min) were excluded from the trial. The ERG noted that the summary of product characteristics specifies that rivaroxaban can be used with caution with dose reductions if needed in this group of patients. The ERG stated that as these patients are at higher risk of bleeding and were excluded from the trial, it is possible that the trial may have underestimated the rate of bleeding that may be seen in clinical practice with rivaroxaban.\n\nThe ERG noted that the trial only assessed outcomes up to a 12‑month treatment period; therefore, effectiveness and safety of long-term treatment with rivaroxaban is unknown. The ERG stated that the manufacturer's Kaplan-Meier plot of cumulative venous thromboembolism rates suggested a worsening of the relative hazard of recurrent venous thromboembolism while on rivaroxaban, compared with LMWH/VKA, towards the end of the 12-month treatment period. The ERG commented that it is plausible that the hazard of recurrent venous thromboembolism might worsen further if treatments are compared in the longer term, particularly if adherence to rivaroxaban (which does not need the regular monitoring of vitamin\xa0K antagonists) declines. The ERG suggested that the long-term adherence to rivaroxaban may be lower than the 80% plus observed in most of the patients in EINSTEIN‑PE.\n\nThe ERG considered the manufacturer's subgroup analyses. The ERG suggested that the outcomes may be worse in the active cancer group than those seen for other patients because of increased bleeding risk. The ERG noted that the manufacturer's presentation of subgroup data suggested consistency across the subgroups in terms of the relative safety and efficacy. It considered that because of the small numbers of people in the trial who had cancer, differences in the incidence of bleeding may not have been apparent because of the small number of events recorded in each treatment arm. The ERG also noted the 95%\xa0confidence intervals around the hazard ratio for recurrent venous thromboembolism in patients with active cancer presented by the manufacturer were wide, and suggested this indicated that there is uncertainty around where the true effect lies and that the manufacturer's analysis of efficacy in the cancer subgroup should be interpreted with caution. The ERG had concerns that the manufacturer had used intended treatment duration as a proxy for both underlying risk of bleeding and provoked or unprovoked pulmonary embolism. However, it suggested that there are no robust markers for determining length of treatment in advance, which suggests that pre-specified treatment durations may not be a good proxy for other variables.\n\nThe ERG considered the structure adopted for the economic model to be reasonable, consistent with current clinical understanding of pulmonary embolism and consistent with the previous economic evaluations of treatments for venous thromboembolism, such as the submission for NICE technology appraisal guidance\xa0261. The ERG also considered that the parameters used in the model were generally appropriate and that the population used in the model, drawn from EINSTEIN‑PE, is broadly representative of the pulmonary embolism population in the UK (with the exception that it did not include people for whom rivaroxaban is contraindicated or people with severe renal impairment who may still be eligible for rivaroxaban).\n\nThe ERG noted that all transition probabilities were treatment-specific in the lifelong model but that there appeared to be an error in the model, because after 36\xa0months, the probability of recurrent venous thromboembolism and bleeding events were the same for rivaroxaban and LMWH/VKA. The ERG stated that the probabilities of these events after 36\xa0months were not explicitly stated in the manufacturer's submission. The ERG believed this to be an unintended error and corrected the model so that the treatment effect of rivaroxaban after 36\xa0months was applied to the LMWH/VKA transition probabilities. After this amendment, the ICER for rivaroxaban compared with LMWH/VKA in the lifelong treatment analysis was reduced from £13,252\xa0per QALY gained to £7072\xa0per QALY gained. For all of the subsequent analyses, the ERG incorporated this correction and referred to this as the amended base case. The amended probabilistic base-case ICER for rivaroxaban compared with LMWH/VKA was £7019\xa0per QALY gained.\n\nThe ERG had concerns about some of the utility values used in the manufacturer's model, particularly as some of the sources of utility values identified and used by the manufacturer were small studies or did not use the EQ-5D instrument that is the preferred measure of health related quality of life in adults in NICE's reference case. The ERG considered the utility value of 0.33\xa0for an intracranial bleed, based on a study of 129\xa0people that had used time trade off rather than the EQ-5D to derive the utility value that the manufacturer had applied for 3\xa0months in the intracranial bleed state model, to be low. The ERG identified a prospective, longitudinal study that suggested a utility value of 0.31\xa0immediately after an intracranial bleed (stroke), increasing to 0.55\xa0after 1\xa0month and to 0.61\xa0by 3\xa0months. As the manufacturer had estimated that rivaroxaban was associated with fewer intracranial bleeds than LMWH/VKA, the ERG stated that a mid-value of 0.55\xa0for the intracranial bleed health-state utility value would be a more conservative assumption. The ERG also questioned the manufacturer's choice of utility values for post-thrombotic syndrome. The manufacturer had used a study of 30\xa0healthy volunteers that had used a standard gamble approach to derive a utility value of 0.93\xa0for severe post-thrombotic syndrome. However, the ERG stated that the study of 129\xa0people, which the manufacturer had used to obtain utility values for some of the health states in its model including the utility value for an intracranial bleed, gave a utility value of 0.86\xa0for post-thrombotic syndrome. The ERG did not consider the manufacturer's choice of utility value for post-thrombotic syndrome to be a conservative assumption.\n\nThe ERG was satisfied that the unit costs used in the economic model were relevant and had been obtained using suitable methods. However, it noted that the costs of reversing the effects of rivaroxaban and warfarin in the case of major bleeding or elective surgery had not been included and that these may be significant. The ERG stated that vitamin\xa0K, fresh frozen plasma and prothrombin complex concentrate (PCC) are used to reverse bleeding events on warfarin but there is no specific antidote for rivaroxaban. The ERG commented that either activated recombinant factor VIIa or PCC may be considered to manage severe and life-threatening bleeding in patients on rivaroxaban. The ERG's clinical adviser considered that the reversal of bleeding on warfarin is likely to need less PCC than rivaroxaban, and that recombinant factor VIIa may be more effective for reversing rivaroxaban than PCC. The ERG estimated that the cost of treating a patient weighing 70\xa0kg with recombinant factor VIIa is £19,303. The ERG also estimated that the cost of treating a bleed while receiving rivaroxaban with PCC would be £1680, and the maximum cost for treating a bleed on warfarin with PCC concentrate would be £1260.\n\nThe ERG conducted the following exploratory analyses:\n\nreduction in assumed frequency of INR-monitoring visits\n\nreduction in mean LMWH treatment length\n\nreduction in the efficacy of rivaroxaban after 12\xa0months in the lifelong treatment analysis in preventing recurrent venous thromboembolism\n\nhigher hazard of major bleed on rivaroxaban in the lifelong treatment analysis\n\nhigher utility values for the intracranial bleed state\n\nhigher mean age of model population\n\ncosts of emergency anticoagulant reversal taken into account in all cases of major bleeding\n\na multiple assumption scenario (reduction in assumed frequency of INR monitoring visits, with a greater proportion of these in secondary care and a greater proportion of the primary care monitoring visits led by nurses; reduction in mean LMWH treatment length; reduction in the efficacy of rivaroxaban after 12\xa0months in the lifelong treatment analysis; higher hazard of major bleed).\n\nThe ERG noted that the manufacturer had assumed 9\xa0INR-monitoring visits in the first quarter for people receiving LMWH/VKA and 5\xa0in each subsequent quarter, and that this was consistent with what the manufacturer presented for NICE technology appraisal guidance\xa0261. The ERG highlighted that in NICE technology appraisal guidance\xa0261, the Committee had concluded that a less intensive INR-monitoring programme of 6\xa0visits in the first 3\xa0months followed by 3\xa0visits every quarter thereafter was reasonable and relevant (when a deep vein thrombosis was the index thromboembolism). The ERG reduced the frequency of INR-monitoring visits to 6\xa0visits in the first quarter and 3\xa0in each subsequent quarter. The ICER for rivaroxaban compared with LMWH/VKA increased from £7072\xa0in the base case to £17,857\xa0per QALY gained in the lifelong treatment duration analysis, and went from dominating LMWH/VKA in the 12-month treatment duration analysis to having an ICER of £3542\xa0per QALY gained. Rivaroxaban continued to dominate LMWH/VKA in the 6-month treatment analysis. The ERG did not present the effect of a reduced INR-monitoring frequency scenario on the 3-month treatment analysis. For the lifelong treatment duration analysis, the ERG assessed a further scenario of 6\xa0visits in the first quarter and 2\xa0in each subsequent quarter. This assumption increased the ICER for rivaroxaban compared with LMWH/VKA from £7072\xa0to £22,912\xa0per QALY gained.\n\nAssuming a shorter treatment duration with LMWH from the manufacturer's estimate in the base case (derived from the academic-in-confidence average duration in EINSTEIN‑PE) of either 9, 8\xa0or 6\xa0days was found to have a minimal cost-saving effect in the 6-month treatment duration analysis. Rivaroxaban continued to dominate LMWH/VKA regardless of treatment duration with LMWH. The ERG did not present the effect of assuming the shorter treatment duration with LMWH on the 3-, 12-month or lifelong treatment duration analyses.\n\nAs there was uncertainty surrounding the long-term efficacy and safety of rivaroxaban, the ERG performed scenario analyses that assessed varying efficacy and safety effects of rivaroxaban. The hazard ratio for recurrent venous thromboembolism for rivaroxaban compared with LMWH/VKA was 1.123\xa0for the entirety of the lifelong treatment base case. The ERG assessed 2\xa0scenarios in which the hazard ratio was increased to either 1.5\xa0or 2.0\xa0after 12\xa0months (that is, rivaroxaban was assumed to be increasingly less effective relative to LMWH/VKA). Assuming a hazard ratio of 1.5\xa0for venous thromboembolism after 12\xa0months for the population in the lifelong treatment analysis increased the ICER for rivaroxaban compared with LMWH/VKA from £7072\xa0to £9043\xa0per QALY gained. When a hazard ratio of 2.0\xa0was assumed, the ICER for rivaroxaban compared with LMWH/VKA increased to £14,090\xa0per QALY gained.\n\nIn the manufacturer's base-case analyses, the hazard ratio for major bleed for rivaroxaban compared with LMWH/VKA was 0.493. The ERG assessed 2\xa0scenarios in the lifelong treatment duration analysis in which the hazard ratio for major bleeds was increased. In the first scenario, the ERG used a hazard ratio for major bleeds of 0.65. This was taken from the EINSTEIN‑DVT trial (one of the key trials supporting the clinical effectiveness of rivaroxaban in the manufacturer's submission for NICE technology appraisal guidance\xa0261) that compared rivaroxaban with LMWH/VKA in preventing recurrent venous thromboembolism in people who had experienced a deep vein thrombosis. In this scenario, the ICER for rivaroxaban compared with LMWH/VKA increased from £7072\xa0to £10,070\xa0per QALY gained for the lifelong treatment duration. In the second scenario, the ERG used a hazard ratio for major bleeds of 0.79, which was the upper limit of the 95% confidence interval surrounding the hazard ratio for a major bleed seen in EINSTEIN‑PE. Applying this hazard ratio, the ICER for rivaroxaban compared with LMWH/VKA increased from £7072\xa0to £14,177\xa0per QALY gained for the lifelong treatment duration.\n\nAssuming an increased utility value in the intracranial bleed state from 0.33\xa0in the base case to 0.55\xa0(see section\xa03.22) did not appreciably change the total QALYs and the model outcomes were hardly altered: rivaroxaban continued to dominate LMWH/VKA for 6- and 12-month treatment durations, and in the lifelong treatment analysis the ICER increased from £7072\xa0to £7098\xa0per QALY gained. The ERG did not present the effect of assuming a higher utility value in the intracranial bleed state on the 3-month treatment analysis.\n\nThe ERG noted that the base-case analyses used a population with a mean age of 58\xa0years, which is lower than the mean age of some other pulmonary embolism and deep vein thrombosis patient populations described in the literature. However, assuming a higher mean age of the model population from 58\xa0years in the base case to 65\xa0years did not have a large effect on the cost-effectiveness estimates: rivaroxaban continued to dominate LMWH/VKA for 6- and 12-month treatment durations, and for a lifelong treatment, the ICER increased from £7072\xa0to £7911\xa0per QALY gained. The ERG did not present the effect of assuming a higher mean age of the model population on the 3-month treatment analysis.\n\nThe ERG assessed 3\xa0scenarios in which the costs of emergency anticoagulant reversal were taken into account. The first scenario assumed that all people received PCC in all cases of major bleeding. This scenario had a modest effect on the base-case analyses for the 12-month and lifelong treatment durations: rivaroxaban continued to dominate LMWH/VKA in the 12-month treatment analysis and the ICER decreased from £7072\xa0to £6868\xa0per QALY gained in the lifelong treatment analysis. The second scenario assumed that people who had a bleed while taking LMWH/VKA received PCC, whereas those taking rivaroxaban received recombinant factor VIIa. This scenario resulted in an ICER for rivaroxaban compared with LMWH/VKA of £2328\xa0per QALY gained for the 12-month treatment duration, and increased the ICER from £7072\xa0to £19,642\xa0per QALY gained for the lifelong treatment duration. The third scenario assumed the same as the second scenario in terms of treatments received to reverse major bleeding but also assumed that the risk of a major bleed with rivaroxaban was more similar to the risk experienced on LMWH/VKA (HR 0.65\xa0from EINSTEIN-DVT) and the frequency of INR monitoring for people receiving LMWH/VKA to be 6\xa0in the first quarter and 3\xa0in each subsequent quarter. In this scenario, the ICER increased for the 12-month treatment cohort to £23,364\xa0per QALY gained and to £44,046\xa0per QALY gained for lifelong treatment.\n\nThe ERG's multiple assumption scenario included a reduction in the frequency of INR-monitoring visits with a greater proportion occurring in secondary care (a 50:50\xa0split rather than the 66\xa0primary care to 34\xa0secondary care split as in the manufacturer's base case); a greater proportion of primary care monitoring visits led by nurses (75% rather than 50%); a reduction in LMWH treatment length; a reduction in rivaroxaban efficacy after 12\xa0months in the lifelong treatment duration analysis; and a raised hazard of major bleed. After applying these assumptions, rivaroxaban continued to dominate LMWH/VKA for the 6-month treatment duration. For the 12-month treatment duration, the ICER for rivaroxaban compared with LMWH/VKA was £11,590\xa0per QALY gained, and for the lifelong treatment duration the ICER was £35,909\xa0per QALY gained. The ERG did not present the effects of these multiple assumptions on the 3-month treatment analysis.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban, having considered evidence on the nature of pulmonary embolism and recurrent thromboembolism and the value placed on the benefits of rivaroxaban by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the clinical management of pulmonary embolism. It noted the statements received from the clinical specialists, which stated that people with suspected pulmonary embolism are generally treated with immediate parenteral anticoagulation, most commonly with a low molecular weight heparin (LMWH) delivered by subcutaneous injection, and when the diagnosis has been confirmed, an oral vitamin\xa0K antagonist such as warfarin. The LMWH is continued for at least 5\xa0days or until the patient's international normalised ratio (INR) has been within the therapeutic range for at least 24\xa0hours, at which point it is stopped. The Committee also heard that a minority of people receive unfractionated heparin or fondaparinux instead of LMWH. People presenting with pulmonary embolism and haemodynamic instability may receive thrombolysis (or undergo embolectomy if thrombolysis is contraindicated) before receiving a vitamin\xa0K antagonist. The Committee discussed the manufacturer's decision problem, noting that the manufacturer had excluded fondaparinux as a comparator even though it was specified in the final scope issued by NICE. The Committee noted the comments from the manufacturer and the ERG highlighting that fondaparinux is rarely used in UK clinical practice. The Committee accepted that fondaparinux is rarely used and agreed that it was appropriate to consider only LMWH and a vitamin\xa0K antagonist as the comparator as listed in the manufacturer's decision problem.\n\nThe Committee considered the treatment duration with anticoagulation. The Committee was aware that the NICE clinical guideline\xa0144\xa0on Venous thromboembolic diseases recommends 3\xa0months' anticoagulation with a vitamin\xa0K antagonist for people with confirmed pulmonary embolism, with treatment continued beyond 3\xa0months for those with permanent risk factors for venous thromboembolism recurrence, taking into account individual risk factors such as bleeding. However, it noted that approximately 95% of people in EINSTEIN‑PE received anticoagulation for 6\xa0months or more. The Committee heard from the clinical specialists that anticoagulation therapy is often started with an expected duration of therapy, but that clinical evaluation is usually carried out at 3\xa0or 6\xa0months, when a decision is made as to whether or not therapy should be continued long term. It also heard that pulmonary embolism is a potentially life-threatening event, and that it would be unusual for people to be treated for less than 6\xa0months. The clinical specialists also explained that people who have had a massive pulmonary embolus, recurrent venous thromboembolism, or are considered to be at significant risk of recurrence would usually receive lifelong anticoagulation. The clinical specialists estimated that overall, as many as 50% of people with pulmonary embolism would subsequently receive lifelong anticoagulation. The Committee accepted that although NICE clinical guideline\xa0144 recommends an initial treatment duration of 3\xa0months, the usual duration of treatment in UK practice was 6\xa0months or more.\n\nThe Committee heard from the patient expert about the perceived benefits of rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolic events over the standard care of LMWH with a vitamin\xa0K antagonist (such as warfarin). The patient expert highlighted the disadvantages of warfarin, including the need for regular monitoring of INR, and dose adjustment. Monitoring, which needs regular visits to hospital or GP appointments, can be costly and inconvenient, and means some people may have to take time off work. The patient expert said young people of school or university age may also experience clots and INR monitoring can lead to disruption of education. The patient expert further explained that the burdens of monitoring and dose adjustments with warfarin may also affect carers of people who have had a pulmonary embolus and they may have to make adjustments to their own schedules to enable the person for whom they are caring to monitor their INR. As warfarin has many drug interactions, it may be unsuitable for people with comorbidities, and because of various food interactions, people may need to adjust and monitor their diet and lifestyle. The patient expert said that there are some people whose INR is unstable on warfarin or who are allergic to it, for whom an alternative is needed. The patient expert highlighted that rivaroxaban can be used at the onset of pulmonary embolism in primary or secondary care. Rivaroxaban has the advantage that it avoids injections, regular blood tests and the diet and lifestyle considerations necessary with the combination of heparin and warfarin. The patient expert said that patients are very interested in rivaroxaban and other newer anticoagulants, but noted that a small proportion of patients are concerned about these new agents and find regular monitoring of INR reassuring to confirm that they are adequately anticoagulated. The patient expert expressed the view that rivaroxaban should be made available as an additional treatment option. The Committee accepted the limitations of treatment with LMWH and a vitamin\xa0K antagonist and acknowledged the potential benefits of rivaroxaban.\n\nThe Committee considered the clinical management of bleeding resulting from treatment with anticoagulants. The clinical specialists highlighted that there are currently no validated guidelines on how to treat bleeding experienced while taking the new anticoagulants. The clinical specialists stated that people who have a bleed while taking a vitamin\xa0K antagonist may receive vitamin\xa0K, which takes 8–12\xa0hours to reverse the effect of the vitamin\xa0K antagonist. One clinical specialist estimated that approximately 0.1% of people receiving warfarin experience a major bleed and for major bleeds needing rapid reversal, the most effective treatment is prothrombin complex concentrate (PCC) that provides correction for 12\xa0hours. However, PCC would only be considered appropriate for a proportion of people with a major bleed. The Committee noted that the Evidence Review Group (ERG) had suggested that recombinant factor VIIa may be used to reverse a bleed. The clinical specialists agreed that recombinant factor VIIa may be used, but as it has a very short duration of action of approximately 2\xa0hours, and is extremely expensive, they considered that PCC would be used in preference. The Committee further noted that recombinant factor VIIa is not licensed for the reversal of bleeding experienced on the new anticoagulants. It heard from the clinical specialists and the patient expert that there is no established antidote for rivaroxaban but because of its relatively short half-life, some bleeds can be managed simply by discontinuing rivaroxaban. The Committee concluded that there are standard approaches to stop bleeding experienced while on standard vitamin\xa0K antagonists such as warfarin, but there is uncertainty about the best approach to reverse bleeding experienced while taking rivaroxaban.\n\nThe Committee considered the generalisability of the EINSTEIN‑PE trial to UK clinical practice. It discussed whether the population in the trial reflects those seen in UK clinical practice. The Committee noted that the mean age of the population in the trial was 58\xa0years. The clinical specialists highlighted that the incidence of deep vein thrombosis and pulmonary embolism increases with age, but EINSTEIN‑PE included few people over 80\xa0years. The clinical specialists considered that the proportion of people in the trial with provoked and unprovoked pulmonary embolism was similar to that observed in clinical practice. The Committee noted the ERG's concern that EINSTEIN‑PE excluded people with severe renal impairment, even though they may be eligible for treatment with rivaroxaban with dose adjustment if needed. The clinical specialists stated that rivaroxaban would probably not be used in routine clinical practice for people with severe renal impairment. The Committee heard from the clinical specialists that in their opinion, the population in EINSTEIN‑PE generally reflected the corresponding UK patient population. The Committee concluded that the baseline characteristics of the population in EINSTEIN‑PE were generalisable to UK clinical practice.\n\nThe Committee discussed the comparator used in EINSTEIN‑PE and its relevance to UK clinical practice. The clinical specialists stated the LMWH used in the trial, enoxaparin, has the largest evidence base of all the LMWHs. The clinical specialists also stated that there were no known differences in the clinical effectiveness of the different available LMWHs. The Committee considered whether the dosage of enoxaparin used in EINSTEIN‑PE is applicable to UK clinical practice. It noted that in EINSTEIN‑PE, the US licensed dose of enoxaparin was used (that is, 1.0\xa0mg/kg twice a day), whereas the dose used in the UK is 1.5\xa0mg/kg once a day. The Committee heard from the clinical specialists that the 2\xa0dosages are similar in terms of efficacy, and although people in EINSTEIN‑PE received a higher overall daily dose of enoxaparin than would be seen in UK clinical practice, this is not expected to have affected the generalisability of the trial to the UK. The Committee accepted that the differences in the dosage did not appear to be clinically significant and was satisfied that the comparators used in the trial represented routine and best practice.\n\nThe Committee considered the time in therapeutic range in the enoxaparin and vitamin\xa0K antagonist arm of the trial. It noted that the average time in therapeutic range for people receiving enoxaparin with a vitamin\xa0K antagonist was 62.7%. The clinical specialists stated that time in therapeutic range varies, but a range of between 60% and 70% would be expected in UK clinical practice. The Committee therefore concluded that the data from the enoxaparin with a vitamin\xa0K antagonist arm in the trial were applicable to routine clinical practice.\n\nThe Committee considered the generalisability of the EINSTEIN‑PE trial to the subgroup of patients who have active cancer. The Committee noted that EINSTEIN‑PE included a small proportion of people with cancer. The clinical specialists stated that people with cancer who experience venous thromboembolism would currently receive extended treatment with a LMWH alone, as evidence has shown that LMWH is more effective than warfarin for this group of people, and has been shown to reduce mortality. The Committee noted that the manufacturer had not presented any clinical evidence for a comparison of LMWH alone with rivaroxaban. The clinical specialists suggested that, without evidence from a direct comparison, it was unlikely that clinicians would offer rivaroxaban as an alternative treatment to LMWH for people with cancer. The Committee agreed that the comparator treatment in EINSTEIN‑PE that included a vitamin\xa0K antagonist did not reflect UK clinical practice for people with cancer, and there was no evidence for the relative efficacy of rivaroxaban compared with long-term LMWH, the standard treatment for these patients. The Committee concluded that without direct evidence of the relative efficacy of rivaroxaban compared with LMWH alone, it would be inappropriate to make a recommendation for this group.\n\nThe Committee considered the trial design and the clinical-effectiveness results of the EINSTEIN‑PE trial. It noted that the trial was designed to assess whether rivaroxaban was non-inferior to LMWH with a vitamin\xa0K antagonist for preventing recurrent thromboembolism after pulmonary embolism and that the manufacturers had also tested for statistical superiority for the primary efficacy outcome. The Committee noted that for the whole trial population, the rates of recurrent venous thromboembolism were not statistically significantly different in the rivaroxaban and LMWH with a vitamin\xa0K antagonist arms in the trial. The Committee concluded that rivaroxaban has acceptable clinical effectiveness compared with low molecular weight heparin and a vitamin\xa0K antagonist.\n\nThe Committee discussed the safety data from EINSTEIN‑PE. It noted that there was no statistically significant difference in the composite end point of major bleeding and clinically relevant non-major bleeding between rivaroxaban and LMWH with a vitamin\xa0K antagonist, but that the incidence of major bleeds was statistically significantly lower with rivaroxaban. The Committee concluded that rivaroxaban has an acceptable safety profile compared with low molecular weight heparin and a vitamin\xa0K antagonist.\n\nThe Committee considered the results from the treatment duration subgroups and noted that groups were based on clinical criteria. It discussed the level of uncertainty around the hazard ratios and noted that the confidence intervals surrounding the hazard ratio for recurrent thromboembolism overlapped. It was aware that the confidence intervals were particularly wide for the 3-month treatment duration subgroup and noted the analysis was based on a small number of people recruited to the group (around 5% of the study population) and on a small number of events in both treatment arms. In addition, the Committee heard from the clinical specialists that they were not aware of any biological reason to expect a differential effect in the 3-month treatment duration subgroup. The Committee therefore concluded that evidence of treatment effect should be based on the whole trial population of EINSTEIN‑PE.\n\nThe Committee considered the issue of long-term or lifelong treatment with rivaroxaban. It noted that the maximum length of treatment in EINSTEIN‑PE was 12\xa0months, but was mindful that it had heard from the clinical specialists that some people will need longer treatment durations in clinical practice (section\xa04.3). In the absence of long-term data, the Committee considered the plausibility of the effects of rivaroxaban being maintained beyond 12\xa0months. The clinical specialists stated that there is no biological or pharmacological reason why the effects of rivaroxaban should not be maintained over time but noted that there was uncertainty about how people would adhere to treatment with rivaroxaban over the long term. The Committee accepted that there was no biological or pharmacological reason why the effects of rivaroxaban would not be maintained over the long term.\n\nThe Committee noted that the manufacturer had presented 4\xa0base-case scenarios for 3-, 6-, 12-month treatments and a lifelong treatment analysis. It noted that the economic model used clinical-effectiveness data from EINSTEIN‑PE and utility data derived through systematic review. The Committee noted that rivaroxaban dominated treatment with LMWH and a vitamin\xa0K antagonist, that is, was less costly and more effective in the manufacturer's deterministic analysis of 3-, 6- and 12-month treatment durations. It noted that for lifelong treatment, the manufacturer's base case incremental cost-effectiveness ratio (ICER) was £13,300\xa0per quality-adjusted life year (QALY) gained but after the corrections made to the model by the ERG, the base case for lifelong treatment was reduced to £7070\xa0per QALY gained. The Committee noted that this figure was calculated using the manufacturer's estimate of INR-monitoring costs.\n\nThe Committee discussed the estimate of the cost of INR monitoring. It heard from the clinical specialists that although there is a trend towards more monitoring being performed in primary care, some people still receive monitoring in secondary care. The clinical specialists also stated that there is huge variation in the frequency of INR monitoring for people receiving a vitamin\xa0K antagonist; some people may need weekly visits, particularly at the beginning of therapy, and some people may only need INR monitoring twice a year. The clinical specialists estimated that, as a guide, on the basis of 1\xa0audit, INR monitoring once every 5–6\xa0weeks might be a reasonable average estimate. The patient expert also highlighted that there is interest from patients in self-monitoring of INR, but there is variation in the availability of INR-home monitoring machines. The Committee concluded that there is considerable variability and uncertainty surrounding service provision and the frequency of INR monitoring that makes determining an accurate cost of INR monitoring problematic. It noted that the ERG had assumed fewer INR-monitoring visits than the manufacturer, which the ERG confirmed resulted in lower first year monitoring costs of between £304\xa0and £379. The application of these scenarios to lifelong treatment increased the ICER from £7070\xa0per QALY gained in the base case to £17,900\xa0and £22,900\xa0per QALY gained respectively. The Committee considered how INR-monitoring costs had been estimated in previous appraisals. In Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism (NICE technology appraisal guidance\xa0261) the Committee had considered that after deep venous thrombosis, an INR-monitoring frequency of 6\xa0visits in the first quarter and 3\xa0in each subsequent quarter, resulting in first-year costs of £320, to be reasonable. The Committee took into account the clinical specialists' estimates of average INR-monitoring frequency (that is, every 5–6\xa0weeks) and also the deliberations during technology appraisal\xa0261\xa0and concluded that the ERG's scenarios were reasonable estimations of the impact of INR monitoring on the cost effectiveness of rivaroxaban, and that the manufacturer's estimate of frequency of monitoring visits was too high.\n\nThe Committee discussed the health-related quality of life data used in the economic model. It noted that health-related quality of life had not been measured in EINSTEIN‑PE and that the manufacturer had obtained the utility values used in its model through systematic review. The Committee was aware that the ERG had considered the utility values used in the economic model to be generally appropriate; however, the Committee considered that some of the studies that the manufacturer had used to obtain the utility values were too small and did not meet the reference case outlined in NICE's Guide to the methods of technology appraisal. The Committee expressed its disappointment that the manufacturer had not followed the reference case to derive the utility values. In particular, it noted that only 1\xa0study fully met NICE's reference case criteria (that is, the source of data for measurement of health-related quality of life was reported directly by patients or carers, the source of preference data for valuation of changes in health-related quality of life was a representative sample of the public, and the preferred measure of health-related quality of life, the EQ-5D, had been used). The Committee noted that similar utility values had been used by the manufacturer in its economic model for NICE technology appraisal guidance\xa0261 and it also noted that in the scenario analysis carried out by the ERG in which the utility value for the intracranial bleed state was increased from 0.33\xa0to 0.55, there was only a minimal effect on the ICER. The Committee concluded that although the health-related quality of life studies selected by the manufacturer to obtain utility values for its economic model did not meet the NICE reference case, the cost-effectiveness estimates did not appear to be sensitive to the utility values used.\n\nThe Committee considered the 2\xa0additional scenario analyses performed by the ERG for lifelong treatment that addressed the impact of an increase in the risk of a thromboembolic event or a bleeding event for rivaroxaban after 12\xa0months. The Committee noted that the worst-case ICER for rivaroxaban compared with LMWH and a vitamin\xa0K antagonist was £14,100\xa0per QALY gained when the hazard ratio for a recurrent venous thromboembolism was increased from 1.12\xa0to 2, and £14,200\xa0per QALY gained when the hazard ratio for a major bleed was increased from 0.49\xa0to 0.79\xa0(the upper limit of the 95% confidence interval for the major bleed hazard ratio seen in EINSTEIN‑PE). The Committee noted that the ERG had also carried out a multiple assumption scenario that resulted in an ICER of £35,900. This included the assumption that both the effectiveness of rivaroxaban in preventing venous thromboembolic events decreased and the risk of bleeds increased relative to conventional therapy after 12\xa0months compared with the base case. The Committee heard from the clinical specialists that if an anticoagulant was less effective in preventing venous thromboembolic events, then it would be expected to have a lower rate of bleeds. The clinical specialists stated that a scenario in which both the risk of venous thromboembolism and bleeding increased was clinically implausible. The Committee concluded that the ERG's multiple assumption scenario was not plausible and the resulting ICER was not appropriate or relevant for this appraisal.\n\nThe Committee considered the 3\xa0scenario analyses undertaken by the ERG in which the costs of reversing a major bleed had been incorporated and had been assessed in the 12-month and lifelong treatment analyses. The Committee noted that in these scenarios, the ERG had assumed that all people who had a major bleed would receive either treatment with PCC or recombinant factor VIIa; however, it was mindful of the testimony from the clinical specialists that only a proportion of people who had a major bleed would receive these treatments and PCC would preferentially be used over recombinant factor VIIa (see section\xa04.5). The Committee noted that recombinant factor VIIa is a particularly expensive drug and that the manufacturer did not consider the costs used by the ERG for recombinant factor VIIa to be relevant to patients in the decision problem. The Committee stated that consideration of bleeding reversal costs was relevant but that the ERG had presented extreme scenarios because it assumed that all people who had a major bleed would receive PCC or recombinant factor VIIa. The Committee agreed that there was too much uncertainty surrounding the treatment of bleeds experienced while on anticoagulants to reliably estimate the impact of treatment costs for reversing bleeding on the cost-effectiveness estimates. The Committee therefore concluded that the ICERs presented by the ERG for the 12-month analysis (worst-case scenario £23,400\xa0per QALY gained) and the lifelong analysis (worst-case scenario £44,000) were not relevant for this appraisal.\n\nThe Committee considered that in all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate, or the ICER compared with LMWH and a vitamin\xa0K antagonist could be considered a cost-effective use of NHS resources. The Committee concluded that rivaroxaban was cost effective for treating pulmonary embolism for 3, 6\xa0or 12\xa0months.\n\nFor lifelong treatment, the Committee considered the ERG's assumptions about the frequency of INR monitoring to be valid and concluded that the most plausible ICER for lifelong treatment with rivaroxaban compared with lifelong treatment with a vitamin\xa0K antagonist after initial treatment with a LMWH was between £17,900\xa0and £22,900\xa0per QALY gained. The Committee concluded that rivaroxaban is a cost-effective treatment option for the lifelong treatment of pulmonary embolism and prevention of recurrent thromboembolism for people in whom long-term treatment is indicated.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA287\n\nAppraisal title: Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism\n\nSection\n\nKey conclusion\n\nRivaroxaban is recommended as an option for treating pulmonary embolism and preventing recurrent deep vein thrombosis and pulmonary embolism in adults.\n\n\n\n\n\nIn all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate or the ICER compared with LMWH and a vitamin\xa0K antagonist could be considered a cost-effective use of NHS resources. The Committee concluded that rivaroxaban was cost effective for treating pulmonary embolism for 3, 6\xa0or 12\xa0months.\n\n\n\n\n\n\n\nFor lifelong treatment, the Committee considered the ERG's assumptions about the frequency of INR monitoring to be valid and concluded that the most plausible ICER for lifelong treatment was between £17,900\xa0and £22,900\xa0per QALY gained. The Committee concluded that rivaroxaban is a cost-effective treatment option for the lifelong treatment of pulmonary embolism and prevention of recurrent thromboembolism for people in whom long-term treatment is indicated.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nPeople with suspected pulmonary embolism are generally treated with immediate parenteral anticoagulation, most commonly with a low molecular weight heparin (LMWH) delivered by subcutaneous injection, and when the diagnosis has been confirmed, an oral vitamin\xa0K antagonist such as warfarin. Duration of treatment is based on individual risk of recurrent venous thromboembolism and bleeding. The usual duration of treatment in UK practice is 6\xa0months or more.\n\n, 4.3\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nDisadvantages of long-term anticoagulation with warfarin include the need for regular monitoring of INR, dose adjustment, multiple food and drug interactions and the impact on people's lifestyle including cost and inconvenience.\n\nRivaroxaban avoids injections, regular blood tests and the diet and lifestyle considerations necessary with the combination of heparin and warfarin. It can be used at the onset of pulmonary embolism in primary or secondary care.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nRivaroxaban is indicated for the 'treatment of deep vein thrombosis and pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism in adults'.\n\n\n\nAdverse reactions\n\nThere was no statistically significant difference in the composite end point of major bleeding and clinically relevant non-major bleeding between rivaroxaban and LMWH with a vitamin\xa0K antagonist, but that the incidence of major bleeds was statistically significantly lower with rivaroxaban. The Committee concluded that rivaroxaban has an acceptable safety profile compared with LMWH and a vitamin\xa0K antagonist.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe EINSTEIN‑PE trial was the key trial supporting the clinical effectiveness of rivaroxaban in the manufacturer's submission.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe baseline characteristics of the population in EINSTEIN‑PE were generalisable to UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe manufacturer had not presented any clinical evidence for a comparison of rivaroxaban with LMWH alone for people with cancer to reflect UK clinical practice for this group of patients. Therefore, the Committee concluded it would be inappropriate to make a recommendation for this group.\n\n\n\n\n\n\n\nThe maximum length of treatment in EINSTEIN‑PE was 12\xa0months, but some people will need longer treatment durations in clinical practice. The Committee accepted that there was no biological or pharmacological reason why the effects of rivaroxaban would not be maintained over the long term.\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nIt was noted that treatment duration was assigned based on clinical criteria. The Committee noted that the confidence intervals surrounding the hazard ratio for recurrent thromboembolism overlapped.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe primary efficacy outcome in EINSTEIN‑PE was symptomatic recurrent venous thromboembolism. The Committee noted that for the whole trial population, the rates of recurrent venous thromboembolism were not statistically significantly different in the rivaroxaban and LMWH with a vitamin\xa0K antagonist arms in the trial. The Committee concluded that rivaroxaban had acceptable clinical effectiveness compared with LMWH and a vitamin\xa0K antagonist.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer presented an economic model, which used clinical-effectiveness data from EINSTEIN‑PE and utility data derived through systematic review, and presented 4\xa0base-case scenarios for 3-, 6-, 12-month treatments and a lifelong treatment analysis.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThere is considerable variability and uncertainty surrounding service provision and the frequency of INR monitoring that makes determining an accurate cost of INR monitoring problematic. The Committee took into account the clinical specialists' estimates, the deliberations during technology appraisal\xa0261 and the ERG's scenarios and concluded that the manufacturer's estimate of frequency of monitoring visits was too high and the ERG's scenarios were reasonable estimates.\n\n\n\n\n\nThe Committee considered that some of the studies that the manufacturer had used to obtain the utility values were too small and did not meet the reference case outlined in NICE's Guide to the methods of technology appraisal. It concluded that the cost effectiveness of rivaroxaban did not appear to be sensitive to the utility values used.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee heard from the patient expert who confirmed regular monitoring of INR, dose adjustment, multiple food and drug interactions with warfarin can impact on people's lifestyle can be costly and inconvenient. The manufacturer applied a disutility due to warfarin therapy of 0.012\xa0in the LMWH/VKA arm.\n\n, 3.13\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone identified\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nINR monitoring costs. In the manufacturer's sensitivity analyses the cost effectiveness of lifelong treatment with rivaroxaban was most sensitive to changes in the frequency of INR-monitoring visits, where the ICER increased from £13,252\xa0per QALY gained to £27,914\xa0per QALY gained if people have 3, rather than 5, visits in each quarter after the first. For lifelong treatment, the Committee considered the ERG's assumptions about the frequency of INR monitoring to be valid resulting in the ICER for lifelong treatment with rivaroxaban compared with lifelong treatment with a vitamin\xa0K antagonist after initial treatment with a LMWH increasing from £7070\xa0in the ERG's amended base case to between £17,900\xa0and £22,900\xa0per QALY gained.\n\n, 4.15, 4.20\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee considered that in all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate or the ICER compared with LMWH and a vitamin\xa0K antagonist could be considered a cost-effective use of NHS resources. The most plausible ICER for lifelong treatment with rivaroxaban compared with lifelong treatment with a vitamin\xa0K antagonist after initial treatment with a LMWH was between £17,900\xa0and £22,900\xa0per QALY gained.\n\n, 4.20\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n\n\nEnd-of-life considerations\n\nNot applicable\n\n\n\nEqualities considerations and social value judgements\n\nNo equalities issues were raised.\n\n", 'Recommendations for further research ': 'There have been no head-to-head trials of rivaroxaban compared with a low molecular weight heparin for people who have cancer and experience an acute pulmonary embolism or deep vein thrombosis. As in NICE technology appraisal guidance\xa0261 it is recommended that further research should be carried out.\n\nResearch into the long-term treatment effects of rivaroxaban is needed.', 'Related NICE guidance': '# Published\n\nVenous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. NICE clinical guideline\xa0144\xa0(2012).\n\nRivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism. NICE technology appraisal guidance\xa0261\xa0(2012).\n\nApixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. NICE technology appraisal guidance\xa0245\xa0(2012).\n\nVenous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. NICE clinical guideline\xa092\xa0(2010).\n\nRivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. NICE technology appraisal guidance\xa0170\xa0(2009).\n\nDabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. NICE technology appraisal guidance\xa0157\xa0(2008).\n\n# NICE pathways\n\nVenous thromboembolism. NICE pathway (2011).\n\n# NICE quality standards\n\nVenous thromboembolism prevention. NICE quality standard\xa03\xa0(2010).\n\nManagement of venous thromboembolic diseases. NICE quality standard\xa029\xa0(2013).', 'Review of guidance': 'The guidance on this technology will be considered for review in May\xa02015\xa0alongside the review of NICE technology appraisal guidance\xa0261. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrews Dillon Chief ExecutiveJune 2013', 'Changes after publication': 'January 2014: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt has been incorporated into the NICE pathway on venous thromboembolism along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0140-1'}	https://www.nice.org.uk/guidance/ta287	Evidence-based recommendations on rivaroxaban (Xarelto) for treating pulmonary embolism and for preventing a further deep vein thrombosis or pulmonary embolism in adults.
3289392cc3223bb770164b9b17cd5f3706f6e23d	nice	Mirabegron for treating symptoms of overactive bladder	Mirabegron for treating symptoms of overactive bladder Evidence-based recommendations on mirabegron (Betmiga) for treating overactive bladder in adults. # Guidance Mirabegron is recommended as an option for treating the symptoms of overactive bladder only for people in whom antimuscarinic drugs are contraindicated or clinically ineffective, or have unacceptable side effects. People currently receiving mirabegron that is not recommended for them in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology Mirabegron (Betmiga, Astellas Pharma) has a marketing authorisation in the UK for the 'symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in patients with overactive bladder (OAB)'. It is a beta-3-adrenoceptor agonist, which activates beta-3-adrenoceptors causing the bladder to relax, which helps it to fill and also to store urine. It is administered orally. Mirabegron will be available as 25 mg and 50 mg tablets, with the recommended dose being 50 mg daily, and 25 mg if there is renal or hepatic impairment. The summary of product characteristics lists the following adverse reactions for mirabegron: urinary tract infection, tachycardia, vaginal infection, cystitis, palpitation, atrial fibrillation, dyspepsia, gastritis, urticaria, rash, rash macular, rash popular, pruritus, joint swelling, vulvovaginal pruritis, increased blood pressure, increased gamma-glutamyl transpeptidase, increased aspartate aminotransferase, increased alanine aminotransferase, eyelid oedema, lip oedema, leukocytoclastic vasculitis and purpura (rash). For full details of adverse reactions and contraindications, see the summary of product characteristics. The list price indicated in the manufacturer's submission is £0.97 (excluding VAT) per 50 mg or 25 mg tablet, or an average cost of £27.06 per 28 days (assuming 1 tablet per day). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of mirabegron and a review of this submission by the Evidence Review Group (ERG; section 9). # Clinical effectiveness The manufacturer conducted 2 systematic reviews to identify published randomised and non-randomised controlled trial evidence on the efficacy and safety of mirabegron in adults with symptoms of overactive bladder (OAB). The clinical evidence submitted by the manufacturer consisted of 3 trials identified by the manufacturer as pivotal (SCORPIO, ARIES and CAPRICORN) and 4 supporting trials (DRAGON, 178-CL-045 and 178-CL-048, and TAURUS, which was a safety study). Additionally, a mixed-treatment comparison was performed of mirabegron against placebo, tolterodine tartrate, oxybutynin hydrochloride, solifenacin succinate, fesoterodine fumarate and trospium chloride. SCORPIO, ARIES and CAPRICORN were randomised controlled trials that compared mirabegron (at varying doses) with placebo and tolterodine tartrate modified release (MR) 4 mg (as an active control in SCORPIO only). The supporting studies included TAURUS, a long-term safety study that compared mirabegron with tolterodine tartrate MR 4 mg (no placebo control), which examined adverse events over 52 weeks and recruited patients mainly from SCORPIO and ARIES; DRAGON, a randomised controlled trial of 12 weeks' duration comparing mirabegron with placebo and tolterodine tartrate MR 4 mg; and 2 randomised controlled trials (178-CL-045 and 178-CL-048) performed in Japan. Trial 178-CL-045 compared mirabegron with placebo and 178-CL-048 compared mirabegron with tolterodine tartrate MR 4 mg and placebo. The manufacturer presented individual results for SCORPIO, ARIES and CAPRICORN and a pooled analysis of the 3 trials with multiplicity adjustments made during the analysis of all outcomes. SCORPIO was a 12-week trial comparing mirabegron (50 mg and 100 mg once daily) and placebo, with tolterodine tartrate MR 4 mg as an active control in adults with symptoms of OAB. The trial population was 72% female, and 63% of all trial participants were under 65 years old. The trial took place in 189 sites in 27 EU (including the UK) and non-EU countries (in Europe, as well as Russia and Australia). There were 1987 participants, with patients randomised to mirabegron 50 mg (n=497), mirabegron 100 mg (n=498), tolterodine tartrate MR 4 mg (n=495), and placebo (n=497) in a 1:1:1:1 ratio. Assessments were conducted at weeks 4, 8 and 12. ARIES was a 12-week trial that compared mirabegron (50 mg and 100 mg) with placebo in adults with symptoms of OAB. The trial had 74.8% female participants, and 60.3% of all trial participants were under 65 years old. The trial was conducted in 132 sites in the USA and Canada. There were 1329 participants, with patients randomised to mirabegron 50 mg (n=442), mirabegron 100 mg (n=433) and placebo control (n=454) in a 1:1:1 ratio. Assessments were conducted at weeks 4, 8 and 12. CAPRICORN was a 12-week trial that compared mirabegron (25 mg and 50 mg) with placebo in adults with symptoms of OAB. The trial had 68.5% female participants, and 62.8% of all trial participants were under 65 years old. The trial took place in 151 sites in Europe (not including the UK) and North America. There were 1306 participants, with patients randomised to mirabegron 25 mg (n=433), mirabegron 50 mg (n=440), and placebo (n=433) in a 1:1:1 ratio. Assessments were conducted at weeks 4, 8 and 12. TAURUS was a safety trial that compared mirabegron (50 mg and 100 mg) with tolterodine tartrate MR 4 mg as an active control in adults with symptoms of OAB. The trial duration was 2 weeks in a single-blind placebo run-in, followed by 12 months on randomised treatment. The trial took place in 306 sites globally, including the UK. There were 2452 participants, with patients randomised to mirabegron 50 mg (n=815), mirabegron 100 mg (n=824) and tolterodine tartrate MR 4 mg (n=813) in a 1:1:1 ratio. Assessments were conducted at screening, baseline and in months 1, 3, 6, 9 and 12. DRAGON was a 12‑week randomised controlled trial that compared mirabegron (25 mg, 50 mg, 100 mg and 200 mg) with placebo, and with tolterodine tartrate MR 4 mg as an active control, in adults with symptoms of OAB, in 14 European countries, including the UK (n=928). The 178-CL-045 randomised controlled trial carried out in Japan compared 25 mg, 50 mg and 100 mg mirabegron with placebo in adults with symptoms of OAB over 12 weeks (n=842). The 178-CL-048 randomised trial carried out in Japan compared 50 mg mirabegron with placebo or tolterodine tartrate MR 4 mg as an active control in adults with symptoms of OAB over 12 weeks (n=1139). The 2 primary outcomes of SCORPIO, ARIES and CAPRICORN were change from baseline to end point for mean number of micturitions per 24 hours and mean number of incontinence episodes per 24 hours. Secondary outcomes were mean volume voided per micturition; mean number of urgency episodes (grade 3 or 4) per 24 hours (grade 3 is severe urgency and grade 4 is urge incontinence ); mean level of urgency (associated urgency according to the 5-point categorical scale Patient Perception of Intensity of Urgency Scale); mean number of urge incontinence episodes (involuntary leakage accompanied by or immediately preceded by urgency) per 24 hours; and mean number of nocturia episodes per 24 hours. For the 3 trials (SCORPIO, ARIES and CAPRICORN), results were reported for several populations. The primary population used in the submission was the full analysis set (patients who had at least 1 post-dose assessment). Other analyses included the intention-to-treat population (all patients randomised to receive treatment), the modified intention-to-treat set for health-related quality of life (patients who were randomised, received at least 1 dose of double-blind study medication and completed the EQ-5D questionnaire at baseline and at least once post-baseline, but excluding any patients who presented serious deviations from the protocol or for whom the EQ-5D questionnaire data was not available at 12 weeks), the incontinence full analysis set (patients who had at least 1 post-dose assessment, but only those with incontinence; these data were used for incontinence outcomes), and the safety analysis set (all randomised patients who took 1 or more doses of double-blind study drug). The doses of mirabegron used in the trials ranged from 25 mg to 100 mg. The manufacturer focused its submission on mirabegron 50 mg as the anticipated licensed dose. ## Comparisons with placebo Urinary frequency was measured as change from baseline in mean number of micturitions in 24 hours (measured by micturition diary). The results from the full set analyses of SCORPIO, ARIES and CAPRICORN all indicated statistically significant improvements in change from baseline to week 12 in the mean number of micturitions in 24 hours in the mirabegron groups compared with placebo (SCORPIO mean difference −0.60, 95% confidence interval −0.90 to −0.29; ARIES mean difference −0.61, 95% CI −0.98 to −0.24; CAPRICORN mean difference −0.42, 95% CI −0.76 to −0.08). In the DRAGON and 178-CL-048 trials there was no statistically significant difference between mirabegron and tolterodine tartrate. In the 178-CL-045 trial significant improvements were seen with mirabegron compared with placebo (mean difference −0.74, 95% CI −1.12 to −0.36). The results of the manufacturer's pooled analysis of 3 trials (ARIES, CAPRICORN and SCORPIO) showed a statistically significant difference between mirabegron 50 mg and placebo (adjusted mean difference −0.55, 95% CI −0.75 to −0.36, p<0.001). Frequency of incontinence was measured as the mean number of incontinence episodes per 24 hours and assessed in the manufacturer's submission by the full analysis set – incontinence population. The results from the SCORPIO, ARIES and CAPRICORN trials all indicated statistically significant improvements in change from baseline to week 12 in mean number of incontinence episodes per 24 hours versus placebo (SCORPIO mean difference −0.41, 95% CI −0.72 to −0.09; ARIES mean difference −0.34, 95% CI −0.66 to −0.03; CAPRICORN mean difference −0.42, 95% CI −0.76 to −0.08). In the DRAGON and 178-CL-048 trials there was no statistically significant difference between mirabegron and tolterodine tartrate. In the 178-CL-045 trial significant improvements were seen with mirabegron compared with placebo (mean difference −0.40, 95% CI −0.67 to −0.13). The results of the manufacturer's pooled analysis for the 3 trials showed a statistically significant difference between mirabegron 50 mg and placebo (mean difference −0.40, 95% CI −0.58 to −0.21 p<0.001). The manufacturer presented results for the secondary outcomes reported in the trials. These were mean volume voided per micturition, frequency of urge urinary incontinence, mean level of urgency, the number of urgency episodes (grade 3 or 4) per 24 hours, and nocturia episodes per 24 hours. ## Subgroup analyses The manufacturer performed pooled subgroup analyses (from SCORPIO, ARIES and CAPRICORN) for men versus women, for the 2 primary outcomes. Mirabegron 50 mg was numerically more effective in the female subgroup than the male subgroup for the pooled trial data for the change in the number of incontinence episodes and micturitions per 24 hours between baseline and final visit. The adjusted mean difference versus placebo for incontinence episodes per 24 hours (incontinence full analysis set) in the male mirabegron 50 mg treatment group was −0.07 (95% CI −0.50 to 0.36), which was not statistically significant. The change in the adjusted mean difference versus placebo for incontinence episodes per 24 hours (incontinence full analysis set) in the female mirabegron 50 mg treatment group was −0.47 (95% CI −0.67 to −0.26), which was statistically significant. The adjusted mean difference versus placebo in the mean number of micturitions per 24 hours was −0.37 (95% CI −0.74 to −0.01) in the male mirabegron 50 mg treatment group, which was statistically significant. The adjusted mean difference versus placebo in the mean number of micturitions per 24 hours in the female mirabegron 50 mg treatment group was −0.62 (95% CI −0.85 to −0.39), which was statistically significant. Tests for treatment by sex interactions were non-significant for both outcomes (p value=0.22 for the change in the mean number of incontinence episodes per 24 hours; p=0.16 for change in the mean number of micturitions per 24 hours) indicating that there was no differential treatment effect between men and women. The manufacturer also performed a pooled subgroup analysis using data from SCORPIO, CAPRICORN and ARIES comparing previously treated and treatment-naive groups. Mirabegron 50 mg was effective in both populations for the 2 primary outcomes. The change in the mean number of incontinence episodes per 24 hours between baseline and final visit (incontinence full analysis set) in the previously treated mirabegron 50 mg treatment group was −1.49 (95% CI −1.66 to −1.32) and the adjusted mean difference versus placebo was −0.57 (95% CI −0.81 to −0.33). The change in the mean number of incontinence episodes per 24 hours between baseline and final visit (incontinence full analysis set) in the treatment-naive mirabegron 50 mg treatment group was −1.50 (95% CI −1.71 to −1.29) and the adjusted mean difference versus placebo was −0.15 (95% CI −0.44 to 0.14). The change in the mean number of micturitions per 24 hours between baseline and final visit (full analysis set) in the previously treated mirabegron 50 mg treatment group was −1.67 (95% CI −1.86 to −1.48) and the adjusted mean difference versus placebo was −0.74 (95% CI −1.01 to −0.47). The change in the mean number of micturitions per 24 hours between baseline and final visit (full analysis set) in the treatment-naive mirabegron 50 mg treatment group was −1.84 (95% CI −2.04 to −1.64) and the adjusted mean difference versus placebo was −0.33 (95% CI −0.62 to −0.05). Mirabegron 50 mg was effective in reducing the mean number of incontinence episodes and micturitions per 24 hours from baseline to final visit for both previously treated and treatment-naive patients. Tests for interaction indicated no treatment effect for either outcome (p=0.095 for the change in the mean number of incontinence episodes and p=0.10 for the mean number of micturitions). ## Safety outcomes Data on adverse events presented in the manufacturer's submission were largely derived from the 52-week study TAURUS (mirabegron versus tolterodine tartrate). Additionally, information was available from the SCORPIO, ARIES and CAPRICORN trials. Treatment-emergent adverse events were adverse events that occurred after treatment, while treatment-related adverse events were directly linked to treatment, although the criteria used by the manufacturer for establishing a direct link with treatment were unclear. The incidence of treatment-related adverse events was similar in the 2 groups, with 26.2% in the mirabegron 50 mg group and 27.6% in the tolterodine tartrate group in TAURUS. In TAURUS the overall incidence of treatment-emergent adverse events was similar across the mirabegron 50 mg (59.7%) and tolterodine tartrate (62.6%) groups. Most treatment-emergent adverse events were mild or moderate in all treatment groups. The overall incidence of treatment-emergent severe adverse events was 5.2% in the mirabegron 50 mg group and 5.4% in the tolterodine tartrate group in TAURUS (safety analysis set). For treatment-emergent adverse events leading to permanent discontinuation of the study drug the rates were 5.9% in the mirabegron 50 mg group and 5.7% in the tolterodine tartrate group in TAURUS (safety analysis set). In SCORPIO, ARIES and CAPRICORN the incidence of treatment-emergent adverse events was similar across all the treatment groups (safety analysis set population). The adverse events that were designated of interest because of their association with antimuscarinic drugs were dry mouth and constipation. The rates of constipation by treatment group for TAURUS were 2.8% and 2.7% for mirabegron and tolterodine tartrate respectively. For dry mouth, the rates were 2.8% and 8.6% for mirabegron and tolterodine tartrate respectively. In SCORPIO, the rates of dry mouth by treatment group were 1.8% and 9.5% for mirabegron and tolterodine tartrate respectively. The rates were not given for SCORPIO for constipation, or for either adverse event in ARIES and CAPRICORN. ## Mixed treatment comparison Based on the 40 studies identified in the manufacturer's literature review, the manufacturer conducted a Bayesian mixed treatment comparison (MTC) to estimate the relative efficacy and safety of mirabegron compared with oxybutynin hydrochloride (5 mg and 10 mg), fesoterodine fumarate (4 mg and 8 mg), trospium chloride (60 mg), tolterodine tartrate (4 mg), solifenacin succinate (5 mg and 10 mg) and placebo. This was done through a network analysis, using direct comparisons when available, or indirect comparison via placebo when available, or through another comparator if necessary. Oxybutynin hydrochloride and tolterodine tartrate have both MR and immediate-release formulations available, which were examined together for efficacy, but separately for safety, by the manufacturer. Analyses were conducted for micturition, urgency, urinary incontinence, dry mouth, constipation, blurred vision and frequency of incontinence for the general OAB population, but the manufacturer deemed that there were insufficient data available to conduct MTC analyses for the subgroups (including sex) identified in the final NICE scope. For each population, fixed and random effects models were used with a non-informative prior distribution. Quality of fit was assessed through the Bayesian deviance information criterion, with the model with the lowest deviance information criterion selected. The results of the manufacturer's MTC for the outcome of number of micturitions per 24 hours indicated that the effect of mirabegron 50 mg did not differ significantly from any other treatments, except for solifenacin succinate 10 mg, which was more effective than mirabegron (odds ratio −0.583 to 95% credible interval −0.8324 to −0.3326) and tolterodine tartrate 4 mg, which was less effective than mirabegron (OR 0.157, 95% CrI −0.0002 to 0.3154). For the outcome of number of incontinence episodes per 24 hours, the results indicate that there was no statistically significant difference between mirabegron and any of the comparators. The manufacturer's MTC results for the adverse effects of dry mouth, constipation and blurred vision indicated that the mirabegron group had probabilities similar to the placebo group for all effects. All antimuscarinic drugs had a significantly higher risk of dry mouth compared with mirabegron 50 mg. The odds ratios for constipation for antimuscarinic drugs compared with mirabegron 50 mg were not statistically significantly different, except for solifenacin succinate 5 mg (OR 2.501, 95% CrI 1.41 to 4.127) and 10 mg (OR 4.369, 95% CrI 2.54 to 7.071), fesoterodine fumarate 8 mg (OR 1.926, 95% CrI 1.142 to 3.059) and trospium chloride 60 mg (OR 7.604, 95% CrI 2.08 to 22.59). These were associated with higher risks of constipation compared with mirabegron 50 mg. No differences in risk between mirabegron 50 mg and other treatments were found, with wide credible intervals around the odds ratios for blurred vision due to the rarity of this adverse event. ## Quality of life Health-related quality of life and treatment satisfaction were assessed using generic scales (EQ-5D, EQ-5D VAS, TS-VAS and WPAI:SHP) and disease specific scales (OABq and PPBC) in SCORPIO, ARIES and CAPRICORN. Data from SCORPIO, ARIES and CAPRICORN were pooled for a post-hoc analysis of EQ-5D results in the modified intention-to-treat set and no data from individual trials were presented in the manufacturer's submission. Adjusting for baseline confounders (the manufacturer's submission did not provide details of which confounders), mirabegron 50 mg had greater mean change from baseline to 12-week utility scores than tolterodine tartrate MR 4 mg in the pooled analysis of ARIES, CAPRICORN and SCORPIO (0.045 and 0.026 respectively, p≤0.05). The change between baseline and 12-week utility scores was not statistically significantly different between mirabegron 50 mg and placebo (placebo utility change 0.038, p=0.30 for difference). SCORPIO, ARIES and CAPRICORN all showed that there was a greater improvement in quality of life in the mirabegron group than in the placebo group as measured by the OAB-q, which reached statistical significance in SCORPIO and ARIES (SCORPIO estimated mean difference 2.3, 95% CI 0.2 to 4.5; ARIES mean difference 4.1, 95% CI 1.6 to 6.6; CAPRICORN mean difference 1.2, 95% CI −1.0 to 3.4). The mirabegron, placebo and tolterodine tartrate groups achieved a clinically meaningful improvement of 10 points above baseline. ## ERG critique of clinical-effectiveness evidence The ERG noted key strengths and weaknesses in the evidence submitted by the manufacturer. The ERG considered ARIES, CAPRICORN and SCORPIO to be well-designed trials, and that the results for the effectiveness of mirabegron were consistent across the trials. The ERG's clinical expert noted that it was recommended in NHS clinical practice that pharmaceutical treatments for OAB are assessed after 3 months. The ERG therefore considered the duration of treatment and follow-up of the trials included in the manufacturer's submission to be sufficient to assess the efficacy and safety of treatment with mirabegron. The ERG questioned the omission of the data from DRAGON, 178-CL-045 and 178-CL-048, as well as TAURUS, from the primary analyses. The ERG also noted that no direct comparison between mirabegron and tolterodine tartrate was drawn, even though SCORPIO, DRAGON, TAURUS and 178-CL-048 used tolterodine tartrate as an active control. The ERG acknowledged that these trials were not powered to evaluate the superiority or non-inferiority of mirabegron versus tolterodine tartrate, but that exclusion of data from the tolterodine tartrate group in SCORPIO limited the evidence available that was relevant for the decision problem. The ERG requested more detailed information on these trials during the clarification phase, and included it in its report. Although one of the manufacturer's exclusion criteria for 178-CL-045 and 178-CL-048 was that they were exclusively conducted in Japan, the ERG's clinical expert stated that ethnicity is unlikely to influence the development of symptoms of OAB and therefore trials from any country and any population involving patients with OAB were likely to be representative of patients with OAB in England and Wales. The ERG considered the use of the full analysis set population appropriate, as was using the last-observation-carried-forward methodology for missing data (in SCORPIO, ARIES, CAPRICORN and TAURUS). The ERG noted that the intention-to-treat population was not reported across all trials for comparators. The ERG considered the multiplicity adjustments used by the manufacturer in SCORPIO, ARIES and CAPRICORN to be reasonable, in order to account for the multiple outcomes and the resulting increased probability of type I errors. The ERG noted that no statistical assessment of heterogeneity was performed on the pooled analysis. For the comparison of mirabegron with tolterodine tartrate, the ERG performed an additional meta-analysis on the data from the 3 randomised controlled trials that had an active control of tolterodine tartrate (SCORPIO, DRAGON and 178-CL-048) for the outcomes of relevance to the cost-effectiveness analysis, but did not include TAURUS in this meta-analysis because the patients were mainly recruited from SCORPIO and ARIES, and this could have led to an 'enriched' dataset that was biased. The results showed that treatment with mirabegron 50 mg led to statistically significantly fewer micturitions per 24 hours compared with treatment with tolterodine tartrate MR 4 mg (mean difference −0.27, 95% CI −0.48 to −0.06, p=0.01). Conversely, data from TAURUS favoured tolterodine tartrate MR 4 mg, although the difference was not statistically significant (mean difference 0.12, 95% CI −0.11 to 0.35, p value not given). For incontinence episodes per 24 hours, the meta-analysis of the 3 trials showed that treatment with mirabegron 50 mg was statistically significantly more effective than treatment with tolterodine tartrate MR 4 mg (mean difference −0.21, 95% CI −0.41 to −0.01, p=0.04). However, the data from TAURUS showed that mirabegron was associated with statistically significantly more episodes per 24 hours (mean difference 0.25, 95% CI 0.01 to 0.49, p=0.04). The ERG noted concerns with the inclusion and exclusion criteria for the manufacturer's MTC, and considered that the results should be interpreted cautiously. The ERG was concerned about potential clinical and methodological heterogeneity in the included studies, the inconsistency identified in 1 or more treatment comparisons for multiple outcomes, and the number of iterations used for sampling the posterior distributions (which may be an indicator of poor mixing of data within the model). The ERG noted that, for the random effects models used, there were no estimates of the between pairwise comparisons of heterogeneity given by the manufacturer. The ERG re-ran the MTC with different inclusion and exclusion criteria on the same 40 studies identified by the manufacturer to perform an analysis on a more homogeneous dataset. The ERG excluded trials that included patients other than those with OAB; that were carried out in a single sex population; that reported on outcomes available at a time point other than 12 weeks; or that were deemed to be of poor methodological quality based on the manufacturer's summary (less than 4 'yes' responses in the first 4 categories assessed). The ERG included only outcomes, treatment formulations and doses used in the economic model supplied by the manufacturer. This decreased the number of studies to 22 and led to a greater degree of concordance and consequently more reliable results. For the outcome of micturition episodes per 24 hours, the ERG found no significant difference between mirabegron 50 mg and any of the other active treatments assessed in their MTC. The manufacturer's analyses indicated that the only significant difference was that solifenacin succinate 10 mg was statistically significantly more effective than mirabegron at reducing the number of micturition episodes (mean difference −0.583, 95% CrI −0.832 to −0.333). For the outcome of incontinence episodes per 24 hours, the results of the ERG's MTC concurred with the manufacturer's MTC results, with the exception that mirabegron 50 mg was statistically significantly less effective in reducing the frequency of incontinence episodes than solifenacin succinate 5 and 10 mg (solifenacin succinate 5 mg mean difference −0.386, 95% CrI −0.717 to −0.055, solifenacin succinate 10 mg mean difference −0.380, 95% CrI −0.694 to −0.067). The manufacturer's analyses also indicated that solifenacin succinate was numerically more effective than mirabegron, but this result was not statistically significant. The ERG also analysed adverse events in its revised MTC analysis. The ERG found that mirabegron was statistically significantly less likely to be associated with constipation than fesoterodine fumarate 8 mg (OR 2.12, 95% CI 1.13 to 3.64), solifenacin succinate 5 mg (OR 2.11, 95% CI 1.16 to 3.59) and 10 mg (OR 4.52, 95% CI 2.60 to 7.47), and trospium chloride MR 60 mg (OR 7.63, 95% CI 2.12 to 22.95). Mirabegron was also found to be associated with a statistically significantly lower risk of dry mouth compared with all other antimuscarinic drugs assessed. Only oxybutynin hydrochloride 15 mg had a statistically significantly higher rate of discontinuation than mirabegron. # Cost effectiveness The manufacturer's cost-effectiveness evidence consisted of a systematic review of relevant literature and a de novo Markov model. None of the studies identified in the systematic review assessed the cost effectiveness of mirabegron and so the manufacturer developed a Markov model to analyse the cost effectiveness of 50 mg mirabegron against the final scope comparators (with the exception of non-oral preparations). The model was designed to simulate the therapeutic management, the course of the condition, and complications in hypothetical cohorts of patients with OAB to estimate costs and quality-adjusted life years (QALYs) over 5 years. The population modelled was the general OAB population (that is, the licensed population) and the model had a 5-year time horizon with a 1-month cycle length and no half-cycle correction. ## Model overview In the manufacturer's model, simulated patients are either allocated mirabegron or treatment A (a single scope comparator). At the end of each monthly cycle patients can remain on the same medication, switch medication or stop all medication. The next line of therapy is considered to have cost, efficacy and safety equivalent to solifenacin succinate 5 mg. Once 2 drugs have failed, or 1 drug has failed followed by a cycle off any drug, botulinum toxin is available as a treatment option (see section 3.36). The manufacturer's model simultaneously simulated 2 key symptoms: frequency of micturition and incontinence. Each symptom was categorised into 5 severity levels, resulting in 25 possible combinations of micturition and incontinence. At the end of each month, a person's symptoms could stay the same, improve or deteriorate. The transitions between symptom severity states were determined by multinomial logistic regression using patient-level data from the SCORPIO trial and defined as a function of treatment, symptom severity in previous month, age and sex. For each symptom (micturition and incontinence), 3 transmission probability matrices were produced: i) transition between baseline and month 1, ii) transition between month 1 and month 2, and iii) transition between month 2 and month 3. For patients remaining on treatment beyond 3 months, the third matrix was applied until discontinuation. To develop transition matrices for antimuscarinic drugs not studied in the mirabegron clinical study programme, a calibration approach was adopted to determine the beta coefficients for use in the multinomial logistic regression model. The only adverse events incorporated into the model were dry mouth and constipation. The manufacturer stated that expert opinion suggested that these 2 were the most likely to occur with antimuscarinic drugs. Monthly probabilities of adverse events were obtained from SCORPIO for mirabegron and tolterodine tartrate MR 4 mg and from the MTC for the other antimuscarinic drugs. It was assumed that people who were on no treatment experienced no adverse events. Discontinuation of treatment was incorporated into the model as a combination of background persistence with OAB medication and the occurrence of adverse events. The background persistence rate for the base case was taken from a published study (Wagg 2012) and a sensitivity analysis was performed on the estimate. The discontinuation rate used in the base-case model was 72%, and was based on that observed with tolterodine tartrate MR 4 mg. The manufacturer estimated that 54.7% of patients without an adverse event would discontinue treatment by 12 months. Discontinuation due to adverse events was based on expert opinion and set at 90%. The manufacturer did not identify any literature on treatment re-initiation rates after treatment discontinuation. The manufacturer assumed that 50% of patients who had stopped treatment with mirabegron or tolterodine tartrate (in the base-case model) would restart treatment annually (5.6% per month) without immediately switching to another drug. Of these, a third would go back to their previous drug, a third would receive next line A, and a third would receive next line B. No data were available to the manufacturer on the probability of moving to botulinum toxin. The model assumed that 1% of people who had discontinued 2 therapies or discontinued 1 and gone to no treatment would receive botulinum toxin. The probability of success of botulinum toxin was taken from a previously published cost-effectiveness analysis. The model assumed that people in whom botulinum toxin was successful moved to the lowest level of symptoms for micturition and incontinence. For those in whom botulinum toxin failed, pre-botulinum toxin symptom severity levels were assumed. Utility values assigned to the different symptom severities used in the base case were derived from EQ-5D index scores, based on health-related quality-of-life data, which were collected in SCORPIO. A linear regression model was used to estimate utilities for each of the 25 combinations of symptoms, with adjustment for age, sex and country (as random effect). No interaction between micturition frequency and incontinence was assumed, despite borderline statistical significance (p=0.0566). The regression model was based on all treatment arms of SCORPIO, and predicted utility values ranging from 0.85 (for people with micturition frequency and incontinence severity levels of 1) to 0.73 (for people with micturition frequency and incontinence severity levels of 5). Patients experiencing an adverse event had an associated disutility of 0.0357 (if they remained on treatment). Additionally, a sensitivity analysis was performed estimating utilities based on OAB-q and EQ-5D collected in the SCORPIO, ARIES and CAPRICORN trials. Costs included in the model were the acquisition prices of the drugs, cost of treatment with botulinum toxin, GP visits, specialist visits and cost of incontinence pads. It was assumed that GP consultations would be 1 visit at the start and then at every treatment switch, and that specialist consultations would occur at every switch and on average 1.5 specialist consultations at the start of treatment. Incontinence pad costs were included in the model and the number of pads was determined by the level of incontinence obtained from SCORPIO. There were no costs associated with managing adverse events except specialist referral in case of a switch in treatment. The manufacturer performed deterministic and probabilistic sensitivity analyses on assumptions and parameter estimates in the model. It also performed subgroup analyses of the base case for men and women, and treatment-naive and previous treatment groups. ## Model results The manufacturer's base-case result comparing mirabegron with tolterodine tartrate MR 4 mg based on the SCORPIO trial gave an incremental cost-effectiveness ratio (ICER) of £4386 per QALY gained. The manufacturer's probabilistic ICER was £4886 per QALY gained. The results of the secondary analysis using the effectiveness results from the MTC gave ICERs of £340 per QALY gained for solifenacin succinate 10 mg versus mirabegron, £3607 per QALY gained for fesoterodine fumarate versus mirabegron, £3715 per QALY gained for tolterodine tartrate MR 4 mg versus mirabegron, £3878 per QALY gained for oxybutynin hydrochloride MR 10 mg versus mirabegron, £8881 per QALY gained for trospium chloride MR 60 mg versus mirabegron, £12,493 per QALY gained for solifenacin succinate 5 mg versus mirabegron, and £14,234 per QALY gained for oxybutynin hydrochloride 10 mg versus mirabegron. The manufacturer performed a fully incremental analysis assuming mirabegron persistence is equivalent to solifenacin succinate. Treatments are dominated when an alternative treatment is less expensive and has greater QALY gains, and a treatment is extendedly dominated if its ICER is higher than the next, more effective, alternative. When the dominated and extendedly dominated options are excluded, the incremental analysis shows that solifenacin succinate 5 mg has an ICER of £10,814 per QALY gained compared with oxybutynin hydrochloride 10 mg, and mirabegron has an ICER of £12,493 per QALY gained when compared with solifenacin succinate 5 mg. Results from the manufacturer's base-case 1-way deterministic sensitivity analyses indicated that the primary base-case results were relatively insensitive to variation in parameter estimates, the transition probabilities between symptom severities having the highest impact. Uncertainty was explored by sensitivity analyses on the model time horizon, impact of OAB-related comorbidities (depression, fractures, urinary tract infections and skin infections) and the use of disease-specific health-related quality-of-life measures. The results of the sensitivity analyses in the primary and secondary base cases were similar. The effects of 1-way sensitivity analyses on the primary base-case parameters that the model results were most sensitive to were: the transition probabilities between symptom levels for incontinence and micturition for tolterodine tartrate; incontinence severity distribution across levels at baseline; the monthly probability of having botulinum toxin injections; and the transition probability between symptom levels for micturition for mirabegron. The manufacturer submitted primary base-case ICERs (mirabegron versus tolterodine tartrate MR 4 mg) for subgroups by treatment status and by sex. The primary base-case ICERs were £3836 per QALY gained for the previously treated patient subgroup and £5315 per QALY gained for the treatment-naive subgroup. The primary base-case ICERs for the subgroups by sex were £38,708 per QALY gained for the male subgroup and £3091 per QALY gained for the female subgroup. The ICER fell to £2266 per QALY gained in the female subgroup but rose to £65,968 per QALY gained in the male subgroup if utilities derived from the OAB-q were used, rather than those from the EQ-5D. ## ERG critique of the manufacturer's model The ERG commented that it thought the manufacturer's model was well constructed, transparent and accurate. The ERG noted that the manufacturer's primary base-case cost-effectiveness analysis was generally robust. The ERG considered that the use of deterministic rather than probabilistic results was appropriate, given the high level of consistency between the deterministic and probabilistic results. The ERG noted that the manufacturer's 1-way sensitivity analyses were thorough, and that the primary base-case result was relatively robust and insensitive to individual parameter estimate changes. The ERG identified several areas of inaccuracy or uncertainty. These included: uncertainty resulting from heterogeneity associated with estimates from the manufacturer's MTC the assumption of variable other-cause discontinuation for mirabegron patients the assumption that immediate (that is, within the same cycle) discontinuation as a result of an adverse event would be equivalent to the rate of other-cause discontinuation the possibility of infinite treatment discontinuation and re-initiation, a factor of the 'lack of memory' associated with the Markov model the use of adverse event rates from SCORPIO rather than the manufacturer's safety study TAURUS the cost associated with botulinum toxin injections the use of NHS payment-by-results tariffs rather than reference costs to inform the cost of outpatient specialist visits the exclusion of correlation from the probabilistic sensitivity analysis. The ERG noted that the manufacturer considered the Pearson's correlation coefficient to assess any potential relationship between the frequency of micturition and incontinence. There was a small positive correlation (r=0.19094, p<0.0001) detected. Within the model, the manufacturer assumed that the frequency of micturition was independent of the frequency of incontinence, which the ERG considers may have compromised the accuracy of the model in the respect of the distribution of patients across different symptom levels. The ERG also noted that the correlation between these outcomes is unlikely to be affected by treatment and therefore may not result in model bias either towards or against mirabegron. The ERG accepted that dry mouth and constipation were likely to be the main drivers of adverse event-related discontinuation, and therefore considered that it was unlikely that exclusion of other adverse events would bias the model either towards or against mirabegron. The ERG noted that most of the parameters were based on clinical opinion that was estimated through open discussion, rather than generated through the use of elicitation techniques, which would lead to greater parameter uncertainty. The ERG's clinical expert indicated that a 90% discontinuation rate with adverse events would be likely to be too high, but acknowledged that the manufacturer included a sensitivity analysis that assumed a 50% adverse event-related discontinuation rate, which had a limited effect on the ICER (£4585 per QALY gained compared with the base-case ICER of £4386 per QALY gained). The ERG noted that there were issues with the disaggregated discontinuation rate (rates for adverse event-related discontinuation, and for discontinuation due to other causes). The probability of other-cause discontinuation was assumed to be treatment specific and, in the manufacturer's base cases (primary and secondary), was derived from the published literature to exclude adverse event-related discontinuation. The ERG considered the application of the adverse event-related discontinuation rate inappropriate to other-cause discontinuation rates. The ERG agreed with the manufacturer that the use of regression analysis to estimate transition probabilities in the model was appropriate, so that the potentially confounding factors of age and sex could be taken account of, and could minimise the risk of overestimating the utility benefit of mirabegron. The ERG also noted that the manufacturer stated that the interaction between the numbers of micturition and incontinence episodes was tested (Wald test: p=0.0566) and found not to be significant. The ERG commented that covariate selection was neither systematic nor rigorous and that expert clinical advice was not sought in the formulation of the linear regression models, but that in comparison with published literature the ERG considered the manufacturer's utility values generated by the regression model reasonable. The ERG also considered the selection of the covariates in the manufacturer's repeated regression model reasonable. The ERG noted that utility values from SCORPIO were comparable to those in the published literature, and considered the use of trial-based data to be appropriate. The ERG thought that the SCORPIO utility data would be likely to be biased against the more effective treatment, as would the use of EQ-5D rather than OAB-q health-related quality-of-life data. The ERG commented that the subgroup analyses indicated that the manufacturer's primary base-case ICER was robust with respect to the subgroups considered, except for the male subgroup. The ERG noted that the proportion of men recruited for the trial was lower, therefore reducing statistical power to detect differences in efficacy. The manufacturer and the ERG also noted that male patients displayed lower baseline severity levels of OAB, and experienced a higher placebo response. The ERG considered that the manufacturer's assumption of long-term use, based on the TAURUS study, was reasonable. The ERG noted that the relative difference between mirabegron and tolterodine tartrate in adverse event rates was higher in SCORPIO than in TAURUS, which was longer term. The primary base-case ICER decreased by £72 (from £4386 to £4314 per QALY gained) when using adverse event data from TAURUS rather than SCORPIO. The ERG's additional sensitivity analyses (described in 3.47 to 3.50) cumulatively increased the primary base-case ICER from £4386 to £5272 per QALY gained. However, the impact on the secondary base case had greater effects. The secondary fully incremental analysis of the ERG's cumulative sensitivity analyses included the assumptions that the persistence rate with mirabegron was 28% and the probability of re-initiating original therapy was set to 0, as well as using the adverse event rates from TAURUS and NHS reference costs for botulinum toxin injections and outpatient specialist visits. The results of the analyses were largely consistent with the manufacturer's analyses (the ICER for trospium chloride MR 60 mg compared with oxybutynin hydrochloride increased by £586, and the ICER for solifenacin succinate 5 mg compared with trospium chloride MR 60 mg increased by £899). The largest change was for the ICER of mirabegron 50 mg compared with solifenacin succinate 5 mg, which changed from £12,493 to £32,712 per QALY gained, an increase of £20,219. The impact of the sensitivity analyses on the ICERs for mirabegron versus solifenacin succinate 10 mg ranged from £573 to mirabegron being dominated by solifenacin succinate 10 mg. The ERG was unable to quantify the impact of using alternative assumptions or parameters for all the uncertainties it identified, including the difference between the manufacturer's MTC (with no statistically significant difference between mirabegron and solifenacin succinate in reducing incontinence episodes) and the ERG's MTC (in which solifenacin succinate 5 mg was statistically significantly more effective at reducing incontinence episodes than mirabegron). The ERG considered that its ICER was likely to be conservative, and that using the ERG's MTC data was likely to result in a higher ICER than £32,712 per QALY gained for mirabegron versus solifenacin succinate 5 mg. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of mirabegron, having considered evidence on the nature of overactive bladder (OAB) and the value placed on the benefits of mirabegron by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee considered the treatment pathway for OAB and where mirabegron might be positioned. It understood that Urinary incontinence in women (NICE clinical guideline 40) and Lower urinary tract symptoms in men (NICE clinical guideline 97) recommend that bladder training and lifestyle advice should be offered as first-line treatments for OAB, and that an antimuscarinic drug should be offered as a second-line treatment. The Committee heard from clinical specialists that there are currently no pharmacological treatments available other than antimuscarinic drugs, and if these failed the only options were invasive procedures (for example, botulinum toxin injections). The Committee heard from clinical specialists and patient experts that there was variation in service provision across the country both for the holistic care and support of people with OAB and incontinence, and the provision of botulinum toxin for OAB. The Committee concluded that mirabegron would be positioned in a complex treatment pathway that varied geographically but potentially offered an additional pharmacological treatment before invasive treatment options were considered. The Committee discussed the effect of OAB on people. It heard from clinical specialists and patient experts that OAB is a broad spectrum condition, and some people develop individual coping strategies (for example, toilet mapping). It noted comments from patient experts about how debilitating the condition can be, with some people finding work and normal social activities difficult, or even becoming so anxious about their bladder symptoms that they do not leave home. The Committee was aware that individual circumstances mean that the effect of OAB is different for different people. The Committee noted comments from clinical specialists that, in frail older people, OAB was associated with increased risk of falls, fractures and urinary tract infections. The Committee discussed the use of antimuscarinic drugs for OAB in clinical practice. The patient experts and clinical specialists discussed the need for pharmacological treatment of OAB within a holistic context, including bladder training, psychological support and lifestyle adjustment. They highlighted the importance of the need to explain treatments for OAB as part of a pathway, rather than pharmacological agents providing a 'quick fix'. The Committee noted that antimuscarinic drugs are known to have side effects, notably dry mouth and constipation. One patient expert explained that pharmacological agents do not necessarily lead to a satisfactory psychosocial outcome, particularly if the side effects are perceived as negative by the patient, but that if the side effects were explained as evidence that the treatment is working, they may be more acceptable and better tolerated. They also indicated that, although the average benefit of these agents seemed modest in clinical trials, some patients may gain significant benefit from them. The Committee heard from patient experts and clinical specialists that a disadvantage of immediate-release oxybutynin hydrochloride is the need for a 2 to 3-times-daily dosage, which may be inconvenient and which also left 6 hours in 24 when no effective drug may be circulating. It also heard from clinical specialists that oxybutynin hydrochloride is rarely prescribed in secondary care because most people will have tried 1 antimuscarinic before referral to a specialist. The Committee also noted that some antimuscarinic drugs may not be suitable for older people with comorbidities. The Committee concluded that an effective agent that was not an antimuscarinic could provide a valuable additional treatment option for people with OAB. The Committee discussed the low persistence rates seen with antimuscarinic drugs. The patient experts indicated that people may stop treatment because of side effects and/or lack of clinical benefit, both of which contribute to the high discontinuation rates. However, the Committee heard from a clinical expert that some people stop treatment because they learn to manage their condition, or it improves. The Committee noted that the side-effect profile of mirabegron differed from that of the antimuscarinic drugs but it was not possible to predict whether this would have an effect on persistence rates. The Committee concluded that there was no clear evidence that persistence rates with mirabegron would differ from current pharmacological treatments. # Clinical effectiveness The Committee discussed the available evidence from the manufacturer and the Evidence Review Group (ERG): the individual trial results, the manufacturer's pooled analysis of SCORPIO, ARIES and CAPRICORN, the ERG's meta-analysis comparing mirabegron with tolterodine tartrate based on results from SCORPIO, DRAGON and 178-CL-048, the manufacturer's mixed treatment comparison (MTC) and the ERG's revised MTC. The Committee noted that the safety trial TAURUS was not incorporated into the ERG's meta-analysis comparing mirabegron with tolterodine tartrate, and that there was a paucity of evidence comparing mirabegron directly with the NICE final scope comparators other than tolterodine tartrate modified release (MR). The Committee concluded that the evidence for a comparison of mirabegron with tolterodine tartrate using direct trial data was more robust than that from the 2 MTCs. The Committee considered the generalisability of the trials to the UK population. It noted that there were no biologically plausible reasons for differences in OAB between different ethnic groups, and that SCORPIO and CAPRICORN were largely conducted in Europe, and ARIES was conducted in North America. There was some disagreement among the patient experts and clinical specialists on the average age of the population with OAB in the UK. The patient experts thought that there was a high incidence in people in their mid-40s and older, whereas the clinical specialists thought that the prevalence was higher in older populations, particularly above the age of 60. The Committee noted the differences of opinion, but concluded that this may reflect the differing demographics of those who accessed various services, such as self-referral continence services compared with secondary care. The Committee concluded that the trials were generalisable to the UK population. The Committee discussed which outcomes are important and relevant when treating OAB. The patient experts and clinical specialists discussed the range of attitudes of people towards their OAB, from it being a mild inconvenience to very debilitating. The patient experts and clinical specialists also commented that the definition of satisfactory treatment outcomes was broad and varied from person to person, with some people feeling that being completely 'dry' was the only important outcome, whereas others felt that being in control of the symptoms or having fewer micturition episodes was a satisfactory response to treatment. The Committee considered the primary and secondary outcomes reported in the trials. The Committee noted that in the draft update to NICE clinical guideline 40, only wet OAB was addressed, and treatment efficacy was assessed using a binary continent/incontinent outcome. However, this guideline was still in development and could be subject to change. The Committee noted that frequency of micturition and incontinence episodes were used as the primary outcomes in this appraisal. It agreed that these outcomes captured the main benefits for people with OAB, and included the benefits both for those who had incontinence and those who did not. The Committee concluded that frequency of micturitions and incontinence episodes were the most relevant outcomes for this appraisal. The Committee discussed the results for micturition frequency and incontinence for mirabegron. It noted that there were modest changes in frequency compared with placebo (see section 3.11). It noted the results of the manufacturer's pooled analysis showing a statistically significant improvement in mean difference from baseline in incontinence and frequency of micturition compared with placebo. It noted comments from a patient expert that the people on placebo could have experienced benefits because they changed their lifestyle as part of the treatment, which they considered showed that medication was more effective when embedded in a holistic programme. The Committee concluded that mirabegron was clinically effective compared with placebo. The Committee explored the evidence of mirabegron compared with tolterodine tartrate. The manufacturer explained that it did not provide a direct analysis of mirabegron against tolterodine tartrate despite it being a comparator arm in SCORPIO because tolterodine tartrate was designated an active control and the trial was not powered to make such comparisons. The Committee was not convinced that this was a good reason for not presenting a comparison, and noted that the manufacturer provided an indirect analysis for mirabegron compared with tolterodine tartrate through its MTC (see section 3.18). Additionally, it was aware that the ERG had performed a meta-analysis of mirabegron compared with tolterodine tartrate, using data from the 3 trials that had tolterodine tartrate as an active comparator (SCORPIO, DRAGON and 178-CL-048) (see section 3.25). The Committee noted that the results of the ERG's meta-analysis showed that mirabegron was statistically significantly more effective at reducing frequency of micturition and reducing incontinence than tolterodine tartrate. The Committee also noted that in TAURUS, a safety trial, there were no statistically significant differences between mirabegron and tolterodine tartrate for number of micturition episodes per day, but that tolterodine tartrate was statistically significantly more effective at reducing incontinence. The Committee noted the ERG's comments that the participants in TAURUS were recruited from SCORPIO and ARIES and so may be a selected rather than representative OAB population. On balance, despite some concerns about the data from TAURUS, the Committee concluded that the evidence for a comparison between mirabegron and tolterodine tartrate was satisfactory, and that mirabegron was likely to be as clinically effective as tolterodine tartrate. The Committee discussed the manufacturer's MTC comparing mirabegron with the other drugs listed in the scope. The Committee noted that, in the manufacturer's MTC, which included 40 trials, there were very small gains or differences in the primary clinical outcomes for all the agents (see section 3.18). The Committee noted the ERG's comments that the manufacturer's MTC contained heterogeneous trials in terms of trial quality and populations. The Committee considered the ERG's MTC using fewer, more homogeneous trials. The Committee noted the ERG's MTC produced similar results to the manufacturer's MTC with the exception of solifenacin succinate 5 mg and 10 mg, which were statistically significantly more effective at reducing incontinence episodes than mirabegron. The ERG, like the manufacturer, generally found very small differences in effect between the comparators. The Committee heard different opinions from the clinical specialists as to whether, in clinical practice, the efficacy of all antimuscarinic drugs was similar to that of tolterodine tartrate. One clinical specialist indicated that solifenacin succinate was regarded as being more effective than other antimuscarinic drugs by some clinicians, particularly tolterodine tartrate. Another clinical specialist disagreed, indicating that solifenacin succinate may be perceived to be more effective, but this is because it is frequently used at a higher dose than is available for the other antimuscarinic agents. The Committee concluded that the MTCs indicated that mirabegron, like antimuscarinic drugs, offers modest improvements compared with placebo, but it was more uncertain whether it had equivalent efficacy to all antimuscarinics. The Committee was aware that the rate of adverse events was no different between the mirabegron and tolterodine tartrate 4 mg arms in TAURUS (see section 3.16), but that the nature of the adverse events experienced differed. In TAURUS and SCORPIO, dry mouth was more common in the tolterodine tartrate arm than in the mirabegron arm, in which the incidence was similar to that in the placebo arm. The Committee understood from the patient experts that dry mouth was the most bothersome side effect of antimuscarinic drugs and contributed to discontinuation with treatment. The Committee acknowledged that the rate of dry mouth was statistically significantly lower for mirabegron than for tolterodine tartrate, and the other antimuscarinic drugs (2.8% versus 8.6% in TAURUS, and for all antimuscarinic drugs in the MTC ). The Committee concluded that the different side effects of mirabegron compared with antimuscarinic drugs could be of benefit for those who cannot tolerate the specific side effects of antimuscarinic drugs, particularly dry mouth. The Committee concluded that, for people who cannot tolerate antimuscarinic drugs, mirabegron may be a suitable alternative treatment. The Committee discussed whether there were any differences in the clinical effectiveness of mirabegron in men and women. It noted that sex was a pre-specified subgroup in the pooled analysis of the SCORPIO, ARIES and CAPRICORN trials. Additionally, it noted that, in the manufacturer's pooled analysis, mirabegron 50 mg was numerically more effective in women than men for micturition frequency and incontinence. However, the Committee noted that the trials contained a minority (approximately 30%) of male participants. Additionally, it was aware that the rate of incontinence was lower in male than in female trial participants, so the number of men with incontinence symptoms was low. The Committee also heard from 1 clinical specialist that, in older men, incontinence may be related to bladder outflow obstruction rather than OAB and that bladder outflow obstruction may have been present in some of the male participants in the trials. The clinical specialists explained that incontinence secondary to bladder outflow obstruction would not be expected to respond to either antimuscarinic drugs or mirabegron, and could therefore confound the results. The clinical specialists indicated that they knew of no biologically plausible reasons why mirabegron would be less effective in men than in women. The Committee concluded that the lower efficacy in men demonstrated in the trials might be explained by the trial design and recruitment, and it did not pursue this further. The Committee discussed the subgroup analyses comparing the clinical effectiveness of mirabegron in treatment-naive and pre-treated populations. The Committee noted there were no statistically significant differences between the effects of mirabegron in these 2 subgroups, and concluded there was no pharmacological reason why the effects of mirabegron would differ between these groups. In addition, the Committee heard from the manufacturer that trials using mirabegron in combination with antimuscarinic drugs were ongoing because it is thought that the different mechanisms of action may enhance the effects of the individual drugs. The Committee considered the need for alternatives to current treatments for OAB. It heard from clinical specialists that, for those who had contraindications to antimuscarinic drugs, had not gained clinical benefit, or who had unacceptable side effects, there was an unmet need for alternative pharmacological treatments. This could avoid invasive treatments such as botulinum toxin, which may have significant side effects (for example, urinary retention needing catheterisation). The Committee heard that, in line with existing NICE clinical guidelines, antimuscarinic drugs are routinely used as the first pharmacological treatment for OAB, and there is long-term evidence that people benefit from them. There is also considerable clinical experience in the use of antimuscarinic drugs and the management of their side effects. However, the Committee concluded that there was a need for pharmacological alternatives to antimuscarinic drugs for people in whom these are contraindicated, or for whom they are ineffective or associated with unacceptable side effects. # Cost effectiveness The Committee considered the available cost-effectiveness evidence. It discussed the manufacturer's base-case incremental cost-effectiveness ratio ICER of £4400 per quality-adjusted life years (QALY) gained for mirabegron 50 mg compared with tolterodine tartrate MR 4 mg. The Committee noted the ERG's comment that the manufacturer's model was accurate and transparent but also its concerns related to some of the costs in the model and assumptions of discontinuation (see section 3.52). The Committee noted the small QALY gains seen in both the manufacturer's and ERG's analyses (see section 3.41). The Committee acknowledged that the ERG's cumulative sensitivity analyses resulted in a similar ICER to the manufacturer's (£4400 per QALY gained in the manufacturer's base case, and £5272 per QALY gained in the ERG's cumulative sensitivity analyses). The Committee concluded that the base-case analyses were similar for the manufacturer and the ERG, and were likely to be robust. The Committee concluded that mirabegron was therefore likely to be cost effective when compared with tolterodine tartrate MR 4 mg. The Committee explored the results from the manufacturer's secondary base case and incremental analysis comparing mirabegron with the other antimuscarinic drugs defined in the scope. It observed that this analysis relied on the effectiveness results from the manufacturer's MTC and that, for technical reasons, it had not been possible for the results from the ERG's MTC to be incorporated into the ERG's economic analyses, leading to some uncertainty about the results. The Committee noted that most of the ERG's sensitivity analyses had a small effect on the resulting ICERs for mirabegron compared with comparators, except for solifenacin succinate 5 mg. In this case, when the assumption of persistence of treatment was set to 28% (as opposed to equal to that of the comparator, 35%) the ICER compared with solifenacin succinate 5 mg rose from £12,500 to £32,700 per QALY gained. The Committee acknowledged there were no data on persistence with mirabegron other than from the clinical trials, and that data from the trials were unlikely to be representative of the persistence rates in clinical practice because, in the trials, patients were actively encouraged to continue taking the drug for the entire trial duration. The Committee concluded that the ERG's analysis using a lower persistence rate for mirabegron than solifenacin succinate resulted in mirabegron being cost ineffective compared with solifenacin succinate 5 mg, and that, if the ERG's MTC had been incorporated into the model, the ICER could have been higher. However, because of the small differences in QALY gains, and the lack of evidence on persistence rates in practice for mirabegron, this was subject to significant uncertainty. The Committee discussed the incorporation of adverse events in the economic analyses. It noted that the only adverse events incorporated into the modelling were dry mouth and constipation, and that dry mouth was a particular side effect of antimuscarinic drugs (see section 3.30). The Committee expressed concern that no side effects that may be more common with mirabegron were included in the model. It questioned whether this might be favourable to mirabegron because it took no account of the similar rate of withdrawal due to adverse events in the mirabegron and tolterodine tartrate arms of TAURUS (5.9% for mirabegron and 5.7% for tolterodine tartrate). As a result, the ICER for mirabegron compared with tolterodine tartrate could be underestimated. The Committee concluded that the specific adverse events incorporated in the model were likely to favour mirabegron over all the antimuscarinic drugs. The Committee discussed the most plausible ICERs for mirabegron. It remained concerned about the fact that it had not been possible to assess the impact of incorporating the ERG's MTC into the economic analysis, which might have given different ICERs. However, the Committee noted that it had more robust evidence comparing mirabegron with tolterodine tartrate 4 mg and was satisfied that it was no less clinically effective than tolterodine tartrate 4 mg. The Committee questioned whether tolterodine tartrate was likely to be representative of the effectiveness of antimuscarinic drugs as a class, or whether the results from the manufacturer's MTC against the other agents were robust. The Committee noted that the ICERs were relatively unstable, and varied with small fluctuations in the QALY calculations. However, the differences between the QALYs calculated were consistently small in both the manufacturer's and ERG's analyses. The Committee accepted that mirabegron has a different mechanism of action than that of antimuscarinic drugs. It also has a different side-effect profile, but the same rate of discontinuation due to adverse events as tolterodine tartrate. It took into consideration that the calculated ICERs were based on small and uncertain differences of clinical efficacy between mirabegron and a range of available antimuscarinic drugs, which may or may not have similar efficacy as a class. Therefore the cost effectiveness compared with antimuscarinic drugs as a class was uncertain. However, the Committee concluded that mirabegron was likely to be a cost-effective treatment for people with OAB for whom antimuscarinic drugs are contraindicated, not effective, or produce unacceptable side effects. The Committee considered a comment the manufacturer submitted in response to the appraisal consultation document, in which the manufacturer requested that the Committee consider how the guidance should be interpreted for more vulnerable groups of patients, for example, older patients or those who already have a high anticholinergic burden due to other prescribed medications. The Committee noted that withdrawal rates due to adverse events did not differ in the mirabegron and tolterodine tartrate arms of the TAURUS trial and the manufacturer did not provide additional evidence of mirabegron having a lower rate of adverse events in older patients. The Committee concluded that there was no evidence to support a different recommendation for older people. With respect to people who had a high anticholinergic burden from other medications, the Committee concluded that normal prescribing practice would involve an assessment of existing medications and potential drug interactions, and it was not necessary to specify this in the guidance. The Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The only potential equality issue identified was whether incontinence disproportionately affects people on a low income, due to the need to purchase incontinence pads and other auxiliary goods. However, the Committee noted that this was not a group protected under equalities legislation, and that the use of mirabegron would be unlikely to affect this group disproportionately. The Committee discussed whether mirabegron should be considered an innovative technology, or if there were any significant and substantial health benefits that were not included in the economic model. The Committee considered the potentially innovative nature of mirabegron in that it targeted different receptors from those targeted by antimuscarinic drugs. The Committee accepted mirabegron's different and innovative mechanism of action, but concluded that all the benefits would be adequately captured in the QALY calculation. # Summary of Appraisal Committee's key conclusions TA290 Appraisal title: Mirabegron for treating symptoms of overactive bladder Section Key conclusion Mirabegron is recommended as an option for treating the symptoms of overactive bladder only for people in whom antimuscarinic drugs are contraindicated or clinically ineffective, or have unacceptable side effects. People currently receiving mirabegron that is not recommended for them in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop. The Committee concluded that the clinical effectiveness of mirabegron is similar to that of antimuscarinic drugs and that it appears to have a different side effect profile. However, the differences in costs and effects between drugs are small, and it is therefore difficult to make a reliable estimate of the ICER. After learning about the treatment pathway and hearing from the clinical specialists, the Committee concluded that it was reasonable to formulate the recommendations as they have done. Current practice Clinical need of patients, including the availability of alternative treatments OAB has a complex treatment pathway. NICE clinical guideline 40, Urinary incontinence in women, and NICE clinical guideline 97, Lower urinary tract symptoms in men, recommend that bladder training and lifestyle advice should be offered as first-line treatments for OAB, followed by an antimuscarinic drug as second-line treatment. There are no other drugs currently available for OAB and, after failure of antimuscarinic drugs, only invasive treatments (such as botulinum toxin) are available. The effect of OAB on patients' lives varies from person to person, and can negatively influence work and social activities. It noted that the condition can be debilitating, with some people finding work and normal social activities difficult, or even becoming so anxious about their bladder symptoms that they do not leave home. The Committee noted comments from clinical specialists that, in frail older people, OAB was associated with increased risk of falls, fractures and urinary tract infections. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee concluded that an effective agent that was not an antimuscarinic could provide a valuable additional treatment option for people with OAB. The Committee was aware that the nature of adverse events experienced with mirabegron differed from those found with antimuscarinic drugs. The Committee considered the potentially innovative nature of mirabegron in that it targeted different receptors to antimuscarinic drugs. The Committee accepted mirabegron's different and innovative mechanism of action, but concluded all the benefits would be adequately captured in the QALY calculation. What is the position of the treatment in the pathway of care for the condition? The Committee concluded that mirabegron would be positioned within a complex treatment pathway that varied geographically but potentially offered an additional pharmacological treatment before invasive treatment options were considered. Adverse reactions The Committee was aware that the rate of adverse events was no different between the mirabegron and tolterodine tartrate 4 mg arms in TAURUS, but that the nature of the adverse events experienced differed. The Committee concluded that the different side effects of mirabegron compared with antimuscarinic drugs could be of benefit for those who cannot tolerate the specific side effects of antimuscarinic drugs, particularly dry mouth. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee discussed the available evidence from the manufacturer and the ERG: the individual trial results, the manufacturer's pooled analysis of SCORPIO, ARIES and CAPRICORN, the ERG's meta-analysis comparing mirabegron with tolterodine tartrate based on results from SCORPIO, DRAGON and 178-CL-048, the manufacturer's MTC and the ERG's revised MTC. The Committee concluded that the evidence for a comparison of mirabegron with tolterodine tartrate using direct trial data was more robust than that from the 2 MTCs. Relevance to general clinical practice in the NHS The Committee noted that there were no biologically plausible reasons for differences in OAB between different ethnic groups, and that the age range was likely to be in line with the demographics of the population with OAB in the UK. The Committee concluded that the trials were generalisable to the UK population. Uncertainties generated by the evidence The Committee was aware that the participants in TAURUS (long-term safety study) were recruited from SCORPIO and ARIES and so may be a selected rather than representative OAB population. The Committee noted the ERG's comments that the manufacturer's MTC contained heterogeneous trials in terms of trial quality and populations. The Committee acknowledged there were no real-life data on persistence with mirabegron, and that data from the trials were unlikely to be representative of the persistence rates in clinical practice because, in the trials, patients were actively encouraged to continue taking the drug for the entire trial duration. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee considered treatment group by age, sex and by treatment status (pre-treated or treatment-naive), but concluded there was no evidence for differential clinical effectiveness in these subgroups. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that mirabegron was clinically effective compared with placebo. The Committee concluded that the MTCs indicated that mirabegron, like antimuscarinic drugs, offers modest improvements compared with placebo, but it was more uncertain whether it had equivalent efficacy to all antimuscarinics. Evidence for cost effectiveness Availability and nature of evidence The manufacturer's cost-effectiveness evidence consisted of a systematic literature review and a de novo Markov model. The Committee noted the ERG's comment that the manufacturer's model was accurate and transparent. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee noted the ERG's concerns related to some of the costs in the model and assumptions of discontinuation. The Committee acknowledged there were no real-life data on persistence with mirabegron, and that data from the trials were unlikely to be representative of the persistence rates in clinical practice because in the trials, patients were actively encouraged to continue taking the drug for the entire trial duration. It observed that this analysis relied on the effectiveness results from the manufacturer's MTC and that, for technical reasons, it had not been possible for the results from the ERG's MTC to be incorporated into the ERG's economic analyses. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The manufacturer used utility values derived from EQ-5D scores collected in SCORPIO for its primary base case. The manufacturer performed sensitivity analyses based on OAB-q and EQ-5D scores collected in SCORPIO, ARIES and CAPRICORN. The ERG thought that SCORPIO utility data would be likely to be biased against the more effective treatment, as would the use of EQ-5D rather than OAB-q data. No potential health-related benefits have been identified that were not included in the model. Are there specific groups of people for whom the technology is particularly cost effective? The Committee considered treatment group by age, sex and by treatment status (pre-treated or treatment-naive), but concluded there was no evidence for differential clinical effectiveness and therefore no evidence for differential cost effectiveness in these subgroups. What are the key drivers of cost effectiveness? The key driver of cost effectiveness was the assumption around the persistence rates. Most likely cost-effectiveness estimate (given as an ICER) The Committee concluded that, because the base-case ICER for mirabegron against tolterodine tartrate 4 mg was £5270 per QALY gained in the ERG's sensitivity analysis, changes to the modelling of adverse events was unlikely to result in an ICER that made mirabegron cost ineffective against tolterodine tartrate 4 mg. The Committee concluded that the effectiveness of mirabegron is similar to that of antimuscarinic drugs and it appears to have a different side-effect profile. However, there is uncertainty about the differences in costs and effects between drugs and the ICERs are therefore unstable. Additional factors taken into account Patient access schemes (PPRS) None End-of-life considerations None Equalities considerations and social value judgements A potential equality issue identified was whether incontinence disproportionately affects people on a low income, due to the need to purchase incontinence pads and other auxiliary goods. However, the Committee noted that this was not a group protected under equalities legislation, and that the use of mirabegron would be unlikely to affect this group disproportionately. # Related NICE guidance # Published Lower urinary tract symptoms in men. NICE clinical guideline 97 (2010). Percutaneous posterior tibial nerve stimulation for overactive bladder syndrome. NICE interventional procedure guidance 362 (2010). Urinary incontinence in women. NICE clinical guideline 40 (2006). Sacral nerve stimulation for urge incontinence and urgency-frequency. NICE interventional procedure guidance 64 (2004). # Under development NICE is developing the following guidance (details available from www.nice.org.uk): Urinary incontinence in women. NICE clinical guideline. Publication expected September 2013.# Review of guidance The guidance on this technology will be considered for review in June 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew Dillon Chief ExecutiveJune 2013# Changes after publication January 2014: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It has been incorporated into the NICE pathway on lower urinary tract symptoms in men along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0198-2	{'Guidance': 'Mirabegron is recommended as an option for treating the symptoms of overactive bladder only for people in whom antimuscarinic drugs are contraindicated or clinically ineffective, or have unacceptable side effects.\n\nPeople currently receiving mirabegron that is not recommended for them in 1.1\xa0should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology ': "Mirabegron (Betmiga, Astellas Pharma) has a marketing authorisation in the UK for the 'symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in patients with overactive bladder (OAB)'. It is a beta-3-adrenoceptor agonist, which activates beta-3-adrenoceptors causing the bladder to relax, which helps it to fill and also to store urine. It is administered orally. Mirabegron will be available as 25\xa0mg and 50\xa0mg tablets, with the recommended dose being 50\xa0mg daily, and 25\xa0mg if there is renal or hepatic impairment.\n\nThe summary of product characteristics lists the following adverse reactions for mirabegron: urinary tract infection, tachycardia, vaginal infection, cystitis, palpitation, atrial fibrillation, dyspepsia, gastritis, urticaria, rash, rash macular, rash popular, pruritus, joint swelling, vulvovaginal pruritis, increased blood pressure, increased gamma-glutamyl transpeptidase, increased aspartate aminotransferase, increased alanine aminotransferase, eyelid oedema, lip oedema, leukocytoclastic vasculitis and purpura (rash). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe list price indicated in the manufacturer's submission is £0.97\xa0(excluding VAT) per 50\xa0mg or 25\xa0mg tablet, or an average cost of £27.06\xa0per 28\xa0days (assuming 1\xa0tablet per day). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of mirabegron and a review of this submission by the Evidence Review Group (ERG; section 9).\n\n# Clinical effectiveness\n\nThe manufacturer conducted 2\xa0systematic reviews to identify published randomised and non-randomised controlled trial evidence on the efficacy and safety of mirabegron in adults with symptoms of overactive bladder (OAB). The clinical evidence submitted by the manufacturer consisted of 3\xa0trials identified by the manufacturer as pivotal (SCORPIO, ARIES and CAPRICORN) and 4\xa0supporting trials (DRAGON, 178-CL-045\xa0and 178-CL-048, and TAURUS, which was a safety study). Additionally, a mixed-treatment comparison was performed of mirabegron against placebo, tolterodine tartrate, oxybutynin hydrochloride, solifenacin succinate, fesoterodine fumarate and trospium chloride.\n\nSCORPIO, ARIES and CAPRICORN were randomised controlled trials that compared mirabegron (at varying doses) with placebo and tolterodine tartrate modified release (MR) 4\xa0mg (as an active control in SCORPIO only). The supporting studies included TAURUS, a long-term safety study that compared mirabegron with tolterodine tartrate MR 4\xa0mg (no placebo control), which examined adverse events over 52\xa0weeks and recruited patients mainly from SCORPIO and ARIES; DRAGON, a randomised controlled trial of 12\xa0weeks' duration comparing mirabegron with placebo and tolterodine tartrate MR 4\xa0mg; and 2\xa0randomised controlled trials (178-CL-045\xa0and 178-CL-048) performed in Japan. Trial 178-CL-045\xa0compared mirabegron with placebo and 178-CL-048\xa0compared mirabegron with tolterodine tartrate MR 4\xa0mg and placebo. The manufacturer presented individual results for SCORPIO, ARIES and CAPRICORN and a pooled analysis of the 3\xa0trials with multiplicity adjustments made during the analysis of all outcomes.\n\nSCORPIO was a 12-week trial comparing mirabegron (50\xa0mg and 100\xa0mg once daily) and placebo, with tolterodine tartrate MR 4\xa0mg as an active control in adults with symptoms of OAB. The trial population was 72% female, and 63% of all trial participants were under 65\xa0years old. The trial took place in 189\xa0sites in 27\xa0EU (including the UK) and non-EU countries (in Europe, as well as Russia and Australia). There were 1987\xa0participants, with patients randomised to mirabegron 50\xa0mg (n=497), mirabegron 100\xa0mg (n=498), tolterodine tartrate MR 4\xa0mg (n=495), and placebo (n=497) in a 1:1:1:1\xa0ratio. Assessments were conducted at weeks\xa04, 8\xa0and 12.\n\nARIES was a 12-week trial that compared mirabegron (50\xa0mg and 100\xa0mg) with placebo in adults with symptoms of OAB. The trial had 74.8% female participants, and 60.3% of all trial participants were under 65\xa0years old. The trial was conducted in 132\xa0sites in the USA and Canada. There were 1329\xa0participants, with patients randomised to mirabegron 50\xa0mg (n=442), mirabegron 100\xa0mg (n=433) and placebo control (n=454) in a 1:1:1\xa0ratio. Assessments were conducted at weeks\xa04, 8\xa0and 12.\n\nCAPRICORN was a 12-week trial that compared mirabegron (25\xa0mg and 50\xa0mg) with placebo in adults with symptoms of OAB. The trial had 68.5% female participants, and 62.8% of all trial participants were under 65\xa0years old. The trial took place in 151\xa0sites in Europe (not including the UK) and North America. There were 1306\xa0participants, with patients randomised to mirabegron 25\xa0mg (n=433), mirabegron 50\xa0mg (n=440), and placebo (n=433) in a 1:1:1\xa0ratio. Assessments were conducted at weeks\xa04, 8\xa0and 12.\n\nTAURUS was a safety trial that compared mirabegron (50\xa0mg and 100\xa0mg) with tolterodine tartrate MR 4\xa0mg as an active control in adults with symptoms of OAB. The trial duration was 2\xa0weeks in a single-blind placebo run-in, followed by 12\xa0months on randomised treatment. The trial took place in 306\xa0sites globally, including the UK. There were 2452\xa0participants, with patients randomised to mirabegron 50\xa0mg (n=815), mirabegron 100\xa0mg (n=824) and tolterodine tartrate MR 4\xa0mg (n=813) in a 1:1:1\xa0ratio. Assessments were conducted at screening, baseline and in months\xa01, 3, 6, 9\xa0and 12.\n\nDRAGON was a 12‑week randomised controlled trial that compared mirabegron (25\xa0mg, 50\xa0mg, 100\xa0mg and 200\xa0mg) with placebo, and with tolterodine tartrate MR 4\xa0mg as an active control, in adults with symptoms of OAB, in 14\xa0European countries, including the UK (n=928). The 178-CL-045\xa0randomised controlled trial carried out in Japan compared 25\xa0mg, 50\xa0mg and 100\xa0mg mirabegron with placebo in adults with symptoms of OAB over 12\xa0weeks (n=842). The 178-CL-048\xa0randomised trial carried out in Japan compared 50\xa0mg mirabegron with placebo or tolterodine tartrate MR 4\xa0mg as an active control in adults with symptoms of OAB over 12\xa0weeks (n=1139).\n\nThe 2\xa0primary outcomes of SCORPIO, ARIES and CAPRICORN were change from baseline to end point for mean number of micturitions per 24\xa0hours and mean number of incontinence episodes per 24\xa0hours. Secondary outcomes were mean volume voided per micturition; mean number of urgency episodes (grade\xa03\xa0or 4) per 24\xa0hours (grade\xa03\xa0is severe urgency [I could not postpone voiding, but had to rush to the toilet in order not to wet myself] and grade 4\xa0is urge incontinence [I leaked before arriving at the toilet]); mean level of urgency (associated urgency according to the 5-point categorical scale Patient Perception of Intensity of Urgency Scale); mean number of urge incontinence episodes (involuntary leakage accompanied by or immediately preceded by urgency) per 24\xa0hours; and mean number of nocturia episodes per 24\xa0hours.\n\nFor the 3\xa0trials (SCORPIO, ARIES and CAPRICORN), results were reported for several populations. The primary population used in the submission was the full analysis set (patients who had at least 1\xa0post-dose assessment). Other analyses included the intention-to-treat population (all patients randomised to receive treatment), the modified intention-to-treat set for health-related quality of life (patients who were randomised, received at least 1\xa0dose of double-blind study medication and completed the EQ-5D questionnaire at baseline and at least once post-baseline, but excluding any patients who presented serious deviations from the protocol or for whom the EQ-5D questionnaire data was not available at 12\xa0weeks), the incontinence full analysis set (patients who had at least 1\xa0post-dose assessment, but only those with incontinence; these data were used for incontinence outcomes), and the safety analysis set (all randomised patients who took 1\xa0or more doses of double-blind study drug). The doses of mirabegron used in the trials ranged from 25\xa0mg to 100\xa0mg. The manufacturer focused its submission on mirabegron 50\xa0mg as the anticipated licensed dose.\n\n## Comparisons with placebo\n\nUrinary frequency was measured as change from baseline in mean number of micturitions in 24\xa0hours (measured by micturition diary). The results from the full set analyses of SCORPIO, ARIES and CAPRICORN all indicated statistically significant improvements in change from baseline to week\xa012\xa0in the mean number of micturitions in 24\xa0hours in the mirabegron groups compared with placebo (SCORPIO mean difference −0.60, 95% confidence interval [CI] −0.90\xa0to −0.29; ARIES mean difference −0.61, 95% CI −0.98\xa0to −0.24; CAPRICORN mean difference −0.42, 95% CI −0.76\xa0to −0.08). In the DRAGON and 178-CL-048\xa0trials there was no statistically significant difference between mirabegron and tolterodine tartrate. In the 178-CL-045\xa0trial significant improvements were seen with mirabegron compared with placebo (mean difference −0.74, 95% CI −1.12\xa0to −0.36). The results of the manufacturer's pooled analysis of 3\xa0trials (ARIES, CAPRICORN and SCORPIO) showed a statistically significant difference between mirabegron 50\xa0mg and placebo (adjusted mean difference −0.55, 95% CI −0.75\xa0to −0.36, p<0.001).\n\nFrequency of incontinence was measured as the mean number of incontinence episodes per 24\xa0hours and assessed in the manufacturer's submission by the full analysis set – incontinence population. The results from the SCORPIO, ARIES and CAPRICORN trials all indicated statistically significant improvements in change from baseline to week\xa012\xa0in mean number of incontinence episodes per 24\xa0hours versus placebo (SCORPIO mean difference −0.41, 95% CI −0.72\xa0to −0.09; ARIES mean difference −0.34, 95% CI −0.66\xa0to −0.03; CAPRICORN mean difference −0.42, 95% CI −0.76\xa0to −0.08). In the DRAGON and 178-CL-048\xa0trials there was no statistically significant difference between mirabegron and tolterodine tartrate. In the 178-CL-045\xa0trial significant improvements were seen with mirabegron compared with placebo (mean difference −0.40, 95% CI −0.67\xa0to −0.13). The results of the manufacturer's pooled analysis for the 3\xa0trials showed a statistically significant difference between mirabegron 50\xa0mg and placebo (mean difference −0.40, 95% CI −0.58\xa0to −0.21\xa0p<0.001).\n\nThe manufacturer presented results for the secondary outcomes reported in the trials. These were mean volume voided per micturition, frequency of urge urinary incontinence, mean level of urgency, the number of urgency episodes (grade 3\xa0or 4) per 24\xa0hours, and nocturia episodes per 24\xa0hours.\n\n## Subgroup analyses\n\nThe manufacturer performed pooled subgroup analyses (from SCORPIO, ARIES and CAPRICORN) for men versus women, for the 2\xa0primary outcomes. Mirabegron 50\xa0mg was numerically more effective in the female subgroup than the male subgroup for the pooled trial data for the change in the number of incontinence episodes and micturitions per 24\xa0hours between baseline and final visit. The adjusted mean difference versus placebo for incontinence episodes per 24\xa0hours (incontinence full analysis set) in the male mirabegron 50\xa0mg treatment group was −0.07\xa0(95% CI −0.50\xa0to 0.36), which was not statistically significant. The change in the adjusted mean difference versus placebo for incontinence episodes per 24\xa0hours (incontinence full analysis set) in the female mirabegron 50\xa0mg treatment group was −0.47\xa0(95% CI −0.67\xa0to −0.26), which was statistically significant. The adjusted mean difference versus placebo in the mean number of micturitions per 24\xa0hours was −0.37\xa0(95% CI −0.74\xa0to −0.01) in the male mirabegron 50\xa0mg treatment group, which was statistically significant. The adjusted mean difference versus placebo in the mean number of micturitions per 24\xa0hours in the female mirabegron 50\xa0mg treatment group was −0.62\xa0(95% CI −0.85\xa0to −0.39), which was statistically significant. Tests for treatment by sex interactions were non-significant for both outcomes (p value=0.22\xa0for the change in the mean number of incontinence episodes per 24\xa0hours; p=0.16\xa0for change in the mean number of micturitions per 24\xa0hours) indicating that there was no differential treatment effect between men and women.\n\nThe manufacturer also performed a pooled subgroup analysis using data from SCORPIO, CAPRICORN and ARIES comparing previously treated and treatment-naive groups. Mirabegron 50\xa0mg was effective in both populations for the 2\xa0primary outcomes. The change in the mean number of incontinence episodes per 24\xa0hours between baseline and final visit (incontinence full analysis set) in the previously treated mirabegron 50\xa0mg treatment group was −1.49\xa0(95% CI −1.66\xa0to −1.32) and the adjusted mean difference versus placebo was −0.57\xa0(95% CI −0.81\xa0to −0.33). The change in the mean number of incontinence episodes per 24\xa0hours between baseline and final visit (incontinence full analysis set) in the treatment-naive mirabegron 50\xa0mg treatment group was −1.50\xa0(95% CI −1.71\xa0to −1.29) and the adjusted mean difference versus placebo was −0.15\xa0(95% CI −0.44\xa0to 0.14). The change in the mean number of micturitions per 24\xa0hours between baseline and final visit (full analysis set) in the previously treated mirabegron 50\xa0mg treatment group was −1.67\xa0(95% CI −1.86\xa0to −1.48) and the adjusted mean difference versus placebo was −0.74\xa0(95% CI −1.01\xa0to −0.47). The change in the mean number of micturitions per 24\xa0hours between baseline and final visit (full analysis set) in the treatment-naive mirabegron 50\xa0mg treatment group was −1.84\xa0(95% CI −2.04\xa0to −1.64) and the adjusted mean difference versus placebo was −0.33\xa0(95% CI −0.62\xa0to −0.05). Mirabegron 50\xa0mg was effective in reducing the mean number of incontinence episodes and micturitions per 24\xa0hours from baseline to final visit for both previously treated and treatment-naive patients. Tests for interaction indicated no treatment effect for either outcome (p=0.095\xa0for the change in the mean number of incontinence episodes and p=0.10\xa0for the mean number of micturitions).\n\n## Safety outcomes\n\nData on adverse events presented in the manufacturer's submission were largely derived from the 52-week study TAURUS (mirabegron versus tolterodine tartrate). Additionally, information was available from the SCORPIO, ARIES and CAPRICORN trials. Treatment-emergent adverse events were adverse events that occurred after treatment, while treatment-related adverse events were directly linked to treatment, although the criteria used by the manufacturer for establishing a direct link with treatment were unclear. The incidence of treatment-related adverse events was similar in the 2\xa0groups, with 26.2% in the mirabegron 50\xa0mg group and 27.6% in the tolterodine tartrate group in TAURUS. In TAURUS the overall incidence of treatment-emergent adverse events was similar across the mirabegron 50\xa0mg (59.7%) and tolterodine tartrate (62.6%) groups. Most treatment-emergent adverse events were mild or moderate in all treatment groups. The overall incidence of treatment-emergent severe adverse events was 5.2% in the mirabegron 50\xa0mg group and 5.4% in the tolterodine tartrate group in TAURUS (safety analysis set). For treatment-emergent adverse events leading to permanent discontinuation of the study drug the rates were 5.9% in the mirabegron 50\xa0mg group and 5.7% in the tolterodine tartrate group in TAURUS (safety analysis set). In SCORPIO, ARIES and CAPRICORN the incidence of treatment-emergent adverse events was similar across all the treatment groups (safety analysis set population).\n\nThe adverse events that were designated of interest because of their association with antimuscarinic drugs were dry mouth and constipation. The rates of constipation by treatment group for TAURUS were 2.8% and 2.7% for mirabegron and tolterodine tartrate respectively. For dry mouth, the rates were 2.8% and 8.6% for mirabegron and tolterodine tartrate respectively. In SCORPIO, the rates of dry mouth by treatment group were 1.8% and 9.5% for mirabegron and tolterodine tartrate respectively. The rates were not given for SCORPIO for constipation, or for either adverse event in ARIES and CAPRICORN.\n\n## Mixed treatment comparison\n\nBased on the 40\xa0studies identified in the manufacturer's literature review, the manufacturer conducted a Bayesian mixed treatment comparison (MTC) to estimate the relative efficacy and safety of mirabegron compared with oxybutynin hydrochloride (5\xa0mg and 10\xa0mg), fesoterodine fumarate (4\xa0mg and 8\xa0mg), trospium chloride (60\xa0mg), tolterodine tartrate (4\xa0mg), solifenacin succinate (5\xa0mg and 10\xa0mg) and placebo. This was done through a network analysis, using direct comparisons when available, or indirect comparison via placebo when available, or through another comparator if necessary. Oxybutynin hydrochloride and tolterodine tartrate have both MR and immediate-release formulations available, which were examined together for efficacy, but separately for safety, by the manufacturer. Analyses were conducted for micturition, urgency, urinary incontinence, dry mouth, constipation, blurred vision and frequency of incontinence for the general OAB population, but the manufacturer deemed that there were insufficient data available to conduct MTC analyses for the subgroups (including sex) identified in the final NICE scope. For each population, fixed and random effects models were used with a non-informative prior distribution. Quality of fit was assessed through the Bayesian deviance information criterion, with the model with the lowest deviance information criterion selected.\n\nThe results of the manufacturer's MTC for the outcome of number of micturitions per 24\xa0hours indicated that the effect of mirabegron 50\xa0mg did not differ significantly from any other treatments, except for solifenacin succinate 10\xa0mg, which was more effective than mirabegron (odds ratio [OR] −0.583\xa0to 95% credible interval [CrI] −0.8324\xa0to −0.3326) and tolterodine tartrate 4\xa0mg, which was less effective than mirabegron (OR 0.157, 95% CrI −0.0002\xa0to 0.3154). For the outcome of number of incontinence episodes per 24\xa0hours, the results indicate that there was no statistically significant difference between mirabegron and any of the comparators.\n\nThe manufacturer's MTC results for the adverse effects of dry mouth, constipation and blurred vision indicated that the mirabegron group had probabilities similar to the placebo group for all effects. All antimuscarinic drugs had a significantly higher risk of dry mouth compared with mirabegron 50\xa0mg. The odds ratios for constipation for antimuscarinic drugs compared with mirabegron 50\xa0mg were not statistically significantly different, except for solifenacin succinate 5\xa0mg (OR 2.501, 95% CrI 1.41\xa0to 4.127) and 10\xa0mg (OR 4.369, 95% CrI 2.54\xa0to 7.071), fesoterodine fumarate 8\xa0mg (OR 1.926, 95% CrI 1.142\xa0to 3.059) and trospium chloride 60\xa0mg (OR 7.604, 95% CrI 2.08\xa0to 22.59). These were associated with higher risks of constipation compared with mirabegron 50\xa0mg. No differences in risk between mirabegron 50\xa0mg and other treatments were found, with wide credible intervals around the odds ratios for blurred vision due to the rarity of this adverse event.\n\n## Quality of life\n\nHealth-related quality of life and treatment satisfaction were assessed using generic scales (EQ-5D, EQ-5D VAS, TS-VAS and WPAI:SHP) and disease specific scales (OABq and PPBC) in SCORPIO, ARIES and CAPRICORN. Data from SCORPIO, ARIES and CAPRICORN were pooled for a post-hoc analysis of EQ-5D results in the modified intention-to-treat set and no data from individual trials were presented in the manufacturer's submission. Adjusting for baseline confounders (the manufacturer's submission did not provide details of which confounders), mirabegron 50\xa0mg had greater mean change from baseline to 12-week utility scores than tolterodine tartrate MR 4\xa0mg in the pooled analysis of ARIES, CAPRICORN and SCORPIO (0.045\xa0and 0.026\xa0respectively, p≤0.05). The change between baseline and 12-week utility scores was not statistically significantly different between mirabegron 50\xa0mg and placebo (placebo utility change 0.038, p=0.30\xa0for difference).\n\nSCORPIO, ARIES and CAPRICORN all showed that there was a greater improvement in quality of life in the mirabegron group than in the placebo group as measured by the OAB-q, which reached statistical significance in SCORPIO and ARIES (SCORPIO estimated mean difference 2.3, 95% CI 0.2\xa0to 4.5; ARIES mean difference 4.1, 95% CI 1.6\xa0to 6.6; CAPRICORN mean difference 1.2, 95% CI −1.0\xa0to 3.4). The mirabegron, placebo and tolterodine tartrate groups achieved a clinically meaningful improvement of 10\xa0points above baseline.\n\n## ERG critique of clinical-effectiveness evidence\n\nThe ERG noted key strengths and weaknesses in the evidence submitted by the manufacturer. The ERG considered ARIES, CAPRICORN and SCORPIO to be well-designed trials, and that the results for the effectiveness of mirabegron were consistent across the trials. The ERG's clinical expert noted that it was recommended in NHS clinical practice that pharmaceutical treatments for OAB are assessed after 3\xa0months. The ERG therefore considered the duration of treatment and follow-up of the trials included in the manufacturer's submission to be sufficient to assess the efficacy and safety of treatment with mirabegron.\n\nThe ERG questioned the omission of the data from DRAGON, 178-CL-045\xa0and 178-CL-048, as well as TAURUS, from the primary analyses. The ERG also noted that no direct comparison between mirabegron and tolterodine tartrate was drawn, even though SCORPIO, DRAGON, TAURUS and 178-CL-048\xa0used tolterodine tartrate as an active control. The ERG acknowledged that these trials were not powered to evaluate the superiority or non-inferiority of mirabegron versus tolterodine tartrate, but that exclusion of data from the tolterodine tartrate group in SCORPIO limited the evidence available that was relevant for the decision problem. The ERG requested more detailed information on these trials during the clarification phase, and included it in its report. Although one of the manufacturer's exclusion criteria for 178-CL-045\xa0and 178-CL-048\xa0was that they were exclusively conducted in Japan, the ERG's clinical expert stated that ethnicity is unlikely to influence the development of symptoms of OAB and therefore trials from any country and any population involving patients with OAB were likely to be representative of patients with OAB in England and Wales.\n\nThe ERG considered the use of the full analysis set population appropriate, as was using the last-observation-carried-forward methodology for missing data (in SCORPIO, ARIES, CAPRICORN and TAURUS). The ERG noted that the intention-to-treat population was not reported across all trials for comparators. The ERG considered the multiplicity adjustments used by the manufacturer in SCORPIO, ARIES and CAPRICORN to be reasonable, in order to account for the multiple outcomes and the resulting increased probability of type\xa0I errors. The ERG noted that no statistical assessment of heterogeneity was performed on the pooled analysis.\n\nFor the comparison of mirabegron with tolterodine tartrate, the ERG performed an additional meta-analysis on the data from the 3\xa0randomised controlled trials that had an active control of tolterodine tartrate (SCORPIO, DRAGON and 178-CL-048) for the outcomes of relevance to the cost-effectiveness analysis, but did not include TAURUS in this meta-analysis because the patients were mainly recruited from SCORPIO and ARIES, and this could have led to an 'enriched' dataset that was biased. The results showed that treatment with mirabegron 50\xa0mg led to statistically significantly fewer micturitions per 24\xa0hours compared with treatment with tolterodine tartrate MR 4\xa0mg (mean difference −0.27, 95% CI −0.48\xa0to −0.06, p=0.01). Conversely, data from TAURUS favoured tolterodine tartrate MR 4\xa0mg, although the difference was not statistically significant (mean difference 0.12, 95% CI −0.11\xa0to 0.35, p value not given). For incontinence episodes per 24\xa0hours, the meta-analysis of the 3\xa0trials showed that treatment with mirabegron 50\xa0mg was statistically significantly more effective than treatment with tolterodine tartrate MR 4\xa0mg (mean difference −0.21, 95% CI −0.41\xa0to −0.01, p=0.04). However, the data from TAURUS showed that mirabegron was associated with statistically significantly more episodes per 24\xa0hours (mean difference 0.25, 95% CI 0.01\xa0to 0.49, p=0.04).\n\nThe ERG noted concerns with the inclusion and exclusion criteria for the manufacturer's MTC, and considered that the results should be interpreted cautiously. The ERG was concerned about potential clinical and methodological heterogeneity in the included studies, the inconsistency identified in 1\xa0or more treatment comparisons for multiple outcomes, and the number of iterations used for sampling the posterior distributions (which may be an indicator of poor mixing of data within the model). The ERG noted that, for the random effects models used, there were no estimates of the between pairwise comparisons of heterogeneity given by the manufacturer.\n\nThe ERG re-ran the MTC with different inclusion and exclusion criteria on the same 40\xa0studies identified by the manufacturer to perform an analysis on a more homogeneous dataset. The ERG excluded trials that included patients other than those with OAB; that were carried out in a single sex population; that reported on outcomes available at a time point other than 12\xa0weeks; or that were deemed to be of poor methodological quality based on the manufacturer's summary (less than 4\xa0'yes' responses in the first 4\xa0categories assessed). The ERG included only outcomes, treatment formulations and doses used in the economic model supplied by the manufacturer. This decreased the number of studies to 22\xa0and led to a greater degree of concordance and consequently more reliable results.\n\nFor the outcome of micturition episodes per 24\xa0hours, the ERG found no significant difference between mirabegron 50\xa0mg and any of the other active treatments assessed in their MTC. The manufacturer's analyses indicated that the only significant difference was that solifenacin succinate 10\xa0mg was statistically significantly more effective than mirabegron at reducing the number of micturition episodes (mean difference −0.583, 95% CrI −0.832\xa0to −0.333).\n\nFor the outcome of incontinence episodes per 24\xa0hours, the results of the ERG's MTC concurred with the manufacturer's MTC results, with the exception that mirabegron 50\xa0mg was statistically significantly less effective in reducing the frequency of incontinence episodes than solifenacin succinate 5\xa0and 10\xa0mg (solifenacin succinate 5\xa0mg mean difference −0.386, 95% CrI −0.717\xa0to −0.055, solifenacin succinate 10\xa0mg mean difference −0.380, 95% CrI −0.694\xa0to −0.067). The manufacturer's analyses also indicated that solifenacin succinate was numerically more effective than mirabegron, but this result was not statistically significant.\n\nThe ERG also analysed adverse events in its revised MTC analysis. The ERG found that mirabegron was statistically significantly less likely to be associated with constipation than fesoterodine fumarate 8\xa0mg (OR 2.12, 95% CI 1.13\xa0to 3.64), solifenacin succinate 5\xa0mg (OR 2.11, 95% CI 1.16\xa0to 3.59) and 10\xa0mg (OR 4.52, 95% CI 2.60\xa0to 7.47), and trospium chloride MR 60\xa0mg (OR 7.63, 95% CI 2.12\xa0to 22.95). Mirabegron was also found to be associated with a statistically significantly lower risk of dry mouth compared with all other antimuscarinic drugs assessed. Only oxybutynin hydrochloride 15\xa0mg had a statistically significantly higher rate of discontinuation than mirabegron.\n\n# Cost effectiveness\n\nThe manufacturer's cost-effectiveness evidence consisted of a systematic review of relevant literature and a de novo Markov model. None of the studies identified in the systematic review assessed the cost effectiveness of mirabegron and so the manufacturer developed a Markov model to analyse the cost effectiveness of 50\xa0mg mirabegron against the final scope comparators (with the exception of non-oral preparations). The model was designed to simulate the therapeutic management, the course of the condition, and complications in hypothetical cohorts of patients with OAB to estimate costs and quality-adjusted life years (QALYs) over 5\xa0years. The population modelled was the general OAB population (that is, the licensed population) and the model had a 5-year time horizon with a 1-month cycle length and no half-cycle correction.\n\n## Model overview\n\nIn the manufacturer's model, simulated patients are either allocated mirabegron or treatment A (a single scope comparator). At the end of each monthly cycle patients can remain on the same medication, switch medication or stop all medication. The next line of therapy is considered to have cost, efficacy and safety equivalent to solifenacin succinate 5\xa0mg. Once 2\xa0drugs have failed, or 1\xa0drug has failed followed by a cycle off any drug, botulinum toxin is available as a treatment option (see section 3.36).\n\nThe manufacturer's model simultaneously simulated 2\xa0key symptoms: frequency of micturition and incontinence. Each symptom was categorised into 5\xa0severity levels, resulting in 25\xa0possible combinations of micturition and incontinence. At the end of each month, a person's symptoms could stay the same, improve or deteriorate. The transitions between symptom severity states were determined by multinomial logistic regression using patient-level data from the SCORPIO trial and defined as a function of treatment, symptom severity in previous month, age and sex. For each symptom (micturition and incontinence), 3\xa0transmission probability matrices were produced: i) transition between baseline and month\xa01, ii) transition between month\xa01\xa0and month\xa02, and iii) transition between month\xa02\xa0and month\xa03. For patients remaining on treatment beyond 3\xa0months, the third matrix was applied until discontinuation. To develop transition matrices for antimuscarinic drugs not studied in the mirabegron clinical study programme, a calibration approach was adopted to determine the beta coefficients for use in the multinomial logistic regression model.\n\nThe only adverse events incorporated into the model were dry mouth and constipation. The manufacturer stated that expert opinion suggested that these 2\xa0were the most likely to occur with antimuscarinic drugs. Monthly probabilities of adverse events were obtained from SCORPIO for mirabegron and tolterodine tartrate MR 4\xa0mg and from the MTC for the other antimuscarinic drugs. It was assumed that people who were on no treatment experienced no adverse events.\n\nDiscontinuation of treatment was incorporated into the model as a combination of background persistence with OAB medication and the occurrence of adverse events. The background persistence rate for the base case was taken from a published study (Wagg\xa02012) and a sensitivity analysis was performed on the estimate. The discontinuation rate used in the base-case model was 72%, and was based on that observed with tolterodine tartrate MR 4\xa0mg. The manufacturer estimated that 54.7% of patients without an adverse event would discontinue treatment by 12\xa0months. Discontinuation due to adverse events was based on expert opinion and set at 90%. The manufacturer did not identify any literature on treatment re-initiation rates after treatment discontinuation. The manufacturer assumed that 50% of patients who had stopped treatment with mirabegron or tolterodine tartrate (in the base-case model) would restart treatment annually (5.6% per month) without immediately switching to another drug. Of these, a third would go back to their previous drug, a third would receive next line A, and a third would receive next line B.\n\nNo data were available to the manufacturer on the probability of moving to botulinum toxin. The model assumed that 1% of people who had discontinued 2\xa0therapies or discontinued 1\xa0and gone to no treatment would receive botulinum toxin. The probability of success of botulinum toxin was taken from a previously published cost-effectiveness analysis. The model assumed that people in whom botulinum toxin was successful moved to the lowest level of symptoms for micturition and incontinence. For those in whom botulinum toxin failed, pre-botulinum toxin symptom severity levels were assumed.\n\nUtility values assigned to the different symptom severities used in the base case were derived from EQ-5D index scores, based on health-related quality-of-life data, which were collected in SCORPIO. A linear regression model was used to estimate utilities for each of the 25\xa0combinations of symptoms, with adjustment for age, sex and country (as random effect). No interaction between micturition frequency and incontinence was assumed, despite borderline statistical significance (p=0.0566). The regression model was based on all treatment arms of SCORPIO, and predicted utility values ranging from 0.85\xa0(for people with micturition frequency and incontinence severity levels of 1) to 0.73\xa0(for people with micturition frequency and incontinence severity levels of 5). Patients experiencing an adverse event had an associated disutility of 0.0357\xa0(if they remained on treatment). Additionally, a sensitivity analysis was performed estimating utilities based on OAB-q and EQ-5D collected in the SCORPIO, ARIES and CAPRICORN trials.\n\nCosts included in the model were the acquisition prices of the drugs, cost of treatment with botulinum toxin, GP visits, specialist visits and cost of incontinence pads. It was assumed that GP consultations would be 1\xa0visit at the start and then at every treatment switch, and that specialist consultations would occur at every switch and on average 1.5\xa0specialist consultations at the start of treatment. Incontinence pad costs were included in the model and the number of pads was determined by the level of incontinence obtained from SCORPIO. There were no costs associated with managing adverse events except specialist referral in case of a switch in treatment.\n\nThe manufacturer performed deterministic and probabilistic sensitivity analyses on assumptions and parameter estimates in the model. It also performed subgroup analyses of the base case for men and women, and treatment-naive and previous treatment groups.\n\n## Model results\n\nThe manufacturer's base-case result comparing mirabegron with tolterodine tartrate MR 4\xa0mg based on the SCORPIO trial gave an incremental cost-effectiveness ratio (ICER) of £4386\xa0per QALY gained. The manufacturer's probabilistic ICER was £4886\xa0per QALY gained. The results of the secondary analysis using the effectiveness results from the MTC gave ICERs of £340\xa0per QALY gained for solifenacin succinate 10\xa0mg versus mirabegron, £3607\xa0per QALY gained for fesoterodine fumarate versus mirabegron, £3715\xa0per QALY gained for tolterodine tartrate MR 4\xa0mg versus mirabegron, £3878\xa0per QALY gained for oxybutynin hydrochloride MR 10\xa0mg versus mirabegron, £8881\xa0per QALY gained for trospium chloride MR 60\xa0mg versus mirabegron, £12,493\xa0per QALY gained for solifenacin succinate 5\xa0mg versus mirabegron, and £14,234\xa0per QALY gained for oxybutynin hydrochloride 10\xa0mg versus mirabegron.\n\nThe manufacturer performed a fully incremental analysis assuming mirabegron persistence is equivalent to solifenacin succinate. Treatments are dominated when an alternative treatment is less expensive and has greater QALY gains, and a treatment is extendedly dominated if its ICER is higher than the next, more effective, alternative. When the dominated and extendedly dominated options are excluded, the incremental analysis shows that solifenacin succinate 5\xa0mg has an ICER of £10,814\xa0per QALY gained compared with oxybutynin hydrochloride 10\xa0mg, and mirabegron has an ICER of £12,493\xa0per QALY gained when compared with solifenacin succinate 5\xa0mg.\n\nResults from the manufacturer's base-case 1-way deterministic sensitivity analyses indicated that the primary base-case results were relatively insensitive to variation in parameter estimates, the transition probabilities between symptom severities having the highest impact. Uncertainty was explored by sensitivity analyses on the model time horizon, impact of OAB-related comorbidities (depression, fractures, urinary tract infections and skin infections) and the use of disease-specific health-related quality-of-life measures. The results of the sensitivity analyses in the primary and secondary base cases were similar. The effects of 1-way sensitivity analyses on the primary base-case parameters that the model results were most sensitive to were: the transition probabilities between symptom levels for incontinence and micturition for tolterodine tartrate; incontinence severity distribution across levels at baseline; the monthly probability of having botulinum toxin injections; and the transition probability between symptom levels for micturition for mirabegron.\n\nThe manufacturer submitted primary base-case ICERs (mirabegron versus tolterodine tartrate MR 4\xa0mg) for subgroups by treatment status and by sex. The primary base-case ICERs were £3836\xa0per QALY gained for the previously treated patient subgroup and £5315\xa0per QALY gained for the treatment-naive subgroup. The primary base-case ICERs for the subgroups by sex were £38,708\xa0per QALY gained for the male subgroup and £3091\xa0per QALY gained for the female subgroup. The ICER fell to £2266\xa0per QALY gained in the female subgroup but rose to £65,968\xa0per QALY gained in the male subgroup if utilities derived from the OAB-q were used, rather than those from the EQ-5D.\n\n## ERG critique of the manufacturer's model\n\nThe ERG commented that it thought the manufacturer's model was well constructed, transparent and accurate. The ERG noted that the manufacturer's primary base-case cost-effectiveness analysis was generally robust. The ERG considered that the use of deterministic rather than probabilistic results was appropriate, given the high level of consistency between the deterministic and probabilistic results. The ERG noted that the manufacturer's 1-way sensitivity analyses were thorough, and that the primary base-case result was relatively robust and insensitive to individual parameter estimate changes.\n\nThe ERG identified several areas of inaccuracy or uncertainty. These included:\n\nuncertainty resulting from heterogeneity associated with estimates from the manufacturer's MTC\n\nthe assumption of variable other-cause discontinuation for mirabegron patients\n\nthe assumption that immediate (that is, within the same cycle) discontinuation as a result of an adverse event would be equivalent to the rate of other-cause discontinuation\n\nthe possibility of infinite treatment discontinuation and re-initiation, a factor of the 'lack of memory' associated with the Markov model\n\nthe use of adverse event rates from SCORPIO rather than the manufacturer's safety study TAURUS\n\nthe cost associated with botulinum toxin injections\n\nthe use of NHS payment-by-results tariffs rather than reference costs to inform the cost of outpatient specialist visits\n\nthe exclusion of correlation from the probabilistic sensitivity analysis.\n\nThe ERG noted that the manufacturer considered the Pearson's correlation coefficient to assess any potential relationship between the frequency of micturition and incontinence. There was a small positive correlation (r=0.19094, p<0.0001) detected. Within the model, the manufacturer assumed that the frequency of micturition was independent of the frequency of incontinence, which the ERG considers may have compromised the accuracy of the model in the respect of the distribution of patients across different symptom levels. The ERG also noted that the correlation between these outcomes is unlikely to be affected by treatment and therefore may not result in model bias either towards or against mirabegron. The ERG accepted that dry mouth and constipation were likely to be the main drivers of adverse event-related discontinuation, and therefore considered that it was unlikely that exclusion of other adverse events would bias the model either towards or against mirabegron. The ERG noted that most of the parameters were based on clinical opinion that was estimated through open discussion, rather than generated through the use of elicitation techniques, which would lead to greater parameter uncertainty.\n\nThe ERG's clinical expert indicated that a 90% discontinuation rate with adverse events would be likely to be too high, but acknowledged that the manufacturer included a sensitivity analysis that assumed a 50% adverse event-related discontinuation rate, which had a limited effect on the ICER (£4585\xa0per QALY gained compared with the base-case ICER of £4386\xa0per QALY gained). The ERG noted that there were issues with the disaggregated discontinuation rate (rates for adverse event-related discontinuation, and for discontinuation due to other causes). The probability of other-cause discontinuation was assumed to be treatment specific and, in the manufacturer's base cases (primary and secondary), was derived from the published literature to exclude adverse event-related discontinuation. The ERG considered the application of the adverse event-related discontinuation rate inappropriate to other-cause discontinuation rates.\n\nThe ERG agreed with the manufacturer that the use of regression analysis to estimate transition probabilities in the model was appropriate, so that the potentially confounding factors of age and sex could be taken account of, and could minimise the risk of overestimating the utility benefit of mirabegron. The ERG also noted that the manufacturer stated that the interaction between the numbers of micturition and incontinence episodes was tested (Wald test: p=0.0566) and found not to be significant. The ERG commented that covariate selection was neither systematic nor rigorous and that expert clinical advice was not sought in the formulation of the linear regression models, but that in comparison with published literature the ERG considered the manufacturer's utility values generated by the regression model reasonable. The ERG also considered the selection of the covariates in the manufacturer's repeated regression model reasonable. The ERG noted that utility values from SCORPIO were comparable to those in the published literature, and considered the use of trial-based data to be appropriate. The ERG thought that the SCORPIO utility data would be likely to be biased against the more effective treatment, as would the use of EQ-5D rather than OAB-q health-related quality-of-life data.\n\nThe ERG commented that the subgroup analyses indicated that the manufacturer's primary base-case ICER was robust with respect to the subgroups considered, except for the male subgroup. The ERG noted that the proportion of men recruited for the trial was lower, therefore reducing statistical power to detect differences in efficacy. The manufacturer and the ERG also noted that male patients displayed lower baseline severity levels of OAB, and experienced a higher placebo response.\n\nThe ERG considered that the manufacturer's assumption of long-term use, based on the TAURUS study, was reasonable. The ERG noted that the relative difference between mirabegron and tolterodine tartrate in adverse event rates was higher in SCORPIO than in TAURUS, which was longer term. The primary base-case ICER decreased by £72\xa0(from £4386\xa0to £4314\xa0per QALY gained) when using adverse event data from TAURUS rather than SCORPIO.\n\nThe ERG's additional sensitivity analyses (described in 3.47\xa0to 3.50) cumulatively increased the primary base-case ICER from £4386\xa0to £5272\xa0per QALY gained. However, the impact on the secondary base case had greater effects. The secondary fully incremental analysis of the ERG's cumulative sensitivity analyses included the assumptions that the persistence rate with mirabegron was 28% and the probability of re-initiating original therapy was set to 0, as well as using the adverse event rates from TAURUS and NHS reference costs for botulinum toxin injections and outpatient specialist visits. The results of the analyses were largely consistent with the manufacturer's analyses (the ICER for trospium chloride MR 60\xa0mg compared with oxybutynin hydrochloride increased by £586, and the ICER for solifenacin succinate 5\xa0mg compared with trospium chloride MR 60\xa0mg increased by £899). The largest change was for the ICER of mirabegron 50\xa0mg compared with solifenacin succinate 5\xa0mg, which changed from £12,493\xa0to £32,712\xa0per QALY gained, an increase of £20,219. The impact of the sensitivity analyses on the ICERs for mirabegron versus solifenacin succinate 10\xa0mg ranged from £573\xa0to mirabegron being dominated by solifenacin succinate 10\xa0mg.\n\nThe ERG was unable to quantify the impact of using alternative assumptions or parameters for all the uncertainties it identified, including the difference between the manufacturer's MTC (with no statistically significant difference between mirabegron and solifenacin succinate in reducing incontinence episodes) and the ERG's MTC (in which solifenacin succinate 5\xa0mg was statistically significantly more effective at reducing incontinence episodes than mirabegron). The ERG considered that its ICER was likely to be conservative, and that using the ERG's MTC data was likely to result in a higher ICER than £32,712\xa0per QALY gained for mirabegron versus solifenacin succinate 5\xa0mg.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of mirabegron, having considered evidence on the nature of overactive bladder (OAB) and the value placed on the benefits of mirabegron by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the treatment pathway for OAB and where mirabegron might be positioned. It understood that Urinary incontinence in women (NICE clinical guideline 40) and Lower urinary tract symptoms in men (NICE clinical guideline 97) recommend that bladder training and lifestyle advice should be offered as first-line treatments for OAB, and that an antimuscarinic drug should be offered as a second-line treatment. The Committee heard from clinical specialists that there are currently no pharmacological treatments available other than antimuscarinic drugs, and if these failed the only options were invasive procedures (for example, botulinum toxin injections). The Committee heard from clinical specialists and patient experts that there was variation in service provision across the country both for the holistic care and support of people with OAB and incontinence, and the provision of botulinum toxin for OAB. The Committee concluded that mirabegron would be positioned in a complex treatment pathway that varied geographically but potentially offered an additional pharmacological treatment before invasive treatment options were considered.\n\nThe Committee discussed the effect of OAB on people. It heard from clinical specialists and patient experts that OAB is a broad spectrum condition, and some people develop individual coping strategies (for example, toilet mapping). It noted comments from patient experts about how debilitating the condition can be, with some people finding work and normal social activities difficult, or even becoming so anxious about their bladder symptoms that they do not leave home. The Committee was aware that individual circumstances mean that the effect of OAB is different for different people. The Committee noted comments from clinical specialists that, in frail older people, OAB was associated with increased risk of falls, fractures and urinary tract infections.\n\nThe Committee discussed the use of antimuscarinic drugs for OAB in clinical practice. The patient experts and clinical specialists discussed the need for pharmacological treatment of OAB within a holistic context, including bladder training, psychological support and lifestyle adjustment. They highlighted the importance of the need to explain treatments for OAB as part of a pathway, rather than pharmacological agents providing a 'quick fix'. The Committee noted that antimuscarinic drugs are known to have side effects, notably dry mouth and constipation. One patient expert explained that pharmacological agents do not necessarily lead to a satisfactory psychosocial outcome, particularly if the side effects are perceived as negative by the patient, but that if the side effects were explained as evidence that the treatment is working, they may be more acceptable and better tolerated. They also indicated that, although the average benefit of these agents seemed modest in clinical trials, some patients may gain significant benefit from them. The Committee heard from patient experts and clinical specialists that a disadvantage of immediate-release oxybutynin hydrochloride is the need for a 2\xa0to 3-times-daily dosage, which may be inconvenient and which also left 6\xa0hours in 24\xa0when no effective drug may be circulating. It also heard from clinical specialists that oxybutynin hydrochloride is rarely prescribed in secondary care because most people will have tried 1\xa0antimuscarinic before referral to a specialist. The Committee also noted that some antimuscarinic drugs may not be suitable for older people with comorbidities. The Committee concluded that an effective agent that was not an antimuscarinic could provide a valuable additional treatment option for people with OAB.\n\nThe Committee discussed the low persistence rates seen with antimuscarinic drugs. The patient experts indicated that people may stop treatment because of side effects and/or lack of clinical benefit, both of which contribute to the high discontinuation rates. However, the Committee heard from a clinical expert that some people stop treatment because they learn to manage their condition, or it improves. The Committee noted that the side-effect profile of mirabegron differed from that of the antimuscarinic drugs but it was not possible to predict whether this would have an effect on persistence rates. The Committee concluded that there was no clear evidence that persistence rates with mirabegron would differ from current pharmacological treatments.\n\n# Clinical effectiveness\n\nThe Committee discussed the available evidence from the manufacturer and the Evidence Review Group (ERG): the individual trial results, the manufacturer's pooled analysis of SCORPIO, ARIES and CAPRICORN, the ERG's meta-analysis comparing mirabegron with tolterodine tartrate based on results from SCORPIO, DRAGON and 178-CL-048, the manufacturer's mixed treatment comparison (MTC) and the ERG's revised MTC. The Committee noted that the safety trial TAURUS was not incorporated into the ERG's meta-analysis comparing mirabegron with tolterodine tartrate, and that there was a paucity of evidence comparing mirabegron directly with the NICE final scope comparators other than tolterodine tartrate modified release (MR). The Committee concluded that the evidence for a comparison of mirabegron with tolterodine tartrate using direct trial data was more robust than that from the 2\xa0MTCs.\n\nThe Committee considered the generalisability of the trials to the UK population. It noted that there were no biologically plausible reasons for differences in OAB between different ethnic groups, and that SCORPIO and CAPRICORN were largely conducted in Europe, and ARIES was conducted in North America. There was some disagreement among the patient experts and clinical specialists on the average age of the population with OAB in the UK. The patient experts thought that there was a high incidence in people in their mid-40s and older, whereas the clinical specialists thought that the prevalence was higher in older populations, particularly above the age of 60. The Committee noted the differences of opinion, but concluded that this may reflect the differing demographics of those who accessed various services, such as self-referral continence services compared with secondary care. The Committee concluded that the trials were generalisable to the UK population.\n\nThe Committee discussed which outcomes are important and relevant when treating OAB. The patient experts and clinical specialists discussed the range of attitudes of people towards their OAB, from it being a mild inconvenience to very debilitating. The patient experts and clinical specialists also commented that the definition of satisfactory treatment outcomes was broad and varied from person to person, with some people feeling that being completely 'dry' was the only important outcome, whereas others felt that being in control of the symptoms or having fewer micturition episodes was a satisfactory response to treatment. The Committee considered the primary and secondary outcomes reported in the trials. The Committee noted that in the draft update to NICE clinical guideline 40, only wet OAB was addressed, and treatment efficacy was assessed using a binary continent/incontinent outcome. However, this guideline was still in development and could be subject to change. The Committee noted that frequency of micturition and incontinence episodes were used as the primary outcomes in this appraisal. It agreed that these outcomes captured the main benefits for people with OAB, and included the benefits both for those who had incontinence and those who did not. The Committee concluded that frequency of micturitions and incontinence episodes were the most relevant outcomes for this appraisal.\n\nThe Committee discussed the results for micturition frequency and incontinence for mirabegron. It noted that there were modest changes in frequency compared with placebo (see section 3.11). It noted the results of the manufacturer's pooled analysis showing a statistically significant improvement in mean difference from baseline in incontinence and frequency of micturition compared with placebo. It noted comments from a patient expert that the people on placebo could have experienced benefits because they changed their lifestyle as part of the treatment, which they considered showed that medication was more effective when embedded in a holistic programme. The Committee concluded that mirabegron was clinically effective compared with placebo.\n\nThe Committee explored the evidence of mirabegron compared with tolterodine tartrate. The manufacturer explained that it did not provide a direct analysis of mirabegron against tolterodine tartrate despite it being a comparator arm in SCORPIO because tolterodine tartrate was designated an active control and the trial was not powered to make such comparisons. The Committee was not convinced that this was a good reason for not presenting a comparison, and noted that the manufacturer provided an indirect analysis for mirabegron compared with tolterodine tartrate through its MTC (see section 3.18). Additionally, it was aware that the ERG had performed a meta-analysis of mirabegron compared with tolterodine tartrate, using data from the 3\xa0trials that had tolterodine tartrate as an active comparator (SCORPIO, DRAGON and 178-CL-048) (see section 3.25). The Committee noted that the results of the ERG's meta-analysis showed that mirabegron was statistically significantly more effective at reducing frequency of micturition and reducing incontinence than tolterodine tartrate. The Committee also noted that in TAURUS, a safety trial, there were no statistically significant differences between mirabegron and tolterodine tartrate for number of micturition episodes per day, but that tolterodine tartrate was statistically significantly more effective at reducing incontinence. The Committee noted the ERG's comments that the participants in TAURUS were recruited from SCORPIO and ARIES and so may be a selected rather than representative OAB population. On balance, despite some concerns about the data from TAURUS, the Committee concluded that the evidence for a comparison between mirabegron and tolterodine tartrate was satisfactory, and that mirabegron was likely to be as clinically effective as tolterodine tartrate.\n\nThe Committee discussed the manufacturer's MTC comparing mirabegron with the other drugs listed in the scope. The Committee noted that, in the manufacturer's MTC, which included 40\xa0trials, there were very small gains or differences in the primary clinical outcomes for all the agents (see section 3.18). The Committee noted the ERG's comments that the manufacturer's MTC contained heterogeneous trials in terms of trial quality and populations. The Committee considered the ERG's MTC using fewer, more homogeneous trials. The Committee noted the ERG's MTC produced similar results to the manufacturer's MTC with the exception of solifenacin succinate 5\xa0mg and 10\xa0mg, which were statistically significantly more effective at reducing incontinence episodes than mirabegron. The ERG, like the manufacturer, generally found very small differences in effect between the comparators. The Committee heard different opinions from the clinical specialists as to whether, in clinical practice, the efficacy of all antimuscarinic drugs was similar to that of tolterodine tartrate. One clinical specialist indicated that solifenacin succinate was regarded as being more effective than other antimuscarinic drugs by some clinicians, particularly tolterodine tartrate. Another clinical specialist disagreed, indicating that solifenacin succinate may be perceived to be more effective, but this is because it is frequently used at a higher dose than is available for the other antimuscarinic agents. The Committee concluded that the MTCs indicated that mirabegron, like antimuscarinic drugs, offers modest improvements compared with placebo, but it was more uncertain whether it had equivalent efficacy to all antimuscarinics.\n\nThe Committee was aware that the rate of adverse events was no different between the mirabegron and tolterodine tartrate 4\xa0mg arms in TAURUS (see section 3.16), but that the nature of the adverse events experienced differed. In TAURUS and SCORPIO, dry mouth was more common in the tolterodine tartrate arm than in the mirabegron arm, in which the incidence was similar to that in the placebo arm. The Committee understood from the patient experts that dry mouth was the most bothersome side effect of antimuscarinic drugs and contributed to discontinuation with treatment. The Committee acknowledged that the rate of dry mouth was statistically significantly lower for mirabegron than for tolterodine tartrate, and the other antimuscarinic drugs (2.8% versus 8.6% in TAURUS, and for all antimuscarinic drugs in the MTC [see sections 3.16\xa0and 3.19]). The Committee concluded that the different side effects of mirabegron compared with antimuscarinic drugs could be of benefit for those who cannot tolerate the specific side effects of antimuscarinic drugs, particularly dry mouth. The Committee concluded that, for people who cannot tolerate antimuscarinic drugs, mirabegron may be a suitable alternative treatment.\n\nThe Committee discussed whether there were any differences in the clinical effectiveness of mirabegron in men and women. It noted that sex was a pre-specified subgroup in the pooled analysis of the SCORPIO, ARIES and CAPRICORN trials. Additionally, it noted that, in the manufacturer's pooled analysis, mirabegron 50\xa0mg was numerically more effective in women than men for micturition frequency and incontinence. However, the Committee noted that the trials contained a minority (approximately 30%) of male participants. Additionally, it was aware that the rate of incontinence was lower in male than in female trial participants, so the number of men with incontinence symptoms was low. The Committee also heard from 1\xa0clinical specialist that, in older men, incontinence may be related to bladder outflow obstruction rather than OAB and that bladder outflow obstruction may have been present in some of the male participants in the trials. The clinical specialists explained that incontinence secondary to bladder outflow obstruction would not be expected to respond to either antimuscarinic drugs or mirabegron, and could therefore confound the results. The clinical specialists indicated that they knew of no biologically plausible reasons why mirabegron would be less effective in men than in women. The Committee concluded that the lower efficacy in men demonstrated in the trials might be explained by the trial design and recruitment, and it did not pursue this further.\n\nThe Committee discussed the subgroup analyses comparing the clinical effectiveness of mirabegron in treatment-naive and pre-treated populations. The Committee noted there were no statistically significant differences between the effects of mirabegron in these 2\xa0subgroups, and concluded there was no pharmacological reason why the effects of mirabegron would differ between these groups. In addition, the Committee heard from the manufacturer that trials using mirabegron in combination with antimuscarinic drugs were ongoing because it is thought that the different mechanisms of action may enhance the effects of the individual drugs.\n\nThe Committee considered the need for alternatives to current treatments for OAB. It heard from clinical specialists that, for those who had contraindications to antimuscarinic drugs, had not gained clinical benefit, or who had unacceptable side effects, there was an unmet need for alternative pharmacological treatments. This could avoid invasive treatments such as botulinum toxin, which may have significant side effects (for example, urinary retention needing catheterisation). The Committee heard that, in line with existing NICE clinical guidelines, antimuscarinic drugs are routinely used as the first pharmacological treatment for OAB, and there is long-term evidence that people benefit from them. There is also considerable clinical experience in the use of antimuscarinic drugs and the management of their side effects. However, the Committee concluded that there was a need for pharmacological alternatives to antimuscarinic drugs for people in whom these are contraindicated, or for whom they are ineffective or associated with unacceptable side effects.\n\n# Cost effectiveness\n\nThe Committee considered the available cost-effectiveness evidence. It discussed the manufacturer's base-case incremental cost-effectiveness ratio ICER of £4400\xa0per quality-adjusted life years (QALY) gained for mirabegron 50\xa0mg compared with tolterodine tartrate MR 4\xa0mg. The Committee noted the ERG's comment that the manufacturer's model was accurate and transparent but also its concerns related to some of the costs in the model and assumptions of discontinuation (see section 3.52). The Committee noted the small QALY gains seen in both the manufacturer's and ERG's analyses (see section 3.41). The Committee acknowledged that the ERG's cumulative sensitivity analyses resulted in a similar ICER to the manufacturer's (£4400\xa0per QALY gained in the manufacturer's base case, and £5272\xa0per QALY gained in the ERG's cumulative sensitivity analyses). The Committee concluded that the base-case analyses were similar for the manufacturer and the ERG, and were likely to be robust. The Committee concluded that mirabegron was therefore likely to be cost effective when compared with tolterodine tartrate MR 4\xa0mg.\n\nThe Committee explored the results from the manufacturer's secondary base case and incremental analysis comparing mirabegron with the other antimuscarinic drugs defined in the scope. It observed that this analysis relied on the effectiveness results from the manufacturer's MTC and that, for technical reasons, it had not been possible for the results from the ERG's MTC to be incorporated into the ERG's economic analyses, leading to some uncertainty about the results. The Committee noted that most of the ERG's sensitivity analyses had a small effect on the resulting ICERs for mirabegron compared with comparators, except for solifenacin succinate 5\xa0mg. In this case, when the assumption of persistence of treatment was set to 28% (as opposed to equal to that of the comparator, 35%) the ICER compared with solifenacin succinate 5\xa0mg rose from £12,500\xa0to £32,700\xa0per QALY gained. The Committee acknowledged there were no data on persistence with mirabegron other than from the clinical trials, and that data from the trials were unlikely to be representative of the persistence rates in clinical practice because, in the trials, patients were actively encouraged to continue taking the drug for the entire trial duration. The Committee concluded that the ERG's analysis using a lower persistence rate for mirabegron than solifenacin succinate resulted in mirabegron being cost ineffective compared with solifenacin succinate 5\xa0mg, and that, if the ERG's MTC had been incorporated into the model, the ICER could have been higher. However, because of the small differences in QALY gains, and the lack of evidence on persistence rates in practice for mirabegron, this was subject to significant uncertainty.\n\nThe Committee discussed the incorporation of adverse events in the economic analyses. It noted that the only adverse events incorporated into the modelling were dry mouth and constipation, and that dry mouth was a particular side effect of antimuscarinic drugs (see section 3.30). The Committee expressed concern that no side effects that may be more common with mirabegron were included in the model. It questioned whether this might be favourable to mirabegron because it took no account of the similar rate of withdrawal due to adverse events in the mirabegron and tolterodine tartrate arms of TAURUS (5.9% for mirabegron and 5.7% for tolterodine tartrate). As a result, the ICER for mirabegron compared with tolterodine tartrate could be underestimated. The Committee concluded that the specific adverse events incorporated in the model were likely to favour mirabegron over all the antimuscarinic drugs.\n\nThe Committee discussed the most plausible ICERs for mirabegron. It remained concerned about the fact that it had not been possible to assess the impact of incorporating the ERG's MTC into the economic analysis, which might have given different ICERs. However, the Committee noted that it had more robust evidence comparing mirabegron with tolterodine tartrate 4\xa0mg and was satisfied that it was no less clinically effective than tolterodine tartrate 4\xa0mg. The Committee questioned whether tolterodine tartrate was likely to be representative of the effectiveness of antimuscarinic drugs as a class, or whether the results from the manufacturer's MTC against the other agents were robust. The Committee noted that the ICERs were relatively unstable, and varied with small fluctuations in the QALY calculations. However, the differences between the QALYs calculated were consistently small in both the manufacturer's and ERG's analyses. The Committee accepted that mirabegron has a different mechanism of action than that of antimuscarinic drugs. It also has a different side-effect profile, but the same rate of discontinuation due to adverse events as tolterodine tartrate. It took into consideration that the calculated ICERs were based on small and uncertain differences of clinical efficacy between mirabegron and a range of available antimuscarinic drugs, which may or may not have similar efficacy as a class. Therefore the cost effectiveness compared with antimuscarinic drugs as a class was uncertain. However, the Committee concluded that mirabegron was likely to be a cost-effective treatment for people with OAB for whom antimuscarinic drugs are contraindicated, not effective, or produce unacceptable side effects.\n\nThe Committee considered a comment the manufacturer submitted in response to the appraisal consultation document, in which the manufacturer requested that the Committee consider how the guidance should be interpreted for more vulnerable groups of patients, for example, older patients or those who already have a high anticholinergic burden due to other prescribed medications. The Committee noted that withdrawal rates due to adverse events did not differ in the mirabegron and tolterodine tartrate arms of the TAURUS trial and the manufacturer did not provide additional evidence of mirabegron having a lower rate of adverse events in older patients. The Committee concluded that there was no evidence to support a different recommendation for older people. With respect to people who had a high anticholinergic burden from other medications, the Committee concluded that normal prescribing practice would involve an assessment of existing medications and potential drug interactions, and it was not necessary to specify this in the guidance.\n\nThe Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The only potential equality issue identified was whether incontinence disproportionately affects people on a low income, due to the need to purchase incontinence pads and other auxiliary goods. However, the Committee noted that this was not a group protected under equalities legislation, and that the use of mirabegron would be unlikely to affect this group disproportionately.\n\nThe Committee discussed whether mirabegron should be considered an innovative technology, or if there were any significant and substantial health benefits that were not included in the economic model. The Committee considered the potentially innovative nature of mirabegron in that it targeted different receptors from those targeted by antimuscarinic drugs. The Committee accepted mirabegron's different and innovative mechanism of action, but concluded that all the benefits would be adequately captured in the QALY calculation.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA290\n\nAppraisal title: Mirabegron for treating symptoms of overactive bladder\n\nSection\n\nKey conclusion\n\nMirabegron is recommended as an option for treating the symptoms of overactive bladder only for people in whom antimuscarinic drugs are contraindicated or clinically ineffective, or have unacceptable side effects.\n\nPeople currently receiving mirabegron that is not recommended for them in 1.1\xa0should be able to continue treatment until they and their clinician consider it appropriate to stop.\n\n\n\n\n\nThe Committee concluded that the clinical effectiveness of mirabegron is similar to that of antimuscarinic drugs and that it appears to have a different side effect profile. However, the differences in costs and effects between drugs are small, and it is therefore difficult to make a reliable estimate of the ICER. After learning about the treatment pathway and hearing from the clinical specialists, the Committee concluded that it was reasonable to formulate the recommendations as they have done.\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nOAB has a complex treatment pathway. NICE clinical guideline 40, Urinary incontinence in women, and NICE clinical guideline 97, Lower urinary tract symptoms in men, recommend that bladder training and lifestyle advice should be offered as first-line treatments for OAB, followed by an antimuscarinic drug as second-line treatment. There are no other drugs currently available for OAB and, after failure of antimuscarinic drugs, only invasive treatments (such as botulinum toxin) are available.\n\nThe effect of OAB on patients' lives varies from person to person, and can negatively influence work and social activities. It noted that the condition can be debilitating, with some people finding work and normal social activities difficult, or even becoming so anxious about their bladder symptoms that they do not leave home. The Committee noted comments from clinical specialists that, in frail older people, OAB was associated with increased risk of falls, fractures and urinary tract infections.\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee concluded that an effective agent that was not an antimuscarinic could provide a valuable additional treatment option for people with OAB.\n\n\n\nThe Committee was aware that the nature of adverse events experienced with mirabegron differed from those found with antimuscarinic drugs.\n\n\n\nThe Committee considered the potentially innovative nature of mirabegron in that it targeted different receptors to antimuscarinic drugs. The Committee accepted mirabegron's different and innovative mechanism of action, but concluded all the benefits would be adequately captured in the QALY calculation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee concluded that mirabegron would be positioned within a complex treatment pathway that varied geographically but potentially offered an additional pharmacological treatment before invasive treatment options were considered.\n\n\n\nAdverse reactions\n\nThe Committee was aware that the rate of adverse events was no different between the mirabegron and tolterodine tartrate 4\xa0mg arms in TAURUS, but that the nature of the adverse events experienced differed. The Committee concluded that the different side effects of mirabegron compared with antimuscarinic drugs could be of benefit for those who cannot tolerate the specific side effects of antimuscarinic drugs, particularly dry mouth.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee discussed the available evidence from the manufacturer and the ERG: the individual trial results, the manufacturer's pooled analysis of SCORPIO, ARIES and CAPRICORN, the ERG's meta-analysis comparing mirabegron with tolterodine tartrate based on results from SCORPIO, DRAGON and 178-CL-048, the manufacturer's MTC and the ERG's revised MTC. The Committee concluded that the evidence for a comparison of mirabegron with tolterodine tartrate using direct trial data was more robust than that from the 2\xa0MTCs.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee noted that there were no biologically plausible reasons for differences in OAB between different ethnic groups, and that the age range was likely to be in line with the demographics of the population with OAB in the UK. The Committee concluded that the trials were generalisable to the UK population.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee was aware that the participants in TAURUS (long-term safety study) were recruited from SCORPIO and ARIES and so may be a selected rather than representative OAB population. The Committee noted the ERG's comments that the manufacturer's MTC contained heterogeneous trials in terms of trial quality and populations.\n\n\n\n\n\nThe Committee acknowledged there were no real-life data on persistence with mirabegron, and that data from the trials were unlikely to be representative of the persistence rates in clinical practice because, in the trials, patients were actively encouraged to continue taking the drug for the entire trial duration.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee considered treatment group by age, sex and by treatment status (pre-treated or treatment-naive), but concluded there was no evidence for differential clinical effectiveness in these subgroups.\n\n\n\n\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that mirabegron was clinically effective compared with placebo. The Committee concluded that the MTCs indicated that mirabegron, like antimuscarinic drugs, offers modest improvements compared with placebo, but it was more uncertain whether it had equivalent efficacy to all antimuscarinics.\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer's cost-effectiveness evidence consisted of a systematic literature review and a de novo Markov model. The Committee noted the ERG's comment that the manufacturer's model was accurate and transparent.\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted the ERG's concerns related to some of the costs in the model and assumptions of discontinuation.\n\n\n\nThe Committee acknowledged there were no real-life data on persistence with mirabegron, and that data from the trials were unlikely to be representative of the persistence rates in clinical practice because in the trials, patients were actively encouraged to continue taking the drug for the entire trial duration.\n\n\n\nIt observed that this analysis relied on the effectiveness results from the manufacturer's MTC and that, for technical reasons, it had not been possible for the results from the ERG's MTC to be incorporated into the ERG's economic analyses.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe manufacturer used utility values derived from EQ-5D scores collected in SCORPIO for its primary base case. The manufacturer performed sensitivity analyses based on OAB-q and EQ-5D scores collected in SCORPIO, ARIES and CAPRICORN. The ERG thought that SCORPIO utility data would be likely to be biased against the more effective treatment, as would the use of EQ-5D rather than OAB-q data.\n\n\n\n\n\nNo potential health-related benefits have been identified that were not included in the model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee considered treatment group by age, sex and by treatment status (pre-treated or treatment-naive), but concluded there was no evidence for differential clinical effectiveness and therefore no evidence for differential cost effectiveness in these subgroups.\n\n, 4.14, 4.20\n\nWhat are the key drivers of cost effectiveness?\n\nThe key driver of cost effectiveness was the assumption around the persistence rates.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that, because the base-case ICER for mirabegron against tolterodine tartrate 4\xa0mg was £5270\xa0per QALY gained in the ERG's sensitivity analysis, changes to the modelling of adverse events was unlikely to result in an ICER that made mirabegron cost ineffective against tolterodine tartrate 4\xa0mg. The Committee concluded that the effectiveness of mirabegron is similar to that of antimuscarinic drugs and it appears to have a different side-effect profile. However, there is uncertainty about the differences in costs and effects between drugs and the ICERs are therefore unstable.\n\n, 3.30, 4.18, 4.19\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNone\n\n\n\nEnd-of-life considerations\n\nNone\n\n\n\nEqualities considerations and social value judgements\n\nA potential equality issue identified was whether incontinence disproportionately affects people on a low income, due to the need to purchase incontinence pads and other auxiliary goods. However, the Committee noted that this was not a group protected under equalities legislation, and that the use of mirabegron would be unlikely to affect this group disproportionately.\n\n", 'Related NICE guidance': '# Published\n\nLower urinary tract symptoms in men. NICE clinical guideline 97\xa0(2010).\n\nPercutaneous posterior tibial nerve stimulation for overactive bladder syndrome. NICE interventional procedure guidance 362\xa0(2010).\n\nUrinary incontinence in women. NICE clinical guideline 40\xa0(2006).\n\nSacral nerve stimulation for urge incontinence and urgency-frequency. NICE interventional procedure guidance 64\xa0(2004).\n\n# Under development\n\nNICE is developing the following guidance (details available from www.nice.org.uk):\n\nUrinary incontinence in women. NICE clinical guideline. Publication expected September 2013.', 'Review of guidance': 'The guidance on this technology will be considered for review in June 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon Chief ExecutiveJune 2013', 'Changes after publication': 'January 2014: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt has been incorporated into the NICE pathway on lower urinary tract symptoms in men along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0198-2'}	https://www.nice.org.uk/guidance/ta290	Evidence-based recommendations on mirabegron (Betmiga) for treating overactive bladder in adults.
91fc08ed547d977f65d167bffc2d2376672d4789	nice	Stroke rehabilitation in adults	Stroke rehabilitation in adults This guideline covers stroke rehabilitation for adults and young people aged 16 and over who have had a stroke with continuing impairment, activity limitation or participation restriction. It aims to improve rehabilitation for people who have had a stroke by specifying how stroke units and multidisciplinary stroke teams should be organised. It makes detailed recommendations on assessments and interventions for the functional difficulties caused by stroke. # Introduction Stroke is a major health problem in the UK. Each year, approximately 110,000 people in England, 11,000 people in Wales and 4,000 people in Northern Ireland have a first or recurrent stroke. Most people survive a first stroke but often have significant morbidity. More than 900,000 people in England are living with the effects of stroke. Stroke mortality rates in the UK have been falling steadily since the late 1960s. The development of stroke units following the publication in 1997 of the Stroke Unit Trialists' Collaboration meta-analysis of stroke unit care, and the further reorganisation of services following the advent of thrombolysis, have resulted in further significant improvements in mortality and morbidity from stroke (as documented in the 2010 National sentinel stroke audit). However, the burden of stroke may increase in the future as a consequence of the ageing population. Despite improvements in mortality and morbidity, people with stroke need access to effective rehabilitation services. Stroke rehabilitation is a multidimensional process, which is designed to facilitate restoration of, or adaptation to the loss of, physiological or psychological function when reversal of the underlying pathological process is incomplete. Rehabilitation aims to enhance functional activities and participation in society and thus improve quality of life. Key aspects of rehabilitation care include multidisciplinary assessment, identification of functional difficulties and their measurement, treatment planning through goal setting, delivery of interventions which may either effect change or support the person in managing persisting change, and evaluation of effectiveness. # Current guidelines Clear standards exist for stroke rehabilitation, for instance as described by the Royal College of Physicians Intercollegiate Stroke Working Party's National clinical guideline for stroke and reflected in the NICE quality standard and the Department of Health's National stroke strategy. Overall there is little doubt that the rehabilitation approach described by the standards is effective; what individual interventions should take place within this structure is less clear. # Why this guideline was developed The aim of this Guideline Development Group was to review the structure, processes and interventions currently used in rehabilitation care, and to evaluate whether they improve outcomes for people with stroke. A modified Delphi survey was conducted (see the full guideline for more information) to obtain formal consensus around areas such as service delivery and care planning. This guideline reviews some of the available interventions that can be used in stroke rehabilitation.# Terms used in this guideline # Aphasia Loss or impairment of the ability to use and comprehend language, usually resulting from brain damage. # Apraxia (of speech) Difficulty in initiating and executing the voluntary movement needed to produce speech when there is no weakness of speech muscles. It may cause difficulty producing the correct speech or changes in the rhythm or rate of speaking. # Assessment A detailed process which aims to define the nature and impact of an impairment and devise a treatment plan. # Dysarthria Difficulty in articulating words. # Dysphagia Difficulty in swallowing. # Dyspraxia Difficulty in planning and executing movement. # Early supported discharge A service for people after stroke which allows transfer of care from an inpatient environment to a primary care setting to continue rehabilitation, at the same level of intensity and expertise that they would have received in the inpatient setting. # Hemianopia Blindness in one half of the visual field of one or both eyes. # Neglect An inability to orient towards and attend to stimuli, including body parts, on the side of the body affected by the stroke. # Orthosis A device that supports or corrects the function of a limb or the torso. # Screening A process of identifying people with particular impairments. People can then be offered information, further assessment and appropriate treatment. Screening may be performed as a precursor to more detailed assessment. # Stroke rehabilitation service A stroke service designed to deliver stroke rehabilitation either in hospital or in the community. # Stroke unit An environment in which multidisciplinary stroke teams deliver stroke care in a dedicated ward which has a bed area, dining area, gym, and access to assessment kitchens.# Recommendations The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. People have the right to be involved in discussions and make informed decisions about their care, as described in your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Organising health and social care for people needing rehabilitation after stroke ## Stroke units People with disability after stroke should receive rehabilitation in a dedicated stroke inpatient unit and subsequently from a specialist stroke team within the community. An inpatient stroke rehabilitation service should consist of the following: a dedicated stroke rehabilitation environment a core multidisciplinary team (see recommendation 1.1.3) who have the knowledge, skills and behaviours to work in partnership with people with stroke and their families and carers to manage the changes experienced as a result of a stroke access to other services that may be needed, for example: continence advice dietetics electronic aids (for example, remote controls for doors, lights and heating, and communication aids) liaison psychiatry -rthoptics -rthotics pharmacy podiatry wheelchair services a multidisciplinary education programme. ## The core multidisciplinary stroke team A core multidisciplinary stroke rehabilitation team should comprise the following professionals with expertise in stroke rehabilitation: consultant physicians nurses physiotherapists -ccupational therapists speech and language therapists clinical psychologists rehabilitation assistants social workers. Throughout the care pathway, the roles and responsibilities of the core multidisciplinary stroke rehabilitation team should be clearly documented and communicated to the person and their family or carer. Members of the core multidisciplinary stroke team should screen the person with stroke for a range of impairments and disabilities, in order to inform and direct further assessment and treatment. ## Health and social care interface Health and social care professionals should work collaboratively to ensure a social care assessment is carried out promptly, where needed, before the person with stroke is transferred from hospital to the community. The assessment should: identify any ongoing needs of the person and their family or carer, for example, access to benefits, care needs, housing, community participation, return to work, transport and access to voluntary services be documented and all needs recorded in the person's health and social care plan, with a copy provided to the person with stroke. Offer training in care (for example, in moving and handling and helping with dressing) to family members or carers who are willing and able to be involved in supporting the person after their stroke. Review family members' and carers' training and support needs regularly (as a minimum at the person's 6‑month and annual reviews), acknowledging that these needs may change over time. ## Transfer of care from hospital to community Offer early supported discharge to people with stroke who are able to transfer from bed to chair independently or with assistance, as long as a safe and secure environment can be provided. Early supported discharge should be part of a skilled stroke rehabilitation service and should consist of the same intensity of therapy and range of multidisciplinary skills available in hospital. It should not result in a delay in delivery of care. Hospitals should have systems in place to ensure that: people after stroke and their families and carers (as appropriate) are involved in planning for transfer of care, and carers receive training in care (for example, in moving and handling and helping with dressing) people after stroke and their families and carers feel adequately informed, prepared and supported GPs and other appropriate people are informed before transfer of care an agreed health and social care plan is in place, and the person knows whom to contact if difficulties arise appropriate equipment (including specialist seating and a wheelchair if needed) is in place at the person's residence, regardless of setting. Before transfer from hospital to home or to a care setting, discuss and agree a health and social care plan with the person with stroke and their family or carer (as appropriate), and provide this to all relevant health and social care providers. Before transfer of care from hospital to home for people with stroke: establish that they have a safe and enabling home environment, for example, check that appropriate equipment and adaptations have been provided and that carers are supported to facilitate independence, and undertake a home visit with them unless their abilities and needs can be identified in other ways, for example, by demonstrating independence in all self-care activities, including meal preparation, while in the rehabilitation unit. On transfer of care from hospital to the community, provide information to all relevant health and social care professionals and the person with stroke. This should include: a summary of rehabilitation progress and current goals diagnosis and health status functional abilities (including communication needs) care needs, including washing, dressing, help with going to the toilet and eating psychological (cognitive and emotional) needs medication needs (including the person's ability to manage their prescribed medications and any support they need to do so) social circumstances, including carers' needs mental capacity regarding the transfer decision management of risk, including the needs of vulnerable adults plans for follow-up, rehabilitation and access to health and social care and voluntary sector services. Ensure that people with stroke who are transferred from hospital to care homes receive assessment and treatment from stroke rehabilitation and social care services to the same standards as they would receive in their own homes. Local health and social care providers should have standard operating procedures to ensure the safe transfer and long-term care of people after stroke, including those in care homes. This should include timely exchange of information between different providers using local protocols. After transfer of care from hospital, people with disabilities after stroke (including people in care homes) should be followed up within 72 hours by the specialist stroke rehabilitation team for assessment of patient-identified needs and the development of shared management plans. Provide advice on prescribed medications for people after stroke in line with recommendations in the NICE guideline on medicines adherence. # Planning and delivering stroke rehabilitation ## Screening and assessment On admission to hospital, to ensure the immediate safety and comfort of the person with stroke, screen them for the following and, if problems are identified, start management as soon as possible: -rientation positioning, moving and handling swallowing transfers (for example, from bed to chair) pressure area risk continence communication, including the ability to understand and follow instructions and to convey needs and wishes nutritional status and hydration (follow the recommendations in the NICE guidelines on stroke and nutrition support for adults). Perform a full medical assessment of the person with stroke, including cognition (attention, memory, spatial awareness, apraxia, perception), vision, hearing, tone, strength, sensation and balance. A comprehensive assessment of a person with stroke should take into account: their previous functional abilities impairment of psychological functioning (cognitive, emotional and communication) impairment of body functions, including pain activity limitations and participation restrictions environmental factors (social, physical and cultural). Information collected routinely from people with stroke using valid, reliable and responsive tools should include the following on admission and discharge: National Institutes of Health Stroke Scale Barthel Index. Information collected from people with stroke using valid, reliable and responsive tools should be fed back to the multidisciplinary team regularly. Take into consideration the impact of the stroke on the person's family, friends and/or carers and, if appropriate, identify sources of support. Inform the family members and carers of people with stroke about their right to have a carer's needs assessment. ## Setting goals for rehabilitation Ensure that people with stroke have goals for their rehabilitation that: are meaningful and relevant to them focus on activity and participation are challenging but achievable include both short-term and long-term elements. Ensure that goal-setting meetings during stroke rehabilitation: are timetabled into the working week involve the person with stroke and, where appropriate, their family or carer in the discussion. Ensure that during goal-setting meetings, people with stroke are provided with: an explanation of the goal-setting process the information they need in a format that is accessible to them the support they need to make decisions and take an active part in setting goals. Give people copies of their agreed goals for stroke rehabilitation after each goal-setting meeting. Review people's goals at regular intervals during their stroke rehabilitation. ## Planning rehabilitation Provide information and support to enable the person with stroke and their family or carer (as appropriate) to actively participate in the development of their stroke rehabilitation plan. Stroke rehabilitation plans should be reviewed regularly by the multidisciplinary team. Time these reviews according to the stage of rehabilitation and the person's needs. Documentation about the person's stroke rehabilitation should be individualised, and should include the following information as a minimum: basic demographics, including contact details and next of kin diagnosis and relevant medical information list of current medications, including allergies standardised screening assessments (see recommendation 1.2.1) the person's rehabilitation goals multidisciplinary progress notes a key contact from the stroke rehabilitation team (including their contact details) to coordinate the person's health and social care needs discharge planning information (including accommodation needs, aids and adaptations) joint health and social care plans, if developed follow-up appointments. ## Intensity of stroke rehabilitation Offer initially at least 45 minutes of each relevant stroke rehabilitation therapy for a minimum of 5 days per week to people who have the ability to participate, and where functional goals can be achieved. If more rehabilitation is needed at a later stage, tailor the intensity to the person's needs at that time (for intensity of therapy for dysphagia, provided as part of speech and language therapy, see recommendation 1.7.2). Consider more than 45 minutes of each relevant stroke rehabilitation therapy 5 days per week for people who have the ability to participate and continue to make functional gains, and where functional goals can be achieved. If people with stroke are unable to participate in 45 minutes of each rehabilitation therapy, ensure that therapy is still offered 5 days per week for a shorter time at an intensity that allows them to actively participate. # Providing support and information Working with the person with stroke and their family or carer, identify their information needs and how to deliver them, taking into account specific impairments such as aphasia and cognitive impairments. Pace the information to the person's emotional adjustment. Provide information about local resources (for example, leisure, housing, social services and the voluntary sector) that can help to support the needs and priorities of the person with stroke and their family or carer. Review information needs at the person's 6-month and annual stroke reviews and at the start and completion of any intervention period. NICE has produced guidance on the components of good patient experience in adult NHS services. Follow the recommendations on continuity of care and relationships and enabling patients to actively participate in their care in the NICE guideline on patient experience in adult NHS services. # Cognitive functioning Screen people after stroke for cognitive deficits. Where a cognitive deficit is identified, carry out a detailed assessment using valid, reliable and responsive tools before designing a treatment programme. Provide education and support for people with stroke and their families and carers to help them understand the extent and impact of cognitive deficits after stroke, recognising that these may vary over time and in different settings. ## Visual neglect Assess the effect of visual neglect after stroke on functional tasks such as mobility, dressing, eating and using a wheelchair, using standardised assessments and behavioural observation. Use interventions for visual neglect after stroke that focus on the relevant functional tasks, taking into account the underlying impairment. For example: interventions to help people scan to the neglected side, such as brightly coloured lines or highlighter on the edge of the page alerting techniques such as auditory cues repetitive task performance such as dressing altering the perceptual input using prism glasses. ## Memory function Assess memory and other relevant domains of cognitive functioning (such as executive functions) in people after stroke, particularly where impairments in memory affect everyday activity. Use interventions for memory and cognitive functions after stroke that focus on the relevant functional tasks, taking into account the underlying impairment. Interventions could include: increasing awareness of the memory deficit enhancing learning using errorless learning and elaborative techniques (making associations, use of mnemonics, internal strategies related to encoding information such as 'preview, question, read, state, test') external aids (for example, diaries, lists, calendars and alarms) environmental strategies (routines and environmental prompts). ## Attention function Assess attention and cognitive functions in people after stroke using standardised assessments. Use behavioural observation to evaluate the impact of the impairment on functional tasks. Consider attention training for people with attention deficits after stroke. Use interventions for attention and cognitive functions after stroke that focus on the relevant functional tasks. For example, use generic techniques such as managing the environment and providing prompts relevant to the functional task. # Emotional functioning Assess emotional functioning in the context of cognitive difficulties in people after stroke. Any intervention chosen should take into consideration the type or complexity of the person's neuropsychological presentation and relevant personal history. Support and educate people after stroke and their families and carers, in relation to emotional adjustment to stroke, recognising that psychological needs may change over time and in different settings. When new or persisting emotional difficulties are identified at the person's 6‑month or annual stroke reviews, refer them to appropriate services for detailed assessment and treatment. Manage depression or anxiety in people after stroke who have no cognitive impairment in line with recommendations in the NICE guidelines on depression in adults with a chronic physical health problem and generalised anxiety disorder. # Vision Screen people after stroke for visual difficulties. Refer people with persisting double vision after stroke for formal orthoptic assessment. Offer eye movement therapy to people who have persisting hemianopia after stroke and who are aware of the condition. When advising people with visual problems after stroke about driving, consult the Driver and Vehicle Licensing Agency (DVLA) regulations. # Swallowing Assess swallowing in people after stroke in line with recommendations in the NICE guideline on stroke. Offer swallowing therapy at least 3 times a week to people with dysphagia after stroke who are able to participate, for as long as they continue to make functional gains. Swallowing therapy could include compensatory strategies, exercises and postural advice. Ensure that effective mouth care is given to people with difficulty swallowing after stroke, in order to decrease the risk of aspiration pneumonia. Healthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders should regularly monitor and reassess people with dysphagia after stroke who are having modified food and liquid until they are stable (this recommendation is from the NICE guideline on nutrition support for adults). Provide nutrition support to people with dysphagia in line with recommendations in the NICE guidelines on nutrition support for adults and stroke. # Communication Screen people after stroke for communication difficulties within 72 hours of onset of stroke symptoms. Each stroke rehabilitation service should devise a standardised protocol for screening for communication difficulties in people after stroke. Refer people with suspected communication difficulties after stroke to a speech and language therapist for detailed analysis of speech and language impairments and assessment of their impact. Provide appropriate information, education and training to the multidisciplinary stroke team to enable them to support and communicate effectively with the person with communication difficulties and their family or carer. Speech and language therapy for people with stroke should be led and supervised by a specialist speech and language therapist working collaboratively with other appropriately trained people – for example, speech and language therapy assistants, carers and friends, and members of the voluntary sector. Provide opportunities for people with communication difficulties after stroke to have conversation and social enrichment with people who have the training, knowledge, skills and behaviours to support communication. This should be in addition to the opportunities provided by families, carers and friends. Speech and language therapists should assess people with limited functional communication after stroke for their potential to benefit from using a communication aid or other technologies (for example, home-based computer therapies or smartphone applications). Provide communication aids for those people after stroke who have the potential to benefit, and offer training in how to use them. Tell the person with communication difficulties after stroke about community-based communication and support groups (such as those provided by the voluntary sector) and encourage them to participate. Speech and language therapists should: provide direct impairment-based therapy for communication impairments (for example, aphasia or dysarthria) help the person with stroke to use and enhance their remaining language and communication abilities teach other methods of communicating, such as gestures, writing and using communication props coach people around the person with stroke (including family members, carers and health and social care staff) to develop supportive communication skills to maximise the person's communication potential help the person with aphasia or dysarthria and their family or carer to adjust to a communication impairment support the person with communication difficulties to rebuild their identity support the person to access information that enables decision making. When persisting communication difficulties are identified at the person's 6‑month or annual stroke reviews, refer them back to a speech and language therapist for detailed assessment, and offer treatment if there is potential for functional improvement. Help and enable people with communication difficulties after stroke to communicate their everyday needs and wishes, and support them to understand and participate in both everyday and major life decisions. Ensure that environmental barriers to communication are minimised for people after stroke. For example, make sure signage is clear and background noise is minimised. Make sure that all written information (including that relating to medical conditions and treatment) is adapted for people with aphasia after stroke. This should include, for example, appointment letters, rehabilitation timetables and menus. Offer training in communication skills (such as slowing down, not interrupting, using communication props, gestures, drawing) to the conversation partners of people with aphasia after stroke. # Movement Provide physiotherapy for people who have weakness in their trunk or upper or lower limb, sensory disturbance or balance difficulties after stroke that have an effect on function. People with movement difficulties after stroke should be treated by physiotherapists who have the relevant skills and training in the diagnosis, assessment and management of movement in people with stroke. Treatment for people with movement difficulties after stroke should continue until the person is able to maintain or progress function either independently or with assistance from others (for example, rehabilitation assistants, family members, carers or fitness instructors). ## Strength training Consider strength training for people with muscle weakness after stroke. This could include progressive strength building through increasing repetitions of body weight activities (for example, sit-to-stand repetitions), weights (for example, progressive resistance exercise), or resistance exercise on machines such as stationary cycles. ## Fitness training Encourage people to participate in physical activity after stroke. Assess people who are able to walk and are medically stable after their stroke for cardiorespiratory and resistance training appropriate to their individual goals. Cardiorespiratory and resistance training for people with stroke should be started by a physiotherapist with the aim that the person continues the programme independently based on the physiotherapist's instructions (see recommendation 1.9.8). For people with stroke who are continuing an exercise programme independently, physiotherapists should supply any necessary information about interventions and adaptations so that where the person is using an exercise provider, the provider can ensure their programme is safe and tailored to their needs and goals. This information may take the form of written instructions, telephone conversations or a joint visit with the provider and the person with stroke, depending on the needs and abilities of the exercise provider and the person with stroke. Tell people who are participating in fitness activities after stroke about common potential problems, such as shoulder pain, and advise them to seek advice from their GP or therapist if these occur. ## Hand and arm therapies – orthoses for the upper limb Do not routinely offer wrist and hand splints to people with upper limb weakness after stroke. Consider wrist and hand splints in people at risk after stroke (for example, people who have immobile hands due to weakness, and people with high tone), to: maintain joint range, soft tissue length and alignment increase soft tissue length and passive range of movement facilitate function (for example, a hand splint to assist grip or function) aid care or hygiene (for example, by enabling access to the palm) increase comfort (for example, using a sheepskin palm protector to keep fingernails away from the palm of the hand). Where wrist and hand splints are used in people after stroke, they should be assessed and fitted by appropriately trained healthcare professionals and a review plan should be established. Teach the person with stroke and their family or carer how to put the splint on and take it off, care for the splint and monitor for signs of redness and skin breakdown. Provide a point of contact for the person if concerned. ## Electrical stimulation: upper limb Do not routinely offer people with stroke electrical stimulation for their hand and arm. Consider a trial of electrical stimulation in people who have evidence of muscle contraction after stroke but cannot move their arm against resistance. If a trial of treatment is considered appropriate, ensure that electrical stimulation therapy is guided by a qualified rehabilitation professional. The aim of electrical stimulation should be to improve strength while practising functional tasks in the context of a comprehensive stroke rehabilitation programme. Continue electrical stimulation if progress towards clear functional goals has been demonstrated (for example, maintaining range of movement, or improving grasp and release). ## Constraint-induced movement therapy Consider constraint-induced movement therapy for people with stroke who have movement of 20 degrees of wrist extension and 10 degrees of finger extension. Be aware of potential adverse events (such as falls, low mood and fatigue). ## Shoulder pain Provide information for people with stroke and their families and carers on how to prevent pain or trauma to the shoulder if they are at risk of developing shoulder pain (for example, if they have upper limb weakness and spasticity). Manage shoulder pain after stroke using appropriate positioning and other treatments according to each person's need. For guidance on managing neuropathic pain follow the advice in the NICE guideline on neuropathic pain in adults. ## Repetitive task training Offer people repetitive task training after stroke on a range of tasks for upper limb weakness (such as reaching, grasping, pointing, moving and manipulating objects in functional tasks) and lower limb weakness (such as sit-to-stand transfers, walking and using stairs). ## Walking therapies: treadmill with or without body weight support Offer walking training to people after stroke who are able to walk, with or without assistance, to help them build endurance and move more quickly. Consider treadmill training, with or without body weight support, as one option of walking training for people after stroke who are able to walk with or without assistance. ## Electromechanical gait training Offer electromechanical gait training to people after stroke only in the context of a research study. ## Ankle–foot orthoses Consider ankle–foot orthoses for people who have difficulty with swing-phase foot clearance after stroke (for example, tripping and falling) and/or stance-phase control (for example, knee and ankle collapse or knee hyper-extensions) that affects walking. Assess the ability of the person with stroke to put on the ankle–foot orthosis or ensure they have the support needed to do so. Assess the effectiveness of the ankle–foot orthosis for the person with stroke, in terms of comfort, speed and ease of walking. Assessment for and treatment with ankle–foot orthoses should only be carried out as part of a stroke rehabilitation programme and performed by qualified professionals. ## Electrical stimulation: lower limb For guidance on functional electrical stimulation for the lower limb see the NICE interventional procedures guidance on functional electrical stimulation for drop foot of central neurological origin. # Self-care Provide occupational therapy for people after stroke who are likely to benefit, to address difficulties with personal activities of daily living. Therapy may consist of restorative or compensatory strategies. Restorative strategies may include: encouraging people with neglect to attend to the neglected side encouraging people with arm weakness to incorporate both arms establishing a dressing routine for people with difficulties such as poor concentration, neglect or dyspraxia which make dressing problematic. Compensatory strategies may include: teaching people to dress one-handed teaching people to use devices such as bathing and dressing aids. People who have difficulties in activities of daily living after stroke should have regular monitoring and treatment by occupational therapists with core skills and training in the analysis and management of activities of daily living. Treatment should continue until the person is stable or able to progress independently. Assess people after stroke for their equipment needs and whether their family or carers need training to use the equipment. This assessment should be carried out by an appropriately qualified professional. Equipment may include hoists, chair raisers and small aids such as long-handled sponges. Ensure that appropriate equipment is provided and available for use by people after stroke when they are transferred from hospital, whatever the setting (including care homes). ## Return to work Return-to-work issues should be identified as soon as possible after the person's stroke, reviewed regularly and managed actively. Active management should include: identifying the physical, cognitive, communication and psychological demands of the job (for example, multi-tasking by answering emails and telephone calls in a busy office) identifying any impairments on work performance (for example, physical limitations, anxiety, fatigue preventing attendance for a full day at work, cognitive impairments preventing multi-tasking, and communication deficits) tailoring an intervention (for example, teaching strategies to support multi-tasking or memory difficulties, teaching the use of voice-activated software for people with difficulty typing, and delivery of work simulations) educating about the Equality Act 2010 and support available (for example, an access to work scheme) workplace visits and liaison with employers to establish reasonable accommodations, such as provision of equipment and graded return to work. Manage return to work or long-term absence from work for people after stroke in line with recommendations in the NICE guideline on workplace health: long-term sickness absence and capability to work. # Long-term health and social support Inform people after stroke that they can self-refer, usually with the support of a GP or named contact, if they need further stroke rehabilitation services. Provide information so that people after stroke are able to recognise the development of complications of stroke, including frequent falls, spasticity, shoulder pain and incontinence. Encourage people to focus on life after stroke and help them to achieve their goals. This may include: facilitating their participation in community activities, such as shopping, civic engagement, sports and leisure pursuits, visiting their place of worship and stroke support groups supporting their social roles, for example, work, education, volunteering, leisure, family and sexual relationships providing information about transport and driving (including DVLA requirements; see the UK Government's web page on stroke and driving). Manage incontinence after stroke in line with recommendations in the NICE guidelines on urinary incontinence in neurological disease and faecal incontinence. Review the health and social care needs of people after stroke and the needs of their carers at 6 months and annually thereafter. These reviews should cover participation and community roles to ensure that people's goals are addressed. For guidance on secondary prevention of stroke, follow recommendations in the NICE guidelines on cardiovascular disease, hypertension in adults, type 2 diabetes in adults and atrial fibrillation. Provide advice on prescribed medications in line with recommendations in the NICE guideline on medicines adherence.# Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. # Upper limb electrical stimulation What is the clinical and cost effectiveness of electrical stimulation (ES) as an adjunct to rehabilitation to improve hand and arm function in people after stroke, from early rehabilitation through to use in the community? ## Why this is important After stroke an estimated 30–70% of people have reduced or no use of one arm and hand. ES has long been thought to be a possible useful adjunct to rehabilitation to improve arm and hand function. ES is believed to enhance the training effect of active, task-specific and strengthening rehabilitation programmes. However, the evidence to date does not inform clinicians or people with stroke whether ES will be an effective addition to rehabilitation for them. A linked-series of studies are needed to: . Identify the dose, practice parameters and rehabilitation programme content needed to effect change in hand and arm function with ES. . Characterise the clinical profiles of people who will benefit from ES in early, middle and late stages of the stroke pathway. The primary outcome measure should be the person's assessment of improvement in function. Secondary outcomes should include measures of impairment, function and quality of life and these should reflect people with low-, middle- and high-functioning upper limbs. # Intensive rehabilitation after stroke In people after stroke what is the clinical and cost effectiveness of intensive rehabilitation (6 hours per day) versus moderate rehabilitation (2 hours per day) on activity, participation and quality of life outcomes? ## Why this is important Rehabilitation aims to maximise activity and participation and minimise distress for people with stroke and their families and carers. The physical and mental capacity to participate in rehabilitation possessed by people with stroke varies widely. Some people who are unwell may not be able to participate at all, whereas others may be able to tolerate 6 hours of therapy a day. The potential long-term cost benefits of even small changes in function may be significant. Evidence suggests that increasing rehabilitation intensity early after stroke results in improved outcomes, but the evidence for this is not robust. Previous studies comparing different levels of intensity have used rehabilitation inputs that are lower than the current levels recommended by the NICE quality standard on stroke. If it were shown that increasing the intensity of rehabilitation in people who are able to participate results in functional and cost benefits, stroke rehabilitation services and funding tariffs should be reviewed. # Neuropsychological therapies Which cognitive and which emotional interventions provide better outcomes for identified subgroups of people with stroke and their families and carers at different stages of the stroke pathway? ## Why this is important There are many well-established studies showing that mood disorders such as depression and anxiety occur frequently after stroke and may occur at any point along the rehabilitation pathway, causing distress to people with stroke and their families and carers and adversely affecting outcomes. Cognitive and communication impairments interact with mood and often compound difficulties by compromising people's abilities to participate in standard evidence-based psychological therapies. The need for psychological input for people with stroke is well recognised (for example, by the 'National service framework for long-term neurological conditions'). However, the literature does not provide robust evidence about which psychological interventions will be most effective for different subgroups of people. # Shoulder pain Which people with a weak arm after stroke are at risk of developing shoulder pain? What management strategies are effective in the prevention or management of shoulder pain of different aetiologies? ## Why this is important Shoulder pain after stroke is a common problem, with some prevalence estimates as high as 84%. Onset has been reported to occur from 2 weeks to several months after the stroke. Most experts agree that prevention of shoulder pain after stroke is an important goal and should be prioritised as an aim of rehabilitation from the first day after a stroke. However, the means of preventing hemiplegic shoulder pain (HSP) is not universally agreed. This may be due, in part, to the large array of identified causes of HSP. Because of this, there is little agreement on which treatment is best. Treatments include positioning, upper limb support (including slings and orthotics), strapping of the shoulder, range-of-motion exercises, ultrasound, oral non-steroidal anti-inflammatory medications, electrical stimulation for muscle contraction, electrical stimulation for pain relief (TENS), surgery, intra-articular steroid injection, and intramuscular botulinum toxin injections.	{'Introduction ': "Stroke is a major health problem in the UK. Each year, approximately 110,000 people in England, 11,000 people in Wales and 4,000 people in Northern Ireland have a first or recurrent stroke. Most people survive a first stroke but often have significant morbidity. More than 900,000 people in England are living with the effects of stroke.\n\nStroke mortality rates in the UK have been falling steadily since the late 1960s. The development of stroke units following the publication in 1997 of the Stroke Unit Trialists' Collaboration meta-analysis of stroke unit care, and the further reorganisation of services following the advent of thrombolysis, have resulted in further significant improvements in mortality and morbidity from stroke (as documented in the 2010 National sentinel stroke audit). However, the burden of stroke may increase in the future as a consequence of the ageing population.\n\nDespite improvements in mortality and morbidity, people with stroke need access to effective rehabilitation services. Stroke rehabilitation is a multidimensional process, which is designed to facilitate restoration of, or adaptation to the loss of, physiological or psychological function when reversal of the underlying pathological process is incomplete. Rehabilitation aims to enhance functional activities and participation in society and thus improve quality of life.\n\nKey aspects of rehabilitation care include multidisciplinary assessment, identification of functional difficulties and their measurement, treatment planning through goal setting, delivery of interventions which may either effect change or support the person in managing persisting change, and evaluation of effectiveness.\n\n# Current guidelines\n\nClear standards exist for stroke rehabilitation, for instance as described by the Royal College of Physicians Intercollegiate Stroke Working Party's National clinical guideline for stroke and reflected in the NICE quality standard and the Department of Health's National stroke strategy. Overall there is little doubt that the rehabilitation approach described by the standards is effective; what individual interventions should take place within this structure is less clear.\n\n# Why this guideline was developed\n\nThe aim of this Guideline Development Group was to review the structure, processes and interventions currently used in rehabilitation care, and to evaluate whether they improve outcomes for people with stroke. A modified Delphi survey was conducted (see the full guideline for more information) to obtain formal consensus around areas such as service delivery and care planning. This guideline reviews some of the available interventions that can be used in stroke rehabilitation.", 'Terms used in this guideline': '# Aphasia\n\nLoss or impairment of the ability to use and comprehend language, usually resulting from brain damage.\n\n# Apraxia (of speech)\n\nDifficulty in initiating and executing the voluntary movement needed to produce speech when there is no weakness of speech muscles. It may cause difficulty producing the correct speech or changes in the rhythm or rate of speaking.\n\n# Assessment\n\nA detailed process which aims to define the nature and impact of an impairment and devise a treatment plan.\n\n# Dysarthria\n\nDifficulty in articulating words.\n\n# Dysphagia\n\nDifficulty in swallowing.\n\n# Dyspraxia\n\nDifficulty in planning and executing movement.\n\n# Early supported discharge\n\nA service for people after stroke which allows transfer of care from an inpatient environment to a primary care setting to continue rehabilitation, at the same level of intensity and expertise that they would have received in the inpatient setting.\n\n# Hemianopia\n\nBlindness in one half of the visual field of one or both eyes.\n\n# Neglect\n\nAn inability to orient towards and attend to stimuli, including body parts, on the side of the body affected by the stroke.\n\n# Orthosis\n\nA device that supports or corrects the function of a limb or the torso.\n\n# Screening\n\nA process of identifying people with particular impairments. People can then be offered information, further assessment and appropriate treatment. Screening may be performed as a precursor to more detailed assessment.\n\n# Stroke rehabilitation service\n\nA stroke service designed to deliver stroke rehabilitation either in hospital or in the community.\n\n# Stroke unit\n\nAn environment in which multidisciplinary stroke teams deliver stroke care in a dedicated ward which has a bed area, dining area, gym, and access to assessment kitchens.', 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Organising health and social care for people needing rehabilitation after stroke\n\n## Stroke units\n\nPeople with disability after stroke should receive rehabilitation in a dedicated stroke inpatient unit and subsequently from a specialist stroke team within the community.\n\nAn inpatient stroke rehabilitation service should consist of the following:\n\na dedicated stroke rehabilitation environment\n\na core multidisciplinary team (see recommendation 1.1.3) who have the knowledge, skills and behaviours to work in partnership with people with stroke and their families and carers to manage the changes experienced as a result of a stroke\n\naccess to other services that may be needed, for example:\n\n\n\ncontinence advice\n\ndietetics\n\nelectronic aids (for example, remote controls for doors, lights and heating, and communication aids)\n\nliaison psychiatry\n\northoptics\n\northotics\n\npharmacy\n\npodiatry\n\nwheelchair services\n\n\n\na multidisciplinary education programme.\n\n## The core multidisciplinary stroke team\n\nA core multidisciplinary stroke rehabilitation team should comprise the following professionals with expertise in stroke rehabilitation:\n\nconsultant physicians\n\nnurses\n\nphysiotherapists\n\noccupational therapists\n\nspeech and language therapists\n\nclinical psychologists\n\nrehabilitation assistants\n\nsocial workers.\n\nThroughout the care pathway, the roles and responsibilities of the core multidisciplinary stroke rehabilitation team should be clearly documented and communicated to the person and their family or carer.\n\nMembers of the core multidisciplinary stroke team should screen the person with stroke for a range of impairments and disabilities, in order to inform and direct further assessment and treatment.\n\n## Health and social care interface\n\nHealth and social care professionals should work collaboratively to ensure a social care assessment is carried out promptly, where needed, before the person with stroke is transferred from hospital to the community. The assessment should:\n\nidentify any ongoing needs of the person and their family or carer, for example, access to benefits, care needs, housing, community participation, return to work, transport and access to voluntary services\n\nbe documented and all needs recorded in the person's health and social care plan, with a copy provided to the person with stroke.\n\nOffer training in care (for example, in moving and handling and helping with dressing) to family members or carers who are willing and able to be involved in supporting the person after their stroke.\n\nReview family members' and carers' training and support needs regularly (as a minimum at the person's 6‑month and annual reviews), acknowledging that these needs may change over time.\n\n## Transfer of care from hospital to community\n\nOffer early supported discharge to people with stroke who are able to transfer from bed to chair independently or with assistance, as long as a safe and secure environment can be provided.\n\nEarly supported discharge should be part of a skilled stroke rehabilitation service and should consist of the same intensity of therapy and range of multidisciplinary skills available in hospital. It should not result in a delay in delivery of care.\n\nHospitals should have systems in place to ensure that:\n\npeople after stroke and their families and carers (as appropriate) are involved in planning for transfer of care, and carers receive training in care (for example, in moving and handling and helping with dressing)\n\npeople after stroke and their families and carers feel adequately informed, prepared and supported\n\nGPs and other appropriate people are informed before transfer of care\n\nan agreed health and social care plan is in place, and the person knows whom to contact if difficulties arise\n\nappropriate equipment (including specialist seating and a wheelchair if needed) is in place at the person's residence, regardless of setting.\n\nBefore transfer from hospital to home or to a care setting, discuss and agree a health and social care plan with the person with stroke and their family or carer (as appropriate), and provide this to all relevant health and social care providers.\n\nBefore transfer of care from hospital to home for people with stroke:\n\nestablish that they have a safe and enabling home environment, for example, check that appropriate equipment and adaptations have been provided and that carers are supported to facilitate independence, and\n\nundertake a home visit with them unless their abilities and needs can be identified in other ways, for example, by demonstrating independence in all self-care activities, including meal preparation, while in the rehabilitation unit.\n\nOn transfer of care from hospital to the community, provide information to all relevant health and social care professionals and the person with stroke. This should include:\n\na summary of rehabilitation progress and current goals\n\ndiagnosis and health status\n\nfunctional abilities (including communication needs)\n\ncare needs, including washing, dressing, help with going to the toilet and eating\n\npsychological (cognitive and emotional) needs\n\nmedication needs (including the person's ability to manage their prescribed medications and any support they need to do so)\n\nsocial circumstances, including carers' needs\n\nmental capacity regarding the transfer decision\n\nmanagement of risk, including the needs of vulnerable adults\n\nplans for follow-up, rehabilitation and access to health and social care and voluntary sector services.\n\nEnsure that people with stroke who are transferred from hospital to care homes receive assessment and treatment from stroke rehabilitation and social care services to the same standards as they would receive in their own homes.\n\nLocal health and social care providers should have standard operating procedures to ensure the safe transfer and long-term care of people after stroke, including those in care homes. This should include timely exchange of information between different providers using local protocols.\n\nAfter transfer of care from hospital, people with disabilities after stroke (including people in care homes) should be followed up within 72\xa0hours by the specialist stroke rehabilitation team for assessment of patient-identified needs and the development of shared management plans.\n\nProvide advice on prescribed medications for people after stroke in line with recommendations in the NICE guideline on medicines adherence.\n\n# Planning and delivering stroke rehabilitation\n\n## Screening and assessment\n\nOn admission to hospital, to ensure the immediate safety and comfort of the person with stroke, screen them for the following and, if problems are identified, start management as soon as possible:\n\norientation\n\npositioning, moving and handling\n\nswallowing\n\ntransfers (for example, from bed to chair)\n\npressure area risk\n\ncontinence\n\ncommunication, including the ability to understand and follow instructions and to convey needs and wishes\n\nnutritional status and hydration (follow the recommendations in the NICE guidelines on stroke and nutrition support for adults).\n\nPerform a full medical assessment of the person with stroke, including cognition (attention, memory, spatial awareness, apraxia, perception), vision, hearing, tone, strength, sensation and balance.\n\nA comprehensive assessment of a person with stroke should take into account:\n\ntheir previous functional abilities\n\nimpairment of psychological functioning (cognitive, emotional and communication)\n\nimpairment of body functions, including pain\n\nactivity limitations and participation restrictions\n\nenvironmental factors (social, physical and cultural).\n\nInformation collected routinely from people with stroke using valid, reliable and responsive tools should include the following on admission and discharge:\n\nNational Institutes of Health Stroke Scale\n\nBarthel Index.\n\nInformation collected from people with stroke using valid, reliable and responsive tools should be fed back to the multidisciplinary team regularly.\n\nTake into consideration the impact of the stroke on the person's family, friends and/or carers and, if appropriate, identify sources of support.\n\nInform the family members and carers of people with stroke about their right to have a carer's needs assessment.\n\n## Setting goals for rehabilitation\n\nEnsure that people with stroke have goals for their rehabilitation that:\n\nare meaningful and relevant to them\n\nfocus on activity and participation\n\nare challenging but achievable\n\ninclude both short-term and long-term elements.\n\nEnsure that goal-setting meetings during stroke rehabilitation:\n\nare timetabled into the working week\n\ninvolve the person with stroke and, where appropriate, their family or carer in the discussion.\n\nEnsure that during goal-setting meetings, people with stroke are provided with:\n\nan explanation of the goal-setting process\n\nthe information they need in a format that is accessible to them\n\nthe support they need to make decisions and take an active part in setting goals.\n\nGive people copies of their agreed goals for stroke rehabilitation after each goal-setting meeting.\n\nReview people's goals at regular intervals during their stroke rehabilitation.\n\n## Planning rehabilitation\n\nProvide information and support to enable the person with stroke and their family or carer (as appropriate) to actively participate in the development of their stroke rehabilitation plan.\n\nStroke rehabilitation plans should be reviewed regularly by the multidisciplinary team. Time these reviews according to the stage of rehabilitation and the person's needs.\n\nDocumentation about the person's stroke rehabilitation should be individualised, and should include the following information as a minimum:\n\nbasic demographics, including contact details and next of kin\n\ndiagnosis and relevant medical information\n\nlist of current medications, including allergies\n\nstandardised screening assessments (see recommendation 1.2.1)\n\nthe person's rehabilitation goals\n\nmultidisciplinary progress notes\n\na key contact from the stroke rehabilitation team (including their contact details) to coordinate the person's health and social care needs\n\ndischarge planning information (including accommodation needs, aids and adaptations)\n\njoint health and social care plans, if developed\n\nfollow-up appointments.\n\n## Intensity of stroke rehabilitation\n\nOffer initially at least 45\xa0minutes of each relevant stroke rehabilitation therapy for a minimum of 5 days per week to people who have the ability to participate, and where functional goals can be achieved. If more rehabilitation is needed at a later stage, tailor the intensity to the person's needs at that time (for intensity of therapy for dysphagia, provided as part of speech and language therapy, see recommendation 1.7.2).\n\nConsider more than 45\xa0minutes of each relevant stroke rehabilitation therapy 5\xa0days per week for people who have the ability to participate and continue to make functional gains, and where functional goals can be achieved.\n\nIf people with stroke are unable to participate in 45\xa0minutes of each rehabilitation therapy, ensure that therapy is still offered 5\xa0days per week for a shorter time at an intensity that allows them to actively participate.\n\n# Providing support and information\n\nWorking with the person with stroke and their family or carer, identify their information needs and how to deliver them, taking into account specific impairments such as aphasia and cognitive impairments. Pace the information to the person's emotional adjustment.\n\nProvide information about local resources (for example, leisure, housing, social services and the voluntary sector) that can help to support the needs and priorities of the person with stroke and their family or carer.\n\nReview information needs at the person's 6-month and annual stroke reviews and at the start and completion of any intervention period.\n\nNICE has produced guidance on the components of good patient experience in adult NHS services. Follow the recommendations on continuity of care and relationships and enabling patients to actively participate in their care in the NICE guideline on patient experience in adult NHS services.\n\n# Cognitive functioning\n\nScreen people after stroke for cognitive deficits. Where a cognitive deficit is identified, carry out a detailed assessment using valid, reliable and responsive tools before designing a treatment programme.\n\nProvide education and support for people with stroke and their families and carers to help them understand the extent and impact of cognitive deficits after stroke, recognising that these may vary over time and in different settings.\n\n## Visual neglect\n\nAssess the effect of visual neglect after stroke on functional tasks such as mobility, dressing, eating and using a wheelchair, using standardised assessments and behavioural observation.\n\nUse interventions for visual neglect after stroke that focus on the relevant functional tasks, taking into account the underlying impairment. For example:\n\ninterventions to help people scan to the neglected side, such as brightly coloured lines or highlighter on the edge of the page\n\nalerting techniques such as auditory cues\n\nrepetitive task performance such as dressing\n\naltering the perceptual input using prism glasses.\n\n## Memory function\n\nAssess memory and other relevant domains of cognitive functioning (such as executive functions) in people after stroke, particularly where impairments in memory affect everyday activity.\n\nUse interventions for memory and cognitive functions after stroke that focus on the relevant functional tasks, taking into account the underlying impairment. Interventions could include:\n\nincreasing awareness of the memory deficit\n\nenhancing learning using errorless learning and elaborative techniques (making associations, use of mnemonics, internal strategies related to encoding information such as 'preview, question, read, state, test')\n\nexternal aids (for example, diaries, lists, calendars and alarms)\n\nenvironmental strategies (routines and environmental prompts).\n\n## Attention function\n\nAssess attention and cognitive functions in people after stroke using standardised assessments. Use behavioural observation to evaluate the impact of the impairment on functional tasks.\n\nConsider attention training for people with attention deficits after stroke.\n\nUse interventions for attention and cognitive functions after stroke that focus on the relevant functional tasks. For example, use generic techniques such as managing the environment and providing prompts relevant to the functional task.\n\n# Emotional functioning\n\nAssess emotional functioning in the context of cognitive difficulties in people after stroke. Any intervention chosen should take into consideration the type or complexity of the person's neuropsychological presentation and relevant personal history.\n\nSupport and educate people after stroke and their families and carers, in relation to emotional adjustment to stroke, recognising that psychological needs may change over time and in different settings.\n\nWhen new or persisting emotional difficulties are identified at the person's 6‑month or annual stroke reviews, refer them to appropriate services for detailed assessment and treatment.\n\nManage depression or anxiety in people after stroke who have no cognitive impairment in line with recommendations in the NICE guidelines on depression in adults with a chronic physical health problem and generalised anxiety disorder.\n\n# Vision\n\nScreen people after stroke for visual difficulties.\n\nRefer people with persisting double vision after stroke for formal orthoptic assessment.\n\nOffer eye movement therapy to people who have persisting hemianopia after stroke and who are aware of the condition.\n\nWhen advising people with visual problems after stroke about driving, consult the Driver and Vehicle Licensing Agency (DVLA) regulations.\n\n# Swallowing\n\nAssess swallowing in people after stroke in line with recommendations in the NICE guideline on stroke.\n\nOffer swallowing therapy at least 3 times a week to people with dysphagia after stroke who are able to participate, for as long as they continue to make functional gains. Swallowing therapy could include compensatory strategies, exercises and postural advice.\n\nEnsure that effective mouth care is given to people with difficulty swallowing after stroke, in order to decrease the risk of aspiration pneumonia.\n\nHealthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders should regularly monitor and reassess people with dysphagia after stroke who are having modified food and liquid until they are stable (this recommendation is from the NICE guideline on nutrition support for adults).\n\nProvide nutrition support to people with dysphagia in line with recommendations in the NICE guidelines on nutrition support for adults and stroke.\n\n# Communication\n\nScreen people after stroke for communication difficulties within 72\xa0hours of onset of stroke symptoms.\n\nEach stroke rehabilitation service should devise a standardised protocol for screening for communication difficulties in people after stroke.\n\nRefer people with suspected communication difficulties after stroke to a speech and language therapist for detailed analysis of speech and language impairments and assessment of their impact.\n\nProvide appropriate information, education and training to the multidisciplinary stroke team to enable them to support and communicate effectively with the person with communication difficulties and their family or carer.\n\nSpeech and language therapy for people with stroke should be led and supervised by a specialist speech and language therapist working collaboratively with other appropriately trained people – for example, speech and language therapy assistants, carers and friends, and members of the voluntary sector.\n\nProvide opportunities for people with communication difficulties after stroke to have conversation and social enrichment with people who have the training, knowledge, skills and behaviours to support communication. This should be in addition to the opportunities provided by families, carers and friends.\n\nSpeech and language therapists should assess people with limited functional communication after stroke for their potential to benefit from using a communication aid or other technologies (for example, home-based computer therapies or smartphone applications).\n\nProvide communication aids for those people after stroke who have the potential to benefit, and offer training in how to use them.\n\nTell the person with communication difficulties after stroke about community-based communication and support groups (such as those provided by the voluntary sector) and encourage them to participate.\n\nSpeech and language therapists should:\n\nprovide direct impairment-based therapy for communication impairments (for example, aphasia or dysarthria)\n\nhelp the person with stroke to use and enhance their remaining language and communication abilities\n\nteach other methods of communicating, such as gestures, writing and using communication props\n\ncoach people around the person with stroke (including family members, carers and health and social care staff) to develop supportive communication skills to maximise the person's communication potential\n\nhelp the person with aphasia or dysarthria and their family or carer to adjust to a communication impairment\n\nsupport the person with communication difficulties to rebuild their identity\n\nsupport the person to access information that enables decision making.\n\nWhen persisting communication difficulties are identified at the person's 6‑month or annual stroke reviews, refer them back to a speech and language therapist for detailed assessment, and offer treatment if there is potential for functional improvement.\n\nHelp and enable people with communication difficulties after stroke to communicate their everyday needs and wishes, and support them to understand and participate in both everyday and major life decisions.\n\nEnsure that environmental barriers to communication are minimised for people after stroke. For example, make sure signage is clear and background noise is minimised.\n\nMake sure that all written information (including that relating to medical conditions and treatment) is adapted for people with aphasia after stroke. This should include, for example, appointment letters, rehabilitation timetables and menus.\n\nOffer training in communication skills (such as slowing down, not interrupting, using communication props, gestures, drawing) to the conversation partners of people with aphasia after stroke.\n\n# Movement\n\nProvide physiotherapy for people who have weakness in their trunk or upper or lower limb, sensory disturbance or balance difficulties after stroke that have an effect on function.\n\nPeople with movement difficulties after stroke should be treated by physiotherapists who have the relevant skills and training in the diagnosis, assessment and management of movement in people with stroke.\n\nTreatment for people with movement difficulties after stroke should continue until the person is able to maintain or progress function either independently or with assistance from others (for example, rehabilitation assistants, family members, carers or fitness instructors).\n\n## Strength training\n\nConsider strength training for people with muscle weakness after stroke. This could include progressive strength building through increasing repetitions of body weight activities (for example, sit-to-stand repetitions), weights (for example, progressive resistance exercise), or resistance exercise on machines such as stationary cycles.\n\n## Fitness training\n\nEncourage people to participate in physical activity after stroke.\n\nAssess people who are able to walk and are medically stable after their stroke for cardiorespiratory and resistance training appropriate to their individual goals.\n\nCardiorespiratory and resistance training for people with stroke should be started by a physiotherapist with the aim that the person continues the programme independently based on the physiotherapist's instructions (see recommendation 1.9.8).\n\nFor people with stroke who are continuing an exercise programme independently, physiotherapists should supply any necessary information about interventions and adaptations so that where the person is using an exercise provider, the provider can ensure their programme is safe and tailored to their needs and goals. This information may take the form of written instructions, telephone conversations or a joint visit with the provider and the person with stroke, depending on the needs and abilities of the exercise provider and the person with stroke.\n\nTell people who are participating in fitness activities after stroke about common potential problems, such as shoulder pain, and advise them to seek advice from their GP or therapist if these occur.\n\n## Hand and arm therapies – orthoses for the upper limb\n\nDo not routinely offer wrist and hand splints to people with upper limb weakness after stroke.\n\nConsider wrist and hand splints in people at risk after stroke (for example, people who have immobile hands due to weakness, and people with high tone), to:\n\nmaintain joint range, soft tissue length and alignment\n\nincrease soft tissue length and passive range of movement\n\nfacilitate function (for example, a hand splint to assist grip or function)\n\naid care or hygiene (for example, by enabling access to the palm)\n\nincrease comfort (for example, using a sheepskin palm protector to keep fingernails away from the palm of the hand).\n\nWhere wrist and hand splints are used in people after stroke, they should be assessed and fitted by appropriately trained healthcare professionals and a review plan should be established.\n\nTeach the person with stroke and their family or carer how to put the splint on and take it off, care for the splint and monitor for signs of redness and skin breakdown. Provide a point of contact for the person if concerned.\n\n## Electrical stimulation: upper limb\n\nDo not routinely offer people with stroke electrical stimulation for their hand and arm.\n\nConsider a trial of electrical stimulation in people who have evidence of muscle contraction after stroke but cannot move their arm against resistance.\n\nIf a trial of treatment is considered appropriate, ensure that electrical stimulation therapy is guided by a qualified rehabilitation professional.\n\nThe aim of electrical stimulation should be to improve strength while practising functional tasks in the context of a comprehensive stroke rehabilitation programme.\n\nContinue electrical stimulation if progress towards clear functional goals has been demonstrated (for example, maintaining range of movement, or improving grasp and release).\n\n## Constraint-induced movement therapy\n\nConsider constraint-induced movement therapy for people with stroke who have movement of 20\xa0degrees of wrist extension and 10\xa0degrees of finger extension. Be aware of potential adverse events (such as falls, low mood and fatigue).\n\n## Shoulder pain\n\nProvide information for people with stroke and their families and carers on how to prevent pain or trauma to the shoulder if they are at risk of developing shoulder pain (for example, if they have upper limb weakness and spasticity).\n\nManage shoulder pain after stroke using appropriate positioning and other treatments according to each person's need.\n\nFor guidance on managing neuropathic pain follow the advice in the NICE guideline on neuropathic pain in adults.\n\n## Repetitive task training\n\nOffer people repetitive task training after stroke on a range of tasks for upper limb weakness (such as reaching, grasping, pointing, moving and manipulating objects in functional tasks) and lower limb weakness (such as sit-to-stand transfers, walking and using stairs).\n\n## Walking therapies: treadmill with or without body weight support\n\nOffer walking training to people after stroke who are able to walk, with or without assistance, to help them build endurance and move more quickly.\n\nConsider treadmill training, with or without body weight support, as one option of walking training for people after stroke who are able to walk with or without assistance.\n\n## Electromechanical gait training\n\nOffer electromechanical gait training to people after stroke only in the context of a research study.\n\n## Ankle–foot orthoses\n\nConsider ankle–foot orthoses for people who have difficulty with swing-phase foot clearance after stroke (for example, tripping and falling) and/or stance-phase control (for example, knee and ankle collapse or knee hyper-extensions) that affects walking.\n\nAssess the ability of the person with stroke to put on the ankle–foot orthosis or ensure they have the support needed to do so.\n\nAssess the effectiveness of the ankle–foot orthosis for the person with stroke, in terms of comfort, speed and ease of walking.\n\nAssessment for and treatment with ankle–foot orthoses should only be carried out as part of a stroke rehabilitation programme and performed by qualified professionals.\n\n## Electrical stimulation: lower limb\n\nFor guidance on functional electrical stimulation for the lower limb see the NICE interventional procedures guidance on functional electrical stimulation for drop foot of central neurological origin.\n\n# Self-care\n\nProvide occupational therapy for people after stroke who are likely to benefit, to address difficulties with personal activities of daily living. Therapy may consist of restorative or compensatory strategies.\n\nRestorative strategies may include:\n\n\n\nencouraging people with neglect to attend to the neglected side\n\nencouraging people with arm weakness to incorporate both arms\n\nestablishing a dressing routine for people with difficulties such as poor concentration, neglect or dyspraxia which make dressing problematic.\n\n\n\nCompensatory strategies may include:\n\n\n\nteaching people to dress one-handed\n\nteaching people to use devices such as bathing and dressing aids.\n\n\n\nPeople who have difficulties in activities of daily living after stroke should have regular monitoring and treatment by occupational therapists with core skills and training in the analysis and management of activities of daily living. Treatment should continue until the person is stable or able to progress independently.\n\nAssess people after stroke for their equipment needs and whether their family or carers need training to use the equipment. This assessment should be carried out by an appropriately qualified professional. Equipment may include hoists, chair raisers and small aids such as long-handled sponges.\n\nEnsure that appropriate equipment is provided and available for use by people after stroke when they are transferred from hospital, whatever the setting (including care homes).\n\n## Return to work\n\nReturn-to-work issues should be identified as soon as possible after the person's stroke, reviewed regularly and managed actively. Active management should include:\n\nidentifying the physical, cognitive, communication and psychological demands of the job (for example, multi-tasking by answering emails and telephone calls in a busy office)\n\nidentifying any impairments on work performance (for example, physical limitations, anxiety, fatigue preventing attendance for a full day at work, cognitive impairments preventing multi-tasking, and communication deficits)\n\ntailoring an intervention (for example, teaching strategies to support multi-tasking or memory difficulties, teaching the use of voice-activated software for people with difficulty typing, and delivery of work simulations)\n\neducating about the Equality Act 2010 and support available (for example, an access to work scheme)\n\nworkplace visits and liaison with employers to establish reasonable accommodations, such as provision of equipment and graded return to work.\n\nManage return to work or long-term absence from work for people after stroke in line with recommendations in the NICE guideline on workplace health: long-term sickness absence and capability to work.\n\n# Long-term health and social support\n\nInform people after stroke that they can self-refer, usually with the support of a GP or named contact, if they need further stroke rehabilitation services.\n\nProvide information so that people after stroke are able to recognise the development of complications of stroke, including frequent falls, spasticity, shoulder pain and incontinence.\n\nEncourage people to focus on life after stroke and help them to achieve their goals. This may include:\n\nfacilitating their participation in community activities, such as shopping, civic engagement, sports and leisure pursuits, visiting their place of worship and stroke support groups\n\nsupporting their social roles, for example, work, education, volunteering, leisure, family and sexual relationships\n\nproviding information about transport and driving (including DVLA requirements; see the UK Government's web page on stroke and driving).\n\nManage incontinence after stroke in line with recommendations in the NICE guidelines on urinary incontinence in neurological disease and faecal incontinence.\n\nReview the health and social care needs of people after stroke and the needs of their carers at 6 months and annually thereafter. These reviews should cover participation and community roles to ensure that people's goals are addressed.\n\nFor guidance on secondary prevention of stroke, follow recommendations in the NICE guidelines on cardiovascular disease, hypertension in adults, type 2 diabetes in adults and atrial fibrillation.\n\nProvide advice on prescribed medications in line with recommendations in the NICE guideline on medicines adherence.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Upper limb electrical stimulation\n\nWhat is the clinical and cost effectiveness of electrical stimulation (ES) as an adjunct to rehabilitation to improve hand and arm function in people after stroke, from early rehabilitation through to use in the community?\n\n## Why this is important\n\nAfter stroke an estimated 30–70% of people have reduced or no use of one arm and hand. ES has long been thought to be a possible useful adjunct to rehabilitation to improve arm and hand function. ES is believed to enhance the training effect of active, task-specific and strengthening rehabilitation programmes. However, the evidence to date does not inform clinicians or people with stroke whether ES will be an effective addition to rehabilitation for them. A linked-series of studies are needed to:\n\n. Identify the dose, practice parameters and rehabilitation programme content needed to effect change in hand and arm function with ES.\n\n. Characterise the clinical profiles of people who will benefit from ES in early, middle and late stages of the stroke pathway.\n\nThe primary outcome measure should be the person's assessment of improvement in function. Secondary outcomes should include measures of impairment, function and quality of life and these should reflect people with low-, middle- and high-functioning upper limbs.\n\n# Intensive rehabilitation after stroke\n\nIn people after stroke what is the clinical and cost effectiveness of intensive rehabilitation (6\xa0hours per day) versus moderate rehabilitation (2\xa0hours per day) on activity, participation and quality of life outcomes?\n\n## Why this is important\n\nRehabilitation aims to maximise activity and participation and minimise distress for people with stroke and their families and carers. The physical and mental capacity to participate in rehabilitation possessed by people with stroke varies widely. Some people who are unwell may not be able to participate at all, whereas others may be able to tolerate 6\xa0hours of therapy a day. The potential long-term cost benefits of even small changes in function may be significant.\n\nEvidence suggests that increasing rehabilitation intensity early after stroke results in improved outcomes, but the evidence for this is not robust. Previous studies comparing different levels of intensity have used rehabilitation inputs that are lower than the current levels recommended by the NICE quality standard on stroke.\n\nIf it were shown that increasing the intensity of rehabilitation in people who are able to participate results in functional and cost benefits, stroke rehabilitation services and funding tariffs should be reviewed.\n\n# Neuropsychological therapies\n\nWhich cognitive and which emotional interventions provide better outcomes for identified subgroups of people with stroke and their families and carers at different stages of the stroke pathway?\n\n## Why this is important\n\nThere are many well-established studies showing that mood disorders such as depression and anxiety occur frequently after stroke and may occur at any point along the rehabilitation pathway, causing distress to people with stroke and their families and carers and adversely affecting outcomes.\n\nCognitive and communication impairments interact with mood and often compound difficulties by compromising people's abilities to participate in standard evidence-based psychological therapies. The need for psychological input for people with stroke is well recognised (for example, by the 'National service framework for long-term neurological conditions'). However, the literature does not provide robust evidence about which psychological interventions will be most effective for different subgroups of people.\n\n# Shoulder pain\n\nWhich people with a weak arm after stroke are at risk of developing shoulder pain? What management strategies are effective in the prevention or management of shoulder pain of different aetiologies?\n\n## Why this is important\n\nShoulder pain after stroke is a common problem, with some prevalence estimates as high as 84%. Onset has been reported to occur from 2\xa0weeks to several months after the stroke.\n\nMost experts agree that prevention of shoulder pain after stroke is an important goal and should be prioritised as an aim of rehabilitation from the first day after a stroke. However, the means of preventing hemiplegic shoulder pain (HSP) is not universally agreed. This may be due, in part, to the large array of identified causes of HSP.\n\nBecause of this, there is little agreement on which treatment is best. Treatments include positioning, upper limb support (including slings and orthotics), strapping of the shoulder, range-of-motion exercises, ultrasound, oral non-steroidal anti-inflammatory medications, electrical stimulation for muscle contraction, electrical stimulation for pain relief (TENS), surgery, intra-articular steroid injection, and intramuscular botulinum toxin injections."}	https://www.nice.org.uk/guidance/cg162	This guideline covers stroke rehabilitation for adults and young people aged 16 and over who have had a stroke with continuing impairment, activity limitation or participation restriction. It aims to improve rehabilitation for people who have had a stroke by specifying how stroke units and multidisciplinary stroke teams should be organised. It makes detailed recommendations on assessments and interventions for the functional difficulties caused by stroke.
30381c071ba8e2f3c029921fc96cf7deb90331b3	nice	Falls in older people: assessing risk and prevention	Falls in older people: assessing risk and prevention This guideline covers assessment of fall risk and interventions to prevent falls in people aged 65 and over. It aims to reduce the risk and incidence of falls and the associated distress, pain, injury, loss of confidence, loss of independence and mortality. # Introduction Falls and fall-related injuries are a common and serious problem for older people. People aged 65 and older have the highest risk of falling, with 30% of people older than 65 and 50% of people older than 80 falling at least once a year. The human cost of falling includes distress, pain, injury, loss of confidence, loss of independence and mortality. Falling also affects the family members and carers of people who fall. Falls are estimated to cost the NHS more than £2.3 billion per year. Therefore falling has an impact on quality of life, health and healthcare costs. This guideline provides recommendations for the assessment and prevention of falls in older people. It is an extension to the remit of NICE guideline CG21 (published November 2004) to include assessing and preventing falls in older people during a hospital stay (inpatients). The new recommendations for older people in hospital (2013) sit alongside the original recommendations from the 2004 guideline. It is important to emphasise that all of the 2004 recommendations are just as relevant and important now as they were when they were originally published. # Who this guideline is for This document is for healthcare and other professionals and staff who care for older people who are at risk of falling. # Populations covered by this guideline All people aged 65 or older are covered by all guideline recommendations. This is because people aged 65 and older have the highest risk of falling. According to the guideline recommendations, all people 65 or older who are admitted to hospital should be considered for a multifactorial assessment for their risk of falling during their hospital stay. They should also be offered a multifactorial assessment of their community-based falls risk, if appropriate. These assessments may be done together or separately. People aged 50 to 64 who are admitted to hospital and are judged by a clinician to be at higher risk of falling because of an underlying condition are also covered by the guideline recommendations about assessing and preventing falls in older people during a hospital stay.# Recommendations People have the right to be involved in discussions and make informed decisions about their care as described in your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding. # Terms used in this guideline ## Extended care A care setting such as a nursing home or supported accommodation. ## Multifactorial assessment or multifactorial falls risk assessment An assessment with multiple components that aims to identify a person's risk factors for falling. ## Multifactorial intervention An intervention with multiple components that aims to address the risk factors for falling that are identified in a person's multifactorial assessment. ## Older people In section 1.1, older people are people aged 65 years and older. In section 1.2, older people are people aged 50 years and older. ## Older people living in the community Older people living in their own home or in extended care. ## Risk prediction tool A tool that aims to calculate a person's risk of falling, either in terms of 'at risk/not at risk', or in terms of 'low/medium/high risk', etc. # Preventing falls in older people ## Case/risk identification Older people in contact with healthcare professionals should be asked routinely whether they have fallen in the past year and asked about the frequency, context and characteristics of the fall/s. Older people reporting a fall or considered at risk of falling should be observed for balance and gait deficits and considered for their ability to benefit from interventions to improve strength and balance. (Tests of balance and gait commonly used in the UK are detailed in section 3.3 of the full guideline.) ## Multifactorial falls risk assessment Older people who present for medical attention because of a fall, or report recurrent falls in the past year, or demonstrate abnormalities of gait and/or balance should be offered a multifactorial falls risk assessment. This assessment should be performed by a healthcare professional with appropriate skills and experience, normally in the setting of a specialist falls service. This assessment should be part of an individualised, multifactorial intervention. Multifactorial assessment may include the following: identification of falls history assessment of gait, balance and mobility, and muscle weakness assessment of osteoporosis risk assessment of the older person's perceived functional ability and fear relating to falling assessment of visual impairment assessment of cognitive impairment and neurological examination assessment of urinary incontinence assessment of home hazards cardiovascular examination and medication review. ## Multifactorial interventions All older people with recurrent falls or assessed as being at increased risk of falling should be considered for an individualised multifactorial intervention. In successful multifactorial intervention programmes the following specific components are common (against a background of the general diagnosis and management of causes and recognised risk factors): strength and balance training home hazard assessment and intervention vision assessment and referral medication review with modification/withdrawal. Following treatment for an injurious fall, older people should be offered a multidisciplinary assessment to identify and address future risk and individualised intervention aimed at promoting independence and improving physical and psychological function. ## Strength and balance training Strength and balance training is recommended. Those most likely to benefit are older people living in the community with a history of recurrent falls and/or balance and gait deficit. A muscle-strengthening and balance programme should be offered. This should be individually prescribed and monitored by an appropriately trained professional. ## Exercise in extended care settings Multifactorial interventions with an exercise component are recommended for older people in extended care settings who are at risk of falling. ## Home hazard and safety intervention Older people who have received treatment in hospital following a fall should be offered a home hazard assessment and safety intervention/modifications by a suitably trained healthcare professional. Normally this should be part of discharge planning and be carried out within a timescale agreed by the patient or carer, and appropriate members of the health care team. Home hazard assessment is shown to be effective only in conjunction with follow-up and intervention, not in isolation. ## Psychotropic medications Older people on psychotropic medications should have their medication reviewed, with specialist input if appropriate, and discontinued if possible to reduce their risk of falling. ## Cardiac pacing Cardiac pacing should be considered for older people with cardioinhibitory carotid sinus hypersensitivity who have experienced unexplained falls. ## Encouraging the participation of older people in falls prevention programmes To promote the participation of older people in falls prevention programmes the following should be considered. Healthcare professionals involved in the assessment and prevention of falls should discuss what changes a person is willing to make to prevent falls. Information should be relevant and available in languages other than English. Falls prevention programmes should also address potential barriers such as low self-efficacy and fear of falling, and encourage activity change as negotiated with the participant. Practitioners who are involved in developing falls prevention programmes should ensure that such programmes are flexible enough to accommodate participants' different needs and preferences and should promote the social value of such programmes. ## Education and information giving All healthcare professionals dealing with patients known to be at risk of falling should develop and maintain basic professional competence in falls assessment and prevention. Individuals at risk of falling, and their carers, should be offered information orally and in writing about: what measures they can take to prevent further falls how to stay motivated if referred for falls prevention strategies that include exercise or strength and balancing components the preventable nature of some falls the physical and psychological benefits of modifying falls risk where they can seek further advice and assistance how to cope if they have a fall, including how to summon help and how to avoid a long lie. ## Interventions that cannot be recommended Brisk walking. There is no evidence that brisk walking reduces the risk of falling. One trial showed that an unsupervised brisk walking programme increased the risk of falling in postmenopausal women with an upper limb fracture in the previous year. However, there may be other health benefits of brisk walking by older people. This refers to evidence reviewed in 2004 ## Interventions that cannot be recommended because of insufficient evidence We do not recommend implementation of the following interventions at present. This is not because there is strong evidence against them, but because there is insufficient or conflicting evidence supporting them. The recommendations in this section refer to evidence reviewed in 2004. Low intensity exercise combined with incontinence programmes. There is no evidence that low intensity exercise interventions combined with continence promotion programmes reduce the incidence of falls in older people in extended care settings. Group exercise (untargeted). Exercise in groups should not be discouraged as a means of health promotion, but there is little evidence that exercise interventions that were not individually prescribed for older people living in the community are effective in falls prevention. Cognitive/behavioural interventions. There is no evidence that cognitive/behavioural interventions alone reduce the incidence of falls in older people living in the community who are of unknown risk status. Such interventions included risk assessment with feedback and counselling and individual education discussions. There is no evidence that complex interventions in which group activities included education, a behaviour modification programme aimed at moderating risk, advice and exercise interventions are effective in falls prevention with older people living in the community. Referral for correction of visual impairment. There is no evidence that referral for correction of vision as a single intervention for older people living in the community is effective in reducing the number of people falling. However, vision assessment and referral has been a component of successful multifactorial falls prevention programmes. Vitamin D. There is evidence that vitamin D deficiency and insufficiency are common among older people and that, when present, they impair muscle strength and possibly neuromuscular function, via CNS-mediated pathways. In addition, the use of combined calcium and vitamin D3 supplementation has been found to reduce fracture rates in older people in residential/nursing homes and sheltered accommodation. Although there is emerging evidence that correction of vitamin D deficiency or insufficiency may reduce the propensity for falling, there is uncertainty about the relative contribution to fracture reduction via this mechanism (as opposed to bone mass) and about the dose and route of administration required. No firm recommendation can therefore currently be made on its use for this indication. The following text has been deleted from the 2004 recommendation: 'Guidance on the use of vitamin D for fracture prevention will be contained in the forthcoming NICE clinical practice guideline on osteoporosis, which is currently under development.' As yet, there is no NICE guidance on the use of vitamin D for fracture prevention. Hip protectors. Reported trials that have used individual patient randomisation have provided no evidence for the effectiveness of hip protectors to prevent fractures when offered to older people living in extended care settings or in their own homes. Data from cluster randomised trials provide some evidence that hip protectors are effective in the prevention of hip fractures in older people living in extended care settings who are considered at high risk. # Preventing falls in older people during a hospital stay ## Predicting patients' risk of falling in hospital Do not use fall risk prediction tools to predict inpatients' risk of falling in hospital. Regard the following groups of inpatients as being at risk of falling in hospital and manage their care according to recommendations 1.2.2.1 to 1.2.3.2: all patients aged 65 years or older patients aged 50 to 64 years who are judged by a clinician to be at higher risk of falling because of an underlying condition. ## Assessment and interventions Ensure that aspects of the inpatient environment (including flooring, lighting, furniture and fittings such as hand holds) that could affect patients' risk of falling are systematically identified and addressed. For patients at risk of falling in hospital (see recommendation 1.2.1.2), consider a multifactorial assessment and a multifactorial intervention. Ensure that any multifactorial assessment identifies the patient's individual risk factors for falling in hospital that can be treated, improved or managed during their expected stay. These may include: cognitive impairment continence problems falls history, including causes and consequences (such as injury and fear of falling) footwear that is unsuitable or missing health problems that may increase their risk of falling medication postural instability, mobility problems and/or balance problems syncope syndrome visual impairment. Ensure that any multifactorial intervention: promptly addresses the patient's identified individual risk factors for falling in hospital and takes into account whether the risk factors can be treated, improved or managed during the patient's expected stay. Do not offer falls prevention interventions that are not tailored to address the patient's individual risk factors for falling. ## Information and support Provide relevant oral and written information and support for patients, and their family members and carers if the patient agrees. Take into account the patient's ability to understand and retain information. Information should include: explaining about the patient's individual risk factors for falling in hospital showing the patient how to use the nurse call system and encouraging them to use it when they need help informing family members and carers about when and how to raise and lower bed rails providing consistent messages about when a patient should ask for help before getting up or moving about helping the patient to engage in any multifactorial intervention aimed at addressing their individual risk factors. Ensure that relevant information is shared across services. Apply the principles in the NICE guideline on Patient experience in adult NHS services in relation to continuity of care. # Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline. # New research recommendations ## Environmental adaptations aimed at reducing the risk of falling in older inpatients What environmental adaptations can be made in existing inpatient units, and should be considered when inpatient units are built, to reduce the risk of falls and injuries in older inpatients? Dementia, delirium, poor mobility and balance, urgent or frequent toilet needs or incontinence and visual impairment are common in older hospital patients. Several multifactorial studies have included adjustments to the ward environment that have plausible mechanisms for reducing falls in patients with these risk factors (such as improved lighting, changes to flooring, furniture, handholds, walking routes, lines of sight and signposting), but the impact of these changes has not been recorded. There is a need to understand which improvements to the inpatient environment are the most effective and cost-effective for preventing falls and injuries in hospital, and the factors that architects should take into account when designing new hospitals. ## Prevalence of risk factors for falling in older inpatients Which risk factors for falling that can be treated, improved or managed during the hospital stay are most prevalent in older patients who fall in inpatient settings in the UK? Many existing studies identify risk factors for falling in the inpatient setting, but these studies are not all relevant to a current UK hospital population. Additionally, existing studies often focus on factors that predict falls but cannot be treated, improved or managed (such as chronological age). Identifying the risk factors for falling that are most prevalent in the current UK older inpatient population underpins the development of more effective and better targeted multifactorial assessments and interventions. ## Causes of unwitnessed falls among older inpatients What are the causes of unwitnessed falls among older inpatients? A large proportion of inpatient falls are unwitnessed. Although staff may deduce reasons for the fall and/or the patient (if able and if asked) may describe their own perception of what happened, research is needed to establish more objectively how and why these falls occur. Research would need to encompass a qualitative exploration of why older inpatients who are vulnerable to falling mobilise without asking for help. ## Interventions for preventing falls in older inpatients How can falls among older inpatients be prevented? Which patients are most likely to benefit from falls prevention interventions, and does the effectiveness of interventions relate to the patient's length of stay? Various single and multifactorial interventions for preventing falls have been the subject of research, but their overall effectiveness in different inpatient settings (such as mental health units for older people) has not been established. The relative effectiveness of different components of a multifactorial assessment and a multifactorial intervention, and which older inpatients would benefit most from each intervention, or each component within a multifactorial assessment and intervention, is unclear. The effectiveness of falls prevention interventions in hospital patients with a short length of stay has not been established, and nor has their effectiveness in specific subgroups such as patients with dementia. High-quality randomised controlled trials conducted in the UK are required to improve the existing evidence base. # Research recommendations from the 2004 guideline The following research gaps were identified by the GDG. Following NICE requirements, the first five are those prioritised by the GDG. Further analysis of existing trial data to identify which components of multifactorial interventions are important in different settings and amongst different patient groups. Future trials designed and analysed with the intention of identifying cost effective components of multifactorial programmes for particular groups of older people in different settings. Evaluation of multi-agency falls prevention programmes to measure the impact of these programmes on reducing falls, injurious falls and fractures in older people. Falls prevention trials with a focus on injury reduction, such as fracture outcomes and fall related outcomes. Research on the optimal methods of risk assessment for falls in older people and evaluation of whether fall-prone individuals can be risk stratified, in terms of whom will most benefit from assessment and intervention. Trials investigating the most effective strategy for preventing falls in older people with cognitive impairment and dementia. UK-based cost effectiveness studies of falls prevention interventions. Trials to investigate the effectiveness of hip protectors compared with other fracture prevention interventions in older people at high risk of falling.	{'Introduction': 'Falls and fall-related injuries are a common and serious problem for older people. People aged 65 and older have the highest risk of falling, with 30% of people older than 65 and 50% of people older than 80 falling at least once a year.\n\nThe human cost of falling includes distress, pain, injury, loss of confidence, loss of independence and mortality. Falling also affects the family members and carers of people who fall. Falls are estimated to cost the NHS more than £2.3 billion per year. Therefore falling has an impact on quality of life, health and healthcare costs.\n\nThis guideline provides recommendations for the assessment and prevention of falls in older people. It is an extension to the remit of NICE guideline CG21 (published November 2004) to include assessing and preventing falls in older people during a hospital stay (inpatients). The new recommendations for older people in hospital (2013) sit alongside the original recommendations from the 2004 guideline. It is important to emphasise that all of the 2004 recommendations are just as relevant and important now as they were when they were originally published.\n\n# Who this guideline is for\n\nThis document is for healthcare and other professionals and staff who care for older people who are at risk of falling.\n\n# Populations covered by this guideline\n\nAll people aged 65 or older are covered by all guideline recommendations. This is because people aged 65 and older have the highest risk of falling. According to the guideline recommendations, all people 65 or older who are admitted to hospital should be considered for a multifactorial assessment for their risk of falling during their hospital stay. They should also be offered a multifactorial assessment of their community-based falls risk, if appropriate. These assessments may be done together or separately.\n\nPeople aged 50 to 64 who are admitted to hospital and are judged by a clinician to be at higher risk of falling because of an underlying condition are also covered by the guideline recommendations about assessing and preventing falls in older people during a hospital stay.', 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.\n\n# Terms used in this guideline\n\n## Extended care\n\nA care setting such as a nursing home or supported accommodation.\n\n## Multifactorial assessment or multifactorial falls risk assessment\n\nAn assessment with multiple components that aims to identify a person's risk factors for falling.\n\n## Multifactorial intervention\n\nAn intervention with multiple components that aims to address the risk factors for falling that are identified in a person's multifactorial assessment.\n\n## Older people\n\nIn section 1.1, older people are people aged 65 years and older. In section 1.2, older people are people aged 50 years and older.\n\n## Older people living in the community\n\nOlder people living in their own home or in extended care.\n\n## Risk prediction tool\n\nA tool that aims to calculate a person's risk of falling, either in terms of 'at risk/not at risk', or in terms of 'low/medium/high risk', etc.\n\n# Preventing falls in older people\n\n## Case/risk identification\n\nOlder people in contact with healthcare professionals should be asked routinely whether they have fallen in the past year and asked about the frequency, context and characteristics of the fall/s. \n\nOlder people reporting a fall or considered at risk of falling should be observed for balance and gait deficits and considered for their ability to benefit from interventions to improve strength and balance. (Tests of balance and gait commonly used in the UK are detailed in section 3.3 of the full guideline.) \n\n## Multifactorial falls risk assessment\n\nOlder people who present for medical attention because of a fall, or report recurrent falls in the past year, or demonstrate abnormalities of gait and/or balance should be offered a multifactorial falls risk assessment. This assessment should be performed by a healthcare professional with appropriate skills and experience, normally in the setting of a specialist falls service. This assessment should be part of an individualised, multifactorial intervention. \n\nMultifactorial assessment may include the following:\n\nidentification of falls history\n\nassessment of gait, balance and mobility, and muscle weakness\n\nassessment of osteoporosis risk\n\nassessment of the older person's perceived functional ability and fear relating to falling\n\nassessment of visual impairment\n\nassessment of cognitive impairment and neurological examination\n\nassessment of urinary incontinence\n\nassessment of home hazards\n\ncardiovascular examination and medication review. \n\n## Multifactorial interventions\n\nAll older people with recurrent falls or assessed as being at increased risk of falling should be considered for an individualised multifactorial intervention. In successful multifactorial intervention programmes the following specific components are common (against a background of the general diagnosis and management of causes and recognised risk factors):\n\nstrength and balance training\n\nhome hazard assessment and intervention\n\nvision assessment and referral\n\nmedication review with modification/withdrawal. \n\nFollowing treatment for an injurious fall, older people should be offered a multidisciplinary assessment to identify and address future risk and individualised intervention aimed at promoting independence and improving physical and psychological function. \n\n## Strength and balance training\n\nStrength and balance training is recommended. Those most likely to benefit are older people living in the community with a history of recurrent falls and/or balance and gait deficit. A muscle-strengthening and balance programme should be offered. This should be individually prescribed and monitored by an appropriately trained professional. \n\n## Exercise in extended care settings\n\nMultifactorial interventions with an exercise component are recommended for older people in extended care settings who are at risk of falling. \n\n## Home hazard and safety intervention\n\nOlder people who have received treatment in hospital following a fall should be offered a home hazard assessment and safety intervention/modifications by a suitably trained healthcare professional. Normally this should be part of discharge planning and be carried out within a timescale agreed by the patient or carer, and appropriate members of the health care team. \n\nHome hazard assessment is shown to be effective only in conjunction with follow-up and intervention, not in isolation. \n\n## Psychotropic medications\n\nOlder people on psychotropic medications should have their medication reviewed, with specialist input if appropriate, and discontinued if possible to reduce their risk of falling. \n\n## Cardiac pacing\n\nCardiac pacing should be considered for older people with cardioinhibitory carotid sinus hypersensitivity who have experienced unexplained falls. \n\n## Encouraging the participation of older people in falls prevention programmes\n\nTo promote the participation of older people in falls prevention programmes the following should be considered.\n\nHealthcare professionals involved in the assessment and prevention of falls should discuss what changes a person is willing to make to prevent falls.\n\nInformation should be relevant and available in languages other than English.\n\nFalls prevention programmes should also address potential barriers such as low self-efficacy and fear of falling, and encourage activity change as negotiated with the participant. \n\nPractitioners who are involved in developing falls prevention programmes should ensure that such programmes are flexible enough to accommodate participants' different needs and preferences and should promote the social value of such programmes. \n\n## Education and information giving\n\nAll healthcare professionals dealing with patients known to be at risk of falling should develop and maintain basic professional competence in falls assessment and prevention. \n\nIndividuals at risk of falling, and their carers, should be offered information orally and in writing about:\n\nwhat measures they can take to prevent further falls\n\nhow to stay motivated if referred for falls prevention strategies that include exercise or strength and balancing components\n\nthe preventable nature of some falls\n\nthe physical and psychological benefits of modifying falls risk\n\nwhere they can seek further advice and assistance\n\nhow to cope if they have a fall, including how to summon help and how to avoid a long lie. \n\n## Interventions that cannot be recommended\n\nBrisk walking. There is no evidence that brisk walking reduces the risk of falling. One trial showed that an unsupervised brisk walking programme increased the risk of falling in postmenopausal women with an upper limb fracture in the previous year. However, there may be other health benefits of brisk walking by older people. This refers to evidence reviewed in 2004\n\n## Interventions that cannot be recommended because of insufficient evidence\n\nWe do not recommend implementation of the following interventions at present. This is not because there is strong evidence against them, but because there is insufficient or conflicting evidence supporting them. \n\nThe recommendations in this section refer to evidence reviewed in 2004.\n\nLow intensity exercise combined with incontinence programmes. There is no evidence that low intensity exercise interventions combined with continence promotion programmes reduce the incidence of falls in older people in extended care settings. \n\nGroup exercise (untargeted). Exercise in groups should not be discouraged as a means of health promotion, but there is little evidence that exercise interventions that were not individually prescribed for older people living in the community are effective in falls prevention. \n\nCognitive/behavioural interventions. There is no evidence that cognitive/behavioural interventions alone reduce the incidence of falls in older people living in the community who are of unknown risk status. Such interventions included risk assessment with feedback and counselling and individual education discussions. There is no evidence that complex interventions in which group activities included education, a behaviour modification programme aimed at moderating risk, advice and exercise interventions are effective in falls prevention with older people living in the community. \n\nReferral for correction of visual impairment. There is no evidence that referral for correction of vision as a single intervention for older people living in the community is effective in reducing the number of people falling. However, vision assessment and referral has been a component of successful multifactorial falls prevention programmes. \n\nVitamin D. There is evidence that vitamin D deficiency and insufficiency are common among older people and that, when present, they impair muscle strength and possibly neuromuscular function, via CNS-mediated pathways. In addition, the use of combined calcium and vitamin D3 supplementation has been found to reduce fracture rates in older people in residential/nursing homes and sheltered accommodation. Although there is emerging evidence that correction of vitamin D deficiency or insufficiency may reduce the propensity for falling, there is uncertainty about the relative contribution to fracture reduction via this mechanism (as opposed to bone mass) and about the dose and route of administration required. No firm recommendation can therefore currently be made on its use for this indication.\xa0[2004, amended 2013]The following text has been deleted from the 2004 recommendation: 'Guidance on the use of vitamin D for fracture prevention will be contained in the forthcoming NICE clinical practice guideline on osteoporosis, which is currently under development.' As yet, there is no NICE guidance on the use of vitamin D for fracture prevention.\n\nHip protectors. Reported trials that have used individual patient randomisation have provided no evidence for the effectiveness of hip protectors to prevent fractures when offered to older people living in extended care settings or in their own homes. Data from cluster randomised trials provide some evidence that hip protectors are effective in the prevention of hip fractures in older people living in extended care settings who are considered at high risk. \n\n# Preventing falls in older people during a hospital stay\n\n## Predicting patients' risk of falling in hospital\n\nDo not use fall risk prediction tools to predict inpatients' risk of falling in hospital. [new 2013]\n\nRegard the following groups of inpatients as being at risk of falling in hospital and manage their care according to recommendations 1.2.2.1 to 1.2.3.2:\n\nall patients aged 65 years or older\n\npatients aged 50 to 64 years who are judged by a clinician to be at higher risk of falling because of an underlying condition. [new 2013]\n\n## Assessment and interventions\n\nEnsure that aspects of the inpatient environment (including flooring, lighting, furniture and fittings such as hand holds) that could affect patients' risk of falling are systematically identified and addressed. [new 2013]\n\nFor patients at risk of falling in hospital (see recommendation 1.2.1.2), consider a multifactorial assessment and a multifactorial intervention. [new 2013]\n\nEnsure that any multifactorial assessment identifies the patient's individual risk factors for falling in hospital that can be treated, improved or managed during their expected stay. These may include:\n\ncognitive impairment\n\ncontinence problems\n\nfalls history, including causes and consequences (such as injury and fear of falling)\n\nfootwear that is unsuitable or missing\n\nhealth problems that may increase their risk of falling\n\nmedication\n\npostural instability, mobility problems and/or balance problems\n\nsyncope syndrome\n\nvisual impairment. [new 2013]\n\nEnsure that any multifactorial intervention:\n\npromptly addresses the patient's identified individual risk factors for falling in hospital and\n\ntakes into account whether the risk factors can be treated, improved or managed during the patient's expected stay. [new 2013]\n\nDo not offer falls prevention interventions that are not tailored to address the patient's individual risk factors for falling. [new 2013]\n\n## Information and support\n\nProvide relevant oral and written information and support for patients, and their family members and carers if the patient agrees. Take into account the patient's ability to understand and retain information. Information should include:\n\nexplaining about the patient's individual risk factors for falling in hospital\n\nshowing the patient how to use the nurse call system and encouraging them to use it when they need help\n\ninforming family members and carers about when and how to raise and lower bed rails\n\nproviding consistent messages about when a patient should ask for help before getting up or moving about\n\nhelping the patient to engage in any multifactorial intervention aimed at addressing their individual risk factors. [new 2013]\n\nEnsure that relevant information is shared across services. Apply the principles in the NICE guideline on Patient experience in adult NHS services in relation to continuity of care. [new 2013]", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.\n\n# New research recommendations\n\n## Environmental adaptations aimed at reducing the risk of falling in older inpatients\n\nWhat environmental adaptations can be made in existing inpatient units, and should be considered when inpatient units are built, to reduce the risk of falls and injuries in older inpatients?\n\nDementia, delirium, poor mobility and balance, urgent or frequent toilet needs or incontinence and visual impairment are common in older hospital patients. Several multifactorial studies have included adjustments to the ward environment that have plausible mechanisms for reducing falls in patients with these risk factors (such as improved lighting, changes to flooring, furniture, handholds, walking routes, lines of sight and signposting), but the impact of these changes has not been recorded. There is a need to understand which improvements to the inpatient environment are the most effective and cost-effective for preventing falls and injuries in hospital, and the factors that architects should take into account when designing new hospitals.\n\n## Prevalence of risk factors for falling in older inpatients\n\nWhich risk factors for falling that can be treated, improved or managed during the hospital stay are most prevalent in older patients who fall in inpatient settings in the UK?\n\nMany existing studies identify risk factors for falling in the inpatient setting, but these studies are not all relevant to a current UK hospital population. Additionally, existing studies often focus on factors that predict falls but cannot be treated, improved or managed (such as chronological age). Identifying the risk factors for falling that are most prevalent in the current UK older inpatient population underpins the development of more effective and better targeted multifactorial assessments and interventions.\n\n## Causes of unwitnessed falls among older inpatients\n\nWhat are the causes of unwitnessed falls among older inpatients?\n\nA large proportion of inpatient falls are unwitnessed. Although staff may deduce reasons for the fall and/or the patient (if able and if asked) may describe their own perception of what happened, research is needed to establish more objectively how and why these falls occur. Research would need to encompass a qualitative exploration of why older inpatients who are vulnerable to falling mobilise without asking for help.\n\n## Interventions for preventing falls in older inpatients\n\nHow can falls among older inpatients be prevented? Which patients are most likely to benefit from falls prevention interventions, and does the effectiveness of interventions relate to the patient's length of stay?\n\nVarious single and multifactorial interventions for preventing falls have been the subject of research, but their overall effectiveness in different inpatient settings (such as mental health units for older people) has not been established. The relative effectiveness of different components of a multifactorial assessment and a multifactorial intervention, and which older inpatients would benefit most from each intervention, or each component within a multifactorial assessment and intervention, is unclear. The effectiveness of falls prevention interventions in hospital patients with a short length of stay has not been established, and nor has their effectiveness in specific subgroups such as patients with dementia. High-quality randomised controlled trials conducted in the UK are required to improve the existing evidence base.\n\n# Research recommendations from the 2004 guideline\n\nThe following research gaps were identified by the GDG. Following NICE requirements, the first five are those prioritised by the GDG. \n\nFurther analysis of existing trial data to identify which components of multifactorial interventions are important in different settings and amongst different patient groups. \n\nFuture trials designed and analysed with the intention of identifying cost effective components of multifactorial programmes for particular groups of older people in different settings. \n\nEvaluation of multi-agency falls prevention programmes to measure the impact of these programmes on reducing falls, injurious falls and fractures in older people. \n\nFalls prevention trials with a focus on injury reduction, such as fracture outcomes and fall related outcomes. \n\nResearch on the optimal methods of risk assessment for falls in older people and evaluation of whether fall-prone individuals can be risk stratified, in terms of whom will most benefit from assessment and intervention. \n\nTrials investigating the most effective strategy for preventing falls in older people with cognitive impairment and dementia. \n\nUK-based cost effectiveness studies of falls prevention interventions. \n\nTrials to investigate the effectiveness of hip protectors compared with other fracture prevention interventions in older people at high risk of falling. "}	https://www.nice.org.uk/guidance/cg161	This guideline covers assessment of fall risk and interventions to prevent falls in people aged 65 and over. It aims to reduce the risk and incidence of falls and the associated distress, pain, injury, loss of confidence, loss of independence and mortality.
b3080b3663a01b0e10ecc93d6bca1c599c390b75	nice	Physical activity: brief advice for adults in primary care	Physical activity: brief advice for adults in primary care This guideline covers providing brief advice on physical activity to adults in primary care. It aims to improve health and wellbeing by raising awareness of the importance of physical activity and encouraging people to increase or maintain their activity level. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The evidence statements underpinning the recommendations are listed in the evidence section. Full details of the evidence are in the evidence reviews and economic modelling report for this guideline. See also the recommendations for research and gaps in the evidence. # Background The recommendations have been made within the context of other national and local strategies and interventions to increase or maintain physical activity levels in the population. These might include addressing barriers to activity, for example, through changes to the physical environment or other measures to support an active lifestyle. (See NICE's guidelines on physical activity and the environment and walking and cycling). The availability of local opportunities to be active will influence whether brief advice has an impact on people's physical activity levels. ## Brief advice The term 'brief advice' is used in this guidance to mean verbal advice, discussion, negotiation or encouragement, with or without written or other support or follow-up. It can vary from basic advice to a more extended, individually focused discussion. Definition Physical activity is defined as any bodily movement produced by skeletal muscles that requires energy expenditure. It takes many forms, occurs in many settings, and has many purposes (such as daily activity, active recreation, and sport). Health-enhancing physical activity includes multiple types of activity: cardiovascular; muscle and bone strengthening; and balance training (see the UK Chief Medical Officers' physical activity guidelines for more information). National recommendations Follow the UK recommendations on the type, intensity and duration of activity (see the UK Chief Medical Officers' physical activity guidelines). Prevents and helps to manage conditions such as coronary heart disease, type 2 diabetes, stroke, mental health problems, musculoskeletal conditions and some cancers. Has a positive effect on wellbeing, mood, sense of achievement, relaxation and release from daily stress. ## Whose health will benefit? Adults aged 19 and older who are inactive ('inactive' refers to those who are not currently meeting the UK physical activity guidelines). ## Recommendations 1 and 2 ## Who should take action? Primary care practitioners – that is anyone working in primary care whose remit includes offering lifestyle advice. Examples include: exercise professionals, GPs, health trainers, health visitors, mental health professionals, midwives, pharmacists, physiotherapists and practice nurses. # Recommendation 1 Identifying adults who are inactive Identify adults who are not currently meeting the UK physical activity guidelines (see box 1). This could be done, for example: when the opportunity arises during a consultation with a primary care practitioner or while people are waiting as part of a planned session on management of long-term conditions. Use professional judgement to determine when this assessment would be most appropriate, for example, when someone is presenting with a condition that could be alleviated by physical activity. When assessing activity levels, remain sensitive to people's overall circumstances. If it is not appropriate during the current consultation, carry out an assessment at the next available opportunity. Do not rely on visual cues (for example, body weight). Use validated tools such as the general practice physical activity questionnaire (GPPAQ) to assess physical activity levels. (This is an example of a validated questionnaire for assessing the current level of physical activity of someone aged 16 to 74. The index can be cross-referred to Read Codes and can be used to determine whether brief advice might be appropriate. See government guidance on using the general practice physical activity questionnaire.) For people who are not meeting the UK guidelines, identify the most appropriate time to discuss physical activity with them. This might be during the current consultation or in a later consultation, and might involve referral to another member of the primary care team. If they agree to a future consultation, make sure it occurs at the earliest opportunity. Ensure the person at least leaves the initial consultation aware of the health benefits of physical activity (see box 2). Record the outcomes of the physical activity assessment. Use Read Codes if appropriate. (Read Codes is the standard clinical terminology system used in general practice in the UK.) Encourage people who are assessed as meeting the UK physical activity guidelines (see box 1) to maintain this level of activity. # Recommendation 2 Delivering and following up on brief advice Advise adults who have been assessed as being inactive to do more physical activity, with the aim of achieving the UK physical activity guidelines. Emphasise the benefits of physical activity. (See box 1.) When delivering brief advice, tailor it to the person's: motivations and goals (see NICE's guideline on behaviour change: general approaches) current level of activity and ability circumstances, preferences and barriers to being physically active health status (for example whether they have a medical condition or a disability). Provide information about local opportunities to be physically active for people with a range of abilities, preferences and needs. Consider giving a written outline of the advice and goals that have been discussed. Record the outcomes of the discussion. Follow up when there is another appointment or opportunity. The follow-up could consist of a conversation about what physical activity someone has been doing, progress towards their goals or towards achieving the UK physical activity guidelines (see box 1). ## Recommendations 3 to 5 ## Who should take action? Commissioners of health services, including primary care and public health services. # Recommendation 3 Incorporating brief advice in commissioning When commissioning services to prevent or treat conditions such as cardiovascular disease, type 2 diabetes and stroke or to improve mental health, ensure brief advice on physical activity is incorporated into the care pathway. Ensure brief advice on physical activity is incorporated into services for groups that are particularly likely to be inactive. This includes people aged 65 years and over, people with a disability and people from certain minority ethnic groups. Include physical activity assessment and brief advice as part of a strategy for addressing domain 2 of the public health outcomes framework indicator on the proportion of physically active and inactive adults. Ensure assessment of physical activity and the delivery of, and follow up on, brief advice (see recommendations 1 and 2) are built into local long-term disease management strategies. Highlight physical activity as an independent modifiable risk factor for many conditions (see box 1). Strategies should also raise awareness of physical activity assessment as part of relevant quality and outcomes framework (QOF) indicators. # Recommendation 4 Systems to support brief advice Ensure systems such as Read Codes are being used to identify opportunities to assess people's physical activity levels and deliver brief advice. Ensure resources (for example, standard documents and forms) and systems are available to assess, record and follow up on the provision of brief advice. Ensure information about local opportunities to be active (including non-sporting activities) is available and up to date. This could include online maps and route finding for walking or adapted cycling. # Recommendation 5 Providing information and training Provide information and training for primary care practitioners. This should cover: how physical activity promotion fits within their remit and how it can help prevent and manage a range of health conditions (see box 2) the definition of physical activity: what constitutes moderate and vigorous physical activity, and what intensity, duration and frequency of physical activity is needed to achieve the UK physical activity guidelines (see box 1) groups more likely to be inactive (see recommendation 3) misconceptions about who needs to increase their physical activity (based, for example, on visual cues such as body weight) how to undertake physical activity assessments local opportunities for physical activity the needs of specific groups, such as people with disabilities, including local opportunities for them to be physically active delivery of brief advice including, for example, the skills to motivate people to change (see NICE's guideline on behaviour change: general approaches).# Public health need and practice Increasing physical activity has the potential to significantly improve both physical and mental wellbeing, reduce all-cause mortality and improve life expectancy. For example, increasing activity levels will help prevent and manage many conditions including coronary heart disease (CHD), cancer, diabetes, musculoskeletal disorders, obesity and stroke (Department of Health's start active, stay active). Physical activity can lower the risk of Alzheimer's disease (Scarmeas et al. 2009). It has also been shown to improve symptoms in those diagnosed with depression (Rimer et al. 2012). Physical activity also has a role in enhancing psychological wellbeing by improving mood, self-perception, self-esteem and reducing stress ('Start active, stay active'). The majority of adults and many children in England do not meet the Chief Medical Officer's (CMO) recommendations for physical activity. In 2008, based on self-reporting, 39% of men and 29% of women aged 16 and over met the CMO recommendations on minimum physical activity levels (Health and Social Care Information Centre's statistics on obesity, physical activity and diet: England, 2011). (The recommended level of activity for adults at that time was 5 episodes of at least moderate-intensity activity on at least 5 days a week. In 2011, this was changed to being active daily and accumulating at least 150 minutes of moderate-intensity activity, or 75 minutes of vigorous activity, in bouts of 10 minutes or more over a week. Additional recommendations on strength and balance, and for older people and children, were also developed .) Physical activity levels vary according to income, gender, age, ethnicity, socioeconomic status and disability. People tend to be less physically active as they get older and levels of physical activity are generally lower among women than men. Physical activity levels are also lower among certain minority ethnic groups, among people from lower socioeconomic groups and among people with disabilities ('Start active, stay active'). Inactivity costs the NHS an estimated at £1.06 billion based on national cases of CHD, stroke, diabetes, colorectal cancer and breast cancer (all conditions that are potentially preventable or manageable through physical activity). This is a conservative estimate, given the exclusion of other health problems that physical activity can help manage and prevent. Examples include osteoporosis, falls and hypertension (Allender et al. 2007). The total cost of inactivity further increases when considering the wider economic costs. These include sickness absence, estimated at £5.5 billion per year, and the premature death of productive people of working age from 'lifestyle-related' diseases, estimated at £1 billion per year (Ossa and Hutton 2002). In 2008, the Department of Health's be active, be healthy plan estimated that the average cost of physical inactivity for every primary care trust (PCT) in England was £5 million. In response to NICE public health guidance 2 (2006), which endorsed brief interventions in primary care to increase physical activity, the DH developed and launched the Department of Health's let's get moving national physical activity care pathway. This care pathway endorses use of the general practitioner physical activity questionnaire (GPPAQ) to identify inactive patients in primary care. It also includes a brief intervention based on the principles of motivational interviewing to help all those classified as less than active to change their behaviour. Two additions to the hypertension quality outcomes framework (QOF) indicator set (HYP004 and HYP005) relate to physical activity (NHS Employers' 2013/14 general medical services contract: guidance and audit requirements for new and amended services). Both include the use of GPPAQ and assessment of physical activity levels in relation to hypertension in a programme aimed at the prevention of CVD (see the NHS Employers website for further information).# Considerations # Introduction The Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations, as follows. Please note: this section does not contain recommendations. # Background The recommendations have been made within the context of other national and local strategies and interventions to increase or maintain physical activity levels. Further, the availability of local opportunities to be active will influence whether brief advice leads to an increase or maintenance in people's physical activity. PHIAC noted changes to the NHS and public health systems which came into force from April 2013, when local authorities took over responsibility for many public health interventions and services. Specifically, it noted that these changes may result in some uncertainty about who will coordinate and commission work in the immediate future. PHIAC acknowledged and considered the 'making every contact count' (MECC) principle, as outlined at the 2012 NHS Future Forum, in developing this guidance. MECC suggests that by ensuring 'primary care professionals are appropriately trained and confident to make the most of opportunities with which to help people stay healthy', this will reduce system-wide costs to the NHS. # Quality and outcomes framework PHIAC considered that physical activity could be more widely linked to the prevention or management of clinical conditions, through mechanisms such as the quality and outcomes framework (QOF). This approach would, it felt, be one way to raise the profile of physical activity among primary care practitioners. In turn, this may also encourage GPs to assess people's physical activity levels and give them brief advice. # Implementation, barriers and facilitators PHIAC acknowledged that there is a need for all healthcare practitioners and policy makers to view the encouragement of physical activity as a normal, routine part of their practice. PHIAC acknowledged that there are a number of competing demands on primary care practitioners' time, both generally and during patient appointments. The recommendations allow for practitioners to deliver very brief informal advice repeatedly, if this fits better with the time available. PHIAC noted evidence that suggests brief advice could be delivered more quickly if the practitioner is knowledgeable about the benefits of (and opportunities for) physical activity. Evidence also points to the value of receiving training in delivering brief advice. PHIAC acknowledged that some primary care practitioners do not talk to people about physical activity. This may be due to a number of reasons, for example, a lack of knowledge of the benefits or the types of activity they should be recommending. PHIAC acknowledged that the attitudes of both primary care practitioners and patients are important in determining whether a brief intervention is carried out and whether it has an effect. PHIAC acknowledged that there may be fewer opportunities to be physically active in areas of high deprivation. This may be because of people's perceptions of personal safety locally or the location and accessibility of facilities such as parks and leisure centres. It could also be due to the lack of opportunities locally for example, the lack of activities such as organised walks and sports events. PHIAC acknowledged that people with long-term conditions would usually benefit from physical activity, as it is an important independent and modifiable risk factor for numerous conditions. PHIAC acknowledged that some people (such as those with a disability) may have fewer opportunities to be physically active than others. PHIAC recognised that adapting physical activity facilities or resources (as outlined in NICE's guideline on walking and cycling) is key to encouraging these groups to get involved. It also noted that knowledge of opportunities for such activity, for example, knowledge of leisure centres that have facilities for people with a disability, is another example of how this could be achieved. PHIAC noted concern from some stakeholders about the use of the general practitioner physical activity questionnaire (GPPAQ) for assessing physical activity levels. It acknowledged that a number of other methods could potentially be used, however, no evidence was available to consider these. PHIAC supported use of GPPAQ as a validated tool developed to support brief interventions. It also noted that training in the use of GPPAQ was available. # Evidence The majority of studies are not from the UK. However, PHIAC considered that most of the evidence was sufficiently applicable to inform the recommendations. PHIAC noted that brief advice has a modest, but consistent, effect on physical activity levels. PHIAC considered that the evidence was insufficient to make recommendations about the differential impact of brief advice based on duration of delivery, content or by who delivers it. There is a lack of evidence on the impact of the current infrastructure, processes and systems on both the delivery and uptake of brief advice. These include: the Department of Health's let's get moving national physical activity care pathway; and incentive systems such as QOF indicators HYP004 and HYP005. # Health economics Data on the effectiveness of brief advice, compared with usual care (that is, not receiving brief advice), were specified in terms of the probability of moving from an inactive state to an active state 1 year later. PHIAC noted that the incremental cost-effectiveness ratio (ICER) of brief advice was £1,730, compared with usual care. Thus, brief advice can be considered cost effective. PHIAC thought this was a conservative estimate.# Recommendations for research The Public Health Interventions Advisory Committee (PHIAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects. Where questions relate to the impact on physical activity, ideally this should be measured objectively as well as using self-reporting. Where relevant, studies to answer the questions below should report the differential effectiveness according to, for example: gender, socioeconomic status, age and disability. How does the duration and frequency of brief advice influence its effectiveness and cost effectiveness? For example, do 'micro interventions' of less than 1 to 2 minutes have an impact on physical activity? What impact does brief advice to promote physical activity have on mental wellbeing? What impact does the delivery of brief advice by different primary care practitioners – for example, GPs and practice nurses – have on physical activity? For example, is the perceived value of the information greater when provided by a particular primary care practitioner? How do different types of training help primary care professionals identify people who are inactive and deliver brief advice? What type of training is most effective? How can brief advice be tailored to have the greatest impact on specific groups? For example, can it be tailored to meet the needs of people of a particular gender, socioeconomic status or with a particular disability? Do primary care practitioners use NICE guidance when encouraging people to be physically active? Are the Department of Health's 'Let's get moving' physical activity care pathway and the general practice physical activity questionnaire (GPPAQ) both commonly used in primary care? How do primary care practitioners view GPPAQ and, if they do not use it, why not? What infrastructures and systems help increase the number of assessments of physical activity undertaken and the delivery of brief advice? (Examples studied could include integration of brief advice into long-term disease management strategies, or the use of incentive strategies.) More detail identified during development of this guidance is provided in gaps in the evidence.# References Allender S, Foster C, Scarborough P et al. (2007) The burden of physical activity-related ill health in the UK. Journal of Epidemiology and Community Health 61: 344–348 Khan KM, Weiler R, Blair SN (2011) Prescribing exercise in primary care. British Medical Journal 343: d4141 Ossa D, Hutton J (2002) The economic burden of physical inactivity in England. London: MEDTAP International Rimer J, Dwan K, Lawlor DA et al. (2012) Exercise for depression. Cochrane Database Systematic Review 11 7: CD004366 Scarmeas N, Luchsinger JA, Schupf N et al. (2009) Physical activity, diet, and risk of Alzheimer's disease. Journal of the American Medical Association 302 (6): 627–37 Weiler R, Stamatakis E (2010) Physical activity in the UK: a unique crossroad? British Journal of Sports Medicine (44) 13: 912–914# Summary of the methods used to develop this guidance # Introduction The reviews, primary research, commissioned reports and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Public Health Interventions Advisory Committee (PHIAC) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations. All supporting documents are listed in finding more information. # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PHIAC to help develop the recommendations. The overarching questions were Question 1: What types of brief advice are effective and cost effective in promoting physical activity in primary care? Does the method of delivery, type of advice and person delivering the advice influence the effectiveness and/or cost effectiveness of the intervention? Question 2: What type of local infrastructure and systems support effective and cost-effective delivery of brief advice on physical activity in primary care? Question 3: What are the barriers to, and facilitators for, the delivery of brief advice on physical activity in primary care? Question 4: What are the barriers to, and facilitators for, the uptake of brief advice on physical activity in primary care? The subsidiary questions were: . What types of advice are given in the intervention? . What is the diversity of the population (for example, in terms of age, gender or ethnicity)? . What is the status of the person delivering the intervention and how is it delivered? . What are the content, frequency, length and duration of the intervention? . Under what circumstances are interventions delivered? . Are there any adverse or unintended effects? . What are the patient/public views of brief advice interventions offered in primary care to promote physical activity? . What are practitioner or expert views of brief advice interventions offered in primary care to promote physical activity? . What is the role of infrastructure and systems in facilitating interventions? These questions were made more specific for each review (see reviews for this guideline for further details). # Reviewing the evidence ## Effectiveness and barriers and facilitators mixed methods review This review consisted of 2 components: Component 1 (Effectiveness) examined the effectiveness of brief advice in increasing physical activity in adults aged 19 and over. It also examined the effect of infrastructure and systems on increasing the delivery of brief advice. Component 2 (Barriers and facilitators) examined and identified factors that impact on the delivery and uptake of brief advice from both practitioner and patient perspectives. The 2 components are presented in 1 report 'Physical activity: brief advice for adults in primary care'. A number of databases were searched in March 2012 for intervention studies and quantitative and qualitative evidence on barriers and facilitators, from 1990 to 2012. See the review for this guideline of effectiveness and barriers and facilitators for details of the databases searched and of the inclusion and exclusion criteria. An initial search strategy was developed that included using categories of key words and subject terms. A focused search strategy of free text and subject heading terms was used, building on the search strategy for brief advice developed by the NICE Public Health Collaborating Centre for Physical Activity (2006). Terms were identified using concepts derived from the guidance scope. Further iterations of this search strategy were developed based on the subsequent identification of relevant records. Iterations were repeated as new concepts were identified, within the time frame of the study. Studies were included in the review if: They covered adults aged 19 years and over. Papers with varying ages were considered provided the focus of the research was adults and not children or adolescents. Participating providers include all health professionals who are responsible for delivering primary care and including, but not restricted to, all those listed as examples in the scope (community nurses, GPs, health visitors, pharmacists, physiotherapists, exercise professionals, health trainers). They covered brief advice to promote physical activity. They considered either brief advice intervention effectiveness from patient and/or practitioner perspectives and/or barriers and facilitators to the delivery and/or uptake of brief advice from patient and/or practitioner perspectives. Studies were excluded if: They covered children and young people aged 18 years and under. Interventions were offered outside of primary care or were not delivered by a primary care professional. Interventions were tailored for individuals with specific medical conditions (but not excluding interventions for individuals with risk factors for chronic conditions, for example hypertension, impaired glucose tolerance, obesity). They covered exercise referral schemes offering an assessment of need, development of a tailored physical activity programme, monitoring and follow-up (see NICE's guideline on exercise referral schemes for recommendations on exercise referral). They covered schemes that encourage physical activity – for example walking and cycling schemes (see NICE's guideline on walking and cycling). As the review was a mixed methods review containing both effectiveness and barriers and facilitators components, the inclusion and exclusion criteria for each review varied and details can be found at 'Physical activity: brief advice for adults in primary care'. ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist. Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. – Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. The evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable). ## Summarising the evidence and making evidence statements The review data was summarised in evidence tables (see the reviews for this guideline). The findings from the review were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors/public health collaborating centres (see finding more information). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope. # Cost effectiveness There was a review of economic evaluations and an economic modelling exercise. ## Review of economic evaluations A database search strategy for MEDLINE and EMBASE was developed using the search strategy for the effectiveness review that had been developed by the effectiveness review team and agreed with NICE. Search terms derived from NHS EED (a database of economic evaluations) were added to identify papers relevant to the economic evaluation. Further search strategies for additional databases specific to the economic evidence review were adapted from terms used in the MEDLINE and EMBASE strategies. Searches were limited to papers reported in English and published between 1990 and March/April 2012. Studies were included if they focused on 'full economic evaluations' (that consider costs and health/non-health consequences) of relevant types of intervention or scheme, and high quality costing studies conducted in the UK or OECD countries. Studies were excluded if they focused on burden of disease and non-comparative costing studies, or other studies which do not involve assessing the cost and related benefits/effectiveness of relevant interventions. Studies were categorised according to study type and methodological rigour and quality. Quality ratings for studies are: ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. – Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. ## Review of economic barriers and facilitators The search strategy for the economic barriers and facilitators review was based on past search strategies and studies around demand for physical activity (Anokye 2010; Harland et al. 1999) in conjunction with the search strategy developed for the effectiveness review. The search for evidence was based on 10 electronic databases, additional papers supplied by NICE and the effectiveness review team, a call for evidence distributed by NICE, a Google Scholar search of citations and a search of 6 organisational websites. Searches were limited to papers reported in English and published between 1990 and March/April 2012. Studies were included if they covered: Quantitative estimates of the statistical association (for example, correlation or regression coefficient) between uptake of/adherence to brief advice interventions and economic variables such as income, employment status, demographics, money/time costs, tastes and preferences. Qualitative data (for example, focus groups and interviews with brief intervention participants) about the economic factors relating to uptake of and adherence to brief interventions. Studies were excluded if they did not involve examining the barriers to uptake and delivery of relevant interventions, or studies that were not conducted in the UK or OECD countries. Quality ratings of included studies were undertaken as per methods outlined by NICE (2009) 'Methods for the development of NICE public health guidance' (second edition). ## Economic modelling A number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see the review modelling report for this guideline for further details). An economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. A Markov model considered a cohort of sedentary, healthy individuals over their remaining lifetime to estimate the costs and benefits of a cohort exposed to brief advice (in the first year of cycle only) compared with a cohort not exposed to brief advice (usual care). People exposed to brief advice were assumed to have a greater probability of becoming 'physically active'. States were defined in line with existing evidence on the relative risks for developing coronary heart disease (both non-fatal and fatal), or stroke (both non-fatal and fatal), or type 2 diabetes. The analysis adopted a lifetime horizon, an NHS/Personal Social Service perspective and discounted quality-adjusted life years (QALY) as a key outcome. A series of sensitivity analyses was undertaken to explore the potential effects of study design and risk of bias on pooled outcomes. In addition, cost-consequence analysis was performed to include a broader range of benefits and dis-benefits associated with brief advice and physical activity. This used data from the cost-utility model, effectiveness review and an update of the previous literature search. The results are reported in the economic modelling report for this guideline. # How PHIAC formulated the recommendations At its meetings in September 2012 the Public Health Interventions Advisory Committee (PHIAC) considered the evidence and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guidance. PHIAC developed draft recommendations through informal consensus, based on the following criteria: Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. Where possible, recommendations were linked to evidence statements (see the evidence documents for this guideline for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).# The evidence This section lists the evidence statements from the review provided by external contractors and links them to the relevant recommendations. The evidence that Public Health Interventions Advisory Committee (PHIAC) considered included: # Evidence review The review of effectiveness and barriers and facilitators was carried out by The University of Sheffield/School of Health and Related Research (ScHARR). The principal authors were: Campbell F, Blank L, Messina J, Day M, Buckley Wood H, Payne N, Goyder E and Armitage C. # Cost effectiveness The review of economic evaluations and the review of economic barriers and facilitators were carried out by Brunel University London/Health Economics Research Group (HERG). The principal authors for both reviews were Anokye N, Jones T and Fox-Rushby J. The economic modelling was carried out by Brunel University London/Health Economics Research Group (HERG). The principal authors were Anokye N, Jones T and Fox-Rushby J. In some cases the evidence was insufficient and PHIAC has made recommendations for future research. See summary of the methods used to develop this guidance for the key to quality assessments. This section also sets out a brief summary of findings from the economic analysis. The evidence statements are short summaries of evidence in a review. Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document. Evidence statement number PA8 indicates that the linked statement is numbered 8 in the review 'Physical activity: brief advice for adults in primary care'. The review and economic analysis for this guideline are available. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: evidence statements PA8, PA9, PA12, PA16, PA20; IDE Recommendation 2: evidence statements PA1, PA8, PA9, PA16, PA18, PA19, PA20; IDE Recommendation 3: evidence statements PA12, PA15, PA16, PA23, PA25, PA30; IDE Recommendation 4: evidence statements PA11, PA16, PA23, PA27, PA30; IDE Recommendation 5: evidence statements PA8, PA9, PA10, PA12, PA13, PA15, PA23, PA26, PA28, PA29, PA30 # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style. ## Evidence statement PA1 Moderate evidence from 15 studies; 4 nRCTs (4 2,3,14,15), 4 cluster RCTs (24,5, 1 6 and 1 7) and 7 RCTs (1 8 4 1,10,11,12 , 2 9,13) suggests that there is an increase in the self-reported physical activity levels in those participants who received brief advice, or who were seen by primary care professionals trained to deliver brief advice. Bull et al. 1998 ( Australia) Calfas et al. 1996 ( USA) Marcus et al. 1997 ([−USA) Elley et al. 2003 ( New Zealand) Grandes et al. 2009 ( Spain) Goldstein et al. 1999 ( USA) Marshall et al. 2005 ( Australia) Petrella et al. 2003 ( Canada) Hillsdon et al. 2002 ( UK) Harland et al. 1999 ( UK) Halbert et al. 2000 ( Australia) Little et al. 2004 ( UK) Lewis et al. 1993 ( USA) Smith et al. 2000 ( Australia) Naylor et al. 1990 ( UK) ## Evidence statement PA8 Moderate evidence from 5 studies; 2 qualitative (1 1 and 1 2) and 3 quantitative studies (all 3,4,5), suggests that perceived patient characteristics affect a practitioner's decision to discuss and/or prescribe physical activity. Ampt et al. 2009 ( Australia) Melillio et al. 2000 ( USA) Booth et al. 2006 ( Australia) Kreutzer et al. 1997 ( USA) Royals et al. 1996 ( USA) ## Evidence statement PA9 Moderate evidence from 18 studies; 8 qualitative (3 1,7,8, 4 11,12,17,18 and 1 8) and 10 quantitative studies (all 2,3,4,5,6,10,13,14,15,16) suggests that perceived likely uptake of advice, motivation to change, and receptiveness affects a practitioner's decision to discuss and/or prescribe physical activity. Practitioners are more likely to provide brief physical activity advice to patients who they perceive are most likely to act on the advice given. Ampt et al. 2009 ( Australia) Bize et al. 2007 (Switzerland) Bull et al. 1995 ( Australia) Bull et al. 1997( Australia) Buchholz et al. 2007 ( USA) Burns et al. 2000 ( USA) Douglas et al. 2006a ( UK) Douglas et al. 2006b (( UK) Gould et al. 1995 ( UK) Heintze et al. 2010 ( Germany) Horsley Tompkins et al. 2009 ( USA) Huang et al. 2004 ( USA) Kennedy et al. 2003 ( Canada) Kreuter et al. 1997 ( USA) Lawlor et al. 1999 (UK) Long et al. 1996 ( USA) Walsh et al. 1999 (, USA) Winzenberg et al. 2009 ( Australia) ## Evidence statement PA10 Moderate evidence from 8 studies; 5 qualitative (1 2, 3 4,7,8 and 1 6) and 3 quantitative studies (all 1,3,5) suggests that practitioner behaviour is influenced by perceived evidence for effectiveness of physical activity advice as well as the perceived effectiveness of physical activity to improve health. Practitioners who believe that physical activity improves health are more likely to deliver brief physical activity advice. Bull et al. 1995 ( Australia) Douglas et al. 2006a ( UK) Horsley Tompkins et al. 2009 ( USA) Huang et al. 2004 ( USA) Kennedy et al. 2003 ( Canada) Swinburn et al. 1997 ( New Zealand) Ribera et al. 2005 ( Spain) Winzenberg et al. 2009 ( Australia) ## Evidence statement PA11 Moderate evidence from 12 studies: 7 qualitative (3 1,6,7, and 4 2,8,11,12) and 5 quantitative studies (all 3,4,5,9,10) suggests that practitioners consider a lack of provision of print materials, incentives, or other support resources to be a barrier to discussing and/or prescribing physical activity. It may be that better provision of print materials to hand out to patients, financial reward for providing brief physical activity advice or addition provision of other support recourses would increase the delivery of brief physical activity advice. Ampt et al. 2009 ( Australia) Bize et al. 2007 ( Switzerland) Bull et al. 1995 ( Australia) Bull et al. 1997( Australia) Burns et al. 2000 ) USA) Douglas et al. 2006a ( UK) Douglas et al. 2006b ( UK) Huang et al. 2004 ( USA) Long et al. 1996 ( USA) McDowell et al. 1997 ( UK) Pinto et al. 1998 ( UK) Ribera et al. 2005 ( Spain) ## Evidence statement PA12 Moderate evidence from 19 papers; 9 qualitative (2 7,8 2,9,14,15,16,19 and 1 17), 9 quantitative studies (all 1,3,4,5,6,10,11,12,13), and 1 mixed methods evaluation 18 suggests that practitioners considered that time resources and conflicting priorities affected their ability to discuss and/or prescribe physical activity. Time acts as a 'proxy' for related factors such as increased workload, resulting in conflicting priorities and a need to choose between physical activity promotion and other factors which may be seen as more central to the practitioner role. Albright et al. 2000 ( USA) Bize et al. 2007 (Switzerland) Bull et al. 1995 ( Australia) Bull et al. 2010 ( UK) Buchholz et al. 2007 ( USA) Burns et al. 2000 ( USA) Douglas et al. 2006a ( UK) Douglas et al. 2006b ( UK) Huang et al. 2004 ( USA) Kennedy et al. 2003 ( Canada) Lawlor et al. 1999 ( UK) Long et al. 1996 ( USA) McKenna et al. 1998 ( UK) Melillo et al. 2000 ( USA) Patel et al. 2011 ( UK) Ribera et al. 2005 ( Spain) Swinburn et al. 1997 ( New Zealand) Van Sluijs et al. 2004 ( Netherlands) Winzenberg et al. 2009 ( Australia) ## Evidence statement PA13 Moderate evidence from 18 studies; 9 qualitative (one 1, 7 7,8,9,12,14,15,16 and 1 3) and 9 quantitative studies (all 2,3,4,5,6,10,12,17,18) suggests that practitioner confidence and knowledge (including the need for further training/support) affected their ability to discuss and/or prescribe physical activity. Greater practitioner confidence/knowledge (created through better training) increases the likelihood of delivery brief advice. Ampt et al. 2009 ( Australia) Buchholz et al. 2007 ( USA) Buffart et al. 2012 ( Australia) Bull et al. 1995 ( Australia) Bull et al.1997( Australia) Burns et al. 2000 (USA) Douglas et al. 2006a ( UK) Douglas et al. 2006b ( UK) Eadie et al. 1996 (, Qualitative, UK) Gould et al. 1995 ( UK) Gribben et al. 2000 ( New Zealand) Huang et al. 2004 ( USA) Kennedy et al. 2003 ( Canada) Pinto et al. 1998 ( UK) Ribera et al. 2005 ( Spain) Sims et al. 2004 (Australia) Van der Ploeg et al. 2007( Australia) Walsh et al. 1999 ( USA) ## Evidence statement PA15 Moderate evidence from 6 studies; 2 qualitative (all 4,5) and 4 quantitative studies (all 1,2,3,6), suggests that practitioner willingness to discuss and/or prescribe physical activity was influenced by whether they perceived this activity to be within their remit/role. Those who saw physical activity promotion as within their role were more likely to provide brief physical activity advice. Booth et al. 2006 ( Australia) Buffart et al. 2012 ( Australia) Bull et al. 1995 ( Australia) Douglas et al. 2006a ( UK) Douglas et al. 2006b ( UK) Van der Ploeg et al. 2007 ( Australia) ## Evidence statement PA16 Moderate evidence from 18 studies; 11 qualitative (3 1,4,5 6 2,11,13,14,15,18 and 2 6,17) and 7 quantitative studies (all 3,7,8,9,10,12,16), suggests that practitioners were more willing to discuss and/or prescribed physical activity where this was linked to the presenting condition (rather than as a preventative measure), that is to provide curative rather than preventative advice. Ampt et al. 2009 ( Australia) Bize et al. 2007 ( Qualitative, Switzerland) Bull et al. 1995 ( Australia) Douglas et al. 2006a ( UK) Douglas et al. 2006b ( UK) Gould et al. 1995 ( UK) Gribben et al. 2000 ( New Zealand) Horsley Tompkins et al. 2009 ( USA) Kreuter et al. 1997 ( USA) Lawlor et al. 1999 (UK) Leijon et al. 2010 ( Sweden) McDowell et al. 1997 ( UK) Melillo et al. 2000 ( USA) Patel et al. 2011 ( UK) Ribera et al. 2005 ( Spain) Schmid et al. 2009 ( Switzerland) Swinburn et al. 1997 ( New Zealand) Winzenberg et al. 2009 ( Australia) ## Evidence statement PA18 Moderate evidence from 4 qualitative studies (all 1,2,3,4) suggests that patient willingness to comply with brief physical activity advice is affected by their recall and understanding of advice. Patients who understand the advice are more likely to comply with it. Huang et al. 2004 ( USA) Ribera et al. 2006 ( Spain) Pinto et al. 1998 ( UK) Sims et al. 2004 ( Australia) ## Evidence statement PA19 Moderate evidence from 1 qualitative study (all 1), suggests that patients felt they needed to receive more preventative advice (that is, advice not linked to a presenting condition). Horne et al. 2010 ( UK) ## Evidence statement PA20 Moderate evidence from 2 qualitative studies (all 1,2) suggests that patients were less receptive to brief physical activity advice if they were unaware of physical activity recommendations. Making patients aware of physical activity recommendations would increase their willingness to comply with brief physical activity advice. Horne et al. 2010 ( UK) Sims et al. 2004 ( Australia) ## Evidence statement PA23 Moderate evidence from 10 studies; 5 qualitative (4 3,5,7,8, and 1 9), 3 quantitative (all 1,2,4), and 2 mixed methods studies (all 6,10), suggests that interventions to encourage practitioners to administer brief physical activity advice can be effective in improving practitioners' views of brief physical activity advice, which may lead to positive effects on patients' physical activity behaviours. Albright et al. 2000 ( USA) Booth et al. 2006 ( Australia) Bull et al. 2010 ( UK) Gribben et al. 2000 ( New Zealand) Leijon et al. 2010 ( Sweden) Long et al. 1996 ( USA) Patel et al. 2011 ( UK) Pinto et al. 1998 ( UK) Swinburn et al. 1997 ( New Zealand) Van Sluijs et al. 2004 ( Netherlands) ## Evidence statement PA25 Moderate evidence from 14 studies; 7 effectiveness studies (2 1,3 3 4,9,13 and 2 )10,12, and 7 barriers and facilitators studies (1 7, 5 2,5,6,11,14 and 1 8), suggests that the provision of incentives to encourage practitioners to administer brief physical activity advice or provision of incentives to patients to encourage them to act on brief physical activity advice may overcome barriers to delivery/uptake but this cannot be validated through the effectiveness evidence. ACT 2001 ( Australia) Bize et al. 2007 ( Switzerland) Bolognesi et al. 2006 ( Italy Bull et al. 1998 ( Australia) Bull et al. 1995 ( Australia) Burns et al. 2000 (USA) Douglas et al. 2006a ( UK) Gould et al. 1995 ( UK) Harland et al. 1999 ( UK) Lewis 1993 ( USA) McDowell et al. 1997 ( UK) Naylor et al. 1999 ([− UK) Pinto et al. 2005 ( USA) Ribera et al. 2005 ( Spain) ## Evidence statement PA26 Moderate evidence from 23 studies; 9 effectiveness studies (5 2,9,12,19,20 2 4,10, and 2 16,17), and 14 barriers and facilitators studies (11, and 13 3,5,6,7,8,11,13,14,15,16,21,22,23) suggests that the provision of training may encourage practitioners to administer brief physical activity advice and that the education of patients may encourage them to act on brief physical advice. In particular this may be effective in improving intervention outcomes in populations where this knowledge is found to be lacking. Ampt et al. 2009 ( Australia) Bolognesi et al. 2006 ( Italy) Buchholz et al. 2007 ( USA) Bull et al.1998 ( Australia) Burns et al.2000 (USA) Douglas et al. 2006a ( UK) Douglas et al. 2006b ( UK) Eadie et al.1996 ( UK) Elley et al. 2003 ( New Zealand) Goldstein et al. 1999 ( USA) Goodman et al. 2011 ( UK) Grandes et al. 2009 ( Spain) Horne et al. 2010 ( UK) Huang et al. 2004 ( USA) Kennedy et al. 2003 ( Canada) Lewis et al. 1993 ( USA) Marcus et al. 1997 ( USA) McDowell et al. 1997 ( UK) Petrella et al. 2003 ( Canada) Pinto et al. 2005 ( USA) Ribera et al. 2006 ( Spain) Sims 2004 ( Australia) Walsh et al. 1999 ( USA) ## Evidence statement PA27 Moderate evidence from 22 studies; 11 effectiveness studies (3 1,9,10,4 4,18,21,22 and 4 12,14,15,17), and 11 barriers and facilitators studies (3 2,7,8 and 8 3,5,6,11,13,16,19,20), suggests no benefit from the addition of written support materials to a brief advice intervention. However, it may be that the quality of currently available materials needs to improve to see an effect. ACT 2001 ( Australia) Ampt et al. 2009 ( Australia) Bize et al. 2007 (Switzerland) Bull et al. 1998 ( Australia) Bull et al. 1995 ( Australia) Burns et al. 2000 (USA) Douglas et al. 2006a ( UK) Douglas et al. 2006b ( UK) Elley et al. 2003 ( New Zealand) Grandes et al. 2009 ( Spain) Huang et al. 2004 ( USA) Little et al. 2004 ( UK) Long et al. 1996 ( USA) Marcus et al. 1997 ( USA) Marshall et al. 2005 ( Australia) McDowell et al. 1997 ( UK) Naylor 1999 ( UK) Pfeiffer et al. 2001( USA) Pinto et al. 1998 ( UK) Ribera et al. 2005 ( Spain) Smith et al. 2000 ( Australia) Swinburn et al. 1998 ( New Zealand) ## Evidence statement PA28 Moderate evidence from 18 studies; 9 effectiveness studies (2 6,9, 4 3,8,10,11 and 3 5,13,15), and 9 barriers and facilitators studies (81,2,4,7,12,14,16,17 and 1 18), suggests that whilst the evidence of relative effectiveness for brief interventions of 5 minutes or longer versus interventions of very short duration (less than 5 minutes) is inconclusive, structured interventions can help to overcome practitioner barriers to prescribing brief advice. Albright et al. 2000 ( (USA) Booth et al. 2006 ( Australia) Bull et al. 1998 ( Australia) Bull et al. 2010 ( UK) Calfas et al. 1996 ( USA) Elley et al. 2003 ( New Zealand) Gribben et al. 2000 ( New Zealand) Goldstein et al. 1999 ( USA) Grandes et al. 2009 ( Spain) Halbert et al. 2000 ( Australia) Hillsdon et al. 2002 ( UK) Leijon et al. 2010 ( Sweden) Lewis et al. 1993 ( USA) .Long et al. 1996 ( USA) Marcus et al. 1997 ( USA) Patel et al. 2011 ( UK) Pinto et al. 1998 ( UK) Swinburn et al. 1997 ( New Zealand) ## Evidence statement PA29 Moderate evidence from 7 barriers and facilitators studies (2 1,2, 4 3,4,5,6, and 1 7), suggests that time constraints resulted from conflicting priorities, and unfavourable working conditions. It seems likely that practitioners report lack of time as a proxy for a wide range of barriers to delivering brief physical activity advice and that overcoming problems such as lack of training, knowledge and confidence could act to remove the perceived barrier of lack of time. Douglas et al. 2006a ( UK) Douglas et al. 2006b ( UK) Huang et al. 2004 ( USA) McKenna et al. 1998 ( UK) Patel et al. 2011 ( UK) Ribera et al. 2005 ( Spain) Swinburn et al. 1997 ( New Zealand) ## Evidence statement PA30 Moderate evidence from 1 effectiveness (6), and 8 barriers and facilitators studies (1 2, and 7 1,3,4,5,6,7,8), suggests that the structure of the actual 'system' in which the intervention is delivered has the potential to affect both the effectiveness of the intervention and its acceptability to both patients and practitioners. It is important to note that all the structural factors outlined here need to be considered together rather than in isolation to facilitate positive changes in intervention delivery and physical activity uptake. Bize et al. 2007 ( Switzerland) Douglas et al. 2006b ( UK) Gribben et al. 2000 ( New Zealand) Leijon et al. 2010 ( Sweden) Long et al. 1996 ( USA) Marcus et al. 1997 ( USA) McDowell et al. 1997 ( UK) Pinto et al. 1998 ( UK) Walsh et al. 1999 ( USA) # Cost effectiveness There was a review of economic evaluations, a review of economic barriers and facilitators and an economic modelling exercise. ## Review of economic evaluations Three papers were reviewed, 2 of which were based on a UK and an Australian population. The only overlap with previous economic literature influencing public health guidance in this area was the cost-effectiveness model developed for the previous NICE guidance (Matrix 2006). Moderate, but limited evidence from 3 studies suggested that brief advice on physical activity in primary care is more cost effective than usual care. The evidence should be interpreted with caution as the evidence based on effectiveness was weak and did not fully explore uncertainty. Therefore, a de novo modelling of the cost effectiveness of brief advice was needed to improve knowledge on its efficiency. ## Review of economic barriers and facilitators Six papers were reviewed: 5 quantitative studies from the USA and 1 qualitative study from New Zealand. Poor quality evidence suggested that a perceived lack of adequate financial incentive for healthcare professionals is a barrier to the delivery of brief advice on physical activity in primary care. This was irrespective of whether the advice was provided by a nurse or GP. Moderate evidence suggested a weakly positive correlation between the time spent on (or available for) counselling and the delivery of brief advice on physical activity in primary care, regardless of whether it was provided by a GP or nurse. There was no interpretable policy-relevant evidence on the role of remuneration in the delivery of brief advice on physical activity. There was no interpretable evidence on the role of other resources in the delivery of brief advice on physical activity. # Economic modelling A number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see the economic modelling report for this guideline for the full modelling report and further details of the results). The analysis adopted a lifetime horizon, an NHS/Personal Social Service perspective and discounted quality-adjusted life years (QALY) as a key outcome. Uncertainty over the model results was estimated by deterministic sensitivity analysis, scenario analysis, and probabilistic sensitivity analysis. Deterministic analysis was used to estimate the impact of alternative model scenarios. Compared with usual care, the incremental cost-effectiveness ratio (ICER) of brief advice was £1730 and thus can be considered cost effective. When brief advice was compared with usual care (the 'base case'), uncertainties were explored through a series of analyses. In most cases the base case results were robust, but they were sensitive to the duration of protective effects of physical activity, mental health gains from physical activity, changes in infrastructure and age of cohort. The impact of changing the age at which physical activity started, post-brief advice, to 54 years and older resulted in brief advice being cheaper and more effective compared with usual care (this is termed as brief advice 'dominating' usual care). Thus, the strength of the cost-effectiveness results was even greater for people aged 54 years and older. Uncertainty over the model results was estimated by probabilistic sensitivity analysis. Probabilistic sensitivity analysis showed a 99.9% chance that brief advice will be cost effective if an additional QALY is valued at £20,000. While the economic model was based on the previous economic model (Matrix 2006) used to support developing NICE public health guidance 2, this model offered a number of improvements including: ) time-based modelling ) mental health and wellbeing as well as infrastructure (considered where permitted by the evidence) ) more extensive exploration of uncertainty around the ICERs ) more conservative assumptions around changes in physical activity over time ) use of meta-analysed effectiveness data. Overall, brief physical activity advice in primary was found to be cost effective.# Gaps in the evidence The Public Health Interventions Advisory Committee (PHIAC) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence and stakeholder comments. These gaps are set out below. . Whether practitioners are more likely to give brief advice if it can be delivered effectively in less than a few minutes. . The effectiveness of differing durations of brief advice on physical activity levels. . What information should be provided (or not provided) when delivering brief advice. . What infrastructure and systems are effective in increasing delivery – for example, whether the use of incentives increases the number of brief interventions carried out by practitioners. . The impact of brief advice in increasing physical activity levels, as quantified by objective measures and in comparison with self-reported measures. . Whether any specific, or combination of, behaviour-change techniques should be used to deliver brief advice. . Whether practitioner knowledge and motivation have an impact on the delivery of brief advice. . Whether brief advice is more effective when delivered as the opportunity arises, or during an appointment made specifically for the task. . The effectiveness and cost effectiveness of brief advice in increasing physical activity levels among identified groups at risk of health conditions due to inactivity. This includes, for example, people with disabilities, those aged 65 and over, and people with a lower socioeconomic status. In other words, whether tailoring brief advice by population group is more effective than giving generic advice. . Barriers to, and facilitators for, increasing physical activity levels in response to brief advice. . The effectiveness of specific brief advice interventions (in terms of frequency, intensity and duration) and maintenance of behaviour change in the longer term . A comparison of the relative effectiveness of brief advice for physical activity in the general population compared with a sedentary population. . Whether there is a differential effect of different durations and frequency of follow-up on the effectiveness of brief advice to increase physical activity. . Current level of use of the original brief intervention recommendations from NICE public health guidance 2, general practice physical activity questionnaire (GPPAQ) and the 'Let's get moving' physical activity care pathway. The Committee made a number of recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in recommendations for research.# Finding more information You can see everything NICE says on this topic in the NICE Pathway on physical activity. To find NICE guidance on related topics, including guidance in development, see the NICE webpage on physical activity. For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed. NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.	{'Recommendations ': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe evidence statements underpinning the recommendations are listed in the evidence section. Full details of the evidence are in the evidence reviews and economic modelling report for this guideline.\n\nSee also the recommendations for research and gaps in the evidence.\n\n# Background\n\nThe recommendations have been made within the context of other national and local strategies and interventions to increase or maintain physical activity levels in the population.\n\nThese might include addressing barriers to activity, for example, through changes to the physical environment or other measures to support an active lifestyle. (See NICE's guidelines on physical activity and the environment and walking and cycling).\n\nThe availability of local opportunities to be active will influence whether brief advice has an impact on people's physical activity levels.\n\n## Brief advice\n\nThe term 'brief advice' is used in this guidance to mean verbal advice, discussion, negotiation or encouragement, with or without written or other support or follow-up. It can vary from basic advice to a more extended, individually focused discussion.\n\nDefinition\n\nPhysical activity is defined as any bodily movement produced by skeletal muscles that requires energy expenditure. It takes many forms, occurs in many settings, and has many purposes (such as daily activity, active recreation, and sport).\n\nHealth-enhancing physical activity includes multiple types of activity: cardiovascular; muscle and bone strengthening; and balance training (see the UK Chief Medical Officers' physical activity guidelines for more information).\n\nNational recommendations\n\nFollow the UK recommendations on the type, intensity and duration of activity (see the UK Chief Medical Officers' physical activity guidelines).\n\nPrevents and helps to manage conditions such as coronary heart disease, type\xa02 diabetes, stroke, mental health problems, musculoskeletal conditions and some cancers.\n\nHas a positive effect on wellbeing, mood, sense of achievement, relaxation and release from daily stress.\n\n## Whose health will benefit?\n\nAdults aged 19 and older who are inactive ('inactive' refers to those who are not currently meeting the UK physical activity guidelines).\n\n## Recommendations 1 and 2\n\n## Who should take action?\n\nPrimary care practitioners – that is anyone working in primary care whose remit includes offering lifestyle advice. Examples include: exercise professionals, GPs, health trainers, health visitors, mental health professionals, midwives, pharmacists, physiotherapists and practice nurses.\n\n# Recommendation 1 Identifying adults who are inactive\n\nIdentify adults who are not currently meeting the UK physical activity guidelines (see box\xa01). This could be done, for example:\n\n\n\nwhen the opportunity arises during a consultation with a primary care practitioner or while people are waiting\n\nas part of a planned session on management of long-term conditions.\n\n\n\nUse professional judgement to determine when this assessment would be most appropriate, for example, when someone is presenting with a condition that could be alleviated by physical activity. When assessing activity levels, remain sensitive to people's overall circumstances. If it is not appropriate during the current consultation, carry out an assessment at the next available opportunity.\n\nDo not rely on visual cues (for example, body weight). Use validated tools such as the general practice physical activity questionnaire (GPPAQ) to assess physical activity levels. (This is an example of a validated questionnaire for assessing the current level of physical activity of someone aged 16 to 74. The index can be cross-referred to Read Codes and can be used to determine whether brief advice might be appropriate. See government guidance on using the general practice physical activity questionnaire.)\n\nFor people who are not meeting the UK guidelines, identify the most appropriate time to discuss physical activity with them. This might be during the current consultation or in a later consultation, and might involve referral to another member of the primary care team. If they agree to a future consultation, make sure it occurs at the earliest opportunity. Ensure the person at least leaves the initial consultation aware of the health benefits of physical activity (see box\xa02).\n\nRecord the outcomes of the physical activity assessment. Use Read Codes if appropriate. (Read Codes is the standard clinical terminology system used in general practice in the UK.)\n\nEncourage people who are assessed as meeting the UK physical activity guidelines (see box\xa01) to maintain this level of activity.\n\n# Recommendation 2 Delivering and following up on brief advice\n\nAdvise adults who have been assessed as being inactive to do more physical activity, with the aim of achieving the UK physical activity guidelines. Emphasise the benefits of physical activity. (See box\xa01.)\n\nWhen delivering brief advice, tailor it to the person's:\n\n\n\nmotivations and goals (see NICE's guideline on behaviour change: general approaches)\n\ncurrent level of activity and ability\n\ncircumstances, preferences and barriers to being physically active\n\nhealth status (for example whether they have a medical condition or a disability).\n\n\n\nProvide information about local opportunities to be physically active for people with a range of abilities, preferences and needs.\n\nConsider giving a written outline of the advice and goals that have been discussed.\n\nRecord the outcomes of the discussion.\n\nFollow up when there is another appointment or opportunity. The follow-up could consist of a conversation about what physical activity someone has been doing, progress towards their goals or towards achieving the UK physical activity guidelines (see box\xa01).\n\n## Recommendations 3 to 5\n\n## Who should take action?\n\nCommissioners of health services, including primary care and public health services.\n\n# Recommendation 3 Incorporating brief advice in commissioning\n\nWhen commissioning services to prevent or treat conditions such as cardiovascular disease, type\xa02 diabetes and stroke or to improve mental health, ensure brief advice on physical activity is incorporated into the care pathway.\n\nEnsure brief advice on physical activity is incorporated into services for groups that are particularly likely to be inactive. This includes people aged 65\xa0years and over, people with a disability and people from certain minority ethnic groups.\n\nInclude physical activity assessment and brief advice as part of a strategy for addressing domain\xa02 of the public health outcomes framework indicator on the proportion of physically active and inactive adults.\n\nEnsure assessment of physical activity and the delivery of, and follow up on, brief advice (see recommendations 1 and\xa02) are built into local long-term disease management strategies. Highlight physical activity as an independent modifiable risk factor for many conditions (see box\xa01). Strategies should also raise awareness of physical activity assessment as part of relevant quality and outcomes framework (QOF) indicators.\n\n# Recommendation 4 Systems to support brief advice\n\nEnsure systems such as Read Codes are being used to identify opportunities to assess people's physical activity levels and deliver brief advice.\n\nEnsure resources (for example, standard documents and forms) and systems are available to assess, record and follow up on the provision of brief advice.\n\nEnsure information about local opportunities to be active (including non-sporting activities) is available and up to date. This could include online maps and route finding for walking or adapted cycling.\n\n# Recommendation 5 Providing information and training\n\nProvide information and training for primary care practitioners. This should cover:\n\nhow physical activity promotion fits within their remit and how it can help prevent and manage a range of health conditions (see box\xa02)\n\nthe definition of physical activity: what constitutes moderate and vigorous physical activity, and what intensity, duration and frequency of physical activity is needed to achieve the UK physical activity guidelines (see box\xa01)\n\ngroups more likely to be inactive (see recommendation\xa03)\n\nmisconceptions about who needs to increase their physical activity (based, for example, on visual cues such as body weight)\n\nhow to undertake physical activity assessments\n\nlocal opportunities for physical activity\n\nthe needs of specific groups, such as people with disabilities, including local opportunities for them to be physically active\n\ndelivery of brief advice including, for example, the skills to motivate people to change (see NICE's guideline on behaviour change: general approaches).", 'Public health need and practice': "Increasing physical activity has the potential to significantly improve both physical and mental wellbeing, reduce all-cause mortality and improve life expectancy. For example, increasing activity levels will help prevent and manage many conditions including coronary heart disease (CHD), cancer, diabetes, musculoskeletal disorders, obesity and stroke (Department of Health's start active, stay active). Physical activity can lower the risk of Alzheimer's disease (Scarmeas et al. 2009). It has also been shown to improve symptoms in those diagnosed with depression (Rimer et al. 2012). Physical activity also has a role in enhancing psychological wellbeing by improving mood, self-perception, self-esteem and reducing stress ('Start active, stay active').\n\nThe majority of adults and many children in England do not meet the Chief Medical Officer's (CMO) recommendations for physical activity. In 2008, based on self-reporting, 39% of men and 29% of women aged 16 and over met the CMO recommendations on minimum physical activity levels (Health and Social Care Information Centre's statistics on obesity, physical activity and diet: England, 2011). (The recommended level of activity for adults at that time was 5\xa0episodes of at least moderate-intensity activity on at least 5\xa0days a week. In 2011, this was changed to being active daily and accumulating at least 150\xa0minutes of moderate-intensity activity, or 75\xa0minutes of vigorous activity, in bouts of 10\xa0minutes or more over a week. Additional recommendations on strength and balance, and for older people and children, were also developed ['Start active, stay active'].)\n\nPhysical activity levels vary according to income, gender, age, ethnicity, socioeconomic status and disability. People tend to be less physically active as they get older and levels of physical activity are generally lower among women than men. Physical activity levels are also lower among certain minority ethnic groups, among people from lower socioeconomic groups and among people with disabilities ('Start active, stay active').\n\nInactivity costs the NHS an estimated at £1.06\xa0billion based on national cases of CHD, stroke, diabetes, colorectal cancer and breast cancer (all conditions that are potentially preventable or manageable through physical activity). This is a conservative estimate, given the exclusion of other health problems that physical activity can help manage and prevent. Examples include osteoporosis, falls and hypertension (Allender et al. 2007).\n\nThe total cost of inactivity further increases when considering the wider economic costs. These include sickness absence, estimated at £5.5\xa0billion per year, and the premature death of productive people of working age from 'lifestyle-related' diseases, estimated at £1\xa0billion per year (Ossa and Hutton 2002). In 2008, the Department of Health's be active, be healthy plan estimated that the average cost of physical inactivity for every primary care trust (PCT) in England was £5\xa0million.\n\nIn response to NICE public health guidance\xa02 (2006), which endorsed brief interventions in primary care to increase physical activity, the DH developed and launched the Department of Health's let's get moving national physical activity care pathway. This care pathway endorses use of the general practitioner physical activity questionnaire (GPPAQ) to identify inactive patients in primary care. It also includes a brief intervention based on the principles of motivational interviewing to help all those classified as less than active to change their behaviour.\n\nTwo additions to the hypertension quality outcomes framework (QOF) indicator set (HYP004 and HYP005) relate to physical activity (NHS Employers' 2013/14 general medical services contract: guidance and audit requirements for new and amended services). Both include the use of GPPAQ and assessment of physical activity levels in relation to hypertension in a programme aimed at the prevention of CVD (see the NHS Employers website for further information).", 'Considerations': "# Introduction\n\nThe Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations, as follows. Please note: this section does not contain recommendations.\n\n# Background\n\nThe recommendations have been made within the context of other national and local strategies and interventions to increase or maintain physical activity levels. Further, the availability of local opportunities to be active will influence whether brief advice leads to an increase or maintenance in people's physical activity.\n\nPHIAC noted changes to the NHS and public health systems which came into force from April\xa02013, when local authorities took over responsibility for many public health interventions and services. Specifically, it noted that these changes may result in some uncertainty about who will coordinate and commission work in the immediate future.\n\nPHIAC acknowledged and considered the 'making every contact count' (MECC) principle, as outlined at the 2012 NHS Future Forum, in developing this guidance. MECC suggests that by ensuring 'primary care professionals are appropriately trained and confident to make the most of opportunities with which to help people stay healthy', this will reduce system-wide costs to the NHS.\n\n# Quality and outcomes framework\n\nPHIAC considered that physical activity could be more widely linked to the prevention or management of clinical conditions, through mechanisms such as the quality and outcomes framework (QOF). This approach would, it felt, be one way to raise the profile of physical activity among primary care practitioners. In turn, this may also encourage GPs to assess people's physical activity levels and give them brief advice.\n\n# Implementation, barriers and facilitators\n\nPHIAC acknowledged that there is a need for all healthcare practitioners and policy makers to view the encouragement of physical activity as a normal, routine part of their practice.\n\nPHIAC acknowledged that there are a number of competing demands on primary care practitioners' time, both generally and during patient appointments. The recommendations allow for practitioners to deliver very brief informal advice repeatedly, if this fits better with the time available.\n\nPHIAC noted evidence that suggests brief advice could be delivered more quickly if the practitioner is knowledgeable about the benefits of (and opportunities for) physical activity. Evidence also points to the value of receiving training in delivering brief advice.\n\nPHIAC acknowledged that some primary care practitioners do not talk to people about physical activity. This may be due to a number of reasons, for example, a lack of knowledge of the benefits or the types of activity they should be recommending. PHIAC acknowledged that the attitudes of both primary care practitioners and patients are important in determining whether a brief intervention is carried out and whether it has an effect.\n\nPHIAC acknowledged that there may be fewer opportunities to be physically active in areas of high deprivation. This may be because of people's perceptions of personal safety locally or the location and accessibility of facilities such as parks and leisure centres. It could also be due to the lack of opportunities locally for example, the lack of activities such as organised walks and sports events.\n\nPHIAC acknowledged that people with long-term conditions would usually benefit from physical activity, as it is an important independent and modifiable risk factor for numerous conditions.\n\nPHIAC acknowledged that some people (such as those with a disability) may have fewer opportunities to be physically active than others. PHIAC recognised that adapting physical activity facilities or resources (as outlined in NICE's guideline on walking and cycling) is key to encouraging these groups to get involved. It also noted that knowledge of opportunities for such activity, for example, knowledge of leisure centres that have facilities for people with a disability, is another example of how this could be achieved.\n\nPHIAC noted concern from some stakeholders about the use of the general practitioner physical activity questionnaire (GPPAQ) for assessing physical activity levels. It acknowledged that a number of other methods could potentially be used, however, no evidence was available to consider these. PHIAC supported use of GPPAQ as a validated tool developed to support brief interventions. It also noted that training in the use of GPPAQ was available.\n\n# Evidence\n\nThe majority of studies are not from the UK. However, PHIAC considered that most of the evidence was sufficiently applicable to inform the recommendations.\n\nPHIAC noted that brief advice has a modest, but consistent, effect on physical activity levels.\n\nPHIAC considered that the evidence was insufficient to make recommendations about the differential impact of brief advice based on duration of delivery, content or by who delivers it.\n\nThere is a lack of evidence on the impact of the current infrastructure, processes and systems on both the delivery and uptake of brief advice. These include: the Department of Health's let's get moving national physical activity care pathway; and incentive systems such as QOF indicators HYP004 and HYP005.\n\n# Health economics\n\nData on the effectiveness of brief advice, compared with usual care (that is, not receiving brief advice), were specified in terms of the probability of moving from an inactive state to an active state 1\xa0year later. PHIAC noted that the incremental cost-effectiveness ratio (ICER) of brief advice was £1,730, compared with usual care. Thus, brief advice can be considered cost effective. PHIAC thought this was a conservative estimate.", 'Recommendations for research': "The Public Health Interventions Advisory Committee (PHIAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects.\n\nWhere questions relate to the impact on physical activity, ideally this should be measured objectively as well as using self-reporting.\n\nWhere relevant, studies to answer the questions below should report the differential effectiveness according to, for example: gender, socioeconomic status, age and disability.\n\nHow does the duration and frequency of brief advice influence its effectiveness and cost effectiveness? For example, do 'micro interventions' of less than 1 to 2\xa0minutes have an impact on physical activity?\n\nWhat impact does brief advice to promote physical activity have on mental wellbeing?\n\nWhat impact does the delivery of brief advice by different primary care practitioners – for example, GPs and practice nurses – have on physical activity? For example, is the perceived value of the information greater when provided by a particular primary care practitioner?\n\nHow do different types of training help primary care professionals identify people who are inactive and deliver brief advice? What type of training is most effective?\n\nHow can brief advice be tailored to have the greatest impact on specific groups? For example, can it be tailored to meet the needs of people of a particular gender, socioeconomic status or with a particular disability?\n\nDo primary care practitioners use NICE guidance when encouraging people to be physically active?\n\nAre the Department of Health's 'Let's get moving' physical activity care pathway and the general practice physical activity questionnaire (GPPAQ) both commonly used in primary care? How do primary care practitioners view GPPAQ and, if they do not use it, why not?\n\nWhat infrastructures and systems help increase the number of assessments of physical activity undertaken and the delivery of brief advice? (Examples studied could include integration of brief advice into long-term disease management strategies, or the use of incentive strategies.)\n\nMore detail identified during development of this guidance is provided in gaps in the evidence.", 'References': "Allender S, Foster C, Scarborough P et al. (2007) The burden of physical activity-related ill health in the UK. Journal of Epidemiology and Community Health 61: 344–348\n\nKhan KM, Weiler R, Blair SN (2011) Prescribing exercise in primary care. British Medical Journal 343: d4141\n\nOssa D, Hutton J (2002) The economic burden of physical inactivity in England. London: MEDTAP International\n\nRimer J, Dwan K, Lawlor DA et al. (2012) Exercise for depression. Cochrane Database Systematic Review 11 7: CD004366\n\nScarmeas N, Luchsinger JA, Schupf N et al. (2009) Physical activity, diet, and risk of Alzheimer's disease. Journal of the American Medical Association 302 (6): 627–37\n\nWeiler R, Stamatakis E (2010) Physical activity in the UK: a unique crossroad? British Journal of Sports Medicine (44) 13: 912–914", 'Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews, primary research, commissioned reports and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Public Health Interventions Advisory Committee (PHIAC) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in finding more information.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PHIAC to help develop the recommendations. The overarching questions were\n\nQuestion 1: What types of brief advice are effective and cost effective in promoting physical activity in primary care? Does the method of delivery, type of advice and person delivering the advice influence the effectiveness and/or cost effectiveness of the intervention?\n\nQuestion 2: What type of local infrastructure and systems support effective and cost-effective delivery of brief advice on physical activity in primary care?\n\nQuestion 3: What are the barriers to, and facilitators for, the delivery of brief advice on physical activity in primary care?\n\nQuestion 4: What are the barriers to, and facilitators for, the uptake of brief advice on physical activity in primary care?\n\nThe subsidiary questions were:\n\n. What types of advice are given in the intervention?\n\n. What is the diversity of the population (for example, in terms of age, gender or ethnicity)?\n\n. What is the status of the person delivering the intervention and how is it delivered?\n\n. What are the content, frequency, length and duration of the intervention?\n\n. Under what circumstances are interventions delivered?\n\n. Are there any adverse or unintended effects?\n\n. What are the patient/public views of brief advice interventions offered in primary care to promote physical activity?\n\n. What are practitioner or expert views of brief advice interventions offered in primary care to promote physical activity?\n\n. What is the role of infrastructure and systems in facilitating interventions?\n\nThese questions were made more specific for each review (see reviews for this guideline for further details).\n\n# Reviewing the evidence\n\n## Effectiveness and barriers and facilitators mixed methods review\n\nThis review consisted of 2 components:\n\nComponent 1 (Effectiveness) examined the effectiveness of brief advice in increasing physical activity in adults aged 19 and over. It also examined the effect of infrastructure and systems on increasing the delivery of brief advice.\n\nComponent 2 (Barriers and facilitators) examined and identified factors that impact on the delivery and uptake of brief advice from both practitioner and patient perspectives.\n\nThe 2 components are presented in 1 report 'Physical activity: brief advice for adults in primary care'.\n\nA number of databases were searched in March 2012 for intervention studies and quantitative and qualitative evidence on barriers and facilitators, from 1990 to 2012. See the review for this guideline of effectiveness and barriers and facilitators for details of the databases searched and of the inclusion and exclusion criteria.\n\nAn initial search strategy was developed that included using categories of key words and subject terms. A focused search strategy of free text and subject heading terms was used, building on the search strategy for brief advice developed by the NICE Public Health Collaborating Centre for Physical Activity (2006). Terms were identified using concepts derived from the guidance scope.\n\nFurther iterations of this search strategy were developed based on the subsequent identification of relevant records. Iterations were repeated as new concepts were identified, within the time frame of the study.\n\nStudies were included in the review if:\n\nThey covered adults aged 19\xa0years and over. Papers with varying ages were considered provided the focus of the research was adults and not children or adolescents. Participating providers include all health professionals who are responsible for delivering primary care and including, but not restricted to, all those listed as examples in the scope (community nurses, GPs, health visitors, pharmacists, physiotherapists, exercise professionals, health trainers).\n\nThey covered brief advice to promote physical activity.\n\nThey considered either brief advice intervention effectiveness from patient and/or practitioner perspectives and/or barriers and facilitators to the delivery and/or uptake of brief advice from patient and/or practitioner perspectives.\n\nStudies were excluded if:\n\nThey covered children and young people aged 18\xa0years and under.\n\nInterventions were offered outside of primary care or were not delivered by a primary care professional.\n\nInterventions were tailored for individuals with specific medical conditions (but not excluding interventions for individuals with risk factors for chronic conditions, for example hypertension, impaired glucose tolerance, obesity).\n\nThey covered exercise referral schemes offering an assessment of need, development of a tailored physical activity programme, monitoring and follow-up (see NICE's guideline on exercise referral schemes for recommendations on exercise referral).\n\nThey covered schemes that encourage physical activity – for example walking and cycling schemes (see NICE's guideline on walking and cycling).\n\nAs the review was a mixed methods review containing both effectiveness and barriers and facilitators components, the inclusion and exclusion criteria for each review varied and details can be found at 'Physical activity: brief advice for adults in primary care'.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist. Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nThe evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable).\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see the reviews for this guideline).\n\nThe findings from the review were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors/public health collaborating centres (see finding more information). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and an economic modelling exercise.\n\n## Review of economic evaluations\n\nA database search strategy for MEDLINE and EMBASE was developed using the search strategy for the effectiveness review that had been developed by the effectiveness review team and agreed with NICE. Search terms derived from NHS EED (a database of economic evaluations) were added to identify papers relevant to the economic evaluation.\n\nFurther search strategies for additional databases specific to the economic evidence review were adapted from terms used in the MEDLINE and EMBASE strategies. Searches were limited to papers reported in English and published between 1990 and March/April\xa02012.\n\nStudies were included if they focused on 'full economic evaluations' (that consider costs and health/non-health consequences) of relevant types of intervention or scheme, and high quality costing studies conducted in the UK or OECD countries. Studies were excluded if they focused on burden of disease and non-comparative costing studies, or other studies which do not involve assessing the cost and related benefits/effectiveness of relevant interventions. Studies were categorised according to study type and methodological rigour and quality. Quality ratings for studies are:\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\n## Review of economic barriers and facilitators\n\nThe search strategy for the economic barriers and facilitators review was based on past search strategies and studies around demand for physical activity (Anokye 2010; Harland et al. 1999) in conjunction with the search strategy developed for the effectiveness review. The search for evidence was based on 10 electronic databases, additional papers supplied by NICE and the effectiveness review team, a call for evidence distributed by NICE, a Google Scholar search of citations and a search of 6 organisational websites. Searches were limited to papers reported in English and published between 1990 and March/April\xa02012.\n\nStudies were included if they covered:\n\nQuantitative estimates of the statistical association (for example, correlation or regression coefficient) between uptake of/adherence to brief advice interventions and economic variables such as income, employment status, demographics, money/time costs, tastes and preferences.\n\nQualitative data (for example, focus groups and interviews with brief intervention participants) about the economic factors relating to uptake of and adherence to brief interventions.\n\nStudies were excluded if they did not involve examining the barriers to uptake and delivery of relevant interventions, or studies that were not conducted in the UK or OECD countries. Quality ratings of included studies were undertaken as per methods outlined by NICE (2009) 'Methods for the development of NICE public health guidance' (second edition).\n\n## Economic modelling\n\nA number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see the review modelling report for this guideline for further details).\n\nAn economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness.\n\nA Markov model considered a cohort of sedentary, healthy individuals over their remaining lifetime to estimate the costs and benefits of a cohort exposed to brief advice (in the first year of cycle only) compared with a cohort not exposed to brief advice (usual care).\n\nPeople exposed to brief advice were assumed to have a greater probability of becoming 'physically active'. States were defined in line with existing evidence on the relative risks for developing coronary heart disease (both non-fatal and fatal), or stroke (both non-fatal and fatal), or type\xa02 diabetes.\n\nThe analysis adopted a lifetime horizon, an NHS/Personal Social Service perspective and discounted quality-adjusted life years (QALY) as a key outcome.\n\nA series of sensitivity analyses was undertaken to explore the potential effects of study design and risk of bias on pooled outcomes. In addition, cost-consequence analysis was performed to include a broader range of benefits and dis-benefits associated with brief advice and physical activity. This used data from the cost-utility model, effectiveness review and an update of the previous literature search.\n\nThe results are reported in the economic modelling report for this guideline.\n\n# How PHIAC formulated the recommendations\n\nAt its meetings in September 2012 the Public Health Interventions Advisory Committee (PHIAC) considered the evidence and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nPHIAC developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to evidence statements (see the evidence documents for this guideline for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).", 'The evidence ': "This section lists the evidence statements from the review provided by external contractors and links them to the relevant recommendations.\n\nThe evidence that Public Health Interventions Advisory Committee (PHIAC) considered included:\n\n# Evidence review\n\nThe review of effectiveness and barriers and facilitators was carried out by The University of Sheffield/School of Health and Related Research (ScHARR). The principal authors were: Campbell F, Blank L, Messina J, Day M, Buckley Wood H, Payne N, Goyder E and Armitage\xa0C.\n\n# Cost effectiveness\n\nThe review of economic evaluations and the review of economic barriers and facilitators were carried out by Brunel University London/Health Economics Research Group (HERG). The principal authors for both reviews were Anokye N, Jones T and Fox-Rushby\xa0J.\n\nThe economic modelling was carried out by Brunel University London/Health Economics Research Group (HERG). The principal authors were Anokye N, Jones T and Fox-Rushby\xa0J.\n\nIn some cases the evidence was insufficient and PHIAC has made recommendations for future research.\n\nSee summary of the methods used to develop this guidance for the key to quality assessments.\n\nThis section also sets out a brief summary of findings from the economic analysis.\n\nThe evidence statements are short summaries of evidence in a review. Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document.\n\nEvidence statement number PA8 indicates that the linked statement is numbered 8 in the review 'Physical activity: brief advice for adults in primary care'.\n\nThe review and economic analysis for this guideline are available.\n\nWhere a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: evidence statements PA8, PA9, PA12, PA16, PA20; IDE\n\nRecommendation 2: evidence statements PA1, PA8, PA9, PA16, PA18, PA19, PA20; IDE\n\nRecommendation 3: evidence statements PA12, PA15, PA16, PA23, PA25, PA30; IDE\n\nRecommendation 4: evidence statements PA11, PA16, PA23, PA27, PA30; IDE\n\nRecommendation 5: evidence statements PA8, PA9, PA10, PA12, PA13, PA15, PA23, PA26, PA28, PA29, PA30\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement PA1\n\nModerate evidence from 15 studies; 4 nRCTs (4 [−]2,3,14,15), 4 cluster RCTs (2[++]4,5, 1 [+]6 and 1 [-]7) and 7 RCTs (1 [++]8 4 [+]1,10,11,12 , 2 [−]9,13) suggests that there is an increase in the self-reported physical activity levels in those participants who received brief advice, or who were seen by primary care professionals trained to deliver brief advice.\n\nBull et al. 1998 ([+] Australia)\n\nCalfas et al. 1996 ([−] USA)\n\nMarcus et al. 1997 ([−USA)\n\nElley et al. 2003 ([++] New Zealand)\n\nGrandes et al. 2009 ([++] Spain)\n\nGoldstein et al. 1999 ([+] USA)\n\nMarshall et al. 2005 ([−] Australia)\n\nPetrella et al. 2003 ([++] Canada)\n\nHillsdon et al. 2002 ([−] UK)\n\nHarland et al. 1999 ([+] UK)\n\nHalbert et al. 2000 ([+] Australia)\n\nLittle et al. 2004 ([+] UK)\n\nLewis et al. 1993 ([−] USA)\n\nSmith et al. 2000 ([−] Australia)\n\nNaylor et al. 1990 ([−] UK)\n\n## Evidence statement PA8\n\nModerate evidence from 5 studies; 2 qualitative (1 [++]1 and 1 [+]2) and 3 quantitative studies (all [+]3,4,5), suggests that perceived patient characteristics affect a practitioner's decision to discuss and/or prescribe physical activity.\n\nAmpt et al. 2009 ([++] Australia)\n\nMelillio et al. 2000 ([+] USA)\n\nBooth et al. 2006 ([+] Australia)\n\nKreutzer et al. 1997 ([+] USA)\n\nRoyals et al. 1996 ([+] USA)\n\n## Evidence statement PA9\n\nModerate evidence from 18 studies; 8 qualitative (3 [++]1,7,8, 4 [+]11,12,17,18 and\xa01 [−]8)\xa0and 10 quantitative studies (all [+]2,3,4,5,6,10,13,14,15,16) suggests that perceived likely uptake of advice, motivation to change, and receptiveness affects a practitioner's decision to discuss and/or prescribe physical activity. Practitioners are more likely to provide brief physical activity advice to patients who they perceive are most likely to act on the advice given.\n\nAmpt et al. 2009 ([++] Australia)\n\nBize et al. 2007 ([+]Switzerland)\n\nBull et al. 1995 ([+] Australia)\n\nBull et al. 1997([+] Australia)\n\nBuchholz et al. 2007 ([+] USA)\n\nBurns et al. 2000 ([+] USA)\n\nDouglas et al. 2006a ([++] UK)\n\nDouglas et al. 2006b (([++] UK)\n\nGould et al. 1995 ([−] UK)\n\nHeintze et al. 2010 ([+] Germany)\n\nHorsley Tompkins et al. 2009 ([+] USA)\n\nHuang et al. 2004 ([+] USA)\n\nKennedy et al. 2003 ([+] Canada)\n\nKreuter et al. 1997 ([+] USA)\n\nLawlor et al. 1999 ([+]UK)\n\nLong et al. 1996 ([+] USA)\n\nWalsh et al. 1999 ([+], USA)\n\nWinzenberg et al. 2009 ([+] Australia)\n\n## Evidence statement PA10\n\nModerate evidence from 8 studies; 5 qualitative (1 [++]2, 3 [+]4,7,8 and 1 [−]6) and 3 quantitative studies (all [+]1,3,5) suggests that practitioner behaviour is influenced by perceived evidence for effectiveness of physical activity advice as well as the perceived effectiveness of physical activity to improve health. Practitioners who believe that physical activity improves health are more likely to deliver brief physical activity advice.\n\nBull et al. 1995 ([+] Australia)\n\nDouglas et al. 2006a ([++] UK)\n\nHorsley Tompkins et al. 2009 ([+] USA)\n\nHuang et al. 2004 ([+] USA)\n\nKennedy et al. 2003 ([+] Canada)\n\nSwinburn et al. 1997 ([−] New Zealand)\n\nRibera et al. 2005 ([+] Spain)\n\nWinzenberg et al. 2009 ([+] Australia)\n\n## Evidence statement PA11\n\nModerate evidence from 12 studies: 7 qualitative (3 [++]1,6,7, and 4 [+]2,8,11,12) and 5 quantitative studies (all [+]3,4,5,9,10) suggests that practitioners consider a lack of provision of print materials, incentives, or other support resources to be a barrier to discussing and/or prescribing physical activity. It may be that better provision of print materials to hand out to patients, financial reward for providing brief physical activity advice or addition provision of other support recourses would increase the delivery of brief physical activity advice.\n\nAmpt et al. 2009 ([++] Australia)\n\nBize et al. 2007 ([+] Switzerland)\n\nBull et al. 1995 ([+] Australia)\n\nBull et al. 1997([+] Australia)\n\nBurns et al. 2000 )[+] USA)\n\nDouglas et al. 2006a ([++] UK)\n\nDouglas et al. 2006b ([++] UK)\n\nHuang et al. 2004 ([+] USA)\n\nLong et al. 1996 ([+] USA)\n\nMcDowell et al. 1997 ([+] UK)\n\nPinto et al. 1998 ([+] UK)\n\nRibera et al. 2005 ([+] Spain)\n\n## Evidence statement PA12\n\nModerate evidence from 19 papers; 9 qualitative (2 [++]7,8 [+]2,9,14,15,16,19 and 1 [−]17), 9 quantitative studies (all [+]1,3,4,5,6,10,11,12,13), and 1 mixed methods evaluation [+]18 suggests that practitioners considered that time resources and conflicting priorities affected their ability to discuss and/or prescribe physical activity. Time acts as a 'proxy' for related factors such as increased workload, resulting in conflicting priorities and a need to choose between physical activity promotion and other factors which may be seen as more central to the practitioner role.\n\nAlbright et al. 2000 ([+] USA)\n\nBize et al. 2007 ([+]Switzerland)\n\nBull et al. 1995 ([+] Australia)\n\nBull et al. 2010 ([+] UK)\n\nBuchholz et al. 2007 ([+] USA)\n\nBurns et al. 2000 ([+] USA)\n\nDouglas et al. 2006a ([++] UK)\n\nDouglas et al. 2006b ([++] UK)\n\nHuang et al. 2004 ([+] USA)\n\nKennedy et al. 2003 ([+] Canada)\n\nLawlor et al. 1999 ([+] UK)\n\nLong et al. 1996 ([+] USA)\n\nMcKenna et al. 1998 ([+] UK)\n\nMelillo et al. 2000 ([+] USA)\n\nPatel et al. 2011 ([+] UK)\n\nRibera et al. 2005 ([+] Spain)\n\nSwinburn et al. 1997 ([−] New Zealand)\n\nVan Sluijs et al. 2004 ([+] Netherlands)\n\nWinzenberg et al. 2009 ([+] Australia)\n\n## Evidence statement PA13\n\nModerate evidence from 18 studies; 9 qualitative (one [++]1, 7 [+]7,8,9,12,14,15,16 and 1 [−]3) and 9 quantitative studies (all [+]2,3,4,5,6,10,12,17,18) suggests that practitioner confidence and knowledge (including the need for further training/support) affected their ability to discuss and/or prescribe physical activity. Greater practitioner confidence/knowledge (created through better training) increases the likelihood of delivery brief advice.\n\nAmpt et al. 2009 ([++] Australia)\n\nBuchholz et al. 2007 ([+] USA)\n\nBuffart et al. 2012 ([+] Australia)\n\nBull et al. 1995 ([+] Australia)\n\nBull et al.1997([+] Australia)\n\nBurns et al. 2000 ([+]USA)\n\nDouglas et al. 2006a ([++] UK)\n\nDouglas et al. 2006b ([++] UK)\n\nEadie et al. 1996 ([+], Qualitative, UK)\n\nGould et al. 1995 ([−] UK)\n\nGribben et al. 2000 ([+] New Zealand)\n\nHuang et al. 2004 ([+] USA)\n\nKennedy et al. 2003 ([+] Canada)\n\nPinto et al. 1998 ([+] UK)\n\nRibera et al. 2005 ([+] Spain)\n\nSims et al. 2004 [+] (Australia)\n\nVan der Ploeg et al. 2007([+] Australia)\n\nWalsh et al. 1999 ([+] USA)\n\n## Evidence statement PA15\n\nModerate evidence from 6 studies; 2 qualitative (all [++]4,5) and 4 quantitative studies (all [+]1,2,3,6), suggests that practitioner willingness to discuss and/or prescribe physical activity was influenced by whether they perceived this activity to be within their remit/role. Those who saw physical activity promotion as within their role were more likely to provide brief physical activity advice.\n\nBooth et al. 2006 ([+] Australia)\n\nBuffart et al. 2012 ([+] Australia)\n\nBull et al. 1995 ([+] Australia)\n\nDouglas et al. 2006a ([++] UK)\n\nDouglas et al. 2006b ([++] UK)\n\nVan der Ploeg et al. 2007 ([+] Australia)\n\n## Evidence statement PA16\n\nModerate evidence from 18 studies; 11 qualitative (3 [++]1,4,5 6 [+]2,11,13,14,15,18 and 2 [−]6,17) and 7 quantitative studies (all [+]3,7,8,9,10,12,16), suggests that practitioners were more willing to discuss and/or prescribed physical activity where this was linked to the presenting condition (rather than as a preventative measure), that is to provide curative rather than preventative advice.\n\nAmpt et al. 2009 ([++] Australia)\n\nBize et al. 2007 ([+] Qualitative, Switzerland)\n\nBull et al. 1995 ([+] Australia)\n\nDouglas et al. 2006a ([++] UK)\n\nDouglas et al. 2006b ([++] UK)\n\nGould et al. 1995 ([−] UK)\n\nGribben et al. 2000 ([+] New Zealand)\n\nHorsley Tompkins et al. 2009 ([+] USA)\n\nKreuter et al. 1997 ([+] USA)\n\nLawlor et al. 1999 ([+]UK)\n\nLeijon et al. 2010 ([+] Sweden)\n\nMcDowell et al. 1997 ([+] UK)\n\nMelillo et al. 2000 ([+] USA)\n\nPatel et al. 2011 ([+] UK)\n\nRibera et al. 2005 ([+] Spain)\n\nSchmid et al. 2009 ([+] Switzerland)\n\nSwinburn et al. 1997 ([−] New Zealand)\n\nWinzenberg et al. 2009 ([+] Australia)\n\n## Evidence statement PA18\n\nModerate evidence from 4 qualitative studies (all [+]1,2,3,4) suggests that patient willingness to comply with brief physical activity advice is affected by their recall and understanding of advice. Patients who understand the advice are more likely to comply with it.\n\nHuang et al. 2004 ([+] USA)\n\nRibera et al. 2006 ([+] Spain)\n\nPinto et al. 1998 ([+] UK)\n\nSims et al. 2004 ([+] Australia)\n\n## Evidence statement PA19\n\nModerate evidence from 1 qualitative study (all [+]1), suggests that patients felt they needed to receive more preventative advice (that is, advice not linked to a presenting condition).\n\nHorne et al. 2010 ([+] UK)\n\n## Evidence statement PA20\n\nModerate evidence from 2 qualitative studies (all [+]1,2) suggests that patients were less receptive to brief physical activity advice if they were unaware of physical activity recommendations. Making patients aware of physical activity recommendations would increase their willingness to comply with brief physical activity advice.\n\nHorne et al. 2010 ([+] UK)\n\nSims et al. 2004 ([+] Australia)\n\n## Evidence statement PA23\n\nModerate evidence from 10 studies; 5 qualitative (4 [+]3,5,7,8, and 1 [−]9), 3 quantitative (all [+]1,2,4), and 2 mixed methods studies (all [+]6,10), suggests that interventions to encourage practitioners to administer brief physical activity advice can be effective in improving practitioners' views of brief physical activity advice, which may lead to positive effects on patients' physical activity behaviours.\n\nAlbright et al. 2000 ([+] USA)\n\nBooth et al. 2006 ([+] Australia)\n\nBull et al. 2010 ([+] UK)\n\nGribben et al. 2000 ([+] New Zealand)\n\nLeijon et al. 2010 ([+] Sweden)\n\nLong et al. 1996 ([+] USA)\n\nPatel et al. 2011 ([+] UK)\n\nPinto et al. 1998 ([+] UK)\n\nSwinburn et al. 1997 ([−] New Zealand)\n\nVan Sluijs et al. 2004 ([+] Netherlands)\n\n## Evidence statement PA25\n\nModerate evidence from 14 studies; 7 effectiveness studies (2 [++]1,3 3 [+]4,9,13 and 2 [−])10,12, and 7 barriers and facilitators studies (1 [++]7, 5 [+]2,5,6,11,14 and 1 [‑]8), suggests that the provision of incentives to encourage practitioners to administer brief physical activity advice or provision of incentives to patients to encourage them to act on brief physical activity advice may overcome barriers to delivery/uptake but this cannot be validated through the effectiveness evidence.\n\nACT 2001 ([++] Australia)\n\nBize et al. 2007 ([+] Switzerland)\n\nBolognesi et al. 2006 ([++] Italy\n\nBull et al. 1998 ([+] Australia)\n\nBull et al. 1995 ([+] Australia)\n\nBurns et al. 2000 ([+]USA)\n\nDouglas et al. 2006a ([++] UK)\n\nGould et al. 1995 ([−] UK)\n\nHarland et al. 1999 ([+] UK)\n\nLewis 1993 ([−] USA)\n\nMcDowell et al. 1997 ([+] UK)\n\nNaylor et al. 1999 ([− UK)\n\nPinto et al. 2005 ([+] USA)\n\nRibera et al. 2005 ([+] Spain)\n\n## Evidence statement PA26\n\nModerate evidence from 23 studies; 9 effectiveness studies (5 [++]2,9,12,19,20 2 [+]4,10, and 2 [−]16,17), and 14 barriers and facilitators studies (1[++]1, and 13 [+]3,5,6,7,8,11,13,14,15,16,21,22,23) suggests that the provision of training may encourage practitioners to administer brief physical activity advice and that the education of patients may encourage them to act on brief physical advice. In particular this may be effective in improving intervention outcomes in populations where this knowledge is found to be lacking.\n\nAmpt et al. 2009 ([++] Australia)\n\nBolognesi et al. 2006 ([++] Italy)\n\nBuchholz et al. 2007 ([+] USA)\n\nBull et al.1998 ([+] Australia)\n\nBurns et al.2000 ([+]USA)\n\nDouglas et al. 2006a ([++] UK)\n\nDouglas et al. 2006b ([++] UK)\n\nEadie et al.1996 ([+] UK)\n\nElley et al. 2003 ([++] New Zealand)\n\nGoldstein et al. 1999 ([+] USA)\n\nGoodman et al. 2011 ([+] UK)\n\nGrandes et al. 2009 ([++] Spain)\n\nHorne et al. 2010 ([+] UK)\n\nHuang et al. 2004 ([+] USA)\n\nKennedy et al. 2003 ([+] Canada)\n\nLewis et al. 1993 ([−] USA)\n\nMarcus et al. 1997 ([−] USA)\n\nMcDowell et al. 1997 ([+] UK)\n\nPetrella et al. 2003 ([++] Canada)\n\nPinto et al. 2005 ([+] USA)\n\nRibera et al. 2006 ([+] Spain)\n\nSims 2004 ([+] Australia)\n\nWalsh et al. 1999 ([+] USA)\n\n## Evidence statement PA27\n\nModerate evidence from 22 studies; 11 effectiveness studies (3 [++]1,9,10,4 [+]4,18,21,22 and 4 [−]12,14,15,17), and 11 barriers and facilitators studies (3 [++]2,7,8 and 8 [+]3,5,6,11,13,16,19,20), suggests no benefit from the addition of written support materials to a brief advice intervention. However, it may be that the quality of currently available materials needs to improve to see an effect.\n\nACT 2001 ([++] Australia)\n\nAmpt et al. 2009 ([++] Australia)\n\nBize et al. 2007 ([+]Switzerland)\n\nBull et al. 1998 ([+] Australia)\n\nBull et al. 1995 ([+] Australia)\n\nBurns et al. 2000 ([+]USA)\n\nDouglas et al. 2006a ([++] UK)\n\nDouglas et al. 2006b ([++] UK)\n\nElley et al. 2003 ([++] New Zealand)\n\nGrandes et al. 2009 ([++] Spain)\n\nHuang et al. 2004 ([+] USA)\n\nLittle et al. 2004 ([-] UK)\n\nLong et al. 1996 ([+] USA)\n\nMarcus et al. 1997 ([−] USA)\n\nMarshall et al. 2005 ([−] Australia)\n\nMcDowell et al. 1997 ([+] UK)\n\nNaylor 1999 ([−] UK)\n\nPfeiffer et al. 2001([+] USA)\n\nPinto et al. 1998 ([+] UK)\n\nRibera et al. 2005 ([+] Spain)\n\nSmith et al. 2000 ([+] Australia)\n\nSwinburn et al. 1998 ([+] New Zealand)\n\n## Evidence statement PA28\n\nModerate evidence from 18 studies; 9 effectiveness studies (2 [++]6,9, 4 [+]3,8,10,11 and 3 [-]5,13,15), and 9 barriers and facilitators studies (8[+]1,2,4,7,12,14,16,17 and 1 [−]18), suggests that whilst the evidence of relative effectiveness for brief interventions of 5\xa0minutes or longer versus interventions of very short duration (less than 5\xa0minutes) is inconclusive, structured interventions can help to overcome practitioner barriers to prescribing brief advice.\n\nAlbright et al. 2000 ([+] (USA)\n\nBooth et al. 2006 ([+] Australia)\n\nBull et al. 1998 ([+] Australia)\n\nBull et al. 2010 ([+] UK)\n\nCalfas et al. 1996 ([−] USA)\n\nElley et al. 2003 ([++] New Zealand)\n\nGribben et al. 2000 ([+] New Zealand)\n\nGoldstein et al. 1999 ([+] USA)\n\nGrandes et al. 2009 ([++] Spain)\n\nHalbert et al. 2000 ([+] Australia)\n\nHillsdon et al. 2002 ([+] UK)\n\nLeijon et al. 2010 ([+] Sweden)\n\nLewis et al. 1993 ([−] USA)\n\n.Long et al. 1996 ([+] USA)\n\nMarcus et al. 1997 ([−] USA)\n\nPatel et al. 2011 ([+] UK)\n\nPinto et al. 1998 ([+] UK)\n\nSwinburn et al. 1997 ([−] New Zealand)\n\n## Evidence statement PA29\n\nModerate evidence from 7 barriers and facilitators studies (2 [++]1,2, 4 [+]3,4,5,6, and 1 [−]7), suggests that time constraints resulted from conflicting priorities, and unfavourable working conditions. It seems likely that practitioners report lack of time as a proxy for a wide range of barriers to delivering brief physical activity advice and that overcoming problems such as lack of training, knowledge and confidence could act to remove the perceived barrier of lack of time.\n\nDouglas et al. 2006a ([++] UK)\n\nDouglas et al. 2006b ([++] UK)\n\nHuang et al. 2004 ([+] USA)\n\nMcKenna et al. 1998 ([+] UK)\n\nPatel et al. 2011 ([+] UK)\n\nRibera et al. 2005 ([+] Spain)\n\nSwinburn et al. 1997 ([−] New Zealand)\n\n## Evidence statement PA30\n\nModerate evidence from 1 effectiveness ([−]6), and 8 barriers and facilitators studies (1 [++]2, and 7 [+]1,3,4,5,6,7,8), suggests that the structure of the actual 'system' in which the intervention is delivered has the potential to affect both the effectiveness of the intervention and its acceptability to both patients and practitioners. It is important to note that all the structural factors outlined here need to be considered together rather than in isolation to facilitate positive changes in intervention delivery and physical activity uptake.\n\nBize et al. 2007 ([+] Switzerland)\n\nDouglas et al. 2006b ([++] UK)\n\nGribben et al. 2000 ([+] New Zealand)\n\nLeijon et al. 2010 ([+] Sweden)\n\nLong et al. 1996 ([+] USA)\n\nMarcus et al. 1997 ([−] USA)\n\nMcDowell et al. 1997 ([+] UK)\n\nPinto et al. 1998 ([+] UK)\n\nWalsh et al. 1999 ([+] USA)\n\n# Cost effectiveness\n\nThere was a review of economic evaluations, a review of economic barriers and facilitators and an economic modelling exercise.\n\n## Review of economic evaluations\n\nThree papers were reviewed, 2 of which were based on a UK and an Australian population. The only overlap with previous economic literature influencing public health guidance in this area was the cost-effectiveness model developed for the previous NICE guidance (Matrix 2006).\n\nModerate, but limited evidence from 3 studies suggested that brief advice on physical activity in primary care is more cost effective than usual care. The evidence should be interpreted with caution as the evidence based on effectiveness was weak and did not fully explore uncertainty. Therefore, a de novo modelling of the cost effectiveness of brief advice was needed to improve knowledge on its efficiency.\n\n## Review of economic barriers and facilitators\n\nSix papers were reviewed: 5 quantitative studies from the USA and 1 qualitative study from New Zealand.\n\nPoor quality evidence suggested that a perceived lack of adequate financial incentive for healthcare professionals is a barrier to the delivery of brief advice on physical activity in primary care. This was irrespective of whether the advice was provided by a nurse or GP.\n\nModerate evidence suggested a weakly positive correlation between the time spent on (or available for) counselling and the delivery of brief advice on physical activity in primary care, regardless of whether it was provided by a GP or nurse. There was no interpretable policy-relevant evidence on the role of remuneration in the delivery of brief advice on physical activity. There was no interpretable evidence on the role of other resources in the delivery of brief advice on physical activity.\n\n# Economic modelling\n\nA number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see the economic modelling report for this guideline for the full modelling report and further details of the results).\n\nThe analysis adopted a lifetime horizon, an NHS/Personal Social Service perspective and discounted quality-adjusted life years (QALY) as a key outcome. Uncertainty over the model results was estimated by deterministic sensitivity analysis, scenario analysis, and probabilistic sensitivity analysis. Deterministic analysis was used to estimate the impact of alternative model scenarios. Compared with usual care, the incremental cost-effectiveness ratio (ICER) of brief advice was £1730 and thus can be considered cost effective.\n\nWhen brief advice was compared with usual care (the 'base case'), uncertainties were explored through a series of analyses. In most cases the base case results were robust, but they were sensitive to the duration of protective effects of physical activity, mental health gains from physical activity, changes in infrastructure and age of cohort.\n\nThe impact of changing the age at which physical activity started, post-brief advice, to 54\xa0years and older resulted in brief advice being cheaper and more effective compared with usual care (this is termed as brief advice 'dominating' usual care). Thus, the strength of the cost-effectiveness results was even greater for people aged 54\xa0years and older. Uncertainty over the model results was estimated by probabilistic sensitivity analysis. Probabilistic sensitivity analysis showed a 99.9% chance that brief advice will be cost effective if an additional QALY is valued at £20,000.\n\nWhile the economic model was based on the previous economic model (Matrix 2006) used to support developing NICE public health guidance 2, this model offered a number of improvements including:\n\n) time-based modelling\n\n) mental health and wellbeing as well as infrastructure (considered where permitted by the evidence)\n\n) more extensive exploration of uncertainty around the ICERs\n\n) more conservative assumptions around changes in physical activity over time\n\n) use of meta-analysed effectiveness data.\n\nOverall, brief physical activity advice in primary was found to be cost effective.", 'Gaps in the evidence': "The Public Health Interventions Advisory Committee (PHIAC) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence and stakeholder comments. These gaps are set out below.\n\n. Whether practitioners are more likely to give brief advice if it can be delivered effectively in less than a few minutes.\n\n. The effectiveness of differing durations of brief advice on physical activity levels.\n\n. What information should be provided (or not provided) when delivering brief advice.\n\n. What infrastructure and systems are effective in increasing delivery – for example, whether the use of incentives increases the number of brief interventions carried out by practitioners.\n\n. The impact of brief advice in increasing physical activity levels, as quantified by objective measures and in comparison with self-reported measures.\n\n. Whether any specific, or combination of, behaviour-change techniques should be used to deliver brief advice.\n\n. Whether practitioner knowledge and motivation have an impact on the delivery of brief advice.\n\n. Whether brief advice is more effective when delivered as the opportunity arises, or during an appointment made specifically for the task.\n\n. The effectiveness and cost effectiveness of brief advice in increasing physical activity levels among identified groups at risk of health conditions due to inactivity. This includes, for example, people with disabilities, those aged 65 and over, and people with a lower socioeconomic status. In other words, whether tailoring brief advice by population group is more effective than giving generic advice.\n\n. Barriers to, and facilitators for, increasing physical activity levels in response to brief advice.\n\n. The effectiveness of specific brief advice interventions (in terms of frequency, intensity and duration) and maintenance of behaviour change in the longer term\n\n. A comparison of the relative effectiveness of brief advice for physical activity in the general population compared with a sedentary population.\n\n. Whether there is a differential effect of different durations and frequency of follow-up on the effectiveness of brief advice to increase physical activity.\n\n. Current level of use of the original brief intervention recommendations from NICE public health guidance 2, general practice physical activity questionnaire (GPPAQ) and the 'Let's get moving' physical activity care pathway.\n\nThe Committee made a number of recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in recommendations for research.", 'Finding more information ': "You can see everything NICE says on this topic in the NICE Pathway on physical activity.\n\nTo find NICE guidance on related topics, including guidance in development, see the NICE webpage on physical activity.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice."}	https://www.nice.org.uk/guidance/ph44	This guideline covers providing brief advice on physical activity to adults in primary care. It aims to improve health and wellbeing by raising awareness of the importance of physical activity and encouraging people to increase or maintain their activity level.
214aec5355b6d9cda5a9e03f854dbb3b04e40600	nice	Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion	Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion # Guidance Ranibizumab is recommended as an option for treating visual impairment caused by macular oedema: following central retinal vein occlusion or following branch retinal vein occlusion only if treatment with laser photocoagulation has not been beneficial, or when laser photocoagulation is not suitable because of the extent of macular haemorrhage and -nly if the manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of NICE technology appraisal guidance 274. People currently receiving ranibizumab whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology Ranibizumab (Lucentis, Novartis) belongs to a class of drugs that block the action of vascular endothelial growth factor (VEGF)‑A. Retinal vein occlusion (RVO) is a common cause of reduced vision as a result of retinal vascular disease. Thrombosis in the retinal veins causes an increase in retinal capillary pressure, resulting in increased capillary permeability and the discharge of blood and plasma into the retina. This leads to macular oedema and varying levels of ischaemia through reduced perfusion of capillaries. These changes trigger an increase in VEGF, which increases vascular permeability and new vessel proliferation. By inhibiting the action of VEGF‑A, ranibizumab reduces oedema and limits visual loss or improves vision. Ranibizumab has a UK marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)'. The summary of product characteristics states that treatment should be given monthly and continued until maximum visual acuity is reached – that is, until visual acuity has been stable for 3 consecutive months. Thereafter, visual acuity should be monitored monthly. Treatment should be resumed if monitoring indicates a loss of visual acuity caused by macular oedema secondary to RVO, and continued until visual acuity has remained stable for 3 consecutive months. The interval between doses should not be shorter than 1 month. If there is no improvement in visual acuity over the course of the first 3 injections, continued treatment is not recommended. Contraindications to ranibizumab include known hypersensitivity to the active substance or to any of its excipients, active or suspected ocular or periocular infections, and active severe intraocular inflammation. Adverse reactions to treatment are mostly limited to the eye. Those commonly reported in clinical trials include vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, sensation of a foreign body in the eye, increased production of tears, blepharitis, dry eye, ocular hyperaemia, itching of the eye and increased intraocular pressure. Nasopharyngitis, arthralgia and headaches are also commonly reported. For full details of adverse reactions and contraindications, see the summary of product characteristics. Ranibizumab is administered as a single 0.5 mg intravitreal injection. Each vial of ranibizumab contains 2.3 mg in 0.23 ml; overfilling is considered necessary to achieve an injectable dose of 0.5 mg. The list price of ranibizumab is £742.17 per vial (excluding VAT; 'British national formulary' edition 64). The manufacturer of ranibizumab (Novartis) has agreed a patient access scheme with the Department of Health, revised in the context of technology appraisal guidance 274, which makes ranibizumab available with a discount applied to all invoices. The level of the discount is commercial‑in‑confidence (see section 5.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this technology by NICE is published.# The manufacturer's submission The Appraisal Committee (section 9) considered evidence submitted by the manufacturer of ranibizumab and a review of this submission by the Evidence Review Group (ERG; section 10). The manufacturer submitted evidence of clinical and cost effectiveness for ranibizumab compared with grid laser photocoagulation in people with visual impairment caused by macular oedema secondary to branch retinal vein occlusion (BRVO) and for ranibizumab compared with best supportive care in people with visual impairment caused by macular oedema secondary to central retinal vein occlusion (CRVO). The manufacturer stated that there was no direct or indirect evidence comparing the clinical effectiveness of ranibizumab with bevacizumab or dexamethasone intravitreal implant (which were defined as comparators in the scope for the appraisal). However, a comparison of the cost effectiveness of ranibizumab with dexamethasone intravitreal implant was included in the manufacturer's submission; this was not the case for bevacizumab (see sections 3.9 and 3.10). The main sources of evidence presented in the manufacturer's submission came from the BRAVO and CRUISE randomised controlled trials (RCTs). These evaluated the efficacy of ranibizumab, compared with a sham procedure, for treating visual impairment caused by macular oedema secondary to BRVO and to CRVO respectively. The BRAVO (n=397) and CRUISE (n=392) trials were both 3‑armed RCTs carried out at multiple centres in the USA. Patients were randomised equally to sham injection, monthly intraocular ranibizumab 0.3 mg or monthly intraocular ranibizumab 0.5 mg. Both trials included people with visual impairment caused by macular oedema who had been diagnosed in the 12 months before study initiation. Patients entered a 6‑month treatment phase during which monthly injections were given, beginning on day 0. In the treatment phase of BRAVO, patients in both the sham injection and ranibizumab groups could receive grid laser photocoagulation for rescue treatment from 3 months. In both BRAVO and CRUISE, the treatment phase was followed by a 6‑month observation phase during which all groups (that is, the sham group and the 2 ranibizumab groups) could receive ranibizumab as needed. Patients in the observation phase of BRAVO (but not CRUISE) could receive grid laser photocoagulation for rescue treatment from 3 months (that is, at month 9 of the study). The final treatment in both BRAVO and CRUISE was given at month 11, with a final study visit at month 12. Patients who completed the 12‑month BRAVO and CRUISE trials could enter an open‑label extension study (HORIZON). The primary outcome in both BRAVO and CRUISE was the mean change from baseline in best corrected visual acuity (BCVA) score in the study eye at 6 months. BCVA score was measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, in which a score of 85 letters corresponds to normal visual acuity ('20/20 vision'). Secondary outcomes reported in both BRAVO and CRUISE included mean change from baseline in BCVA score over time up to 6 and 12 months, and the proportion of patients gaining or losing more than 15 letters in BCVA score at 6 and 12 months compared with baseline. The trials also reported results for several exploratory outcomes, including the mean change from baseline in the National Eye Institute Visual Function Questionnaire‑25 (NEI VFQ‑25) composite score up to 6 months. The NEI VFQ‑25 has 25 questions that are designed to measure the effect of visual impairment on daily functioning and quality of life. This appraisal considered the 0.5 mg dose of ranibizumab, which is the only dose with a UK marketing authorisation. In BRAVO, 91.7% of patients in the sham group and 95.4% in the ranibizumab group were treated in the 'worse‑seeing eye' (that is, the eye affected by RVO). In CRUISE, 90.0% of patients in the sham group and 92.3% in the ranibizumab group were treated in their 'worse‑seeing eye'. The mean number of ranibizumab injections in the treatment phase was 5.7 (BRAVO) and 5.6 (CRUISE). The average number of ranibizumab injections in the observation phase was 2.7 (BRAVO) and 3.3 (CRUISE). More than 80% of patients from the sham injection group in both BRAVO and CRUISE received ranibizumab as needed during the observation phase. During the first 6 months of the BRAVO trial, grid laser photocoagulation was used in 57.6% of patients in the sham injection group and in 21.4% of the patients in the ranibizumab group. Over the 12‑month study period in BRAVO, 61.4% of patients in the sham (plus ranibizumab) group and 34.4% of patients in the ranibizumab group received rescue treatment with grid laser photocoagulation. In BRAVO, at month 6, patients in the ranibizumab group had gained an average of 18.3 letters (95% confidence interval 16.0 to 20.6) from baseline BCVA score. This gain was statistically significant compared with the gain of 7.3 letters (95% CI 5.1 to 9.5) in the group receiving sham injection (p<0.0001). At month 12 of the BRAVO trial (that is, at the end of the 6‑month observation period, during which all patients could receive ranibizumab as needed), the 0.5 mg ranibizumab group reported an average gain in BCVA baseline score of 18.3 letters (95% CI 15.8 to 20.9) compared with the sham (plus ranibizumab) group, which had gained 12.1 letters (95% CI 9.6 to 14.6, p<0.01). The observed improvement at month 6 from baseline in the NEI VFQ‑25 composite score was statistically significantly greater in patients receiving ranibizumab (10.4 points, 95% CI 8.3 to 12.4) than in patients receiving sham injection (5.4 points, 95% CI 3.6 to 7.3; p<0.005). The manufacturer reported that overall the BRAVO trial showed a clinically meaningful and statistically significant effect of ranibizumab on visual acuity and patient‑reported outcomes based on the NEI VFQ‑25 at 6 months. The manufacturer carried out a post‑hoc analysis stratified by rescue treatment with grid laser photocoagulation to investigate the effects of adding this treatment to ranibizumab. The manufacturer concluded that treating patients with grid laser photocoagulation as well as ranibizumab did not lead to the efficacy of ranibizumab being overestimated. At month 6 in the CRUISE trial, patients in the ranibizumab group achieved a statistically significant mean gain in BCVA score from baseline of 14.9 letters (95% CI 12.6 to 17.2) compared with the sham group, who gained 0.8 letters (95% CI −2.0 to 3.6, p<0.0001). The manufacturer reported that the improvements in BCVA in the ranibizumab group at month 6 were generally maintained through to month 12 with treatment as needed (13.9 letters for ranibizumab; 7.3 letters for sham group; p<0.001). Patients receiving ranibizumab 0.5 mg showed statistically significantly greater improvements in patient‑reported outcomes as measured by the NEI VFQ‑25 (6.2 points, 95% CI 4.3 to 8.0) than patients receiving sham injection (2.8 points, 95% CI 0.8 to 4.7; p<0.05). For patients who entered the open‑label extension study (HORIZON), ranibizumab 0.5 mg was given at intervals of at least 30 days. Sixty‑seven per cent of patients from BRAVO and 60% of patients from CRUISE completed month 12 of HORIZON. The primary outcome for the HORIZON extension study was mean change from HORIZON baseline in BCVA score up to 24 months. The manufacturer presented results from the first 12 months. From the BRAVO trial baseline, patients receiving sham (plus ranibizumab) and those receiving 0.5 mg ranibizumab had mean gains in BCVA score of 15.6 letters and 17.5 letters respectively. From the CRUISE trial baseline, patients receiving sham (plus ranibizumab) and those receiving 0.5 mg ranibizumab had mean gains in BCVA score of 7.6 and 12.0 letters respectively (no confidence intervals reported). Adverse events were reported at 6 months and 12 months in both BRAVO and CRUISE trials, and for a further 12 months' follow‑up in the HORIZON extension study. In BRAVO, at 6 months there were 7 ocular adverse events (5.4%) in the ranibizumab group compared with 17 (13%) in the sham group, excluding occurrences of raised intraocular pressure. Non‑ocular serious adverse events (potentially related to vascular endothelial growth factor inhibition) at 6 months were higher in the ranibizumab group (5 events ) than in the sham group (1 event ). In CRUISE, at 6 months there were 13 ocular adverse events (10.1%) in the ranibizumab group compared with 25 (19.4%) in the sham group, excluding occurrences of raised intraocular pressure. In CRUISE, non‑ocular serious adverse events (potentially related to VEGF inhibition) were similar in both the ranibizumab and sham groups (3 and 2 respectively). The most common adverse event reported in BRAVO and CRUISE at 12 months was cataract, with 8 (6.2%) and 9 (7%) instances associated with ranibizumab treatment respectively; in the sham (plus ranibizumab) group, 3 (2.6%) and 2 (1.8%) instances of cataract were reported for the treatment period of 6 to 12 months. Instances of raised intraocular pressure were reported in both BRAVO and CRUISE at 6 months but were academic in confidence, and therefore not reported here. In the HORIZON extension study, the incidence of any adverse event in the sham (plus ranibizumab) and ranibizumab groups was 2.2% and 5.8% respectively for the patients (with BRVO) recruited from BRAVO, 5.2% and 3% respectively for the patients (with CRVO) recruited from CRUISE. A systematic review was undertaken to identify RCTs involving potential comparators for ranibizumab in the treatment of visual impairment caused by macular oedema secondary to RVO. The manufacturer discussed the feasibility of conducting a formal indirect comparison of ranibizumab with dexamethasone intravitreal implant or bevacizumab in CRVO, and an indirect comparison of ranibizumab with dexamethasone intravitreal implant, bevacizumab or grid laser photocoagulation in BRVO. For a comparison of ranibizumab and bevacizumab in CRVO, the manufacturer identified a study by Faghihi et al. (2008) but stated that there was not enough information about the baseline characteristics of patients in the study. For a comparison with bevacizumab in BRVO, studies by Moradian et al. (2011) and Russo et al. (2009) were identified. The manufacturer stated that an indirect comparison could not be conducted without bias because the length of time since diagnosis of macular oedema differed in Moradian et al. (2011) and BRAVO, and because the trial duration was different in all 3 studies. The manufacturer also considered that bevacizumab was not an appropriate comparator because it did not consider that its use in the NHS was routine or best practice. The manufacturer stated that an indirect comparison of ranibizumab and dexamethasone intravitreal implant could not be undertaken for CRVO or BRVO because of the population differences in trials involving these 2 treatments: patients had different lengths of time since diagnosis of macular oedema, different baseline ranges of BCVA and different retinal thickness in the BRAVO and CRUISE trials compared with the GENEVA studies (which compared dexamethasone with sham injection). The manufacturer also stated that ranibizumab could not be compared indirectly with grid laser photocoagulation because of fundamental differences in trial design between BRAVO, which was sham‑injection‑controlled, and the laser studies BVOS (1984) and Battaglia et al. (1999), which were not. Although no formal indirect comparison of ranibizumab with other drug treatments was performed, the relative systemic safety profiles of ranibizumab and bevacizumab were discussed in the manufacturer's submission. The manufacturer stated that ranibizumab was associated with a better safety profile than bevacizumab. The manufacturer provided data from 3 large retrospective studies by Carneiro et al. (2011), Curtis et al. (2010) and Gower et al. (2011) in support of this statement, but these studies compared bevacizumab with ranibizumab for the treatment of age‑related macular degeneration (AMD) rather than RVO. The manufacturer acknowledged that AMD manifests later in life than RVO, and so the average age of patients in the BRAVO and CRUISE trials was lower than in the studies of AMD. For evidence of cost effectiveness, the manufacturer submitted a Markov state transition model comparing treatment with ranibizumab with grid laser photocoagulation (standard care) for visual impairment caused by macular oedema secondary to BRVO and with best supportive care for CRVO. Treatment was modelled over a 15‑year time horizon for a hypothetical cohort of 1000 patients with visual impairment because of macular oedema secondary to RVO, with a starting age of around 66 years. Eight BCVA health states and death are included in the model structure, with each health state having an associated utility and mortality risk depending on whether the 'better‑seeing eye' or 'worse‑seeing eye' is treated. In the manufacturer's base‑case analysis, it was assumed that all patients are treated in their 'better‑seeing eye'. People move through the model in monthly cycles, accumulating the utility associated with each health state they enter, together with the costs of treatment and subsequent monitoring. Additional costs and disutility associated with blindness were applied for people with a visual acuity equal to or less than 35 letters in the 'better‑seeing eye'. The model assumed that a person's risk of mortality would increase with worsening visual acuity in the 'better‑seeing eye'. A published study by Christ et al. (2008) was used to provide the risk levels by ETDRS bands. The manufacturer asserted that mortality associated with RVO would not be expected to result in any additional risk of mortality over and above that of the general population and as a consequence, the model did not include an assumption of excess mortality associated with RVO. Transition probabilities were determined monthly and subsequently used to calculate overall monthly transition probabilities for months 0 to 1, months 2 to 6 and months 7 to 12. For CRVO, the probabilities derived from the sham group of the CRUISE trial for months 2 to 6 were applied to months 2 to 6, 7 to 12 and 13 to 24 in the best supportive care arm of the model. The manufacturer stated that this was because there were no comparative data beyond month 6; from this point in the trial treatment with ranibizumab could be given to people in either arm as needed. Similarly for BRVO, no comparative data existed beyond month 6. However, this was further complicated by the use of grid laser photocoagulation as a rescue treatment in both arms of the trial beyond month 3. Therefore the probabilities for months 7 to 12 were pooled from the sham and ranibizumab groups of BRAVO and applied to months 7 to 12 and months 13 to 24 in both arms of the model. Dexamethasone intravitreal implant was incorporated into the model by a combination of applying relative risks from 2 trials (GENEVA studies) and assigning probabilities observed in the control groups of the BRAVO and CRUISE trials. The manufacturer conducted a systematic review of the literature to identify utility values for populations with visual impairment because of RVO, with priority given to populations with macular oedema secondary to BRVO or CRVO. From the results of this review, the manufacturer chose a study by Brown (1999) as the source of utilities for the model, stating that this was the only relevant study that reported utility values related to visual acuity. This is a US study assessing preferences for different levels of visual acuity in patients with vision loss from various causes, 7% of whom had RVO. The manufacturer's model applies different utility values to each BCVA health state, depending on whether the 'better‑seeing eye' or 'worse‑seeing eye' is treated. Although separate utility values for visual acuity in the 'better‑seeing eye' and 'worse‑seeing eye' were available from the study by Brown, the manufacturer stated that there was little difference between the worst and best health states for people treated in their 'worse‑seeing eye' and therefore assumed a value of 0.85 for all BCVA health states for people treated in the 'worse‑seeing eye' (that is, no gain from treatment). In addition, the base‑case model assumed all people would be treated in their best‑seeing eye and therefore this issue of utility gain for people treated in their 'worse‑seeing eye' was not relevant to the base case. For people treated in their 'best‑seeing eye' the maximum utility gain from treatment was 0.41 (that is, the difference between the best visual health state of 0.92 and the worst visual health state of 0.51). Utilities were not adjusted for age. Costs included intervention and comparator costs, administration costs and follow‑up visits. Grid laser photocoagulation (BRVO only) was assumed to incur no cost but an administration cost as an outpatient procedure was applied. The ranibizumab injection administration visit was costed as an office‑based outpatient procedure, whereas the dexamethasone intravitreal implant injection was based on a weighted average of the cost of an outpatient procedure (25%) and day case procedure (75%) to account for its greater complexity. For ranibizumab, the frequency of injections was taken from the BRAVO and CRUISE trials. In addition, patients experiencing adverse events had an associated cost applied, and patients considered to be blind had the additional costs associated with blindness. All of the manufacturer's base‑case incremental cost‑effectiveness ratios (ICERs) that were presented included an approved patient access scheme, which was offered by the manufacturer at the time of submission (and which was subsequently superseded). In the base case for BRVO, the ICER for ranibizumab compared with grid laser photocoagulation was £20,494 per quality‑adjusted life year (QALY) gained. In the base case for CRVO, the ICER for ranibizumab compared with best supportive care was £8643 per QALY gained. The base‑case ICERs for ranibizumab compared with dexamethasone for BRVO and CRVO were £5486 and £7174 per QALY gained respectively. Incremental costs and QALYs for the base‑case results were commercial in confidence and therefore cannot be presented here. The manufacturer performed a deterministic sensitivity analysis and found the model to be sensitive to the frequency of injections and follow‑up visits. The manufacturer performed scenario analyses to assess the impact of varying the proportion of people treated in their 'worse‑seeing eye' and commented that this was a key driver of cost effectiveness. The manufacturer also presented probabilistic sensitivity analyses and concluded that the probability that ranibizumab was cost effective when compared with grid laser photocoagulation in BRVO was 45.5% and 57.2% at thresholds of £20,000 and £30,000 per QALY gained respectively. For ranibizumab compared with best supportive care in CRVO, the probability of cost effectiveness was estimated by the manufacturer to be 74.5% and 83.3% at thresholds of £20,000 and £30,000 per QALY gained respectively. # Evidence Review Group comments on the manufacturer's submission The ERG noted that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because one of the exclusion criteria was brisk afferent pupillary defect, which, as the manufacturer stated, equates to severe retinal ischaemia. Therefore, the ERG considered that the results of any analyses could only be applied to people without retinal ischaemia. The ERG considered that the concomitant use of grid laser photocoagulation from month 3 confounded the results of the BRAVO study and that definite conclusions could not be drawn about the effects of ranibizumab compared with sham injection or grid laser photocoagulation alone. The ERG noted that there was not enough evidence to conclude that grid laser photocoagulation had no effect in the ranibizumab group. It also noted that the treatment period of the BRAVO trial was not long enough to capture any benefits of grid laser photocoagulation on patient outcomes, which may last longer than 3 years. Furthermore, clinical advice to the ERG suggested that ranibizumab and grid laser photocoagulation would not be used together to treat patients in clinical practice. The ERG noted that from month 6 onwards people were allowed to have ranibizumab as needed and therefore considered the data up to month 6 to be the most relevant data for determining the comparative effectiveness of ranibizumab in treating visual impairment caused by macular oedema secondary to RVO. However, the ERG noted that this period may not be long enough to determine the long‑term effects of ranibizumab. The ERG questioned the manufacturer's view that an indirect estimate of the efficacy of ranibizumab compared with bevacizumab, dexamethasone and grid laser photocoagulation (for BRVO only) was not possible. Although the ERG accepted that there were differences in baseline characteristics between patients in the CRUISE, BRAVO and GENEVA trials (see section 3.9), it stated that this would not prevent an indirect comparison between ranibizumab and dexamethasone, and would likely favour ranibizumab. This was because at baseline the mean duration of macular oedema secondary to CRVO was 3 months in CRUISE and 5 months in GENEVA, and a greater mean duration of RVO tends to result in a poorer response to treatment. The ERG suggested that the impact of any bias could have been explored through critical assessment. The ERG agreed with the manufacturer that it was not possible to incorporate bevacizumab for people with CRVO into an adjusted indirect comparison because only 1 study of bevacizumab for CRVO had been identified in the manufacturer's submission (Faghihi et al. 2008), and this did not adequately report baseline characteristics. For BRVO, the ERG considered that studies of bevacizumab reported in the manufacturer's submission (see section 3.9) were suitable for inclusion in an indirect comparison with the first 3 months of data from BRAVO (that is, before rescue treatment with grid laser photocoagulation was permitted). Again, the ERG accepted that there would be some bias in this comparison, but overall the biases would likely favour ranibizumab because the duration of macular oedema in BRAVO was longer than in the study by Moradian et al. and because the Moradian study included more patients with ischaemia than BRAVO. The ERG highlighted that this could be explored in critical assessment. From the trials reported in the manufacturer's submission, the ERG was able to construct a linear network of trials using BRAVO (ranibizumab compared with sham), Moradian et al. 2011 (bevacizumab compared with sham) and Russo et al. 2009 (bevacizumab compared with grid laser photocoagulation). The ERG commented that although the results should be treated with caution because they are exploratory, they estimated an approximately 3‑letter improvement in visual acuity with ranibizumab over bevacizumab and an 8‑letter improvement with ranibizumab over grid laser photocoagulation at month 3. However, the ERG did not consider the difference between bevacizumab and ranibizumab to be clinically meaningful from this analysis. The ERG noted that in the base‑case analysis the model assumed all patients were treated in the 'better‑seeing eye', despite the fact that over 90% of patients in the BRAVO and CRUISE trials were treated in their 'worse‑seeing eye'. The ERG considered that it was not reasonable to assume equivalent gains in utility and reductions in costs when treating a patient in their 'worse‑seeing eye'. The ERG considered the manufacturer's use of a 'better‑seeing eye' model to be inappropriate because RVO is predominantly a unilateral condition, and therefore most patients would receive treatment in their 'worse‑seeing eye' only. The ERG considered the pooled transition probabilities for ranibizumab, which the manufacturer stated had been necessary to account for the effect of grid laser photocoagulation in people with BRVO. The ERG commented that pooling would lead to an overestimate of the efficacy of ranibizumab because the benefit seen in patients in the sham group who received ranibizumab after the first 6 months would be added to the continued effect of ranibizumab in those patients initially randomised to receive ranibizumab. The ERG conducted sensitivity analyses using unpooled transition probabilities. It noted that the ICER for ranibizumab compared with grid laser photocoagulation (for BRVO) with this change alone increased the manufacturer's original base‑case from £20,494 to £52,004 per QALY gained for months 7 to 12, and ranibizumab was dominated (was less clinically effective and more expensive) for months 13 to 24, and months 7 to 12 plus months 13 to 24 together. Incremental costs and QALYs for the base‑case results were commercial in confidence and therefore cannot be presented here. The ERG considered the manufacturer's exploratory economic analysis that incorporated dexamethasone intravitreal implant. The ERG commented that there was a potential bias towards ranibizumab in the manufacturer's approach (see section 3.20). The ERG conducted an exploratory indirect comparison of ranibizumab with dexamethasone intravitreal implant, which provided relative risks of an improvement in visual acuity of 10 letters (2 lines) or more for patients with macular oedema secondary to BRVO and CRVO (a relative risk of less than 1 favours ranibizumab). The relative risks increased from 0.55 to 0.79 for ranibizumab compared with dexamethasone in BRVO. For CRVO, the corresponding figures were 0.30 to 0.40. The ERG commented that the relative risks calculated from the manufacturer's model were more favourable to ranibizumab in both BRVO and CRVO. Moreover, because the ERG's indirect comparison was known to be biased towards ranibizumab, the manufacturer's approach to modelling dexamethasone was largely biased towards ranibizumab. However, the ERG commented that these results were exploratory and should therefore be interpreted with caution. The ERG noted the manufacturer's assumption in the economic model that there is no mortality risk attributable to RVO. The ERG identified a UK‑based study (Tsaloumas et al. 2000) that concluded that patients with RVO were at a significantly greater risk of death from myocardial infarction than the general population. The ERG was of the opinion that it would have been appropriate to include the relative risk of 1.6 reported by Tsaloumas in the manufacturer's base‑case analysis. The ERG noted the manufacturer had applied a mortality risk associated with the visual acuity level in the patient's 'better‑seeing eye' using data from Christ et al. (2008). The ERG noted that this mortality risk would only apply to patients being treated in their 'better‑seeing eye'. The ERG commented that if the model was amended to treat those with visual impairment in their 'worse‑seeing eye' it would be appropriate to use a mortality risk associated with 'some' visual impairment in these patients. The ERG noted that the utility values for visual acuity in the 'better‑seeing eye' were taken from Brown (1999) rather than Czoski‑Murray et al. (2009), an earlier version of which had been used (referred to as Brazier et al. 2006) in Ranibizumab and pegaptanib for the treatment of age\u2011\related macular degeneration (NICE technology appraisal guidance 155). The ERG noted that the manufacturer's model assumes utilities are independent of age, although age adjustment is expected to have minimal impact on the ICERs. However, the ERG commented that age adjustment of the utilities presented by Czoski‑Murray et al. (2009) was not necessary because age had already been adjusted for. The ERG commented that the study by Czoski‑Murray et al. (2009) should therefore be used as the source for utility associated with visual acuity in the 'better‑seeing eye' in this assessment. For the 'worse‑seeing eye' the ERG was of the opinion that the available evidence from the Brown publication (which reported utilities by worse‑ and better‑seeing eyes) suggested the maximum gain from treating a person's 'worse‑seeing eye' would be 0.1. The ERG carried out exploratory analyses varying several parameters. Assuming that only 10% (and not 100%) of people are treated in their 'better‑seeing eye', applying utilities derived from Czoski‑Murray et al. (2009), a 0.1 overall benefit associated with treating the 'worse‑seeing eye' and an increased risk of mortality associated with RVO, the ICERs for ranibizumab compared with best supportive care and with dexamethasone in CRVO were £43,760 and £37,443 per QALY gained respectively. This formed the ERG's base‑case estimate for CRVO. The ERG did not present further economic evaluation of ranibizumab compared with grid laser photocoagulation because it considered that the confounded data from BRAVO (in which grid laser photocoagulation was permitted in the ranibizumab arm after 3 months of treatment) was insufficient to inform an indirect comparison and be used in the economic model. When the ERG applied their preferred assumptions as above for ranibizumab compared with dexamethasone intravitreal implant in BRVO, this increased the manufacturer's base‑case ICER from £5486 to £31,122 per QALY gained. The ERG's exploratory analyses highlighted that the key drivers that increased the manufacturer's base‑case ICERs were amending the proportion of patients treated in their 'better‑seeing eye' (10% instead of 100%) and the assumption of some benefit associated with treating the 'worse‑seeing eye'. The ERG commented that its comparisons of ranibizumab with dexamethasone intravitreal implant for both BRVO and CRVO used relative risks derived from the manufacturer's model (0.55 for BRVO and 0.30 for CRVO) rather than those derived from the ERG's indirect comparison (0.79 and 0.40 respectively). The ERG commented that this would bias the results in favour of ranibizumab and if the ERG's suggested relative risks were applied, the ICER would increase further. The ERG also commented that the efficacy of dexamethasone was potentially underestimated because of differing patient characteristics in the trials that informed the comparison (patients had differing durations of macular oedema from diagnosis in the GENEVA trials compared with BRAVO and CRUISE). Therefore, the manufacturer's base‑case ICERs may be underestimates. The ERG also highlighted that the ICER generated for ranibizumab compared with dexamethasone from the BRAVO trial is derived using the pooled transition probabilities in the original submission. Using the unpooled transition probabilities would increase the ICER further. The ERG conducted an exploratory cost‑minimisation analysis for ranibizumab compared with bevacizumab, assuming equivalent efficacy for the 2 treatments (in BRVO and CRVO) and an acquisition cost of £50 per month for bevacizumab. The ERG presented data on the incremental costs of ranibizumab compared with bevacizumab that included commercial‑in‑confidence information and so cannot be presented here. The ERG's analysis using the manufacturer's model suggested that ranibizumab would need to generate 1.5 times more QALYs than bevacizumab (each month between months 2 and 6) in macular oedema secondary to BRVO (without considering the revised patient access scheme implemented in NICE technology appraisal guidance 274) to give an ICER at the top end of the range usually considered cost effective. Ranibizumab would need to generate 1.7 times more QALYs than bevacizumab for macular oedema secondary to CRVO (without considering the revised patient access scheme implemented in NICE technology appraisal guidance 274) to give an ICER at the top end of the range usually considered cost effective. # Revised economic model submitted by the manufacturer during consultation In response to the consultation on the appraisal consultation document the manufacturer submitted a revised cost–utility analysis addressing the Committee's concerns about the original model. The revised economic model included the ERG's preferred assumptions relating to 10% of patients being treated in their 'better‑seeing eye', utilities from Czoski‑Murray et al. (2009). The manufacturer also applied some alternative assumptions (see sections 3.33 to 3.36) to present revised base‑case cost‑effectiveness estimates for ranibizumab compared with dexamethasone in both BRVO and CRVO. The manufacturer considered that the ERG's approach to deriving utilities from Czoski‑Murray et al. (2009) underestimated the utility gains associated with improving visual acuity. The manufacturer therefore provided an alternative to the ERG's derivation of utilities by applying a regression equation from the Czoski‑Murray et al. (2009) publication to derive utilities for each of the 8 BCVA health states in a similar way to that employed in the guidance on Ranibizumab and pegaptanib in age\u2011\related macular degeneration (NICE technology appraisal guidance 155). The manufacturer also applied a 0.3 overall benefit of treating the 'worse‑seeing eye' because it felt that a 0.1 benefit, as applied by the ERG, did not capture the difference in utility for people with blindness in their 'worse‑seeing eye'. The manufacturer did not apply an excess mortality risk specifically associated with RVO in its revised model because the available evidence was conflicting, and it considered the evidence base to be inconclusive. In addition, the manufacturer highlighted that an excess mortality risk had not been included in the evidence submitted for the published guidance on Dexamethasone intravitreal implant in macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229). However, the manufacturer did amend the model to include mortality risk associated with visual impairment in the 'worse‑seeing eye' as originally suggested by the ERG (see section 3.26). The manufacturer acknowledged the Committee's concerns about the use of pooled transition probabilities during months 7–24 of the BRAVO trial, which were originally used to account for the confounding effect of patients being treated with grid laser photocoagulation at the same time as treatment with ranibizumab. In its revised model, the manufacturer applied data for months 7–24 from only the ranibizumab arm of BRAVO to inform the transitions of all BRAVO patients. The manufacturer's revised model included updated adverse event rates for year 2 for ranibizumab as well as updated adverse event rates for dexamethasone for year 1, based on 12‑month outcomes from the GENEVA studies published since the manufacturer's original submission. In addition, the manufacturer considered that the dexamethasone re‑treatment frequency included in the original model (every 6 months) was conservative and therefore applied a re‑treatment frequency of 4 months to the revised model. Finally, the manufacturer applied a lifetime time horizon instead of the 15‑year time horizon included in the original submission in order to derive its base‑case cost‑effectiveness estimates. The manufacturer stated that this was consistent with the approach taken in the guidance on Dexamethasone intravitreal implant in macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229). The manufacturer highlighted in its consultation response that although patients with brisk afferent pupillary defect were excluded from the BRAVO and CRUISE studies, this only represents those at the more severe end of the ischaemic spectrum and therefore did not exclude those with milder ischaemia. After consultation on the appraisal consultation document, the manufacturer responded to the Committee's concerns regarding the extent of bias generated by the differences in the duration of macular oedema between GENEVA and BRAVO/CRUISE. The manufacturer commented that the extent of bias was not known and that the implications for the ICER may be minimal. They also re‑examined the reported mean durations of macular oedema in the GENEVA (dexamethasone) and BRAVO and CRUISE (ranibizumab) studies noting that in the GENEVA studies, the mean duration of macular oedema was assessed at a screening visit which occurred at least 1 month earlier than in the BRAVO and CRUISE studies. The manufacturer further noted that its cost‑effectiveness analysis of ranibizumab compared with dexamethasone was already favourable to dexamethasone because the relative effectiveness of ranibizumab and dexamethasone was assessed at 3 months, and conservative assumptions related to the number of dexamethasone injections and the rate of adverse events associated with dexamethasone were used. In their response to the appraisal consultation document consultation the manufacturer reiterated their view that bevacizumab is not a valid comparator because it does not satisfy the definition of a comparator as set out in the NICE Guide to the methods of technology appraisal because, in their view, the use of bevacizumab is not routine or best practice, and because bevacizumab is not licensed for RVO. The manufacturer further highlighted that the studies included in the ERG's indirect comparison of ranibizumab with bevacizumab had methodological shortcomings and that the inclusion of the study by Russo et al. (2009) was inappropriate because standard deviations were not reported in this study for the values of change from baseline. The manufacturer considered the ERG's conclusion about the direction of bias in the indirect comparison to be overly speculative and not evidence‑based. In addition the manufacturer reiterated its concerns over comparisons with an unlicensed drug that might compromise patient safety, further noting that the absence of a full pharmacovigilance programme (normally funded by the drug sponsor), would mean that the cost of safety surveillance would be a significant burden to the NHS and was not included in the ERG's cost‑minimisation analysis. The manufacturer provided an estimate of the per‑patient cost of a basic pharmacovigilance programme, which was submitted as commercial in confidence and cannot therefore be reported. Finally, the manufacturer highlighted that the ERG's use of a cost‑minimisation analysis is fundamentally flawed and that it was not appropriate to assume equivalent safety and efficacy of ranibizumab and bevacizumab, an assumption required for cost‑minimisation methodology, when this has not been established. # Evidence Review Group's comments on the manufacturer's revised model The ERG noted the manufacturer's approach to applying the 'better‑seeing eye' utilities from Czoski‑Murray et al. (2009) to the model and agreed that this was appropriate because it provided utilities for each of the health states in the model rather than the ERG's smaller set of utility values (see section 3.32), and was consistent with the approach taken by the Assessment Group for the guidance on Ranibizumab and pegaptanib in age\u2011\related macular degeneration (NICE technology appraisal guidance 155). The ERG considered the manufacturer's approach of applying a maximum utility gain of 0.3 from treatment of the 'worse‑seeing eye'. The ERG noted that the manufacturer extrapolated the 0.1 utility loss estimated by Brown et al. (2001) to apply further loss in the 'worse‑seeing eye'. However, the ERG considered that the evidence presented by Brown et al. (2001) suggested that further deterioration in visual acuity in the 'worse‑seeing eye' did not affect utility and therefore applying a 0.3 utility gain was not evidence‑based. They also considered that it lacked face validity. The ERG noted the manufacturer's response suggesting that the extent of bias towards ranibizumab in comparison with dexamethasone was overestimated (in the original ERG report). The ERG acknowledged that there is uncertainty surrounding the extent of bias but that this is difficult to quantify. With respect to duration of macular oedema at baseline, the ERG did not have access to data from BRAVO and CRUISE to adjust for the difference in the timing of measurement of duration of macular oedema compared with GENEVA. The ERG also noted that although the manufacturer's revised model uses data from months 7–12 of the ranibizumab arm of BRAVO to inform all transition probabilities from month 7 to 24, this assumes equivalent efficacy between dexamethasone and ranibizumab when given as needed. The ERG noted that it is not clear whether this assumption is conservative, and that evidence provided by the manufacturer from the BRAVO trial showed that there is a decline in ranibizumab's efficacy when given as needed rather than as monthly treatment. The ERG considered the manufacturer's consultation response to dexamethasone re‑treatment frequency and adverse events associated with dexamethasone. The ERG noted that the manufacturer's approach should have also modelled the effectiveness of dexamethasone re‑treatment given less frequently than every 4 months (for example, every 5 months) and that the manufacturer did not take into account that a higher re‑treatment frequency would result in a more stable efficacy for dexamethasone. In addition, the ERG agreed that a higher re‑treatment frequency for dexamethasone would have the impact of increasing the number and severity of adverse events. The ERG noted the manufacturer's response to the issue of ischaemic disease. The ERG agreed that the exclusion criterion in BRAVO and CRUISE of brisk afferent pupillary defect would not exclude patients with minor ischaemic disease. However, the ERG noted that none of the key trials used in the ERG's exploratory analysis, including BRAVO and CRUISE, reported data on the number of patients with baseline macular ischaemia. Therefore, the ERG highlighted that it could not be assumed that patients with ischaemia could have been included in BRAVO and CRUISE and stated that the effects of ranibizumab in the subgroup of patients with macular oedema secondary to ischaemic RVO were unknown. # Patient access scheme as revised in the context of NICE technology appraisal guidance 274 The manufacturer submitted a revised patient access scheme in 2013 for consideration in this appraisal (as revised in the context of NICE technology appraisal guidance 274), in which it applied a revised discount to ranibizumab for all indications (see section 2.4). The manufacturer did not submit any additional clinical‑effectiveness data but submitted an economic model that incorporated the revised patient access scheme discount and employed all of the revised assumptions from the manufacturer's response to consultation (outlined in more detail in sections 3.31 to 3.39). In summary these were as follows: deriving utilities from Czoski‑Murray et al. (2009) for each of the 8 BCVA health states in a similar way to that employed in the guidance on Ranibizumab and pegaptanib in age\u2011\related macular degeneration (NICE technology appraisal guidance 155) by applying a regression equation from Czoski‑Murray et al. (2009) applying a 0.3 overall utility benefit for treating the 'worse‑seeing eye' including mortality risk associated with visual impairment as suggested by the ERG applying data for months 7–24 from only the ranibizumab arm of BRAVO to inform the transition probabilities of all BRAVO patients including updated adverse event rates for year 2 for ranibizumab as well as updated adverse event rates for dexamethasone for year 1 applying a lifetime time horizon to be consistent with the published guidance for Dexamethasone intravitreal implant for macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229). By applying all of their revised assumptions (see section 3.44), the manufacturer's revised base‑case ICERs (with the revised patient access scheme as implemented in NICE technology appraisal guidance 274) for ranibizumab compared with dexamethasone were £2370 and £6995 per QALY gained for BRVO and CRVO respectively. For ranibizumab compared with best supportive care in CRVO the ICER was £13,851 per QALY gained, whereas for ranibizumab compared with grid laser photocoagulation in BRVO, the ICER was £23,073 per QALY gained. The manufacturer performed a deterministic sensitivity analysis and found the model to be sensitive to the frequency of injections and follow‑up visits; for example in BRVO, increasing the number of injections in year 2 (from 2.5 to 6) increased the ICER for ranibizumab compared with dexamethasone from £2370 to £9892 per QALY gained. The manufacturer provided scenario analyses (one‑way sensitivity analysis) which explored the effect of changing some of the parameters in the model individually. The manufacturer explored the effect of applying a 0.2 overall utility gain for treating the 'worse‑seeing eye'. This increased the base‑case ICERs of ranibizumab compared with dexamethasone from £2370 to £3029 per QALY gained for BRVO, and from £6995 to £9005 per QALY gained for CRVO. For ranibizumab compared with best supportive care in CRVO, the ICER increased from £13,851 to £18,332 per QALY gained. For ranibizumab compared with grid laser photocoagulation, the manufacturer's ICER increased from £23,073 to £30,778 per QALY gained. Other scenario analyses included reducing the mean number of ranibizumab injections in year 2 (the revised number of mean injections was submitted as academic in confidence and cannot be presented). This reduced the ICERs of ranibizumab compared with dexamethasone by 54% in BRVO and by 58% in CRVO. A scenario which included longer follow‑up data based on year 2 of the HORIZON extension study reduced the ICERs for ranibizumab compared with dexamethasone from £2370 to £1599 per QALY gained and from £23,073 to £20,911 per QALY gained for ranibizumab compared with grid laser photocoagulation in BRVO. The corresponding scenario analysis for CRVO was not presented. The manufacturer also presented probabilistic sensitivity analyses and concluded that from the base‑case results the probability that ranibizumab was cost effective when compared with grid laser photocoagulation in BRVO was 44.2% at a threshold of £20,000 per QALY gained and 58.6% at a threshold of £30,000 per QALY gained. For ranibizumab compared with best supportive care in CRVO, the probability of cost effectiveness was estimated by the manufacturer to be 67.9% and 82.0% at thresholds of £20,000 and £30,000 per QALY gained respectively. # ERG critique of manufacturer's revised base case with the patient access scheme as revised in the context of NICE technology appraisal guidance 274 The ERG noted that the revised model used to inform the current patient access scheme submission is the same as that submitted as part of the manufacturer's response to the original consultation, but that not all issues raised by the Committee have been addressed. Therefore, the ERG's views outlined in sections 3.40 to 3.43 (relating to deriving utilities, transition probabilities, re‑treatment frequency and adverse events associated with dexamethasone and ischaemic disease) still apply. Overall, the ERG accepted the manufacturer's approach to: modelling 90% of people in the model as being treated in their 'worse‑seeing eye' the use and implementation of the 'better‑seeing eye' utilities derived from Czoski‑Murray et al. (2009) excess mortality associated with visual impairment in the 'worse‑seeing eye' updated adverse events. However, the ERG maintained that the available evidence relating to utility gain from treating the 'worse‑seeing eye' suggests a utility decrement of 0.1 (rather than the manufacturer's assumption of 0.3) between the best and worst 'worse‑seeing eye' BCVA health states. Therefore, the ERG provided amended exploratory cost‑effectiveness estimates to include the assumption of a 0.1 utility decrement. For BRVO, this increased the manufacturer's base‑case ICER for ranibizumab compared with grid laser photocoagulation from £23,073 to £44,713 per QALY gained. In the ERG's incremental analysis in BRVO, dexamethasone was extendedly dominated by ranibizumab (that is, the ICER for dexamethasone compared with grid laser photocoagulation was higher than for ranibizumab compared with grid laser photocoagulation) and the ICER compared with best supportive care was £44,713 per QALY gained. The ERG highlighted that there is considerable uncertainty in the comparisons of ranibizumab with grid laser photocoagulation and with dexamethasone as a result of the confounded data from BRAVO (grid laser photocoagulation was permitted in the ranibizumab arm after 3 months of treatment) used to inform the comparison with grid laser photocoagulation and the absence of a direct comparison with dexamethasone. For ranibizumab compared with dexamethasone in BRVO, the ERG's amendment of including a 0.1 utility decrement increased the manufacturer's base‑case ICER from £2370 to £4092 per QALY gained. The ERG performed the same amendment for CRVO, and the ICER for ranibizumab compared with best supportive care increased from £13,851 to £26,263 per QALY gained, and for ranibizumab compared with dexamethasone the ICER increased from £6995 to £12,306 per QALY gained. In the ERG's incremental analysis for CRVO, dexamethasone was extendedly dominated by ranibizumab (that is, the ICER for dexamethasone compared with best supportive care was higher than for ranibizumab compared with grid laser photocoagulation) and the ICER for ranibizumab compared with best supportive care was £26,263 per QALY gained. The ERG highlighted that the absence of a direct comparison of ranibizumab with dexamethasone generates considerable uncertainty in these results. In particular, the manufacturer assumed that from month 7 onwards, the efficacy of dexamethasone is equivalent to ranibizumab when given as needed (rather than monthly). The ERG note that it remains unclear whether this assumption would lead to bias towards or against ranibizumab. # NICE Decision Support Unit report Following the Committee's consideration of comparators in this appraisal, and in line with NICE processes (specifically section 3.5.49 of the Guide to the single technology appraisals process), the NICE Board asked for additional work to be commissioned from the NICE Decision Support Unit (DSU) related specifically to the consideration of intravitreal bevacizumab as a comparator. The DSU report considered 4 questions: What evidence is there relating to the pharmaceutical quality of reformulated bevacizumab as used in eye conditions in general? How widespread is intravitreal bevacizumab use in the UK? What is the evidence for efficacy of intravitreal bevacizumab in adults with RVO (and diabetic macular oedema) specifically? What evidence is there regarding adverse events for intravitreal bevacizumab in eye conditions in general? The DSU report noted that the process of diluting and aliquoting bevacizumab into the smaller doses required for intravitreal injections requires a 'specials' licence issued by the Medicines and Healthcare products Regulatory Agency (MHRA) and can be performed by hospital pharmacists or on a larger scale by specialist units under tightly controlled conditions. The DSU identified Moorfields Pharmaceuticals (a manufacturing arm of Moorfields Eye Hospital NHS Foundation Trust) and Liverpool and Broadgreen University Hospitals pharmacy as the 2 major suppliers of intravitreal bevacizumab in the UK, both of which hold 'specials' licences. The DSU report highlighted that the greatest risk from reformulation of bevacizumab is infection such as endophthalmitis, which can lead to loss of vision or even the eye itself, and that there has been a warning issued about this by the US Food and Drug Administration (FDA). Reports of sterile endophthalmitis or uveitis by Moorfields to the MHRA have resulted in the recall of 27 batches of bevacizumab. The DSU report investigated the extent of use of intravitreal bevacizumab in the UK by reviewing commissioning policy documents, data from the 2 major suppliers of intravitreal bevacizumab, and a survey of consultant ophthalmologists. The findings suggested that there is substantial use of intravitreal bevacizumab across the UK in eye conditions in general and that its use is even more widespread in private practice. The report also reviewed the evidence relating to efficacy of intravitreal bevacizumab specifically in RVO. The DSU identified 5 RCTs that examined the effectiveness of bevacizumab on BCVA in people with RVO, 3 of which were in populations with CRVO; the remaining 2 studies were in BRVO. The studies all suggested that intravitreal bevacizumab appeared to confer some improvement in BCVA in both BRVO and CRVO compared with sham injection. However, because 3 of the studies were only available as conference abstracts, detailed data were not available. In addition, the DSU highlighted that interpretations of the findings should be made with caution because of the small number of studies with relatively small sample sizes and differences in participants' age, gender distribution and type of RVO. The studies also had relatively short follow‑up durations (the maximum was 24 weeks). The report assessed the evidence relating to adverse events associated with intravitreal bevacizumab in eye conditions in general. A total of 22 RCTs were identified, which evaluated the safety of bevacizumab compared with laser therapy, sham injection, triamcinolone, ranibizumab, pegaptanib and observational control. In addition, 67 observational non‑RCT studies were included in the safety review of intravitreal bevacizumab. Overall, the DSU report commented that adverse event rates following intravitreal bevacizumab treatment were low when compared with other intravitreal treatments, sham injection and laser therapy and most of these studies were in people with AMD, diabetic macular oedema or RVO. Most outcomes were not significantly different between groups. The DSU report noted that higher rates of adverse events have been reported in the bevacizumab group in the head‑to‑head studies of intravitreal bevacizumab and ranibizumab (CATT and IVAN trials in AMD) and although this was not significant in the IVAN trial, when added to the meta‑analysis with the CATT trial, the overall finding was statistically significant. Overall the DSU considered that the 22 RCTs offer the most robust assessment of adverse events. The DSU commented that the evidence on safety of intravitreal bevacizumab from observational studies was inconclusive. However, with respect to larger studies, observational data from Curtis et al. suggested no difference in the risk of adverse events between bevacizumab and ranibizumab, and another population‑based case–control study reported no relationship between the risk of systemic events such as myocardial infarction, venous thromboembolism, stroke or congestive heart failure and the administration of intravitreal bevacizumab or ranibizumab. Comments on the DSU report consultation highlighted that the quality of reformulated bevacizumab might vary between studies and in clinical practice, and there are concerns about the reports of endophthalmitis. However it is unclear how this compares with ranibizumab. Consultees commented that there was insufficient evidence to evaluate the safety of intravitreal bevacizumab, while other consultees noted that the pooled analysis of IVAN and CATT trials, which compared ranibizumab and bevacizumab directly (in people with AMD), showed significantly higher serious systemic adverse events in the bevacizumab group. Some consultees noted that although there is some favourable evidence for efficacy of intravitreal bevacizumab for RVO in comparison with sham injection, the evidence is limited. However, some consultees noted that the use of intravitreal bevacizumab could be substantial but may have declined since the publication of Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229). Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of visual impairment caused by macular oedema secondary to retinal vein occlusion (RVO) and the value placed on the benefits of ranibizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee heard from patient experts about the problems associated with visual impairment caused by macular oedema. It heard that the loss of vision has a significant effect on the independence of people with the condition. The patient experts also stated that the condition affects ability to work and hobbies such as reading and gardening. The patient experts acknowledged that although people may be worried about having an injection in the eye, they are willing to receive injections in order to keep their sight. The Committee agreed that loss of vision caused by macular oedema secondary to retinal vein occlusion seriously impairs health‑related quality of life. The Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to branch RVO (BRVO) is grid laser photocoagulation but that in interim guidelines from the Royal College of Ophthalmologists it is only recommended after a period of 3 to 6 months following the initial event (obstruction of retinal veins) and following the absorption of the majority of the haemorrhage. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with central RVO (CRVO), because CRVO does not respond to grid laser photocoagulation (as outlined in the Royal College of Ophthalmologists' interim guidelines on RVO) and the current standard treatment is dexamethasone or anti‑vascular endothelial growth factor (VEGF) drugs such as bevacizumab. The Committee considered the comparators for the appraisal, and specifically bevacizumab intravitreal injection. It was aware that bevacizumab does not have a UK marketing authorisation for the treatment of RVO and heard from patient experts that they were concerned about using unlicensed treatments for which there was no formal post‑marketing surveillance, particularly if there were alternatives that have a UK marketing authorisation. The Committee noted that a marketing authorisation is not a prerequisite for a comparator in a NICE technology appraisal. It noted that NICE's Guide to the methods of technology appraisal, in recommending comparison with technologies that are 'best practice' or in 'routine use', is not intended to be restrictive but to emphasise the need for comparison with all relevant comparators; any medicine in routine use or considered to be best practice should be considered a comparator. The Committee was minded to conclude that bevacizumab fulfils the requirements for inclusion as a comparator but noted the advice from the NICE Board that this decision should be based on a careful consideration of its use in clinical practice for the condition concerned and, critically, a thorough assessment of its efficacy and safety. The Committee considered the information in the Decision Support Unit (DSU) report on the product quality of reformulated bevacizumab. It was aware of consultation comments on the DSU report raising concerns on quality and reports of endophthalmitis and uveitis with intravitreal bevacizumab, although it was not clear how the number of reports compared with those observed with ranibizumab. The Committee also noted the comments from consultation on the DSU report that reformulation of pharmaceutical products is not an unusual practice and is routinely performed in many other circumstances under a 'specials' licence. The Committee noted that reformulating bevacizumab for intravitreal use requires a 'specials' licence from the Medicines and Healthcare products Regulatory Agency (MHRA) and that this means manufacturers must adhere to a range of conditions and inspections. The Committee was satisfied that there is some level of good manufacturing practice in place when pharmaceutical products are reformulated under a 'specials' licence and that such practice is not exceptional. The Committee considered the evidence relating to the safety of bevacizumab as reported by the DSU. It was aware that in the 22 randomised controlled trials (RCTs) identified for age‑related macular degeneration (AMD), diabetic macular oedema and RVO, adverse events were few compared with sham injection, laser photocoagulation and other intravitreal treatments. The Committee noted the pooled analysis from the IVAN and CATT trials (both in patients with AMD), which showed a statistically significantly higher rate of systemic adverse events in the bevacizumab group than in the ranibizumab group. However, it also noted observational data from a large study by Curtis et al. suggesting no difference in the risk of adverse events between bevacizumab and ranibizumab. It also noted a population‑based case–control study, including over 90,000 patients, that reported no relationship between the risk of systemic events such as myocardial infarction, venous thromboembolism, stroke or congestive heart failure and the administration of intravitreal bevacizumab or ranibizumab. The Committee concluded that the evidence base relating to the safety of bevacizumab was sufficient to inform judgement of whether bevacizumab is an appropriate comparator. The Committee considered the evidence base for the efficacy of bevacizumab in treating visual impairment caused by macular oedema secondary to BRVO and CRVO. It noted the small trials (2 in BRVO, 3 in CRVO) identified in the DSU report, of which 3 were published only as abstracts. The Committee agreed that all trials reported significant mean improvements in best corrected visual acuity (BCVA) for bevacizumab compared with sham injections, but because no direct comparisons of ranibizumab with intravitreal bevacizumab are currently available, a mixed treatment comparison would be needed to answer the question of relative effectiveness between the 2 treatments. The Committee noted that the DSU was not asked to address this question specifically. The Committee concluded that the available evidence was limited with small sample sizes and differences in study populations but on balance sufficient to inform judgement of whether bevacizumab is an appropriate comparator. Having noted the available evidence and comments from consultation on the safety, efficacy and quality of intravitreal bevacizumab, the Committee concluded that bevacizumab is an appropriate potential comparator in this appraisal. However, the Committee further concluded that there is currently insufficient evidence to make robust comparisons with ranibizumab needed for a cost‑effectiveness analysis. # Clinical effectiveness The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. It noted that the main sources of evidence came from the BRAVO and CRUISE RCTs, which included patients with macular oedema secondary to BRVO and CRVO respectively. It also noted the evidence from the 12‑month open‑label extension of both trials, the HORIZON study. The Committee noted that the decision problem for the appraisal included people with or without retinal ischaemia. However it was aware that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because patients with a brisk afferent pupillary defect (which equates to severe retinal ischaemia) were excluded. It heard from the clinical specialists and the manufacturer that this meant that there was no evidence of ranibizumab for treating visual impairment caused by RVO in patients with significant ischaemia. The Committee noted that in both BRAVO and CRUISE ranibizumab was associated with statistically significant mean gains in BCVA in the treated eye compared with sham injection for the 6‑month treatment phase. It also noted that ranibizumab was associated with sustained gains in BCVA at 12 months in both BRAVO and CRUISE, and that these were statistically significant (p<0.01 and p<0.001 respectively). The Committee was aware that ranibizumab could be used as needed in both arms of both trials from 6 months. In addition, the Committee was aware that in the BRAVO trial, grid laser photocoagulation was permitted after 3 months in both the sham group and the ranibizumab group, confounding the results of the treatment phase from month 3 onwards. Despite this, the Committee concluded that ranibizumab is a clinically effective treatment for visual impairment caused by macular oedema secondary to BRVO and CRVO compared with sham injection, if there is no significant retinal ischaemia. The Committee considered the evidence for adverse effects associated with ranibizumab. It noted that the safety of ranibizumab had been shown previously in patients with wet AMD (NICE technology appraisal guidance 155) and diabetic macular oedema (NICE technology appraisal guidance 274 – rapid review of TA237). The Committee also noted that the overall frequency of adverse effects in the BRAVO and CRUISE trials at month 6 was low. It agreed that ranibizumab was safe and well tolerated in patients with macular oedema secondary to RVO. The Committee noted that the BRAVO and CRUISE trials collected data on the effect of visual impairment on quality of life using the National Eye Institute Visual Function Questionnaire‑25 (NEI VFQ‑25) questionnaire. It noted that both trials reported a statistically significant difference in NEI VFQ‑25 score at month 6 between the ranibizumab and sham injection groups. The Committee concluded that treating patients with ranibizumab improves the quality of life of people with visual impairment caused by macular oedema secondary to RVO. # Cost effectiveness The Committee considered the manufacturer's original economic model and the critique and exploratory analyses performed by the Evidence Review Group (ERG). It noted the manufacturer's original base‑case incremental cost‑effectiveness ratios (ICERs) of £8600 and £20,500 per quality‑adjusted life year (QALY) gained for ranibizumab compared with standard care for CRVO and BRVO respectively and the ICERs for ranibizumab compared with dexamethasone in CRVO and BRVO which were £7200 and £5500 per QALY gained respectively. The Committee broadly accepted the model structure, but was concerned by some of the uncertainties highlighted by the ERG around the assumptions used by the manufacturer. In particular, the Committee did not accept: the assumption that all patients would be treated in their 'better‑seeing eye', having heard from clinical specialists that this is not the case in clinical practice, and that most patients in the CRUISE and BRAVO trials were treated in their 'worse‑seeing eye' (see section 3.22) the manufacturer's use of 'better‑seeing eye' utility values from the Brown study, without age adjustment (see section 3.27) the absence of a mortality risk associated with RVO in the model (see section 3.25) the use of pooled transition probabilities during months 7–12 of the BRAVO trial, which overestimated the efficacy of ranibizumab compared with sham injection (see section 3.23) the potential bias in the indirect comparison between ranibizumab and dexamethasone (both BRVO and CRVO), with different exclusion rules for ischaemia, patients with different durations of macular oedema and different severities in the trials of each drug (see section 3.24).The Committee concluded that the most plausible ICERs for ranibizumab compared with standard care and dexamethasone intravitreal implant, based on the manufacturer's base case modified appropriately by the ERG, were likely to range from £31,100 to £52,000 per QALY gained and would therefore be well in excess of £20,000 to £30,000 per QALY gained. It also noted that there was additional uncertainty about the cost‑effectiveness estimates for ranibizumab in people with BRVO because grid laser photocoagulation was permitted after 3 months in both the sham and the ranibizumab groups, confounding the results of the treatment phase from month 3 onwards. The Committee proceeded to consider the revised model submitted by the manufacturer. The Committee noted the manufacturer's revisions to its economic model submitted in response to consultation. It first noted the amendment to reflect the fact that most patients (90%) would be treated in their 'worse‑seeing eye'. The Committee considered that this was consistent with the BRAVO and CRUISE trials and clinical practice, and concluded that this amendment was appropriate. The Committee next considered the manufacturer's revised approach to deriving utilities for the 'better‑seeing eye' from Czoski‑Murray et al. (2009) for use in the economic model. It understood that these utilities would only apply to 10% of the people in the revised economic model which now assumed that 90% of people would be treated in their 'worse‑seeing eye' (section 4.14). The Committee noted that the manufacturer had applied a regression equation from Czoski‑Murray et al. (2009) to produce a finer degradation of the utilities. The Committee noted that the ERG accepted the manufacturer's use and implementation of the utilities as applied using the Czoski‑Murray equation and further noted the provisional guidance from the rapid review of NICE technology appraisal guidance 237 (now published as NICE technology appraisal guidance 274) in which the range of utility values was accepted to lie somewhere in between those estimated by Czoski‑Murray and those from the Brown study. The Committee concluded that although uncertain, the use of utilities as applied using the Czoski‑Murray equation was acceptable. The Committee understood that the manufacturer's submission initially assumed that all people in the economic model would be treated in their 'better‑seeing eye' and therefore did not apply a utility gain associated with treating the 'worse‑seeing eye'. It noted that in the revised economic model (submitted in response to the appraisal consultation document) it was assumed that most people (90%) would be treated in their 'worse‑seeing eye' in line with the ERG's suggestion. The Committee therefore considered the manufacturer's revised assumption of applying a 0.3 utility gain associated with treating the 'worse‑seeing eye'. The Committee heard from the ERG that the manufacturer's assumption was based on an extrapolation of evidence from Brown et al. (2001). It understood that the ERG had used a gain of 0.1 from the Brown study in which utility values were collected separately for the 'worse‑seeing' and 'better‑seeing' eyes. The Committee considered that a 0.3 utility gain associated with treating the 'worse‑seeing eye' seems high given that utility is driven primarily by the 'better‑seeing eye', and therefore lacked face validity. It further noted that the manufacturer had originally suggested that no gain in utility would be obtained from treating the 'worse‑seeing eye'. The Committee was also aware of the results of an analysis from NICE technology appraisal guidance 229 (Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion) the details of which are commercial in confidence. The Committee concluded that a utility gain of 0.1 associated with treating the 'worse‑seeing eye' was appropriate. The Committee considered evidence supplied by the manufacturer during consultation relating to excess cardiovascular mortality associated with RVO, that is, the additional risk caused by cardiovascular complications associated with RVO, compared with the general population. The Committee noted that the excess mortality risk incorporated in the ERG base case was based on a paper from 2000 (Tsaloumas), which suggested that a person with RVO would have 1.6 times that of the general population. It noted that, of the papers referenced by the manufacturer in response to the original consultation, none suggested that overall mortality was lower for RVO patients than for the population at large. Some suggested it was greater. But the Committee was also aware that excess cardiovascular mortality had not been applied in Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229). The Committee concluded that the evidence on the risk of cardiovascular mortality associated with RVO was unclear, and therefore it need not be included in the base‑case model to the degree applied in the original ERG report. However, it would remain an uncertainty in the analysis. The Committee considered the manufacturer's response to the Committee's concerns about the use of pooled transition probabilities. The Committee was aware that the revised model used data from the ranibizumab arm of BRAVO to inform the transitions of all BRVO patients from month 7–24 which, in the view of the manufacturer, was a more conservative approach. The Committee noted that this had the effect of boosting the model's mean efficacy of the ranibizumab group after 6 months of treatment, because it assumes the same response to treatment for a person previously treated with ranibizumab as for a person naïve to ranibizumab treatment. It also noted that patients treated with grid laser photocoagulation or dexamethasone will experience the same benefit as patients treated with ranibizumab who are moving onto treatment with ranibizumab given as needed. The Committee heard from the ERG that because of the decline in efficacy of ranibizumab when given as needed in the extension arm of the trial, compared with monthly ranibizumab, it was unclear if the manufacturer's assumption was conservative. The Committee noted that the manufacturer's approach had minimal impact on the revised ICER for ranibizumab compared with dexamethasone in BRVO. The Committee acknowledged that there were advantages and disadvantages to the manufacturer and ERG's approaches. But it concluded that, given the lack of clear data, the approach taken by the manufacturer was appropriate. The Committee discussed the manufacturer's revised assumption relating to adverse events. The Committee noted that the revised model included updated adverse event rates in year 2, which included iris neovascularisation as an adverse event for ranibizumab and dexamethasone and an updated estimate of the rate of cataract development for dexamethasone (based on 12‑month outcomes from the GENEVA studies). The Committee noted the ERG's concern that it is not clear how the rate of iris neovascularisation was calculated for year 2. Although it acknowledged the ERG's concerns with the methods used to estimate adverse events in year 2, it cautiously accepted the updated safety data in the model. The Committee considered the manufacturer's consultation response to the ERG's opinion that its exploratory economic comparison of ranibizumab with dexamethasone was biased in favour of ranibizumab. The Committee considered the manufacturer's points that the duration of macular oedema may have been underestimated by up to 1 month and that the rates of ischaemic disease were higher in the ranibizumab studies, and that the comparison at 3 months does not take into consideration the declining efficacy of dexamethasone. The Committee heard from the ERG that there may still be greater bias in favour of ranibizumab. This was because dexamethasone's efficacy starts declining at 2 months (which was incorporated in the analysis at 3 months) so in the first cycle of treatment dexamethasone's efficacy was in between that of the sham and ranibizumab treatment and was assumed to be equivalent to best supportive care in months 2–6, after which the same efficacy as ranibizumab was assumed. The Committee accepted that the relative effectiveness of ranibizumab and dexamethasone was uncertain and concluded that it was difficult to quantify any bias. Having discussed the assumptions in the manufacturer's revised base‑case model the Committee went on to discuss the ICERs produced from this model. It was aware that the manufacturer's revised model included the patient access scheme as revised in the context of NICE technology appraisal 274. It noted the ICERs for BRVO of £23,100 and £2400 per QALY gained for ranibizumab compared with standard care (grid laser photocoagulation) and with dexamethasone respectively, and the base‑case ICERs for CRVO of £13,900 and £7000 per QALY gained for ranibizumab compared with best supportive care and dexamethasone respectively. The Committee noted that the ERG had accepted the manufacturer's assumptions relating to 90% of patients being treated in the 'worse‑seeing eye', use of the 'better‑seeing eye' utilities from Czoski‑Murray et al. (2009) as modelled by the manufacturer, excess mortality associated with visual impairment in the 'worse‑seeing eye', updated adverse events for year 2, and a lifetime time horizon. However, the Committee was aware that the ERG had undertaken an exploratory analysis on the revised model in which a maximum utility benefit of 0.1 from treating the 'worse‑seeing eye', instead of the manufacturer's value of 0.3, had been applied. The Committee understood that this was the only difference in the calculation of the ICERs between the analyses. On the basis of its discussions relating to the maximum possible gain in utility from treating the 'worse‑seeing eye' (section 4.16), the Committee concluded that its decision should be made on the basis of the ERG's adjustment to the manufacturer's calculations. The Committee considered the ICERs for ranibizumab for CRVO calculated in the ERG's exploratory analyses. It noted that in this incremental analysis dexamethasone was extendedly dominated (that is, dexamethasone is dominated by a combination of 2 other alternatives, in this case best supportive care and ranibizumab) and therefore can be discounted from the analysis. Therefore, the Committee went on to consider the comparison of ranibizumab with best supportive care. It noted that, incorporating the patient access scheme (as revised in the context of NICE technology appraisal 274), ranibizumab was associated with an ICER of £26,200 per QALY gained compared with best supportive care in CRVO. The Committee was aware of remaining uncertainties regarding the possible confounding in the data resulting from both groups in the CRUISE trial receiving ranibizumab as needed from month 7 (section 4.10). It was also aware of the remaining uncertainty because of the absence of a direct comparison with dexamethasone, however on balance the Committee considered that the most plausible ICER for ranibizumab for visual impairment caused by macular oedema secondary to CRVO was between the £20,000 and £30,000 per QALY gained thresholds. It could therefore be considered a cost‑effective use of NHS resources. The Committee therefore concluded that ranibizumab should be recommended as an option for treating visual impairment caused by macular oedema following CRVO. However, there remained uncertainties because of the absence of a direct comparison with dexamethasone. The Committee considered the ICERs calculated in the ERG's exploratory analyses for ranibizumab for BRVO. The Committee noted that the key comparison was standard care with laser photocoagulation, rather than with dexamethasone, which is only recommended when laser treatment is inappropriate (NICE technology appraisal guidance 229). The Committee therefore considered the ERG's exploratory ICER of £44,800 per QALY gained for ranibizumab compared with standard care. The Committee was aware that people receiving ranibizumab in the BRAVO trial could receive grid laser photocoagulation from month 3 and that this represented a significant confounding factor in both the manufacturer's and the ERG's calculations of the ICER for BRVO compared with standard care. It therefore considered that this ICER would be an underestimate of the most plausible ICER. The Committee concluded that the most plausible ICER for ranibizumab compared with standard care in treating BRVO was in excess of £44,800 per QALY gained. It further concluded that ranibizumab could not be recommended as an option for treating visual impairment caused macular oedema following BRVO when laser photocoagulation is an appropriate treatment option. The Committee next considered the population with BRVO for whom grid laser photocoagulation is not an option. It considered that this population would include both those for whom grid laser photocoagulation has not been beneficial and those for whom grid laser photocoagulation is not a suitable treatment. It was aware that the NICE appraisal of dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229) had accepted the extent of macular haemorrhage as the definition for the subgroup of people for whom grid laser photocoagulation is not a suitable treatment option. Noting the Royal College of Ophthalmologists' 2010 Interim Guidelines on Retinal Vein Occlusion in which grid laser photocoagulation is only recommended following absorption of the majority of haemorrhage (section 4.3), the Committee accepted the extent of macular haemorrhage as the definition of the group of people for whom grid laser photocoagulation is not an option. The Committee understood that, when grid laser photocoagulation is not an option, the comparator in this analysis would be dexamethasone. It considered the ERG's exploratory analysis in which the ICER was £4100 per QALY gained for ranibizumab compared with dexamethasone. Consistent with its previous conclusions it recognised that this ICER would be subject to uncertainty because of the absence of a direct comparison between ranibizumab and dexamethasone and because of confounding in the BRAVO trial. However, the Committee remained satisfied that the most plausible ICER would be below £20,000 per QALY gained. The Committee therefore concluded that ranibizumab should be recommended as an option for treating visual impairment caused by macular oedema following BRVO when grid laser photocoagulation has not been beneficial or is not suitable because of the extent of macular haemorrhage. The Committee discussed how innovative ranibizumab is in its potential to make a significant and substantial impact on health‑related benefits. It agreed that anti‑VEGF treatments were a substantial improvement over previous treatments, but considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was in the scientific step forward, not the act of licensing. In addition the Committee was not aware of any substantial benefits of ranibizumab over its comparators that would not be already captured into the QALY estimation in the modelling. The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal in the guidance. # Summary of Appraisal Committee's key conclusions TA283 Appraisal title: Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion Section Key conclusion Ranibizumab is recommended as an option for treating visual impairment caused by macular oedema: following central retinal vein occlusion or following branch retinal vein occlusion only if treatment with laser photocoagulation has not been beneficial, or when laser photocoagulation is not suitable because of the extent of macular haemorrhage and -nly if the manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of NICE technology appraisal guidance 274. Current practice Clinical need of patients, including the availability of alternative treatments The Committee heard that the loss of vision has a significant effect on the independence of people with the condition. The Committee agreed that loss of vision caused by macular oedema secondary to retinal vein occlusion seriously impairs health‑related quality of life. The Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to branch retinal vein occlusion (BRVO) is grid laser photocoagulation but that in interim guidelines from the Royal College of Ophthalmologists it is only recommended after a period of 3 to 6 months following the initial event (obstruction of retinal veins) and following the absorption of the majority of the haemorrhage. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with central retinal vein occlusion (CRVO) and the current standard treatment is dexamethasone or anti‑vascular endothelial growth factor (VEGF) drugs such as bevacizumab. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits? The Committee was not aware of any substantial benefits of ranibizumab over its comparators that would not be already captured into the quality‑adjusted life year (QALY) estimation in the modelling. What is the position of the treatment in the pathway of care for the condition? Ranibizumab has a marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)'. Adverse reactions The Committee noted that the overall frequency of adverse effects in the BRAVO and CRUISE trials at month 6 was low. It agreed that ranibizumab was safe and well tolerated in patients with macular oedema secondary to RVO. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee was aware that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because patients with a brisk afferent pupillary defect (which equates to severe retinal ischaemia) were excluded. It heard from the clinical specialists and the manufacturer that this meant that there was no evidence of ranibizumab for treating visual impairment caused by RVO in patients with significant ischaemia. Having noted the available evidence and comments from consultation (of the Decision Support Unit report) on the safety, efficacy and quality of intravitreal bevacizumab, the Committee concluded that bevacizumab is an appropriate potential comparator in this appraisal. However, the Committee further concluded that there is currently insufficient evidence to make the robust comparisons with ranibizumab needed for a cost‑effectiveness analysis. Relevance to general clinical practice in the NHS The Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to branch RVO is grid laser photocoagulation but that it is only recommended after a period of 3 to 6 months following the initial event (obstruction of retinal veins) and following the absorption of the majority of the haemorrhage. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with central RVO because CRVO does not respond to grid laser photocoagulation and the current standard treatment is dexamethasone or anti‑vascular endothelial growth factor (VEGF) drugs such as bevacizumab. Uncertainties generated by the evidence The Committee was aware that ranibizumab could be used as needed in both arms of the BRAVO and CRUISE trials from 6 months, and that in the BRAVO trial, grid laser photocoagulation was permitted after 3 months in both the sham and the ranibizumab groups, confounding the results of the treatment phase from month 3 onwards. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee concluded that ranibizumab is a clinically effective treatment for visual impairment caused by macular oedema secondary to BRVO and CRVO compared with sham injection, if there is no significant retinal ischaemia. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that in both BRAVO and CRUISE ranibizumab was associated with statistically significant mean gains in BCVA in the treated eye compared with sham injection for the 6‑month treatment phase. It also noted that ranibizumab was associated with sustained gains in BCVA at 12 months in both BRAVO and CRUISE, and that these were statistically significant (p<0.01 and p<0.001 respectively). The Committee concluded that ranibizumab is a clinically effective treatment for visual impairment caused by macular oedema secondary to BRVO and CRVO compared with sham injection, if there is no significant retinal ischaemia. Evidence for cost effectiveness Availability and nature of evidence The Committee considered the manufacturer's original economic model and the critique and exploratory analyses performed by the Evidence Review Group (ERG). It broadly accepted the model structure, but was aware of the uncertainties highlighted by the ERG around the assumptions used by the manufacturer. The Committee also considered the manufacturer's revisions to its economic model submitted in response to consultation and broadly accepted the manufacturer's approach to: reflecting that most patients (90%) would be treated in their 'worse‑seeing eye' the use of utilities as applied using the Czoski‑Murray equation, in absence of further evidence applying unpooled transition probabilities although there was a lack of clear data the inclusion of updated adverse event rates in year 2, albeit cautiously. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee considered that a 0.3 utility gain associated with treating the 'worse‑seeing eye' seems high given that utility is driven primarily by the 'better‑seeing eye', and therefore lacked face validity. The Committee concluded that a utility gain of 0.1 associated with treating the 'worse‑seeing eye' was appropriate. The Committee concluded that the evidence on the risk of cardiovascular mortality associated with RVO was unclear, and therefore it need not be included in the base‑case model to the degree applied in the original ERG report. However it would remain an uncertainty in the analysis. The Committee acknowledged that there were advantages and disadvantages to the manufacturer and ERG's approaches (to applying unpooled transition probabilities). But it concluded that, given the lack of clear data, the approach taken by the manufacturer was appropriate. Although the Committee acknowledged the ERG's concerns with the methods used to estimate adverse events in year 2, it cautiously accepted the updated safety data in the model. The Committee accepted that the relative effectiveness of ranibizumab and dexamethasone was uncertain and concluded that it was difficult to quantify any bias. The Committee was aware of the remaining uncertainty because of the absence of a direct comparison with dexamethasone. The Committee was aware that people receiving ranibizumab in the BRAVO trial could receive grid laser photocoagulation from month 3 and that this represented a significant confounding factor in both the manufacturer's and the ERG's calculations of the ICER for BRVO compared with standard care. It therefore considered that this ICER would be an underestimate of the most plausible ICER. Incorporation of health‑related quality‑of‑life benefits and utility values Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered? The Committee noted that the BRAVO and CRUISE trials reported a statistically significant difference in NEI VFQ‑25 score at month 6 between the ranibizumab and sham injection groups. The Committee concluded that treating patients with ranibizumab improved the quality of life of people with macular oedema secondary to RVO. The Committee concluded that although uncertain, the use of utilities as applied using the Czoski‑Murray equation was acceptable. The Committee concluded that a utility gain of 0.1 associated with treating the 'worse‑seeing eye' was appropriate. The Committee was not aware of any substantial benefits of ranibizumab over its comparators that would not be already captured into the QALY estimation in the modelling. Are there specific groups of people for whom the technology is particularly cost effective? The Committee concluded that ranibizumab should be recommended as an option for treating visual impairment caused by macular oedema following BRVO if grid laser photocoagulation has not been beneficial or is not suitable because of the extent of macular haemorrhage. What are the key drivers of cost effectiveness? The ERG exploratory analyses highlighted that the key drivers that increased the manufacturer's base‑case ICERs were amending the proportion of patients treated in their 'better‑seeing eye' (10% instead of 100%) and the assumption of some benefit associated with treating the 'worse‑seeing eye'. The Committee considered that a 0.3 utility gain associated with treating the 'worse‑seeing eye' seems high given that utility is driven primarily by the 'better‑seeing eye', and therefore lacked face validity. Most likely cost‑effectiveness estimate (given as an ICER) Ranibizumab was associated with an ICER of £26,200 per QALY gained compared with best supportive care in CRVO. The Committee concluded that the most plausible ICER for ranibizumab compared with standard care in treating BRVO was in excess of £44,800 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) The Department of Health and the manufacturer have agreed that ranibizumab will be available to the NHS with a patient access scheme which makes ranibizumab available with a discount. The level of the discount is commercial in confidence. End‑of‑life considerations Not applicable. Equalities considerations and social value judgements The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance. # Recommendations for further research The Committee concluded that further research directly comparing the clinical and cost effectiveness of ranibizumab and bevacizumab in people with macular oedema secondary to retinal vein occlusion should be conducted.# Related NICE guidance Details are correct at the time of publication. Further information is available on the NICE website. Published Ranibizumab for treating diabetic macular oedema (rapid review of technology appraisal 237). NICE technology appraisal guidance 274 (2013). Fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema after an inadequate response to prior therapy. NICE technology appraisal guidance 271 (2013). Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229 (2011). Ranibizumab and pegaptanib for the treatment of age\u2011\related macular degeneration. NICE technology appraisal guidance 155 (2008). Under development Aflibercept solution for injection for the treatment of macular oedema caused by central retinal vein occlusion. NICE technology appraisal. Publication date to be confirmed.# Review of guidance The guidance on this technology will be considered for review in March 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveMay 2013# Changes after publication January 2014: minor maintenance.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0134-0	{'Guidance ': 'Ranibizumab is recommended as an option for treating visual impairment caused by macular oedema:\n\nfollowing central retinal vein occlusion or\n\nfollowing branch retinal vein occlusion only if treatment with laser photocoagulation has not been beneficial, or when laser photocoagulation is not suitable because of the extent of macular haemorrhage and\n\nonly if the manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of NICE technology appraisal guidance\xa0274.\n\nPeople currently receiving ranibizumab whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology ': "Ranibizumab (Lucentis, Novartis) belongs to a class of drugs that block the action of vascular endothelial growth factor (VEGF)‑A. Retinal vein occlusion (RVO) is a common cause of reduced vision as a result of retinal vascular disease. Thrombosis in the retinal veins causes an increase in retinal capillary pressure, resulting in increased capillary permeability and the discharge of blood and plasma into the retina. This leads to macular oedema and varying levels of ischaemia through reduced perfusion of capillaries. These changes trigger an increase in VEGF, which increases vascular permeability and new vessel proliferation. By inhibiting the action of VEGF‑A, ranibizumab reduces oedema and limits visual loss or improves vision. Ranibizumab has a UK marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)'.\n\nThe summary of product characteristics states that treatment should be given monthly and continued until maximum visual acuity is reached – that is, until visual acuity has been stable for 3\xa0consecutive months. Thereafter, visual acuity should be monitored monthly. Treatment should be resumed if monitoring indicates a loss of visual acuity caused by macular oedema secondary to RVO, and continued until visual acuity has remained stable for 3\xa0consecutive months. The interval between doses should not be shorter than 1\xa0month. If there is no improvement in visual acuity over the course of the first 3\xa0injections, continued treatment is not recommended.\n\nContraindications to ranibizumab include known hypersensitivity to the active substance or to any of its excipients, active or suspected ocular or periocular infections, and active severe intraocular inflammation. Adverse reactions to treatment are mostly limited to the eye. Those commonly reported in clinical trials include vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, sensation of a foreign body in the eye, increased production of tears, blepharitis, dry eye, ocular hyperaemia, itching of the eye and increased intraocular pressure. Nasopharyngitis, arthralgia and headaches are also commonly reported. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRanibizumab is administered as a single 0.5\xa0mg intravitreal injection. Each vial of ranibizumab contains 2.3\xa0mg in 0.23\xa0ml; overfilling is considered necessary to achieve an injectable dose of 0.5\xa0mg. The list price of ranibizumab is £742.17 per vial (excluding VAT; 'British national formulary' [BNF] edition\xa064). The manufacturer of ranibizumab (Novartis) has agreed a patient access scheme with the Department of Health, revised in the context of technology appraisal guidance\xa0274, which makes ranibizumab available with a discount applied to all invoices. The level of the discount is commercial‑in‑confidence (see section\xa05.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this technology by NICE is published.", "The manufacturer's submission": "The Appraisal Committee (section\xa09) considered evidence submitted by the manufacturer of ranibizumab and a review of this submission by the Evidence Review Group (ERG; section\xa010).\n\nThe manufacturer submitted evidence of clinical and cost effectiveness for ranibizumab compared with grid laser photocoagulation in people with visual impairment caused by macular oedema secondary to branch retinal vein occlusion (BRVO) and for ranibizumab compared with best supportive care in people with visual impairment caused by macular oedema secondary to central retinal vein occlusion (CRVO). The manufacturer stated that there was no direct or indirect evidence comparing the clinical effectiveness of ranibizumab with bevacizumab or dexamethasone intravitreal implant (which were defined as comparators in the scope for the appraisal). However, a comparison of the cost effectiveness of ranibizumab with dexamethasone intravitreal implant was included in the manufacturer's submission; this was not the case for bevacizumab (see sections\xa03.9 and 3.10).\n\nThe main sources of evidence presented in the manufacturer's submission came from the BRAVO and CRUISE randomised controlled trials (RCTs). These evaluated the efficacy of ranibizumab, compared with a sham procedure, for treating visual impairment caused by macular oedema secondary to BRVO and to CRVO respectively. The BRAVO (n=397) and CRUISE (n=392) trials were both 3‑armed RCTs carried out at multiple centres in the USA. Patients were randomised equally to sham injection, monthly intraocular ranibizumab 0.3\xa0mg or monthly intraocular ranibizumab 0.5\xa0mg. Both trials included people with visual impairment caused by macular oedema who had been diagnosed in the 12\xa0months before study initiation. Patients entered a 6‑month treatment phase during which monthly injections were given, beginning on day\xa00. In the treatment phase of BRAVO, patients in both the sham injection and ranibizumab groups could receive grid laser photocoagulation for rescue treatment from 3\xa0months. In both BRAVO and CRUISE, the treatment phase was followed by a 6‑month observation phase during which all groups (that is, the sham group and the 2\xa0ranibizumab groups) could receive ranibizumab as needed. Patients in the observation phase of BRAVO (but not CRUISE) could receive grid laser photocoagulation for rescue treatment from 3\xa0months (that is, at month\xa09 of the study). The final treatment in both BRAVO and CRUISE was given at month\xa011, with a final study visit at month\xa012. Patients who completed the 12‑month BRAVO and CRUISE trials could enter an open‑label extension study (HORIZON).\n\nThe primary outcome in both BRAVO and CRUISE was the mean change from baseline in best corrected visual acuity (BCVA) score in the study eye at 6\xa0months. BCVA score was measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, in which a score of 85\xa0letters corresponds to normal visual acuity ('20/20 vision'). Secondary outcomes reported in both BRAVO and CRUISE included mean change from baseline in BCVA score over time up to 6 and 12\xa0months, and the proportion of patients gaining or losing more than 15\xa0letters in BCVA score at 6 and 12\xa0months compared with baseline. The trials also reported results for several exploratory outcomes, including the mean change from baseline in the National Eye Institute Visual Function Questionnaire‑25 (NEI VFQ‑25) composite score up to 6\xa0months. The NEI VFQ‑25 has 25\xa0questions that are designed to measure the effect of visual impairment on daily functioning and quality of life.\n\nThis appraisal considered the 0.5\xa0mg dose of ranibizumab, which is the only dose with a UK marketing authorisation. In BRAVO, 91.7% of patients in the sham group and 95.4% in the ranibizumab group were treated in the 'worse‑seeing eye' (that is, the eye affected by RVO). In CRUISE, 90.0% of patients in the sham group and 92.3% in the ranibizumab group were treated in their 'worse‑seeing eye'. The mean number of ranibizumab injections in the treatment phase was 5.7 (BRAVO) and 5.6 (CRUISE). The average number of ranibizumab injections in the observation phase was 2.7 (BRAVO) and 3.3 (CRUISE). More than 80% of patients from the sham injection group in both BRAVO and CRUISE received ranibizumab as needed during the observation phase. During the first 6\xa0months of the BRAVO trial, grid laser photocoagulation was used in 57.6% of patients in the sham injection group and in 21.4% of the patients in the ranibizumab group. Over the 12‑month study period in BRAVO, 61.4% of patients in the sham (plus ranibizumab) group and 34.4% of patients in the ranibizumab group received rescue treatment with grid laser photocoagulation.\n\nIn BRAVO, at month 6, patients in the ranibizumab group had gained an average of 18.3\xa0letters (95% confidence interval [CI] 16.0 to 20.6) from baseline BCVA score. This gain was statistically significant compared with the gain of 7.3\xa0letters (95%\xa0CI 5.1 to 9.5) in the group receiving sham injection (p<0.0001). At month\xa012 of the BRAVO trial (that is, at the end of the 6‑month observation period, during which all patients could receive ranibizumab as needed), the 0.5\xa0mg ranibizumab group reported an average gain in BCVA baseline score of 18.3\xa0letters (95%\xa0CI 15.8 to 20.9) compared with the sham (plus ranibizumab) group, which had gained 12.1\xa0letters (95%\xa0CI 9.6 to 14.6, p<0.01). The observed improvement at month\xa06 from baseline in the NEI VFQ‑25 composite score was statistically significantly greater in patients receiving ranibizumab (10.4\xa0points, 95%\xa0CI 8.3 to 12.4) than in patients receiving sham injection (5.4\xa0points, 95%\xa0CI 3.6 to 7.3; p<0.005). The manufacturer reported that overall the BRAVO trial showed a clinically meaningful and statistically significant effect of ranibizumab on visual acuity and patient‑reported outcomes based on the NEI VFQ‑25 at 6\xa0months. The manufacturer carried out a post‑hoc analysis stratified by rescue treatment with grid laser photocoagulation to investigate the effects of adding this treatment to ranibizumab. The manufacturer concluded that treating patients with grid laser photocoagulation as well as ranibizumab did not lead to the efficacy of ranibizumab being overestimated.\n\nAt month\xa06 in the CRUISE trial, patients in the ranibizumab group achieved a statistically significant mean gain in BCVA score from baseline of 14.9\xa0letters (95%\xa0CI 12.6 to 17.2) compared with the sham group, who gained 0.8\xa0letters (95%\xa0CI −2.0 to 3.6, p<0.0001). The manufacturer reported that the improvements in BCVA in the ranibizumab group at month\xa06 were generally maintained through to month\xa012 with treatment as needed (13.9\xa0letters [95%\xa0CI 11.5 to 16.4] for ranibizumab; 7.3\xa0letters [95%\xa0CI 4.5 to 10.0] for sham [plus ranibizumab] group; p<0.001). Patients receiving ranibizumab 0.5\xa0mg showed statistically significantly greater improvements in patient‑reported outcomes as measured by the NEI VFQ‑25 (6.2\xa0points, 95%\xa0CI 4.3 to 8.0) than patients receiving sham injection (2.8\xa0points, 95%\xa0CI 0.8 to 4.7; p<0.05).\n\nFor patients who entered the open‑label extension study (HORIZON), ranibizumab 0.5\xa0mg was given at intervals of at least 30\xa0days. Sixty‑seven per cent of patients from BRAVO and 60% of patients from CRUISE completed month\xa012 of HORIZON. The primary outcome for the HORIZON extension study was mean change from HORIZON baseline in BCVA score up to 24\xa0months. The manufacturer presented results from the first 12\xa0months. From the BRAVO trial baseline, patients receiving sham (plus ranibizumab) and those receiving 0.5\xa0mg ranibizumab had mean gains in BCVA score of 15.6\xa0letters and 17.5\xa0letters respectively. From the CRUISE trial baseline, patients receiving sham (plus ranibizumab) and those receiving 0.5\xa0mg ranibizumab had mean gains in BCVA score of 7.6 and 12.0\xa0letters respectively (no confidence intervals reported).\n\nAdverse events were reported at 6\xa0months and 12\xa0months in both BRAVO and CRUISE trials, and for a further 12\xa0months' follow‑up in the HORIZON extension study. In BRAVO, at 6\xa0months there were 7\xa0ocular adverse events (5.4%) in the ranibizumab group compared with 17 (13%) in the sham group, excluding occurrences of raised intraocular pressure. Non‑ocular serious adverse events (potentially related to vascular endothelial growth factor [VEGF] inhibition) at 6\xa0months were higher in the ranibizumab group (5\xa0events [3.8%]) than in the sham group (1\xa0event [0.8%]). In CRUISE, at 6\xa0months there were 13\xa0ocular adverse events (10.1%) in the ranibizumab group compared with 25 (19.4%) in the sham group, excluding occurrences of raised intraocular pressure. In CRUISE, non‑ocular serious adverse events (potentially related to VEGF inhibition) were similar in both the ranibizumab and sham groups (3 [2.3%] and 2 [1.6%] respectively). The most common adverse event reported in BRAVO and CRUISE at 12\xa0months was cataract, with 8 (6.2%) and 9 (7%) instances associated with ranibizumab treatment respectively; in the sham (plus ranibizumab) group, 3 (2.6%) and 2 (1.8%) instances of cataract were reported for the treatment period of 6 to 12\xa0months. Instances of raised intraocular pressure were reported in both BRAVO and CRUISE at 6\xa0months but were academic in confidence, and therefore not reported here. In the HORIZON extension study, the incidence of any adverse event in the sham (plus ranibizumab) and ranibizumab groups was 2.2% and 5.8% respectively for the patients (with BRVO) recruited from BRAVO, 5.2% and 3% respectively for the patients (with CRVO) recruited from CRUISE.\n\nA systematic review was undertaken to identify RCTs involving potential comparators for ranibizumab in the treatment of visual impairment caused by macular oedema secondary to RVO. The manufacturer discussed the feasibility of conducting a formal indirect comparison of ranibizumab with dexamethasone intravitreal implant or bevacizumab in CRVO, and an indirect comparison of ranibizumab with dexamethasone intravitreal implant, bevacizumab or grid laser photocoagulation in BRVO. For a comparison of ranibizumab and bevacizumab in CRVO, the manufacturer identified a study by Faghihi et al. (2008) but stated that there was not enough information about the baseline characteristics of patients in the study. For a comparison with bevacizumab in BRVO, studies by Moradian et al. (2011) and Russo et al. (2009) were identified. The manufacturer stated that an indirect comparison could not be conducted without bias because the length of time since diagnosis of macular oedema differed in Moradian et al. (2011) and BRAVO, and because the trial duration was different in all 3\xa0studies. The manufacturer also considered that bevacizumab was not an appropriate comparator because it did not consider that its use in the NHS was routine or best practice. The manufacturer stated that an indirect comparison of ranibizumab and dexamethasone intravitreal implant could not be undertaken for CRVO or BRVO because of the population differences in trials involving these 2\xa0treatments: patients had different lengths of time since diagnosis of macular oedema, different baseline ranges of BCVA and different retinal thickness in the BRAVO and CRUISE trials compared with the GENEVA studies (which compared dexamethasone with sham injection). The manufacturer also stated that ranibizumab could not be compared indirectly with grid laser photocoagulation because of fundamental differences in trial design between BRAVO, which was sham‑injection‑controlled, and the laser studies BVOS (1984) and Battaglia et al. (1999), which were not.\n\nAlthough no formal indirect comparison of ranibizumab with other drug treatments was performed, the relative systemic safety profiles of ranibizumab and bevacizumab were discussed in the manufacturer's submission. The manufacturer stated that ranibizumab was associated with a better safety profile than bevacizumab. The manufacturer provided data from 3\xa0large retrospective studies by Carneiro et al. (2011), Curtis et al. (2010) and Gower et al. (2011) in support of this statement, but these studies compared bevacizumab with ranibizumab for the treatment of age‑related macular degeneration (AMD) rather than RVO. The manufacturer acknowledged that AMD manifests later in life than RVO, and so the average age of patients in the BRAVO and CRUISE trials was lower than in the studies of AMD.\n\nFor evidence of cost effectiveness, the manufacturer submitted a Markov state transition model comparing treatment with ranibizumab with grid laser photocoagulation (standard care) for visual impairment caused by macular oedema secondary to BRVO and with best supportive care for CRVO. Treatment was modelled over a 15‑year time horizon for a hypothetical cohort of 1000\xa0patients with visual impairment because of macular oedema secondary to RVO, with a starting age of around 66\xa0years. Eight BCVA health states and death are included in the model structure, with each health state having an associated utility and mortality risk depending on whether the 'better‑seeing eye' or 'worse‑seeing eye' is treated. In the manufacturer's base‑case analysis, it was assumed that all patients are treated in their 'better‑seeing eye'. People move through the model in monthly cycles, accumulating the utility associated with each health state they enter, together with the costs of treatment and subsequent monitoring. Additional costs and disutility associated with blindness were applied for people with a visual acuity equal to or less than 35\xa0letters in the 'better‑seeing eye'. The model assumed that a person's risk of mortality would increase with worsening visual acuity in the 'better‑seeing eye'. A published study by Christ et al. (2008) was used to provide the risk levels by ETDRS bands. The manufacturer asserted that mortality associated with RVO would not be expected to result in any additional risk of mortality over and above that of the general population and as a consequence, the model did not include an assumption of excess mortality associated with RVO.\n\nTransition probabilities were determined monthly and subsequently used to calculate overall monthly transition probabilities for months\xa00 to 1, months\xa02 to 6 and months\xa07 to 12. For CRVO, the probabilities derived from the sham group of the CRUISE trial for months\xa02 to 6 were applied to months\xa02 to 6, 7 to 12 and 13 to 24 in the best supportive care arm of the model. The manufacturer stated that this was because there were no comparative data beyond month\xa06; from this point in the trial treatment with ranibizumab could be given to people in either arm as needed. Similarly for BRVO, no comparative data existed beyond month\xa06. However, this was further complicated by the use of grid laser photocoagulation as a rescue treatment in both arms of the trial beyond month\xa03. Therefore the probabilities for months\xa07 to 12 were pooled from the sham and ranibizumab groups of BRAVO and applied to months\xa07 to 12 and months\xa013 to 24 in both arms of the model. Dexamethasone intravitreal implant was incorporated into the model by a combination of applying relative risks from 2\xa0trials (GENEVA studies) and assigning probabilities observed in the control groups of the BRAVO and CRUISE trials.\n\nThe manufacturer conducted a systematic review of the literature to identify utility values for populations with visual impairment because of RVO, with priority given to populations with macular oedema secondary to BRVO or CRVO. From the results of this review, the manufacturer chose a study by Brown (1999) as the source of utilities for the model, stating that this was the only relevant study that reported utility values related to visual acuity. This is a US study assessing preferences for different levels of visual acuity in patients with vision loss from various causes, 7% of whom had RVO. The manufacturer's model applies different utility values to each BCVA health state, depending on whether the 'better‑seeing eye' or 'worse‑seeing eye' is treated. Although separate utility values for visual acuity in the 'better‑seeing eye' and 'worse‑seeing eye' were available from the study by Brown, the manufacturer stated that there was little difference between the worst and best health states for people treated in their 'worse‑seeing eye' and therefore assumed a value of 0.85 for all BCVA health states for people treated in the 'worse‑seeing eye' (that is, no gain from treatment). In addition, the base‑case model assumed all people would be treated in their best‑seeing eye and therefore this issue of utility gain for people treated in their 'worse‑seeing eye' was not relevant to the base case. For people treated in their 'best‑seeing eye' the maximum utility gain from treatment was 0.41 (that is, the difference between the best visual health state of 0.92 and the worst visual health state of 0.51). Utilities were not adjusted for age.\n\nCosts included intervention and comparator costs, administration costs and follow‑up visits. Grid laser photocoagulation (BRVO only) was assumed to incur no cost but an administration cost as an outpatient procedure was applied. The ranibizumab injection administration visit was costed as an office‑based outpatient procedure, whereas the dexamethasone intravitreal implant injection was based on a weighted average of the cost of an outpatient procedure (25%) and day case procedure (75%) to account for its greater complexity. For ranibizumab, the frequency of injections was taken from the BRAVO and CRUISE trials. In addition, patients experiencing adverse events had an associated cost applied, and patients considered to be blind had the additional costs associated with blindness.\n\nAll of the manufacturer's base‑case incremental cost‑effectiveness ratios (ICERs) that were presented included an approved patient access scheme, which was offered by the manufacturer at the time of submission (and which was subsequently superseded). In the base case for BRVO, the ICER for ranibizumab compared with grid laser photocoagulation was £20,494 per quality‑adjusted life year (QALY) gained. In the base case for CRVO, the ICER for ranibizumab compared with best supportive care was £8643 per QALY gained. The base‑case ICERs for ranibizumab compared with dexamethasone for BRVO and CRVO were £5486 and £7174 per QALY gained respectively. Incremental costs and QALYs for the base‑case results were commercial in confidence and therefore cannot be presented here.\n\nThe manufacturer performed a deterministic sensitivity analysis and found the model to be sensitive to the frequency of injections and follow‑up visits. The manufacturer performed scenario analyses to assess the impact of varying the proportion of people treated in their 'worse‑seeing eye' and commented that this was a key driver of cost effectiveness. The manufacturer also presented probabilistic sensitivity analyses and concluded that the probability that ranibizumab was cost effective when compared with grid laser photocoagulation in BRVO was 45.5% and 57.2% at thresholds of £20,000 and £30,000 per QALY gained respectively. For ranibizumab compared with best supportive care in CRVO, the probability of cost effectiveness was estimated by the manufacturer to be 74.5% and 83.3% at thresholds of £20,000 and £30,000 per QALY gained respectively.\n\n# Evidence Review Group comments on the manufacturer's submission\n\nThe ERG noted that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because one of the exclusion criteria was brisk afferent pupillary defect, which, as the manufacturer stated, equates to severe retinal ischaemia. Therefore, the ERG considered that the results of any analyses could only be applied to people without retinal ischaemia.\n\nThe ERG considered that the concomitant use of grid laser photocoagulation from month\xa03 confounded the results of the BRAVO study and that definite conclusions could not be drawn about the effects of ranibizumab compared with sham injection or grid laser photocoagulation alone. The ERG noted that there was not enough evidence to conclude that grid laser photocoagulation had no effect in the ranibizumab group. It also noted that the treatment period of the BRAVO trial was not long enough to capture any benefits of grid laser photocoagulation on patient outcomes, which may last longer than 3\xa0years. Furthermore, clinical advice to the ERG suggested that ranibizumab and grid laser photocoagulation would not be used together to treat patients in clinical practice.\n\nThe ERG noted that from month\xa06 onwards people were allowed to have ranibizumab as needed and therefore considered the data up to month\xa06 to be the most relevant data for determining the comparative effectiveness of ranibizumab in treating visual impairment caused by macular oedema secondary to RVO. However, the ERG noted that this period may not be long enough to determine the long‑term effects of ranibizumab.\n\nThe ERG questioned the manufacturer's view that an indirect estimate of the efficacy of ranibizumab compared with bevacizumab, dexamethasone and grid laser photocoagulation (for BRVO only) was not possible. Although the ERG accepted that there were differences in baseline characteristics between patients in the CRUISE, BRAVO and GENEVA trials (see section\xa03.9), it stated that this would not prevent an indirect comparison between ranibizumab and dexamethasone, and would likely favour ranibizumab. This was because at baseline the mean duration of macular oedema secondary to CRVO was 3\xa0months in CRUISE and 5\xa0months in GENEVA, and a greater mean duration of RVO tends to result in a poorer response to treatment. The ERG suggested that the impact of any bias could have been explored through critical assessment. The ERG agreed with the manufacturer that it was not possible to incorporate bevacizumab for people with CRVO into an adjusted indirect comparison because only 1\xa0study of bevacizumab for CRVO had been identified in the manufacturer's submission (Faghihi et al. 2008), and this did not adequately report baseline characteristics. For BRVO, the ERG considered that studies of bevacizumab reported in the manufacturer's submission (see section\xa03.9) were suitable for inclusion in an indirect comparison with the first 3\xa0months of data from BRAVO (that is, before rescue treatment with grid laser photocoagulation was permitted). Again, the ERG accepted that there would be some bias in this comparison, but overall the biases would likely favour ranibizumab because the duration of macular oedema in BRAVO was longer than in the study by Moradian et al. and because the Moradian study included more patients with ischaemia than BRAVO. The ERG highlighted that this could be explored in critical assessment.\n\nFrom the trials reported in the manufacturer's submission, the ERG was able to construct a linear network of trials using BRAVO (ranibizumab compared with sham), Moradian et al. 2011 (bevacizumab compared with sham) and Russo et al. 2009 (bevacizumab compared with grid laser photocoagulation). The ERG commented that although the results should be treated with caution because they are exploratory, they estimated an approximately 3‑letter improvement in visual acuity with ranibizumab over bevacizumab and an 8‑letter improvement with ranibizumab over grid laser photocoagulation at month\xa03. However, the ERG did not consider the difference between bevacizumab and ranibizumab to be clinically meaningful from this analysis.\n\nThe ERG noted that in the base‑case analysis the model assumed all patients were treated in the 'better‑seeing eye', despite the fact that over 90% of patients in the BRAVO and CRUISE trials were treated in their 'worse‑seeing eye'. The ERG considered that it was not reasonable to assume equivalent gains in utility and reductions in costs when treating a patient in their 'worse‑seeing eye'. The ERG considered the manufacturer's use of a 'better‑seeing eye' model to be inappropriate because RVO is predominantly a unilateral condition, and therefore most patients would receive treatment in their 'worse‑seeing eye' only.\n\nThe ERG considered the pooled transition probabilities for ranibizumab, which the manufacturer stated had been necessary to account for the effect of grid laser photocoagulation in people with BRVO. The ERG commented that pooling would lead to an overestimate of the efficacy of ranibizumab because the benefit seen in patients in the sham group who received ranibizumab after the first 6\xa0months would be added to the continued effect of ranibizumab in those patients initially randomised to receive ranibizumab. The ERG conducted sensitivity analyses using unpooled transition probabilities. It noted that the ICER for ranibizumab compared with grid laser photocoagulation (for BRVO) with this change alone increased the manufacturer's original base‑case from £20,494 to £52,004 per QALY gained for months\xa07 to 12, and ranibizumab was dominated (was less clinically effective and more expensive) for months\xa013 to 24, and months\xa07 to 12 plus months\xa013 to 24 together. Incremental costs and QALYs for the base‑case results were commercial in confidence and therefore cannot be presented here.\n\nThe ERG considered the manufacturer's exploratory economic analysis that incorporated dexamethasone intravitreal implant. The ERG commented that there was a potential bias towards ranibizumab in the manufacturer's approach (see section\xa03.20). The ERG conducted an exploratory indirect comparison of ranibizumab with dexamethasone intravitreal implant, which provided relative risks of an improvement in visual acuity of 10\xa0letters (2\xa0lines) or more for patients with macular oedema secondary to BRVO and CRVO (a relative risk of less than 1 favours ranibizumab). The relative risks increased from 0.55 to 0.79 for ranibizumab compared with dexamethasone in BRVO. For CRVO, the corresponding figures were 0.30 to 0.40. The ERG commented that the relative risks calculated from the manufacturer's model were more favourable to ranibizumab in both BRVO and CRVO. Moreover, because the ERG's indirect comparison was known to be biased towards ranibizumab, the manufacturer's approach to modelling dexamethasone was largely biased towards ranibizumab. However, the ERG commented that these results were exploratory and should therefore be interpreted with caution.\n\nThe ERG noted the manufacturer's assumption in the economic model that there is no mortality risk attributable to RVO. The ERG identified a UK‑based study (Tsaloumas et al. 2000) that concluded that patients with RVO were at a significantly greater risk of death from myocardial infarction than the general population. The ERG was of the opinion that it would have been appropriate to include the relative risk of 1.6 reported by Tsaloumas in the manufacturer's base‑case analysis.\n\nThe ERG noted the manufacturer had applied a mortality risk associated with the visual acuity level in the patient's 'better‑seeing eye' using data from Christ et al. (2008). The ERG noted that this mortality risk would only apply to patients being treated in their 'better‑seeing eye'. The ERG commented that if the model was amended to treat those with visual impairment in their 'worse‑seeing eye' it would be appropriate to use a mortality risk associated with 'some' visual impairment in these patients.\n\nThe ERG noted that the utility values for visual acuity in the 'better‑seeing eye' were taken from Brown (1999) rather than Czoski‑Murray et al. (2009), an earlier version of which had been used (referred to as Brazier et al. 2006) in Ranibizumab and pegaptanib for the treatment of age\\u2011\\related macular degeneration (NICE technology appraisal guidance 155). The ERG noted that the manufacturer's model assumes utilities are independent of age, although age adjustment is expected to have minimal impact on the ICERs. However, the ERG commented that age adjustment of the utilities presented by Czoski‑Murray et al. (2009) was not necessary because age had already been adjusted for. The ERG commented that the study by Czoski‑Murray et al. (2009) should therefore be used as the source for utility associated with visual acuity in the 'better‑seeing eye' in this assessment. For the 'worse‑seeing eye' the ERG was of the opinion that the available evidence from the Brown publication (which reported utilities by worse‑ and better‑seeing eyes) suggested the maximum gain from treating a person's 'worse‑seeing eye' would be 0.1.\n\nThe ERG carried out exploratory analyses varying several parameters. Assuming that only 10% (and not 100%) of people are treated in their 'better‑seeing eye', applying utilities derived from Czoski‑Murray et al. (2009), a 0.1 overall benefit associated with treating the 'worse‑seeing eye' and an increased risk of mortality associated with RVO, the ICERs for ranibizumab compared with best supportive care and with dexamethasone in CRVO were £43,760 and £37,443 per QALY gained respectively. This formed the ERG's base‑case estimate for CRVO. The ERG did not present further economic evaluation of ranibizumab compared with grid laser photocoagulation because it considered that the confounded data from BRAVO (in which grid laser photocoagulation was permitted in the ranibizumab arm after 3\xa0months of treatment) was insufficient to inform an indirect comparison and be used in the economic model. When the ERG applied their preferred assumptions as above for ranibizumab compared with dexamethasone intravitreal implant in BRVO, this increased the manufacturer's base‑case ICER from £5486 to £31,122 per QALY gained. The ERG's exploratory analyses highlighted that the key drivers that increased the manufacturer's base‑case ICERs were amending the proportion of patients treated in their 'better‑seeing eye' (10% instead of 100%) and the assumption of some benefit associated with treating the 'worse‑seeing eye'.\n\nThe ERG commented that its comparisons of ranibizumab with dexamethasone intravitreal implant for both BRVO and CRVO used relative risks derived from the manufacturer's model (0.55 for BRVO and 0.30 for CRVO) rather than those derived from the ERG's indirect comparison (0.79 and 0.40 respectively). The ERG commented that this would bias the results in favour of ranibizumab and if the ERG's suggested relative risks were applied, the ICER would increase further. The ERG also commented that the efficacy of dexamethasone was potentially underestimated because of differing patient characteristics in the trials that informed the comparison (patients had differing durations of macular oedema from diagnosis in the GENEVA trials compared with BRAVO and CRUISE). Therefore, the manufacturer's base‑case ICERs may be underestimates. The ERG also highlighted that the ICER generated for ranibizumab compared with dexamethasone from the BRAVO trial is derived using the pooled transition probabilities in the original submission. Using the unpooled transition probabilities would increase the ICER further.\n\nThe ERG conducted an exploratory cost‑minimisation analysis for ranibizumab compared with bevacizumab, assuming equivalent efficacy for the 2\xa0treatments (in BRVO and CRVO) and an acquisition cost of £50 per month for bevacizumab. The ERG presented data on the incremental costs of ranibizumab compared with bevacizumab that included commercial‑in‑confidence information and so cannot be presented here. The ERG's analysis using the manufacturer's model suggested that ranibizumab would need to generate 1.5\xa0times more QALYs than bevacizumab (each month between months\xa02 and 6) in macular oedema secondary to BRVO (without considering the revised patient access scheme implemented in NICE technology appraisal guidance\xa0274) to give an ICER at the top end of the range usually considered cost effective. Ranibizumab would need to generate 1.7\xa0times more QALYs than bevacizumab for macular oedema secondary to CRVO (without considering the revised patient access scheme implemented in NICE technology appraisal guidance\xa0274) to give an ICER at the top end of the range usually considered cost effective.\n\n# Revised economic model submitted by the manufacturer during consultation\n\nIn response to the consultation on the appraisal consultation document the manufacturer submitted a revised cost–utility analysis addressing the Committee's concerns about the original model. The revised economic model included the ERG's preferred assumptions relating to 10% of patients being treated in their 'better‑seeing eye', utilities from Czoski‑Murray et al. (2009). The manufacturer also applied some alternative assumptions (see sections\xa03.33 to 3.36) to present revised base‑case cost‑effectiveness estimates for ranibizumab compared with dexamethasone in both BRVO and CRVO.\n\nThe manufacturer considered that the ERG's approach to deriving utilities from Czoski‑Murray et al. (2009) underestimated the utility gains associated with improving visual acuity. The manufacturer therefore provided an alternative to the ERG's derivation of utilities by applying a regression equation from the Czoski‑Murray et al. (2009) publication to derive utilities for each of the 8\xa0BCVA health states in a similar way to that employed in the guidance on Ranibizumab and pegaptanib in age\\u2011\\related macular degeneration (NICE technology appraisal guidance 155). The manufacturer also applied a 0.3 overall benefit of treating the 'worse‑seeing eye' because it felt that a 0.1 benefit, as applied by the ERG, did not capture the difference in utility for people with blindness in their 'worse‑seeing eye'.\n\nThe manufacturer did not apply an excess mortality risk specifically associated with RVO in its revised model because the available evidence was conflicting, and it considered the evidence base to be inconclusive. In addition, the manufacturer highlighted that an excess mortality risk had not been included in the evidence submitted for the published guidance on Dexamethasone intravitreal implant in macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229). However, the manufacturer did amend the model to include mortality risk associated with visual impairment in the 'worse‑seeing eye' as originally suggested by the ERG (see section\xa03.26).\n\nThe manufacturer acknowledged the Committee's concerns about the use of pooled transition probabilities during months\xa07–24 of the BRAVO trial, which were originally used to account for the confounding effect of patients being treated with grid laser photocoagulation at the same time as treatment with ranibizumab. In its revised model, the manufacturer applied data for months\xa07–24 from only the ranibizumab arm of BRAVO to inform the transitions of all BRAVO patients.\n\nThe manufacturer's revised model included updated adverse event rates for year\xa02 for ranibizumab as well as updated adverse event rates for dexamethasone for year\xa01, based on 12‑month outcomes from the GENEVA studies published since the manufacturer's original submission. In addition, the manufacturer considered that the dexamethasone re‑treatment frequency included in the original model (every 6\xa0months) was conservative and therefore applied a re‑treatment frequency of 4\xa0months to the revised model.\n\nFinally, the manufacturer applied a lifetime time horizon instead of the 15‑year time horizon included in the original submission in order to derive its base‑case cost‑effectiveness estimates. The manufacturer stated that this was consistent with the approach taken in the guidance on Dexamethasone intravitreal implant in macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229).\n\nThe manufacturer highlighted in its consultation response that although patients with brisk afferent pupillary defect were excluded from the BRAVO and CRUISE studies, this only represents those at the more severe end of the ischaemic spectrum and therefore did not exclude those with milder ischaemia.\n\nAfter consultation on the appraisal consultation document, the manufacturer responded to the Committee's concerns regarding the extent of bias generated by the differences in the duration of macular oedema between GENEVA and BRAVO/CRUISE. The manufacturer commented that the extent of bias was not known and that the implications for the ICER may be minimal. They also re‑examined the reported mean durations of macular oedema in the GENEVA (dexamethasone) and BRAVO and CRUISE (ranibizumab) studies noting that in the GENEVA studies, the mean duration of macular oedema was assessed at a screening visit which occurred at least 1\xa0month earlier than in the BRAVO and CRUISE studies. The manufacturer further noted that its cost‑effectiveness analysis of ranibizumab compared with dexamethasone was already favourable to dexamethasone because the relative effectiveness of ranibizumab and dexamethasone was assessed at 3\xa0months, and conservative assumptions related to the number of dexamethasone injections and the rate of adverse events associated with dexamethasone were used.\n\nIn their response to the appraisal consultation document consultation the manufacturer reiterated their view that bevacizumab is not a valid comparator because it does not satisfy the definition of a comparator as set out in the NICE Guide to the methods of technology appraisal because, in their view, the use of bevacizumab is not routine or best practice, and because bevacizumab is not licensed for RVO. The manufacturer further highlighted that the studies included in the ERG's indirect comparison of ranibizumab with bevacizumab had methodological shortcomings and that the inclusion of the study by Russo et al. (2009) was inappropriate because standard deviations were not reported in this study for the values of change from baseline. The manufacturer considered the ERG's conclusion about the direction of bias in the indirect comparison to be overly speculative and not evidence‑based. In addition the manufacturer reiterated its concerns over comparisons with an unlicensed drug that might compromise patient safety, further noting that the absence of a full pharmacovigilance programme (normally funded by the drug sponsor), would mean that the cost of safety surveillance would be a significant burden to the NHS and was not included in the ERG's cost‑minimisation analysis. The manufacturer provided an estimate of the per‑patient cost of a basic pharmacovigilance programme, which was submitted as commercial in confidence and cannot therefore be reported. Finally, the manufacturer highlighted that the ERG's use of a cost‑minimisation analysis is fundamentally flawed and that it was not appropriate to assume equivalent safety and efficacy of ranibizumab and bevacizumab, an assumption required for cost‑minimisation methodology, when this has not been established.\n\n# Evidence Review Group's comments on the manufacturer's revised model\n\nThe ERG noted the manufacturer's approach to applying the 'better‑seeing eye' utilities from Czoski‑Murray et al. (2009) to the model and agreed that this was appropriate because it provided utilities for each of the health states in the model rather than the ERG's smaller set of utility values (see section\xa03.32), and was consistent with the approach taken by the Assessment Group for the guidance on Ranibizumab and pegaptanib in age\\u2011\\related macular degeneration (NICE technology appraisal guidance 155). The ERG considered the manufacturer's approach of applying a maximum utility gain of 0.3 from treatment of the 'worse‑seeing eye'. The ERG noted that the manufacturer extrapolated the 0.1\xa0utility loss estimated by Brown et al. (2001) to apply further loss in the 'worse‑seeing eye'. However, the ERG considered that the evidence presented by Brown et al. (2001) suggested that further deterioration in visual acuity in the 'worse‑seeing eye' did not affect utility and therefore applying a 0.3\xa0utility gain was not evidence‑based. They also considered that it lacked face validity.\n\nThe ERG noted the manufacturer's response suggesting that the extent of bias towards ranibizumab in comparison with dexamethasone was overestimated (in the original ERG report). The ERG acknowledged that there is uncertainty surrounding the extent of bias but that this is difficult to quantify. With respect to duration of macular oedema at baseline, the ERG did not have access to data from BRAVO and CRUISE to adjust for the difference in the timing of measurement of duration of macular oedema compared with GENEVA. The ERG also noted that although the manufacturer's revised model uses data from months\xa07–12 of the ranibizumab arm of BRAVO to inform all transition probabilities from month\xa07 to 24, this assumes equivalent efficacy between dexamethasone and ranibizumab when given as needed. The ERG noted that it is not clear whether this assumption is conservative, and that evidence provided by the manufacturer from the BRAVO trial showed that there is a decline in ranibizumab's efficacy when given as needed rather than as monthly treatment.\n\nThe ERG considered the manufacturer's consultation response to dexamethasone re‑treatment frequency and adverse events associated with dexamethasone. The ERG noted that the manufacturer's approach should have also modelled the effectiveness of dexamethasone re‑treatment given less frequently than every 4\xa0months (for example, every 5\xa0months) and that the manufacturer did not take into account that a higher re‑treatment frequency would result in a more stable efficacy for dexamethasone. In addition, the ERG agreed that a higher re‑treatment frequency for dexamethasone would have the impact of increasing the number and severity of adverse events.\n\nThe ERG noted the manufacturer's response to the issue of ischaemic disease. The ERG agreed that the exclusion criterion in BRAVO and CRUISE of brisk afferent pupillary defect would not exclude patients with minor ischaemic disease. However, the ERG noted that none of the key trials used in the ERG's exploratory analysis, including BRAVO and CRUISE, reported data on the number of patients with baseline macular ischaemia. Therefore, the ERG highlighted that it could not be assumed that patients with ischaemia could have been included in BRAVO and CRUISE and stated that the effects of ranibizumab in the subgroup of patients with macular oedema secondary to ischaemic RVO were unknown.\n\n# Patient access scheme as revised in the context of NICE technology appraisal guidance 274\n\nThe manufacturer submitted a revised patient access scheme in 2013 for consideration in this appraisal (as revised in the context of NICE technology appraisal guidance\xa0274), in which it applied a revised discount to ranibizumab for all indications (see section\xa02.4). The manufacturer did not submit any additional clinical‑effectiveness data but submitted an economic model that incorporated the revised patient access scheme discount and employed all of the revised assumptions from the manufacturer's response to consultation (outlined in more detail in sections\xa03.31 to 3.39). In summary these were as follows:\n\nderiving utilities from Czoski‑Murray et al. (2009) for each of the 8\xa0BCVA health states in a similar way to that employed in the guidance on Ranibizumab and pegaptanib in age\\u2011\\related macular degeneration (NICE technology appraisal guidance\xa0155) by applying a regression equation from Czoski‑Murray et al. (2009)\n\napplying a 0.3 overall utility benefit for treating the 'worse‑seeing eye'\n\nincluding mortality risk associated with visual impairment as suggested by the ERG\n\napplying data for months\xa07–24 from only the ranibizumab arm of BRAVO to inform the transition probabilities of all BRAVO patients\n\nincluding updated adverse event rates for year\xa02 for ranibizumab as well as updated adverse event rates for dexamethasone for year\xa01\n\napplying a lifetime time horizon to be consistent with the published guidance for Dexamethasone intravitreal implant for macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance\xa0229).\n\nBy applying all of their revised assumptions (see section\xa03.44), the manufacturer's revised base‑case ICERs (with the revised patient access scheme as implemented in NICE technology appraisal guidance\xa0274) for ranibizumab compared with dexamethasone were £2370 and £6995 per QALY gained for BRVO and CRVO respectively. For ranibizumab compared with best supportive care in CRVO the ICER was £13,851 per QALY gained, whereas for ranibizumab compared with grid laser photocoagulation in BRVO, the ICER was £23,073 per QALY gained.\n\nThe manufacturer performed a deterministic sensitivity analysis and found the model to be sensitive to the frequency of injections and follow‑up visits; for example in BRVO, increasing the number of injections in year\xa02 (from 2.5 to 6) increased the ICER for ranibizumab compared with dexamethasone from £2370 to £9892 per QALY gained.\n\nThe manufacturer provided scenario analyses (one‑way sensitivity analysis) which explored the effect of changing some of the parameters in the model individually. The manufacturer explored the effect of applying a 0.2 overall utility gain for treating the 'worse‑seeing eye'. This increased the base‑case ICERs of ranibizumab compared with dexamethasone from £2370 to £3029 per QALY gained for BRVO, and from £6995 to £9005 per QALY gained for CRVO. For ranibizumab compared with best supportive care in CRVO, the ICER increased from £13,851 to £18,332 per QALY gained. For ranibizumab compared with grid laser photocoagulation, the manufacturer's ICER increased from £23,073 to £30,778 per QALY gained.\n\nOther scenario analyses included reducing the mean number of ranibizumab injections in year\xa02 (the revised number of mean injections was submitted as academic in confidence and cannot be presented). This reduced the ICERs of ranibizumab compared with dexamethasone by 54% in BRVO and by 58% in CRVO. A scenario which included longer follow‑up data based on year\xa02 of the HORIZON extension study reduced the ICERs for ranibizumab compared with dexamethasone from £2370 to £1599 per QALY gained and from £23,073 to £20,911 per QALY gained for ranibizumab compared with grid laser photocoagulation in BRVO. The corresponding scenario analysis for CRVO was not presented.\n\nThe manufacturer also presented probabilistic sensitivity analyses and concluded that from the base‑case results the probability that ranibizumab was cost effective when compared with grid laser photocoagulation in BRVO was 44.2% at a threshold of £20,000 per QALY gained and 58.6% at a threshold of £30,000 per QALY gained. For ranibizumab compared with best supportive care in CRVO, the probability of cost effectiveness was estimated by the manufacturer to be 67.9% and 82.0% at thresholds of £20,000 and £30,000 per QALY gained respectively.\n\n# ERG critique of manufacturer's revised base case with the patient access scheme as revised in the context of NICE technology appraisal guidance 274\n\nThe ERG noted that the revised model used to inform the current patient access scheme submission is the same as that submitted as part of the manufacturer's response to the original consultation, but that not all issues raised by the Committee have been addressed. Therefore, the ERG's views outlined in sections\xa03.40 to 3.43 (relating to deriving utilities, transition probabilities, re‑treatment frequency and adverse events associated with dexamethasone and ischaemic disease) still apply. Overall, the ERG accepted the manufacturer's approach to:\n\nmodelling 90% of people in the model as being treated in their 'worse‑seeing eye'\n\nthe use and implementation of the 'better‑seeing eye' utilities derived from Czoski‑Murray et al. (2009)\n\nexcess mortality associated with visual impairment in the 'worse‑seeing eye'\n\nupdated adverse events. However, the ERG maintained that the available evidence relating to utility gain from treating the 'worse‑seeing eye' suggests a utility decrement of 0.1 (rather than the manufacturer's assumption of 0.3) between the best and worst 'worse‑seeing eye' BCVA health states. Therefore, the ERG provided amended exploratory cost‑effectiveness estimates to include the assumption of a 0.1\xa0utility decrement. For BRVO, this increased the manufacturer's base‑case ICER for ranibizumab compared with grid laser photocoagulation from £23,073 to £44,713 per QALY gained. In the ERG's incremental analysis in BRVO, dexamethasone was extendedly dominated by ranibizumab (that is, the ICER for dexamethasone compared with grid laser photocoagulation was higher than for ranibizumab compared with grid laser photocoagulation) and the ICER compared with best supportive care was £44,713 per QALY gained. The ERG highlighted that there is considerable uncertainty in the comparisons of ranibizumab with grid laser photocoagulation and with dexamethasone as a result of the confounded data from BRAVO (grid laser photocoagulation was permitted in the ranibizumab arm after 3\xa0months of treatment) used to inform the comparison with grid laser photocoagulation and the absence of a direct comparison with dexamethasone.\n\nFor ranibizumab compared with dexamethasone in BRVO, the ERG's amendment of including a 0.1\xa0utility decrement increased the manufacturer's base‑case ICER from £2370 to £4092 per QALY gained. The ERG performed the same amendment for CRVO, and the ICER for ranibizumab compared with best supportive care increased from £13,851 to £26,263 per QALY gained, and for ranibizumab compared with dexamethasone the ICER increased from £6995 to £12,306 per QALY gained. In the ERG's incremental analysis for CRVO, dexamethasone was extendedly dominated by ranibizumab (that is, the ICER for dexamethasone compared with best supportive care was higher than for ranibizumab compared with grid laser photocoagulation) and the ICER for ranibizumab compared with best supportive care was £26,263 per QALY gained. The ERG highlighted that the absence of a direct comparison of ranibizumab with dexamethasone generates considerable uncertainty in these results. In particular, the manufacturer assumed that from month\xa07\xa0onwards, the efficacy of dexamethasone is equivalent to ranibizumab when given as needed (rather than monthly). The ERG note that it remains unclear whether this assumption would lead to bias towards or against ranibizumab.\n\n# NICE Decision Support Unit report\n\nFollowing the Committee's consideration of comparators in this appraisal, and in line with NICE processes (specifically section\xa03.5.49 of the Guide to the single technology appraisals process), the NICE Board asked for additional work to be commissioned from the NICE Decision Support Unit (DSU) related specifically to the consideration of intravitreal bevacizumab as a comparator.\n\nThe DSU report considered 4\xa0questions:\n\nWhat evidence is there relating to the pharmaceutical quality of reformulated bevacizumab as used in eye conditions in general?\n\nHow widespread is intravitreal bevacizumab use in the UK?\n\nWhat is the evidence for efficacy of intravitreal bevacizumab in adults with RVO (and diabetic macular oedema) specifically?\n\nWhat evidence is there regarding adverse events for intravitreal bevacizumab in eye conditions in general?\n\nThe DSU report noted that the process of diluting and aliquoting bevacizumab into the smaller doses required for intravitreal injections requires a 'specials' licence issued by the Medicines and Healthcare products Regulatory Agency (MHRA) and can be performed by hospital pharmacists or on a larger scale by specialist units under tightly controlled conditions. The DSU identified Moorfields Pharmaceuticals (a manufacturing arm of Moorfields Eye Hospital NHS Foundation Trust) and Liverpool and Broadgreen University Hospitals pharmacy as the 2\xa0major suppliers of intravitreal bevacizumab in the UK, both of which hold 'specials' licences. The DSU report highlighted that the greatest risk from reformulation of bevacizumab is infection such as endophthalmitis, which can lead to loss of vision or even the eye itself, and that there has been a warning issued about this by the US Food and Drug Administration (FDA). Reports of sterile endophthalmitis or uveitis by Moorfields to the MHRA have resulted in the recall of 27\xa0batches of bevacizumab.\n\nThe DSU report investigated the extent of use of intravitreal bevacizumab in the UK by reviewing commissioning policy documents, data from the 2\xa0major suppliers of intravitreal bevacizumab, and a survey of consultant ophthalmologists. The findings suggested that there is substantial use of intravitreal bevacizumab across the UK in eye conditions in general and that its use is even more widespread in private practice.\n\nThe report also reviewed the evidence relating to efficacy of intravitreal bevacizumab specifically in RVO. The DSU identified 5\xa0RCTs that examined the effectiveness of bevacizumab on BCVA in people with RVO, 3 of which were in populations with CRVO; the remaining 2\xa0studies were in BRVO. The studies all suggested that intravitreal bevacizumab appeared to confer some improvement in BCVA in both BRVO and CRVO compared with sham injection. However, because 3 of the studies were only available as conference abstracts, detailed data were not available. In addition, the DSU highlighted that interpretations of the findings should be made with caution because of the small number of studies with relatively small sample sizes and differences in participants' age, gender distribution and type of RVO. The studies also had relatively short follow‑up durations (the maximum was 24\xa0weeks).\n\nThe report assessed the evidence relating to adverse events associated with intravitreal bevacizumab in eye conditions in general. A total of 22\xa0RCTs were identified, which evaluated the safety of bevacizumab compared with laser therapy, sham injection, triamcinolone, ranibizumab, pegaptanib and observational control. In addition, 67\xa0observational non‑RCT studies were included in the safety review of intravitreal bevacizumab. Overall, the DSU report commented that adverse event rates following intravitreal bevacizumab treatment were low when compared with other intravitreal treatments, sham injection and laser therapy and most of these studies were in people with AMD, diabetic macular oedema or RVO. Most outcomes were not significantly different between groups. The DSU report noted that higher rates of adverse events have been reported in the bevacizumab group in the head‑to‑head studies of intravitreal bevacizumab and ranibizumab (CATT and IVAN trials in AMD) and although this was not significant in the IVAN trial, when added to the meta‑analysis with the CATT trial, the overall finding was statistically significant. Overall the DSU considered that the 22\xa0RCTs offer the most robust assessment of adverse events. The DSU commented that the evidence on safety of intravitreal bevacizumab from observational studies was inconclusive. However, with respect to larger studies, observational data from Curtis et al. suggested no difference in the risk of adverse events between bevacizumab and ranibizumab, and another population‑based case–control study reported no relationship between the risk of systemic events such as myocardial infarction, venous thromboembolism, stroke or congestive heart failure and the administration of intravitreal bevacizumab or ranibizumab.\n\nComments on the DSU report consultation highlighted that the quality of reformulated bevacizumab might vary between studies and in clinical practice, and there are concerns about the reports of endophthalmitis. However it is unclear how this compares with ranibizumab. Consultees commented that there was insufficient evidence to evaluate the safety of intravitreal bevacizumab, while other consultees noted that the pooled analysis of IVAN and CATT trials, which compared ranibizumab and bevacizumab directly (in people with AMD), showed significantly higher serious systemic adverse events in the bevacizumab group. Some consultees noted that although there is some favourable evidence for efficacy of intravitreal bevacizumab for RVO in comparison with sham injection, the evidence is limited. However, some consultees noted that the use of intravitreal bevacizumab could be substantial but may have declined since the publication of Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance\xa0229).\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of visual impairment caused by macular oedema secondary to retinal vein occlusion (RVO) and the value placed on the benefits of ranibizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from patient experts about the problems associated with visual impairment caused by macular oedema. It heard that the loss of vision has a significant effect on the independence of people with the condition. The patient experts also stated that the condition affects ability to work and hobbies such as reading and gardening. The patient experts acknowledged that although people may be worried about having an injection in the eye, they are willing to receive injections in order to keep their sight. The Committee agreed that loss of vision caused by macular oedema secondary to retinal vein occlusion seriously impairs health‑related quality of life.\n\nThe Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to branch RVO (BRVO) is grid laser photocoagulation but that in interim guidelines from the Royal College of Ophthalmologists it is only recommended after a period of 3 to 6\xa0months following the initial event (obstruction of retinal veins) and following the absorption of the majority of the haemorrhage. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with central RVO (CRVO), because CRVO does not respond to grid laser photocoagulation (as outlined in the Royal College of Ophthalmologists' interim guidelines on RVO) and the current standard treatment is dexamethasone or anti‑vascular endothelial growth factor (VEGF) drugs such as bevacizumab.\n\nThe Committee considered the comparators for the appraisal, and specifically bevacizumab intravitreal injection. It was aware that bevacizumab does not have a UK marketing authorisation for the treatment of RVO and heard from patient experts that they were concerned about using unlicensed treatments for which there was no formal post‑marketing surveillance, particularly if there were alternatives that have a UK marketing authorisation. The Committee noted that a marketing authorisation is not a prerequisite for a comparator in a NICE technology appraisal. It noted that NICE's Guide to the methods of technology appraisal, in recommending comparison with technologies that are 'best practice' or in 'routine use', is not intended to be restrictive but to emphasise the need for comparison with all relevant comparators; any medicine in routine use or considered to be best practice should be considered a comparator. The Committee was minded to conclude that bevacizumab fulfils the requirements for inclusion as a comparator but noted the advice from the NICE Board that this decision should be based on a careful consideration of its use in clinical practice for the condition concerned and, critically, a thorough assessment of its efficacy and safety.\n\nThe Committee considered the information in the Decision Support Unit (DSU) report on the product quality of reformulated bevacizumab. It was aware of consultation comments on the DSU report raising concerns on quality and reports of endophthalmitis and uveitis with intravitreal bevacizumab, although it was not clear how the number of reports compared with those observed with ranibizumab. The Committee also noted the comments from consultation on the DSU report that reformulation of pharmaceutical products is not an unusual practice and is routinely performed in many other circumstances under a 'specials' licence. The Committee noted that reformulating bevacizumab for intravitreal use requires a 'specials' licence from the Medicines and Healthcare products Regulatory Agency (MHRA) and that this means manufacturers must adhere to a range of conditions and inspections. The Committee was satisfied that there is some level of good manufacturing practice in place when pharmaceutical products are reformulated under a 'specials' licence and that such practice is not exceptional.\n\nThe Committee considered the evidence relating to the safety of bevacizumab as reported by the DSU. It was aware that in the 22\xa0randomised controlled trials (RCTs) identified for age‑related macular degeneration (AMD), diabetic macular oedema and RVO, adverse events were few compared with sham injection, laser photocoagulation and other intravitreal treatments. The Committee noted the pooled analysis from the IVAN and CATT trials (both in patients with AMD), which showed a statistically significantly higher rate of systemic adverse events in the bevacizumab group than in the ranibizumab group. However, it also noted observational data from a large study by Curtis et al. suggesting no difference in the risk of adverse events between bevacizumab and ranibizumab. It also noted a population‑based case–control study, including over 90,000\xa0patients, that reported no relationship between the risk of systemic events such as myocardial infarction, venous thromboembolism, stroke or congestive heart failure and the administration of intravitreal bevacizumab or ranibizumab. The Committee concluded that the evidence base relating to the safety of bevacizumab was sufficient to inform judgement of whether bevacizumab is an appropriate comparator.\n\nThe Committee considered the evidence base for the efficacy of bevacizumab in treating visual impairment caused by macular oedema secondary to BRVO and CRVO. It noted the small trials (2\xa0in BRVO, 3\xa0in CRVO) identified in the DSU report, of which 3 were published only as abstracts. The Committee agreed that all trials reported significant mean improvements in best corrected visual acuity (BCVA) for bevacizumab compared with sham injections, but because no direct comparisons of ranibizumab with intravitreal bevacizumab are currently available, a mixed treatment comparison would be needed to answer the question of relative effectiveness between the 2\xa0treatments. The Committee noted that the DSU was not asked to address this question specifically. The Committee concluded that the available evidence was limited with small sample sizes and differences in study populations but on balance sufficient to inform judgement of whether bevacizumab is an appropriate comparator.\n\nHaving noted the available evidence and comments from consultation on the safety, efficacy and quality of intravitreal bevacizumab, the Committee concluded that bevacizumab is an appropriate potential comparator in this appraisal. However, the Committee further concluded that there is currently insufficient evidence to make robust comparisons with ranibizumab needed for a cost‑effectiveness analysis.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. It noted that the main sources of evidence came from the BRAVO and CRUISE RCTs, which included patients with macular oedema secondary to BRVO and CRVO respectively. It also noted the evidence from the 12‑month open‑label extension of both trials, the HORIZON study. The Committee noted that the decision problem for the appraisal included people with or without retinal ischaemia. However it was aware that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because patients with a brisk afferent pupillary defect (which equates to severe retinal ischaemia) were excluded. It heard from the clinical specialists and the manufacturer that this meant that there was no evidence of ranibizumab for treating visual impairment caused by RVO in patients with significant ischaemia.\n\nThe Committee noted that in both BRAVO and CRUISE ranibizumab was associated with statistically significant mean gains in BCVA in the treated eye compared with sham injection for the 6‑month treatment phase. It also noted that ranibizumab was associated with sustained gains in BCVA at 12\xa0months in both BRAVO and CRUISE, and that these were statistically significant (p<0.01 and p<0.001 respectively). The Committee was aware that ranibizumab could be used as needed in both arms of both trials from 6\xa0months. In addition, the Committee was aware that in the BRAVO trial, grid laser photocoagulation was permitted after 3\xa0months in both the sham group and the ranibizumab group, confounding the results of the treatment phase from month\xa03 onwards. Despite this, the Committee concluded that ranibizumab is a clinically effective treatment for visual impairment caused by macular oedema secondary to BRVO and CRVO compared with sham injection, if there is no significant retinal ischaemia.\n\nThe Committee considered the evidence for adverse effects associated with ranibizumab. It noted that the safety of ranibizumab had been shown previously in patients with wet AMD (NICE technology appraisal guidance 155) and diabetic macular oedema (NICE technology appraisal guidance 274 – rapid review of TA237). The Committee also noted that the overall frequency of adverse effects in the BRAVO and CRUISE trials at month\xa06 was low. It agreed that ranibizumab was safe and well tolerated in patients with macular oedema secondary to RVO.\n\nThe Committee noted that the BRAVO and CRUISE trials collected data on the effect of visual impairment on quality of life using the National Eye Institute Visual Function Questionnaire‑25 (NEI VFQ‑25) questionnaire. It noted that both trials reported a statistically significant difference in NEI VFQ‑25 score at month\xa06 between the ranibizumab and sham injection groups. The Committee concluded that treating patients with ranibizumab improves the quality of life of people with visual impairment caused by macular oedema secondary to RVO.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's original economic model and the critique and exploratory analyses performed by the Evidence Review Group (ERG). It noted the manufacturer's original base‑case incremental cost‑effectiveness ratios (ICERs) of £8600 and £20,500 per quality‑adjusted life year (QALY) gained for ranibizumab compared with standard care for CRVO and BRVO respectively and the ICERs for ranibizumab compared with dexamethasone in CRVO and BRVO which were £7200 and £5500 per QALY gained respectively. The Committee broadly accepted the model structure, but was concerned by some of the uncertainties highlighted by the ERG around the assumptions used by the manufacturer. In particular, the Committee did not accept:\n\nthe assumption that all patients would be treated in their 'better‑seeing eye', having heard from clinical specialists that this is not the case in clinical practice, and that most patients in the CRUISE and BRAVO trials were treated in their 'worse‑seeing eye' (see section\xa03.22)\n\nthe manufacturer's use of 'better‑seeing eye' utility values from the Brown study, without age adjustment (see section\xa03.27)\n\nthe absence of a mortality risk associated with RVO in the model (see section\xa03.25)\n\nthe use of pooled transition probabilities during months\xa07–12 of the BRAVO trial, which overestimated the efficacy of ranibizumab compared with sham injection (see section\xa03.23)\n\nthe potential bias in the indirect comparison between ranibizumab and dexamethasone (both BRVO and CRVO), with different exclusion rules for ischaemia, patients with different durations of macular oedema and different severities in the trials of each drug (see section\xa03.24).The Committee concluded that the most plausible ICERs for ranibizumab compared with standard care and dexamethasone intravitreal implant, based on the manufacturer's base case modified appropriately by the ERG, were likely to range from £31,100 to £52,000 per QALY gained and would therefore be well in excess of £20,000 to £30,000 per QALY gained. It also noted that there was additional uncertainty about the cost‑effectiveness estimates for ranibizumab in people with BRVO because grid laser photocoagulation was permitted after 3\xa0months in both the sham and the ranibizumab groups, confounding the results of the treatment phase from month\xa03 onwards. The Committee proceeded to consider the revised model submitted by the manufacturer.\n\nThe Committee noted the manufacturer's revisions to its economic model submitted in response to consultation. It first noted the amendment to reflect the fact that most patients (90%) would be treated in their 'worse‑seeing eye'. The Committee considered that this was consistent with the BRAVO and CRUISE trials and clinical practice, and concluded that this amendment was appropriate.\n\nThe Committee next considered the manufacturer's revised approach to deriving utilities for the 'better‑seeing eye' from Czoski‑Murray et al. (2009) for use in the economic model. It understood that these utilities would only apply to 10% of the people in the revised economic model which now assumed that 90% of people would be treated in their 'worse‑seeing eye' (section\xa04.14). The Committee noted that the manufacturer had applied a regression equation from Czoski‑Murray et al. (2009) to produce a finer degradation of the utilities. The Committee noted that the ERG accepted the manufacturer's use and implementation of the utilities as applied using the Czoski‑Murray equation and further noted the provisional guidance from the rapid review of NICE technology appraisal guidance\xa0237 (now published as NICE technology appraisal guidance 274) in which the range of utility values was accepted to lie somewhere in between those estimated by Czoski‑Murray and those from the Brown study. The Committee concluded that although uncertain, the use of utilities as applied using the Czoski‑Murray equation was acceptable.\n\nThe Committee understood that the manufacturer's submission initially assumed that all people in the economic model would be treated in their 'better‑seeing eye' and therefore did not apply a utility gain associated with treating the 'worse‑seeing eye'. It noted that in the revised economic model (submitted in response to the appraisal consultation document) it was assumed that most people (90%) would be treated in their 'worse‑seeing eye' in line with the ERG's suggestion. The Committee therefore considered the manufacturer's revised assumption of applying a 0.3\xa0utility gain associated with treating the 'worse‑seeing eye'. The Committee heard from the ERG that the manufacturer's assumption was based on an extrapolation of evidence from Brown et al. (2001). It understood that the ERG had used a gain of 0.1 from the Brown study in which utility values were collected separately for the 'worse‑seeing' and 'better‑seeing' eyes. The Committee considered that a 0.3\xa0utility gain associated with treating the 'worse‑seeing eye' seems high given that utility is driven primarily by the 'better‑seeing eye', and therefore lacked face validity. It further noted that the manufacturer had originally suggested that no gain in utility would be obtained from treating the 'worse‑seeing eye'. The Committee was also aware of the results of an analysis from NICE technology appraisal guidance\xa0229 (Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion) the details of which are commercial in confidence. The Committee concluded that a utility gain of 0.1 associated with treating the 'worse‑seeing eye' was appropriate.\n\nThe Committee considered evidence supplied by the manufacturer during consultation relating to excess cardiovascular mortality associated with RVO, that is, the additional risk caused by cardiovascular complications associated with RVO, compared with the general population. The Committee noted that the excess mortality risk incorporated in the ERG base case was based on a paper from 2000 (Tsaloumas), which suggested that a person with RVO would have 1.6\xa0times that of the general population. It noted that, of the papers referenced by the manufacturer in response to the original consultation, none suggested that overall mortality was lower for RVO patients than for the population at large. Some suggested it was greater. But the Committee was also aware that excess cardiovascular mortality had not been applied in Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance\xa0229). The Committee concluded that the evidence on the risk of cardiovascular mortality associated with RVO was unclear, and therefore it need not be included in the base‑case model to the degree applied in the original ERG report. However, it would remain an uncertainty in the analysis.\n\nThe Committee considered the manufacturer's response to the Committee's concerns about the use of pooled transition probabilities. The Committee was aware that the revised model used data from the ranibizumab arm of BRAVO to inform the transitions of all BRVO patients from month\xa07–24 which, in the view of the manufacturer, was a more conservative approach. The Committee noted that this had the effect of boosting the model's mean efficacy of the ranibizumab group after 6\xa0months of treatment, because it assumes the same response to treatment for a person previously treated with ranibizumab as for a person naïve to ranibizumab treatment. It also noted that patients treated with grid laser photocoagulation or dexamethasone will experience the same benefit as patients treated with ranibizumab who are moving onto treatment with ranibizumab given as needed. The Committee heard from the ERG that because of the decline in efficacy of ranibizumab when given as needed in the extension arm of the trial, compared with monthly ranibizumab, it was unclear if the manufacturer's assumption was conservative. The Committee noted that the manufacturer's approach had minimal impact on the revised ICER for ranibizumab compared with dexamethasone in BRVO. The Committee acknowledged that there were advantages and disadvantages to the manufacturer and ERG's approaches. But it concluded that, given the lack of clear data, the approach taken by the manufacturer was appropriate.\n\nThe Committee discussed the manufacturer's revised assumption relating to adverse events. The Committee noted that the revised model included updated adverse event rates in year\xa02, which included iris neovascularisation as an adverse event for ranibizumab and dexamethasone and an updated estimate of the rate of cataract development for dexamethasone (based on 12‑month outcomes from the GENEVA studies). The Committee noted the ERG's concern that it is not clear how the rate of iris neovascularisation was calculated for year\xa02. Although it acknowledged the ERG's concerns with the methods used to estimate adverse events in year\xa02, it cautiously accepted the updated safety data in the model.\n\nThe Committee considered the manufacturer's consultation response to the ERG's opinion that its exploratory economic comparison of ranibizumab with dexamethasone was biased in favour of ranibizumab. The Committee considered the manufacturer's points that the duration of macular oedema may have been underestimated by up to 1\xa0month and that the rates of ischaemic disease were higher in the ranibizumab studies, and that the comparison at 3\xa0months does not take into consideration the declining efficacy of dexamethasone. The Committee heard from the ERG that there may still be greater bias in favour of ranibizumab. This was because dexamethasone's efficacy starts declining at 2\xa0months (which was incorporated in the analysis at 3\xa0months) so in the first cycle of treatment dexamethasone's efficacy was in between that of the sham and ranibizumab treatment and was assumed to be equivalent to best supportive care in months\xa02–6, after which the same efficacy as ranibizumab was assumed. The Committee accepted that the relative effectiveness of ranibizumab and dexamethasone was uncertain and concluded that it was difficult to quantify any bias.\n\nHaving discussed the assumptions in the manufacturer's revised base‑case model the Committee went on to discuss the ICERs produced from this model. It was aware that the manufacturer's revised model included the patient access scheme as revised in the context of NICE technology appraisal\xa0274. It noted the ICERs for BRVO of £23,100 and £2400 per QALY gained for ranibizumab compared with standard care (grid laser photocoagulation) and with dexamethasone respectively, and the base‑case ICERs for CRVO of £13,900 and £7000 per QALY gained for ranibizumab compared with best supportive care and dexamethasone respectively. The Committee noted that the ERG had accepted the manufacturer's assumptions relating to 90% of patients being treated in the 'worse‑seeing eye', use of the 'better‑seeing eye' utilities from Czoski‑Murray et al. (2009) as modelled by the manufacturer, excess mortality associated with visual impairment in the 'worse‑seeing eye', updated adverse events for year\xa02, and a lifetime time horizon. However, the Committee was aware that the ERG had undertaken an exploratory analysis on the revised model in which a maximum utility benefit of 0.1 from treating the 'worse‑seeing eye', instead of the manufacturer's value of 0.3, had been applied. The Committee understood that this was the only difference in the calculation of the ICERs between the analyses. On the basis of its discussions relating to the maximum possible gain in utility from treating the 'worse‑seeing eye' (section\xa04.16), the Committee concluded that its decision should be made on the basis of the ERG's adjustment to the manufacturer's calculations.\n\nThe Committee considered the ICERs for ranibizumab for CRVO calculated in the ERG's exploratory analyses. It noted that in this incremental analysis dexamethasone was extendedly dominated (that is, dexamethasone is dominated by a combination of 2\xa0other alternatives, in this case best supportive care and ranibizumab) and therefore can be discounted from the analysis. Therefore, the Committee went on to consider the comparison of ranibizumab with best supportive care. It noted that, incorporating the patient access scheme (as revised in the context of NICE technology appraisal\xa0274), ranibizumab was associated with an ICER of £26,200 per QALY gained compared with best supportive care in CRVO. The Committee was aware of remaining uncertainties regarding the possible confounding in the data resulting from both groups in the CRUISE trial receiving ranibizumab as needed from month\xa07 (section\xa04.10). It was also aware of the remaining uncertainty because of the absence of a direct comparison with dexamethasone, however on balance the Committee considered that the most plausible ICER for ranibizumab for visual impairment caused by macular oedema secondary to CRVO was between the £20,000 and £30,000 per QALY gained thresholds. It could therefore be considered a cost‑effective use of NHS resources. The Committee therefore concluded that ranibizumab should be recommended as an option for treating visual impairment caused by macular oedema following CRVO. However, there remained uncertainties because of the absence of a direct comparison with dexamethasone.\n\nThe Committee considered the ICERs calculated in the ERG's exploratory analyses for ranibizumab for BRVO. The Committee noted that the key comparison was standard care with laser photocoagulation, rather than with dexamethasone, which is only recommended when laser treatment is inappropriate (NICE technology appraisal guidance 229). The Committee therefore considered the ERG's exploratory ICER of £44,800 per QALY gained for ranibizumab compared with standard care. The Committee was aware that people receiving ranibizumab in the BRAVO trial could receive grid laser photocoagulation from month\xa03 and that this represented a significant confounding factor in both the manufacturer's and the ERG's calculations of the ICER for BRVO compared with standard care. It therefore considered that this ICER would be an underestimate of the most plausible ICER. The Committee concluded that the most plausible ICER for ranibizumab compared with standard care in treating BRVO was in excess of £44,800 per QALY gained. It further concluded that ranibizumab could not be recommended as an option for treating visual impairment caused macular oedema following BRVO when laser photocoagulation is an appropriate treatment option.\n\nThe Committee next considered the population with BRVO for whom grid laser photocoagulation is not an option. It considered that this population would include both those for whom grid laser photocoagulation has not been beneficial and those for whom grid laser photocoagulation is not a suitable treatment. It was aware that the NICE appraisal of dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance\xa0229) had accepted the extent of macular haemorrhage as the definition for the subgroup of people for whom grid laser photocoagulation is not a suitable treatment option. Noting the Royal College of Ophthalmologists' 2010 Interim Guidelines on Retinal Vein Occlusion in which grid laser photocoagulation is only recommended following absorption of the majority of haemorrhage (section\xa04.3), the Committee accepted the extent of macular haemorrhage as the definition of the group of people for whom grid laser photocoagulation is not an option. The Committee understood that, when grid laser photocoagulation is not an option, the comparator in this analysis would be dexamethasone. It considered the ERG's exploratory analysis in which the ICER was £4100 per QALY gained for ranibizumab compared with dexamethasone. Consistent with its previous conclusions it recognised that this ICER would be subject to uncertainty because of the absence of a direct comparison between ranibizumab and dexamethasone and because of confounding in the BRAVO trial. However, the Committee remained satisfied that the most plausible ICER would be below £20,000 per QALY gained. The Committee therefore concluded that ranibizumab should be recommended as an option for treating visual impairment caused by macular oedema following BRVO when grid laser photocoagulation has not been beneficial or is not suitable because of the extent of macular haemorrhage.\n\nThe Committee discussed how innovative ranibizumab is in its potential to make a significant and substantial impact on health‑related benefits. It agreed that anti‑VEGF treatments were a substantial improvement over previous treatments, but considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was in the scientific step forward, not the act of licensing. In addition the Committee was not aware of any substantial benefits of ranibizumab over its comparators that would not be already captured into the QALY estimation in the modelling.\n\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal in the guidance.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA283\n\nAppraisal title: Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion\n\nSection\n\nKey conclusion\n\nRanibizumab is recommended as an option for treating visual impairment caused by macular oedema:\n\nfollowing central retinal vein occlusion or\n\nfollowing branch retinal vein occlusion only if treatment with laser photocoagulation has not been beneficial, or when laser photocoagulation is not suitable because of the extent of macular haemorrhage and\n\nonly if the manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of NICE technology appraisal guidance\xa0274.\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard that the loss of vision has a significant effect on the independence of people with the condition. The Committee agreed that loss of vision caused by macular oedema secondary to retinal vein occlusion seriously impairs health‑related quality of life.\n\nThe Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to branch retinal vein occlusion (BRVO) is grid laser photocoagulation but that in interim guidelines from the Royal College of Ophthalmologists it is only recommended after a period of 3 to 6 months following the initial event (obstruction of retinal veins) and following the absorption of the majority of the haemorrhage. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with central retinal vein occlusion (CRVO) and the current standard treatment is dexamethasone or anti‑vascular endothelial growth factor (VEGF) drugs such as bevacizumab.\n\n, 4.3\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee was not aware of any substantial benefits of ranibizumab over its comparators that would not be already captured into the quality‑adjusted life year (QALY) estimation in the modelling.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nRanibizumab has a marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)'.\n\n\n\nAdverse reactions\n\nThe Committee noted that the overall frequency of adverse effects in the BRAVO and CRUISE trials at month\xa06 was low. It agreed that ranibizumab was safe and well tolerated in patients with macular oedema secondary to RVO.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee was aware that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because patients with a brisk afferent pupillary defect (which equates to severe retinal ischaemia) were excluded. It heard from the clinical specialists and the manufacturer that this meant that there was no evidence of ranibizumab for treating visual impairment caused by RVO in patients with significant ischaemia.\n\nHaving noted the available evidence and comments from consultation (of the Decision Support Unit report) on the safety, efficacy and quality of intravitreal bevacizumab, the Committee concluded that bevacizumab is an appropriate potential comparator in this appraisal. However, the Committee further concluded that there is currently insufficient evidence to make the robust comparisons with ranibizumab needed for a cost‑effectiveness analysis.\n\n, 4.8\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to branch RVO is grid laser photocoagulation but that it is only recommended after a period of 3 to 6\xa0months following the initial event (obstruction of retinal veins) and following the absorption of the majority of the haemorrhage. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with central RVO because CRVO does not respond to grid laser photocoagulation and the current standard treatment is dexamethasone or anti‑vascular endothelial growth factor (VEGF) drugs such as bevacizumab.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee was aware that ranibizumab could be used as needed in both arms of the BRAVO and CRUISE trials from 6\xa0months, and that in the BRAVO trial, grid laser photocoagulation was permitted after 3\xa0months in both the sham and the ranibizumab groups, confounding the results of the treatment phase from month\xa03 onwards.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee concluded that ranibizumab is a clinically effective treatment for visual impairment caused by macular oedema secondary to BRVO and CRVO compared with sham injection, if there is no significant retinal ischaemia.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that in both BRAVO and CRUISE ranibizumab was associated with statistically significant mean gains in BCVA in the treated eye compared with sham injection for the 6‑month treatment phase. It also noted that ranibizumab was associated with sustained gains in BCVA at 12\xa0months in both BRAVO and CRUISE, and that these were statistically significant (p<0.01 and p<0.001 respectively). The Committee concluded that ranibizumab is a clinically effective treatment for visual impairment caused by macular oedema secondary to BRVO and CRVO compared with sham injection, if there is no significant retinal ischaemia.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the manufacturer's original economic model and the critique and exploratory analyses performed by the Evidence Review Group (ERG). It broadly accepted the model structure, but was aware of the uncertainties highlighted by the ERG around the assumptions used by the manufacturer.\n\nThe Committee also considered the manufacturer's revisions to its economic model submitted in response to consultation and broadly accepted the manufacturer's approach to:\n\nreflecting that most patients (90%) would be treated in their 'worse‑seeing eye'\n\nthe use of utilities as applied using the Czoski‑Murray equation, in absence of further evidence\n\napplying unpooled transition probabilities although there was a lack of clear data\n\nthe inclusion of updated adverse event rates in year 2, albeit cautiously.\n\n, 4.14, 4.15, 4.18, 4.19\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered that a 0.3 utility gain associated with treating the 'worse‑seeing eye' seems high given that utility is driven primarily by the 'better‑seeing eye', and therefore lacked face validity.\n\nThe Committee concluded that a utility gain of 0.1 associated with treating the 'worse‑seeing eye' was appropriate.\n\nThe Committee concluded that the evidence on the risk of cardiovascular mortality associated with RVO was unclear, and therefore it need not be included in the base‑case model to the degree applied in the original ERG report. However it would remain an uncertainty in the analysis.\n\nThe Committee acknowledged that there were advantages and disadvantages to the manufacturer and ERG's approaches (to applying unpooled transition probabilities). But it concluded that, given the lack of clear data, the approach taken by the manufacturer was appropriate.\n\nAlthough the Committee acknowledged the ERG's concerns with the methods used to estimate adverse events in year\xa02, it cautiously accepted the updated safety data in the model.\n\nThe Committee accepted that the relative effectiveness of ranibizumab and dexamethasone was uncertain and concluded that it was difficult to quantify any bias.\n\nThe Committee was aware of the remaining uncertainty because of the absence of a direct comparison with dexamethasone.\n\nThe Committee was aware that people receiving ranibizumab in the BRAVO trial could receive grid laser photocoagulation from month\xa03 and that this represented a significant confounding factor in both the manufacturer's and the ERG's calculations of the ICER for BRVO compared with standard care. It therefore considered that this ICER would be an underestimate of the most plausible ICER.\n\n–4.20, 4.22–4.23\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that the BRAVO and CRUISE trials reported a statistically significant difference in NEI VFQ‑25 score at month\xa06 between the ranibizumab and sham injection groups. The Committee concluded that treating patients with ranibizumab improved the quality of life of people with macular oedema secondary to RVO.\n\nThe Committee concluded that although uncertain, the use of utilities as applied using the Czoski‑Murray equation was acceptable.\n\nThe Committee concluded that a utility gain of 0.1 associated with treating the 'worse‑seeing eye' was appropriate.\n\nThe Committee was not aware of any substantial benefits of ranibizumab over its comparators that would not be already captured into the QALY estimation in the modelling.\n\n, 4.15, 4.16,\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee concluded that ranibizumab should be recommended as an option for treating visual impairment caused by macular oedema following BRVO if grid laser photocoagulation has not been beneficial or is not suitable because of the extent of macular haemorrhage.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe ERG exploratory analyses highlighted that the key drivers that increased the manufacturer's base‑case ICERs were amending the proportion of patients treated in their 'better‑seeing eye' (10% instead of 100%) and the assumption of some benefit associated with treating the 'worse‑seeing eye'.\n\nThe Committee considered that a 0.3 utility gain associated with treating the 'worse‑seeing eye' seems high given that utility is driven primarily by the 'better‑seeing eye', and therefore lacked face validity.\n\n, 4.16\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nRanibizumab was associated with an ICER of £26,200 per QALY gained compared with best supportive care in CRVO.\n\n\n\n\n\nThe Committee concluded that the most plausible ICER for ranibizumab compared with standard care in treating BRVO was in excess of £44,800 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe Department of Health and the manufacturer have agreed that ranibizumab will be available to the NHS with a patient access scheme which makes ranibizumab available with a discount. The level of the discount is commercial in confidence.\n\n\n\nEnd‑of‑life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance.\n\n", 'Recommendations for further research ': 'The Committee concluded that further research directly comparing the clinical and cost effectiveness of ranibizumab and bevacizumab in people with macular oedema secondary to retinal vein occlusion should be conducted.', 'Related NICE guidance': 'Details are correct at the time of publication. Further information is available on the NICE website.\n\nPublished\n\nRanibizumab for treating diabetic macular oedema (rapid review of technology appraisal 237). NICE technology appraisal guidance 274 (2013).\n\nFluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema after an inadequate response to prior therapy. NICE technology appraisal guidance 271 (2013).\n\nDexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229 (2011).\n\nRanibizumab and pegaptanib for the treatment of age\\u2011\\related macular degeneration. NICE technology appraisal guidance 155 (2008).\n\nUnder development\n\nAflibercept solution for injection for the treatment of macular oedema caused by central retinal vein occlusion. NICE technology appraisal. Publication date to be confirmed.', 'Review of guidance': 'The guidance on this technology will be considered for review in March 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveMay 2013', 'Changes after publication': 'January 2014:\n minor maintenance.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0134-0'}	https://www.nice.org.uk/guidance/ta283
86a12bfc1358dd8ea93d9f63ccdb556dd884b5a9	nice	Bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer	Bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer Evidence-based recommendations on bevacizumab (Avastin), with paclitaxel and carboplatin, for treating advanced ovarian cancer in adults. # Guidance Please note that NICE can only issue guidance on any drug within the terms of its marketing authorisation. Consequently, bevacizumab for first-line treatment of advanced ovarian cancer has only been appraised at its licensed dose of 15 mg/kg body weight. Bevacizumab in combination with paclitaxel and carboplatin is not recommended for first-line treatment of advanced ovarian cancer (International Federation of Gynaecology and Obstetrics stages IIIB, IIIC and IV epithelial ovarian, fallopian tube or primary peritoneal cancer). People currently receiving bevacizumab for first-line treatment of advanced ovarian cancer should be able to continue treatment until they and their clinicians consider it appropriate to stop.# The technology Bevacizumab (Avastin, Roche) is a humanised monoclonal antibody that inhibits both vascular endothelial growth factor (VEGF)-induced signalling and VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. Bevacizumab in combination with carboplatin and paclitaxel has a UK marketing authorisation for 'the front-line treatment of advanced (International Federation of Gynaecology and Obstetrics stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube or primary peritoneal cancer'. The licensed dose is 15 mg/kg body weight given once every 3 weeks in addition to carboplatin and paclitaxel for up to 6 cycles of treatment, followed by continued use of bevacizumab as single agent until disease progression, or for a maximum of 15 months, or until unacceptable toxicity is reached, whichever occurs earlier. The summary of product characteristics lists the following adverse reactions that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage or haemoptysis, congestive heart failure, posterior reversible encephalopathy syndrome, hypersensitivity or infusion reactions, osteonecrosis of the jaw, ovarian failure and neutropenia. For full details of adverse reactions and contraindications, see the summary of product characteristics. Bevacizumab is available in 100 mg and 400 mg vials at prices of £242.66 and £924.40 respectively (excluding VAT; 'British national formulary' edition 64). The manufacturer estimated the cost of bevacizumab (excluding VAT and assuming wastage) to be £36,078 for a patient weighing 65 kg at a dosage of 15 mg/kg every 3 weeks, amounting to an average monthly cost of £2577. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of bevacizumab and a review of this submission by the Evidence Review Group (ERG; section 9). The key evidence for the clinical effectiveness of bevacizumab plus paclitaxel and carboplatin came from 1 randomised controlled trial (GOG‑0218). The trial assessed the efficacy and safety of bevacizumab (at its licensed dose of 15 mg/kg body weight) plus paclitaxel and carboplatin in people with previously untreated stage III (incompletely resected) or stage IV epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone debulking surgery. This evidence was supported by results from a randomised open-label trial (ICON7) that assessed the efficacy and safety of bevacizumab at an unlicensed dose (7.5 mg/kg body weight) plus paclitaxel and carboplatin in people with high-risk early stage or advanced epithelial ovarian, fallopian tube or primary peritoneal cancer. GOG‑0218 was a double-blind randomised placebo-controlled multicentre trial conducted in North America and Asia, and included 1873 patients with previously untreated stage III or stage IV epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone debulking surgery. The trial was for up to 15 months and patients were randomised to 1 of 3 treatment arms: The CPP (carboplatin, paclitaxel and placebo) control group (n=625) received standard chemotherapy (carboplatin at a target area under the curve of 6 mg/mlmin and paclitaxel 175 mg/m2 every 3 weeks for 6 cycles), plus placebo for cycles 2 to 22. The CPB15 (carboplatin, paclitaxel and bevacizumab ) group (n=625) received the same standard chemotherapy as the CPP group, plus bevacizumab (15 mg/kg) for cycles 2 to 6 and placebo as monotherapy for cycles 7 to 22. The CPB15+ group (n=623) received the same standard chemotherapy as the CPP group, plus bevacizumab (15 mg/kg) for cycles 2 to 22. Cycles lasted 3 weeks and treatment was discontinued at the onset of disease progression, unacceptable toxic effects, completion of all 22 cycles or withdrawal. Patients in the control arm were allowed to cross over to receive bevacizumab after disease progression. Randomisation was stratified for Gynaecologic Oncology Group (GOG) performance status (0, 1 or 2), and cancer stage and debulking status (optimally debulked stage III , suboptimally debulked stage III or stage IV). The primary outcome was progression-free survival (PFS), defined as the period from randomisation to disease progression or death. Progression was assessed by the investigator based on any of the following measures: global clinical deterioration, Response Evaluation Criteria in Solid Tumours (RECIST) or rising serum cancer antigen‑125 (CA‑125). CA‑125 progression was defined as at least twice the nadir or upper limit of normal. Secondary outcomes included overall survival, objective response rate and health-related quality of life measured using the Functional Assessment of Cancer Therapy‑Ovarian (FACT‑O) questionnaire, the Ovarian Cancer Subscale measure and abdominal discomfort score. The primary efficacy analysis of PFS used censored data from September 2009 in which patients with disease progression based on rising serum CA‑125 alone and patients who received non-protocol therapies before progression were censored at the time of their previous scan and excluded from the analysis. Based on an investigator assessment, the censored data showed a statistically significant improvement of 6 months in the difference between the median PFS of the CPB15+ arm and the CPP arm (CPP 12 months, CPB15+ 18 months; hazard ratio 0.645, 95% confidence interval 0.551 to 0.756, p<0.001). There was a 0.7-month difference in median PFS in favour of the CPB15 arm compared with the CPP arm (CPP 12 months, CPB15 12.7 months; HR 0.84, 95% CI 0.71 to 0.99, p=0.0204). An Independent Review Committee assessment of these data showed similar results: a 6-month difference in median PFS in favour of the CPB15+ arm compared with the CPP arm (CPP 13.1 months, CPB15+ 19.1 months; HR 0.62, 95% CI 0.50 to 0.77, p<0.0001) but only a non-statistically significant 0.1-month difference in median PFS in the CPB15 arm compared with the CPP arm (CPP 13.1 months, CPB15 13.2 months; HR 0.93, 95% CI 0.76 to 1.13, p=0.222). A GOG protocol-specified analysis of PFS was undertaken in February 2010 and the results were presented without censoring for CA‑125 progression or use of non-protocol therapy before disease progression. The difference in the median PFS was 3.8 months in favour of the CPB15+ arm compared with the CPP arm (CPP 10.3 months, CPB15+ 14.1 months; HR 0.717, 95% CI 0.625 to 0.824, p<0.0001) and 0.9 months in favour of the CPB15 arm compared with the CPP arm, although this difference was not statistically significant (CPP 10.3 months, CPB15 11.2 months; HR 0.908, 95% CI 0.795 to 1.040, p=0.16). A subgroup analysis by cancer stage and debulking status using the uncensored data from February 2010 suggested that the improvement in PFS between CPB15+ and CPP was maintained across all subgroups: patients with stage III optimally debulked cancer showed a 5.1-month improvement in PFS in the CPB15+ compared with the CPP arm (CPP 12.4 months, CPB15+ 17.5 months; HR 0.66, 95% CI 0.5 to 0.86); patients with stage III suboptimally debulked cancer showed a 3.8-month improvement in PFS in the CPB15+ compared with the CPP arm (CPP 10.1 months, CPB15+ 13.9 months; HR 0.78, 95% CI 0.63 to 0.96); patients with stage IV cancer showed a 3.3-month improvement in PFS in the CPB15+ compared with the CPP arm (CPP 9.5 months, CPB15+ 12.8 months; HR 0.64, 95% CI 0.49 to 0.82). The overall survival analysis was calculated in August 2011 when 46.9% of patients had died. The median overall survival was 3.2 months longer in the CPB15+ arm than in the CPP arm (CPP 40.6 months, CPB15+ 43.8 months; HR 0.88, 95% CI 0.75 to 1.04, p=0.0641). However, this was not statistically significant at the p value boundary of 0.0116. The manufacturer stated that significant patient crossover from the control arm after progression would have confounded the data. The manufacturer's submission contained 2 estimates of the proportion of patients in the control arm receiving bevacizumab after progression: 27.7% and up to 40%. ICON7 was a randomised open-label multicentre study conducted in Europe, and included 1528 patients with high-risk early stage or advanced stage IV epithelial ovarian, fallopian tube or primary peritoneal cancer. The trial was for up to 12 months and patients were randomised to 1 of 2 treatment arms: The CP (carboplatin and paclitaxel) control group (n=764) received standard chemotherapy (carboplatin at a target area under the curve of 5 or 6 mg/mlmin and paclitaxel 175 mg/m2 every 3 weeks for 6 cycles). The CPB7.5+ arm (n=764) received the same standard chemotherapy as the CP group plus bevacizumab (7.5 mg/kg) every 3 weeks for 6 cycles, and continued for an additional 12 cycles or until disease progression. Randomisation was stratified for cancer stage and residual disease post surgery (category 1 – FIGO stage I–III with residual disease less than 1 cm; category 2 – FIGO stage I–III with residual disease more than 1 cm; category 3 – FIGO stage IV and inoperable FIGO stage III) and the time of initiation of chemotherapy (intention-to-start chemotherapy 4 weeks after surgery or sooner, or intention-to-start chemotherapy more than 4 weeks after surgery). Patients received treatment until disease progression, unacceptable toxicity or completion of 6 or 18 cycles of therapy as appropriate. No crossover was permitted. A pre-specified, but not stratified, subgroup included 31% (n=462) of patients with high-risk disease (defined as stage III suboptimally debulked or stage IV debulked ovarian cancer). The primary outcome of the trial was PFS based on RECIST on the basis of radiological, clinical and symptomatic indicators of progression. Secondary outcome measures included overall survival and quality of life. Health-related quality of life was measured using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ‑C30 and QLQ‑OV28 questionnaires. The manufacturer's submission presented analysis of PFS from ICON7 based on a data cut-off of November 2010. For the intention-to-treat population, the difference in median PFS was 2.4 months in favour of bevacizumab (CP 17.4 months, CPB7.5+ 19.8 months; HR 0.87, 95% CI 0.77 to 0.99, p<0.04). For the high-risk subgroup there was a statistically significant difference in median PFS of 5.5 months in favour of bevacizumab (CP 10.5 months, CPB7.5+ 16.0 months; HR 0.73, 95% CI 0.60 to 0.93, p=0.002). A pre-planned exploratory analysis of PFS using subgroups defined by cancer stage and debulking status was also reported. These analyses showed a statistically significant improvement in favour of bevacizumab for patients with stage III suboptimally debulked cancer (difference in median PFS of 6.8 months based on CP 10.1 months and CPB7.5+ 16.9 months ; HR 0.67, 95% CI 0.52 to 0.87). However, no statistically significant differences between treatment arms were observed for stage III patients with optimally debulked cancer (difference in median PFS of 1.6 months based on CP 17.7 months and CPB7.5+ 19.3 months ; HR 0.89, 95% CI 0.74 to 1.07) or patients with stage IV cancer (difference in median PFS of 3.4 months based on CP 10.1 months and CPB7.5+ 13.5 months ; HR 0.74, 95% CI 0.55 to 1.01). The protocol-specified final overall survival analysis for ICON7 has not yet been reported. An exploratory overall survival analysis of the intention-to-treat population, conducted when approximately 25% of patients had died, could not calculate the median duration of overall survival because of low numbers, but gave a hazard ratio of 0.85 (95% CI 0.69 to 1.04). An interim overall survival analysis was conducted in the high-risk subgroup when approximately 47% of patients had died in the CP arm and 34% had died in the CPB7.5+ arm. There was a statistically significant difference in the median overall survival of 7.8 months in favour of bevacizumab (CP 28.8 months, CPB7.5+ 36.6 months; HR 0.64, 95% CI 0.48 to 0.85, p=0.002). The manufacturer did not consider that a meta-analysis was appropriate because GOG‑0218 and ICON7 used different doses and durations of bevacizumab, and different study populations. Almost all patients in GOG‑0218 experienced at least 1 adverse event. Incidences of stomatitis, dysarthria, headache, epistaxis and hypertension were more than 10% higher in the bevacizumab arms than in the placebo arm. Incidences of hypertension, gastrointestinal perforation and non-central nervous system bleeding (adverse events of special interest, grade 3–5) were at least 1% higher in the CPB15+ arm than in the CPP arm. The manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of bevacizumab plus carboplatin and paclitaxel compared with carboplatin and paclitaxel only for first-line treatment in women with stage III or IV ovarian cancer. The model was a 3-state semi-Markov model with health states consisting of PFS, progressed disease and death. Data from GOG‑0218 were used to inform model inputs for dosing, survival and safety. Both the intervention and comparator in the model were used in accordance with their marketing authorisations. The manufacturer also presented an economic analysis of bevacizumab at its unlicensed dose of 7.5 mg/kg based on ICON7, the results of which are not presented here. The analysis was conducted from an NHS and personal social services perspective, the costs and outcomes were discounted at 3.5% per year and a 10-year time horizon was used. PFS in the model uses the Kaplan–Meier survival curves from the GOG‑0218 trial data up to the convergence of the intervention and comparator arms at month 28. The data are from the updated PFS analysis (February 2010), which includes censoring of patients who were presumed to experience progression based on rising CA‑125 levels or who switched to non-protocol therapies. The manufacturer examined the fit of various parametric survival models to the progression-free data and considered a log-logistic model the best fit to extrapolate survival times beyond month 28. In the progressed disease state, the weekly probability of death was assumed to be constant and the same for both arms of the model. The model incorporates patients' health-related quality-of-life outcomes using health-state utility values for the PFS and progressed disease states. The manufacturer applied EQ‑5D utility values from an expanded high-risk subgroup in the ICON7 study, which included all patients with stage III disease with suboptimal debulking or stage IV disease or patients with unresectable disease (n=495). In the PFS state, a log-rank test showed that there was no difference in the utility values across the intervention and comparator arms; therefore, the same utility values were used in both arms of the model. In the PFS state, the values varied with time and in the progressed state, a constant value was used because of the limited data available. The disutilities associated with adverse effects were assumed to have been captured in the assessment of health-related quality of life in ICON7. Drug costs were estimated using the dose and frequency of administration in the summary of product characteristics. Data from a UK cohort study were used in the dose calculations. The base case assumed that any unused carboplatin or paclitaxel from a vial is reallocated and not wasted, whereas for bevacizumab it assumed that any unused drug in a vial is wasted. The costs per patient per cycle were £2229 for bevacizumab, £21.80 for paclitaxel and £18.51 for carboplatin. The costs associated with pharmacy preparation of the infusion and its outpatient administration in hospital (based on NHS reference costs 2010/11) were included in the model. The weekly costs of supporting patients in the PFS and progressed health states were included in the model. Post-progression drug acquisition costs were not included in the model because this information was not available in sufficient detail from GOG‑0218. Costs associated with adverse events that occurred at grade 3 or 4 severity in more than 2% of patients were incorporated into the analysis. The base-case results estimated that adding bevacizumab to standard chemotherapy provides an additional 0.228 life years (0.188 quality-adjusted life years , resulting from a 0.243 QALY gain in the PFS state and a 0.055 QALY loss in the progressed disease state) to patients with an expected survival of approximately 4 years. This benefit is achieved with an incremental cost of £27,089, resulting in an incremental cost-effectiveness ratio (ICER) of £144,066 per QALY gained for the licensed dose of bevacizumab plus carboplatin and paclitaxel, compared with carboplatin and paclitaxel alone. The manufacturer's deterministic sensitivity analysis suggested that the cost-effectiveness results are influenced by the parametric functions used for the PFS extrapolation and the time horizon used in the model. The manufacturer's scenario analyses identified the key drivers of the cost-effectiveness results as the dose and duration of bevacizumab treatment. The ERG considered that GOG‑0218 provided evidence of the clinical effectiveness of bevacizumab plus carboplatin and paclitaxel for the first-line treatment of people in the NHS with advanced ovarian cancer, as defined in the scope. It noted that the population from the trial is generally representative of patients treated in secondary care in the UK, although it may not fully represent patients with comorbidities. The ERG was concerned that the different assessments of PFS (by investigator and Independent Review Committee, CA‑125 censored, CA‑125 not censored) were not consistently reported for all time points. It commented that there may have been selective reporting of data and it is not clear what impact this may have on conclusions. In response to a request for clarification, the manufacturer stated that updated PFS data censored for CA‑125 are not available; also, exploratory analyses were not updated because they were intended only to confirm the validity of investigator-assessed PFS. The ERG considered that, although the direction of the evidence is consistent, the size of effect varies with the different analyses and over time. For example, the difference in median PFS varied from 4 to 6 months; the hazard ratio varied from 0.62 (assessed by Independent Review Committee, data censored) to 0.77 (updated investigator assessed, without data censoring). Clinical advice to the ERG suggested that CA‑125 is used routinely in UK clinical practice; therefore, the ERG considered that results not censored for CA‑125 rises were most relevant to the UK. The ERG considered that the structure adopted for the economic model based on GOG‑0218 was reasonable, and consistent with previous economic evaluations developed for advanced cancer. The methods of analysis were generally appropriate and conformed to the NICE reference case. The ERG noted that a time horizon of 10 years was used in the model. However, the ERG considered a longer time horizon would have been more appropriate because approximately 10% of patients were still alive after 10 years. The ERG agreed that the parameters used for the model were generally appropriate. The ERG highlighted that the clinical-effectiveness data used in the model included censoring for patients with rising CA‑125 levels and for patients who switched to non-protocol therapies. It considered that the hazard ratio from these data was relatively favourable compared with other PFS hazard ratios from the trial and this may have produced a more favourable cost-effectiveness estimate. The ERG also noted that the treatment duration was 12 months rather than the 15 months specified in the summary of product characteristics. The ERG highlighted that, in the trial, overall survival between the arms was similar, with median values of 39.8 months for the bevacizumab arm and 39.4 months for the chemotherapy-only arm. However, in the model, there is a 2-month difference in mean overall survival between the arms (bevacizumab: 47 months, chemotherapy-only: 45 months). The ERG also considered that the uncertainty around the model results had not been fully examined. Not all model parameters were considered in either the deterministic or probabilistic sensitivity analyses. Key parameters missing from the probabilistic sensitivity analysis included the variability in the clinical-effectiveness estimates based on the Kaplan–Meier survival data taken from the trial and variability in the cost of bevacizumab. In the deterministic sensitivity analysis, input parameters that might be expected to be highly influential on the cost-effectiveness results were omitted, such as the cost of bevacizumab, treatment duration and variation in effectiveness. The ERG undertook several exploratory deterministic sensitivity analyses that examined the impact of changes to treatment duration, treatment cost and time horizon. Using the trial discontinuation rates in GOG‑0218 and with treatment for a maximum of 15 months instead of the 12 months in the base case, the ICER for bevacizumab increased from the base case of £144,066 per QALY gained to £160,788 per QALY gained. The ERG investigated the effect of changing the 10-year time horizon to the maximum permitted in the model of 25 years; this reduced the ICER to £127,701 per QALY gained. Finally, the ERG combined the analyses for a treatment duration of 15 months and a time horizon of 25 years, which produced an ICER similar to the base case of £142,477 per QALY gained. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab plus paclitaxel and carboplatin, having considered evidence on the nature of advanced ovarian cancer and the value placed on the benefits of bevacizumab plus paclitaxel and carboplatin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee discussed the current management of advanced ovarian cancer. The clinical specialists confirmed that chemotherapy with paclitaxel and carboplatin was current standard clinical practice in the NHS in England and Wales for first-line treatment of advanced ovarian cancer after debulking surgery. The Committee heard from the clinical specialists that 3 cycles of chemotherapy may be given before surgery for some patients expected to have residual disease left after surgery. After first-line treatment, decisions about progression are usually made using symptomatic and radiological evidence, and rises in CA‑125 alone are not considered sufficient reason to consider changes in treatment. The clinical specialists also highlighted that the 10-year survival rate in ovarian cancer is only 35% and that, in clinical practice, only 1% of people with advanced ovarian cancer were likely to be alive at 10 years. This has improved in recent years but is below the rates for many other cancers. The Committee heard from the clinical specialists that they considered bevacizumab to be an innovative technology because there have been few new beneficial developments in ovarian cancer for several years. The Committee also heard from the clinical specialists that bevacizumab, at its unlicensed dose of 7.5 mg/kg, is currently being used in the NHS in England in combination with standard chemotherapy for patients with stage IV cancer or those who have undergone surgery with more than 1 cm residual disease, followed by bevacizumab continued as maintenance therapy until progression. This is the dose that was used in ICON7, which was conducted across Europe and involved some centres in the UK. The commissioning representatives and patient experts also confirmed that the unlicensed dose of bevacizumab is the dose most commonly used in the NHS for advanced ovarian cancer. NICE informed the Committee that it would be unable to issue guidance on a technology used outside the terms of its marketing authorisation. The Committee heard from the patient experts that treatment options are limited for people with advanced ovarian cancer and that bevacizumab provided an additional treatment option. The patient experts highlighted that the end of first-line treatment is a critical time for patients and it is important not to underestimate the impact of any extension to progression-free survival (PFS) for these patients and their families. They also highlighted the importance of patients' beliefs that they are receiving the best possible treatment to their wellbeing, and suggested that patients often choose to tolerate serious side effects in the hope of gaining additional PFS. # Clinical effectiveness The Committee considered that the main source of evidence for the clinical effectiveness of bevacizumab plus paclitaxel and carboplatin was GOG‑0218. The Committee agreed this was a well-designed double-blind randomised trial. It noted the Evidence Review Group's (ERG's) assessment of the quality of this trial, and accepted that the results of the trial are relevant to the first-line treatment of patients with advanced ovarian cancer in the NHS. The Committee noted that there were 3 arms in the trial but only the CPB15+ arm (bevacizumab given with chemotherapy and then for up to 15 months as maintenance therapy) showed a statistically significant improvement in PFS compared with chemotherapy alone. The CPB15 arm of the trial (bevacizumab given only with chemotherapy) showed no statistically significant PFS benefit compared with the control arm. The Committee concluded that GOG‑0218 provided relevant evidence for this appraisal and that bevacizumab was shown to be clinically effective only when it is given within its marketing authorisation, that is, at the same time as paclitaxel and carboplatin and then as a maintenance treatment for up to 15 months. The Committee noted that PFS results from GOG‑0218 were reported in the manufacturer's submission using both censored data (in which patients with a CA‑125 rise were censored at the time of their previous scan and their results removed from further PFS analysis), and uncensored data (in which a CA‑125 rise indicated progression). The Committee heard from the clinical specialists that a rise in CA‑125 alone was not used as an indication to change treatment because this approach had not been shown to alter prognosis and also approximately a third of patients did not express CA‑125. The clinical specialists also commented that a CA‑125 rise often suggested the disease was progressing but that it could take up to 6 months or so for progression to become apparent. The Committee concluded that a significant rise in CA‑125 is an indicator of progression and might be an early marker, but is not usually used in clinical practice in the UK as the sole indicator of progression. The Committee discussed the most relevant PFS results for the clinical effectiveness of bevacizumab plus paclitaxel and carboplatin in the UK. The Committee noted that the results from the uncensored data of a 3.8-month difference in median PFS in favour of bevacizumab was less than the 6-month difference in median PFS obtained from the censored data. The Committee noted the ERG's concerns about the lack of consistent reporting of the various PFS assessments at all time points. The Committee noted that clinical advice to the ERG was that the uncensored data are the most relevant to the NHS. However, the Committee heard from the clinical specialists that, in their opinion, the censored data are more relevant because patients in the NHS would not be treated as progressed based on a CA‑125 rise alone (see section 4.5). The Committee was aware that the censored data had excluded patients with raised CA‑125 from the analysis and, because these patients could be regarded as being at high risk of progression, this could have led to bias in the results. The Committee noted that all the analyses of PFS data presented in the manufacturer's submission taken at different time points, both censored and uncensored, showed a difference in median PFS in favour of bevacizumab of between 3.8 and 6 months. The Committee concluded that bevacizumab plus paclitaxel and carboplatin improved PFS compared with paclitaxel and carboplatin alone and that, of the available data, the censored PFS data are more relevant to UK clinical practice, although the Committee was aware of the potential bias introduced by censoring the data from patients with raised CA‑125. The Committee considered the overall survival results from GOG‑0218 and noted concerns from the ERG that switching patients in the control arm to bevacizumab after progression had confounded the overall survival analysis. The Committee noted the various estimates given in the manufacturer's submission of the percentage of patients switching and concluded that the precise extent of switching was unclear. It heard from the manufacturer that approximately 40% of patients in the chemotherapy arm compared with 20% of patients in the bevacizumab arm subsequently received bevacizumab after disease progression. The Committee considered that patient crossover from the control arm would have an impact on the overall survival results only if second-line treatment with bevacizumab was more effective than other therapies given after progression, and the Committee did not have this information. Nevertheless, the Committee accepted that the interpretation of overall survival figures from GOG‑0218 was problematic, and that the non-statistically significant difference in median overall survival of 3.2 months attributed to bevacizumab should be interpreted cautiously. The Committee concluded that the overall survival benefit of bevacizumab plus carboplatin and paclitaxel is uncertain from the results of GOG‑0218 because of the uncertainty related to the extent to which patients received bevacizumab after progression and the impact of this. The Committee noted the adverse events reported in GOG‑0218. It understood that these events were as predicted from other studies with bevacizumab and did not raise new safety concerns. The Committee heard from the clinical specialists that most adverse events could be satisfactorily managed. The Committee concluded that adding bevacizumab to a paclitaxel and carboplatin regimen did not lead to unacceptable toxicity compared with paclitaxel and carboplatin alone and that adverse events were manageable. The Committee discussed the evidence from the supporting ICON7 trial. It heard from the clinical specialists that the strengths of this trial were that it included some UK patients, and used the most appropriate definitions of progression, disease staging and surgical debulking. The clinical specialists stated that patients in the optimal debulking subgroups differed between the GOG‑0218 and ICON7 trials. The clinical specialists considered that this is shown by fewer patients in the group with optimally debulked cancer in GOG‑0218 having complete resection (that is, no visible disease) than in ICON7. The Committee also heard from the clinical specialists that this might be because another trial, conducted at the same time as GOG‑0218, may have enrolled the patients who had complete resection. The Committee noted that the information on the proportion of patients with stage III and IV disease in ICON7 who had completely resected disease was not available, and that the marketing authorisation for bevacizumab did not specify complete or incomplete resection. The Committee also noted that, in ICON7, no patient crossover was allowed after disease progression. The Committee was aware of the disadvantages of ICON7 relative to the NICE decision problem, including its open-label design and inclusion of some patients with stage I and II cancer, which is not covered by the marketing authorisation for bevacizumab. In addition, the trial used a lower dose and shorter duration of bevacizumab treatment than is now licensed. Nevertheless, 81% of the patients were covered by the marketing authorisation and the Committee considered that the results from the trial contributed to the body of knowledge about the efficacy of bevacizumab plus paclitaxel and carboplatin for advanced ovarian cancer. The Committee considered the PFS results from ICON7. It noted that the overall difference between the PFS medians in the intention-to-treat population was 2.4 months, which was less than the 6 months in the intention-to-treat population in GOG‑0218 using the censored data. The clinical specialists emphasised that professional opinion was that this difference was related to patient selection and patient characteristics, not to the lower dose and duration of treatment in ICON7. The Committee also noted that, PFS in the chemotherapy comparator arm was worse in the high-risk subgroup from ICON7 than in the intention-to-treat population in GOG‑0218 using the censored data, which could affect interpretation of the results. However, the Committee noted that the high-risk subgroup from ICON7 excluded patients with optimally debulked cancer, whereas the intention-to-treat population in GOG‑0218 included approximately one-third of patients with optimally debulked cancer who might be expected to have a better prognosis, and who experienced the longest PFS of the subgroups in the GOG‑0218 chemotherapy arm. The Committee concluded that the trials were difficult to compare because of different inclusion criteria, bevacizumab dose and duration of treatment, definitions of progression and optimal debulking, and differing baseline factors between the trials. The Committee considered the results presented for the ICON7 high-risk subgroup. This subgroup was broadly comparable with 2 of the 3 stratified groups in GOG‑0218 but did not represent the whole population covered by the marketing authorisation, which does not specify debulking status. Separate analysis of the high-risk subgroup showed a difference in median PFS of 5.5 months in favour of bevacizumab. This was higher than the 2.4-month difference in the ICON7 intention-to-treat population, and was comparable to the gain in the intention-to-treat GOG‑0218 population using the censored data (6 months; see section 3.4). Hazard ratios were not provided for the non-high-risk subgroup (that is, the intention-to-treat population minus the high-risk subgroup) but the Committee assumed that they would have shown little or no benefit. The Committee also considered the PFS results by cancer stage and debulking status in the population of ICON7 covered by the marketing authorisation. It noted that there was an apparent differential response, with little benefit shown in the stage III population with optimally debulked cancer (difference in median PFS 1.6 months in favour of bevacizumab) compared with the population with stage III suboptimally debulked cancer (difference in median PFS 6.8 months) or stage IV cancer (difference in median PFS 3.4 months). The Committee heard from the clinical specialists that these PFS analyses from ICON7 showed benefit in only a proportion of the population covered by the marketing authorisation. The Committee noted that the subgroup data from GOG‑0218 showed a benefit, which was not dependent on debulking status in stage III and IV cancer, with the greatest PFS benefit shown in the optimally debulked subgroup (based on uncensored data from GOG‑0218; corresponding censored subgroup data were not supplied by the manufacturer, see section 3.5). The Committee also noted that, although the results from ICON7 suggested a greater PFS benefit in patients with stage III suboptimally debulked or stage IV cancer, the uncensored subgroup data from GOG‑0218 did not appear to support the manufacturer's suggestion that bevacizumab provides greater benefit for ovarian cancer patients with a poor prognosis. The Committee agreed that the results of the open-label ICON7 trial indicated a smaller PFS benefit in the intention-to-treat population than was seen in GOG‑0218, and also suggested a different benefit based on cancer stage and debulking status that had not been shown in GOG‑0218. The Committee was aware that several hypotheses could explain these differences. The Committee concluded that the ICON7 data contributed to confidence that treatment with bevacizumab could delay progression, but that the reasons for the apparent differential response and differences in PFS suggested by the ICON7 subgroup analysis compared with the analysis of GOG‑0218 uncensored data remained uncertain. The Committee examined the overall survival data from ICON7 and noted that mature data on the intention-to-treat population were not yet available but an interim analysis of the high-risk subgroup showed a difference in median overall survival of 7.8 months in favour of bevacizumab. The Committee noted that, taking into account the shape of the Kaplan–Meier curve from the interim analysis of the high-risk patients, it is likely that the mean overall survival benefit would be much less than the median. The Committee concluded that the interim data for a subgroup in the trial suggested a difference in overall survival in favour of bevacizumab, but that this should be interpreted with caution. # Cost effectiveness The Committee discussed the cost-effectiveness estimates and the assumptions on which these were based from the manufacturer's economic model based on GOG‑0218. The Committee concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer. The Committee considered the model inputs including clinical effectiveness, patient outcomes, resource use and costs. It noted that PFS was based on the Kaplan–Meier curve from the censored data of GOG‑0218 until month 28, after which PFS is represented by a log-logistic parametric function. The Committee also noted that the model used an equal post-progression death rate between the arms. It understood the ERG's concerns about the treatment duration of 12 months instead of the15 months specified in the marketing authorisation and the time horizon of 10 years. The ERG did not consider this time horizon to be long enough, although the Committee heard from the clinical specialists that 10 years was probably appropriate because only a very small number of patients are likely to survive beyond 10 years. The Committee noted that the EQ‑5D utilities from the expanded high-risk subgroup of ICON7 (see section 3.15) were used in the model and that the same utilities were assumed in both arms of the model. It also noted that no disutilities associated with adverse events had been incorporated into the model. The Committee concluded that the model inputs used by the manufacturer were reasonable. The Committee considered the most plausible incremental cost-effectiveness ratios (ICERs) from the model based on the GOG‑0218 trial presented by the manufacturer and by the ERG in their exploratory analyses. It noted that the manufacturer's base-case ICER was approximately £144,000 per quality-adjusted life year (QALY) gained. The Committee considered the ERG's exploratory analyses, which examined the changes in the ICER with a treatment duration of 15 months or a time horizon of 25 years or both, and gave a range of ICERs from £128,000 to £161,000 per QALY gained. The Committee agreed that the range of ICERs obtained from the cost-effectiveness model of bevacizumab plus paclitaxel and carboplatin were outside the range normally considered as a cost-effective use of NHS resources. It therefore concluded that bevacizumab within its marketing authorisation (that is, at a dose of 15 mg/kg), plus paclitaxel and carboplatin, would not be a cost-effective use of NHS resources for first-line treatment of advanced ovarian cancer compared with paclitaxel and carboplatin alone. After receiving comments from the manufacturer in response to the appraisal consultation document, the Committee further considered the impact of patient crossover on overall survival in the GOG‑0218 study as previously discussed (see section 4.7) and how this had been accounted for in the economic model. The Committee was aware that, because a proportion of patients in the chemotherapy arm from the GOG‑0218 study subsequently received bevacizumab after disease progression, the manufacturer had assumed a similar probability of death in both treatment arms in its base-case analysis. The Committee also noted from the ERG that, by using this approach, the model resulted in a greater survival difference in favour of bevacizumab than was observed in the GOG‑0218 study (see section 3.22). The Committee noted that this would result in a lower ICER than if the overall survival observed in the GOG‑0218 study had been used. The Committee heard from the manufacturer that it did not consider it appropriate to use other alternative approaches to adjust for crossover, such as the rank-preserving structural failure time method. The Committee noted the manufacturer's response to the appraisal consultation document, which attempted to adjust for crossover in the trial by applying the overall survival curves estimated for the control and treatment arms in the expanded high-risk subgroup from the ICON7 study, rather than using post-progression survival data from the GOG‑0218 study. The manufacturer justified this approach on the basis that the expanded high-risk subgroup from the ICON7 study, which did not permit crossover at progression, was broadly comparable to the intention-to-treat population in the GOG‑0218 study. However, the Committee agreed that this was an unconventional approach that lacked credibility because of the significant differences identified between the expanded high-risk subgroup in the ICON7 study and the intention-to-treat population in the GOG‑0218 study (see section 4.10). The Committee concluded that the manufacturer's novel approach to adjust for patient crossover in the GOG‑0218 study was not a robust basis on which to estimate the cost effectiveness of bevacizumab, and agreed that the base-case ICER remained the most plausible one on which to base its decision. The Committee considered the comments received by the consultees and commentators on the cost-effectiveness estimate for bevacizumab at its unlicensed dose of 7.5 mg/kg, noting that the manufacturer had submitted an economic analysis of bevacizumab at the unlicensed dose based on ICON7. The Committee also noted from 1 consultee comment that an estimate of the cost effectiveness of bevacizumab at its unlicensed dose had been submitted to and presented by the Scottish Medicines Consortium. The Committee noted that the cost-effectiveness estimate presented to the Scottish Medicines Consortium by the manufacturer differed from the one that was submitted to NICE. The Committee was aware that the ERG had not provided a detailed critique of the ICON7 economic model because it was based on the unlicensed dose of bevacizumab and therefore outside the scope of this appraisal. Therefore, the Committee concluded that it was unable to comment on the validity of the cost-effectiveness analysis of bevacizumab for the first-line treatment of advanced ovarian cancer at its unlicensed dose of 7.5 mg/kg. The Committee also discussed whether it could comment on the use of bevacizumab for the first-line treatment of advanced ovarian cancer at its unlicensed dose of 7.5 mg/kg, noting the request for this from the comments received from consultees and commentators in response to the appraisal consultation document. The Committee noted from the European Medicines Agency's statement that there was insufficient evidence of an acceptable balance of clinically relevant benefit to risk at the lower dose (7.5 mg/kg) used in the ICON7 study. In response to the Committee's question as to whether it was able to recommend a drug outside its licensed dose, NICE reiterated its position that the Committee was only permitted to make a recommendation on the licensed dose of bevacizumab (15 mg/kg). The Committee therefore concluded that it was reasonable not to consider further the cost effectiveness of bevacizumab at its unlicensed dose. The Committee discussed whether bevacizumab should be considered an innovative treatment. The Committee acknowledged that advanced ovarian cancer is a disease with limited treatment options, and that bevacizumab represented a novel biological approach to therapy. It also noted the clinical specialists' comments (see section 4.2). However, the Committee concluded that all benefits of a substantial nature relating to treatment with bevacizumab plus paclitaxel and carboplatin had been captured in the QALY calculation. # Summary of Appraisal Committee's key conclusions TA284 Appraisal title: Bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer Section Key conclusion Bevacizumab in combination with paclitaxel and carboplatin is not recommended for first-line treatment of advanced ovarian cancer (International Federation of Gynaecology and Obstetrics stages IIIB, IIIC and IV epithelial ovarian, fallopian tube or primary peritoneal cancer). The Committee concluded that bevacizumab was shown to be clinically effective only when it is given at the same time as paclitaxel and carboplatin and then as a maintenance treatment for up to 15 months. The Committee agreed that the range of ICERs obtained from the cost-effectiveness model of bevacizumab plus paclitaxel and carboplatin were outside the range normally considered as a cost-effective use of NHS resources. It therefore concluded that bevacizumab within its marketing authorisation (that is, at a dose of 15 mg/kg), plus paclitaxel and carboplatin, would not be a cost-effective use of NHS resources for first-line treatment of advanced ovarian cancer compared with paclitaxel and carboplatin alone. Current practice Clinical need of patients, including the availability of alternative treatments The clinical specialists confirmed that chemotherapy with paclitaxel and carboplatin was current standard clinical practice in the NHS in England and Wales for first-line treatment of advanced ovarian cancer after debulking surgery. They also highlighted that the 10-year survival rate in ovarian cancer is only 35% and that, in clinical practice, only 1% of people with advanced ovarian cancer were likely to be alive at 10 years. This has improved in recent years, but is below the rates for many other cancers. The Committee heard from the patient experts of the limited treatment options available for people with advanced ovarian cancer and noted that bevacizumab provided an additional treatment option. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee heard from the clinical specialists that they considered bevacizumab to be an innovative technology because there have been few new beneficial developments in ovarian cancer for several years. Patient experts highlighted that the end of first-line treatment is a critical time for patients, and it is important not to underestimate the impact of any extension to progression-free survival for these patients and their families. What is the position of the treatment in the pathway of care for the condition? Bevacizumab in combination with carboplatin and paclitaxel has a UK marketing authorisation for 'the front-line treatment of advanced (FIGO stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube or primary peritoneal cancer'. Adverse reactions The Committee concluded that adding bevacizumab to a paclitaxel and carboplatin regimen did not lead to unacceptable toxicity compared with paclitaxel and carboplatin alone and that adverse events were manageable. Evidence for clinical effectiveness Availability, nature and quality of evidence The key evidence for the clinical effectiveness of bevacizumab in combination with paclitaxel and carboplatin came from 1 randomised controlled trial (GOG‑0218). The trial assessed the efficacy and safety of bevacizumab (at its licensed dose of 15 mg/kg body weight) plus paclitaxel and carboplatin in people with previously untreated stage III (incompletely resected) or stage IV epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone debulking surgery. This evidence was supported by results from a randomised open-label trial (ICON7) that assessed the efficacy and safety of bevacizumab at an unlicensed dose (7.5 mg/kg body weight) plus paclitaxel and carboplatin in people with high-risk early stage or advanced epithelial ovarian, fallopian tube or primary peritoneal cancer. Relevance to general clinical practice in the NHS The Committee accepted that the results of GOG‑0218 are relevant to the first-line treatment of patients with advanced ovarian cancer in the NHS. Uncertainties generated by the evidence The Committee noted the ERG's concerns about the lack of consistent reporting of the various PFS assessments at all time points in GOG‑0218. There was also some uncertainty about which set of PFS results (censored or uncensored) from GOG‑0218 is most appropriate for the NHS. The Committee concluded that the censored PFS data are more relevant to UK clinical practice. The Committee concluded that the overall survival benefit of bevacizumab plus carboplatin and paclitaxel is uncertain from the results of GOG‑0218 because of the uncertainty related to the extent to which patients received bevacizumab after progression and the impact of this. The Committee concluded that the GOG‑0218 and ICON7 trials were difficult to compare because of different inclusion criteria, bevacizumab dose and duration of treatment, definitions of progression and optimal debulking, and differing baseline factors between the trials. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee noted that there was an apparent differential response, with little benefit shown in the stage III population with optimally debulked cancer (difference in median PFS 1.6 months in favour of bevacizumab) compared with the population with stage III suboptimally debulked cancer (difference in median PFS 6.8 months) or stage IV cancer (difference in median PFS 3.4 months). The Committee heard from the clinical specialists that these PFS analyses from ICON7 showed benefit in only a proportion of the population covered by the marketing authorisation, whereas GOG‑0218 results indicated a benefit not dependent on debulking status in stage III and IV cancer. The Committee was aware that several hypotheses could explain these differences. Estimate of the size of the clinical effectiveness including strength of supporting evidence The difference in median PFS in favour of bevacizumab using the censored data from GOG‑0218 was 6 months. The Committee concluded that bevacizumab plus paclitaxel and carboplatin improved PFS compared with paclitaxel and carboplatin alone and that, of the available data, the censored PFS data are more relevant to UK clinical practice. Evidence for cost effectiveness Availability and nature of evidence The manufacturer submitted a 3-state semi-Markov model with health states consisting of PFS, progressed disease and death. Data from GOG‑0218 were used to inform model inputs for dosing, survival and safety. Both the intervention and comparator in the model were used in accordance with their marketing authorisations. The Committee concluded that the manufacturer's model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee considered the model inputs, including clinical effectiveness, patient outcomes, resource use and costs, and concluded that they were reasonable. The Committee understood the ERG concerns about the treatment duration of 12 months instead of the 15 months specified in the marketing authorisation and a time horizon of 10 years. The ERG did not consider this time horizon to be long enough, although the Committee heard from the clinical specialists that 10 years was probably appropriate because only a very small number of patients are likely to survive beyond 10 years. The Committee noted the manufacturer's response to the appraisal consultation document, which attempted to adjust for crossover in the GOG‑0218 study by applying the overall survival curves estimated for the control and treatment arms in the expanded high-risk subgroup from the ICON7 study, rather than using post-progression survival data from the GOG‑0218 study. The Committee agreed that this was an unconventional approach that lacked credibility because of the significant differences identified between the 2 studies. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee noted that the EQ-5D utilities from the expanded high-risk subgroup of ICON7 were used in the model and that the same utilities were assumed in both arms of the model. Are there specific groups of people for whom the technology is particularly cost effective? No. The Committee agreed that the range of ICERs obtained from the cost-effectiveness model of bevacizumab plus paclitaxel and carboplatin were outside the range normally considered as a cost-effective use of NHS resources. It therefore concluded that bevacizumab within its marketing authorisation (that is, at a dose of 15 mg/kg), plus paclitaxel and carboplatin, would not be a cost-effective use of NHS resources for first-line treatment of advanced ovarian cancer compared with paclitaxel and carboplatin alone. What are the key drivers of cost effectiveness? The manufacturer's deterministic sensitivity analysis for GOG‑0218 suggested that the cost-effectiveness results are influenced by the parametric functions used for the PFS extrapolation and the time horizon used in the model. The manufacturer's scenario analyses identified the key drivers of the cost-effectiveness results as the dose and duration of bevacizumab treatment. Most likely cost-effectiveness estimate (given as an ICER) The Committee noted that the manufacturer's base-case ICER was approximately £144,000 per QALY gained. The Committee considered the ERG's exploratory analyses, which examined the changes in the ICER with a treatment duration of 15 months or a time horizon of 25 years or both, and gave a range of ICERs from £128,000 to £161,000 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) Not applicable End-of-life considerations Not applicable Equalities considerations and social value judgements No issues relating to equality considerations were raised in the submissions or the Committee meeting. # Related NICE guidance Details are correct at the time of consultation. Further information is available on the NICE website. # Published Bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer. NICE technology appraisal guidance 285 (2013). Ovarian cancer: The recognition and initial management of ovarian cancer. NICE clinical guideline 122 (2011). Trabectedin for the treatment of relapsed ovarian cancer. NICE technology appraisal guidance 222 (2011). Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for the treatment of advanced ovarian cancer. NICE technology appraisal guidance 91 (2005). Review of the clinical effectiveness and cost effectiveness of paclitaxel for ovarian cancer. NICE technology appraisal guidance 55 (2003). # Under development Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for the treatment of recurrent ovarian cancer (including review of technology appraisal no. 91 and technology appraisal no. 222). NICE technology appraisal guidance, publication expected February 2014. Vintafolide in combination with pegylated liposomal doxorubicin hydrochloride for the treatment of folate receptor positive, platinum-resistant ovarian cancer. NICE technology appraisal guidance, publication expected July 2014.# Review of guidance The guidance on this technology will be considered for review in April 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveMay 2013# Changes after publication January 2014: minor maintenance.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It has been incorporated into the NICE pathway on ovarian cancer along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0136-4	{'Guidance': 'Please note that NICE can only issue guidance on any drug within the terms of its marketing authorisation. Consequently, bevacizumab for first-line treatment of advanced ovarian cancer has only been appraised at its licensed dose of 15\xa0mg/kg body weight.\n\nBevacizumab in combination with paclitaxel and carboplatin is not recommended for first-line treatment of advanced ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] stages\xa0IIIB, IIIC and IV epithelial ovarian, fallopian tube or primary peritoneal cancer).\n\nPeople currently receiving bevacizumab for first-line treatment of advanced ovarian cancer should be able to continue treatment until they and their clinicians consider it appropriate to stop.', 'The technology': "Bevacizumab (Avastin, Roche) is a humanised monoclonal antibody that inhibits both vascular endothelial growth factor (VEGF)-induced signalling and VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. Bevacizumab in combination with carboplatin and paclitaxel has a UK marketing authorisation for 'the front-line treatment of advanced (International Federation of Gynaecology and Obstetrics [FIGO] stages\xa0IIIB, IIIC and IV) epithelial ovarian, fallopian tube or primary peritoneal cancer'. The licensed dose is 15\xa0mg/kg body weight given once every 3\xa0weeks in addition to carboplatin and paclitaxel for up to 6\xa0cycles of treatment, followed by continued use of bevacizumab as single agent until disease progression, or for a maximum of 15\xa0months, or until unacceptable toxicity is reached, whichever occurs earlier.\n\nThe summary of product characteristics lists the following adverse reactions that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage or haemoptysis, congestive heart failure, posterior reversible encephalopathy syndrome, hypersensitivity or infusion reactions, osteonecrosis of the jaw, ovarian failure and neutropenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nBevacizumab is available in 100\xa0mg and 400\xa0mg vials at prices of £242.66 and £924.40 respectively (excluding VAT; 'British national formulary' [BNF] edition 64). The manufacturer estimated the cost of bevacizumab (excluding VAT and assuming wastage) to be £36,078 for a patient weighing 65\xa0kg at a dosage of 15\xa0mg/kg every 3\xa0weeks, amounting to an average monthly cost of £2577. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (section\xa08) considered evidence submitted by the manufacturer of bevacizumab and a review of this submission by the Evidence Review Group (ERG; section\xa09).\n\nThe key evidence for the clinical effectiveness of bevacizumab plus paclitaxel and carboplatin came from 1\xa0randomised controlled trial (GOG‑0218). The trial assessed the efficacy and safety of bevacizumab (at its licensed dose of 15\xa0mg/kg body weight) plus paclitaxel and carboplatin in people with previously untreated stage\xa0III (incompletely resected) or stage\xa0IV epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone debulking surgery. This evidence was supported by results from a randomised open-label trial (ICON7) that assessed the efficacy and safety of bevacizumab at an unlicensed dose (7.5\xa0mg/kg body weight) plus paclitaxel and carboplatin in people with high-risk early stage or advanced epithelial ovarian, fallopian tube or primary peritoneal cancer.\n\nGOG‑0218 was a double-blind randomised placebo-controlled multicentre trial conducted in North America and Asia, and included 1873\xa0patients with previously untreated stage\xa0III or stage\xa0IV epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone debulking surgery. The trial was for up to 15\xa0months and patients were randomised to\xa01 of 3\xa0treatment arms:\n\nThe CPP (carboplatin, paclitaxel and placebo) control group (n=625) received standard chemotherapy (carboplatin at a target area under the curve of 6\xa0mg/ml•min and paclitaxel 175\xa0mg/m2 every 3\xa0weeks for 6\xa0cycles), plus placebo for cycles\xa02 to 22.\n\nThe CPB15 (carboplatin, paclitaxel and bevacizumab [15\xa0mg/kg]) group (n=625) received the same standard chemotherapy as the CPP group, plus bevacizumab (15\xa0mg/kg) for cycles\xa02 to 6 and placebo as monotherapy for cycles\xa07 to 22.\n\nThe CPB15+ group (n=623) received the same standard chemotherapy as the CPP group, plus bevacizumab (15\xa0mg/kg) for cycles\xa02 to 22.\n\nCycles lasted 3\xa0weeks and treatment was discontinued at the onset of disease progression, unacceptable toxic effects, completion of all 22\xa0cycles or withdrawal. Patients in the control arm were allowed to cross over to receive bevacizumab after disease progression. Randomisation was stratified for Gynaecologic Oncology Group (GOG) performance status (0, 1 or 2), and cancer stage and debulking status (optimally debulked stage\xa0III [with maximum residual lesion diameter of 1\xa0cm or less], suboptimally debulked stage\xa0III [with maximum residual diameter of more than 1\xa0cm] or stage\xa0IV). The primary outcome was progression-free survival (PFS), defined as the period from randomisation to disease progression or death. Progression was assessed by the investigator based on any of the following measures: global clinical deterioration, Response Evaluation Criteria in Solid Tumours (RECIST) or rising serum cancer antigen‑125 (CA‑125). CA‑125 progression was defined as at least twice the nadir or upper limit of normal. Secondary outcomes included overall survival, objective response rate and health-related quality of life measured using the Functional Assessment of Cancer Therapy‑Ovarian (FACT‑O) questionnaire, the Ovarian Cancer Subscale measure and abdominal discomfort score.\n\nThe primary efficacy analysis of PFS used censored data from September 2009 in which patients with disease progression based on rising serum CA‑125 alone and patients who received non-protocol therapies before progression were censored at the time of their previous scan and excluded from the analysis. Based on an investigator assessment, the censored data showed a statistically significant improvement of 6\xa0months in the difference between the median PFS of the CPB15+ arm and the CPP arm (CPP 12\xa0months, CPB15+ 18\xa0months; hazard ratio [HR] 0.645, 95%\xa0confidence interval [CI] 0.551 to 0.756, p<0.001). There was a 0.7-month difference in median PFS in favour of the CPB15 arm compared with the CPP arm (CPP 12\xa0months, CPB15 12.7\xa0months; HR\xa00.84, 95%\xa0CI 0.71 to 0.99, p=0.0204). An Independent Review Committee assessment of these data showed similar results: a 6-month difference in median PFS in favour of the CPB15+ arm compared with the CPP arm (CPP 13.1\xa0months, CPB15+ 19.1\xa0months; HR\xa00.62, 95%\xa0CI 0.50 to 0.77, p<0.0001) but only a non-statistically significant 0.1-month difference in median PFS in the CPB15 arm compared with the CPP arm (CPP 13.1\xa0months, CPB15 13.2\xa0months; HR\xa00.93, 95%\xa0CI 0.76 to 1.13, p=0.222). A GOG protocol-specified analysis of PFS was undertaken in February\xa02010 and the results were presented without censoring for CA‑125 progression or use of non-protocol therapy before disease progression. The difference in the median PFS was 3.8\xa0months in favour of the CPB15+ arm compared with the CPP arm (CPP 10.3\xa0months, CPB15+ 14.1\xa0months; HR\xa00.717, 95%\xa0CI 0.625 to 0.824, p<0.0001) and 0.9\xa0months in favour of the CPB15 arm compared with the CPP arm, although this difference was not statistically significant (CPP 10.3\xa0months, CPB15 11.2\xa0months; HR\xa00.908, 95%\xa0CI 0.795 to 1.040, p=0.16).\n\nA subgroup analysis by cancer stage and debulking status using the uncensored data from February\xa02010 suggested that the improvement in PFS between CPB15+ and CPP was maintained across all subgroups: patients with stage\xa0III optimally debulked cancer showed a 5.1-month improvement in PFS in the CPB15+ compared with the CPP arm (CPP 12.4\xa0months, CPB15+ 17.5\xa0months; HR\xa00.66, 95%\xa0CI 0.5 to 0.86); patients with stage\xa0III suboptimally debulked cancer showed a 3.8-month improvement in PFS in the CPB15+ compared with the CPP arm (CPP 10.1\xa0months, CPB15+ 13.9\xa0months; HR\xa00.78, 95%\xa0CI 0.63 to 0.96); patients with stage\xa0IV cancer showed a 3.3-month improvement in PFS in the CPB15+ compared with the CPP arm (CPP 9.5\xa0months, CPB15+ 12.8\xa0months; HR\xa00.64, 95%\xa0CI 0.49 to 0.82).\n\nThe overall survival analysis was calculated in August\xa02011 when 46.9% of patients had died. The median overall survival was 3.2\xa0months longer in the CPB15+ arm than in the CPP arm (CPP 40.6\xa0months, CPB15+ 43.8\xa0months; HR\xa00.88, 95%\xa0CI 0.75 to 1.04, p=0.0641). However, this was not statistically significant at the p\xa0value boundary of 0.0116. The manufacturer stated that significant patient crossover from the control arm after progression would have confounded the data. The manufacturer's submission contained 2\xa0estimates of the proportion of patients in the control arm receiving bevacizumab after progression: 27.7% and up to 40%.\n\nICON7 was a randomised open-label multicentre study conducted in Europe, and included 1528\xa0patients with high-risk early stage or advanced stage\xa0IV epithelial ovarian, fallopian tube or primary peritoneal cancer. The trial was for up to 12\xa0months and patients were randomised to\xa01 of 2\xa0treatment arms:\n\nThe CP (carboplatin and paclitaxel) control group (n=764) received standard chemotherapy (carboplatin at a target area under the curve of 5 or 6\xa0mg/ml•min and paclitaxel 175\xa0mg/m2 every 3\xa0weeks for 6\xa0cycles).\n\nThe CPB7.5+ arm (n=764) received the same standard chemotherapy as the CP group plus bevacizumab (7.5\xa0mg/kg) every 3\xa0weeks for 6\xa0cycles, and continued for an additional 12\xa0cycles or until disease progression.\n\nRandomisation was stratified for cancer stage and residual disease post surgery (category\xa01 – FIGO stage\xa0I–III with residual disease less than 1\xa0cm; category\xa02 – FIGO stage\xa0I–III with residual disease more than 1\xa0cm; category\xa03 – FIGO stage\xa0IV and inoperable FIGO stage\xa0III) and the time of initiation of chemotherapy (intention-to-start chemotherapy 4\xa0weeks after surgery or sooner, or intention-to-start chemotherapy more than 4\xa0weeks after surgery). Patients received treatment until disease progression, unacceptable toxicity or completion of 6 or 18\xa0cycles of therapy as appropriate. No crossover was permitted. A pre-specified, but not stratified, subgroup included 31% (n=462) of patients with high-risk disease (defined as stage\xa0III suboptimally debulked or stage\xa0IV debulked ovarian cancer). The primary outcome of the trial was PFS based on RECIST on the basis of radiological, clinical and symptomatic indicators of progression. Secondary outcome measures included overall survival and quality of life. Health-related quality of life was measured using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ‑C30 and QLQ‑OV28 questionnaires.\n\nThe manufacturer's submission presented analysis of PFS from ICON7 based on a data cut-off of November\xa02010. For the intention-to-treat population, the difference in median PFS was 2.4\xa0months in favour of bevacizumab (CP 17.4\xa0months, CPB7.5+ 19.8\xa0months; HR\xa00.87, 95%\xa0CI 0.77 to 0.99, p<0.04). For the high-risk subgroup there was a statistically significant difference in median PFS of 5.5\xa0months in favour of bevacizumab (CP 10.5\xa0months, CPB7.5+ 16.0\xa0months; HR\xa00.73, 95%\xa0CI 0.60 to 0.93, p=0.002). A pre-planned exploratory analysis of PFS using subgroups defined by cancer stage and debulking status was also reported. These analyses showed a statistically significant improvement in favour of bevacizumab for patients with stage\xa0III suboptimally debulked cancer (difference in median PFS of 6.8\xa0months based on CP 10.1\xa0months [n=154] and CPB7.5+ 16.9\xa0months [n=140]; HR\xa00.67, 95%\xa0CI 0.52 to 0.87). However, no statistically significant differences between treatment arms were observed for stage\xa0III patients with optimally debulked cancer (difference in median PFS of 1.6\xa0months based on CP 17.7\xa0months [n=368] and CPB7.5+ 19.3\xa0months [n=383]; HR\xa00.89, 95%\xa0CI 0.74 to 1.07) or patients with stage\xa0IV cancer (difference in median PFS of 3.4\xa0months based on CP 10.1\xa0months [n=97] and CPB7.5+ 13.5\xa0months [n=104]; HR\xa00.74, 95%\xa0CI 0.55 to 1.01).\n\nThe protocol-specified final overall survival analysis for ICON7 has not yet been reported. An exploratory overall survival analysis of the intention-to-treat population, conducted when approximately 25% of patients had died, could not calculate the median duration of overall survival because of low numbers, but gave a hazard ratio of 0.85 (95%\xa0CI 0.69 to 1.04). An interim overall survival analysis was conducted in the high-risk subgroup when approximately 47% of patients had died in the CP arm and 34% had died in the CPB7.5+ arm. There was a statistically significant difference in the median overall survival of 7.8\xa0months in favour of bevacizumab (CP 28.8\xa0months, CPB7.5+ 36.6\xa0months; HR\xa00.64, 95%\xa0CI 0.48 to 0.85, p=0.002).\n\nThe manufacturer did not consider that a meta-analysis was appropriate because GOG‑0218 and ICON7 used different doses and durations of bevacizumab, and different study populations.\n\nAlmost all patients in GOG‑0218 experienced at least 1\xa0adverse event. Incidences of stomatitis, dysarthria, headache, epistaxis and hypertension were more than 10% higher in the bevacizumab arms than in the placebo arm. Incidences of hypertension, gastrointestinal perforation and non-central nervous system bleeding (adverse events of special interest, grade\xa03–5) were at least 1% higher in the CPB15+ arm than in the CPP arm.\n\nThe manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of bevacizumab plus carboplatin and paclitaxel compared with carboplatin and paclitaxel only for first-line treatment in women with stage\xa0III or IV ovarian cancer. The model was a 3-state semi-Markov model with health states consisting of PFS, progressed disease and death. Data from GOG‑0218 were used to inform model inputs for dosing, survival and safety. Both the intervention and comparator in the model were used in accordance with their marketing authorisations. The manufacturer also presented an economic analysis of bevacizumab at its unlicensed dose of 7.5\xa0mg/kg based on ICON7, the results of which are not presented here. The analysis was conducted from an NHS and personal social services perspective, the costs and outcomes were discounted at 3.5% per year and a 10-year time horizon was used.\n\nPFS in the model uses the Kaplan–Meier survival curves from the GOG‑0218 trial data up to the convergence of the intervention and comparator arms at month\xa028. The data are from the updated PFS analysis (February\xa02010), which includes censoring of patients who were presumed to experience progression based on rising CA‑125 levels or who switched to non-protocol therapies. The manufacturer examined the fit of various parametric survival models to the progression-free data and considered a log-logistic model the best fit to extrapolate survival times beyond month\xa028. In the progressed disease state, the weekly probability of death was assumed to be constant and the same for both arms of the model.\n\nThe model incorporates patients' health-related quality-of-life outcomes using health-state utility values for the PFS and progressed disease states. The manufacturer applied EQ‑5D utility values from an expanded high-risk subgroup in the ICON7 study, which included all patients with stage\xa0III disease with suboptimal debulking or stage\xa0IV disease or patients with unresectable disease (n=495). In the PFS state, a log-rank test showed that there was no difference in the utility values across the intervention and comparator arms; therefore, the same utility values were used in both arms of the model. In the PFS state, the values varied with time and in the progressed state, a constant value was used because of the limited data available. The disutilities associated with adverse effects were assumed to have been captured in the assessment of health-related quality of life in ICON7.\n\nDrug costs were estimated using the dose and frequency of administration in the summary of product characteristics. Data from a UK cohort study were used in the dose calculations. The base case assumed that any unused carboplatin or paclitaxel from a vial is reallocated and not wasted, whereas for bevacizumab it assumed that any unused drug in a vial is wasted. The costs per patient per cycle were £2229 for bevacizumab, £21.80 for paclitaxel and £18.51 for carboplatin. The costs associated with pharmacy preparation of the infusion and its outpatient administration in hospital (based on NHS reference costs 2010/11) were included in the model. The weekly costs of supporting patients in the PFS and progressed health states were included in the model. Post-progression drug acquisition costs were not included in the model because this information was not available in sufficient detail from GOG‑0218. Costs associated with adverse events that occurred at grade\xa03 or 4 severity in more than 2% of patients were incorporated into the analysis.\n\nThe base-case results estimated that adding bevacizumab to standard chemotherapy provides an additional 0.228\xa0life years (0.188\xa0quality-adjusted life years [QALYs], resulting from a 0.243 QALY gain in the PFS state and a 0.055 QALY loss in the progressed disease state) to patients with an expected survival of approximately 4\xa0years. This benefit is achieved with an incremental cost of £27,089, resulting in an incremental cost-effectiveness ratio (ICER) of £144,066 per QALY gained for the licensed dose of bevacizumab plus carboplatin and paclitaxel, compared with carboplatin and paclitaxel alone. The manufacturer's deterministic sensitivity analysis suggested that the cost-effectiveness results are influenced by the parametric functions used for the PFS extrapolation and the time horizon used in the model. The manufacturer's scenario analyses identified the key drivers of the cost-effectiveness results as the dose and duration of bevacizumab treatment.\n\nThe ERG considered that GOG‑0218 provided evidence of the clinical effectiveness of bevacizumab plus carboplatin and paclitaxel for the first-line treatment of people in the NHS with advanced ovarian cancer, as defined in the scope. It noted that the population from the trial is generally representative of patients treated in secondary care in the UK, although it may not fully represent patients with comorbidities.\n\nThe ERG was concerned that the different assessments of PFS (by investigator and Independent Review Committee, CA‑125 censored, CA‑125 not censored) were not consistently reported for all time points. It commented that there may have been selective reporting of data and it is not clear what impact this may have on conclusions. In response to a request for clarification, the manufacturer stated that updated PFS data censored for CA‑125 are not available; also, exploratory analyses were not updated because they were intended only to confirm the validity of investigator-assessed PFS. The ERG considered that, although the direction of the evidence is consistent, the size of effect varies with the different analyses and over time. For example, the difference in median PFS varied from 4 to 6\xa0months; the hazard ratio varied from 0.62 (assessed by Independent Review Committee, data censored) to 0.77 (updated investigator assessed, without data censoring). Clinical advice to the ERG suggested that CA‑125 is used routinely in UK clinical practice; therefore, the ERG considered that results not censored for CA‑125 rises were most relevant to the UK.\n\nThe ERG considered that the structure adopted for the economic model based on GOG‑0218 was reasonable, and consistent with previous economic evaluations developed for advanced cancer. The methods of analysis were generally appropriate and conformed to the NICE reference case. The ERG noted that a time horizon of 10\xa0years was used in the model. However, the ERG considered a longer time horizon would have been more appropriate because approximately 10% of patients were still alive after 10\xa0years. The ERG agreed that the parameters used for the model were generally appropriate.\n\nThe ERG highlighted that the clinical-effectiveness data used in the model included censoring for patients with rising CA‑125 levels and for patients who switched to non-protocol therapies. It considered that the hazard ratio from these data was relatively favourable compared with other PFS hazard ratios from the trial and this may have produced a more favourable cost-effectiveness estimate. The ERG also noted that the treatment duration was 12\xa0months rather than the 15\xa0months specified in the summary of product characteristics.\n\nThe ERG highlighted that, in the trial, overall survival between the arms was similar, with median values of 39.8\xa0months for the bevacizumab arm and 39.4\xa0months for the chemotherapy-only arm. However, in the model, there is a 2-month difference in mean overall survival between the arms (bevacizumab: 47\xa0months, chemotherapy-only: 45\xa0months).\n\nThe ERG also considered that the uncertainty around the model results had not been fully examined. Not all model parameters were considered in either the deterministic or probabilistic sensitivity analyses. Key parameters missing from the probabilistic sensitivity analysis included the variability in the clinical-effectiveness estimates based on the Kaplan–Meier survival data taken from the trial and variability in the cost of bevacizumab. In the deterministic sensitivity analysis, input parameters that might be expected to be highly influential on the cost-effectiveness results were omitted, such as the cost of bevacizumab, treatment duration and variation in effectiveness.\n\nThe ERG undertook several exploratory deterministic sensitivity analyses that examined the impact of changes to treatment duration, treatment cost and time horizon. Using the trial discontinuation rates in GOG‑0218 and with treatment for a maximum of 15\xa0months instead of the 12\xa0months in the base case, the ICER for bevacizumab increased from the base case of £144,066 per QALY gained to £160,788 per QALY gained. The ERG investigated the effect of changing the 10-year time horizon to the maximum permitted in the model of 25\xa0years; this reduced the ICER to £127,701 per QALY gained. Finally, the ERG combined the analyses for a treatment duration of 15\xa0months and a time horizon of 25\xa0years, which produced an ICER similar to the base case of £142,477 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab plus paclitaxel and carboplatin, having considered evidence on the nature of advanced ovarian cancer and the value placed on the benefits of bevacizumab plus paclitaxel and carboplatin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the current management of advanced ovarian cancer. The clinical specialists confirmed that chemotherapy with paclitaxel and carboplatin was current standard clinical practice in the NHS in England and Wales for first-line treatment of advanced ovarian cancer after debulking surgery. The Committee heard from the clinical specialists that 3\xa0cycles of chemotherapy may be given before surgery for some patients expected to have residual disease left after surgery. After first-line treatment, decisions about progression are usually made using symptomatic and radiological evidence, and rises in CA‑125 alone are not considered sufficient reason to consider changes in treatment. The clinical specialists also highlighted that the 10-year survival rate in ovarian cancer is only 35% and that, in clinical practice, only 1% of people with advanced ovarian cancer were likely to be alive at 10\xa0years. This has improved in recent years but is below the rates for many other cancers. The Committee heard from the clinical specialists that they considered bevacizumab to be an innovative technology because there have been few new beneficial developments in ovarian cancer for several years. The Committee also heard from the clinical specialists that bevacizumab, at its unlicensed dose of 7.5\xa0mg/kg, is currently being used in the NHS in England in combination with standard chemotherapy for patients with stage\xa0IV cancer or those who have undergone surgery with more than 1\xa0cm residual disease, followed by bevacizumab continued as maintenance therapy until progression. This is the dose that was used in ICON7, which was conducted across Europe and involved some centres in the UK. The commissioning representatives and patient experts also confirmed that the unlicensed dose of bevacizumab is the dose most commonly used in the NHS for advanced ovarian cancer. NICE informed the Committee that it would be unable to issue guidance on a technology used outside the terms of its marketing authorisation.\n\nThe Committee heard from the patient experts that treatment options are limited for people with advanced ovarian cancer and that bevacizumab provided an additional treatment option. The patient experts highlighted that the end of first-line treatment is a critical time for patients and it is important not to underestimate the impact of any extension to progression-free survival (PFS) for these patients and their families. They also highlighted the importance of patients' beliefs that they are receiving the best possible treatment to their wellbeing, and suggested that patients often choose to tolerate serious side effects in the hope of gaining additional PFS.\n\n# Clinical effectiveness\n\nThe Committee considered that the main source of evidence for the clinical effectiveness of bevacizumab plus paclitaxel and carboplatin was GOG‑0218. The Committee agreed this was a well-designed double-blind randomised trial. It noted the Evidence Review Group's (ERG's) assessment of the quality of this trial, and accepted that the results of the trial are relevant to the first-line treatment of patients with advanced ovarian cancer in the NHS. The Committee noted that there were 3\xa0arms in the trial but only the CPB15+ arm (bevacizumab given with chemotherapy and then for up to 15\xa0months as maintenance therapy) showed a statistically significant improvement in PFS compared with chemotherapy alone. The CPB15 arm of the trial (bevacizumab given only with chemotherapy) showed no statistically significant PFS benefit compared with the control arm. The Committee concluded that GOG‑0218 provided relevant evidence for this appraisal and that bevacizumab was shown to be clinically effective only when it is given within its marketing authorisation, that is, at the same time as paclitaxel and carboplatin and then as a maintenance treatment for up to 15\xa0months.\n\nThe Committee noted that PFS results from GOG‑0218 were reported in the manufacturer's submission using both censored data (in which patients with a CA‑125 rise were censored at the time of their previous scan and their results removed from further PFS analysis), and uncensored data (in which a CA‑125 rise indicated progression). The Committee heard from the clinical specialists that a rise in CA‑125 alone was not used as an indication to change treatment because this approach had not been shown to alter prognosis and also approximately a third of patients did not express CA‑125. The clinical specialists also commented that a CA‑125 rise often suggested the disease was progressing but that it could take up to 6\xa0months or so for progression to become apparent. The Committee concluded that a significant rise in CA‑125 is an indicator of progression and might be an early marker, but is not usually used in clinical practice in the UK as the sole indicator of progression.\n\nThe Committee discussed the most relevant PFS results for the clinical effectiveness of bevacizumab plus paclitaxel and carboplatin in the UK. The Committee noted that the results from the uncensored data of a 3.8-month difference in median PFS in favour of bevacizumab was less than the 6-month difference in median PFS obtained from the censored data. The Committee noted the ERG's concerns about the lack of consistent reporting of the various PFS assessments at all time points. The Committee noted that clinical advice to the ERG was that the uncensored data are the most relevant to the NHS. However, the Committee heard from the clinical specialists that, in their opinion, the censored data are more relevant because patients in the NHS would not be treated as progressed based on a CA‑125 rise alone (see section\xa04.5). The Committee was aware that the censored data had excluded patients with raised CA‑125 from the analysis and, because these patients could be regarded as being at high risk of progression, this could have led to bias in the results. The Committee noted that all the analyses of PFS data presented in the manufacturer's submission taken at different time points, both censored and uncensored, showed a difference in median PFS in favour of bevacizumab of between 3.8 and 6\xa0months. The Committee concluded that bevacizumab plus paclitaxel and carboplatin improved PFS compared with paclitaxel and carboplatin alone and that, of the available data, the censored PFS data are more relevant to UK clinical practice, although the Committee was aware of the potential bias introduced by censoring the data from patients with raised CA‑125.\n\nThe Committee considered the overall survival results from GOG‑0218 and noted concerns from the ERG that switching patients in the control arm to bevacizumab after progression had confounded the overall survival analysis. The Committee noted the various estimates given in the manufacturer's submission of the percentage of patients switching and concluded that the precise extent of switching was unclear. It heard from the manufacturer that approximately 40% of patients in the chemotherapy arm compared with 20% of patients in the bevacizumab arm subsequently received bevacizumab after disease progression. The Committee considered that patient crossover from the control arm would have an impact on the overall survival results only if second-line treatment with bevacizumab was more effective than other therapies given after progression, and the Committee did not have this information. Nevertheless, the Committee accepted that the interpretation of overall survival figures from GOG‑0218 was problematic, and that the non-statistically significant difference in median overall survival of 3.2\xa0months attributed to bevacizumab should be interpreted cautiously. The Committee concluded that the overall survival benefit of bevacizumab plus carboplatin and paclitaxel is uncertain from the results of GOG‑0218 because of the uncertainty related to the extent to which patients received bevacizumab after progression and the impact of this.\n\nThe Committee noted the adverse events reported in GOG‑0218. It understood that these events were as predicted from other studies with bevacizumab and did not raise new safety concerns. The Committee heard from the clinical specialists that most adverse events could be satisfactorily managed. The Committee concluded that adding bevacizumab to a paclitaxel and carboplatin regimen did not lead to unacceptable toxicity compared with paclitaxel and carboplatin alone and that adverse events were manageable.\n\nThe Committee discussed the evidence from the supporting ICON7 trial. It heard from the clinical specialists that the strengths of this trial were that it included some UK patients, and used the most appropriate definitions of progression, disease staging and surgical debulking. The clinical specialists stated that patients in the optimal debulking subgroups differed between the GOG‑0218 and ICON7 trials. The clinical specialists considered that this is shown by fewer patients in the group with optimally debulked cancer in GOG‑0218 having complete resection (that is, no visible disease) than in ICON7. The Committee also heard from the clinical specialists that this might be because another trial, conducted at the same time as GOG‑0218, may have enrolled the patients who had complete resection. The Committee noted that the information on the proportion of patients with stage\xa0III and IV disease in ICON7 who had completely resected disease was not available, and that the marketing authorisation for bevacizumab did not specify complete or incomplete resection. The Committee also noted that, in ICON7, no patient crossover was allowed after disease progression. The Committee was aware of the disadvantages of ICON7 relative to the NICE decision problem, including its open-label design and inclusion of some patients with stage\xa0I and II cancer, which is not covered by the marketing authorisation for bevacizumab. In addition, the trial used a lower dose and shorter duration of bevacizumab treatment than is now licensed. Nevertheless, 81% of the patients were covered by the marketing authorisation and the Committee considered that the results from the trial contributed to the body of knowledge about the efficacy of bevacizumab plus paclitaxel and carboplatin for advanced ovarian cancer.\n\nThe Committee considered the PFS results from ICON7. It noted that the overall difference between the PFS medians in the intention-to-treat population was 2.4\xa0months, which was less than the 6\xa0months in the intention-to-treat population in GOG‑0218 using the censored data. The clinical specialists emphasised that professional opinion was that this difference was related to patient selection and patient characteristics, not to the lower dose and duration of treatment in ICON7. The Committee also noted that, PFS in the chemotherapy comparator arm was worse in the high-risk subgroup from ICON7 than in the intention-to-treat population in GOG‑0218 using the censored data, which could affect interpretation of the results. However, the Committee noted that the high-risk subgroup from ICON7 excluded patients with optimally debulked cancer, whereas the intention-to-treat population in GOG‑0218 included approximately one-third of patients with optimally debulked cancer who might be expected to have a better prognosis, and who experienced the longest PFS of the subgroups in the GOG‑0218 chemotherapy arm. The Committee concluded that the trials were difficult to compare because of different inclusion criteria, bevacizumab dose and duration of treatment, definitions of progression and optimal debulking, and differing baseline factors between the trials.\n\nThe Committee considered the results presented for the ICON7 high-risk subgroup. This subgroup was broadly comparable with 2\xa0of the 3\xa0stratified groups in GOG‑0218 but did not represent the whole population covered by the marketing authorisation, which does not specify debulking status. Separate analysis of the high-risk subgroup showed a difference in median PFS of 5.5\xa0months in favour of bevacizumab. This was higher than the 2.4-month difference in the ICON7 intention-to-treat population, and was comparable to the gain in the intention-to-treat GOG‑0218 population using the censored data (6\xa0months; see section\xa03.4). Hazard ratios were not provided for the non-high-risk subgroup (that is, the intention-to-treat population minus the high-risk subgroup) but the Committee assumed that they would have shown little or no benefit. The Committee also considered the PFS results by cancer stage and debulking status in the population of ICON7 covered by the marketing authorisation. It noted that there was an apparent differential response, with little benefit shown in the stage\xa0III population with optimally debulked cancer (difference in median PFS 1.6\xa0months in favour of bevacizumab) compared with the population with stage\xa0III suboptimally debulked cancer (difference in median PFS 6.8\xa0months) or stage\xa0IV cancer (difference in median PFS 3.4\xa0months). The Committee heard from the clinical specialists that these PFS analyses from ICON7 showed benefit in only a proportion of the population covered by the marketing authorisation. The Committee noted that the subgroup data from GOG‑0218 showed a benefit, which was not dependent on debulking status in stage\xa0III and IV cancer, with the greatest PFS benefit shown in the optimally debulked subgroup (based on uncensored data from GOG‑0218; corresponding censored subgroup data were not supplied by the manufacturer, see section\xa03.5). The Committee also noted that, although the results from ICON7 suggested a greater PFS benefit in patients with stage\xa0III suboptimally debulked or stage\xa0IV cancer, the uncensored subgroup data from GOG‑0218 did not appear to support the manufacturer's suggestion that bevacizumab provides greater benefit for ovarian cancer patients with a poor prognosis. The Committee agreed that the results of the open-label ICON7 trial indicated a smaller PFS benefit in the intention-to-treat population than was seen in GOG‑0218, and also suggested a different benefit based on cancer stage and debulking status that had not been shown in GOG‑0218. The Committee was aware that several hypotheses could explain these differences. The Committee concluded that the ICON7 data contributed to confidence that treatment with bevacizumab could delay progression, but that the reasons for the apparent differential response and differences in PFS suggested by the ICON7 subgroup analysis compared with the analysis of GOG‑0218 uncensored data remained uncertain.\n\nThe Committee examined the overall survival data from ICON7 and noted that mature data on the intention-to-treat population were not yet available but an interim analysis of the high-risk subgroup showed a difference in median overall survival of 7.8\xa0months in favour of bevacizumab. The Committee noted that, taking into account the shape of the Kaplan–Meier curve from the interim analysis of the high-risk patients, it is likely that the mean overall survival benefit would be much less than the median. The Committee concluded that the interim data for a subgroup in the trial suggested a difference in overall survival in favour of bevacizumab, but that this should be interpreted with caution.\n\n# Cost effectiveness\n\nThe Committee discussed the cost-effectiveness estimates and the assumptions on which these were based from the manufacturer's economic model based on GOG‑0218. The Committee concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer.\n\nThe Committee considered the model inputs including clinical effectiveness, patient outcomes, resource use and costs. It noted that PFS was based on the Kaplan–Meier curve from the censored data of GOG‑0218 until month\xa028, after which PFS is represented by a log-logistic parametric function. The Committee also noted that the model used an equal post-progression death rate between the arms. It understood the ERG's concerns about the treatment duration of 12\xa0months instead of the15\xa0months specified in the marketing authorisation and the time horizon of 10\xa0years. The ERG did not consider this time horizon to be long enough, although the Committee heard from the clinical specialists that 10\xa0years was probably appropriate because only a very small number of patients are likely to survive beyond 10\xa0years. The Committee noted that the EQ‑5D utilities from the expanded high-risk subgroup of ICON7 (see section\xa03.15) were used in the model and that the same utilities were assumed in both arms of the model. It also noted that no disutilities associated with adverse events had been incorporated into the model. The Committee concluded that the model inputs used by the manufacturer were reasonable.\n\nThe Committee considered the most plausible incremental cost-effectiveness ratios (ICERs) from the model based on the GOG‑0218 trial presented by the manufacturer and by the ERG in their exploratory analyses. It noted that the manufacturer's base-case ICER was approximately £144,000 per quality-adjusted life year (QALY) gained. The Committee considered the ERG's exploratory analyses, which examined the changes in the ICER with a treatment duration of 15\xa0months or a time horizon of 25\xa0years or both, and gave a range of ICERs from £128,000 to £161,000 per QALY gained. The Committee agreed that the range of ICERs obtained from the cost-effectiveness model of bevacizumab plus paclitaxel and carboplatin were outside the range normally considered as a cost-effective use of NHS resources. It therefore concluded that bevacizumab within its marketing authorisation (that is, at a dose of 15\xa0mg/kg), plus paclitaxel and carboplatin, would not be a cost-effective use of NHS resources for first-line treatment of advanced ovarian cancer compared with paclitaxel and carboplatin alone.\n\nAfter receiving comments from the manufacturer in response to the appraisal consultation document, the Committee further considered the impact of patient crossover on overall survival in the GOG‑0218 study as previously discussed (see section\xa04.7) and how this had been accounted for in the economic model. The Committee was aware that, because a proportion of patients in the chemotherapy arm from the GOG‑0218 study subsequently received bevacizumab after disease progression, the manufacturer had assumed a similar probability of death in both treatment arms in its base-case analysis. The Committee also noted from the ERG that, by using this approach, the model resulted in a greater survival difference in favour of bevacizumab than was observed in the GOG‑0218 study (see section\xa03.22). The Committee noted that this would result in a lower ICER than if the overall survival observed in the GOG‑0218 study had been used. The Committee heard from the manufacturer that it did not consider it appropriate to use other alternative approaches to adjust for crossover, such as the rank-preserving structural failure time method. The Committee noted the manufacturer's response to the appraisal consultation document, which attempted to adjust for crossover in the trial by applying the overall survival curves estimated for the control and treatment arms in the expanded high-risk subgroup from the ICON7 study, rather than using post-progression survival data from the GOG‑0218 study. The manufacturer justified this approach on the basis that the expanded high-risk subgroup from the ICON7 study, which did not permit crossover at progression, was broadly comparable to the intention-to-treat population in the GOG‑0218 study. However, the Committee agreed that this was an unconventional approach that lacked credibility because of the significant differences identified between the expanded high-risk subgroup in the ICON7 study and the intention-to-treat population in the GOG‑0218 study (see section\xa04.10). The Committee concluded that the manufacturer's novel approach to adjust for patient crossover in the GOG‑0218 study was not a robust basis on which to estimate the cost effectiveness of bevacizumab, and agreed that the base-case ICER remained the most plausible one on which to base its decision.\n\nThe Committee considered the comments received by the consultees and commentators on the cost-effectiveness estimate for bevacizumab at its unlicensed dose of 7.5\xa0mg/kg, noting that the manufacturer had submitted an economic analysis of bevacizumab at the unlicensed dose based on ICON7. The Committee also noted from 1\xa0consultee comment that an estimate of the cost effectiveness of bevacizumab at its unlicensed dose had been submitted to and presented by the Scottish Medicines Consortium. The Committee noted that the cost-effectiveness estimate presented to the Scottish Medicines Consortium by the manufacturer differed from the one that was submitted to NICE. The Committee was aware that the ERG had not provided a detailed critique of the ICON7 economic model because it was based on the unlicensed dose of bevacizumab and therefore outside the scope of this appraisal. Therefore, the Committee concluded that it was unable to comment on the validity of the cost-effectiveness analysis of bevacizumab for the first-line treatment of advanced ovarian cancer at its unlicensed dose of 7.5\xa0mg/kg.\n\nThe Committee also discussed whether it could comment on the use of bevacizumab for the first-line treatment of advanced ovarian cancer at its unlicensed dose of 7.5\xa0mg/kg, noting the request for this from the comments received from consultees and commentators in response to the appraisal consultation document. The Committee noted from the European Medicines Agency's statement that there was insufficient evidence of an acceptable balance of clinically relevant benefit to risk at the lower dose (7.5\xa0mg/kg) used in the ICON7 study. In response to the Committee's question as to whether it was able to recommend a drug outside its licensed dose, NICE reiterated its position that the Committee was only permitted to make a recommendation on the licensed dose of bevacizumab (15\xa0mg/kg). The Committee therefore concluded that it was reasonable not to consider further the cost effectiveness of bevacizumab at its unlicensed dose.\n\nThe Committee discussed whether bevacizumab should be considered an innovative treatment. The Committee acknowledged that advanced ovarian cancer is a disease with limited treatment options, and that bevacizumab represented a novel biological approach to therapy. It also noted the clinical specialists' comments (see section\xa04.2). However, the Committee concluded that all benefits of a substantial nature relating to treatment with bevacizumab plus paclitaxel and carboplatin had been captured in the QALY calculation.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA284\n\nAppraisal title: Bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer\n\nSection\n\nKey conclusion\n\nBevacizumab in combination with paclitaxel and carboplatin is not recommended for first-line treatment of advanced ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] stages\xa0IIIB, IIIC and IV epithelial ovarian, fallopian tube or primary peritoneal cancer).\n\n\n\nThe Committee concluded that bevacizumab was shown to be clinically effective only when it is given at the same time as paclitaxel and carboplatin and then as a maintenance treatment for up to 15\xa0months.\n\n\n\nThe Committee agreed that the range of ICERs obtained from the cost-effectiveness model of bevacizumab plus paclitaxel and carboplatin were outside the range normally considered as a cost-effective use of NHS resources. It therefore concluded that bevacizumab within its marketing authorisation (that is, at a dose of 15\xa0mg/kg), plus paclitaxel and carboplatin, would not be a cost-effective use of NHS resources for first-line treatment of advanced ovarian cancer compared with paclitaxel and carboplatin alone.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe clinical specialists confirmed that chemotherapy with paclitaxel and carboplatin was current standard clinical practice in the NHS in England and Wales for first-line treatment of advanced ovarian cancer after debulking surgery. They also highlighted that the 10-year survival rate in ovarian cancer is only 35% and that, in clinical practice, only 1% of people with advanced ovarian cancer were likely to be alive at 10\xa0years. This has improved in recent years, but is below the rates for many other cancers.\n\n\n\nThe Committee heard from the patient experts of the limited treatment options available for people with advanced ovarian cancer and noted that bevacizumab provided an additional treatment option.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee heard from the clinical specialists that they considered bevacizumab to be an innovative technology because there have been few new beneficial developments in ovarian cancer for several years. Patient experts highlighted that the end of first-line treatment is a critical time for patients, and it is important not to underestimate the impact of any extension to progression-free survival for these patients and their families.\n\n, 4.3\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nBevacizumab in combination with carboplatin and paclitaxel has a UK marketing authorisation for 'the front-line treatment of advanced (FIGO stages\xa0IIIB, IIIC and IV) epithelial ovarian, fallopian tube or primary peritoneal cancer'.\n\n\n\nAdverse reactions\n\nThe Committee concluded that adding bevacizumab to a paclitaxel and carboplatin regimen did not lead to unacceptable toxicity compared with paclitaxel and carboplatin alone and that adverse events were manageable.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe key evidence for the clinical effectiveness of bevacizumab in combination with paclitaxel and carboplatin came from 1\xa0randomised controlled trial (GOG‑0218). The trial assessed the efficacy and safety of bevacizumab (at its licensed dose of 15\xa0mg/kg body weight) plus paclitaxel and carboplatin in people with previously untreated stage\xa0III (incompletely resected) or stage\xa0IV epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone debulking surgery. This evidence was supported by results from a randomised open-label trial (ICON7) that assessed the efficacy and safety of bevacizumab at an unlicensed dose (7.5\xa0mg/kg body weight) plus paclitaxel and carboplatin in people with high-risk early stage or advanced epithelial ovarian, fallopian tube or primary peritoneal cancer.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee accepted that the results of GOG‑0218 are relevant to the first-line treatment of patients with advanced ovarian cancer in the NHS.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted the ERG's concerns about the lack of consistent reporting of the various PFS assessments at all time points in GOG‑0218. There was also some uncertainty about which set of PFS results (censored or uncensored) from GOG‑0218 is most appropriate for the NHS. The Committee concluded that the censored PFS data are more relevant to UK clinical practice.\n\n\n\nThe Committee concluded that the overall survival benefit of bevacizumab plus carboplatin and paclitaxel is uncertain from the results of GOG‑0218 because of the uncertainty related to the extent to which patients received bevacizumab after progression and the impact of this.\n\n\n\nThe Committee concluded that the GOG‑0218 and ICON7 trials were difficult to compare because of different inclusion criteria, bevacizumab dose and duration of treatment, definitions of progression and optimal debulking, and differing baseline factors between the trials.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee noted that there was an apparent differential response, with little benefit shown in the stage\xa0III population with optimally debulked cancer (difference in median PFS 1.6\xa0months in favour of bevacizumab) compared with the population with stage\xa0III suboptimally debulked cancer (difference in median PFS 6.8\xa0months) or stage\xa0IV cancer (difference in median PFS 3.4\xa0months). The Committee heard from the clinical specialists that these PFS analyses from ICON7 showed benefit in only a proportion of the population covered by the marketing authorisation, whereas GOG‑0218 results indicated a benefit not dependent on debulking status in stage\xa0III and IV cancer. The Committee was aware that several hypotheses could explain these differences.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe difference in median PFS in favour of bevacizumab using the censored data from GOG‑0218 was 6\xa0months. The Committee concluded that bevacizumab plus paclitaxel and carboplatin improved PFS compared with paclitaxel and carboplatin alone and that, of the available data, the censored PFS data are more relevant to UK clinical practice.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer submitted a 3-state semi-Markov model with health states consisting of PFS, progressed disease and death. Data from GOG‑0218 were used to inform model inputs for dosing, survival and safety. Both the intervention and comparator in the model were used in accordance with their marketing authorisations.\n\n\n\nThe Committee concluded that the manufacturer's model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered the model inputs, including clinical effectiveness, patient outcomes, resource use and costs, and concluded that they were reasonable.\n\nThe Committee understood the ERG concerns about the treatment duration of 12\xa0months instead of the 15\xa0months specified in the marketing authorisation and a time horizon of 10\xa0years. The ERG did not consider this time horizon to be long enough, although the Committee heard from the clinical specialists that 10\xa0years was probably appropriate because only a very small number of patients are likely to survive beyond 10\xa0years.\n\n\n\nThe Committee noted the manufacturer's response to the appraisal consultation document, which attempted to adjust for crossover in the GOG‑0218 study by applying the overall survival curves estimated for the control and treatment arms in the expanded high-risk subgroup from the ICON7 study, rather than using post-progression survival data from the GOG‑0218 study. The Committee agreed that this was an unconventional approach that lacked credibility because of the significant differences identified between the 2\xa0studies.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that the EQ-5D utilities from the expanded high-risk subgroup of ICON7 were used in the model and that the same utilities were assumed in both arms of the model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo. The Committee agreed that the range of ICERs obtained from the cost-effectiveness model of bevacizumab plus paclitaxel and carboplatin were outside the range normally considered as a cost-effective use of NHS resources. It therefore concluded that bevacizumab within its marketing authorisation (that is, at a dose of 15\xa0mg/kg), plus paclitaxel and carboplatin, would not be a cost-effective use of NHS resources for first-line treatment of advanced ovarian cancer compared with paclitaxel and carboplatin alone.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe manufacturer's deterministic sensitivity analysis for GOG‑0218 suggested that the cost-effectiveness results are influenced by the parametric functions used for the PFS extrapolation and the time horizon used in the model. The manufacturer's scenario analyses identified the key drivers of the cost-effectiveness results as the dose and duration of bevacizumab treatment.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that the manufacturer's base-case ICER was approximately £144,000 per QALY gained. The Committee considered the ERG's exploratory analyses, which examined the changes in the ICER with a treatment duration of 15\xa0months or a time horizon of 25\xa0years or both, and gave a range of ICERs from £128,000 to £161,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable\n\n\n\nEnd-of-life considerations\n\nNot applicable\n\n\n\nEqualities considerations and social value judgements\n\nNo issues relating to equality considerations were raised in the submissions or the Committee meeting.\n\n", 'Related NICE guidance': 'Details are correct at the time of consultation. Further information is available on the NICE website.\n\n# Published\n\nBevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer. NICE technology appraisal guidance 285 (2013).\n\nOvarian cancer: The recognition and initial management of ovarian cancer. NICE clinical guideline 122 (2011).\n\nTrabectedin for the treatment of relapsed ovarian cancer. NICE technology appraisal guidance 222 (2011).\n\nTopotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for the treatment of advanced ovarian cancer. NICE technology appraisal guidance 91 (2005).\n\nReview of the clinical effectiveness and cost effectiveness of paclitaxel for ovarian cancer. NICE technology appraisal guidance 55 (2003).\n\n# Under development\n\nTopotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for the treatment of recurrent ovarian cancer (including review of technology appraisal no. 91 and technology appraisal no. 222). NICE technology appraisal guidance, publication expected February 2014.\n\nVintafolide in combination with pegylated liposomal doxorubicin hydrochloride for the treatment of folate receptor positive, platinum-resistant ovarian cancer. NICE technology appraisal guidance, publication expected July 2014.', 'Review of guidance': 'The guidance on this technology will be considered for review in April\xa02016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveMay 2013', 'Changes after publication': 'January 2014:\n minor maintenance.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt has been incorporated into the NICE pathway on ovarian cancer along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0136-4'}	https://www.nice.org.uk/guidance/ta284	Evidence-based recommendations on bevacizumab (Avastin), with paclitaxel and carboplatin, for treating advanced ovarian cancer in adults.
a85fff147c9fa81c4215d098215d443cfe964b68	nice	Bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer	Bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer Evidence-based recommendations on bevacizumab (Avastin), with gemcitabine and carboplatin, for treating platinum-sensitive advanced ovarian cancer in adults. # Guidance Bevacizumab in combination with gemcitabine and carboplatin is not recommended within its marketing authorisation, that is, for treating people with the first recurrence of platinum-sensitive advanced ovarian cancer (including fallopian tube and primary peritoneal cancer) who have not received prior therapy with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor-targeted agents. People currently receiving bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology Bevacizumab (Avastin, Roche) is a humanised monoclonal antibody that inhibits both vascular endothelial growth factor (VEGF)-induced signalling and VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. Bevacizumab in combination with carboplatin and gemcitabine has a marketing authorisation for 'treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents'. The licensed dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks in combination with carboplatin and gemcitabine for 6 cycles and up to 10 cycles, followed by continued use of bevacizumab as single agent until disease progression. The summary of product characteristics lists the following adverse reactions that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage or haemoptysis, congestive heart failure, posterior reversible encephalopathy syndrome, hypersensitivity or infusion reactions, osteonecrosis of the jaw, ovarian failure and neutropenia. For full details of adverse reactions and contraindications, see the summary of product characteristics. Bevacizumab is available in 100 mg and 400 mg vials at net prices of £242.66 and £924.40 respectively (excluding VAT; 'British national formulary' edition 65). The manufacturer estimated the cost of a course of treatment with bevacizumab (excluding VAT and assuming vials are not shared between patients) to be £25,208 for a patient weighing 60.5 kg at a dosage of 15 mg/kg every 3 weeks for a mean treatment duration of 10.8 cycles (7.5 months). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of bevacizumab and a review of this submission by the Evidence Review Group (ERG; section 9). The key evidence for the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin came from 1 randomised controlled trial (OCEANS). This double-blind, randomised, placebo-controlled trial assessed the safety and efficacy of bevacizumab plus gemcitabine and carboplatin in 484 adults with platinum-sensitive recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, with a first recurrence of ovarian cancer and who had not previously received vascular endothelial growth factor (VEGF) receptor-targeted agents. The trial was a multicentre study conducted in 96 centres in the USA. Patients were randomised to 1 of the following 2 treatment arms: Bevacizumab plus gemcitabine and carboplatin (n=242) (bevacizumab 15 mg/kg body weight on day 1 every 3 weeks, carboplatin at a dose corresponding to an area under the curve of concentration versus time of 4 mg/mlmin on day 1 every 3 weeks, and gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks for 6–10 cycles; followed by bevacizumab 15 mg/kg body weight alone on day 1 every 3 weeks until disease progression or unacceptable toxicity). Placebo plus gemcitabine and carboplatin (n=242) (placebo on day 1 every 3 weeks, carboplatin area under the curve 4 mg/mlmin on day 1 every 3 weeks, and gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks for 6–10 cycles; followed by placebo alone on day 1 every 3 weeks until disease progression or unacceptable toxicity).Randomisation was stratified by platinum-sensitive category (platinum sensitive or partially platinum sensitive) and incidence of cytoreductive surgery for recurrent disease. The primary outcome was progression-free survival (PFS), defined as the period from randomisation to disease progression or death (from any cause). Progression was assessed by investigators using radiological evaluation according to the Response Evaluation Criteria for Solid Tumours (RECIST) criteria. Progression could also be determined by symptomatic progression, but not by cancer antigen-125 (CA‑125) elevation alone. Sensitivity analysis of PFS included an assessment by an Independent Review Committee (IRC) using RECIST criteria. For the IRC analysis, the definition of PFS was the period from randomisation until disease progression or on-study death (that is, death occurring within 9 weeks of the last dose of chemotherapy or study drug). All patients needed to undergo CT scans every 9 weeks from day 1 of cycle 1. Secondary outcomes were overall survival, objective response rate and duration of objective response. Objective response rate and duration of objective response were also assessed by the IRC using RECIST criteria as exploratory analyses. Safety outcome measures were frequency and severity of adverse events. Analysis of the primary outcome, PFS in the intention-to-treat population, was based on a cut-off date of 17 September 2010, once 338 (70%) patients had experienced disease progression or died (62.4% of patients in the bevacizumab arm and 77.3% in the placebo arm). The median follow-up was 24 months. Data for patients whose disease had not progressed or who had not died at the time of the last tumour assessment were censored (that is, excluded from the analysis from that point onwards). Data for patients who received non-protocol therapy before disease progression were also censored at the time of the last tumour assessment before therapy was initiated. At 29.8 months, all patients still at risk in the bevacizumab arm had experienced disease progression or had died, and at 24.9 months, 2 patients remained at risk in the placebo arm. Results of the investigator-assessed analysis showed that there was a statistically significant difference of 4 months between the median PFS in the bevacizumab arm compared with the placebo arm (bevacizumab 12.4 months, placebo 8.4 months). In the stratified analysis, there was a 51.6% reduction in disease progression in patients in the bevacizumab arm compared with those in the placebo arm (hazard ratio 0.48, 95% confidence interval 0.39 to 0.61, p<0.0001). An unstratified analysis showed a reduction in disease progression of 50.8% with bevacizumab compared with placebo (HR 0.49, 95% CI 0.40 to 0.61, p<0.0001). An IRC analysis of PFS on the same data and a sensitivity analysis without censoring patients for receiving non-protocol therapies were also conducted. The IRC analysis results of PFS were consistent with the primary analysis showing a reduction in disease progression in patients in the bevacizumab arm compared with the placebo arm (bevacizumab 12.3 months, placebo 8.6 months; HR 0.45, 95% CI 0.35 to 0.58, p<0.0001). Results from the sensitivity analysis that did not censor for non-protocol specified therapy were also consistent with the primary analysis results (bevacizumab 12.4 months, placebo 8.4 months; HR 0.52, 95% CI 0.43 to 0.65). PFS results for subgroups based on the predefined stratification factors (platinum-sensitive classification and incidence of cytoreductive surgery for recurrent disease) showed that there was a statistically significant reduction in PFS observed for patients in the bevacizumab arm, irrespective of whether they had undergone cytoreductive surgery for recurrent disease or not. Patients whose disease was partially platinum sensitive showed a median PFS of 11.9 months and 8.0 months with bevacizumab and placebo respectively (HR 0.41, 95% CI 0.29 to 0.58). There was also an increase in PFS in patients whose disease was fully platinum sensitive seen in the bevacizumab arm (HR 0.55, 95% CI 0.41 to 0.73). Three interim analyses of overall survival were conducted, 2 of which were protocol specified. None of the interim analyses found a statistically significant difference between bevacizumab and placebo in the duration of overall survival. The first interim analysis was carried out at the time of final PFS analysis (17 September 2010), when approximately 29% of patients had died (median overall survival: 35.5 and 29.9 months in the bevacizumab and placebo arms respectively; HR 0.75, 95% CI 0.54 to 1.05). The second analysis was carried out on 29 August 2011, when approximately 49% of the patients had died (median overall survival: 33.3 and 35.2 months in the bevacizumab and placebo arms respectively; HR 1.03, 95% CI 0.79 to 1.33). The third analysis, using a data cut-off date of 30 March 2012 (required by the European Medicine Agency), was conducted when approximately 59% of the patients had died (median overall survival: 33.4 and 33.7 months in the bevacizumab and placebo arms respectively; HR 0.96, 95% CI 0.76 to 1.21). The manufacturer stated that patients in both study arms in third and subsequent lines of therapy received post-progression bevacizumab (at least 18.1% of patients in the bevacizumab arm and 34.7% in the placebo arm received bevacizumab), and therefore confounding may have occurred. Objective response rate, according to investigator assessment, was statistically significantly different between the 2 arms (78.5% in the bevacizumab arm compared with 57.4% in the placebo arm, p<0.0001). Median duration of response was 10.4 and 7.4 months in patients in the bevacizumab and placebo arms respectively. IRC assessment of objective response rate was consistent with the results of the investigator-assessed analysis (bevacizumab 74.8%, placebo 53.7%, p<0.0001). All patients in the OCEANS trial experienced an adverse event. More patients in the bevacizumab arm experienced a serious adverse event compared with patients in the placebo arm (34.8% and 24.9% respectively). Adverse events for which the incidence was more than 10% higher in the bevacizumab arm than in the placebo arm were hypertension, nose bleeds, headache and proteinuria. Adverse events of special interest (grades 3–5) that occurred with an incidence of at least 2% higher in the bevacizumab arm compared with the placebo arm were hypertension, proteinuria and non-central nervous system bleeding. The proportion of patients who experienced an adverse event that led to discontinuation was larger in the bevacizumab arm (19.8%) compared with the placebo arm (4.7%). However, the absolute number of patients stopping treatment because of adverse events was unclear. The manufacturer carried out a literature review and identified 4 randomised controlled trials (CALYPSO, ICON4, AGO‑OVAR‑2.5 and OCEANS) that had assessed the comparative clinical effectiveness of the following comparators: paclitaxel plus platinum-based treatment compared with pegylated liposomal doxorubicin hydrochloride plus platinum-based treatment platinum-based treatment (monotherapy) compared with paclitaxel plus platinum-based treatment gemcitabine plus platinum-based treatment compared with platinum-based treatment (monotherapy) bevacizumab plus gemcitabine and carboplatin compared with gemcitabine plus carboplatin treatment.After assessing the feasibility of conducting an indirect comparison of bevacizumab plus gemcitabine and carboplatin with the comparators listed in the final scope, the manufacturer decided against carrying out a network meta-analysis. The manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of bevacizumab plus carboplatin and gemcitabine compared with placebo plus carboplatin and gemcitabine for treating people with advanced, recurrent, platinum-sensitive ovarian cancer. The model was a 3‑state semi-Markov model with health states consisting of PFS, progressed disease and death. Data from the OCEANS trial were used to guide model inputs. Because the drug dose is dependent on characteristics (such as body weight, body surface area and creatinine clearance rates) that are influenced by age, demographic data from a UK study were used by the manufacturer in their base case to calculate the dose of bevacizumab, carboplatin and gemcitabine. The cost-effectiveness analysis was conducted from an NHS and personal social services perspective, costs and outcomes were discounted at 3.5% per annum and a 10‑year time horizon was used. The cycle length was 1 week. PFS in the model used the Kaplan–Meier survival curves from the OCEANS trial based on the (intention-to-treat population) investigator-assessed analysis (data cut-off date September 2010). The manufacturer examined the fit of various parametric functions to the PFS data and considered a log-logistic model as the best fit to estimate and extrapolate the proportion of patients in the PFS health state. The overall survival from the OCEANS trial (data cut-off date September 2010) was used in the model to estimate the proportion of people in the progressed-disease health state and, implicitly, the death state. The manufacturer also applied a log-logistic distribution to the Kaplan–Meier curves. The incidence of adverse events adopted in the model was derived from adverse events (cut-off September 2010) of at least grade 3 that occurred in more than 2% regardless of the study arm. The manufacturer used the number of patient events to assign a cost associated with each adverse event. Health-related quality of life and utilities applied in the model were obtained from Trabectedin for the treatment of relapsed ovarian cancer (NICE technology appraisal guidance 222). The data used in this guidance were taken from the OVA‑301 trial using EQ‑5D. The utility values used in the model for PFS and progressed-disease health states were 0.718 and 0.649 respectively. The manufacturer assumed in the model that health-related quality of life remained constant during PFS and reduced once disease progressed but remained constant after that. The manufacturer did not apply disutilities caused by adverse events in the model. Drug costs were estimated using the dose and frequency of administration in the summary of product characteristics. Data from a UK cohort study (Sacco et al. 2010) were used in the dose calculations. The base case assumed that any unused carboplatin and paclitaxel from a vial was reallocated and not wasted, whereas for bevacizumab, it was assumed that any unused drug in a vial was wasted. For bevacizumab and carboplatin, the manufacturer used public list prices from the 'British national formulary', and the price of gemcitabine (£12.57 for a 1000 mg vial) was obtained from the Commercial Medicines Unit (CMU) 2012 electronic Market Information Tool (eMit). Costs of drug administration were taken from the Unit Costs of Health and Social Care and NHS reference cost data, and included in the model. The weekly costs of supporting patients in the PFS and progressed health states were also included. Costs of palliative care were applied to patients as they moved to the death state. Costs of post-progression therapies were taken from the OCEANS trial (cut-off date September 2010) and included other chemotherapy drugs, radiotherapy or surgery. These costs were added together and applied as a one-off cost in the model, and so were not subject to discounting. Costs associated with adverse events that occurred at grade 3 or 4 severity in more than 2% of patients from the OCEANS trial (cut-off date September 2010) were incorporated into the analysis. NHS reference costs were utilised when possible; all adverse events were assumed to occur in cycle 1 of the model, so costs were not discounted. The base-case results estimated that adding bevacizumab to carboplatin and gemcitabine provides an additional 0.42 life years and 0.298 quality-adjusted life years (QALYs). These benefits are achieved with an incremental cost of £44,428, resulting in an incremental cost-effectiveness ratio (ICER) of £149,050 per QALY gained for bevacizumab plus carboplatin and gemcitabine compared with carboplatin and gemcitabine alone. The manufacturer's deterministic sensitivity analysis suggested that the cost-effectiveness results were most sensitive to assumptions around the extrapolation of overall survival, the duration of treatment and the utility of patients in PFS. The manufacturer's probabilistic sensitivity analyses concluded that the probability of bevacizumab plus carboplatin and gemcitabine being cost effective compared with carboplatin and gemcitabine alone at a threshold of £30,000 per QALY gained was 0%. The manufacturer identified the key drivers of the cost-effectiveness results to be the cost and duration of treatment with bevacizumab and the time horizon of the analysis. The ERG considered the OCEANS trial to be well designed and agreed that, except for baseline weight, the characteristics of the patient population enrolled in the trial were representative of people with first recurrence of ovarian cancer in England and Wales. The ERG noted that the course of treatment assumed in the OCEANS trial (allowing up to a maximum of 10 cycles of bevacizumab plus carboplatin and gemcitabine) may not fully represent clinical practice in the UK (where a maximum of 6 cycles of chemotherapy would be administered). The ERG also noted that the main comparator in the manufacturer's submission was gemcitabine plus carboplatin, whereas this may not be the treatment routinely used in the NHS. The ERG highlighted the differences between the number of recorded events in terms of PFS in the investigator-assessed analysis and the IRC-determined analysis. The ERG also highlighted that the number of patients censored in each group at the time of final PFS analysis (September 2010), and the mean PFS and the number of patients lost to follow-up at the time of the final analysis were unknown. The ERG also noted that the absolute number of patients stopping treatment because of an adverse event varied in the manufacturer's submission, and the correct number remained unclear after seeking clarification from the manufacturer. The ERG considered the literature search and the reasons given by the manufacturer for not performing an indirect comparison between bevacizumab plus carboplatin and gemcitabine, and the other comparators listed in the scope. The ERG considered that the differences between trials were sufficiently minor such that their inclusion would have a minimal impact on clinical heterogeneity, and decided to perform a network meta-analysis for the primary outcome measure (PFS). Results from the network meta-analysis performed by the ERG suggested that bevacizumab plus carboplatin and gemcitabine is associated with a statistically significant improvement in duration of PFS compared with all comparators listed in the scope (bevacizumab plus carboplatin and gemcitabine compared with: paclitaxel plus carboplatin, HR 0.47, 95% credible interval 0.33 to 0.66; pegylated liposomal doxorubicin hydrochloride plus carboplatin, HR 0.58, 95% CrI 0.39 to 0.82; platinum monotherapy, HR 0.35, 95% CrI 0.25 to 0.47; gemcitabine plus carboplatin, HR 0.48, 95% CrI 0.38 to 0.60). Results from the network meta-analysis also suggested that there were no statistically significant differences between most of the other comparators. The ERG considered the manufacturer's model structure was appropriate to describe the decision problem and was well constructed and transparent. The ERG highlighted and agreed with the manufacturer that the main criticism of the submitted economic evaluation was the use of the September 2010 OCEANS clinical-effectiveness, cost and adverse-event incidence data. The ERG suggested that the use of data from September 2010, when 29% of the patients had died (rather than data from March 2012, when available, when 59% of the patients had died), may have introduced unnecessary uncertainty into the estimate of the ICER and may have overestimated the overall survival benefit associated with bevacizumab because the analysis of overall survival in September 2010 showed a non-statistically significant overall survival increase for patients in the bevacizumab group, which was not sustained in the 2 later interim analyses. The ERG noted that overall survival was a key driver in the model and estimated that approximately 90% of the QALYs gained in the model were a function of the overall survival. The ERG conducted a scenario analysis assuming that overall survival was the same for patients in both treatment groups. The result of the analysis was an increase in the ICER to over £1.7 million per QALY gained. The ERG noted that the manufacturer applied a parametric log-logistic function to the Kaplan–Meier PFS data (cut-off date September 2010) from the OCEANS trial to estimate and extrapolate the proportion of patients in the progression-free health state. At a median follow-up of 24 months (final PFS analysis), 70% of the patients had either experienced disease progression or died. Patients in the bevacizumab arm reached 0% PFS at month 29.8, whereas 2 patients remained at risk at month 24.9 in the placebo arm. The ERG assumed in their exploratory analysis that, by 29 months, all patients would have had disease progression or died according to the last Kaplan–Meier data available, and suggested that mean values for PFS might be available, rather than only medians. The ERG also had concerns about fitting a parametric distribution for PFS given the Kaplan–Meier data available and undertook a scenario analysis using only the Kaplan–Meier data, although this did not have a significant impact on the ICER. The ERG noted that adverse events experienced by patients in the model were not subject to estimates of disutility and suggested that this was likely to favour the cost effectiveness of bevacizumab because a larger proportion of patients in the bevacizumab treatment group experienced a serious adverse event compared with the placebo group in the OCEANS trial. The ERG conducted a scenario analysis and assessed a range of average duration of adverse event disutilities. It concluded that, for example, for an average event duration of 1 week, the ICER increased to £149,391 per QALY gained and, for an average adverse event duration of 1 month, the ICER increased to £150,544 per additional QALY gained. The ERG explored the impact of the network meta-analysis results in terms of cost effectiveness. The ERG assumed, based on the these results, that overall survival and PFS estimates for patients in every comparator group were the same as for patients in the placebo group in the manufacturer's model. Cost-effectiveness results from the ERG exploratory analysis were: ICER for bevacizumab plus gemcitabine and carboplatin compared with carboplatin £159,273 per QALY gained ICER for bevacizumab plus gemcitabine and carboplatin compared with paclitaxel plus carboplatin £148,014 per QALY gained ICER for bevacizumab plus gemcitabine and carboplatin compared with pegylated liposomal doxorubicin hydrochloride plus carboplatin £145,621 per QALY gained. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab plus gemcitabine and carboplatin, having considered evidence on the nature of recurrent advanced ovarian cancer and the value placed on the benefits of bevacizumab plus gemcitabine and carboplatin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee discussed the current management of recurrent advanced ovarian cancer. It noted comments received from the professional groups that paclitaxel plus carboplatin; carboplatin as monotherapy; cisplatin monotherapy (in patients who are allergic to carboplatin); gemcitabine plus carboplatin; pegylated liposomal doxorubicin hydrochloride monotherapy; pegylated liposomal doxorubicin hydrochloride plus carboplatin; and pegylated liposomal doxorubicin hydrochloride plus trabectedin (which in some cases is considered a key treatment for patients whose disease is partially platinum sensitive, specifically those who are allergic to platinum) are the most relevant therapies for treating recurrent advanced ovarian cancer in patients whose disease is platinum sensitive or partially platinum sensitive. The Committee also heard from clinical specialists that pegylated liposomal doxorubicin hydrochloride is not currently available and for patients whose disease is platinum sensitive, the most commonly used treatment would be paclitaxel plus carboplatin. The clinical specialists highlighted that gemcitabine plus carboplatin is not the most commonly used treatment in UK clinical practice but stated that its use may increase in the future, particularly in light of the combination therapy being appraised (bevacizumab plus gemcitabine and carboplatin). The Committee heard from the clinical specialists that this new combination therapy had been used in the UK in this patient group only on a compassionate basis before it received its marketing authorisation. The Committee heard from patient experts the importance of increasing progression-free survival (PFS). The patient experts highlighted that, once the cancer relapses, further recurrence is expected. Therefore, increasing PFS gives additional time to deal with the physical, emotional and psychological effects of ovarian cancer and its treatment, and allows patients and their families to come to terms with the implications of relapse. The patient experts also noted that gains in PFS may seem small to people not affected by the disease; however, to patients and their families, this additional period of time is extremely important in helping them to recover from the shock of relapse, and enables them to use the period of wellbeing to make the most of their lives. The clinical specialists reiterated the patient experts' comments about the importance of PFS. The Committee also noted comments received from a consultee in response to the appraisal consultation document restating the importance of PFS to patients. The Committee also heard from the patient experts that they considered bevacizumab to be an innovative technology because, outside clinical trials, there are very few options for treating recurrent ovarian cancer other than standard chemotherapy, and therefore this was seen as a new beneficial development. The Committee considered the importance of platinum sensitivity and the platinum-free interval for the prognosis of the disease. It heard from the clinical specialists that the most effective treatment for ovarian cancer is platinum-based chemotherapy. Some people's tumours respond better to this than others and the term platinum sensitivity refers to the length of initial remission after first-line platinum chemotherapy. For people whose disease shows a response to platinum, there is an arbitrary classification into platinum-resistant disease (less than a 6‑month disease-free interval) and platinum-sensitive disease (more than a 6‑month disease-free interval). The Committee heard that the development of drugs that increase the length of the platinum-induced remission will allow some people to achieve a platinum-free interval of 6 months or more. It also heard that there is an underlying assumption that, if the platinum-free interval is longer, the disease will respond better to platinum (that is, be more platinum sensitive) when the drug is re-administered. Some of the assumptions related to platinum sensitivity and the platinum-free interval are currently being tested in trials. # Clinical effectiveness The Committee considered that the main source of evidence for the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin was the OCEANS trial that had been conducted in the USA. The Committee agreed with the Evidence Review Group's (ERG's) comments that overall, this was a well-designed double-blind, randomised, placebo-controlled trial. The Committee understood from the clinical specialists that there were no clinical differences between the patients in the trial and patients in the UK with recurrent ovarian cancer, apart from body weight and body surface area. The Committee heard from the clinical specialists that the comparator used in the trial, gemcitabine and carboplatin, is not the most widely used treatment option for recurrent advanced ovarian cancer in the NHS. However, it also heard that gemcitabine and carboplatin could be considered to have a similar efficacy to other treatment options currently used in the NHS, particularly in terms of PFS. The Committee concluded that the results from the OCEANS trial were generalisable to UK clinical practice. The Committee discussed PFS results reported in the manufacturer's submission based on the OCEANS trial. It noted that the results for the intention-to-treat population at the September 2010 cut-off date gave a difference in median PFS of 4 months in favour of bevacizumab and this was statistically significant. The Committee noted that in the OCEANS trial, there was a statistically significant difference of approximately 20% in response rate with bevacizumab plus gemcitabine and carboplatin compared with gemcitabine and carboplatin, indicating that bevacizumab is an active drug. Nevertheless, it also acknowledged the ERG's concerns about the issue of censoring. The Committee noted that the data from approximately 30% of the patients had been censored and it was unclear whether these data had been censored because of patients stopping treatment because of adverse events or patients being lost to follow-up. It heard from the manufacturer that information on the number of patients for whom data were censored and the reason why, was not available at the time of the submission. The Committee concluded that, although the trial showed an increase in PFS for bevacizumab plus gemcitabine and carboplatin compared with gemcitabine and carboplatin, it was unclear what effect censoring might have had on these results. The Committee considered the most relevant overall survival results for the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin. It explored the 3 interim analyses presented by the manufacturer and noted that none of the analyses showed a statistically significant increase in overall survival in the bevacizumab-treated group. Although the first interim analysis showed a trend towards increased overall survival in the bevacizumab arm (35.5 and 29.9 months in the bevacizumab and placebo groups respectively), in the second and third interim analyses, the difference in median overall survival favoured placebo (1.9 months and 0.3 months respectively). The Committee agreed with the manufacturer's comments that the lack of statistically significant differences between bevacizumab and placebo could have been affected by confounding effects of post-progression treatments. It noted that 18.1% of patients in the bevacizumab arm and 34.7% of patients in the placebo arm received bevacizumab post progression, but also noted that bevacizumab is not licensed for this stage in the treatment pathway because its licence is for first recurrence only. The Committee noted that more than 85% of the patients in both study arms had 3 or more lines of anti-cancer therapy post progression, and it heard from the clinical specialists that it would therefore be very difficult to see any overall survival benefit from bevacizumab with this high level of post-progression treatment without a very much larger trial population. The Committee also heard from the clinical specialists that, although the third interim analysis (March 2012) may be the most reliable because at this stage 59% of patients had died, there could be a bigger issue with confounding. In contrast, the first interim analysis (September 2010) contained overall survival data for only 29% of patients, but may be less confounded by post-progression treatments. The Committee expressed a preference for the more mature and complete overall survival data, but acknowledged that the argument about which were the most reliable data was finely balanced. The Committee concluded that no overall survival benefit for bevacizumab plus gemcitabine and carboplatin had been shown in the OCEANS trial, but the results could have been confounded by post-progression therapies. The Committee considered reasons for the discrepancy between the PFS and overall survival results in the OCEANS trial for bevacizumab plus gemcitabine and carboplatin for treating recurrent advanced ovarian cancer. It noted that there were 3 possible underlying causes for the differences: the high degree of censoring and the lack of clarity regarding how this might have affected the PFS results (see section 4.6) the confounding effects on overall survival results because of the use of post-progression treatments (see section 4.7) the potential biological action of bevacizumab. The Committee heard from the clinical specialists that, although not substantiated in clinical practice, it was biologically plausible that bevacizumab could increase PFS, but once the disease has progressed, disease progression could be accelerated once bevacizumab is stopped. This might be an argument for continuing maintenance treatments such as bevacizumab beyond the stage of progression. Following comments received from the manufacturer in response to the appraisal consultation document, the Committee reconsidered the 3 possible underlying causes for the differences between PFS and overall survival results. It noted the manufacturer's comment that the overall survival results could have been affected by confounding effects because of the use of post-progression treatments. However, the Committee agreed that the high degree of censoring of PFS estimates and the potential biological action of bevacizumab could also be explanations for the difference in the results. The Committee remained unable to draw any firm conclusions as to which of these issues explained the mismatch, and to what extent. The Committee considered the adverse events reported in the OCEANS trial and noted that more patients in the bevacizumab arm (19.8%) stopped treatment because of adverse events than in the placebo arm (4.7%). It heard from the clinical specialists that the discontinuation rate in UK clinical practice would be expected to be lower than in the clinical trial and that most adverse events can be satisfactorily managed. The Committee also heard from one of the patient experts that they had experienced gastrointestinal problems during and after chemotherapy. However, it heard from the patient experts that these problems are usually well managed by clinicians and do not necessarily disrupt a patient's daily life or quality of life. The Committee concluded that the adverse events related to treatment with bevacizumab plus gemcitabine and carboplatin were similar to those related to other chemotherapy regimens and that these events were manageable. # Cost effectiveness The Committee discussed the manufacturer's cost-effectiveness estimates, derived from the manufacturer's economic model based on data from the OCEANS trial, and the assumptions in the model. The Committee noted the ERG's comments that it considered the manufacturer's model structure to be generally appropriate, well constructed and transparent. The Committee concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus gemcitabine and carboplatin for treating recurrent advanced ovarian cancer. The Committee did, however, acknowledge that there were potential shortcomings with some of the assumptions used in the manufacturer's economic model. It noted that health-related quality-of-life data were not collected in the OCEANS trial. The Committee agreed that health-related quality-of-life data collected in the trial would have been preferable for deriving the utilities for the economic model. It noted that the estimates of utility for the PFS and progressed-disease health states were derived from a previous model submitted to NICE (Trabectedin for the treatment of relapsed ovarian cancer ) and that the difference between the utilities for PFS and progressed disease was relatively small (0.718 and 0.649 respectively). The Committee heard from the patient experts that patients may experience a good health-related quality of life while they are progression free. It also noted the comments received from a consultee in response to the appraisal consultation document that reiterated the importance of PFS to patients, and the Committee therefore agreed that it may be plausible for a larger decrement in utility to occur when a person moves from the progression-free health state to a progressed-disease health state and that the difference in utility between the PFS state and progressed state used by the manufacturer could be an underestimate. The Committee also noted that a disutility associated with adverse events was not applied and that there were more serious adverse events in the bevacizumab arm than in the placebo arm. It also discussed how the PFS results were incorporated in the manufacturer's economic model. The Committee noted the ERG's comments on the extrapolation of PFS results by fitting a log-logistic distribution when the Kaplan–Meier data were available. It acknowledged the manufacturer's and ERG's sensitivity and scenario analyses, and concluded that taking all these relevant issues into account (that is, using a higher utility value for the PFS state, including a disutility for adverse events or using the Kaplan–Meier data for PFS) would not be likely to have a significant effect on the incremental cost-effectiveness ratio (ICER). The Committee discussed the overall survival data used in the model and noted the ERG's comments that 90% of the quality-adjusted life years (QALYs) gained in the model were a function of the overall survival. It noted that the overall survival data from the first interim analysis (September 2010), in which bevacizumab showed a non-statistically significant increase in overall survival compared with placebo, had been used by the manufacturer in the model with a resulting ICER of £149,000 per QALY gained. The Committee acknowledged its earlier discussion about the uncertainty around the overall survival estimates (see section 4.7). It noted that the manufacturer was unable to provide the ERG with the March 2012 overall survival data and noted that the ERG scenario analysis, which assumed an equivalent overall survival gain for patients in both treatment arms, had resulted in an ICER of over £1.7 million per QALY gained. The Committee concluded that overall survival was the biggest driver of the cost-effectiveness estimate and that, in principle, it would have liked to have seen a sensitivity analysis from the manufacturer that used the March 2012 data, which would have resulted in a higher ICER than the base case. The Committee noted the cost-effectiveness results based on the network meta-analysis presented by the ERG. It noted that there were no significant differences in the ICERs for any of the other comparators listed in the scope. The Committee acknowledged that these analyses were exploratory and the underlying assumption was that all comparators had an efficacy similar to that of gemcitabine and carboplatin. It considered this to be a reasonable assumption (see section 4.5) and therefore concluded that the ICER for other comparators was unlikely to be significantly different from that calculated for gemcitabine and carboplatin. The Committee considered the most plausible ICER from the model based on the OCEANS trial presented by the manufacturer and by the ERG in their exploratory analyses. It agreed that the manufacturer's base-case ICER, using the September 2010 overall survival data of £149,000 per QALY gained, was likely to be an optimistic cost-effectiveness estimate and that the most plausible ICER could be much higher than this. The Committee noted that the cost-effectiveness estimates for bevacizumab plus gemcitabine and carboplatin were outside the range normally considered to be a cost-effective use of NHS resources. It therefore concluded that bevacizumab plus gemcitabine and carboplatin would not be a cost-effective use of NHS resources for treating the first recurrence of platinum-sensitive advanced ovarian cancer compared with gemcitabine and carboplatin alone. The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The Committee discussed whether bevacizumab plus gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer fulfilled the criteria for a life-extending, end-of-life treatment. It noted that bevacizumab is licensed for a relatively large population across a range of indications in the treatment of breast, colorectal, renal and non-small-cell lung cancers. Therefore, it does not meet the criterion of the supplementary advice that the treatment should be licensed for small populations. Having established that bevacizumab did not meet the population criterion, the Committee decided it was not necessary to make a decision about the life-expectancy or extension-to-life criteria. It concluded that, on this basis, bevacizumab plus gemcitabine and carboplatin did not fulfil the criteria for being a life-extending, end-of-life treatment. The Committee noted the manufacturer's opinion that bevacizumab was an innovative treatment. It acknowledged that advanced recurrent ovarian cancer is a disease with limited treatment options, and that bevacizumab represented a novel biological approach to therapy. It also noted the patient expert comment (see section 4.3). However, the Committee concluded that all substantial benefits related to treatment with bevacizumab plus gemcitabine and carboplatin had been captured in the QALY calculation. # Summary of Appraisal Committee's key conclusions TA285 Appraisal title: Bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer Section Key conclusion Bevacizumab in combination with gemcitabine and carboplatin is not recommended within its marketing authorisation, that is, for treating people with the first recurrence of platinum-sensitive advanced ovarian cancer (including fallopian tube and primary peritoneal cancer) who have not received prior therapy with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor-targeted agents. The Committee agreed that the OCEANS trial had shown the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin in terms of progression-free survival (PFS) but noted that there was insufficient evidence of clinical benefit in terms of overall survival. The Committee noted that the cost-effectiveness estimates for bevacizumab plus gemcitabine and carboplatin were outside the range normally considered to be a cost-effective use of NHS resources. It therefore concluded that bevacizumab plus gemcitabine and carboplatin would not be a cost-effective use of NHS resources for treating the first recurrence of platinum-sensitive advanced ovarian cancer compared with gemcitabine and carboplatin alone. Current practice Clinical need of patients, including the availability of alternative treatments The Committee noted comments received from the professional groups that paclitaxel plus carboplatin; carboplatin as monotherapy; cisplatin monotherapy (in patients who are allergic to carboplatin); gemcitabine plus carboplatin; pegylated liposomal doxorubicin hydrochloride monotherapy; pegylated liposomal doxorubicin hydrochloride plus carboplatin; and pegylated liposomal doxorubicin hydrochloride plus trabectedin (which in some cases is considered a key treatment for patients whose disease is partially platinum sensitive, specifically those who are allergic to platinum) are the most relevant therapies for treating recurrent advanced ovarian cancer in patients whose disease is platinum sensitive or partially platinum sensitive. The Committee heard from the patient experts that they considered bevacizumab to be an innovative technology because, outside clinical trials, there are very few options for treating recurrent ovarian cancer other than standard chemotherapy, and therefore this was seen as a new beneficial development. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee heard from the patient experts and the clinical specialists about the importance of increasing PFS. The patient experts highlighted that, once the cancer relapses, further recurrence is expected. Therefore, increasing PFS gives additional time to deal with the physical, emotional and psychological effects of ovarian cancer and its treatment, and allows patients and their families to come to terms with the implications of relapse. The patient experts also noted that gains in PFS may seem small to people not affected by the disease; however, to patients and their families, this additional period of time is extremely important in helping them to recover from the shock of relapse, and enables them to use the period of wellbeing to make the most of their lives. The Committee noted the manufacturer's opinion that bevacizumab was an innovative treatment. It acknowledged that advanced recurrent ovarian cancer is a disease with limited treatment options, and that bevacizumab represented a novel biological approach to therapy. It also noted the patient expert comment (see section 4.3). However, it concluded that all substantial benefits related to treatment with bevacizumab plus gemcitabine and carboplatin had been captured in the QALY calculation. What is the position of the treatment in the pathway of care for the condition? Bevacizumab in combination with carboplatin and gemcitabine has a marketing authorisation for 'treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents'. Adverse reactions The Committee concluded that the adverse events related to treatment with bevacizumab plus gemcitabine and carboplatin were similar to other chemotherapy regimens and that these events were manageable. Evidence for clinical effectiveness Availability, nature and quality of evidence The key evidence for the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin came from 1 randomised controlled trial (OCEANS). This double-blind, randomised, placebo-controlled trial assessed the safety and efficacy of bevacizumab plus gemcitabine and carboplatin in 484 adults with platinum-sensitive recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, with a first recurrence of ovarian cancer and who had not previously received VEGF receptor-targeted agents. Relevance to general clinical practice in the NHS The Committee concluded that the results from the OCEANS trial were generalisable to UK clinical practice. Uncertainties generated by the evidence The Committee concluded that, although the trial showed an increase in PFS for bevacizumab plus gemcitabine and carboplatin compared with gemcitabine and carboplatin, it was unclear what effect censoring might have had on these results. The Committee concluded that no overall survival benefit for bevacizumab plus gemcitabine and carboplatin had been shown in the OCEANS trial, but the results could have been confounded by post-progression therapies. The Committee concluded that there were various theoretical explanations for the mismatch between the PFS and overall survival results, but was unable to draw any firm conclusions on which of these explained the mismatch, and to what extent. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? None. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that the results for the intention-to-treat population at the September 2010 cut-off date gave a difference in median PFS of 4 months in favour of bevacizumab and this was statistically significant. Evidence for cost effectiveness Availability and nature of evidence The manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of bevacizumab plus carboplatin and gemcitabine compared with placebo plus carboplatin and gemcitabine for treating people with advanced, recurrent, platinum-sensitive ovarian cancer. The model was a 3-state semi-Markov model with health states consisting of PFS, progressed disease and death. The Committee concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus gemcitabine and carboplatin for treating recurrent advanced ovarian cancer. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee acknowledged that there were potential shortcomings with some of the assumptions used in the manufacturer's economic model and considered some alternatives (that is, using a higher utility value for the PFS state, including a disutility for adverse events or using the Kaplan–Meier data for PFS) but it concluded that these would not be likely to have a significant effect on the ICER. The Committee concluded that overall survival was the biggest driver of the cost-effectiveness estimate. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee noted that health-related quality-of-life data were not collected in the OCEANS trial. It agreed that health-related quality-of-life data collected in the trial would have been preferable for deriving the utilities for the economic model. It also noted that the estimates of utility for the PFS and progressed-disease health states were derived from a previous model submitted to NICE (Trabectedin for the treatment of relapsed ovarian cancer ). The Committee agreed that it may be plausible for a larger decrement in utility to occur when a person moves from the progression-free health state to a progressed-disease health state and that the difference in utility between the PFS state and progressed state used by the manufacturer could be an underestimate. It also noted that a disutility associated with adverse events was not applied and that there were more serious adverse events in the bevacizumab arm than in the placebo arm. Are there specific groups of people for whom the technology is particularly cost effective? None. The Committee noted that the cost-effectiveness estimates for bevacizumab plus gemcitabine and carboplatin were outside the range normally considered to be a cost-effective use of NHS resources. It therefore concluded that bevacizumab plus gemcitabine and carboplatin would not be a cost-effective use of NHS resources for treating the first recurrence of platinum-sensitive advanced ovarian cancer compared with gemcitabine and carboplatin alone. What are the key drivers of cost effectiveness? The Committee concluded that overall survival was the biggest driver of the cost-effectiveness estimate and that, in principle, it would have liked to have seen a sensitivity analysis from the manufacturer that used the March 2012 data, which would have resulted in a higher ICER than the base case. Most likely cost-effectiveness estimate (given as an ICER) The Committee agreed that the manufacturer's base-case ICER, using the September 2010 overall survival data of £149,000 per QALY gained, was likely to be an optimistic cost-effectiveness estimate and that the most plausible ICER could be much higher than this. Additional factors taken into account Patient access schemes (PPRS) Not applicable End-of-life considerations Having established that bevacizumab did not meet the population criterion, the Committee decided it was not necessary to make a decision about the life-expectancy or extension-to-life criteria. The Committee concluded that, on this basis, bevacizumab plus gemcitabine and carboplatin did not fulfil the criteria for being a life-extending, end-of-life treatment. Equalities considerations and social value judgements No issues relating to equality considerations were raised in the submissions or the Committee meeting. # Related NICE guidance # Published Bevacizumab in combination with paclitaxel and carboplatin for the first-line treatment of ovarian cancer. NICE technology appraisal guidance 284 (2013). Ovarian cancer: the recognition and initial management of ovarian cancer. NICE clinical guideline 122 (2011). Trabectedin for the treatment of relapsed ovarian cancer. NICE technology appraisal guidance 222 (2011). Paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer: review of technology appraisal guidance 28, 45 and 55. NICE technology appraisal guidance 91 (2005). Guidance on the use of paclitaxel in the treatment of ovarian cancer. NICE technology appraisal guidance 55 (2003). # Under development NICE is developing the following guidance (details available from www.nice.org.uk): Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced ovarian cancer (for recurrent disease only) (review of technology appraisal guidance 91 and 222). NICE technology appraisal guidance. Publication expected February 2014. Vintafolide in combination with pegylated liposomal doxorubicin hydrochloride for the treatment of folate receptor positive, platinum-resistant ovarian cancer. NICE technology appraisal guidance. Publication expected July 2014.# Review of guidance The guidance on this technology will be considered for review in June 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew Dillon Chief Executive May 2013# Changes after publication January 2014: minor maintenance.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It has been incorporated into the NICE pathway on ovarian cancer along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence, 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0138-8	{'Guidance': 'Bevacizumab in combination with gemcitabine and carboplatin is not recommended within its marketing authorisation, that is, for treating people with the first recurrence of platinum-sensitive advanced ovarian cancer (including fallopian tube and primary peritoneal cancer) who have not received prior therapy with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor-targeted agents.\n\nPeople currently receiving bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology': "Bevacizumab (Avastin, Roche) is a humanised monoclonal antibody that inhibits both vascular endothelial growth factor (VEGF)-induced signalling and VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. Bevacizumab in combination with carboplatin and gemcitabine has a marketing authorisation for 'treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents'. The licensed dose of bevacizumab is 15\xa0mg/kg of body weight given once every 3\xa0weeks in combination with carboplatin and gemcitabine for 6\xa0cycles and up to 10\xa0cycles, followed by continued use of bevacizumab as single agent until disease progression.\n\nThe summary of product characteristics lists the following adverse reactions that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage or haemoptysis, congestive heart failure, posterior reversible encephalopathy syndrome, hypersensitivity or infusion reactions, osteonecrosis of the jaw, ovarian failure and neutropenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nBevacizumab is available in 100\xa0mg and 400\xa0mg vials at net prices of £242.66 and £924.40 respectively (excluding VAT; 'British national formulary' edition\xa065). The manufacturer estimated the cost of a course of treatment with bevacizumab (excluding VAT and assuming vials are not shared between patients) to be £25,208 for a patient weighing 60.5\xa0kg at a dosage of 15\xa0mg/kg every 3\xa0weeks for a mean treatment duration of 10.8\xa0cycles (7.5\xa0months). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (section\xa08) considered evidence submitted by the manufacturer of bevacizumab and a review of this submission by the Evidence Review Group (ERG; section\xa09).\n\nThe key evidence for the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin came from 1\xa0randomised controlled trial (OCEANS). This double-blind, randomised, placebo-controlled trial assessed the safety and efficacy of bevacizumab plus gemcitabine and carboplatin in 484\xa0adults with platinum-sensitive recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, with a first recurrence of ovarian cancer and who had not previously received vascular endothelial growth factor (VEGF) receptor-targeted agents. The trial was a multicentre study conducted in 96\xa0centres in the USA. Patients were randomised to 1 of the following 2\xa0treatment arms:\n\nBevacizumab plus gemcitabine and carboplatin (n=242) (bevacizumab 15\xa0mg/kg body weight on day\xa01 every 3\xa0weeks, carboplatin at a dose corresponding to an area under the curve of concentration versus time of 4\xa0mg/ml•min on day\xa01 every 3\xa0weeks, and gemcitabine 1000\xa0mg/m2 on days\xa01 and 8 every 3\xa0weeks for 6–10\xa0cycles; followed by bevacizumab 15\xa0mg/kg body weight alone on day\xa01 every 3\xa0weeks until disease progression or unacceptable toxicity).\n\nPlacebo plus gemcitabine and carboplatin (n=242) (placebo on day\xa01 every 3\xa0weeks, carboplatin area under the curve 4\xa0mg/ml•min on day\xa01 every 3\xa0weeks, and gemcitabine 1000\xa0mg/m2 on days\xa01 and 8 every 3\xa0weeks for 6–10\xa0cycles; followed by placebo alone on day\xa01 every 3\xa0weeks until disease progression or unacceptable toxicity).Randomisation was stratified by platinum-sensitive category (platinum sensitive or partially platinum sensitive) and incidence of cytoreductive surgery for recurrent disease.\n\nThe primary outcome was progression-free survival (PFS), defined as the period from randomisation to disease progression or death (from any cause). Progression was assessed by investigators using radiological evaluation according to the Response Evaluation Criteria for Solid Tumours (RECIST) criteria. Progression could also be determined by symptomatic progression, but not by cancer antigen-125 (CA‑125) elevation alone. Sensitivity analysis of PFS included an assessment by an Independent Review Committee (IRC) using RECIST criteria. For the IRC analysis, the definition of PFS was the period from randomisation until disease progression or on-study death (that is, death occurring within 9\xa0weeks of the last dose of chemotherapy or study drug). All patients needed to undergo CT scans every 9\xa0weeks from day\xa01 of cycle\xa01. Secondary outcomes were overall survival, objective response rate and duration of objective response. Objective response rate and duration of objective response were also assessed by the IRC using RECIST criteria as exploratory analyses. Safety outcome measures were frequency and severity of adverse events.\n\nAnalysis of the primary outcome, PFS in the intention-to-treat population, was based on a cut-off date of 17\xa0September\xa02010, once 338 (70%) patients had experienced disease progression or died (62.4% of patients in the bevacizumab arm and 77.3% in the placebo arm). The median follow-up was 24\xa0months. Data for patients whose disease had not progressed or who had not died at the time of the last tumour assessment were censored (that is, excluded from the analysis from that point onwards). Data for patients who received non-protocol therapy before disease progression were also censored at the time of the last tumour assessment before therapy was initiated. At 29.8\xa0months, all patients still at risk in the bevacizumab arm had experienced disease progression or had died, and at 24.9\xa0months, 2\xa0patients remained at risk in the placebo arm. Results of the investigator-assessed analysis showed that there was a statistically significant difference of 4\xa0months between the median PFS in the bevacizumab arm compared with the placebo arm (bevacizumab 12.4\xa0months, placebo 8.4\xa0months). In the stratified analysis, there was a 51.6% reduction in disease progression in patients in the bevacizumab arm compared with those in the placebo arm (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.39 to 0.61, p<0.0001). An unstratified analysis showed a reduction in disease progression of 50.8% with bevacizumab compared with placebo (HR\xa00.49, 95% CI\xa00.40 to 0.61, p<0.0001). An IRC analysis of PFS on the same data and a sensitivity analysis without censoring patients for receiving non-protocol therapies were also conducted. The IRC analysis results of PFS were consistent with the primary analysis showing a reduction in disease progression in patients in the bevacizumab arm compared with the placebo arm (bevacizumab 12.3\xa0months, placebo 8.6\xa0months; HR\xa00.45, 95%\xa0CI\xa00.35 to 0.58, p<0.0001). Results from the sensitivity analysis that did not censor for non-protocol specified therapy were also consistent with the primary analysis results (bevacizumab 12.4\xa0months, placebo 8.4\xa0months; HR\xa00.52, 95%\xa0CI 0.43 to 0.65).\n\nPFS results for subgroups based on the predefined stratification factors (platinum-sensitive classification and incidence of cytoreductive surgery for recurrent disease) showed that there was a statistically significant reduction in PFS observed for patients in the bevacizumab arm, irrespective of whether they had undergone cytoreductive surgery for recurrent disease or not. Patients whose disease was partially platinum sensitive showed a median PFS of 11.9\xa0months and 8.0\xa0months with bevacizumab and placebo respectively (HR\xa00.41, 95%\xa0CI 0.29 to 0.58). There was also an increase in PFS in patients whose disease was fully platinum sensitive seen in the bevacizumab arm (HR\xa00.55, 95%\xa0CI 0.41 to 0.73).\n\nThree interim analyses of overall survival were conducted, 2 of which were protocol specified. None of the interim analyses found a statistically significant difference between bevacizumab and placebo in the duration of overall survival. The first interim analysis was carried out at the time of final PFS analysis (17\xa0September\xa02010), when approximately 29% of patients had died (median overall survival: 35.5 and 29.9\xa0months in the bevacizumab and placebo arms respectively; HR\xa00.75, 95%\xa0CI\xa00.54 to 1.05). The second analysis was carried out on 29\xa0August\xa02011, when approximately 49% of the patients had died (median overall survival: 33.3 and 35.2\xa0months in the bevacizumab and placebo arms respectively; HR\xa01.03, 95% CI\xa00.79 to 1.33). The third analysis, using a data cut-off date of 30\xa0March\xa02012 (required by the European Medicine Agency), was conducted when approximately 59% of the patients had died (median overall survival: 33.4 and 33.7\xa0months in the bevacizumab and placebo arms respectively; HR\xa00.96, 95% CI\xa00.76 to 1.21). The manufacturer stated that patients in both study arms in third and subsequent lines of therapy received post-progression bevacizumab (at least 18.1% of patients in the bevacizumab arm and 34.7% in the placebo arm received bevacizumab), and therefore confounding may have occurred.\n\nObjective response rate, according to investigator assessment, was statistically significantly different between the 2\xa0arms (78.5% in the bevacizumab arm compared with 57.4% in the placebo arm, p<0.0001). Median duration of response was 10.4 and 7.4\xa0months in patients in the bevacizumab and placebo arms respectively. IRC assessment of objective response rate was consistent with the results of the investigator-assessed analysis (bevacizumab 74.8%, placebo 53.7%, p<0.0001).\n\nAll patients in the OCEANS trial experienced an adverse event. More patients in the bevacizumab arm experienced a serious adverse event compared with patients in the placebo arm (34.8% and 24.9% respectively). Adverse events for which the incidence was more than 10% higher in the bevacizumab arm than in the placebo arm were hypertension, nose bleeds, headache and proteinuria. Adverse events of special interest (grades 3–5) that occurred with an incidence of at least 2% higher in the bevacizumab arm compared with the placebo arm were hypertension, proteinuria and non-central nervous system bleeding. The proportion of patients who experienced an adverse event that led to discontinuation was larger in the bevacizumab arm (19.8%) compared with the placebo arm (4.7%). However, the absolute number of patients stopping treatment because of adverse events was unclear.\n\nThe manufacturer carried out a literature review and identified 4\xa0randomised controlled trials (CALYPSO, ICON4, AGO‑OVAR‑2.5 and OCEANS) that had assessed the comparative clinical effectiveness of the following comparators:\n\npaclitaxel plus platinum-based treatment compared with pegylated liposomal doxorubicin hydrochloride plus platinum-based treatment\n\nplatinum-based treatment (monotherapy) compared with paclitaxel plus platinum-based treatment\n\ngemcitabine plus platinum-based treatment compared with platinum-based treatment (monotherapy)\n\nbevacizumab plus gemcitabine and carboplatin compared with gemcitabine plus carboplatin treatment.After assessing the feasibility of conducting an indirect comparison of bevacizumab plus gemcitabine and carboplatin with the comparators listed in the final scope, the manufacturer decided against carrying out a network meta-analysis.\n\nThe manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of bevacizumab plus carboplatin and gemcitabine compared with placebo plus carboplatin and gemcitabine for treating people with advanced, recurrent, platinum-sensitive ovarian cancer. The model was a 3‑state semi-Markov model with health states consisting of PFS, progressed disease and death. Data from the OCEANS trial were used to guide model inputs. Because the drug dose is dependent on characteristics (such as body weight, body surface area and creatinine clearance rates) that are influenced by age, demographic data from a UK study were used by the manufacturer in their base case to calculate the dose of bevacizumab, carboplatin and gemcitabine. The cost-effectiveness analysis was conducted from an NHS and personal social services perspective, costs and outcomes were discounted at 3.5% per annum and a 10‑year time horizon was used. The cycle length was 1\xa0week.\n\nPFS in the model used the Kaplan–Meier survival curves from the OCEANS trial based on the (intention-to-treat population) investigator-assessed analysis (data cut-off date September\xa02010). The manufacturer examined the fit of various parametric functions to the PFS data and considered a log-logistic model as the best fit to estimate and extrapolate the proportion of patients in the PFS health state. The overall survival from the OCEANS trial (data cut-off date September\xa02010) was used in the model to estimate the proportion of people in the progressed-disease health state and, implicitly, the death state. The manufacturer also applied a log-logistic distribution to the Kaplan–Meier curves. The incidence of adverse events adopted in the model was derived from adverse events (cut-off September\xa02010) of at least grade\xa03 that occurred in more than 2% regardless of the study arm. The manufacturer used the number of patient events to assign a cost associated with each adverse event.\n\nHealth-related quality of life and utilities applied in the model were obtained from Trabectedin for the treatment of relapsed ovarian cancer (NICE technology appraisal guidance\xa0222). The data used in this guidance were taken from the OVA‑301 trial using EQ‑5D. The utility values used in the model for PFS and progressed-disease health states were 0.718 and 0.649 respectively. The manufacturer assumed in the model that health-related quality of life remained constant during PFS and reduced once disease progressed but remained constant after that. The manufacturer did not apply disutilities caused by adverse events in the model.\n\nDrug costs were estimated using the dose and frequency of administration in the summary of product characteristics. Data from a UK cohort study (Sacco et al. 2010) were used in the dose calculations. The base case assumed that any unused carboplatin and paclitaxel from a vial was reallocated and not wasted, whereas for bevacizumab, it was assumed that any unused drug in a vial was wasted. For bevacizumab and carboplatin, the manufacturer used public list prices from the 'British national formulary', and the price of gemcitabine (£12.57 for a 1000\xa0mg vial) was obtained from the Commercial Medicines Unit (CMU) 2012 electronic Market Information Tool (eMit). Costs of drug administration were taken from the Unit Costs of Health and Social Care and NHS reference cost data, and included in the model. The weekly costs of supporting patients in the PFS and progressed health states were also included. Costs of palliative care were applied to patients as they moved to the death state. Costs of post-progression therapies were taken from the OCEANS trial (cut-off date September\xa02010) and included other chemotherapy drugs, radiotherapy or surgery. These costs were added together and applied as a one-off cost in the model, and so were not subject to discounting. Costs associated with adverse events that occurred at grade\xa03 or 4 severity in more than 2% of patients from the OCEANS trial (cut-off date September\xa02010) were incorporated into the analysis. NHS reference costs were utilised when possible; all adverse events were assumed to occur in cycle\xa01 of the model, so costs were not discounted.\n\nThe base-case results estimated that adding bevacizumab to carboplatin and gemcitabine provides an additional 0.42\xa0life years and 0.298\xa0quality-adjusted life years (QALYs). These benefits are achieved with an incremental cost of £44,428, resulting in an incremental cost-effectiveness ratio (ICER) of £149,050 per QALY gained for bevacizumab plus carboplatin and gemcitabine compared with carboplatin and gemcitabine alone. The manufacturer's deterministic sensitivity analysis suggested that the cost-effectiveness results were most sensitive to assumptions around the extrapolation of overall survival, the duration of treatment and the utility of patients in PFS. The manufacturer's probabilistic sensitivity analyses concluded that the probability of bevacizumab plus carboplatin and gemcitabine being cost effective compared with carboplatin and gemcitabine alone at a threshold of £30,000 per QALY gained was 0%. The manufacturer identified the key drivers of the cost-effectiveness results to be the cost and duration of treatment with bevacizumab and the time horizon of the analysis.\n\nThe ERG considered the OCEANS trial to be well designed and agreed that, except for baseline weight, the characteristics of the patient population enrolled in the trial were representative of people with first recurrence of ovarian cancer in England and Wales. The ERG noted that the course of treatment assumed in the OCEANS trial (allowing up to a maximum of 10\xa0cycles of bevacizumab plus carboplatin and gemcitabine) may not fully represent clinical practice in the UK (where a maximum of 6\xa0cycles of chemotherapy would be administered). The ERG also noted that the main comparator in the manufacturer's submission was gemcitabine plus carboplatin, whereas this may not be the treatment routinely used in the NHS.\n\nThe ERG highlighted the differences between the number of recorded events in terms of PFS in the investigator-assessed analysis and the IRC-determined analysis. The ERG also highlighted that the number of patients censored in each group at the time of final PFS analysis (September 2010), and the mean PFS and the number of patients lost to follow-up at the time of the final analysis were unknown. The ERG also noted that the absolute number of patients stopping treatment because of an adverse event varied in the manufacturer's submission, and the correct number remained unclear after seeking clarification from the manufacturer.\n\nThe ERG considered the literature search and the reasons given by the manufacturer for not performing an indirect comparison between bevacizumab plus carboplatin and gemcitabine, and the other comparators listed in the scope. The ERG considered that the differences between trials were sufficiently minor such that their inclusion would have a minimal impact on clinical heterogeneity, and decided to perform a network meta-analysis for the primary outcome measure (PFS). Results from the network meta-analysis performed by the ERG suggested that bevacizumab plus carboplatin and gemcitabine is associated with a statistically significant improvement in duration of PFS compared with all comparators listed in the scope (bevacizumab plus carboplatin and gemcitabine compared with: paclitaxel plus carboplatin, HR\xa00.47, 95%\xa0credible interval [CrI]\xa00.33 to 0.66; pegylated liposomal doxorubicin hydrochloride plus carboplatin, HR\xa00.58, 95% CrI\xa00.39 to 0.82; platinum monotherapy, HR\xa00.35, 95% CrI\xa00.25 to 0.47; gemcitabine plus carboplatin, HR\xa00.48, 95%\xa0CrI 0.38 to 0.60). Results from the network meta-analysis also suggested that there were no statistically significant differences between most of the other comparators.\n\nThe ERG considered the manufacturer's model structure was appropriate to describe the decision problem and was well constructed and transparent. The ERG highlighted and agreed with the manufacturer that the main criticism of the submitted economic evaluation was the use of the September\xa02010 OCEANS clinical-effectiveness, cost and adverse-event incidence data. The ERG suggested that the use of data from September\xa02010, when 29% of the patients had died (rather than data from March\xa02012, when available, when 59% of the patients had died), may have introduced unnecessary uncertainty into the estimate of the ICER and may have overestimated the overall survival benefit associated with bevacizumab because the analysis of overall survival in September\xa02010 showed a non-statistically significant overall survival increase for patients in the bevacizumab group, which was not sustained in the 2\xa0later interim analyses. The ERG noted that overall survival was a key driver in the model and estimated that approximately 90% of the QALYs gained in the model were a function of the overall survival. The ERG conducted a scenario analysis assuming that overall survival was the same for patients in both treatment groups. The result of the analysis was an increase in the ICER to over £1.7\xa0million per QALY gained.\n\nThe ERG noted that the manufacturer applied a parametric log-logistic function to the Kaplan–Meier PFS data (cut-off date September\xa02010) from the OCEANS trial to estimate and extrapolate the proportion of patients in the progression-free health state. At a median follow-up of 24\xa0months (final PFS analysis), 70% of the patients had either experienced disease progression or died. Patients in the bevacizumab arm reached 0% PFS at month\xa029.8, whereas 2\xa0patients remained at risk at month\xa024.9 in the placebo arm. The ERG assumed in their exploratory analysis that, by 29\xa0months, all patients would have had disease progression or died according to the last Kaplan–Meier data available, and suggested that mean values for PFS might be available, rather than only medians. The ERG also had concerns about fitting a parametric distribution for PFS given the Kaplan–Meier data available and undertook a scenario analysis using only the Kaplan–Meier data, although this did not have a significant impact on the ICER.\n\nThe ERG noted that adverse events experienced by patients in the model were not subject to estimates of disutility and suggested that this was likely to favour the cost effectiveness of bevacizumab because a larger proportion of patients in the bevacizumab treatment group experienced a serious adverse event compared with the placebo group in the OCEANS trial. The ERG conducted a scenario analysis and assessed a range of average duration of adverse event disutilities. It concluded that, for example, for an average event duration of 1\xa0week, the ICER increased to £149,391 per QALY gained and, for an average adverse event duration of 1\xa0month, the ICER increased to £150,544 per additional QALY gained.\n\nThe ERG explored the impact of the network meta-analysis results in terms of cost effectiveness. The ERG assumed, based on the these results, that overall survival and PFS estimates for patients in every comparator group were the same as for patients in the placebo group in the manufacturer's model. Cost-effectiveness results from the ERG exploratory analysis were:\n\nICER for bevacizumab plus gemcitabine and carboplatin compared with carboplatin £159,273 per QALY gained\n\nICER for bevacizumab plus gemcitabine and carboplatin compared with paclitaxel plus carboplatin £148,014 per QALY gained\n\nICER for bevacizumab plus gemcitabine and carboplatin compared with pegylated liposomal doxorubicin hydrochloride plus carboplatin £145,621 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab plus gemcitabine and carboplatin, having considered evidence on the nature of recurrent advanced ovarian cancer and the value placed on the benefits of bevacizumab plus gemcitabine and carboplatin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the current management of recurrent advanced ovarian cancer. It noted comments received from the professional groups that paclitaxel plus carboplatin; carboplatin as monotherapy; cisplatin monotherapy (in patients who are allergic to carboplatin); gemcitabine plus carboplatin; pegylated liposomal doxorubicin hydrochloride monotherapy; pegylated liposomal doxorubicin hydrochloride plus carboplatin; and pegylated liposomal doxorubicin hydrochloride plus trabectedin (which in some cases is considered a key treatment for patients whose disease is partially platinum sensitive, specifically those who are allergic to platinum) are the most relevant therapies for treating recurrent advanced ovarian cancer in patients whose disease is platinum sensitive or partially platinum sensitive. The Committee also heard from clinical specialists that pegylated liposomal doxorubicin hydrochloride is not currently available and for patients whose disease is platinum sensitive, the most commonly used treatment would be paclitaxel plus carboplatin. The clinical specialists highlighted that gemcitabine plus carboplatin is not the most commonly used treatment in UK clinical practice but stated that its use may increase in the future, particularly in light of the combination therapy being appraised (bevacizumab plus gemcitabine and carboplatin). The Committee heard from the clinical specialists that this new combination therapy had been used in the UK in this patient group only on a compassionate basis before it received its marketing authorisation.\n\nThe Committee heard from patient experts the importance of increasing progression-free survival (PFS). The patient experts highlighted that, once the cancer relapses, further recurrence is expected. Therefore, increasing PFS gives additional time to deal with the physical, emotional and psychological effects of ovarian cancer and its treatment, and allows patients and their families to come to terms with the implications of relapse. The patient experts also noted that gains in PFS may seem small to people not affected by the disease; however, to patients and their families, this additional period of time is extremely important in helping them to recover from the shock of relapse, and enables them to use the period of wellbeing to make the most of their lives. The clinical specialists reiterated the patient experts' comments about the importance of PFS. The Committee also noted comments received from a consultee in response to the appraisal consultation document restating the importance of PFS to patients. The Committee also heard from the patient experts that they considered bevacizumab to be an innovative technology because, outside clinical trials, there are very few options for treating recurrent ovarian cancer other than standard chemotherapy, and therefore this was seen as a new beneficial development.\n\nThe Committee considered the importance of platinum sensitivity and the platinum-free interval for the prognosis of the disease. It heard from the clinical specialists that the most effective treatment for ovarian cancer is platinum-based chemotherapy. Some people's tumours respond better to this than others and the term platinum sensitivity refers to the length of initial remission after first-line platinum chemotherapy. For people whose disease shows a response to platinum, there is an arbitrary classification into platinum-resistant disease (less than a 6‑month disease-free interval) and platinum-sensitive disease (more than a 6‑month disease-free interval). The Committee heard that the development of drugs that increase the length of the platinum-induced remission will allow some people to achieve a platinum-free interval of 6\xa0months or more. It also heard that there is an underlying assumption that, if the platinum-free interval is longer, the disease will respond better to platinum (that is, be more platinum sensitive) when the drug is re-administered. Some of the assumptions related to platinum sensitivity and the platinum-free interval are currently being tested in trials.\n\n# Clinical effectiveness\n\nThe Committee considered that the main source of evidence for the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin was the OCEANS trial that had been conducted in the USA. The Committee agreed with the Evidence Review Group's (ERG's) comments that overall, this was a well-designed double-blind, randomised, placebo-controlled trial. The Committee understood from the clinical specialists that there were no clinical differences between the patients in the trial and patients in the UK with recurrent ovarian cancer, apart from body weight and body surface area. The Committee heard from the clinical specialists that the comparator used in the trial, gemcitabine and carboplatin, is not the most widely used treatment option for recurrent advanced ovarian cancer in the NHS. However, it also heard that gemcitabine and carboplatin could be considered to have a similar efficacy to other treatment options currently used in the NHS, particularly in terms of PFS. The Committee concluded that the results from the OCEANS trial were generalisable to UK clinical practice.\n\nThe Committee discussed PFS results reported in the manufacturer's submission based on the OCEANS trial. It noted that the results for the intention-to-treat population at the September\xa02010 cut-off date gave a difference in median PFS of 4\xa0months in favour of bevacizumab and this was statistically significant. The Committee noted that in the OCEANS trial, there was a statistically significant difference of approximately 20% in response rate with bevacizumab plus gemcitabine and carboplatin compared with gemcitabine and carboplatin, indicating that bevacizumab is an active drug. Nevertheless, it also acknowledged the ERG's concerns about the issue of censoring. The Committee noted that the data from approximately 30% of the patients had been censored and it was unclear whether these data had been censored because of patients stopping treatment because of adverse events or patients being lost to follow-up. It heard from the manufacturer that information on the number of patients for whom data were censored and the reason why, was not available at the time of the submission. The Committee concluded that, although the trial showed an increase in PFS for bevacizumab plus gemcitabine and carboplatin compared with gemcitabine and carboplatin, it was unclear what effect censoring might have had on these results.\n\nThe Committee considered the most relevant overall survival results for the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin. It explored the 3\xa0interim analyses presented by the manufacturer and noted that none of the analyses showed a statistically significant increase in overall survival in the bevacizumab-treated group. Although the first interim analysis showed a trend towards increased overall survival in the bevacizumab arm (35.5 and 29.9\xa0months in the bevacizumab and placebo groups respectively), in the second and third interim analyses, the difference in median overall survival favoured placebo (1.9\xa0months and 0.3\xa0months respectively). The Committee agreed with the manufacturer's comments that the lack of statistically significant differences between bevacizumab and placebo could have been affected by confounding effects of post-progression treatments. It noted that 18.1% of patients in the bevacizumab arm and 34.7% of patients in the placebo arm received bevacizumab post progression, but also noted that bevacizumab is not licensed for this stage in the treatment pathway because its licence is for first recurrence only. The Committee noted that more than 85% of the patients in both study arms had 3\xa0or more lines of anti-cancer therapy post progression, and it heard from the clinical specialists that it would therefore be very difficult to see any overall survival benefit from bevacizumab with this high level of post-progression treatment without a very much larger trial population. The Committee also heard from the clinical specialists that, although the third interim analysis (March\xa02012) may be the most reliable because at this stage 59% of patients had died, there could be a bigger issue with confounding. In contrast, the first interim analysis (September\xa02010) contained overall survival data for only 29% of patients, but may be less confounded by post-progression treatments. The Committee expressed a preference for the more mature and complete overall survival data, but acknowledged that the argument about which were the most reliable data was finely balanced. The Committee concluded that no overall survival benefit for bevacizumab plus gemcitabine and carboplatin had been shown in the OCEANS trial, but the results could have been confounded by post-progression therapies.\n\nThe Committee considered reasons for the discrepancy between the PFS and overall survival results in the OCEANS trial for bevacizumab plus gemcitabine and carboplatin for treating recurrent advanced ovarian cancer. It noted that there were 3\xa0possible underlying causes for the differences:\n\nthe high degree of censoring and the lack of clarity regarding how this might have affected the PFS results (see section\xa04.6)\n\nthe confounding effects on overall survival results because of the use of post-progression treatments (see section\xa04.7)\n\nthe potential biological action of bevacizumab. The Committee heard from the clinical specialists that, although not substantiated in clinical practice, it was biologically plausible that bevacizumab could increase PFS, but once the disease has progressed, disease progression could be accelerated once bevacizumab is stopped. This might be an argument for continuing maintenance treatments such as bevacizumab beyond the stage of progression. Following comments received from the manufacturer in response to the appraisal consultation document, the Committee reconsidered the 3\xa0possible underlying causes for the differences between PFS and overall survival results. It noted the manufacturer's comment that the overall survival results could have been affected by confounding effects because of the use of post-progression treatments. However, the Committee agreed that the high degree of censoring of PFS estimates and the potential biological action of bevacizumab could also be explanations for the difference in the results. The Committee remained unable to draw any firm conclusions as to which of these issues explained the mismatch, and to what extent.\n\nThe Committee considered the adverse events reported in the OCEANS trial and noted that more patients in the bevacizumab arm (19.8%) stopped treatment because of adverse events than in the placebo arm (4.7%). It heard from the clinical specialists that the discontinuation rate in UK clinical practice would be expected to be lower than in the clinical trial and that most adverse events can be satisfactorily managed. The Committee also heard from one of the patient experts that they had experienced gastrointestinal problems during and after chemotherapy. However, it heard from the patient experts that these problems are usually well managed by clinicians and do not necessarily disrupt a patient's daily life or quality of life. The Committee concluded that the adverse events related to treatment with bevacizumab plus gemcitabine and carboplatin were similar to those related to other chemotherapy regimens and that these events were manageable.\n\n# Cost effectiveness\n\nThe Committee discussed the manufacturer's cost-effectiveness estimates, derived from the manufacturer's economic model based on data from the OCEANS trial, and the assumptions in the model. The Committee noted the ERG's comments that it considered the manufacturer's model structure to be generally appropriate, well constructed and transparent. The Committee concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus gemcitabine and carboplatin for treating recurrent advanced ovarian cancer.\n\nThe Committee did, however, acknowledge that there were potential shortcomings with some of the assumptions used in the manufacturer's economic model. It noted that health-related quality-of-life data were not collected in the OCEANS trial. The Committee agreed that health-related quality-of-life data collected in the trial would have been preferable for deriving the utilities for the economic model. It noted that the estimates of utility for the PFS and progressed-disease health states were derived from a previous model submitted to NICE (Trabectedin for the treatment of relapsed ovarian cancer [NICE technology appraisal guidance\xa0222]) and that the difference between the utilities for PFS and progressed disease was relatively small (0.718 and 0.649 respectively). The Committee heard from the patient experts that patients may experience a good health-related quality of life while they are progression free. It also noted the comments received from a consultee in response to the appraisal consultation document that reiterated the importance of PFS to patients, and the Committee therefore agreed that it may be plausible for a larger decrement in utility to occur when a person moves from the progression-free health state to a progressed-disease health state and that the difference in utility between the PFS state and progressed state used by the manufacturer could be an underestimate. The Committee also noted that a disutility associated with adverse events was not applied and that there were more serious adverse events in the bevacizumab arm than in the placebo arm. It also discussed how the PFS results were incorporated in the manufacturer's economic model. The Committee noted the ERG's comments on the extrapolation of PFS results by fitting a log-logistic distribution when the Kaplan–Meier data were available. It acknowledged the manufacturer's and ERG's sensitivity and scenario analyses, and concluded that taking all these relevant issues into account (that is, using a higher utility value for the PFS state, including a disutility for adverse events or using the Kaplan–Meier data for PFS) would not be likely to have a significant effect on the incremental cost-effectiveness ratio (ICER).\n\nThe Committee discussed the overall survival data used in the model and noted the ERG's comments that 90% of the quality-adjusted life years (QALYs) gained in the model were a function of the overall survival. It noted that the overall survival data from the first interim analysis (September\xa02010), in which bevacizumab showed a non-statistically significant increase in overall survival compared with placebo, had been used by the manufacturer in the model with a resulting ICER of £149,000 per QALY gained. The Committee acknowledged its earlier discussion about the uncertainty around the overall survival estimates (see section\xa04.7). It noted that the manufacturer was unable to provide the ERG with the March\xa02012 overall survival data and noted that the ERG scenario analysis, which assumed an equivalent overall survival gain for patients in both treatment arms, had resulted in an ICER of over £1.7\xa0million per QALY gained. The Committee concluded that overall survival was the biggest driver of the cost-effectiveness estimate and that, in principle, it would have liked to have seen a sensitivity analysis from the manufacturer that used the March\xa02012 data, which would have resulted in a higher ICER than the base case.\n\nThe Committee noted the cost-effectiveness results based on the network meta-analysis presented by the ERG. It noted that there were no significant differences in the ICERs for any of the other comparators listed in the scope. The Committee acknowledged that these analyses were exploratory and the underlying assumption was that all comparators had an efficacy similar to that of gemcitabine and carboplatin. It considered this to be a reasonable assumption (see section\xa04.5) and therefore concluded that the ICER for other comparators was unlikely to be significantly different from that calculated for gemcitabine and carboplatin.\n\nThe Committee considered the most plausible ICER from the model based on the OCEANS trial presented by the manufacturer and by the ERG in their exploratory analyses. It agreed that the manufacturer's base-case ICER, using the September\xa02010 overall survival data of £149,000 per QALY gained, was likely to be an optimistic cost-effectiveness estimate and that the most plausible ICER could be much higher than this. The Committee noted that the cost-effectiveness estimates for bevacizumab plus gemcitabine and carboplatin were outside the range normally considered to be a cost-effective use of NHS resources. It therefore concluded that bevacizumab plus gemcitabine and carboplatin would not be a cost-effective use of NHS resources for treating the first recurrence of platinum-sensitive advanced ovarian cancer compared with gemcitabine and carboplatin alone.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether bevacizumab plus gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer fulfilled the criteria for a life-extending, end-of-life treatment. It noted that bevacizumab is licensed for a relatively large population across a range of indications in the treatment of breast, colorectal, renal and non-small-cell lung cancers. Therefore, it does not meet the criterion of the supplementary advice that the treatment should be licensed for small populations. Having established that bevacizumab did not meet the population criterion, the Committee decided it was not necessary to make a decision about the life-expectancy or extension-to-life criteria. It concluded that, on this basis, bevacizumab plus gemcitabine and carboplatin did not fulfil the criteria for being a life-extending, end-of-life treatment.\n\nThe Committee noted the manufacturer's opinion that bevacizumab was an innovative treatment. It acknowledged that advanced recurrent ovarian cancer is a disease with limited treatment options, and that bevacizumab represented a novel biological approach to therapy. It also noted the patient expert comment (see section\xa04.3). However, the Committee concluded that all substantial benefits related to treatment with bevacizumab plus gemcitabine and carboplatin had been captured in the QALY calculation.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA285\n\nAppraisal title: Bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer\n\nSection\n\nKey conclusion\n\nBevacizumab in combination with gemcitabine and carboplatin is not recommended within its marketing authorisation, that is, for treating people with the first recurrence of platinum-sensitive advanced ovarian cancer (including fallopian tube and primary peritoneal cancer) who have not received prior therapy with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor-targeted agents.\n\n\n\nThe Committee agreed that the OCEANS trial had shown the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin in terms of progression-free survival (PFS) but noted that there was insufficient evidence of clinical benefit in terms of overall survival.\n\n, 4.7\n\nThe Committee noted that the cost-effectiveness estimates for bevacizumab plus gemcitabine and carboplatin were outside the range normally considered to be a cost-effective use of NHS resources. It therefore concluded that bevacizumab plus gemcitabine and carboplatin would not be a cost-effective use of NHS resources for treating the first recurrence of platinum-sensitive advanced ovarian cancer compared with gemcitabine and carboplatin alone.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee noted comments received from the professional groups that paclitaxel plus carboplatin; carboplatin as monotherapy; cisplatin monotherapy (in patients who are allergic to carboplatin); gemcitabine plus carboplatin; pegylated liposomal doxorubicin hydrochloride monotherapy; pegylated liposomal doxorubicin hydrochloride plus carboplatin; and pegylated liposomal doxorubicin hydrochloride plus trabectedin (which in some cases is considered a key treatment for patients whose disease is partially platinum sensitive, specifically those who are allergic to platinum) are the most relevant therapies for treating recurrent advanced ovarian cancer in patients whose disease is platinum sensitive or partially platinum sensitive.\n\n\n\nThe Committee heard from the patient experts that they considered bevacizumab to be an innovative technology because, outside clinical trials, there are very few options for treating recurrent ovarian cancer other than standard chemotherapy, and therefore this was seen as a new beneficial development.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee heard from the patient experts and the clinical specialists about the importance of increasing PFS. The patient experts highlighted that, once the cancer relapses, further recurrence is expected. Therefore, increasing PFS gives additional time to deal with the physical, emotional and psychological effects of ovarian cancer and its treatment, and allows patients and their families to come to terms with the implications of relapse. The patient experts also noted that gains in PFS may seem small to people not affected by the disease; however, to patients and their families, this additional period of time is extremely important in helping them to recover from the shock of relapse, and enables them to use the period of wellbeing to make the most of their lives.\n\n\n\nThe Committee noted the manufacturer's opinion that bevacizumab was an innovative treatment. It acknowledged that advanced recurrent ovarian cancer is a disease with limited treatment options, and that bevacizumab represented a novel biological approach to therapy. It also noted the patient expert comment (see section\xa04.3). However, it concluded that all substantial benefits related to treatment with bevacizumab plus gemcitabine and carboplatin had been captured in the QALY calculation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nBevacizumab in combination with carboplatin and gemcitabine has a marketing authorisation for 'treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents'.\n\n\n\nAdverse reactions\n\nThe Committee concluded that the adverse events related to treatment with bevacizumab plus gemcitabine and carboplatin were similar to other chemotherapy regimens and that these events were manageable.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe key evidence for the clinical effectiveness of bevacizumab plus gemcitabine and carboplatin came from 1\xa0randomised controlled trial (OCEANS). This double-blind, randomised, placebo-controlled trial assessed the safety and efficacy of bevacizumab plus gemcitabine and carboplatin in 484\xa0adults with platinum-sensitive recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, with a first recurrence of ovarian cancer and who had not previously received VEGF receptor-targeted agents.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee concluded that the results from the OCEANS trial were generalisable to UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that, although the trial showed an increase in PFS for bevacizumab plus gemcitabine and carboplatin compared with gemcitabine and carboplatin, it was unclear what effect censoring might have had on these results.\n\n\n\nThe Committee concluded that no overall survival benefit for bevacizumab plus gemcitabine and carboplatin had been shown in the OCEANS trial, but the results could have been confounded by post-progression therapies.\n\n\n\nThe Committee concluded that there were various theoretical explanations for the mismatch between the PFS and overall survival results, but was unable to draw any firm conclusions on which of these explained the mismatch, and to what extent.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that the results for the intention-to-treat population at the September 2010 cut-off date gave a difference in median PFS of 4\xa0months in favour of bevacizumab and this was statistically significant.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of bevacizumab plus carboplatin and gemcitabine compared with placebo plus carboplatin and gemcitabine for treating people with advanced, recurrent, platinum-sensitive ovarian cancer. The model was a 3-state semi-Markov model with health states consisting of PFS, progressed disease and death.\n\n\n\nThe Committee concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus gemcitabine and carboplatin for treating recurrent advanced ovarian cancer.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee acknowledged that there were potential shortcomings with some of the assumptions used in the manufacturer's economic model and considered some alternatives (that is, using a higher utility value for the PFS state, including a disutility for adverse events or using the Kaplan–Meier data for PFS) but it concluded that these would not be likely to have a significant effect on the ICER.\n\n\n\nThe Committee concluded that overall survival was the biggest driver of the cost-effectiveness estimate.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that health-related quality-of-life data were not collected in the OCEANS trial. It agreed that health-related quality-of-life data collected in the trial would have been preferable for deriving the utilities for the economic model. It also noted that the estimates of utility for the PFS and progressed-disease health states were derived from a previous model submitted to NICE (Trabectedin for the treatment of relapsed ovarian cancer [NICE technology appraisal guidance\xa0222]). The Committee agreed that it may be plausible for a larger decrement in utility to occur when a person moves from the progression-free health state to a progressed-disease health state and that the difference in utility between the PFS state and progressed state used by the manufacturer could be an underestimate. It also noted that a disutility associated with adverse events was not applied and that there were more serious adverse events in the bevacizumab arm than in the placebo arm.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone. The Committee noted that the cost-effectiveness estimates for bevacizumab plus gemcitabine and carboplatin were outside the range normally considered to be a cost-effective use of NHS resources. It therefore concluded that bevacizumab plus gemcitabine and carboplatin would not be a cost-effective use of NHS resources for treating the first recurrence of platinum-sensitive advanced ovarian cancer compared with gemcitabine and carboplatin alone.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee concluded that overall survival was the biggest driver of the cost-effectiveness estimate and that, in principle, it would have liked to have seen a sensitivity analysis from the manufacturer that used the March 2012 data, which would have resulted in a higher ICER than the base case.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee agreed that the manufacturer's base-case ICER, using the September\xa02010 overall survival data of £149,000 per QALY gained, was likely to be an optimistic cost-effectiveness estimate and that the most plausible ICER could be much higher than this.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable\n\n\n\nEnd-of-life considerations\n\nHaving established that bevacizumab did not meet the population criterion, the Committee decided it was not necessary to make a decision about the life-expectancy or extension-to-life criteria. The Committee concluded that, on this basis, bevacizumab plus gemcitabine and carboplatin did not fulfil the criteria for being a life-extending, end-of-life treatment.\n\n\n\nEqualities considerations and social value judgements\n\nNo issues relating to equality considerations were raised in the submissions or the Committee meeting.\n\n", 'Related NICE guidance': '# Published\n\nBevacizumab in combination with paclitaxel and carboplatin for the first-line treatment of ovarian cancer. NICE technology appraisal guidance 284 (2013).\n\nOvarian cancer: the recognition and initial management of ovarian cancer. NICE clinical guideline 122 (2011).\n\nTrabectedin for the treatment of relapsed ovarian cancer. NICE technology appraisal guidance 222 (2011).\n\nPaclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer: review of technology appraisal guidance 28, 45 and 55. NICE technology appraisal guidance 91 (2005).\n\nGuidance on the use of paclitaxel in the treatment of ovarian cancer. NICE technology appraisal guidance 55 (2003).\n\n# Under development\n\nNICE is developing the following guidance (details available from www.nice.org.uk):\n\nTopotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced ovarian cancer (for recurrent disease only) (review of technology appraisal guidance 91 and 222). NICE technology appraisal guidance. Publication expected February 2014.\n\nVintafolide in combination with pegylated liposomal doxorubicin hydrochloride for the treatment of folate receptor positive, platinum-resistant ovarian cancer. NICE technology appraisal guidance. Publication expected July 2014.', 'Review of guidance': 'The guidance on this technology will be considered for review in June\xa02016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon Chief Executive May 2013', 'Changes after publication': 'January 2014: minor maintenance.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt has been incorporated into the NICE pathway on ovarian cancer along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence, 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0138-8'}	https://www.nice.org.uk/guidance/ta285	Evidence-based recommendations on bevacizumab (Avastin), with gemcitabine and carboplatin, for treating platinum-sensitive advanced ovarian cancer in adults.
d22540f7cf2ff24d4b68b4a76872aecf6c920c70	nice	Loxapine inhalation for treating acute agitation and disturbed behaviours associated with schizophrenia and bipolar disorder (terminated appraisal)	Loxapine inhalation for treating acute agitation and disturbed behaviours associated with schizophrenia and bipolar disorder (terminated appraisal) # Background The manufacturer (Alexza Pharmaceuticals) was invited to submit evidence for this single technology appraisal in January 2013. In January 2013 the manufacturer informed NICE that they would not be making a submission for this appraisal. The manufacturer said that they have received the marketing authorisation for loxapine inhalation (Adusave) but that this restricts administration to adults with mild to moderate agitation associated with schizophrenia and bipolar disorder and to the hospital setting. The manufacturer stated that there is insufficient evidence available to develop the appropriate analytical model required to estimate cost effectiveness in line with NICE single technology appraisal procedures. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of loxapine inhalation for treating mild to moderate agitation in adults with schizophrenia or bipolar disorder. If, after doing this, organisations still wish to consider loxapine inhalation for treating mild to moderate agitation in adults with schizophrenia or bipolar disorder, they should follow the advice set out in the Department of Health's Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance, which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable. NICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission. # Related NICE guidance For information about NICE guidance that has been issued or is in development, see the NICE website. Core interventions in the treatment and management of schizophrenia in primary and secondary care (update). NICE clinical guideline 82 (2009). The management of bipolar disorder in adults, children and adolescents in primary and secondary care. NICE clinical guideline 38 (2006). Violence: The short-term management of disturbed/violent behaviour in in-patient psychiatric settings and emergency departments. NICE clinical guideline 25 (2005). ISBN 978-1-4731-0147-0	{'Background': 'The manufacturer (Alexza Pharmaceuticals) was invited to submit evidence for this single technology appraisal in January 2013.\n\nIn January 2013 the manufacturer informed NICE that they would not be making a submission for this appraisal. The manufacturer said that they have received the marketing authorisation for loxapine inhalation (Adusave) but that this restricts administration to adults with mild to moderate agitation associated with schizophrenia and bipolar disorder and to the hospital setting. The manufacturer stated that there is insufficient evidence available to develop the appropriate analytical model required to estimate cost effectiveness in line with NICE single technology appraisal procedures.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': "NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of loxapine inhalation for treating mild to moderate agitation in adults with schizophrenia or bipolar disorder. If, after doing this, organisations still wish to consider loxapine inhalation for treating mild to moderate agitation in adults with schizophrenia or bipolar disorder, they should follow the advice set out in the Department of Health's Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance, which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable.\n\nNICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission.\n\n# Related NICE guidance\n\nFor information about NICE guidance that has been issued or is in development, see the NICE website.\n\nCore interventions in the treatment and management of schizophrenia in primary and secondary care (update). NICE clinical guideline 82 (2009).\n\nThe management of bipolar disorder in adults, children and adolescents in primary and secondary care. NICE clinical guideline 38 (2006).\n\nViolence: The short-term management of disturbed/violent behaviour in in-patient psychiatric settings and emergency departments. NICE clinical guideline 25 (2005).\n\nISBN 978-1-4731-0147-0"}	https://www.nice.org.uk/guidance/ta286
60876f15f41213f5614e77175803d1c8dcc25985	nice	Social anxiety disorder: recognition, assessment and treatment	Social anxiety disorder: recognition, assessment and treatment This guideline covers recognising, assessing and treating social anxiety disorder (also known as ‘social phobia’) in children and young people (from school age to 17 years) and adults (aged 18 years and older). It aims to improve symptoms, educational, occupational and social functioning, and quality of life in people with social anxiety disorder. # Introduction This guidance updates and replaces the section of NICE technology appraisal guidance 97 (published February 2006) that deals with phobia. Social anxiety disorder (previously known as 'social phobia') is one of the most common of the anxiety disorders. Estimates of lifetime prevalence vary but according to a US study, 12% of adults in the US will have social anxiety disorder at some point in their lives, compared with estimates of around 6% for generalised anxiety disorder (GAD), 5% for panic disorder, 7% for post-traumatic stress disorder (PTSD) and 2% for obsessive–compulsive disorder. There is a significant degree of comorbidity between social anxiety disorder and other mental health problems, most notably depression (19%), substance-use disorder (17%), GAD (5%), panic disorder (6%), and PTSD (3%). Social anxiety disorder is persistent fear of or anxiety about one or more social or performance situations that is out of proportion to the actual threat posed by the situation. Typical situations that might be anxiety-provoking include meeting people, including strangers, talking in meetings or in groups, starting conversations, talking to authority figures, working, eating or drinking while being observed, going to school, going shopping, being seen in public, using public toilets and public performances such as public speaking. Although worries about some of these situations are common in the general population, people with social anxiety disorder worry excessively about them at the time and before and afterwards. They fear that they will do or say something that they think will be humiliating or embarrassing (such as blushing, sweating, appearing boring or stupid, shaking, appearing incompetent, looking anxious). Social anxiety disorder can have a great impact on a person's functioning, disrupting normal life, interfering with social relationships and quality of life and impairing performance at work or school. People with the disorder may misuse alcohol or drugs to try to reduce their anxiety (and alleviate depression). Children may show their anxiety in different ways from adults: as well as shrinking from interactions, they may be more likely to cry, freeze or have tantrums. They may also be less likely to acknowledge that their fears are irrational when they are away from a social situation. Particular situations that can cause difficulty for socially anxious children and young people include participating in classroom activities, asking for help in class, joining activities with peers (such as attending parties or clubs), and being involved in school performances. Social anxiety disorder has an early median age of onset (13 years) and is one of the most persistent anxiety disorders. Despite the extent of distress and impairment, only about half of those with the disorder ever seek treatment, and those who do generally only seek treatment after 15–20 years of symptoms. A significant number of people who develop social anxiety disorder in adolescence may recover before reaching adulthood. However, if the disorder has persisted into adulthood, the chance of recovery in the absence of treatment is modest when compared with many other common mental health problems. Effective psychological and pharmacological interventions for social anxiety disorder exist but may not be accessed due to poor recognition, inadequate assessment and limited awareness or availability of treatments. Social anxiety disorder is under-recognised in primary care. When it coexists with depression the depressive episode may be recognised without detecting the underlying and more persistent social anxiety disorder. The early age of onset means that recognition in educational settings is also challenging. Some recommendations in this guideline have been adapted from recommendations in other NICE clinical guidance. In these cases the Guideline Development Group was careful to preserve the meaning and intent of the original recommendations. Changes to wording or structure were made to fit the recommendations into this guideline. The original sources of the adapted recommendations are shown in the recommendations. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual service users. This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The service user (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. The recommendations relate to children and young people (from school age to 17 years) and adults (aged 18 years and older). # General principles of care in mental health and general medical settings ## Improving access to services Be aware that people with social anxiety disorder may: not know that social anxiety disorder is a recognised condition and can be effectively treated perceive their social anxiety as a personal flaw or failing be vulnerable to stigma and embarrassment avoid contact with and find it difficult or distressing to interact with healthcare professionals, staff and other service users avoid disclosing information, asking and answering questions and making complaints have difficulty concentrating when information is explained to them. Primary and secondary care clinicians, managers and commissioners should consider arranging services flexibly to promote access and avoid exacerbating social anxiety disorder symptoms by offering: appointments at times when the service is least crowded or busy appointments before or after normal hours, or at home initially self-check-in and other ways to reduce distress on arrival -pportunities to complete forms or paperwork before or after an appointment in a private space support with concerns related to social anxiety (for example, using public transport) a choice of professional if possible. When a person with social anxiety disorder is first offered an appointment, in particular in specialist services, provide clear information in a letter about: where to go on arrival and where they can wait (offer the use of a private waiting area or the option to wait elsewhere, for example outside the service's premises) location of facilities available at the service (for example, the car park and toilets) what will happen and what will not happen during assessment and treatment. When the person arrives for the appointment, offer to meet or alert them (for example, by text message) when their appointment is about to begin. Be aware that changing healthcare professionals or services may be particularly stressful for people with social anxiety disorder. Minimise such disruptions, discuss concerns beforehand and provide detailed information about any changes, especially those that were not requested by the service user. For people with social anxiety disorder using inpatient mental health or medical services, arrange meals, activities and accommodation by: regularly discussing how such provisions fit into their treatment plan and their preferences providing the opportunity for them to eat on their own if they find eating with others too distressing providing a choice of activities they can do on their own or with others. Offer to provide treatment in settings where children and young people with social anxiety disorder and their parents or carers feel most comfortable, for example, at home or in schools or community centres. Consider providing childcare (for example, for siblings) to support parent and carer involvement. If possible, organise appointments in a way that does not interfere with school or other peer and social activities. ## Communication When assessing a person with social anxiety disorder: suggest that they communicate with you in the manner they find most comfortable, including writing (for example, in a letter or questionnaire) -ffer to communicate with them by phone call, text and email make sure they have opportunities to ask any questions and encourage them to do so provide opportunities for them to make and change appointments by various means, including text, email or phone. When communicating with children and young people and their parents or carers: take into account the child or young person's developmental level, emotional maturity and cognitive capacity, including any learning disabilities, sight or hearing problems and delays in language development be aware that children who are socially anxious may be reluctant to speak to an unfamiliar person, and that children with a potential diagnosis of selective mutism may be unable to speak at all during assessment or treatment; accept information from parents or carers, but ensure that the child or young person is given the opportunity to answer for themselves, through writing, drawing or speaking through a parent or carer if necessary use plain language if possible and clearly explain any clinical terms check that the child or young person and their parents or carers understand what is being said use communication aids (such as pictures, symbols, large print, braille, different languages or sign language) if needed. ## Competence Healthcare, social care and educational professionals working with children and young people should be trained and skilled in: negotiating and working with parents and carers, including helping parents with relationship difficulties find support managing issues related to information sharing and confidentiality as these apply to children and young people referring children with possible social anxiety disorder to appropriate services. ## Consent and confidentiality If the young person is 'Gillick competent' seek their consent before speaking to their parents or carers. When working with children and young people and their parents or carers: make sure that discussions take place in settings in which confidentiality, privacy and dignity are respected be clear with the child or young person and their parents or carers about limits of confidentiality (that is, which health and social care professionals have access to information about their diagnosis and its treatment and in what circumstances this may be shared with others). . Ensure that children and young people and their parents or carers understand the purpose of any meetings and the reasons for sharing information. Respect their rights to confidentiality throughout the process and adapt the content and duration of meetings to take into account the impact of the social anxiety disorder on the child or young person's participation. ## Working with parents and carers If a parent or carer cannot attend meetings for assessment or treatment, ensure that written information is provided and shared with them. If parents or carers are involved in the assessment or treatment of a young person with social anxiety disorder, discuss with the young person (taking into account their developmental level, emotional maturity and cognitive capacity) what form they would like this involvement to take. Such discussions should take place at intervals to take account of any changes in circumstances, including developmental level, and should not happen only once. As the involvement of parents and carers can be quite complex, staff should receive training in the skills needed to negotiate and work with parents and carers, and also in managing issues relating to information sharing and confidentiality.. Offer parents and carers an assessment of their own needs (see NICE's guideline on supporting adult carers) including: personal, social and emotional support support in their caring role, including emergency plans advice on and help with obtaining practical support. Maintain links with adult mental health services so that referrals for any mental health needs of parents or carers can be made quickly and smoothly. # Identification and assessment of adults ## Identification of adults with possible social anxiety disorder Ask the identification questions for anxiety disorders in line with recommendation 1.3.1.2 in the NICE guideline on common mental health problems, and if social anxiety disorder is suspected: use the 3-item Mini-Social Phobia Inventory (Mini-SPIN) or consider asking the following 2 questions: Do you find yourself avoiding social situations or activities? Are you fearful or embarrassed in social situations? If the person scores 6 or more on the Mini-SPIN, or answers yes to either of the 2 questions above, refer for or conduct a comprehensive assessment for social anxiety disorder (see recommendations 1.2.5 to 1.2.9). If the identification questions (see recommendation 1.2.1) indicate possible social anxiety disorder, but the practitioner is not competent to perform a mental health assessment, refer the person to an appropriate healthcare professional. If this professional is not the person's GP, inform the GP of the referral. If the identification questions (see recommendation 1.2.1) indicate possible social anxiety disorder, a practitioner who is competent to perform a mental health assessment should review the person's mental state and associated functional, interpersonal and social difficulties. ## Assessment of adults with possible social anxiety disorder If an adult with possible social anxiety disorder finds it difficult or distressing to attend an initial appointment in person, consider making the first contact by phone or internet, but aim to see the person face to face for subsequent assessments and treatment. When assessing an adult with possible social anxiety disorder: conduct an assessment that considers fear, avoidance, distress and functional impairment be aware of comorbid disorders, including avoidant personality disorder, alcohol and substance misuse, mood disorders, other anxiety disorders, psychosis and autism. Follow the recommendations in the NICE guideline on common mental health problems for the structure and content of the assessment and adjust them to take into account the need to obtain a more detailed description of the social anxiety disorder (see recommendation 1.2.8 in this guideline). Consider using the following to inform the assessment and support the evaluation of any intervention: a diagnostic or problem identification tool as recommended in recommendation 1.3.2.3 in the NICE guideline on common mental health problems a validated measure for social anxiety, for example, the Social Phobia Inventory (SPIN) or the Liebowitz Social Anxiety Scale (LSAS). Obtain a detailed description of the person's current social anxiety and associated problems and circumstances including: feared and avoided social situations what they are afraid might happen in social situations (for example, looking anxious, blushing, sweating, trembling or appearing boring) anxiety symptoms view of self content of self-image safety-seeking behaviours focus of attention in social situations anticipatory and post-event processing -ccupational, educational, financial and social circumstances medication, alcohol and recreational drug use. If a person with possible social anxiety disorder does not return after an initial assessment, contact them (using their preferred method of communication) to discuss the reason for not returning. Remove any obstacles to further assessment or treatment that the person identifies. ## Planning treatment for adults diagnosed with social anxiety disorder After diagnosis of social anxiety disorder in an adult, identify the goals for treatment and provide information about the disorder and its treatment including: the nature and course of the disorder and commonly occurring comorbidities the impact on social and personal functioning commonly held beliefs about the cause of the disorder beliefs about what can be changed or treated choice and nature of evidence-based treatments. If the person also has symptoms of depression, assess their nature and extent and determine their functional link with the social anxiety disorder by asking them which existed first. If the person has only experienced significant social anxiety since the start of a depressive episode, treat the depression in line with recommendations in the NICE guideline on depression in adults. If the social anxiety disorder preceded the onset of depression, ask: "if I gave you a treatment that ensured you were no longer anxious in social situations, would you still be depressed?" If the person answers 'no', treat the social anxiety (unless the severity of the depression prevents this, then offer initial treatment for the depression). If the person answers 'yes', consider treating both the social anxiety disorder and the depression, taking into account their preference when deciding which to treat first. If the depression is treated first, treat the social anxiety disorder when improvement in the depression allows. For people (including young people) with social anxiety disorder who misuse substances, be aware that alcohol or drug misuse is often an attempt to reduce anxiety in social situations and should not preclude treatment for social anxiety disorder. Assess the nature of the substance misuse to determine if it is primarily a consequence of social anxiety disorder and: -ffer a brief intervention for hazardous alcohol or drug misuse (see the NICE guideline on alcohol-use disorders or drug misuse in over 16s) for harmful or dependent alcohol or drug misuse consider referral to a specialist alcohol or drug misuse service. # Interventions for adults with social anxiety disorder ## Treatment principles All interventions for adults with social anxiety disorder should be delivered by competent practitioners. Psychological interventions should be based on the relevant treatment manual(s), which should guide the structure and duration of the intervention. Practitioners should consider using competence frameworks developed from the relevant treatment manual(s) and for all interventions should: receive regular, high-quality outcome-informed supervision use routine sessional outcome measures (for example, the SPIN or LSAS) and ensure that the person with social anxiety is involved in reviewing the efficacy of the treatment engage in monitoring and evaluation of treatment adherence and practitioner competence – for example, by using video and audio tapes, and external audit and scrutiny if appropriate. ## Initial treatment options for adults with social anxiety disorder Offer adults with social anxiety disorder individual cognitive behavioural therapy (CBT) that has been specifically developed to treat social anxiety disorder (based on the Clark and Wells model or the Heimberg model; see recommendations 1.3.13 and 1.3.14 in the section on delivering psychological interventions for adults). Do not routinely offer group CBT in preference to individual CBT. Although there is evidence that group CBT is more effective than most other interventions, it is less clinically and cost effective than individual CBT. For adults who decline CBT and wish to consider another psychological intervention, offer CBT-based supported self-help (see recommendation 1.3.15 in the section on delivering psychological interventions for adults). For adults who decline cognitive behavioural interventions and express a preference for a pharmacological intervention, discuss their reasons for declining cognitive behavioural interventions and address any concerns. If the person wishes to proceed with a pharmacological intervention, offer a selective serotonin reuptake inhibitor (SSRI) (escitalopram or sertraline). Monitor the person carefully for adverse reactions (see recommendations 1.3.17 to 1.3.23 in the section on prescribing and monitoring pharmacological interventions in adults). For adults who decline cognitive behavioural and pharmacological interventions, consider short-term psychodynamic psychotherapy that has been specifically developed to treat social anxiety disorder (see recommendation 1.3.16 in the section on delivering psychological interventions for adults). Be aware of the more limited clinical effectiveness and lower cost effectiveness of this intervention compared with CBT, self-help and pharmacological interventions. ## Options for adults with no or a partial response to initial treatment For adults whose symptoms of social anxiety disorder have only partially responded to individual CBT after an adequate course of treatment, consider a pharmacological intervention (see recommendation 1.3.6 in the section on initial treatment options for adults with social anxiety disorder) in combination with individual CBT. For adults whose symptoms have only partially responded to an SSRI (escitalopram or sertraline) after 10 to 12 weeks of treatment, offer individual CBT in addition to the SSRI. For adults whose symptoms have not responded to an SSRI (escitalopram or sertraline) or who cannot tolerate the side effects, offer an alternative SSRI (fluvoxamine or paroxetine) or a serotonin noradrenaline reuptake inhibitor (SNRI) (venlafaxine), taking into account: the tendency of paroxetine and venlafaxine to produce a discontinuation syndrome (which may be reduced by extended-release preparations) the risk of suicide and likelihood of toxicity in overdose. At the time of publication (May 2013) fluvoxamine did not have a UK marketing authorisation for use in adults with social anxiety disorder. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. For adults whose symptoms have not responded to an alternative SSRI or an SNRI, offer a monoamine oxidase inhibitor (phenelzine or moclobemide). At the time of publication (May 2013) phenelzine did not have a UK marketing authorisation for use in adults with social anxiety disorder. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. Discuss the option of individual CBT with adults whose symptoms have not responded to pharmacological interventions. ## Delivering psychological interventions for adults Individual CBT (the Clark and Wells model) for social anxiety disorder should consist of up to 14 sessions of 90 minutes' duration over approximately 4 months and include the following: education about social anxiety experiential exercises to demonstrate the adverse effects of self-focused attention and safety-seeking behaviours video feedback to correct distorted negative self-imagery systematic training in externally focused attention within-session behavioural experiments to test negative beliefs with linked homework assignments discrimination training or rescripting to deal with problematic memories of social trauma examination and modification of core beliefs modification of problematic pre- and post-event processing relapse prevention. Individual CBT (the Heimberg model) for social anxiety disorder should consist of 15 sessions of 60 minutes' duration, and 1 session of 90 minutes for exposure, over approximately 4 months, and include the following: education about social anxiety cognitive restructuring graduated exposure to feared social situations, both within treatment sessions and as homework examination and modification of core beliefs relapse prevention. Supported self-help for social anxiety disorder should consist of: typically up to 9 sessions of supported use of a CBT-based self-help book over 3−4 months support to use the materials, either face to face or by telephone, for a total of 3 hours over the course of the treatment. Short-term psychodynamic psychotherapy for social anxiety disorder should consist of typically up to 25−30 sessions of 50 minutes' duration over 6−8 months and include the following: education about social anxiety disorder establishing a secure positive therapeutic alliance to modify insecure attachments a focus on a core conflictual relationship theme associated with social anxiety symptoms a focus on shame encouraging exposure to feared social situations outside therapy sessions support to establish a self-affirming inner dialogue help to improve social skills. ## Prescribing and monitoring pharmacological interventions in adults For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. Before prescribing a pharmacological intervention for social anxiety disorder, discuss the treatment options and any concerns the person has about taking medication. Explain fully the reasons for prescribing and provide written and verbal information on: the likely benefits of different drugs the different propensities of each drug for side effects, discontinuation syndromes and drug interactions the risk of early activation symptoms with SSRIs and SNRIs, such as increased anxiety, agitation, jitteriness and problems sleeping the gradual development, over 2 weeks or more, of the full anxiolytic effect the importance of taking medication as prescribed, reporting side effects and discussing any concerns about stopping medication with the prescriber, and the need to continue treatment after remission to avoid relapse. Arrange to see people aged 30 years and older who are not assessed to be at risk of suicide within 1 to 2 weeks of first prescribing SSRIs or SNRIs to: discuss any possible side effects and potential interaction with symptoms of social anxiety disorder (for example, increased restlessness or agitation) advise and support them to engage in graduated exposure to feared or avoided social situations. After the initial meeting (see recommendation 1.3.18), arrange to see the person every 2–4 weeks during the first 3 months of treatment and every month thereafter. Continue to support them to engage in graduated exposure to feared or avoided social situations. For people aged under 30 years who are offered an SSRI or SNRI: warn them that these drugs are associated with an increased risk of suicidal thinking and self-harm in a minority of people under 30 and see them within 1 week of first prescribing and monitor the risk of suicidal thinking and self-harm weekly for the first month. . Arrange to see people who are assessed to be at risk of suicide weekly until there is no indication of increased suicide risk, then every 2–4 weeks during the first 3 months of treatment and every month thereafter. Continue to support them to engage in graduated exposure to feared or avoided social situations. Advise people taking a monoamine oxidase inhibitor of the dietary and pharmacological restrictions concerning the use of these drugs as set out in the British National Formulary. For people who develop side effects soon after starting a pharmacological intervention, provide information and consider 1 of the following strategies: monitoring the person's symptoms closely (if the side effects are mild and acceptable to the person) reducing the dose of the drug stopping the drug and offering either an alternative drug or individual CBT, according to the person's preference.. If the person's symptoms of social anxiety disorder have responded well to a pharmacological intervention in the first 3 months, continue it for at least a further 6 months. When stopping a pharmacological intervention, reduce the dose of the drug gradually. If symptoms reappear after the dose is lowered or the drug is stopped, consider increasing the dose, reintroducing the drug or offering individual CBT. # Identification and assessment of children and young people ## Identification of children and young people with possible social anxiety disorder Health and social care professionals in primary care and education and community settings should be alert to possible anxiety disorders in children and young people, particularly those who avoid school, social or group activities or talking in social situations, or are irritable, excessively shy or overly reliant on parents or carers. Consider asking the child or young person about their feelings of anxiety, fear, avoidance, distress and associated behaviours (or a parent or carer) to help establish if social anxiety disorder is present, using these questions: "Sometimes people get very scared when they have to do things with other people, especially people they don't know. They might worry about doing things with other people watching. They might get scared that they will do something silly or that people will make fun of them. They might not want to do these things or, if they have to do them, they might get very upset or cross." "Do you/does your child get scared about doing things with other people, like talking, eating, going to parties, or other things at school or with friends?" "Do you/does your child find it difficult to do things when other people are watching, like playing sport, being in plays or concerts, asking or answering questions, reading aloud, or giving talks in class?" "Do you/does your child ever feel that you/your child can't do these things or try to get out of them?" If the child or young person (or a parent or carer) answers 'yes' to one or more of the questions in recommendation 1.4.1 consider a comprehensive assessment for social anxiety disorder (see recommendations 1.4.5 to 1.4.11 in the section on assessment of children and young people with possible social anxiety disorder). If the identification questions (see recommendation 1.4.1 in the section on identification of children and young people with possible social anxiety disorder) indicate possible social anxiety disorder, but the practitioner is not competent to perform a mental health assessment, refer the child or young person to an appropriate healthcare professional. If this professional is not the child or young person's GP, inform the GP of the referral. If the identification questions (see recommendation 1.4.1 in the section on identification of children and young people with possible social anxiety disorder) indicate possible social anxiety disorder, a practitioner who is competent to perform a mental health assessment should review the child or young person's mental state and associated functional, interpersonal and social difficulties. ## Assessment of children and young people with possible social anxiety disorder A comprehensive assessment of a child or young person with possible social anxiety disorder should: provide an opportunity for the child or young person to be interviewed alone at some point during the assessment if possible involve a parent, carer or other adult known to the child or young person who can provide information about current and past behaviour if necessary involve more than one professional to ensure a comprehensive assessment can be undertaken. When assessing a child or young person obtain a detailed description of their current social anxiety and associated problems including: feared and avoided social situations what they are afraid might happen in social situations (for example, looking anxious, blushing, sweating, trembling or appearing boring) anxiety symptoms view of self content of self-image safety-seeking behaviours focus of attention in social situations anticipatory and post-event processing, particularly for older children family circumstances and support friendships and peer groups, educational and social circumstances medication, alcohol and recreational drug use. As part of a comprehensive assessment, assess for causal and maintaining factors for social anxiety disorder in the child or young person's home, school and social environment, in particular: parenting behaviours that promote and support anxious behaviours or do not support positive behaviours peer victimisation in school or other settings. As part of a comprehensive assessment, assess for possible coexisting conditions such as: -ther mental health problems (for example, other anxiety disorders and depression) neurodevelopmental conditions such as attention deficit hyperactivity disorder, autism and learning disabilities drug and alcohol misuse (see recommendation 1.2.12 in the section on planning treatment for adults diagnosed with social anxiety disorder) speech and language problems. To aid the assessment of social anxiety disorder and other common mental health problems consider using formal instruments (both the child and parent versions if available and indicated), such as: the LSAS – child version or the Social Phobia and Anxiety Inventory for Children (SPAI-C) for children, or the SPIN or the LSAS for young people the Multidimensional Anxiety Scale for Children (MASC), the Revised Child Anxiety and Depression Scale (RCADS) for children and young people who may have comorbid depression or other anxiety disorders, the Spence Children's Anxiety Scale (SCAS) or the Screen for Child Anxiety Related Emotional Disorders (SCARED) for children. Use formal assessment instruments to aid the diagnosis of other problems, such as: a validated measure of cognitive ability for a child or young person with a suspected learning disability the Strengths and Difficulties Questionnaire for all children and young people. Assess the risks and harm faced by the child or young person and if needed develop a risk management plan for risk of self-neglect, familial abuse or neglect, exploitation by others, self-harm or harm to others. Develop a profile of the child or young person to identify their needs and any further assessments that may be needed, including the extent and nature of: the social anxiety disorder and any associated difficulties (for example, selective mutism) any coexisting mental health problems neurodevelopmental conditions such as attention deficit hyperactivity disorder, autism and learning disabilities experience of bullying or social ostracism friendships with peers speech, language and communication skills physical health problems personal and social functioning to indicate any needs (personal, social, housing, educational and occupational) educational and occupational goals parent or carer needs, including mental health needs. # Interventions for children and young people with social anxiety disorder ## Treatment principles All interventions for children and young people with social anxiety disorder should be delivered by competent practitioners. Psychological interventions should be based on the relevant treatment manual(s), which should guide the structure and duration of the intervention. Practitioners should consider using competence frameworks developed from the relevant treatment manual(s) and for all interventions should: receive regular high-quality supervision use routine sessional outcome measures, for example: the LSAS – child version or the SPAI-C, and the SPIN or LSAS for young people the MASC, RCADS, SCAS or SCARED for children engage in monitoring and evaluation of treatment adherence and practitioner competence – for example, by using video and audio tapes, and external audit and scrutiny if appropriate. Be aware of the impact of the home, school and wider social environments on the maintenance and treatment of social anxiety disorder. Maintain a focus on the child or young person's emotional, educational and social needs and work with parents, teachers, other adults and the child or young person's peers to create an environment that supports the achievement of the agreed goals of treatment. ## Treatment for children and young people with social anxiety disorder Offer individual or group CBT focused on social anxiety (see recommendations 1.5.4 and 1.5.5) to children and young people with social anxiety disorder. Consider involving parents or carers to ensure the effective delivery of the intervention, particularly in young children. ## Delivering psychological interventions for children and young people Individual CBT should consist of the following, taking into account the child or young person's cognitive and emotional maturity: −12 sessions of 45 minutes' duration psychoeducation, exposure to feared or avoided social situations, training in social skills and opportunities to rehearse skills in social situations psychoeducation and skills training for parents, particularly of young children, to promote and reinforce the child's exposure to feared or avoided social situations and development of skills. Group CBT should consist of the following, taking into account the child or young person's cognitive and emotional maturity: −12 sessions of 90 minutes' duration with groups of children or young people of the same age range psychoeducation, exposure to feared or avoided social situations, training in social skills and opportunities to rehearse skills in social situations psychoeducation and skills training for parents, particularly of young children, to promote and reinforce the child's exposure to feared or avoided social situations and development of skills. Consider psychological interventions that were developed for adults (see the section on interventions for adults with social anxiety disorder) for young people (typically aged 15 years and older) who have the cognitive and emotional capacity to undertake a treatment developed for adults. # Interventions that are not recommended to treat social anxiety disorder Do not routinely offer pharmacological interventions to treat social anxiety disorder in children and young people. Do not routinely offer anticonvulsants, tricyclic antidepressants, benzodiazepines or antipsychotic medication to treat social anxiety disorder in adults. Do not routinely offer mindfulness-based interventions or supportive therapy to treat social anxiety disorder.Mindfulness-based interventions include mindfulness-based stress reduction and mindfulness-based cognitive therapy. Do not offer St John's wort or other over-the-counter medications and preparations for anxiety to treat social anxiety disorder. Explain the potential interactions with other prescribed and over-the-counter medications and the lack of evidence to support their safe use. Do not offer botulinum toxin to treat hyperhidrosis (excessive sweating) in people with social anxiety disorder. This is because there is no good-quality evidence showing benefit from botulinum toxin in the treatment of social anxiety disorder and it may be harmful. Do not offer endoscopic thoracic sympathectomy to treat hyperhidrosis or facial blushing in people with social anxiety disorder. This is because there is no good-quality evidence showing benefit from endoscopic thoracic sympathectomy in the treatment of social anxiety disorder and it may be harmful. # Specific phobias ## Interventions that are not recommended Do not routinely offer computerised CBT to treat specific phobias in adults.# Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. # Adults' uptake of and engagement with interventions for social anxiety disorder What methods are effective in improving uptake of and engagement with interventions for adults with social anxiety disorder? ## Why this is important Effective interventions exist for social anxiety disorder but access to and uptake of services is limited and over 50% of people with social anxiety disorder never receive treatment; of those who do receive treatment many wait 10 years or more for it. This question should be addressed by a programme of work that tests a number of strategies to improve uptake and engagement, including: Development and evaluation of improved pathways into care, in collaboration with low users of services, through a series of cohort studies with the outcomes including increased uptake of and retention in services. Adapting the delivery of existing interventions for social anxiety disorder in collaboration with service users. Adaptations could include changes to the settings for, methods of delivery of, or staff delivering the interventions. These interventions should be tested in a randomised controlled trial (RCT) design that reports short- and medium-term outcomes (including cost effectiveness) of at least 18 months' duration. # Specific versus generic CBT for children and young people with social anxiety disorder What is the clinical and cost effectiveness of specific CBT for children and young people with social anxiety disorder compared with generic anxiety-focused CBT? ## Why this is important Children and young people with social anxiety disorder have commonly been treated with psychological interventions that cover a broad range of anxiety disorders, rather than interventions specifically focused on social anxiety disorder. This approach may be considered to be easier and cheaper to deliver, but emerging evidence suggests that children and young people with social anxiety disorder may do less well with these generic treatments than those with other anxiety disorders. There have, however, been no direct comparisons of treatment outcomes using generic compared with social anxiety-specific treatment programmes. This question should be answered using an RCT design, reporting short- and medium-term outcomes (including cost-effectiveness) with a follow-up of at least 12 months. The outcomes should be assessed by structured clinical interviews, parent- and self-reports using validated questionnaires and objective measures of behaviour. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators (in particular the child or young person's age) should be investigated. # The role of parents in the treatment of children and young people with social anxiety disorder What is the best way of involving parents in the treatment of children and young people (at different stages of development) with social anxiety disorder? ## Why this is important There is very little evidence to guide the treatment of social anxiety disorder in children aged under 7 years. It is likely that treatment will be most effectively delivered either wholly or partly by parents. Parenting interventions have been effective in treating other psychological difficulties in this age group, and this guideline found emerging evidence that these approaches might be useful for the treatment of young socially anxious children. Furthermore, when considering all age groups, parental mental health difficulties and parenting practices have been linked with the development and maintenance of social anxiety disorder in children and young people. This suggests that interventions targeting these parental factors may improve treatment outcomes. However, interventions for children and young people with social anxiety disorder have varied widely in the extent and manner in which parents are involved in treatment and the benefit of including parents in interventions has not been established. This question should be addressed in 2 stages. Parent-focused interventions should be developed based on a systematic review of the literature and in collaboration with service users. The clinical and cost effectiveness of these interventions at different stages of development should be tested using an RCT design with standard care (for example, group CBT) as the comparison. It should report short- and medium-term outcomes (including cost effectiveness) with a follow-up of at least 12 months. The outcomes should be assessed by structured clinical interviews, parent- and self-reports using validated questionnaires and objective measures of behaviour. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators (in particular the child or young person's age) should be investigated. # Individual versus group CBT for children and young people with social anxiety disorder What is the clinical and cost effectiveness of individual and group CBT for children and young people with social anxiety disorder? ## Why this is important The majority of systematic evaluations of interventions for social anxiety disorder in children and young people have taken a group approach. Studies with adult populations, however, indicate that individually-delivered treatments are associated with better treatment outcomes and are more cost effective. This question should be addressed using an RCT design comparing the clinical and cost effectiveness of individual and group-based treatments for children and young people with social anxiety disorder. It should report short- and medium-term outcomes (including cost effectiveness) with a follow-up of at least 12 months. The outcomes should be assessed by structured clinical interviews, parent- and self-reports using validated questionnaires and objective measures of behaviour. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators (in particular the child or young person's age and familial and social context) should be investigated. # Combined interventions for adults with social anxiety disorder What is the clinical and cost effectiveness of combined psychological and pharmacological interventions compared with either intervention alone in the treatment of adults with social anxiety disorder? ## Why this is important There is evidence for the effectiveness of both CBT and medication, in particular SSRIs, in the treatment of social anxiety disorder. However, little is known about the effects of combined pharmacological and psychological interventions despite their widespread use. Understanding the costs and benefits of combined treatment could lead to more effective and targeted combinations if they prove to be more effective than single treatments. The study will also provide important information on the long-term benefits of medication. This question should be addressed in a large-scale 3-arm RCT comparing the clinical and cost effectiveness of combined individual CBT and SSRI treatment with individual CBT or an SSRI alone. Trial participants receiving medication should be offered it for 1 year. The study should report short- and medium-term outcomes (including cost effectiveness) with a follow-up of at least 24 months. The primary outcome should be recovery, with important secondary outcomes being retention in treatment, experience and side effects of medication, and social and personal functioning. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators should be investigated.	{'Introduction': "This guidance updates and replaces the section of NICE technology appraisal guidance\xa097 (published February\xa02006) that deals with phobia.\n\nSocial anxiety disorder (previously known as 'social phobia') is one of the most common of the anxiety disorders. Estimates of lifetime prevalence vary but according to a US study, 12% of adults in the US will have social anxiety disorder at some point in their lives, compared with estimates of around 6% for generalised anxiety disorder (GAD), 5% for panic disorder, 7% for post-traumatic stress disorder (PTSD) and 2% for obsessive–compulsive disorder. There is a significant degree of comorbidity between social anxiety disorder and other mental health problems, most notably depression (19%), substance-use disorder (17%), GAD (5%), panic disorder (6%), and PTSD (3%).\n\nSocial anxiety disorder is persistent fear of or anxiety about one or more social or performance situations that is out of proportion to the actual threat posed by the situation. Typical situations that might be anxiety-provoking include meeting people, including strangers, talking in meetings or in groups, starting conversations, talking to authority figures, working, eating or drinking while being observed, going to school, going shopping, being seen in public, using public toilets and public performances such as public speaking. Although worries about some of these situations are common in the general population, people with social anxiety disorder worry excessively about them at the time and before and afterwards. They fear that they will do or say something that they think will be humiliating or embarrassing (such as blushing, sweating, appearing boring or stupid, shaking, appearing incompetent, looking anxious). Social anxiety disorder can have a great impact on a person's functioning, disrupting normal life, interfering with social relationships and quality of life and impairing performance at work or school. People with the disorder may misuse alcohol or drugs to try to reduce their anxiety (and alleviate depression).\n\nChildren may show their anxiety in different ways from adults: as well as shrinking from interactions, they may be more likely to cry, freeze or have tantrums. They may also be less likely to acknowledge that their fears are irrational when they are away from a social situation. Particular situations that can cause difficulty for socially anxious children and young people include participating in classroom activities, asking for help in class, joining activities with peers (such as attending parties or clubs), and being involved in school performances.\n\nSocial anxiety disorder has an early median age of onset (13\xa0years) and is one of the most persistent anxiety disorders. Despite the extent of distress and impairment, only about half of those with the disorder ever seek treatment, and those who do generally only seek treatment after 15–20\xa0years of symptoms. A significant number of people who develop social anxiety disorder in adolescence may recover before reaching adulthood. However, if the disorder has persisted into adulthood, the chance of recovery in the absence of treatment is modest when compared with many other common mental health problems.\n\nEffective psychological and pharmacological interventions for social anxiety disorder exist but may not be accessed due to poor recognition, inadequate assessment and limited awareness or availability of treatments. Social anxiety disorder is under-recognised in primary care. When it coexists with depression the depressive episode may be recognised without detecting the underlying and more persistent social anxiety disorder. The early age of onset means that recognition in educational settings is also challenging.\n\nSome recommendations in this guideline have been adapted from recommendations in other NICE clinical guidance. In these cases the Guideline Development Group was careful to preserve the meaning and intent of the original recommendations. Changes to wording or structure were made to fit the recommendations into this guideline. The original sources of the adapted recommendations are shown in the recommendations.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual service users.\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The service user (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.", 'Recommendations': 'People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nThe recommendations relate to children and young people (from school age to 17\xa0years) and adults (aged 18\xa0years and older).\n\n# General principles of care in mental health and general medical settings\n\n## Improving access to services\n\nBe aware that people with social anxiety disorder may:\n\nnot know that social anxiety disorder is a recognised condition and can be effectively treated\n\nperceive their social anxiety as a personal flaw or failing\n\nbe vulnerable to stigma and embarrassment\n\navoid contact with and find it difficult or distressing to interact with healthcare professionals, staff and other service users\n\navoid disclosing information, asking and answering questions and making complaints\n\nhave difficulty concentrating when information is explained to them.\n\nPrimary and secondary care clinicians, managers and commissioners should consider arranging services flexibly to promote access and avoid exacerbating social anxiety disorder symptoms by offering:\n\nappointments at times when the service is least crowded or busy\n\nappointments before or after normal hours, or at home initially\n\nself-check-in and other ways to reduce distress on arrival\n\nopportunities to complete forms or paperwork before or after an appointment in a private space\n\nsupport with concerns related to social anxiety (for example, using public transport)\n\na choice of professional if possible.\n\nWhen a person with social anxiety disorder is first offered an appointment, in particular in specialist services, provide clear information in a letter about:\n\nwhere to go on arrival and where they can wait (offer the use of a private waiting area or the option to wait elsewhere, for example outside the service\'s premises)\n\nlocation of facilities available at the service (for example, the car park and toilets)\n\nwhat will happen and what will not happen during assessment and treatment. When the person arrives for the appointment, offer to meet or alert them (for example, by text message) when their appointment is about to begin.\n\nBe aware that changing healthcare professionals or services may be particularly stressful for people with social anxiety disorder. Minimise such disruptions, discuss concerns beforehand and provide detailed information about any changes, especially those that were not requested by the service user.\n\nFor people with social anxiety disorder using inpatient mental health or medical services, arrange meals, activities and accommodation by:\n\nregularly discussing how such provisions fit into their treatment plan and their preferences\n\nproviding the opportunity for them to eat on their own if they find eating with others too distressing\n\nproviding a choice of activities they can do on their own or with others.\n\nOffer to provide treatment in settings where children and young people with social anxiety disorder and their parents or carers feel most comfortable, for example, at home or in schools or community centres.\n\nConsider providing childcare (for example, for siblings) to support parent and carer involvement.\n\nIf possible, organise appointments in a way that does not interfere with school or other peer and social activities.\n\n## Communication\n\nWhen assessing a person with social anxiety disorder:\n\nsuggest that they communicate with you in the manner they find most comfortable, including writing (for example, in a letter or questionnaire)\n\noffer to communicate with them by phone call, text and email\n\nmake sure they have opportunities to ask any questions and encourage them to do so\n\nprovide opportunities for them to make and change appointments by various means, including text, email or phone.\n\nWhen communicating with children and young people and their parents or carers:\n\ntake into account the child or young person\'s developmental level, emotional maturity and cognitive capacity, including any learning disabilities, sight or hearing problems and delays in language development\n\nbe aware that children who are socially anxious may be reluctant to speak to an unfamiliar person, and that children with a potential diagnosis of selective mutism may be unable to speak at all during assessment or treatment; accept information from parents or carers, but ensure that the child or young person is given the opportunity to answer for themselves, through writing, drawing or speaking through a parent or carer if necessary\n\nuse plain language if possible and clearly explain any clinical terms\n\ncheck that the child or young person and their parents or carers understand what is being said\n\nuse communication aids (such as pictures, symbols, large print, braille, different languages or sign language) if needed.\n\n## Competence\n\nHealthcare, social care and educational professionals working with children and young people should be trained and skilled in:\n\nnegotiating and working with parents and carers, including helping parents with relationship difficulties find support\n\nmanaging issues related to information sharing and confidentiality as these apply to children and young people\n\nreferring children with possible social anxiety disorder to appropriate services.\n\n## Consent and confidentiality\n\nIf the young person is \'Gillick competent\' seek their consent before speaking to their parents or carers.\n\nWhen working with children and young people and their parents or carers:\n\nmake sure that discussions take place in settings in which confidentiality, privacy and dignity are respected\n\nbe clear with the child or young person and their parents or carers about limits of confidentiality (that is, which health and social care professionals have access to information about their diagnosis and its treatment and in what circumstances this may be shared with others). [This recommendation is adapted from the NICE guideline on service user experience in adult mental health].\n\nEnsure that children and young people and their parents or carers understand the purpose of any meetings and the reasons for sharing information. Respect their rights to confidentiality throughout the process and adapt the content and duration of meetings to take into account the impact of the social anxiety disorder on the child or young person\'s participation.\n\n## Working with parents and carers\n\nIf a parent or carer cannot attend meetings for assessment or treatment, ensure that written information is provided and shared with them.\n\nIf parents or carers are involved in the assessment or treatment of a young person with social anxiety disorder, discuss with the young person (taking into account their developmental level, emotional maturity and cognitive capacity) what form they would like this involvement to take. Such discussions should take place at intervals to take account of any changes in circumstances, including developmental level, and should not happen only once. As the involvement of parents and carers can be quite complex, staff should receive training in the skills needed to negotiate and work with parents and carers, and also in managing issues relating to information sharing and confidentiality.[This recommendation is adapted from the NICE guideline on service user experience in adult mental health].\n\nOffer parents and carers an assessment of their own needs (see NICE\'s guideline on supporting adult carers) including:\n\npersonal, social and emotional support\n\nsupport in their caring role, including emergency plans\n\nadvice on and help with obtaining practical support.\n\nMaintain links with adult mental health services so that referrals for any mental health needs of parents or carers can be made quickly and smoothly.\n\n# Identification and assessment of adults\n\n## Identification of adults with possible social anxiety disorder\n\nAsk the identification questions for anxiety disorders in line with recommendation\xa01.3.1.2 in the NICE guideline on common mental health problems, and if social anxiety disorder is suspected:\n\nuse the 3-item Mini-Social Phobia Inventory (Mini-SPIN) or\n\nconsider asking the following 2\xa0questions:\n\n\n\nDo you find yourself avoiding social situations or activities?\n\nAre you fearful or embarrassed in social situations? If the person scores 6 or more on the Mini-SPIN, or answers yes to either of the 2\xa0questions above, refer for or conduct a comprehensive assessment for social anxiety disorder (see recommendations\xa01.2.5 to 1.2.9).\n\n\n\nIf the identification questions (see recommendation\xa01.2.1) indicate possible social anxiety disorder, but the practitioner is not competent to perform a mental health assessment, refer the person to an appropriate healthcare professional. If this professional is not the person\'s GP, inform the GP of the referral.\n\nIf the identification questions (see recommendation\xa01.2.1) indicate possible social anxiety disorder, a practitioner who is competent to perform a mental health assessment should review the person\'s mental state and associated functional, interpersonal and social difficulties.\n\n## Assessment of adults with possible social anxiety disorder\n\nIf an adult with possible social anxiety disorder finds it difficult or distressing to attend an initial appointment in person, consider making the first contact by phone or internet, but aim to see the person face to face for subsequent assessments and treatment.\n\nWhen assessing an adult with possible social anxiety disorder:\n\nconduct an assessment that considers fear, avoidance, distress and functional impairment\n\nbe aware of comorbid disorders, including avoidant personality disorder, alcohol and substance misuse, mood disorders, other anxiety disorders, psychosis and autism.\n\nFollow the recommendations in the NICE guideline on common mental health problems for the structure and content of the assessment and adjust them to take into account the need to obtain a more detailed description of the social anxiety disorder (see recommendation\xa01.2.8 in this guideline).\n\nConsider using the following to inform the assessment and support the evaluation of any intervention:\n\na diagnostic or problem identification tool as recommended in recommendation\xa01.3.2.3 in the NICE guideline on common mental health problems\n\na validated measure for social anxiety, for example, the Social Phobia Inventory (SPIN) or the Liebowitz Social Anxiety Scale (LSAS).\n\nObtain a detailed description of the person\'s current social anxiety and associated problems and circumstances including:\n\nfeared and avoided social situations\n\nwhat they are afraid might happen in social situations (for example, looking anxious, blushing, sweating, trembling or appearing boring)\n\nanxiety symptoms\n\nview of self\n\ncontent of self-image\n\nsafety-seeking behaviours\n\nfocus of attention in social situations\n\nanticipatory and post-event processing\n\noccupational, educational, financial and social circumstances\n\nmedication, alcohol and recreational drug use.\n\nIf a person with possible social anxiety disorder does not return after an initial assessment, contact them (using their preferred method of communication) to discuss the reason for not returning. Remove any obstacles to further assessment or treatment that the person identifies.\n\n## Planning treatment for adults diagnosed with social anxiety disorder\n\nAfter diagnosis of social anxiety disorder in an adult, identify the goals for treatment and provide information about the disorder and its treatment including:\n\nthe nature and course of the disorder and commonly occurring comorbidities\n\nthe impact on social and personal functioning\n\ncommonly held beliefs about the cause of the disorder\n\nbeliefs about what can be changed or treated\n\nchoice and nature of evidence-based treatments.\n\nIf the person also has symptoms of depression, assess their nature and extent and determine their functional link with the social anxiety disorder by asking them which existed first.\n\nIf the person has only experienced significant social anxiety since the start of a depressive episode, treat the depression in line with recommendations in the NICE guideline on depression in adults.\n\nIf the social anxiety disorder preceded the onset of depression, ask: "if I gave you a treatment that ensured you were no longer anxious in social situations, would you still be depressed?"\n\n\n\nIf the person answers \'no\', treat the social anxiety (unless the severity of the depression prevents this, then offer initial treatment for the depression).\n\nIf the person answers \'yes\', consider treating both the social anxiety disorder and the depression, taking into account their preference when deciding which to treat first.\n\n\n\nIf the depression is treated first, treat the social anxiety disorder when improvement in the depression allows.\n\nFor people (including young people) with social anxiety disorder who misuse substances, be aware that alcohol or drug misuse is often an attempt to reduce anxiety in social situations and should not preclude treatment for social anxiety disorder. Assess the nature of the substance misuse to determine if it is primarily a consequence of social anxiety disorder and:\n\noffer a brief intervention for hazardous alcohol or drug misuse (see the NICE guideline on alcohol-use disorders or drug misuse in over 16s)\n\nfor harmful or dependent alcohol or drug misuse consider referral to a specialist alcohol or drug misuse service.\n\n# Interventions for adults with social anxiety disorder\n\n## Treatment principles\n\nAll interventions for adults with social anxiety disorder should be delivered by competent practitioners. Psychological interventions should be based on the relevant treatment manual(s), which should guide the structure and duration of the intervention. Practitioners should consider using competence frameworks developed from the relevant treatment manual(s) and for all interventions should:\n\nreceive regular, high-quality outcome-informed supervision\n\nuse routine sessional outcome measures (for example, the SPIN or LSAS) and ensure that the person with social anxiety is involved in reviewing the efficacy of the treatment\n\nengage in monitoring and evaluation of treatment adherence and practitioner competence – for example, by using video and audio tapes, and external audit and scrutiny if appropriate.\n\n## Initial treatment options for adults with social anxiety disorder\n\nOffer adults with social anxiety disorder individual cognitive behavioural therapy (CBT) that has been specifically developed to treat social anxiety disorder (based on the Clark and Wells model or the Heimberg model; see recommendations\xa01.3.13 and 1.3.14 in the section on delivering psychological interventions for adults).\n\nDo not routinely offer group CBT in preference to individual CBT. Although there is evidence that group CBT is more effective than most other interventions, it is less clinically and cost effective than individual CBT.\n\nFor adults who decline CBT and wish to consider another psychological intervention, offer CBT-based supported self-help (see recommendation\xa01.3.15 in the section on delivering psychological interventions for adults).\n\nFor adults who decline cognitive behavioural interventions and express a preference for a pharmacological intervention, discuss their reasons for declining cognitive behavioural interventions and address any concerns.\n\nIf the person wishes to proceed with a pharmacological intervention, offer a selective serotonin reuptake inhibitor (SSRI) (escitalopram or sertraline). Monitor the person carefully for adverse reactions (see recommendations\xa01.3.17 to 1.3.23 in the section on prescribing and monitoring pharmacological interventions in adults).\n\nFor adults who decline cognitive behavioural and pharmacological interventions, consider short-term psychodynamic psychotherapy that has been specifically developed to treat social anxiety disorder (see recommendation\xa01.3.16 in the section on delivering psychological interventions for adults). Be aware of the more limited clinical effectiveness and lower cost effectiveness of this intervention compared with CBT, self-help and pharmacological interventions.\n\n## Options for adults with no or a partial response to initial treatment\n\nFor adults whose symptoms of social anxiety disorder have only partially responded to individual CBT after an adequate course of treatment, consider a pharmacological intervention (see recommendation 1.3.6 in the section on initial treatment options for adults with social anxiety disorder) in combination with individual CBT.\n\nFor adults whose symptoms have only partially responded to an SSRI (escitalopram or sertraline) after 10 to 12\xa0weeks of treatment, offer individual CBT in addition to the SSRI.\n\nFor adults whose symptoms have not responded to an SSRI (escitalopram or sertraline) or who cannot tolerate the side effects, offer an alternative SSRI (fluvoxamine or paroxetine) or a serotonin noradrenaline reuptake inhibitor (SNRI) (venlafaxine), taking into account:\n\nthe tendency of paroxetine and venlafaxine to produce a discontinuation syndrome (which may be reduced by extended-release preparations)\n\nthe risk of suicide and likelihood of toxicity in overdose. At the time of publication (May 2013) fluvoxamine did not have a UK marketing authorisation for use in adults with social anxiety disorder. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council\'s Good practice in prescribing and managing medicines and devices for further information.\n\nFor adults whose symptoms have not responded to an alternative SSRI or an SNRI, offer a monoamine oxidase inhibitor (phenelzine or moclobemide). At the time of publication (May 2013) phenelzine did not have a UK marketing authorisation for use in adults with social anxiety disorder. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council\'s Good practice in prescribing and managing medicines and devices for further information.\n\nDiscuss the option of individual CBT with adults whose symptoms have not responded to pharmacological interventions.\n\n## Delivering psychological interventions for adults\n\nIndividual CBT (the Clark and Wells model) for social anxiety disorder should consist of up to 14 sessions of 90\xa0minutes\' duration over approximately 4\xa0months and include the following:\n\neducation about social anxiety\n\nexperiential exercises to demonstrate the adverse effects of self-focused attention and safety-seeking behaviours\n\nvideo feedback to correct distorted negative self-imagery\n\nsystematic training in externally focused attention\n\nwithin-session behavioural experiments to test negative beliefs with linked homework assignments\n\ndiscrimination training or rescripting to deal with problematic memories of social trauma\n\nexamination and modification of core beliefs\n\nmodification of problematic pre- and post-event processing\n\nrelapse prevention.\n\nIndividual CBT (the Heimberg model) for social anxiety disorder should consist of 15 sessions of 60\xa0minutes\' duration, and 1 session of 90 minutes for exposure, over approximately 4\xa0months, and include the following:\n\neducation about social anxiety\n\ncognitive restructuring\n\ngraduated exposure to feared social situations, both within treatment sessions and as homework\n\nexamination and modification of core beliefs\n\nrelapse prevention.\n\nSupported self-help for social anxiety disorder should consist of:\n\ntypically up to 9\xa0sessions of supported use of a CBT-based self-help book over 3−4\xa0months\n\nsupport to use the materials, either face to face or by telephone, for a total of 3\xa0hours over the course of the treatment.\n\nShort-term psychodynamic psychotherapy for social anxiety disorder should consist of typically up to 25−30\xa0sessions of 50\xa0minutes\' duration over 6−8\xa0months and include the following:\n\neducation about social anxiety disorder\n\nestablishing a secure positive therapeutic alliance to modify insecure attachments\n\na focus on a core conflictual relationship theme associated with social anxiety symptoms\n\na focus on shame\n\nencouraging exposure to feared social situations outside therapy sessions\n\nsupport to establish a self-affirming inner dialogue\n\nhelp to improve social skills.\n\n## Prescribing and monitoring pharmacological interventions in adults\n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE\'s guideline on medicines associated with dependence or withdrawal symptoms.\n\nBefore prescribing a pharmacological intervention for social anxiety disorder, discuss the treatment options and any concerns the person has about taking medication. Explain fully the reasons for prescribing and provide written and verbal information on:\n\nthe likely benefits of different drugs\n\nthe different propensities of each drug for side effects, discontinuation syndromes and drug interactions\n\nthe risk of early activation symptoms with SSRIs and SNRIs, such as increased anxiety, agitation, jitteriness and problems sleeping\n\nthe gradual development, over 2\xa0weeks or more, of the full anxiolytic effect\n\nthe importance of taking medication as prescribed, reporting side effects and discussing any concerns about stopping medication with the prescriber, and the need to continue treatment after remission to avoid relapse.\n\nArrange to see people aged 30\xa0years and older who are not assessed to be at risk of suicide within 1\xa0to 2\xa0weeks of first prescribing SSRIs or SNRIs to:\n\ndiscuss any possible side effects and potential interaction with symptoms of social anxiety disorder (for example, increased restlessness or agitation)\n\nadvise and support them to engage in graduated exposure to feared or avoided social situations.\n\nAfter the initial meeting (see recommendation\xa01.3.18), arrange to see the person every 2–4\xa0weeks during the first 3\xa0months of treatment and every\xa0month thereafter. Continue to support them to engage in graduated exposure to feared or avoided social situations.\n\nFor people aged under 30\xa0years who are offered an SSRI or SNRI:\n\nwarn them that these drugs are associated with an increased risk of suicidal thinking and self-harm in a minority of people under 30 and\n\nsee them within 1\xa0week of first prescribing and\n\nmonitor the risk of suicidal thinking and self-harm weekly for the first month. [This recommendation is from the NICE guideline on generalised anxiety disorder and panic disorder in adults].\n\nArrange to see people who are assessed to be at risk of suicide weekly until there is no indication of increased suicide risk, then every 2–4\xa0weeks during the first 3\xa0months of treatment and every\xa0month thereafter. Continue to support them to engage in graduated exposure to feared or avoided social situations.\n\nAdvise people taking a monoamine oxidase inhibitor of the dietary and pharmacological restrictions concerning the use of these drugs as set out in the British National Formulary.\n\nFor people who develop side effects soon after starting a pharmacological intervention, provide information and consider 1 of the following strategies:\n\nmonitoring the person\'s symptoms closely (if the side effects are mild and acceptable to the person)\n\nreducing the dose of the drug\n\nstopping the drug and offering either an alternative drug or individual CBT, according to the person\'s preference.[This recommendation is adapted from the NICE guideline on generalised anxiety disorder and panic disorder in adults].\n\nIf the person\'s symptoms of social anxiety disorder have responded well to a pharmacological intervention in the first 3\xa0months, continue it for at least a further 6\xa0months.\n\nWhen stopping a pharmacological intervention, reduce the dose of the drug gradually. If symptoms reappear after the dose is lowered or the drug is stopped, consider increasing the dose, reintroducing the drug or offering individual CBT.\n\n# Identification and assessment of children and young people\n\n## Identification of children and young people with possible social anxiety disorder\n\nHealth and social care professionals in primary care and education and community settings should be alert to possible anxiety disorders in children and young people, particularly those who avoid school, social or group activities or talking in social situations, or are irritable, excessively shy or overly reliant on parents or carers. Consider asking the child or young person about their feelings of anxiety, fear, avoidance, distress and associated behaviours (or a parent or carer) to help establish if social anxiety disorder is present, using these questions:\n\n"Sometimes people get very scared when they have to do things with other people, especially people they don\'t know. They might worry about doing things with other people watching. They might get scared that they will do something silly or that people will make fun of them. They might not want to do these things or, if they have to do them, they might get very upset or cross."\n\n\n\n"Do you/does your child get scared about doing things with other people, like talking, eating, going to parties, or other things at school or with friends?"\n\n"Do you/does your child find it difficult to do things when other people are watching, like playing sport, being in plays or concerts, asking or answering questions, reading aloud, or giving talks in class?"\n\n"Do you/does your child ever feel that you/your child can\'t do these things or try to get out of them?"\n\n\n\nIf the child or young person (or a parent or carer) answers \'yes\' to one or more of the questions in recommendation\xa01.4.1 consider a comprehensive assessment for social anxiety disorder (see recommendations\xa01.4.5 to 1.4.11 in the section on assessment of children and young people with possible social anxiety disorder).\n\nIf the identification questions (see recommendation\xa01.4.1 in the section on identification of children and young people with possible social anxiety disorder) indicate possible social anxiety disorder, but the practitioner is not competent to perform a mental health assessment, refer the child or young person to an appropriate healthcare professional. If this professional is not the child or young person\'s GP, inform the GP of the referral.\n\nIf the identification questions (see recommendation\xa01.4.1 in the section on identification of children and young people with possible social anxiety disorder) indicate possible social anxiety disorder, a practitioner who is competent to perform a mental health assessment should review the child or young person\'s mental state and associated functional, interpersonal and social difficulties.\n\n## Assessment of children and young people with possible social anxiety disorder\n\nA comprehensive assessment of a child or young person with possible social anxiety disorder should:\n\nprovide an opportunity for the child or young person to be interviewed alone at some point during the assessment\n\nif possible involve a parent, carer or other adult known to the child or young person who can provide information about current and past behaviour\n\nif necessary involve more than one\xa0professional to ensure a comprehensive assessment can be undertaken.\n\nWhen assessing a child or young person obtain a detailed description of their current social anxiety and associated problems including:\n\nfeared and avoided social situations\n\nwhat they are afraid might happen in social situations (for example, looking anxious, blushing, sweating, trembling or appearing boring)\n\nanxiety symptoms\n\nview of self\n\ncontent of self-image\n\nsafety-seeking behaviours\n\nfocus of attention in social situations\n\nanticipatory and post-event processing, particularly for older children\n\nfamily circumstances and support\n\nfriendships and peer groups, educational and social circumstances\n\nmedication, alcohol and recreational drug use.\n\nAs part of a comprehensive assessment, assess for causal and maintaining factors for social anxiety disorder in the child or young person\'s home, school and social environment, in particular:\n\nparenting behaviours that promote and support anxious behaviours or do not support positive behaviours\n\npeer victimisation in school or other settings.\n\nAs part of a comprehensive assessment, assess for possible coexisting conditions such as:\n\nother mental health problems (for example, other anxiety disorders and depression)\n\nneurodevelopmental conditions such as attention deficit hyperactivity disorder, autism and learning disabilities\n\ndrug and alcohol misuse (see recommendation\xa01.2.12 in the section on planning treatment for adults diagnosed with social anxiety disorder)\n\nspeech and language problems.\n\nTo aid the assessment of social anxiety disorder and other common mental health problems consider using formal instruments (both the child and parent versions if available and indicated), such as:\n\nthe LSAS – child version or the Social Phobia and Anxiety Inventory for Children (SPAI-C) for children, or the SPIN or the LSAS for young people\n\nthe Multidimensional Anxiety Scale for Children (MASC), the Revised Child Anxiety and Depression Scale (RCADS) for children and young people who may have comorbid depression or other anxiety disorders, the Spence Children\'s Anxiety Scale (SCAS) or the Screen for Child Anxiety Related Emotional Disorders (SCARED) for children.\n\nUse formal assessment instruments to aid the diagnosis of other problems, such as:\n\na validated measure of cognitive ability for a child or young person with a suspected learning disability\n\nthe Strengths and Difficulties Questionnaire for all children and young people.\n\nAssess the risks and harm faced by the child or young person and if needed develop a risk management plan for risk of self-neglect, familial abuse or neglect, exploitation by others, self-harm or harm to others.\n\nDevelop a profile of the child or young person to identify their needs and any further assessments that may be needed, including the extent and nature of:\n\nthe social anxiety disorder and any associated difficulties (for example, selective mutism)\n\nany coexisting mental health problems\n\nneurodevelopmental conditions such as attention deficit hyperactivity disorder, autism and learning disabilities\n\nexperience of bullying or social ostracism\n\nfriendships with peers\n\nspeech, language and communication skills\n\nphysical health problems\n\npersonal and social functioning to indicate any needs (personal, social, housing, educational and occupational)\n\neducational and occupational goals\n\nparent or carer needs, including mental health needs.\n\n# Interventions for children and young people with social anxiety disorder\n\n## Treatment principles\n\nAll interventions for children and young people with social anxiety disorder should be delivered by competent practitioners. Psychological interventions should be based on the relevant treatment manual(s), which should guide the structure and duration of the intervention. Practitioners should consider using competence frameworks developed from the relevant treatment manual(s) and for all interventions should:\n\nreceive regular high-quality supervision\n\nuse routine sessional outcome measures, for example:\n\n\n\nthe LSAS – child version or the SPAI-C, and the SPIN or LSAS for young people\n\nthe MASC, RCADS, SCAS or SCARED for children\n\n\n\nengage in monitoring and evaluation of treatment adherence and practitioner competence – for example, by using video and audio tapes, and external audit and scrutiny if appropriate.\n\nBe aware of the impact of the home, school and wider social environments on the maintenance and treatment of social anxiety disorder. Maintain a focus on the child or young person\'s emotional, educational and social needs and work with parents, teachers, other adults and the child or young person\'s peers to create an environment that supports the achievement of the agreed goals of treatment.\n\n## Treatment for children and young people with social anxiety disorder\n\nOffer individual or group CBT focused on social anxiety (see recommendations\xa01.5.4 and 1.5.5) to children and young people with social anxiety disorder. Consider involving parents or carers to ensure the effective delivery of the intervention, particularly in young children.\n\n## Delivering psychological interventions for children and young people\n\nIndividual CBT should consist of the following, taking into account the child or young person\'s cognitive and emotional maturity:\n\n−12\xa0sessions of 45\xa0minutes\' duration\n\npsychoeducation, exposure to feared or avoided social situations, training in social skills and opportunities to rehearse skills in social situations\n\npsychoeducation and skills training for parents, particularly of young children, to promote and reinforce the child\'s exposure to feared or avoided social situations and development of skills.\n\nGroup CBT should consist of the following, taking into account the child or young person\'s cognitive and emotional maturity:\n\n−12 sessions of 90\xa0minutes\' duration with groups of children or young people of the same age range\n\npsychoeducation, exposure to feared or avoided social situations, training in social skills and opportunities to rehearse skills in social situations\n\npsychoeducation and skills training for parents, particularly of young children, to promote and reinforce the child\'s exposure to feared or avoided social situations and development of skills.\n\nConsider psychological interventions that were developed for adults (see the section on interventions for adults with social anxiety disorder) for young people (typically aged 15\xa0years and older) who have the cognitive and emotional capacity to undertake a treatment developed for adults.\n\n# Interventions that are not recommended to treat social anxiety disorder\n\nDo not routinely offer pharmacological interventions to treat social anxiety disorder in children and young people.\n\nDo not routinely offer anticonvulsants, tricyclic antidepressants, benzodiazepines or antipsychotic medication to treat social anxiety disorder in adults.\n\nDo not routinely offer mindfulness-based interventions or supportive therapy to treat social anxiety disorder.Mindfulness-based interventions include mindfulness-based stress reduction and mindfulness-based cognitive therapy.\n\nDo not offer St John\'s wort or other over-the-counter medications and preparations for anxiety to treat social anxiety disorder. Explain the potential interactions with other prescribed and over-the-counter medications and the lack of evidence to support their safe use.\n\nDo not offer botulinum toxin to treat hyperhidrosis (excessive sweating) in people with social anxiety disorder. This is because there is no good-quality evidence showing benefit from botulinum toxin in the treatment of social anxiety disorder and it may be harmful.\n\nDo not offer endoscopic thoracic sympathectomy to treat hyperhidrosis or facial blushing in people with social anxiety disorder. This is because there is no good-quality evidence showing benefit from endoscopic thoracic sympathectomy in the treatment of social anxiety disorder and it may be harmful.\n\n# Specific phobias\n\n## Interventions that are not recommended\n\nDo not routinely offer computerised CBT to treat specific phobias in adults.', 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Adults' uptake of and engagement with interventions for social anxiety disorder\n\nWhat methods are effective in improving uptake of and engagement with interventions for adults with social anxiety disorder?\n\n## Why this is important\n\nEffective interventions exist for social anxiety disorder but access to and uptake of services is limited and over 50% of people with social anxiety disorder never receive treatment; of those who do receive treatment many wait 10\xa0years or more for it.\n\nThis question should be addressed by a programme of work that tests a number of strategies to improve uptake and engagement, including:\n\nDevelopment and evaluation of improved pathways into care, in collaboration with low users of services, through a series of cohort studies with the outcomes including increased uptake of and retention in services.\n\nAdapting the delivery of existing interventions for social anxiety disorder in collaboration with service users. Adaptations could include changes to the settings for, methods of delivery of, or staff delivering the interventions. These interventions should be tested in a randomised controlled trial (RCT) design that reports short- and medium-term outcomes (including cost effectiveness) of at least 18\xa0months' duration.\n\n# Specific versus generic CBT for children and young people with social anxiety disorder\n\nWhat is the clinical and cost effectiveness of specific CBT for children and young people with social anxiety disorder compared with generic anxiety-focused CBT?\n\n## Why this is important\n\nChildren and young people with social anxiety disorder have commonly been treated with psychological interventions that cover a broad range of anxiety disorders, rather than interventions specifically focused on social anxiety disorder. This approach may be considered to be easier and cheaper to deliver, but emerging evidence suggests that children and young people with social anxiety disorder may do less well with these generic treatments than those with other anxiety disorders. There have, however, been no direct comparisons of treatment outcomes using generic compared with social anxiety-specific treatment programmes.\n\nThis question should be answered using an RCT design, reporting short- and medium-term outcomes (including cost-effectiveness) with a follow-up of at least 12\xa0months. The outcomes should be assessed by structured clinical interviews, parent- and self-reports using validated questionnaires and objective measures of behaviour. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators (in particular the child or young person's age) should be investigated.\n\n# The role of parents in the treatment of children and young people with social anxiety disorder\n\nWhat is the best way of involving parents in the treatment of children and young people (at different stages of development) with social anxiety disorder?\n\n## Why this is important\n\nThere is very little evidence to guide the treatment of social anxiety disorder in children aged under 7\xa0years. It is likely that treatment will be most effectively delivered either wholly or partly by parents. Parenting interventions have been effective in treating other psychological difficulties in this age group, and this guideline found emerging evidence that these approaches might be useful for the treatment of young socially anxious children.\n\nFurthermore, when considering all age groups, parental mental health difficulties and parenting practices have been linked with the development and maintenance of social anxiety disorder in children and young people. This suggests that interventions targeting these parental factors may improve treatment outcomes. However, interventions for children and young people with social anxiety disorder have varied widely in the extent and manner in which parents are involved in treatment and the benefit of including parents in interventions has not been established.\n\nThis question should be addressed in 2\xa0stages.\n\nParent-focused interventions should be developed based on a systematic review of the literature and in collaboration with service users.\n\nThe clinical and cost effectiveness of these interventions at different stages of development should be tested using an RCT design with standard care (for example, group CBT) as the comparison. It should report short- and medium-term outcomes (including cost effectiveness) with a follow-up of at least 12\xa0months. The outcomes should be assessed by structured clinical interviews, parent- and self-reports using validated questionnaires and objective measures of behaviour. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators (in particular the child or young person's age) should be investigated.\n\n# Individual versus group CBT for children and young people with social anxiety disorder\n\nWhat is the clinical and cost effectiveness of individual and group CBT for children and young people with social anxiety disorder?\n\n## Why this is important\n\nThe majority of systematic evaluations of interventions for social anxiety disorder in children and young people have taken a group approach. Studies with adult populations, however, indicate that individually-delivered treatments are associated with better treatment outcomes and are more cost effective.\n\nThis question should be addressed using an RCT design comparing the clinical and cost effectiveness of individual and group-based treatments for children and young people with social anxiety disorder. It should report short- and medium-term outcomes (including cost effectiveness) with a follow-up of at least 12\xa0months. The outcomes should be assessed by structured clinical interviews, parent- and self-reports using validated questionnaires and objective measures of behaviour. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators (in particular the child or young person's age and familial and social context) should be investigated.\n\n# Combined interventions for adults with social anxiety disorder\n\nWhat is the clinical and cost effectiveness of combined psychological and pharmacological interventions compared with either intervention alone in the treatment of adults with social anxiety disorder?\n\n## Why this is important\n\nThere is evidence for the effectiveness of both CBT and medication, in particular SSRIs, in the treatment of social anxiety disorder. However, little is known about the effects of combined pharmacological and psychological interventions despite their widespread use. Understanding the costs and benefits of combined treatment could lead to more effective and targeted combinations if they prove to be more effective than single treatments. The study will also provide important information on the long-term benefits of medication.\n\nThis question should be addressed in a large-scale 3-arm RCT comparing the clinical and cost effectiveness of combined individual CBT and SSRI treatment with individual CBT or an SSRI alone. Trial participants receiving medication should be offered it for 1\xa0year. The study should report short- and medium-term outcomes (including cost effectiveness) with a follow-up of at least 24\xa0months. The primary outcome should be recovery, with important secondary outcomes being retention in treatment, experience and side effects of medication, and social and personal functioning. The study needs to be large enough to determine the presence of clinically important effects, and mediators and moderators should be investigated."}	https://www.nice.org.uk/guidance/cg159	This guideline covers recognising, assessing and treating social anxiety disorder (also known as ‘social phobia’) in children and young people (from school age to 17 years) and adults (aged 18 years and older). It aims to improve symptoms, educational, occupational and social functioning, and quality of life in people with social anxiety disorder.
c8714c528e32cef4cb3d062ca36e0c4fd66e3796	nice	Occipital nerve stimulation for intractable chronic migraine	Occipital nerve stimulation for intractable chronic migraine Evidence-based recommendations on occipital nerve stimulation for intractable chronic migraine. This involves using implanted electrodes to deliver electrical impulses to the occipital nerve to mask migraine pain. # Guidance The evidence on occipital nerve stimulation (ONS) for intractable chronic migraine shows some efficacy in the short term but there is very little evidence about long‑term outcomes. With regard to safety, there is a risk of complications, needing further surgery. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Clinicians wishing to undertake ONS for intractable chronic migraine should take the following actions: Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Selection of patients for treatment using ONS for intractable chronic migraine should be done by a multidisciplinary team, including specialists in headache, pain management and neurosurgery. Clinicians should enter details about all patients undergoing ONS for intractable chronic migraine onto the UK Neuromodulation Register when access to that database is available. They should audit and review clinical outcomes locally and should document and consider their relationship to patient characteristics. NICE encourages publication of further information from comparative studies and from collaborative data collection to guide future use of this procedure and to provide patients with the best possible advice. Publications should include full details of any complications, and of adjunctive or subsequent treatments. Outcomes should include measures of pain, function and quality of life, particularly in the long term. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Migraine is a severe headache, often accompanied by sensitivity to light and sound. It may be preceded by an aura, consisting of perception of an unusual light, an unpleasant smell or, occasionally, confusing thoughts or experiences. The International Classification of Headache Disorders (International Headache Society 2004) provides a classification of migraine types. Current treatment for patients with migraine aims to prevent or stop episodes with drugs such as painkillers, anti‑emetics and triptans (as recommended in NICE clinical guideline 150). If these fail, invasive treatments such as nerve blocks, botulinum toxin type A (NICE technology appraisal guidance 260) or acupuncture are sometimes used. # Outline of the procedure ONS for intractable chronic migraine is usually done in 2 stages, although a single‑stage procedure is sometimes used. In the first, trial stage, using local anaesthesia and usually with fluoroscopic guidance, electrodes are passed through a subcutaneous tunnel and placed over the occipital nerve(s) around the level of C1. Correct placement of electrodes is verified by intraoperative stimulation and patient feedback before they are sutured to subcutaneous tissue. A lead is tunnelled under the skin from the electrode to an exit site in the posterior cervical region, where it is connected by an external extension lead to a hand‑held neurostimulator. The second stage is carried out if the trial is successful. With the patient under general anaesthesia, an implantable neurostimulator is secured in a subcutaneous pocket, usually in the infraclavicular region or the abdominal wall. A lead is tunnelled from the electrode to the implantable neurostimulator. The patient uses a remote control to stimulate the occipital nerves when needed. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the systematic review and the addendum to the systematic review. # Efficacy A randomised controlled trial (RCT) of 157 patients compared ONS (active stimulation, n=105) against sham stimulation (n=52). It reported a statistically significantly greater decrease in the 'Migraine disability assessment score' (MIDAS), which takes into account headache days and their impact on the patient's life (maximum score 200), at 12‑week follow‑up for the ONS group than for the sham stimulation group (64.6 and 20.4 reduction respectively, p=0.001). An RCT of 67 patients comparing ONS (n=33) against sham stimulation (n=17) or medical management (n=17) reported a responder rate (defined as a reduction in headache days per month of 50% or more, or a 3‑point or greater reduction in average overall pain intensity compared with baseline at 3 months) of 39% (11/28) in the ONS group, 6% (1/16) in the sham stimulation group and 0% (0/17) in the medication group (p value not reported). A case series of 25 patients reported that headache frequency per 90 days reduced from 75.56 (standard deviation 26.81) before implantation to 37.45 (SD 7.49) over a mean follow‑up of 18 months (p<0.001). The RCT of 157 patients reported no significant difference between the groups in the proportion of patients whose pain reduced by 50% or more (measured on a visual analogue scale) (17% for ONS and 14% for sham stimulation, p=0.55) at 12‑week follow‑up. The case series of 25 patients reported a significant reduction in headache severity (0–10 scale) from a baseline of 9.32 (SD 1.28) to 5.72 (SD 3.31) over a mean follow‑up of 18 months (p<0.001). The Specialist Advisers listed key efficacy outcomes as a reduction in migraine or headache days, headache severity, frequency and duration, disability score (measured by MIDAS), medication use and improvements in quality of life (SF‑36). # Safety Infections at the implant site were reported in 14% (7/51) of patients in the RCT of 67 patients at 3‑month follow‑up. Infection was reported in 4% (4/105) of patients in the ONS group and 6% (3/52) of patients in the sham stimulation group in the RCT of 157 patients at 12‑week follow‑up (no further details available). Skin erosion was reported in 4% (4/105) of patients in the ONS group and 4% (2/52) of patients in the sham stimulation group in the RCT of 157 patients at 12‑week follow‑up. Lead migration or dislodgement was reported in 10% (5/52) of patients in the sham stimulation group and 14% (15/105) of patients in the ONS group in the RCT of 157 patients after 3 months; and in 24% (12/51) of patients in the RCT of 67 patients at 3‑month follow‑up. Lead migration was reported in 36% (9/25) of patients in the case series of 25 patients at mean 18‑month follow‑up. Problems with ineffective device programming and ineffective leads were reported in 12% (6/51) and 4% (2/51) of patients respectively, in the RCT of 67 patients at 3‑month follow‑up. Persistent pain or numbness at the implant site was reported in 13% (14/105) of patients in the ONS group and 17% (9/52) of patients in the sham stimulation group in the RCT of 157 patients at 12‑week follow‑up. Loss of motor or musculoskeletal control was reported in 1% (1/105) of patients in the ONS group in the same RCT (timing not reported). Unintended stimulation effect (no further details available) was reported in 6% (6/105) of patients in the ONS group and 2% (1/52) of patients in the sham stimulation group in the RCT of 157 patients. In addition to the above, the Specialist Advisers listed haemorrhage, nerve damage and lead fracture as theoretical adverse events. # Other comments The Committee recognised that patients being considered for ONS for intractable chronic migraine commonly have very distressing and long‑term symptoms that other methods of treatment have failed to control. The Committee recognised that research in this area is difficult because there is uncertainty about the percentage level of relief that should be considered significant and it is difficult to achieve blinding in trials, and because of the complex and heterogeneous nature of chronic migraine. Currently, there are not enough good‑quality comparative studies to be able confidently to evaluate the procedure's efficacy. This underpins the recommendations in section 1. The Committee recognised that techniques and technology are evolving and, implicitly, this may produce better results.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence, 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Care ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk ISBN 978‑1‑4731‑0099‑2	{'Guidance': "The evidence on occipital nerve stimulation (ONS) for intractable chronic migraine shows some efficacy in the short term but there is very little evidence about long‑term outcomes. With regard to safety, there is a risk of complications, needing further surgery. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.\n\nClinicians wishing to undertake ONS for intractable chronic migraine should take the following actions:\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nSelection of patients for treatment using ONS for intractable chronic migraine should be done by a multidisciplinary team, including specialists in headache, pain management and neurosurgery.\n\nClinicians should enter details about all patients undergoing ONS for intractable chronic migraine onto the UK Neuromodulation Register when access to that database is available. They should audit and review clinical outcomes locally and should document and consider their relationship to patient characteristics.\n\nNICE encourages publication of further information from comparative studies and from collaborative data collection to guide future use of this procedure and to provide patients with the best possible advice. Publications should include full details of any complications, and of adjunctive or subsequent treatments. Outcomes should include measures of pain, function and quality of life, particularly in the long term.\n\nNICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nMigraine is a severe headache, often accompanied by sensitivity to light and sound. It may be preceded by an aura, consisting of perception of an unusual light, an unpleasant smell or, occasionally, confusing thoughts or experiences. The International Classification of Headache Disorders (International Headache Society 2004) provides a classification of migraine types.\n\nCurrent treatment for patients with migraine aims to prevent or stop episodes with drugs such as painkillers, anti‑emetics and triptans (as recommended in NICE clinical guideline 150). If these fail, invasive treatments such as nerve blocks, botulinum toxin type A (NICE technology appraisal guidance 260) or acupuncture are sometimes used.\n\n# Outline of the procedure\n\nONS for intractable chronic migraine is usually done in 2 stages, although a single‑stage procedure is sometimes used. In the first, trial stage, using local anaesthesia and usually with fluoroscopic guidance, electrodes are passed through a subcutaneous tunnel and placed over the occipital nerve(s) around the level of C1. Correct placement of electrodes is verified by intraoperative stimulation and patient feedback before they are sutured to subcutaneous tissue. A lead is tunnelled under the skin from the electrode to an exit site in the posterior cervical region, where it is connected by an external extension lead to a hand‑held neurostimulator.\n\nThe second stage is carried out if the trial is successful. With the patient under general anaesthesia, an implantable neurostimulator is secured in a subcutaneous pocket, usually in the infraclavicular region or the abdominal wall. A lead is tunnelled from the electrode to the implantable neurostimulator. The patient uses a remote control to stimulate the occipital nerves when needed.\n\nSections\xa02.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the systematic review and the addendum to the systematic review.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 157\xa0patients compared ONS (active stimulation, n=105) against sham stimulation (n=52). It reported a statistically significantly greater decrease in the 'Migraine disability assessment score' (MIDAS), which takes into account headache days and their impact on the patient's life (maximum score 200), at 12‑week follow‑up for the ONS group than for the sham stimulation group (64.6 and 20.4 reduction respectively, p=0.001).\n\nAn RCT of 67\xa0patients comparing ONS (n=33) against sham stimulation (n=17) or medical management (n=17) reported a responder rate (defined as a reduction in headache days per month of 50% or more, or a 3‑point or greater reduction in average overall pain intensity compared with baseline at 3\xa0months) of 39% (11/28) in the ONS group, 6% (1/16) in the sham stimulation group and 0% (0/17) in the medication group (p\xa0value not reported).\n\nA case series of 25\xa0patients reported that headache frequency per 90\xa0days reduced from 75.56 (standard deviation [SD]\xa026.81) before implantation to 37.45 (SD\xa07.49) over a mean follow‑up of 18\xa0months (p<0.001).\n\nThe RCT of 157\xa0patients reported no significant difference between the groups in the proportion of patients whose pain reduced by 50% or more (measured on a visual analogue scale) (17% for ONS and 14% for sham stimulation, p=0.55) at 12‑week follow‑up.\n\nThe case series of 25\xa0patients reported a significant reduction in headache severity (0–10 scale) from a baseline of 9.32 (SD 1.28) to 5.72 (SD 3.31) over a mean follow‑up of 18\xa0months (p<0.001).\n\nThe Specialist Advisers listed key efficacy outcomes as a reduction in migraine or headache days, headache severity, frequency and duration, disability score (measured by MIDAS), medication use and improvements in quality of life (SF‑36).\n\n# Safety\n\nInfections at the implant site were reported in 14% (7/51) of patients in the RCT of 67\xa0patients at 3‑month follow‑up. Infection was reported in 4% (4/105) of patients in the ONS group and 6% (3/52) of patients in the sham stimulation group in the RCT of 157\xa0patients at 12‑week follow‑up (no further details available).\n\nSkin erosion was reported in 4% (4/105) of patients in the ONS group and 4% (2/52) of patients in the sham stimulation group in the RCT of 157\xa0patients at 12‑week follow‑up.\n\nLead migration or dislodgement was reported in 10% (5/52) of patients in the sham stimulation group and 14% (15/105) of patients in the ONS group in the RCT of 157\xa0patients after 3\xa0months; and in 24% (12/51) of patients in the RCT of 67\xa0patients at 3‑month follow‑up. Lead migration was reported in 36% (9/25) of patients in the case series of 25\xa0patients at mean 18‑month follow‑up.\n\nProblems with ineffective device programming and ineffective leads were reported in 12% (6/51) and 4% (2/51) of patients respectively, in the RCT of 67\xa0patients at 3‑month follow‑up.\n\nPersistent pain or numbness at the implant site was reported in 13% (14/105) of patients in the ONS group and 17% (9/52) of patients in the sham stimulation group in the RCT of 157\xa0patients at 12‑week follow‑up. Loss of motor or musculoskeletal control was reported in 1% (1/105) of patients in the ONS group in the same RCT (timing not reported).\n\nUnintended stimulation effect (no further details available) was reported in 6% (6/105) of patients in the ONS group and 2% (1/52) of patients in the sham stimulation group in the RCT of 157\xa0patients.\n\nIn addition to the above, the Specialist Advisers listed haemorrhage, nerve damage and lead fracture as theoretical adverse events.\n\n# Other comments\n\nThe Committee recognised that patients being considered for ONS for intractable chronic migraine commonly have very distressing and long‑term symptoms that other methods of treatment have failed to control.\n\nThe Committee recognised that research in this area is difficult because there is uncertainty about the percentage level of relief that should be considered significant and it is difficult to achieve blinding in trials, and because of the complex and heterogeneous nature of chronic migraine. Currently, there are not enough good‑quality comparative studies to be able confidently to evaluate the procedure's efficacy. This underpins the recommendations in section\xa01.\n\nThe Committee recognised that techniques and technology are evolving and, implicitly, this may produce better results.", 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence, 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Care ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780\n\nISBN 978‑1‑4731‑0099‑2'}	https://www.nice.org.uk/guidance/ipg452	Evidence-based recommendations on occipital nerve stimulation for intractable chronic migraine. This involves using implanted electrodes to deliver electrical impulses to the occipital nerve to mask migraine pain.
53cfaff3a954d2bcf74625483019cd460460af72	nice	Corneal inlay implantation for correction of presbyopia	Corneal inlay implantation for correction of presbyopia # Guidance The evidence for corneal inlay implantation for correction of presbyopia is limited in quantity and quality and comes predominantly from case series; there is some evidence of efficacy in the short term. In addition, there are reports that adverse effects occur frequently. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake corneal inlay implantation for correction of presbyopia should take the following actions: Inform the clinical governance leads in their Trusts. Ensure that patients understand that this is principally a cosmetic procedure that may reduce their need to wear spectacles or contact lenses. They should be made aware of other management options for presbyopia. They should be informed about the possible adverse events associated with the procedure and encouraged to balance these carefully against the expected benefits. Patients should be provided with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having corneal inlay implantation for the correction of presbyopia (see section 3.1). Both clinicians and manufacturers are encouraged to collect details of complications and long-term outcomes following corneal inlay implantation for correction of presbyopia, and to publish their findings. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Presbyopia results from age-related deterioration of the lens in the cornea of the eye and usually begins to develop at around 40 years of age. This form of lens deterioration causes difficulty with accommodation (focusing on near objects). Standard treatment for presbyopia is corrective spectacles or contact lenses. Surgery (monovision or blended-vision laser in situ keratomileusis , or refractive lens exchange or replacement) may be considered in some patients. # Outline of the procedure Corneal inlay implantation aims to improve near visual acuity and increase depth of focus. It may particularly benefit people who find it difficult to use spectacles or contact lenses, for instance, those with limited dexterity. The procedure is usually performed on the non-dominant eye, under topical anaesthesia. The patient fixates their eye on a light source on a surgical microscope so that the surgeon can identify the target position on the centre of the visual axis. Laser or microkeratome techniques are used to create either a lamellar corneal flap or a pocket within the corneal stroma. The flap or pocket is separated with a spatula and a special tool is used to position the inlay within it, at the marked centre of the axis. The flap or pocket self-seals, holding the inlay in place. Patients are normally prescribed corticosteroids and antibiotic eye drops in the short term and artificial tears for as long as needed. The inlay can be removed or replaced if needed. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 32 patients reported that mean uncorrected near visual acuity (UNVA) in the treated eye improved from J7/8 preoperatively to J1 at 3 years, and binocular UNVA improved from J6 to J1 (p<0.00001). Mean uncorrected intermediate visual acuity (UIVA) in the treated eye improved from 20/40 to 20/25 at 3 years (p<0.00001); binocular UIVA also improved from 20/32 to 20/20 (p<0.001). Mean uncorrected distance visual acuity (UDVA) in the treated eye decreased slightly from 20/16 to 20/20 at 3 years (p<0.001). The change in binocular UDVA was not statistically significant (p=0.77). A case series of 39 patients reported an improvement in mean UNVA in the treated eye from 20/50 preoperatively to 20/20 in 22 patients followed up for 4 years (p<0.001). Mean UDVA in the treated eye changed from 20/20 to 20/25 after 4 years (p=0.107). The case series of 32 patients reported an increase in mean reading speed per minute from 142 words before treatment to 149 words after a mean follow-up of 2 years (p=0.029). Mean reading distance decreased from 48.1 cm to 38.9 cm (p<0.0001). The case series of 32 patients reported that the percentage of patients using glasses all or most of the time decreased from 88% to 6% at 3 years (absolute numbers not given). A case series of 24 patients reported a mean satisfaction with the procedure of 5.0 (on a scale of 1–7 where higher scores show more satisfaction) at 2 years after treatment. Mean satisfaction with reduction in reading glasses was 5.3 in bright light and 3.1 in dim light, using the same scale. It was reported that 75% (18/24) of patients said that they would have the procedure again, 21% (5/24) were undecided and 1 patient said he would not have the procedure again (exact question not reported). The Specialist Advisers listed key efficacy outcomes as improved unaided near or reading vision with maintained distance vision. # Safety Removal of the inlay was reported in 4 patients in the case series of 39 patients because of a buttonhole flap (in 1 patient at 6 weeks), refractive shifts and reported glare and halos (in 2 patients after 3 months) and a thin corneal flap causing symptoms (in 1 patient after 17 months). Following removal of the inlay, visual acuity returned to pretreatment values in all 4 patients. Inlays were re-centred after 6 months because of initial misplacement in 2 patients in the case series of 32 patients. Both patients' visual acuity for near, intermediate and distance improved after recentration (reported graphically). Cataracts affecting visual function and needing surgical treatment developed in 5 treated eyes after 3–4 years in the case series of 39 patients. Loss of visual acuity at 3 years was reported in 14 patients in the case series of 32 patients (2 lines of UDVA were lost by 4 patients, 1 line of corrected distance visual acuity was lost by 9 patients, and 3.8 lines of CDVA were lost by 1 patient). Flap striae developed in 1 patient after 1 month in the case series of 32 patients, resulting in epithelial ingrowth that needed repeated flap lift and debridement and was resolved by suturing after 2 months. Hyperopic shifts greater than +0.5 D were measured in 4 patients in the case series of 32 patients at 3 years' follow-up. Myopic refractive shifts were also noted in 4 patients. Severe, moderate and mild halo was reported by 1, 8 and 11 patients respectively in the case series of 32 patients at 3 years. Mild or moderate halo had been reported by 3 patients before treatment. Five patients in the same study reported severe problems with night vision. A significant decrease in photopic (p<0.001) and mesopic (p<0.0001) contrast sensitivity at all spatial frequencies was reported in a case series of 508 patients at 1 year after treatment. Very mild edge haze around the cornea was reported at 2 years' follow-up in all the patients in a case series of 8 patients. The Specialist Advisers listed additional theoretical adverse events as infectious keratitis, corneal scarring or opacification, corneal thinning and melting, difficulty measuring intraocular pressure, failure to adapt to near monovision, reduction in unaided distance vision and reduction in best spectacle-corrected distance visual acuity. # Other comments The Committee recognised that although this procedure is usually undertaken for cosmetic reasons, some patients with presbyopia might be unable to use spectacles or contact lenses. The Committee recognised that presbyopia is a progressive condition and therefore long-term data on efficacy and safety are important. The Committee recognised that a number of inlays are available and they may differ in their efficacy, their safety and the way they work.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Care ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk ISBN 978-1-4731-0126-5	{'Guidance': "The evidence for corneal inlay implantation for correction of presbyopia is limited in quantity and quality and comes predominantly from case series; there is some evidence of efficacy in the short term. In addition, there are reports that adverse effects occur frequently. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake corneal inlay implantation for correction of presbyopia should take the following actions:\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand that this is principally a cosmetic procedure that may reduce their need to wear spectacles or contact lenses. They should be made aware of other management options for presbyopia. They should be informed about the possible adverse events associated with the procedure and encouraged to balance these carefully against the expected benefits. Patients should be provided with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having corneal inlay implantation for the correction of presbyopia (see section\xa03.1).\n\nBoth clinicians and manufacturers are encouraged to collect details of complications and long-term outcomes following corneal inlay implantation for correction of presbyopia, and to publish their findings. NICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nPresbyopia results from age-related deterioration of the lens in the cornea of the eye and usually begins to develop at around 40\xa0years of age. This form of lens deterioration causes difficulty with accommodation (focusing on near objects).\n\nStandard treatment for presbyopia is corrective spectacles or contact lenses. Surgery (monovision or blended-vision laser in situ keratomileusis [LASIK], or refractive lens exchange or replacement) may be considered in some patients.\n\n# Outline of the procedure\n\nCorneal inlay implantation aims to improve near visual acuity and increase depth of focus. It may particularly benefit people who find it difficult to use spectacles or contact lenses, for instance, those with limited dexterity.\n\nThe procedure is usually performed on the non-dominant eye, under topical anaesthesia. The patient fixates their eye on a light source on a surgical microscope so that the surgeon can identify the target position on the centre of the visual axis. Laser or microkeratome techniques are used to create either a lamellar corneal flap or a pocket within the corneal stroma. The flap or pocket is separated with a spatula and a special tool is used to position the inlay within it, at the marked centre of the axis. The flap or pocket self-seals, holding the inlay in place. Patients are normally prescribed corticosteroids and antibiotic eye drops in the short term and artificial tears for as long as needed. The inlay can be removed or replaced if needed.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 32\xa0patients reported that mean uncorrected near visual acuity (UNVA) in the treated eye improved from J7/8 preoperatively to J1 at 3\xa0years, and binocular UNVA improved from J6 to J1 (p<0.00001). Mean uncorrected intermediate visual acuity (UIVA) in the treated eye improved from 20/40 to 20/25 at 3\xa0years (p<0.00001); binocular UIVA also improved from 20/32 to 20/20 (p<0.001). Mean uncorrected distance visual acuity (UDVA) in the treated eye decreased slightly from 20/16 to 20/20 at 3\xa0years (p<0.001). The change in binocular UDVA was not statistically significant (p=0.77).\n\nA case series of 39\xa0patients reported an improvement in mean UNVA in the treated eye from 20/50 preoperatively to 20/20 in 22\xa0patients followed up for 4\xa0years (p<0.001). Mean UDVA in the treated eye changed from 20/20 to 20/25 after 4\xa0years (p=0.107).\n\nThe case series of 32\xa0patients reported an increase in mean reading speed per minute from 142\xa0words before treatment to 149\xa0words after a mean follow-up of 2\xa0years (p=0.029). Mean reading distance decreased from 48.1\xa0cm to 38.9\xa0cm (p<0.0001).\n\nThe case series of 32\xa0patients reported that the percentage of patients using glasses all or most of the time decreased from 88% to 6% at 3\xa0years (absolute numbers not given).\n\nA case series of 24\xa0patients reported a mean satisfaction with the procedure of 5.0 (on a scale of 1–7 where higher scores show more satisfaction) at 2\xa0years after treatment. Mean satisfaction with reduction in reading glasses was 5.3 in bright light and 3.1 in dim light, using the same scale. It was reported that 75% (18/24) of patients said that they would have the procedure again, 21% (5/24) were undecided and 1\xa0patient said he would not have the procedure again (exact question not reported).\n\nThe Specialist Advisers listed key efficacy outcomes as improved unaided near or reading vision with maintained distance vision.\n\n# Safety\n\nRemoval of the inlay was reported in 4\xa0patients in the case series of 39\xa0patients because of a buttonhole flap (in 1\xa0patient at 6\xa0weeks), refractive shifts and reported glare and halos (in 2\xa0patients after 3\xa0months) and a thin corneal flap causing symptoms (in 1\xa0patient after 17\xa0months). Following removal of the inlay, visual acuity returned to pretreatment values in all 4\xa0patients.\n\nInlays were re-centred after 6\xa0months because of initial misplacement in 2\xa0patients in the case series of 32\xa0patients. Both patients' visual acuity for near, intermediate and distance improved after recentration (reported graphically).\n\nCataracts affecting visual function and needing surgical treatment developed in 5\xa0treated eyes after 3–4\xa0years in the case series of 39\xa0patients.\n\nLoss of visual acuity at 3\xa0years was reported in 14\xa0patients in the case series of 32\xa0patients (2\xa0lines of UDVA were lost by 4\xa0patients, 1\xa0line of corrected distance visual acuity [CDVA] was lost by 9\xa0patients, and 3.8\xa0lines of CDVA were lost by 1\xa0patient).\n\nFlap striae developed in 1\xa0patient after 1\xa0month in the case series of 32\xa0patients, resulting in epithelial ingrowth that needed repeated flap lift and debridement and was resolved by suturing after 2\xa0months.\n\nHyperopic shifts greater than +0.5\xa0D were measured in 4\xa0patients in the case series of 32\xa0patients at 3\xa0years' follow-up. Myopic refractive shifts were also noted in 4\xa0patients.\n\nSevere, moderate and mild halo was reported by 1, 8 and 11\xa0patients respectively in the case series of 32\xa0patients at 3\xa0years. Mild or moderate halo had been reported by 3\xa0patients before treatment. Five patients in the same study reported severe problems with night vision.\n\nA significant decrease in photopic (p<0.001) and mesopic (p<0.0001) contrast sensitivity at all spatial frequencies was reported in a case series of 508\xa0patients at 1\xa0year after treatment.\n\nVery mild edge haze around the cornea was reported at 2\xa0years' follow-up in all the patients in a case series of 8\xa0patients.\n\nThe Specialist Advisers listed additional theoretical adverse events as infectious keratitis, corneal scarring or opacification, corneal thinning and melting, difficulty measuring intraocular pressure, failure to adapt to near monovision, reduction in unaided distance vision and reduction in best spectacle-corrected distance visual acuity.\n\n# Other comments\n\nThe Committee recognised that although this procedure is usually undertaken for cosmetic reasons, some patients with presbyopia might be unable to use spectacles or contact lenses.\n\nThe Committee recognised that presbyopia is a progressive condition and therefore long-term data on efficacy and safety are important.\n\nThe Committee recognised that a number of inlays are available and they may differ in their efficacy, their safety and the way they work.", 'Further information': 'This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Care ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780\n\nISBN 978-1-4731-0126-5'}	https://www.nice.org.uk/guidance/ipg455
d06dfa726c4be7225d9575517020512a1dba0ee9	nice	Omalizumab for treating severe persistent allergic asthma	Omalizumab for treating severe persistent allergic asthma Evidence-based recommendations on omalizumab (Xolair) for treating severe persistent allergic asthma in people aged 6 and over. # Guidance Omalizumab is recommended as an option for treating severe persistent confirmed allergic IgE‑mediated asthma as an add‑on to optimised standard therapy in people aged 6 years and older: who need continuous or frequent treatment with oral corticosteroids (defined as 4 or more courses in the previous year), and -nly if the manufacturer makes omalizumab available with the discount agreed in the patient access scheme. Optimised standard therapy is defined as a full trial of and, if tolerated, documented compliance with inhaled high‑dose corticosteroids, long‑acting beta2 agonists, leukotriene receptor antagonists, theophyllines, oral corticosteroids, and smoking cessation if clinically appropriate. People currently receiving omalizumab whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# Clinical need and practice Asthma is a long‑term inflammatory disorder of the airways characterised by signs or symptoms including breathlessness, chest tightness, wheezing, sputum production, airflow obstruction, hyper‑responsiveness of airways and cough (particularly at night). Symptoms vary in frequency and severity, from intermittent and mild, to frequent and severe. Allergic and non‑allergic forms of asthma exist. Allergic asthma results from excess immunoglobulin E (IgE) produced in response to environmental allergens such as house dust mites, pollen and moulds. Non‑allergic asthma can be triggered by factors such as anxiety, stress, exercise, cold air, smoke and infection. The Quality and Outcomes Framework (2008) estimated that 5.9% of the UK population receives treatment for asthma. Prevalence is highest in children aged 5 to 15 years, and decreases in adulthood until the age range of 55 to 64 years, when it rises again. In 2008/09, there were over 67,000 emergency hospital visits for asthma in the UK, with more than 40% of these for children aged 15 years or under. People with asthma may have an impaired quality of life, with symptoms leading to fatigue, and absence from school or work. Psychological problems, which can include stress, anxiety and depression, are up to 6 times more common than in the general population, and are particularly common in people with severe and difficult‑to‑control asthma. There are between 1000 and 1200 deaths from asthma each year in the UK, where, in 2008, the rate of premature death from asthma was 1.5 times higher than in the rest of Europe. There is no cure for asthma and the aim of treatment is to control symptoms while minimising the adverse reactions to treatment. Current guidelines from the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) recommend a stepwise approach to treatment aligned with the pathway of the Global Initiative for Asthma (GINA). Good control, characterised by no symptoms, normal lung function and no exacerbations, is achieved by stepping up or down treatment as necessary. Severe persistent allergic asthma is defined as poor control despite eliminating environmental allergens and correctly optimising standard care. Step 1 (for mild intermittent asthma) of the GINA pathway recommends using inhaled short‑acting beta2 agonists occasionally, and step 2 recommends introducing inhaled corticosteroids at 200–800 micrograms per day in people aged 12 years and over and at 200–400 micrograms per day in children aged 5 to 12 years. Step 3 recommends adding an inhaled long‑acting beta2 agonist and, if control remains inadequate, increasing the dosage of inhaled corticosteroids to 800 micrograms per day in adults and adolescents and to 400 micrograms per day in children. If a person's asthma does not respond to an inhaled long‑acting beta2 agonist, a leukotriene receptor antagonist (oral), a theophylline (oral) or a slow‑release beta2 agonist (oral) may be considered instead. Step 4 recommends increasing the dosage of inhaled corticosteroids to up to 2000 micrograms per day in adults and adolescents and up to 800 micrograms per day in children. As with step 3, adding a leukotriene receptor antagonist, a theophylline or an oral beta2 agonist may also be considered. Before moving to step 5, clinicians should refer people whose asthma is inadequately controlled to specialist care. Step 5 recommends daily corticosteroid tablets at the lowest dose that provides adequate control, alongside high‑dose inhaled corticosteroids. Treatments that can minimise the use of corticosteroid tablets may also be considered. The adverse effects of long‑term oral corticosteroids are significant and include adrenal suppression, glucose intolerance, decreased bone mineral density, cataracts and glaucoma, and growth failure in children.# The technology Omalizumab (Xolair, Novartis) is a monoclonal antibody that binds to IgE. It has a UK marketing authorisation as add‑on therapy to improve control of asthma in adults and adolescents 12 years and over (hereafter referred to as adults and adolescents) and children aged 6 to 11 years (hereafter referred to as children) with severe persistent allergic asthma who have: a positive skin test or in vitro reactivity to a perennial aeroallergen reduced lung function (forced expiratory volume at 1 second less than 80% in adults and adolescents) frequent daytime symptoms or night‑time awakenings multiple documented severe exacerbations despite daily high‑dose inhaled corticosteroids plus a long‑acting inhaled beta2 agonist. The marketing authorisation states that omalizumab treatment 'should only be considered for patients with convincing IgE (immunoglobulin E) mediated asthma'. It also specifies that, 16 weeks after the start of omalizumab, physicians should assess how effective the treatment is, and should continue omalizumab only in patients whose asthma has markedly improved. It also specifies that omalizumab should be initiated and monitored in a specialist centre by a physician experienced in the diagnosis and treatment of severe persistent asthma. Omalizumab is given subcutaneously every 2 or 4 weeks. The dosage is determined by the concentration of serum IgE before the start of treatment and body weight. (See the summary of product characteristics.) The summary of product characteristics lists injection site pain, swelling, erythema and pruritus, and headaches as the most commonly reported adverse reactions for omalizumab treatment in adults and adolescents. The most commonly reported adverse reactions for omalizumab treatment in children are headaches, pyrexia and upper abdominal pain. For full details of adverse reactions and contraindications, see the summary of product characteristics. The price of omalizumab is £256.15 for a 150‑mg vial and £128.07 for a 75‑mg vial (excluding VAT; 'British national formulary' edition 63). The dosage administered is 75–600 mg every 2 or 4 weeks, up to a maximum dosage of 600 mg every 2 weeks. The cost of omalizumab ranges from approximately £1665 per patient per year (excluding VAT) for a 75 mg dose administered every 4 weeks to approximately £26,640 per patient per year (excluding VAT) for a 600 mg dose (the maximum recommended dose in the summary of product characteristics) administered every 2 weeks. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of omalizumab has agreed a patient access scheme with the Department of Health, which makes omalizumab available with a discount applied to all invoices. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from several sources (appendix B). # Clinical effectiveness The Assessment Group focused on 5 specific questions: the efficacy of omalizumab; the long‑term efficacy of omalizumab; the corticosteroid‑sparing effect of omalizumab; the safety of omalizumab; and the adverse effects of oral corticosteroids. The Assessment Group identified 11 randomised controlled trials to include in its review on efficacy, which compared omalizumab with placebo or no added treatment. Nine of the randomised controlled trials were relevant only to adults and adolescents, 1 trial was relevant only to children and 1 trial was relevant to both age groups (the trial included people between the ages of 6 and 20 years). Three of the randomised controlled trials had populations that met or closely approximated the criteria in the marketing authorisation for adults and adolescents (INNOVATE , EXALT and a study by Chanez et al. 2010 ). Two randomised controlled trials had populations that were broader than those specified in the UK marketing authorisation, but contained relevant subgroups resembling the marketing authorisation (IA‑04 in adults and IA‑05 European population subgroup in children ). The Assessment Group also identified 6 trials as supporting evidence in which an unknown proportion of the population met the criteria in the marketing authorisation (Hanania et al. 2011 , Bardelas et al. 2012 , Vignola et al. 2004 , Hoshino et al. 2012 and Ohta et al. 2009 , and the trial by Busse et al. 2011 in children and young adults). The 10 randomised controlled trials enrolling adults and adolescents lasted from 16 to 52 weeks. Trials in which the entire population met the criteria in the marketing authorisation lasted from 16 weeks (Chanez et al.) to 32 weeks (EXALT); INNOVATE ran for 28 weeks. In children, IA‑05 ran for 52 weeks, of which the final 28 weeks was a corticosteroid‑sparing phase. The study by Busse et al. included in the review by the Assessment Group as supporting evidence ran for 60 weeks. The inclusion criteria and treatment regimen varied even among trials in which the whole population or a defined subgroup met the criteria in the marketing authorisation. For example, EXALT included people on a lower dose of inhaled corticosteroids (800 micrograms or more of beclometasone dipropionate or its equivalent) than did the IA‑04 study European population subgroup or INNOVATE (both 1000 micrograms or more of beclometasone dipropionate equivalent). All of the trials in which the whole population or a defined subgroup met marketing authorisation criteria required the use of a long‑acting beta2 agonist, but the concomitant treatments used (such as leukotriene antagonists and theophylline) varied between studies. The proportion of people taking oral corticosteroids was comparable (approximately 20%) between EXALT, INNOVATE and the trial by Chanez et al.; oral corticosteroid use was not reported in IA‑04. In the European population subgroup in the IA‑05 study, all children took 500 micrograms or more of inhaled fluticasone or the equivalent plus a long‑acting beta2 agonist. The mean dose of inhaled fluticasone was 743 micrograms and 58% took an additional drug; most of the children received a leukotriene antagonist. The primary outcomes of the trials selected varied. The primary outcome for INNOVATE was the rate of clinically significant asthma exacerbations. Secondary outcomes included the rate of clinically significant severe exacerbations and the rate of emergency visits for asthma. The IA‑05 trial and Hanania et al. had clinically significant exacerbations as a primary outcome; in SOLAR it was 1 of the designated primary outcomes together with disease‑related quality of life. In other trials, persistence of response (EXALT), asthma deterioration‑related incidents (IA‑04), Asthma Control Test score, and other measures of symptoms and lung function were the primary outcomes measured. The Assessment Group considered that the quality of the included randomised controlled trials was generally high, and that the 5 studies in which the population or a defined subgroup represented the licensed population adequately allocated and concealed randomisation. Eight of the 11 trials included in the review were double blind and placebo controlled and had a low risk of bias. However, the Assessment Group considered that the open‑label EXALT and IA‑04 trials in adults had a higher risk of bias. The Assessment Group therefore did not pool the data from EXALT and IA‑04 with the INNOVATE trial for the base‑case analysis, but did so for EXALT and INNOVATE in the exploratory sensitivity analysis in the economic evaluation. In addition to the trial data presented, the Assessment Group used data from observational studies to support evidence from the trials and, in particular, observational studies that provided data on longer‑term response to omalizumab and on corticosteroid sparing. These included open‑label continuation studies, uncontrolled cohort studies (in which all patients took omalizumab) and post‑marketing studies. ## Clinical effectiveness results For effectiveness of treatment, 4 of the 10 randomised controlled trials for the adult population (INNOVATE, EXALT, SOLAR and Bardelas et al.) and 1 randomised controlled trial in children (IA‑05 European population subgroup) reported the global evaluation of treatment effectiveness (GETE). There was a response to treatment in a higher proportion of people randomised to omalizumab compared with the comparator as assessed by the GETE ratings of good or excellent. Response to treatment with omalizumab was higher in the open‑label EXALT trial (70% compared with 28.2% at 16 weeks, relative risk 2.24, 95% confidence interval 1.71 to 2.92) than in the double‑blind trials (INNOVATE, 56.5% compared with 41.0% at 28 weeks ; SOLAR, 59.3% compared with 41.3% at 28 weeks ; Bardelas et al., 55.1% compared with 48.1% at 24 weeks ). Response rates in adults measured by the GETE were also reported in 4 uncontrolled observational studies and were higher than in the double‑blind INNOVATE trial. In the IA‑05 European population subgroup of children, 74% of the omalizumab group responded to treatment as assessed by the GETE ratings of good or excellent at 52 weeks compared with 64.5% in the placebo group, but this was not statistically significant (RR 1.15, 95% CI 0.95 to 1.39). For the outcome of clinically significant exacerbations, all of the 11 randomised controlled trials reported data with the exceptions of Bardelas et al. and Hoshino et al. The Assessment Group observed that clinically significant exacerbations were defined differently between trials, but still considered it appropriate to compare these trials. The Assessment Group found a consistent benefit for people randomised to omalizumab compared with the comparator group, both in terms of the rate of exacerbations and the proportion of people who experienced no exacerbations during follow‑up. For example, the rate of total exacerbations in the INNOVATE trial over 28 weeks was 0.68 for omalizumab compared with 0.91 in the placebo arm (rate ratio 0.738, 95% CI 0.552 to 0.998). In EXALT, the rate of total exacerbations over 32 weeks was 0.55 for omalizumab compared with 0.98 for the comparator (no added treatment; rate ratio 0.570, 95% CI 0.417 to 0.778) and, in the IA‑04 European population subgroup, the rates over 52 weeks were 1.26 and 3.06 respectively (rate ratio 0.41, 95% CI 0.288 to 0.583). The trial by Chanez et al. showed no statistically significant difference between the groups at 16 weeks (RR 0.71, 95% CI 0.37 to 1.37). For children, the results from the IA‑05 European population subgroup showed a statistically significant benefit in the rate of total exacerbations for omalizumab (0.42 compared with 0.63 in the comparator arm at 24 weeks, rate ratio 0.662, 95% CI 0.441 to 0.995). In both children and adults, observational studies and trials used to support trial evidence showed that people taking omalizumab had reductions in the exacerbation rate from baseline. Three of the included trials reported separately the incidence of clinically significant severe exacerbations (defined as an exacerbation in which peak expiratory flow or FEV1 is less than 60% of a patient's personal best) and clinically significant non‑severe exacerbations. For adults, the rate of clinically significant severe exacerbations was statistically significantly lower in patients randomised to omalizumab compared with the comparator (INNOVATE, 0.24 compared with 0.48, rate ratio 0.50, 95% CI 0.32 to 0.78; EXALT, 0.24 compared with 0.42, rate ratio 0.56, 95% CI 0.34 to 0.92). For children, the results from the IA‑05 European population subgroup favoured omalizumab, but were not statistically significant (0.14 compared with 0.22 at 24 weeks follow‑up, rate ratio 0.66, 95% CI 0.30 to 1.42). The Assessment Group commented that this small subgroup lacked power. Evidence from a single non‑comparative observational study (Deschildre et al. 2010) showed a reduction in severe exacerbations in children (from 4.4 severe exacerbations per year to 0.51 per year (statistical significance not recorded). The manufacturer provided rates of exacerbations for the following 5 subgroups defined post hoc in the studies: people who were hospitalised before the onset of the study; people on oral corticosteroids at baseline; people not on oral corticosteroids at baseline; people who had 2 or fewer exacerbations per year at baseline; and people who had 3 or more exacerbations per year at baseline. The Assessment Group commented that data from the INNOVATE trial show that omalizumab may work better in people on maintenance oral corticosteroid therapy than the overall population. The relative risk of total exacerbations in the population taking maintenance oral corticosteroids was 0.662 (compared with 0.74 in the total population) and the relative risk of clinically significant severe exacerbations was 0.36 (compared with 0.50 in the total population), but with no statistical significance reported. Four trials (INNOVATE, EXALT, the IA‑04 European population subgroup in adults and the IA‑05 European population subgroup in children) reported results on the effectiveness of omalizumab for the 'responder' subgroup (that is, patients randomised to omalizumab whose asthma responded compared with patients randomised to placebo or standard care alone) using GETE ratings or Asthma Quality of Life Questionnaire scores (IA‑04 European population subgroup). In these analyses, the relative risk for total exacerbations was 0.37 (95% CI 0.27 to 0.52) in INNOVATE, 0.41 (95% CI 0.31 to 0.55) in EXALT, 0.37 (95% CI 0.24 to 0.55) in the IA‑04 European population subgroup and 0.38 (95% CI 0.15 to 0.91) in the IA‑05 European population subgroup, showing a statistically significant advantage for omalizumab. This pattern in the results was similar for the outcome of clinically significant severe exacerbations. Six randomised controlled trials (INNOVATE, EXALT, IA‑04, Chanez et al., IA‑05 and Busse et al.) compared rates of hospitalisation during the studies. The results favoured the omalizumab group but were not statistically significant, apart from in the EXALT study in which randomisation to omalizumab compared with no additional treatment was associated with a rate ratio of 0.33 (95% CI 0.12 to 0.94). Three studies in adults (INNOVATE, EXALT and IA‑04) presented data separately for the outcomes of emergency department visits and unscheduled doctor visits. As with rates of hospitalisation, the only study to show a statistically significant benefit with omalizumab for these outcomes was EXALT. There were, however, statistically significant reductions associated with omalizumab in total emergency visits, including hospital admissions, emergency department and unscheduled visits to the doctor (INNOVATE compared with placebo: risk ratio 0.56, 95% CI 0.33 to 0.97; EXALT: risk ratio 0.40, 95% CI 0.24 to 0.65; IA‑04 European population subgroup: risk ratio 0.76, 95% CI 0.64 to 0.89). For children, the IA‑05 European population subgroup showed no difference between treatment groups for emergency department visits, unscheduled doctor visits or total emergency visits. The Assessment Group commented that limited data from observational studies showed evidence of fewer hospitalisations and unscheduled healthcare visits compared with baseline; when statistical tests were reported, these showed statistically significant benefits of omalizumab treatment relative to baseline or standard care. However, there were no data available for children from observational studies on visits to the doctor or emergency room, or hospitalisations. Analyses limited to people receiving omalizumab whose asthma responded compared with people receiving placebo or standard care showed evidence of statistically significant benefit from both INNOVATE and EXALT for hospitalisation and other unscheduled medical care except emergency department visits in INNOVATE. Children in the IA‑05 European population subgroup with a response to omalizumab had a statistically significant reduction in hospitalisation rates compared with children in the placebo arm with a response, but no benefits for other unscheduled healthcare measures. The various studies assessed asthma severity differently and used a wide range of scales and measures to assess response to treatment. In INNOVATE, total asthma symptom score improved more at 28 weeks with omalizumab than with placebo (change from baseline −0.66 with omalizumab compared with −0.40 with placebo, p=0.039). In EXALT, people randomised to open‑label omalizumab experienced a greater improvement in total asthma symptom score at 32 weeks than people randomised to standard care without omalizumab using the Asthma Control Questionnaire (change from baseline −0.91 with omalizumab compared with −0.04 without omalizumab, RR 0.87, 95% CI −1.09 to −0.65) and in the IA‑04 European population subgroup at 52 weeks using the Wasserfallen symptom score (change from baseline −6.7 with omalizumab compared with 0.5 with no additional treatment, p0.05 for both measures at 24 weeks and at 52 weeks). In addition, an observational study in children with severe uncontrolled allergic asthma (Brodlie et al. 2000) found statistically significant increases in the scores of the Asthma Control Test (measuring asthma symptoms) after treatment with omalizumab (p=0.001). Evidence on the impact of individual symptom measures for children, adolescents and adults was limited and mixed. There was limited evidence about whether treatment with omalizumab changed the need for rescue treatment, most commonly salbutamol (albuterol) and terbutaline. In the population that met marketing authorisation criteria, INNOVATE, the IA‑04 European population subgroup and the trial by Chanez et al. reported data on rescue treatment for adults, and the IA‑05 European population subgroup reported data for children. The IA‑04 European population subgroup was the only trial in the licensed population to show a statistically significant difference between the treatment groups. This trial found that the mean puffs of salbutamol per day per patient over 14 days was 3.91 in the omalizumab group compared with 5.33 in the group not taking omalizumab (p=0.008). Data from Hanania et al. included by the Assessment Group as supporting data, reported a statistically significant reduction in the use of rescue treatment in people randomised to omalizumab compared with placebo. Observational studies provided limited evidence, with 2 studies reporting reduced use of rescue treatment compared with baseline use, but with no results of statistical tests. In children the IA‑05 European population subgroup initially showed a statistically significant benefit but this lost significance after adjustment for multiple testing. There was no additional evidence from supporting randomised controlled trials or observational studies in children. Randomised controlled trials of the population reflecting the marketing authorisation showed benefits of omalizumab compared with the comparator arm in improving lung capacity as measured by percentage of predicted FEV1, although these absolute benefits were small. These included INNOVATE at 28 weeks (67.0% with omalizumab compared with 64.2% without omalizumab, p=0.043), EXALT at 32 weeks (68.1% with omalizumab compared with 63.7% with no omalizumab, p=0.007), and the IA‑04 European population subgroup at 52 weeks (71% with omalizumab compared with 60% with no additional treatment, p<0.01). Supporting trials did not show a statistically significant benefit, but the Assessment Group commented that these studies were conducted in people with better lung function. Some observational studies provided additional evidence that omalizumab is associated with statistically significant improvements in lung function in adults with uncontrolled severe asthma. In children, there was no randomised controlled trial evidence for FEV1 for the licensed population. The trial of children and young adults by Busse et al. included in the Assessment Group's review as supporting evidence and the observational studies in children reported no statistically significant differences between treatment groups. Six trials in adults (INNOVATE, EXALT and IA‑04 European population subgroup in the licensed population, and SOLAR, Hanania et al. and Hoshino et al. among the supporting studies) plus 1 trial in children (the IA‑05 European population subgroup) reported some measure of asthma‑related quality of life. All trials employed either the Asthma Quality of Life Questionnaire or, in the case of the IA‑05 European population subgroup, the paediatric Asthma Quality of Life Questionnaire. EXALT also reported EuroQol 5‑D (EQ‑5D) scores. In INNOVATE, there was a statistically significant improvement at 28 weeks in the Asthma Quality of Life Questionnaire score (ranging from 1 to 7, with a higher score indicative of a better quality of life) in the intention‑to‑treat omalizumab group compared with placebo (change from baseline 0.91 with omalizumab compared with 0.46 with placebo, p<0.001; 61% of people randomised to omalizumab experienced a 0.5‑point or greater increase compared with 48% with the comparator, p=0.008). Statistically significant improvements favouring omalizumab were also found in EXALT at 31 weeks using the Asthma Quality of Life Questionnaire (change from baseline 1.06 with omalizumab compared with −0.07 with no omalizumab treatment; 74% of people randomised to omalizumab experienced a 0.5‑point or greater increase compared with 26% with the comparator, p<0.001) and in the IA‑04 European population subgroup at 52 weeks (change from baseline 1.32 with omalizumab compared with 0.17 with no additional treatment, p<0.001; 77% of people randomised to omalizumab experienced a 0.5‑point or greater increase compared with 42% with the comparator, p<0.001). The supporting trials also showed quality‑of‑life benefits associated with omalizumab. In children, the IA‑05 European population subgroup reflecting the licensed indication demonstrated a substantial placebo response and showed no statistically significant evidence of treatment benefit (change from baseline 0.78 with omalizumab compared with 0.70 with the comparator, p=0.566; 62% of people randomised to omalizumab experienced a 0.5‑point or greater increase compared with 58% with the comparator, p=0.654). The Assessment Group stated that the lack of evidence for improvements in symptoms and quality of life in children may reflect the subgroup of the IA‑05 European population being underpowered to detect differences. The Assessment Group commented that 3 (APEX, eXpeRience, and PERSIST) of the 5 observational studies that reported a measure of quality of life showed at least a minimally important increase of 0.5 points in score for the Asthma Quality of Life Questionnaire. In the uncontrolled prospective therapeutic trial by Brodlie et al., there was evidence of statistically significant increases in mini‑Asthma Quality of Life Questionnaire scores associated with taking omalizumab in children dependent on oral corticosteroids in the UK. Statistically significant improvements in scores were observed in children aged under 12 years (change from 2.3 at baseline to 5.2 , p=0.019) and in young people aged 12 to 16 years (change from 3.8 at baseline to 6.1 , p=0.0037). The Assessment Group commented that, although the population for this analysis was small (n=24), it represented the only evidence for children with very severe asthma who need oral corticosteroids. Nine randomised controlled trials reported rates of discontinuing omalizumab or the comparator. The double‑blind randomised controlled trials in adults reported discontinuation rates in the omalizumab arm of between 2.4% and 19.4% compared with 7.7% and 22.2% in the placebo arms. In the open‑label trials the discontinuation rates were much higher in the comparator than the omalizumab arm (EXALT: 19.1% compared with 8.1%; IA‑04: 30.6% compared with 17.4%). In the 1 trial in children (IA‑05 European population subgroup), the discontinuation rate was approximately 20% in both arms. The Assessment Group commented that there was very limited evidence relating to the effectiveness of omalizumab beyond 12 months in either adults and adolescents, or children. Three randomised controlled trials and 4 observational studies reported follow‑up data at 52 weeks or longer. Although the PERSIST observational study reported some follow‑up data at 120 weeks, these were limited. Two randomised controlled trials provided data on changes in oral corticosteroid use, 1 in the licensed population (EXALT) and 1 in a population with controlled asthma (trial 011). Trial 011, published by Holgate et al. (2004), was a randomised placebo‑controlled trial evaluating the effect of omalizumab on disease control and oral corticosteroid reduction. The Assessment Group commented that it excluded trial 011 from the other sections of its review because only a few patients received a long‑acting beta2 agonist, but included it in its analysis of corticosteroids because data on changes in oral corticosteroid use were scarce. In the EXALT trial, at 32 weeks, people in the omalizumab group were more likely to have stopped or reduced their use of oral corticosteroids (62.7% compared with 30.4% in the control group, RR 2.06, 95% CI 1.08 to 3.94) and to have reduced their dose of oral corticosteroid (mean difference 6.70 mg/day, 95% CI 12.93 to 0.47). In contrast, in trial 011, the proportions reducing or stopping oral corticosteroids at 32 weeks follow‑up were similar in both the omalizumab and the placebo groups (74.0% compared with 73.3%, RR 1.01, 95% CI 0.79 to 1.28). The Assessment Group commented that the EXALT study was unblinded and trial 011 did not sufficiently adjust oral corticosteroid doses during the run‑in phase. Randomised controlled trial data on oral corticosteroid use in children were not available. Ten uncontrolled observational studies reported data on oral corticosteroid use after omalizumab treatment. The Assessment Group commented that all except 1 of these studies were uncontrolled, with greater potential for bias, relatively small, and did not provide data beyond 12 months. For adults on maintenance oral corticosteroids, the proportion of patients reducing or stopping oral corticosteroids ranged from 25.9% to 71.2% after omalizumab treatment. The outcomes for children on oral corticosteroid maintenance were reported in uncontrolled studies by Brodlie et al. and Kirk et al. (2011) performed in study populations that may have overlapped. Patients in both studies showed a statistically significant decrease in oral corticosteroid use after 16 weeks of treatment with omalizumab, with the proportion of patients reducing or stopping oral corticosteroids being 13.3% (in the subgroup of children aged 5 to 12 years) and 22.2% (in children aged 6 to 11 years). The median baseline daily oral corticosteroid dose in the Brodlie et al. study was 20 mg (range 5–50 mg), which fell to 5 mg (range 0–40 mg). All patients in the Kirk et al. study either reduced or stopped oral corticosteroid treatment at follow‑up, with a mean daily oral corticosteroid dose reduction of 14 mg. Those patients who did not stop oral corticosteroids had a mean reduction from 20 mg to 5 mg per day. The Assessment Group included a summary of published systematic reviews of the adverse effects of oral corticosteroids, stating that the reliability of the data was unclear. The reviews included the known adverse effects of bone fracture, diabetes mellitus, peptic ulcer, cardiovascular events including myocardial infarction and stroke, cataract and glaucoma, sleep and mood disturbance, and weight gain and, for children, failure to reach expected adult height. The Assessment Group identified 4 reviews of adverse effects associated with omalizumab; these were published between 2007 and 2011 and had a sample size ranging from 3429 to 57,300 people. Two of the reviews included randomised controlled trials and 1 included both randomised controlled trials and open‑label studies. One review included people with severe persistent allergic asthma, the second included people with moderate‑to‑severe persistent allergic asthma, the third included people who had received omalizumab, but in whom the indication was unclear, and the fourth review assessed the incidence of anaphylaxis from the Adverse Event Reporting System in people with asthma who had received omalizumab. The key adverse events considered by the Assessment Group were anaphylaxis and arterial thrombotic events. The Assessment Group stated that both occur rarely and have not been conclusively linked to omalizumab. The Assessment Group commented that the evidence that associated omalizumab with cancer is also uncertain. The Assessment Group concluded that, although evidence exists for the short‑term safety of omalizumab, there was insufficient evidence on long‑term safety to draw any conclusion. # Cost effectiveness The Assessment Group identified 6 published studies that evaluated the cost effectiveness of omalizumab for asthma. All studies compared omalizumab with standard care, which differed between studies. For example, Oba and Salzman (2004), Wu et al. (2007) and Campbell et al. (2010) considered inhaled corticosteroid plus additional rescue treatment (as needed) as standard care, whereas Dewilde et al. (2007), Brown et al. (2007) and Dal Negro et al. (2011) considered high‑dose inhaled corticosteroids and long‑acting beta2 agonists as standard care. All of the cost‑effectiveness models in these studies assumed that omalizumab conferred benefits, compared with standard care, by reducing clinically significant exacerbations. The studies varied in methodology and conclusions; 5 of 6 studies used quality‑adjusted life years (QALYs) to assess effectiveness for omalizumab compared with standard care, and the resulting incremental cost‑effectiveness ratios (ICERs) ranged from approximately £21,700 to £516,500 per QALY gained. Brown et al. concluded that omalizumab was cost effective, Oba and Salzman and Dewilde et al. concluded that omalizumab may be cost effective for people with severe asthma, Wu et al. concluded that omalizumab was not cost effective unless its acquisition price was reduced substantially, and Campbell et al. and Dal Negro et al. concluded that, although omalizumab improves health‑related quality of life, it also increases costs substantially. The Assessment Group commented that the studies had common issues and limitations that precluded reliable conclusions, and included differing populations, differing relative efficacy and adverse effects of omalizumab compared with oral corticosteroids, lacked robust data for asthma‑related mortality and health‑related quality of life, lacked consensus on treatment duration, and differed as to whether treatment persists over time. ## Manufacturer's economic model The manufacturer submitted an economic evaluation with a model structure identical to that used in NICE technology appraisals 133 and 201. This compared the costs and health outcomes of omalizumab as an add‑on treatment to standard care compared with standard care alone in people with severe persistent allergic asthma uncontrolled despite daily high‑dose inhaled corticosteroids plus a long‑acting beta2 agonist at BTS/SIGN step 4 or 5. The manufacturer used a Markov model that extrapolates the effects of omalizumab treatment for 10 years and follows a hypothetical cohort over a lifetime time horizon (up to age 100 years). People enter the model on either omalizumab in addition to standard care, or standard care alone in a health state characterising day‑to‑day symptoms of asthma. At 16 weeks (the end of the first cycle), asthma in people taking omalizumab either does or does not respond to treatment based on the proportion of response in the trials. People whose asthma responds to omalizumab remain on it for the treatment duration, and the model assumes that they experience exacerbations at the rates observed for people whose asthma has responded in the clinical trials. The model assumes that people whose asthma does not respond stop taking omalizumab revert to standard care alone and have rates of exacerbation experienced by patients in trials randomised to standard care. During each subsequent cycle of the model, people either remain in the day‑to‑day symptom state or can experience an exacerbation. The manufacturer assumed that an asthma‑related death occurs only during a clinically significant severe exacerbation, with each exacerbation being associated with a mortality risk of 0.097% for children under 12 years, 0.319% for those aged 12 to 16 years, 0.383% for those aged 17 to 44 years, and 2.478% for those aged 45 years and over, all of which the manufacturer derived from mortality data for people hospitalised for acute severe asthma from Watson et al. (2007). The model also assumes that people with asthma can die from non‑asthma related causes. After a non‑fatal exacerbation, a person returns to the day‑to‑day asthma symptoms health state. The manufacturer's model includes 2 separate base‑case populations: adults plus adolescents aged 12 years and over (average age approximately 40 years), and children aged 6 to 11 years (average age 9 years) and 2 subgroups: people who are hospitalised in the year before entering the model, and a subgroup of people who receive maintenance oral corticosteroids when entering the model. The model evaluates costs from the perspective of the NHS and personal social services, and discounts costs and health outcomes at a rate of 3.5% per annum, in accordance with the NICE reference case. The manufacturer derived the evidence on the clinical effectiveness of omalizumab as add‑on treatment in the model's base case from the results of INNOVATE (adults and adolescents) and IA‑05 (children) and, for the model's scenario analysis in adults and adolescents, from EXALT and APEX. The effectiveness of treatment was based on data from trials on whether or not patients' asthma responded to omalizumab and their rates of clinically significant non‑severe exacerbation and clinically significant severe exacerbation. The manufacturer included the costs of acquiring, administering and monitoring omalizumab. Omalizumab dose depends on a patient's baseline serum IgE and weight, and the base‑case model assumes an average dose corresponding to the dose distribution in the populations in INNOVATE, EXALT, APEX and IA‑05. The manufacturer estimated the costs of administration by assuming that it takes a specialist asthma nurse 10 minutes to administer omalizumab, and that specialist asthma nursing care costs the NHS £47 per hour. The manufacturer included costs to monitor for anaphylaxis and for the 16‑week assessment. Standard care costs included 2 routine outpatient appointments per year with a hospital specialist and 2 extra visits for people taking omalizumab. The cost of standard care in the model corresponded to the standard care used in the trials. In addition, the cost of exacerbations, including GP consultations, outpatient appointments, emergency admissions, rehabilitation appointments, general ward stays and intensive care were calculated from the INNOVATE, EXALT, APEX and IA‑05 trials. The manufacturer estimated health‑related quality of life (expressed in QALYs) by quality adjusting the period of time the average patient was alive within the model and applying a corresponding utility score. The 2 key elements determining health‑related quality of life were day‑to‑day symptoms and exacerbations (clinically significant non‑severe and severe). For day‑to‑day symptoms in the base‑case analysis, the manufacturer estimated utility values from the Asthma Quality of Life Questionnaire scores collected in INNOVATE and mapped these onto EQ‑5D values; the values were 0.669 for people receiving standard care and 0.779 for people taking omalizumab whose asthma responded to omalizumab (resulting in a difference in EQ‑5D of 0.110). For the subgroup reflecting patients from INNOVATE who were hospitalised in the year before trial entry, the manufacturer used a utility difference of 0.138 and, for the subgroup from INNOVATE who required maintenance oral corticosteroids, the manufacturer used a utility difference of 0.106. To estimate a person's utility decline associated with a clinically significant non‑severe or severe exacerbation, the manufacturer used values from a prospective study conducted in the UK in 4 specialist asthma centres where health‑related quality‑of‑life data were collected (n=112) using the EQ‑5D, mini Asthma Quality of Life Questionnaire, and Asthma Symptom Utility measures (Lloyd et al. 2007). The mean utility value assigned to a clinically significant non‑severe exacerbation was 0.572, and to a clinically significant severe exacerbation was 0.326, compared with 0.889 for no exacerbations. The manufacturer assumed that children aged 6 to 11 years taking omalizumab did not experience any improvement in health‑related quality of life. ## Results of manufacturer's economic model The base‑case deterministic ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone in adults and adolescents was estimated by the manufacturer to be £32,076 per QALY gained, and the probabilistic ICER to be £33,268 per QALY gained. The deterministic base‑case ICER for children was estimated to be £80,747 per QALY gained and the probabilistic ICER to be £88,998 per QALY gained. The manufacturer estimated that the probability that omalizumab is cost effective at £20,000 and £30,000 per QALY gained for adults and adolescents is 0.005 and 0.267 respectively. The manufacturer presented cost‑effectiveness results for alternative scenarios based on data from the EXALT study, the best study to provide a scenario for open‑label use of omalizumab, and APEX, the best observational study to provide a scenario relevant to UK practice. The ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone was £61,687 per QALY gained using data from EXALT and £29,773 per QALY gained using data from APEX. The difference in ICER between the INNOVATE base case and the EXALT scenario resulted largely from the lower effect of treatment with omalizumab among people whose asthma responded to omalizumab observed in EXALT compared with INNOVATE, and the difference in improvement in health‑related quality of life for day‑to‑day symptoms estimated in INNOVATE (Asthma Quality of Life Questionnaire mapped to EQ‑5D) being greater than that in EXALT (directly observed EQ‑5D data). Omalizumab reduced the rate of total exacerbations more in INNOVATE (RR 0.373) than in EXALT (RR 0.410), and the health utility improvement was also greater in INNOVATE than in EXALT. The manufacturer conducted several deterministic sensitivity analyses on the base‑case populations (INNOVATE and IA‑05 European population). The manufacturer concluded that the results were sensitive to changes in the time horizon, exacerbation rates, asthma‑related mortality, health‑related quality‑of‑life values for day‑to‑day asthma symptoms, omalizumab drug costs and the discount rate. The parameters that had the most effect on the results in the manufacturer's model were asthma‑related mortality and assumptions around health‑related quality of life with omalizumab. The ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone in adults and adolescents increased from £32,076 to £72,113 per QALY gained when asthma‑related mortality risk was set to zero. For children, the effect on the ICER was less pronounced because the asthma‑related risk of dying is much lower in children than in adults and adolescents. For children, treatment duration and the age at which a child starts treatment with omalizumab impacts on the cost effectiveness of omalizumab, reflecting the manufacturer's assumption that treatment with omalizumab does not improve health‑related quality of life until age 12 years or over. Assuming a treatment duration of 2 years instead of 10 years increased the ICER from £80,747 to £662,893 per QALY gained. .Similarly, reducing the age of starting treatment from 9 to 6 years increased the ICER to £130,475 per QALY gained. Assuming a health‑related quality‑of‑life gain with omalizumab in children equal to that seen in adults and adolescents (0.779) reduced the ICER in children to £61,731 per QALY gained. For the subgroup reflecting people who had been hospitalised in the year before starting therapy with omalizumab, the ICERs for omalizumab as an add‑on treatment to standard care compared with standard care alone were £27,928, £35,198 and £30,407 per QALY gained for adults and adolescents (based on data from INNOVATE, EXALT and APEX respectively) and £65,100 per QALY gained for children (based on data from the IA‑05 European population). For the subgroup reflecting people who required maintenance oral corticosteroids at the time of starting omalizumab, the ICERs for adults and adolescents were £26,320, £37,604 and £29,685 per QALY gained (based on data from INNOVATE, EXALT and APEX respectively). Data for the maintenance oral corticosteroid subgroup were not available from the IA‑05 European population because only 6 patients were on maintenance oral corticosteroids at baseline. The manufacturer conducted a sensitivity analysis, acknowledging the adverse effects of using maintenance oral corticosteroids, and calculated a potential 'oral corticosteroids‑sparing' effect of treatment with omalizumab. The manufacturer conducted these analyses in the subgroup of patients on maintenance oral corticosteroids in EXALT and APEX; the protocol of INNOVATE did not allow investigators to change a patient's ongoing standard care during the study period. In EXALT, 41.9% of people whose asthma responded to omalizumab stopped maintenance oral corticosteroids after 32 weeks, whereas in APEX 45.1% of people whose asthma responded to omalizumab had stopped maintenance oral corticosteroids at follow‑up. For people whose asthma responded to omalizumab and who stopped maintenance oral corticosteroids, the manufacturer applied lower costs and higher QALYs in the model, and the ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone was reduced from £37,604 to £28,319 per QALY gained (using data from EXALT) and from £29,685 to £25,099 per QALY gained (using data from APEX). ## Assessment Group's critique of manufacturer's cost‑effectiveness analysis The Assessment Group commented that the manufacturer assumed that the effectiveness of treatment with omalizumab (in people whose asthma had responded to omalizumab by a given time point) did not diminish over time. In contrast, in the EXALT study, 8.6% of patients whose asthma had responded to omalizumab at 16 weeks no longer responded to omalizumab at 32 weeks. The Assessment Group commented that the study's open‑label design may have influenced the results in favour of omalizumab because knowing the patient's treatment may have affected how the investigator assessed response to omalizumab as well as how the patients reported exacerbations. The Assessment Group commented that, to estimate the health‑related quality‑of‑life benefit with omalizumab, measuring EQ‑5D directly is more appropriate than the manufacturer's method of mapping Asthma Quality of Life Questionnaire scores (from INNOVATE) onto EQ‑5D values. In addition, the manufacturer assumed that children under 12 years do not experience any improvement in health‑related quality of life with omalizumab until they reach 12 years whereas the Assessment Group considered that the observational study of children by Brodlie suggested that young children also experience an improvement in asthma‑related quality of life. The Assessment Group considered that the manufacturer's subgroup sensitivity analyses in people on maintenance oral corticosteroids were generally reasonable, considering the limited evidence. However, to estimate health utility losses from adverse effects related to oral corticosteroids, the manufacturer used disability‑adjusted life‑years (DALYs), which it assumed are equivalent to QALYs, an assumption the Assessment Group considered may not have been appropriate. The Assessment Group commented that the manufacturer had addressed some of the uncertainties previously identified in NICE technology appraisals 133 and 201: in particular, the relative efficacy, safety and costs of omalizumab compared with maintenance oral corticosteroids, and a subgroup consisting of people who were hospitalised for asthma in the year before starting omalizumab, but also that several key uncertainties remained. For example, according to the Assessment Group the manufacturer had not adequately addressed the mortality associated with asthma; the relationship between mortality, age and severity of exacerbations; the degree to which omalizumab improves health‑related quality of life; and the influence of age on the cost‑effectiveness results. The Assessment Group commented that the asthma‑related mortality rates applied by the manufacturer in the model may have overestimated the number of asthma deaths because the manufacturer assumed that an individual dies from asthma only when experiencing a clinically significant severe exacerbation (from the health state of 'clinically significant exacerbation'), whether or not hospitalised; however, the manufacturer applied a mortality risk derived only from hospitalised patients. Data from INNOVATE showed that only about 20% of clinically significant severe exacerbations resulted in admission to hospital. In addition, the manufacturer used the mean age at which patients in trials started omalizumab in the model, which made the effect of omalizumab in different age groups difficult to discern. The Assessment Group commented that, because age affects the risk of asthma‑related mortality, the manufacturer should have considered the impact of age at the start of treatment, either by presenting ICERs by subgroups based on age or by combining estimates for different ages into a weighted ICER estimate. The Assessment Group commented that there is uncertainty about the association between clinically significant severe exacerbations and death. The Assessment Group considered that, because the manufacturer only included studies that linked severe exacerbations to asthma deaths in its systematic review on asthma‑related mortality, it may have excluded studies relevant to the appraisal. The Assessment Group also highlighted that, if the asthma‑related mortality rate used by the manufacturer (2.478% in adults aged 45 years and over; derived from Watson et al.) was applied to the INNOVATE study, 2 or 3 asthma deaths would have been expected out of the 100 observed clinically significant severe exacerbations. In addition, if the same ratio of clinically significant exacerbations to clinically significant severe exacerbations in the INNOVATE study was applied to the APEX study, 3 deaths per year from asthma would have been expected among the 261 observed exacerbations. However, because nobody in these trials died from asthma, the Assessment Group commented that the rates for asthma‑related mortality used in the manufacturer's submission for adults and adolescents were likely to have overestimated mortality. ## Assessment Group's economic model The Assessment Group developed an economic model from the perspective of the UK NHS to assess the cost effectiveness of omalizumab as an add‑on treatment to optimised standard care of severe asthma compared with optimised standard care alone. The outcomes of the model are expressed in costs per QALY and costs in UK pound sterling at a 2009/10 price base. The Assessment Group evaluated both costs and outcomes over a lifetime, assuming an omalizumab treatment duration of 10 years and discounting at an annual rate of 3.5%, in accordance with the NICE reference case. The evidence of effectiveness of omalizumab compared with not using omalizumab for the base‑case population in the Assessment Group's model came from INNOVATE for adults and adolescents, and from the IA‑05 European population subgroup for children. In addition, the model included a subgroup defined as people admitted to hospital in the year before starting omalizumab (for adults and adolescents, 38.4% of the total INNOVATE trial population at baseline and, for children, 17% of the IA‑05 European population subgroup at baseline), and a subgroup of adults and adolescents who reflect people receiving maintenance oral corticosteroids at the start of treatment with omalizumab (21.7% of the INNOVATE population at trial baseline; for children, data were not available from the IA‑05 trial). The model structure used by the Assessment Group was similar to the manufacturer's but differed in the assumptions for asthma‑related mortality and health‑related quality of life. In its model, the manufacturer linked asthma‑related deaths directly to a clinically significant severe exacerbation, whereas the Assessment Group's model assumed that people in the state of day‑to‑day asthma symptoms (and not only the state of clinically significant severe exacerbation) have an elevated risk of asthma‑related death compared with people without asthma. The Assessment Group systematically reviewed the literature for estimates of asthma‑related mortality and considered that the most appropriate data for the base case comes from de Vries et al. (2010), which used data from the General Practice Research Database from patients without chronic obstructive pulmonary disease registered in general practice in England aged 18 years and over who received a prescription for inhaled short‑acting or long‑acting beta2 agonists. The study followed patients from 1993 and until death, death from asthma or hospitalisation for asthma, and derived incidence rates stratified by treatment steps (1 to 5) of the BTS. In sensitivity analyses, the Assessment Group used alternative mortality rates from Watson et al., as used in the manufacturer's model. In the base case, the Assessment Group estimated, using the de Vries et al. data, that the probability of death over a 3‑month period (the cycle length used in the model) was 0.001 for all ages and acknowledged an absence of data for children. The Assessment Group also estimated, using the Watson et al. data, that the probability of death specifically related to asthma over a 3‑month period was 0.0049 for people 45 years and over, 0.0008 for those 17 to 44 years, 0.0006 for those 12 to 16 years, and 0.0001 for children under 12 years. As in the manufacturer's model, the Assessment Group's model considered health‑related quality of life associated with day‑to‑day symptoms of asthma, the degree to which exacerbations worsen the symptoms, and the degree to which treatment with omalizumab improves them. However, to estimate health‑related quality of life for day‑to‑day symptoms, the Assessment Group used EQ‑5D data from EXALT, whereas the manufacturer mapped Asthma Quality of Life Questionnaire scores from INNOVATE onto EQ‑5D values. The Assessment Group assumed that children experience the same improvement in health‑related quality of life from omalizumab treatment as do adults and adolescents, whereas the manufacturer's model assumed no health‑related quality‑of‑life benefit from treatment with omalizumab in children. In the base‑case population, the Assessment Group applied a health utility value for day‑to‑day asthma symptoms for people receiving standard care of 0.719 (compared with 0.669 in the manufacturer's model) and for people taking omalizumab and whose asthma responded to omalizumab at 32 weeks, a utility value of 0.767 (compared with 0.779 in the manufacturer's model). The improvement in utility attributed to omalizumab was smaller in the Assessment Group's model at 0.048 than in the manufacturer's model, with a difference of 0.110. For patients hospitalised in the year before starting (or not starting) omalizumab, the Assessment Group estimated that the difference in utility attributable to omalizumab was 0.130 (compared with 0.138 in the manufacturer's model) and for patients on maintenance oral corticosteroids at the start (or not) of treatment with omalizumab was a difference in utility of 0.105 (compared with 0.106 in the manufacturer's model). To estimate the decrease in utility caused by clinically significant non‑severe and severe exacerbations, the Assessment Group and the manufacturer used data from a prospective study conducted in 4 UK specialist asthma centres, which collected EQ‑5D data (Lloyd et al.). The Assessment Group commented that exacerbations leading to hospitalisation may have been more severe in the Lloyd et al. study than in the INNOVATE study, which could have led to overestimation of the effect of an exacerbation on health‑related quality of life. The Assessment Group indicated that the combined impact of these factors is unclear. The Assessment Group included in its model the costs of omalizumab and its administration, and costs related to monitoring patients. The costs of omalizumab reflected every 2 to 4 week dosing dependent on serum IgE and body weight. The Assessment Group used the unit price of the 75‑mg syringe (£128.07) to estimate an average annual cost of omalizumab per patient based on the dose distribution used in the trials (INNOVATE for adults and adolescents and IA‑05 European population subgroup for children) obtained from the manufacturer's submission. The Assessment Group assumed 10 minutes of a specialist asthma nurse's time to administer omalizumab, and 15 minutes of nurse's time (both at £47/hour) to monitor the patient up to the third time a patient received omalizumab. From the fourth administration up to the 16‑week assessment, monitoring by the specialist nurse was assumed to take 1 hour. From 16 weeks onwards, no monitoring costs were incurred. The Assessment Group assumed that a patient's 16‑week assessment took place during a routine appointment. This differs from the manufacturer's model, which assumed that clinicians assess the patient during an additional follow‑up appointment. The Assessment Group calculated the annual average cost of omalizumab for adults and adolescents as £8056 plus administration costs of £260 in the first year and £146 in subsequent years; for children, the annual average cost of omalizumab was £8455 plus administration costs of £268 in the first year and £151 in subsequent years. The distribution of the dose of omalizumab for the subgroups (when starting omalizumab when hospitalised in the previous year, or on maintenance corticosteroids) was not available; therefore, the Assessment Group used data from the base‑case patient population for the subgroups. The Assessment Group took the costs of exacerbations and standard care from the manufacturer's submission and applied them to both modelled treatment groups. ## Results of Assessment Group's economic model For adults and adolescents, and for children, omalizumab add‑on treatment was more costly and more effective than standard care alone. For adults and adolescents, the mean cost of omalizumab add‑on treatment was £72,938 compared with £33,218 for standard care without omalizumab; the mean QALYs were 14.13 and 13.66 respectively. This resulted in an ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone of £83,822 per QALY gained. For children the mean cost of omalizumab add‑on treatment was £92,497 compared with £40,218 for standard care without omalizumab; the mean QALYs were 17.39 and 16.72 respectively. This resulted in an ICER for omalizumab of £78,009 per QALY gained. The Assessment Group estimated that the probability that omalizumab was cost effective at £30,000 per QALY was zero in both populations. For the modelled subgroup reflecting people who had been hospitalised the year before starting treatment, omalizumab add‑on treatment was more costly and more effective than standard care without omalizumab. For adults and adolescents, the mean cost of treatment with omalizumab was £75,826 compared with £36,449 for standard care with mean QALYs of 12.68 and 11.83 respectively. This resulted in an ICER for omalizumab of £46,431 per QALY gained. For children, the mean cost of omalizumab was £83,145 compared with £44,718 for standard care; the mean QALYs were 15.32 and 14.45 respectively. This resulted in an ICER for omalizumab of £44,142 per QALY gained. The Assessment Group estimated that the probability that omalizumab was cost effective at £30,000 per QALY gained was zero in both populations. For the modelled subgroup reflecting people who took maintenance oral corticosteroids, omalizumab add‑on treatment was more costly but also more effective than standard care alone. For adults and adolescents, the mean cost of omalizumab add‑on treatment was £68,995 compared with £35,902 for standard care; the mean QALYs were 13.44 and 12.78 respectively. This resulted in an ICER for omalizumab of £50,181 per QALY gained. As with the hospitalisation subgroup, the Assessment Group estimated that the probability that omalizumab was cost effective at £30,000 per QALY was zero. The Assessment Group presented results for several scenarios reflecting different assumptions. This included a scenario that took into account the adverse effects of maintenance oral corticosteroids, following a similar approach taken by the manufacturer. The Assessment Group assumed that: patients who do not receive omalizumab continue maintenance oral corticosteroids for the rest of their lives the excess relative risk of developing diseases attributable to use of oral corticosteroids does not persist once an individual has stopped taking oral corticosteroids, and health losses expressed in disability‑adjusted life years (DALYs) are equivalent to health gains expressed in QALYs. The Assessment Group commented that the key drivers of cost effectiveness were the asthma‑related mortality rates, the degree to which omalizumab improves health‑related quality of life and, for people who take maintenance oral corticosteroids, whether or not the model included adverse effects from oral corticosteroids. When the model incorporated the higher asthma‑related mortality rates reported by Watson et al. and adopted by the manufacturer, the ICERs for omalizumab as an add‑on treatment compared with standard care alone for the base‑case populations were £46,029 per QALY gained for adults and adolescents, and £98,688 per QALY gained for children. In the subgroup reflecting patients hospitalised in the year before starting therapy, the ICERs for omalizumab were £31,576 per QALY gained for adults and adolescents and £47,430 per QALY gained for children, and in the subgroup taking maintenance oral corticosteroids, the ICER was £29,657 per QALY gained for adults and adolescents and was not estimated for children. Whether the model included the assumption that omalizumab did or did not improve a child's health‑related quality of life also had a substantial impact on the ICERs. However, the ICER did not fall below £30,000 per QALY gained in children (the lowest ICER was £42,296 per QALY gained in the subgroup of children hospitalised in the previous year). Incorporating the adverse effects of oral corticosteroids in the maintenance oral corticosteroids subgroup reduced the ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone from £50,181 to £44,292. An additional subgroup consisting of people experiencing 3 or more exacerbations in the previous year was considered by the Assessment Group. The ICERs for omalizumab in this subgroup were lower than the ICERs for the base‑case populations of adults and adolescents (£77,868 per QALY gained compared with £83,822 per QALY gained) and children (£71,513 per QALY gained compared with £78,009 per QALY gained). The Assessment Group commented that using the health‑related quality‑of‑life data from INNOVATE (EQ‑5D mapped from Asthma Quality of Life Questionnaire scores) reduced the ICERs in this subgroup to £52,236 per QALY gained in adults and adolescents, and to £50,139 per QALY gained in children. ## Additional analyses requested by the Appraisal Committee at the first Appraisal Committee meeting (3 July 2012) After the first appraisal committee meeting, NICE requested on behalf of the Appraisal Committee that the Assessment Group undertake additional analyses in order to model scenarios with alternative assumptions on: mortality rates for very severe asthma rates of clinically significant exacerbations for very severe asthma treatment duration adverse effects of oral corticosteroids, and carer benefits. The Committee requested additional analyses for 3 scenarios including populations who are covered by the marketing authorisation, whose therapy is optimised and who are followed in a specialist centre: Population 1: people with very severe persistent allergic asthma maintained on oral corticosteroids and who were hospitalised in the year before treatment. Population 2: people with very severe persistent allergic asthma maintained on oral corticosteroids, but who have not necessarily been hospitalised in the year before treatment. Population 3: people with very severe persistent allergic asthma who are on maintenance or frequent courses of oral corticosteroids (for example, 4 or more courses per year), but who have not necessarily been hospitalised in the year before treatment. The Assessment Group requested additional data from the manufacturer for populations 1 and 3, and used data for subgroup 2 available in the manufacturer's submission. The Assessment Group also received additional information requested from clinical specialists about omalizumab use in the UK. The additional analyses conducted by the Assessment Group were presented for the following: children aged 6 to 11 years; adults and adolescents aged 12 years and over; and the overall population consisting of adults, adolescents and children. For adults and adolescents, and the overall population, the results presented were based on a weighted average of the ICERs for different age cohorts to reflect the mortality risk that differs by age. The weighting was based on the percentage of people at each age in the APEX study. The Assessment Group's additional analyses incorporated the following assumptions in the base case: asthma‑related mortality risk from Watson et al.; adverse effects of oral corticosteroids; 5‑year treatment duration for children, 10‑year treatment duration for adults and adolescents; EQ‑5D utility values from EXALT for the subgroup taking maintenance oral corticosteroids (population 2) used for all populations; and the same exacerbation rates at start of treatment, treatment effectiveness, and health‑related quality of life assumed for children as for adults and adolescents. The ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone for children was £62,945, £61,361 and £61,096 per QALY gained in populations 1, 2 and 3, respectively. The ICER for adults and adolescents was £32,398 and £32,508 per QALY gained in populations 1 and 2 respectively, with the lowest ICER in population 3 (£31,573). The ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone for the overall population (adults, adolescents and children) was £33,077, £33,150 and £32,229 per QALY gained in populations 1, 2 and 3 respectively. The Assessment Group commented that the ICERs for the overall population (adults, adolescents and children), and for adults and adolescents alone, were similar because children represent a small proportion of the overall population (2.2%). The Assessment Group further commented that asthma‑related mortality risk was the main driver of the cost‑effectiveness results and of the differences in the results between the adult and adolescent population and children. The Assessment Group presented cost‑effectiveness results for populations 1, 2 and 3 based on alternative scenarios, as requested by the Appraisal Committee. Increasing the clinical effectiveness of omalizumab observed in INNOVATE by 10% in all subgroups reduced the ICERs for omalizumab very slightly across all 3 populations, with all the ICERs remaining above £30,000 per QALY gained. Using the improvement in utility (0.1300) from EXALT for the group hospitalised in the year before starting therapy applied to all populations also reduced the ICERs for omalizumab, though they remained above £30,000 per QALY gained for all 3 populations. Increasing the asthma‑related mortality risk from Watson et al. by 15% across all age groups also reduced the ICERs slightly. In the overall population, increasing the asthma‑related mortality risk from Watson et al. by 15% reduced the ICER to £32,047, £32,134 and £31,159 per QALY gained for populations 1, 2 and 3 respectively. Using asthma‑related mortality risk from de Vries et al. and increasing the risk by 15% reduced the ICERs for children in all 3 populations to approximately £53,000 per QALY gained. For adults and adolescents, the ICERs increased to approximately £42,000 per QALY gained for each population. For the overall population, the ICERs increased to £42,613, £42,634 and £41,868 per QALY gained for populations 1, 2 and 3 respectively. The Assessment Group also incorporated an additional QALY burden from non‑Hodgkin's lymphoma, adrenal insufficiency and sleep disturbance, which resulted in an annual total QALY loss of 0.04978. This reduced the ICERs for omalizumab slightly across all 3 populations, again with all the ICERs remaining above £30,000 per QALY gained. The Assessment Group conducted a threshold analysis to estimate the minimum health‑related quality‑of‑life losses associated with oral corticosteroid‑related adverse effects that would be needed to achieve an ICER for omalizumab of less than or equal to £30,000 per QALY gained. The Assessment Group's results showed that the QALY loss associated with oral corticosteroids would need to be at least 0.115 QALYs per patient per year for population 1, at least 0.120 QALYs per patient per year for population 2 and at least 0.095 QALYs per patient per year for population 3. To achieve an ICER of £30,000 per QALY gained, identified health consequences would need to be 2.3, 2.4 and 1.9 times their current values in populations 1, 2 and 3 respectively. The Assessment Group was not aware of any evidence to provide adequate estimates on health‑related quality‑of‑life benefits not currently captured in the economic modelling, including in carers. For patients, the model captured the health‑related quality‑of‑life improvements with omalizumab. ## Additional analyses and the patient access scheme submitted by the manufacturer after the second Appraisal Committee meeting (3 October 2012) In its response to the appraisal consultation document, the manufacturer provided additional analyses for population 2 (people with very severe persistent allergic asthma who require maintenance oral corticosteroids) and population 3 (people with very severe persistent allergic asthma who require maintenance or frequent courses of oral corticosteroids ). In contrast to its original analyses, the manufacturer assumed that the utility gain from omalizumab for adolescents and adults applied also to children. The manufacturer calculated an asthma‑related mortality rate midway between the estimates from Watson et al. and de Vries et al., and increased the result by 15% to represent those patients with the most severe asthma. The manufacturer varied the proportion of children in the age‑weighted ICER calculations. The 3 proportions were: %, used in the Assessment Group's weighted average cost‑effectiveness analyses %, based on mid‑2011 census data for England and Wales; and %, the midpoint value between 2.2% and 7.3%. The manufacturer agreed a patient access scheme with the Department of Health, in which the manufacturer offers a discount on the list price of omalizumab to the NHS. The resulting ICERs for population 2 were £24,183, £24,591 and £25,010 per QALY gained when the proportions of children were assumed to be 2.2%, 4.75% and 7.3% respectively. The resulting ICERs for population 3 were £23,453, £23,902 and £24,370 per QALY gained with the same proportions of children. The Assessment Group reviewed the manufacturer's additional analyses and reported that the manufacturer had assumed that the risk of asthma‑related mortality reported in Watson et al. and de Vries et al. used the same measure of risk. However, Watson et al. reported a conditional probability of death after hospitalisation for acute severe asthma, and de Vries et al. reported an annual mortality rate for patients treated at BTS/SIGN step 5. The Assessment Group considered that the probability and the rate should have been converted into the same measure of risk before averaging across risks. The Assessment Group also commented that, by averaging the proportion of patients in the overall population for the different age categories to obtain an average midpoint mortality risk by age, then using this risk to calculate the age‑weighted ICER, the manufacturer had not accurately weighted the proportion of patients in each age category. The Assessment Group corrected these errors and, using the midpoint mortality estimates increased by 15%, estimated ICERs for population 2 of £23,626, £23,817 and £24,008 per QALY gained when the proportions of children were assumed to be 2.2%, 4.75% and 7.3% respectively. The resulting ICERs for population 3 were £23,011, £23,203 and £23,395 per QALY gained with the same proportions of children. # Innovation The manufacturer considered that omalizumab's innovative characteristics included its ability to substantially improve quality of life. The manufacturer highlighted its opinion that omalizumab represents the only significant advance in the management of severe asthma in the past 30 years. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of omalizumab, having considered evidence on the nature of severe persistent allergic asthma and the value placed on the benefits of omalizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. ## Management of severe persistent allergic asthma in UK clinical practice The Committee discussed the clinical need of people with severe persistent allergic asthma. It heard from the clinical specialists and the patient experts that severe exacerbations have a large impact on people with severe persistent allergic asthma and their families. This may include frequent attendance at accident and emergency departments, emergency GP visits, reduced attendance and poor performance at school or work, limitations to social life and inability to exercise. The Committee also heard that the impact on families and carers may include anxiety, sleep deprivation, and emotional and financial pressures. The Committee accepted that severe uncontrolled asthma can severely reduce quality of life among people with the condition, as well as their families and carers. The Committee discussed the role of omalizumab in UK clinical practice. It heard from the clinical specialists that UK clinical practice is based on the 'British guideline on the management of asthma' (BTS/SIGN) and uses a stepped treatment approach, with drugs added or withdrawn depending on symptoms and control. The Committee heard from the clinical specialists and patient experts that, in current UK clinical practice, the population for which omalizumab would be considered was smaller than that covered by the marketing authorisation. Clinicians currently optimise a person's asthma treatment before considering omalizumab; for those whose asthma remains poorly controlled, and affects their quality of life, omalizumab is considered as an add‑on treatment. One clinical specialist estimated that the number of people currently being offered omalizumab in his practice accounts for approximately 1 in 200 people with asthma and approximately 8 in 200 people with asthma are at step 5 of the 'British guideline on the management of asthma'. The Committee concluded that only people with the most severe persistent allergic asthma despite optimised treatment would currently be offered omalizumab. The Committee was aware that NICE technology appraisal 133 requires a person to have been hospitalised for a clinically significant severe exacerbation in the year before starting omalizumab. The Committee heard from a patient expert that requiring hospitalisation as a prerequisite for treatment with omalizumab provides the perverse incentive to let the condition worsen. The Committee heard from the clinical specialists that there are various reasons why people might choose not to go into hospital, and that some people tolerate respiratory distress better than others. It heard from a patient expert that he chose not to go to hospital even when extremely ill, and heard from the clinical specialists that this behaviour is not unusual for people with severe uncontrolled asthma. The Committee noted that the clinical specialists preferred other ways of identifying candidates for treatment with omalizumab, that is, people with asthma at step 5 of the 'British guideline on the management of asthma' (BTS/SIGN) with poorly controlled asthma who are treated with continuous or multiple courses of oral corticosteroids per year, irrespective of whether they had recently been admitted to hospital. The Committee accepted that there are limitations to using the requirement of previous hospitalisation as a criterion for determining clinical need for omalizumab. The Committee discussed oral corticosteroid use, including the significant physical and psychiatric long‑term adverse effects associated with frequent use. The Committee noted that these include bone fracture, diabetes mellitus, peptic ulcer, myocardial infarction, stroke, cataracts, glaucoma, sleep and mood disturbance, and weight gain, and, for children, failure to reach expected adult height. It also noted that the patient experts and clinical specialists highly valued any therapy that would help a person with severe asthma taper or stop oral corticosteroid use. The clinical specialists explained that they would offer omalizumab not only to people on maintenance oral corticosteroids, but also to some people who required frequent courses of oral corticosteroids. The Committee heard from the clinical specialists that omalizumab enables people with severe allergic asthma to reduce their use of high‑dose oral corticosteroids, and that patients and their carers are prepared to accept the inconvenience of attending specialist centres to have injections of omalizumab. The Committee accepted that there are significant risks associated with oral corticosteroids, and that frequent use may have a considerable impact on the lives of people with severe asthma. ## Clinical effectiveness The Committee considered the evidence on the clinical effectiveness of omalizumab from the manufacturer's submission and the assessment report. The Committee noted that omalizumab as an add‑on to standard care reduced the rate of clinically significant exacerbations and clinically significant severe exacerbations in adults, adolescents and children, although the effect on clinically significant severe exacerbations was not statistically significant in children. The Committee noted that the conclusions from the double‑blind INNOVATE trial were supported by the results from several other clinical trials. The Committee also noted that, in adults, omalizumab reduced total emergency visits (including hospital admissions, emergency department visits and unscheduled visits to the doctor), and reduced hospital admissions in children whose asthma responded to omalizumab compared with children randomised to placebo. The Committee noted that omalizumab treatment resulted in small increases in lung function in adults as measured by percentage of predicted FEV1 but that no FEV1 data were collected in the children's trials. The Committee also noted that there was some evidence that adults and adolescents taking omalizumab used rescue medication less frequently and oral corticosteroids in lower doses. The Committee heard from patient experts and clinical specialists, and again from comments received during consultation, that omalizumab has resulted in life‑changing improvements in reducing the number of asthma‑related clinically significant exacerbations. The Committee concluded that omalizumab as an add‑on to optimised standard care is more clinically effective in treating severe persistent allergic asthma than optimised standard care alone. The Committee understood that health‑related quality of life was generally collected using the Asthma Quality of Life Questionnaire, with a paediatric version for children participating in the IA‑05 trial. The Committee noted that EXALT was the only trial that also reported EQ‑5D scores. The Committee also noted that there were statistically significant improvements in health‑related quality of life favouring omalizumab in adults from both INNOVATE and EXALT, but not in children. The Committee agreed with the Assessment Group's suggestion that the IA‑05 trial may have been underpowered to detect differences in health‑related quality of life in children. The Committee heard from a patient expert that treatment with omalizumab resulted in a marked improvement in her child's health‑related quality of life, including the ability to attend school, participate in sports and play in the park. The Committee accepted from the testimonies of the patient experts and the evidence from the clinical studies that omalizumab was likely to improve health‑related quality of life in adults, adolescents and children with severe persistent allergic asthma. The Committee also agreed that there could be additional health‑related benefits for carers as a result of omalizumab use, and that these could be included within NICE's reference case if quantifiable. The Committee noted that the clinical trials included people whose asthma was less severe than those currently being treated with omalizumab in the UK. The Committee concluded that the trial evidence may not be fully applicable to people who would be offered omalizumab in the UK, who, having more severe asthma, might receive more benefit from omalizumab treatment, a conclusion supported by the clinical specialists. ## Cost effectiveness The Committee considered the cost‑effectiveness results from the manufacturer's submission and the assessment report, and noted that the main differences between the manufacturer's and the Assessment Group's economic models were the assumptions on asthma‑related mortality and how health‑related quality of life improvements from omalizumab were incorporated in the models. The Committee discussed which estimates for asthma‑related mortality risk were most plausible. The manufacturer's model included mortality rates from Watson et al. for people hospitalised with acute severe asthma, categorised by age. By contrast, the Assessment Group used data from de Vries et al., which stratified people with asthma aged 18 years and over from the General Practice Research Database according to their GINA stage, with GINA step 5 as the Assessment Group's base case. The Committee noted that the mortality rate from de Vries et al. was constant across all ages, and that the Assessment Group assumed that this mortality rate also applied to children. The Committee heard from the clinical specialists that the asthma‑related mortality risk in children is much lower than in adults, and that in adults mortality risk increases with age. The Committee concluded that it was inappropriate to accept the same mortality risk across all ages because it did not reflect the natural history of the disease. However, the Committee was concerned that the Watson et al. data were inconsistent with the observation that no deaths attributable to asthma were observed in the APEX trial. On the other hand, the Committee considered that mortality rates may have been underestimated in the de Vries et al. data, if people offered omalizumab in the UK reflected the more severe end of step 5 with higher mortality rates than those reported for people at step 5 as a whole. Additionally, the Committee was aware that both studies may have overestimated the true mortality rate from asthma by attributing deaths from chronic obstructive pulmonary disease to asthma, although the de Vries et al. study tried to exclude people with chronic obstructive pulmonary disease. The Committee concluded that both the Watson et al. and the de Vries et al. studies had limitations, that considerable uncertainty remained about the mortality associated with severe persistent asthma, and that neither may reflect mortality among the subgroups of people with very severe persistent asthma, to whom omalizumab is offered in clinical practice. The Committee agreed that the asthma‑related mortality rates applicable to this appraisal were likely to be between the Watson et al. and de Vries et al. estimates. The Committee considered that assumptions around the utility gain associated with omalizumab also accounted for some of the differences in the results between the Assessment Group's and the manufacturer's models. Firstly, it noted that the Assessment Group assumed that children experienced the same improvement in health‑related quality of life as adults and adolescents, whereas the manufacturer assumed there was no health‑related quality of life improvement from omalizumab treatment in children. The Committee concluded that the evidence presented by a patient expert, and the results from an observational study in children, showed that the utility values used in the manufacturer's economic model did not adequately capture the potential health‑related quality‑of‑life benefits of omalizumab for children. The Committee therefore preferred the Assessment Group's approach in which the same utility gain was assumed for adults, adolescents and children. Secondly, the Committee was aware that the manufacturer and the Assessment Group used different methods of estimating health‑related quality of life for day‑to‑day asthma symptoms. The Committee noted that the Assessment Group's approach, using EQ‑5D values directly collected in the EXALT trial, resulted in a lower quality‑of‑life benefit for people whose asthma responded to omalizumab than did the manufacturer's approach of mapping Asthma Quality of Life Questionnaire scores collected in the INNOVATE trial onto EQ‑5D values. The Committee preferred the direct estimates of EQ‑5D, in line with the NICE reference case. The Committee considered which discount rates to use in this appraisal, noting the clarification of the Guide to the methods of technology appraisal issued by the Board of NICE. This states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. The Committee considered that restoring and sustaining health for a very long period equated to a cure. The Committee heard from the clinical specialists that severe persistent asthma is not considered to be curable. It concluded that it did not have evidence that omalizumab cured asthma and that there was no case to apply differential discounting. The Committee noted that the manufacturer's original probabilistic base‑case ICERs (see section 4.2.7) (for omalizumab as an add‑on treatment to standard care compared with standard care alone, and using the Watson et al. mortality rates) were £33,300 per QALY gained for adults and adolescents and £89,000 per QALY gained for children. By contrast, the Committee noted that the original Assessment Group's base‑case ICERs (using the de Vries et al. mortality rates) were £83,800 per QALY gained for adults and adolescents and £78,000 per QALY gained for children, and using the Watson et al. mortality data the Assessment Group's ICERs were £46,000 per QALY gained for adults and adolescents and £98,700 per QALY gained for children. The Committee acknowledged that using the mapped utility values as done in the manufacturer's model would reduce the ICERs from £83,800 to £52,200 per QALY gained for adults and adolescents, but it considered the use of direct EQ‑5D values more appropriate (see section 4.4.10). The Committee concluded that the ICERs for omalizumab for the whole population were higher than what can be considered a cost‑effective use of NHS resources. The Committee acknowledged that the analyses carried out for subgroups of people hospitalised in the year before trial entry or on maintenance oral corticosteroids resulted in lower ICERs in both the manufacturer's and Assessment Group's analyses. However, the Committee noted that the Assessment Group's ICERs were still above £30,000 per QALY gained in adults and adolescents even with the use of the more favourable Watson et al. mortality data. The Committee noted that the Assessment Group's analysis had taken into account the disutility from several long‑term adverse effects including bone fracture, diabetes mellitus, peptic ulcer, myocardial infarction and stroke, cataract and glaucoma, weight gain, non‑Hodgkin's lymphoma, adrenal insufficiency and sleep disturbance. However, the Committee concluded that other adverse effects, such as obesity, hypertension, mood changes, depression, psychosis, thinning skin, delayed wound healing, reduced growth in children and increased risk of infection were additional important factors that had not been captured when calculating the QALY. The Committee recognised that omalizumab was an effective therapy, and that the analyses presented may not have been applicable to the population of people with very severe asthma for whom omalizumab is used in clinical practice. The Committee considered whether it was possible to describe more clearly the clinical characteristics of this population and model the use of omalizumab more accurately, thereby identifying people with very severe asthma for whom omalizumab may potentially be cost effective. The Committee requested more information about the clinical characteristics of the population for which omalizumab would be considered, and asked the Assessment Group to carry out additional analysis in 3 high‑risk populations with very severe persistent allergic asthma: people who are on maintenance oral corticosteroids and who were hospitalised in the year before treatment people who are on maintenance oral corticosteroids but who have not necessarily been hospitalised in the year before treatment people who are on maintenance or frequent courses of oral corticosteroids (for example, 4 or more courses per year) but who have not necessarily been hospitalised in the year before treatment. The Committee also asked the Assessment Group to assume higher efficacy for omalizumab and higher asthma‑related mortality estimates to reflect people with very severe uncontrolled asthma, as well as analyses incorporating more adverse effects from oral corticosteroids and carer benefits associated with omalizumab. The Committee also requested pooled analyses for the overall population of children, adolescents and adults for which omalizumab is licensed to explore the possibility of developing a single recommendation for all licensed populations. The Committee considered the additional information and analyses provided by clinical specialists and the manufacturer, who provided the Assessment Group with the information necessary to conduct the further analyses requested by the Committee at the first appraisal committee meeting (see section 4.2.28). The Committee was aware that the new analyses incorporated the Watson et al. asthma‑related mortality data, with a sensitivity analysis using the de Vries et al. data, and shorter treatment duration for children (5 instead of 10 years in the Assessment Group's original analyses following the advice of the clinical specialists). The Committee noted that the base‑case ICERs were similar across the 3 high‑risk populations, that is, £31,600 to £32,500 per QALY gained for adults and adolescents, £61,100 to £62,900 per QALY gained for children and £32,200 to £33,200 per QALY gained for the overall population. The Committee acknowledged that the ICERs for the overall population and for adults and adolescents were similar because children were assumed to represent only a very small proportion of the overall population treated with omalizumab (2.2%). However, the Committee acknowledged that the lower use of omalizumab in children may reflect the recommendation in NICE technology appraisal 201, and therefore the proportion of children who might otherwise be considered for omalizumab treatment may be underestimated. The Committee concluded that, even assuming 15% higher mortality rates because of the severity of the disease, the ICERs in the overall population were still high at £32,000 and £42,000 per QALY gained using the Watson et al. or de Vries et al. data respectively. The Committee considered the Assessment Group's additional analysis on the health‑related quality‑of‑life losses associated with oral corticosteroid‑related adverse effects. The Committee noted that the Assessment Group had conducted a threshold analysis to explore the necessary size of the unidentified health effects of oral corticosteroid use, in addition to those already modelled, to reduce the cost per QALY gained of omalizumab to £30,000. The Committee noted that the additional QALYs from unidentified adverse effects of oral corticosteroids would need to be twice or more of those derived from known adverse effects, and was not persuaded that this was a plausible assumption. The Committee considered omalizumab to be innovative in its potential to make a significant and substantial impact on health‑related benefits, and explored if any potential significant and substantial health‑related benefits have been identified that were not included in the economic model. The Committee recognised that some benefits of avoiding the adverse effects of oral corticosteroid use had not been fully captured in the QALY measure (see section 4.4.13). The Committee also considered the benefits to carers associated with omalizumab, which may not have been captured in the QALY calculations. The Committee noted that the manufacturer included no empirical and quantifiable evidence relating to potential carer benefits in its submission, and the Assessment Group did not include any carer benefits formally in its additional analyses. The Committee concluded that the potential additional health‑related benefits for carers as a result of omalizumab use could not currently be quantified. The Committee recognised that the approach to estimate utility gain in light of the lack of evidence taken in Pharmalgen for the treatment of bee and wasp venom allergy (NICE technology appraisal 246) was not appropriate to use here, because omalizumab does not provide a cure for asthma. The Committee considered the additional analyses, including a patient access scheme, submitted by the manufacturer after consultation on the appraisal consultation document (see section 4.4.14). The Committee noted that the manufacturer calculated an asthma‑related mortality rate midpoint between the conditional probability in Watson et al. and the mortality risk in de Vries et al., and increased both by 15% to reflect mortality in people with very severe uncontrolled asthma, acknowledging the Assessment Group's concerns about averaging proportions and rates. The Committee concluded that the 15% increase in mortality risk was an appropriate approximation of the mortality risk in very severe allergic asthma. The Committee also concluded that a more realistic mortality rate likely lay between the midpoint and the estimate from de Vries et al. and that the average rate as corrected by the Assessment Group was a more plausible mortality rate, though some uncertainty remained. The Committee noted the manufacturer's analyses of different proportions of children in the overall population eligible for omalizumab, which were carried out because of concerns that the 2.2% value assumed in the original Assessment Group's weighted average cost‑effectiveness analyses might underestimate the true value (see section 4.4.15). The Committee was aware that increasing the proportion of children from 2.2% to 7.3% in line with 2011 census data did not have a large impact on the ICERs (see section 4.2.35) and it concluded that, given uncertainties in the true value, it would be reasonable to accept the midpoint value of 4.75%. The Committee also concluded that, because the proportion of children used was very small and it did not have a large impact on the ICERs, it was appropriate to use the pooled analyses presented by the Assessment Group as the basis for a recommendation. The Committee considered the results of the additional cost‑effective analyses using the asthma‑related mortality rate midpoint between Watson et al. and de Vries et al. increased by 15%, the 4.75% proportion of children aged 6 to 11 in the overall population eligible for omalizumab, and incorporating the patient access scheme for omalizumab. The Committee concluded that applying the Assessment Group's corrections to the manufacturer's analysis resulted in a most plausible ICER of £23,200 per QALY gained for the combined population of adults, adolescents and children on maintenance or frequent courses of oral corticosteroids, defined as 4 or more courses in the year before receiving omalizumab. The Committee considered the comments received during consultation on the appraisal consultation document indicating the 'life‑changing' effect that omalizumab had on patients' lives and the lives of their families and carers. The Committee noted that many consultees had emphasised the need to acknowledge the uncaptured benefits of reducing dependence on oral corticosteroids and it was persuaded that these uncaptured benefits were sufficient to justify accepting an ICER of £23,200 per QALY gained. The Committee concluded that, with the patient access scheme submitted after consultation on the appraisal consultation document, omalizumab as an add‑on to optimised standard therapy is a cost‑effective use of NHS resources for treating severe persistent confirmed allergic IgE‑mediated asthma in people aged 6 years and over who need continuous or frequent oral corticosteroid treatment (defined as 4 or more courses in the previous year) and should be recommended as an option for treatment in this population. The Committee noted that optimised standard therapy was specified in NICE technology appraisal 133, and that oral beta2 agonists were listed as a component of optimised standard therapy but are now rarely used in clinical practice. For the purposes of this guidance, the Committee agreed that optimised standard therapy should be defined as a full trial of, and documented compliance with, inhaled high‑dose corticosteroids, long‑acting beta2 agonists, leukotriene receptor antagonists, theophyllines, oral corticosteroids, and smoking cessation if clinically appropriate. # Summary of Appraisal Committee's key conclusions TA278 Appraisal title: Omalizumab for treating severe persistent allergic asthma Section Key conclusion Omalizumab is recommended as an option for treating severe persistent confirmed allergic IgE‑mediated asthma as an add‑on to optimised standard therapy for people aged 6 years and older who need continuous or frequent oral corticosteroid treatment (defined as 4 or more courses in the previous year), and only if the manufacturer makes omalizumab available with the discount agreed in the patient access scheme. The Committee concluded that, using an asthma‑related mortality rate calculated as the midpoint between Watson et al. and de Vries et al. increased by 15% to account for very severe disease; using a proportion of children aged 6 to 11 in the overall population eligible for omalizumab of 4.75%; and incorporating the patient access scheme for omalizumab, resulted in a most plausible ICER of £23,200 per QALY gained for the combined population of adults, adolescents and children on maintenance or frequent courses of oral corticosteroids, defined as 4 or more courses in the year before receiving omalizumab. The Committee acknowledged the uncaptured benefits of reducing dependence on oral corticosteroids and was persuaded that these uncaptured benefits were sufficient to justify accepting an ICER of £23,200 per QALY gained. Current practice Clinical need of patients, including the availability of alternative treatments The Committee concluded that severe uncontrolled asthma can severely reduce quality of life among people with severe persistent asthma as well as their families and carers. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits? The Committee concluded that omalizumab as an add‑on to optimised standard care is more clinically effective in treating severe persistent allergic asthma than optimised standard care alone, leading to a reduction in total emergency visits (including hospital admissions, emergency department visits and unscheduled visits to the doctor) in adults, reduced hospital admissions in children, improved lung function in adults as measured by percentage of predicted FEV1 and a reduction in the frequency and use of rescue medication and oral corticosteroids. The Committee concluded that omalizumab could be considered innovative, but the additional health‑related benefits for carers as a result of omalizumab use cannot currently be quantified. What is the position of the treatment in the pathway of care for the condition? The Committee concluded that only people with the most severe persistent allergic asthma despite optimised treatment are currently offered omalizumab. Adverse reactions There was no specific Committee discussion on adverse reactions of omalizumab. n/a Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee noted that the conclusions from the pivotal double‑blind INNOVATE trial were supported by the results from several other clinical trials. Relevance to general clinical practice in the NHS The Committee noted that the clinical trials included people whose asthma was less severe than those currently being treated with omalizumab in the UK. The Committee concluded that the trial evidence may not be fully applicable to people who would be offered omalizumab in the UK, who, having more severe asthma, might receive more benefit from omalizumab treatment, a conclusion supported by the clinical specialists. Uncertainties generated by the evidence No other specific uncertainties with respect to the clinical effectiveness of omalizumab were discussed by the Committee. n/a Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee considered that people with very severe asthma such as people who are on maintenance oral corticosteroids or who have been hospitalised because of asthma in the previous year may benefit the most from omalizumab. The Committee requested additional analyses for 3 populations covered by the marketing authorisation, whose therapy is optimised, and who are treated in a specialist centre: Population 1: people with very severe persistent allergic asthma maintained on oral corticosteroids and who were hospitalised in the year before treatment. Population 2: people with very severe persistent allergic asthma maintained on oral corticosteroids, but who have not necessarily been hospitalised in the year before treatment. Population 3: people with very severe persistent allergic asthma who are on maintenance or frequent courses of oral corticosteroids (for example, 4 or more courses per year), but who have not necessarily been hospitalised in the year before treatment. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that omalizumab as an add‑on to optimised standard therapy is more clinically effective in treating severe persistent allergic asthma than optimised standard therapy alone. Evidence for cost effectiveness Availability and nature of evidence There were no specific conclusions made by the Committee about the availability and nature of the cost‑effectiveness evidence. n/a Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee noted that the main differences between the manufacturer's and the Assessment Group's economic models were the assumptions on asthma‑related mortality and how health‑related quality of life improvements from omalizumab treatment were incorporated in the models. The Committee concluded that considerable uncertainty remained about the asthma‑related mortality associated with severe persistent asthma, and that the Watson et al. and the de Vries et al. studies may not reflect mortality among the subgroups of people with very severe persistent asthma, to whom omalizumab is offered in clinical practice. Incorporation of health‑related quality‑of‑life benefits and utility values Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered? The Committee preferred the Assessment Group's approach in which the same utility gain was assumed for adults, adolescents and children. The Committee preferred the Assessment Group's method of using direct estimates of EQ‑5D values, in line with the NICE reference case, to the manufacturer's approach of mapping Asthma Quality of Life Questionnaire scores collected in the INNOVATE trial onto EQ‑5D values. The Committee concluded that some adverse effects of oral corticosteroid use, such as obesity, hypertension, mood changes, depression, psychosis, thinning skin, delayed wound healing, reduced growth in children, and increased risk of infection were additional important factors that had not been captured when calculating the QALY. The Committee concluded that the potential additional health‑related benefits conferred to carers as a result of omalizumab use could not currently be quantified. Are there specific groups of people for whom the technology is particularly cost effective? The Committee noted that the base‑case ICERs in the overall population of adults, adolescents and children were similar across the 3 high‑risk populations, ranging from £32,200 to £33,200 per QALY gained without incorporating the patient access scheme for omalizumab. What are the key drivers of cost effectiveness? The key drivers of cost effectiveness were the asthma‑related mortality rates, the degree to which omalizumab improves health‑related quality of life, and, for people who take maintenance oral corticosteroids, whether or not the model included adverse effects from oral corticosteroids. Most likely cost‑effectiveness estimate (given as an ICER) The Committee concluded that the most plausible ICER was £23,200 per QALY gained for the combined population of adults, adolescents and children on continuous or frequent courses of oral corticosteroids, defined as 4 or more courses in the year before receiving omalizumab incorporating the patient access scheme for omalizumab. Additional factors taken into account Patient access schemes (PPRS) The Committee noted that the manufacturer agreed a patient access scheme with the Department of Health including a discount on the list price of omalizumab. End‑of‑life considerations Not applicable. n/a Equalities, considerations and social value judgements No equality issues relevant to the Committees recommendations were raised. n/a# Related NICE guidance # Published Bronchial thermoplasty for severe asthma. NICE interventional procedure guidance 419 (2012). Omalizumab for the treatment of severe persistent allergic asthma in children aged 6 to 11 years. NICE technology appraisal guidance 201 (2010). Inhaled corticosteroids for the treatment of chronic asthma in adults and children aged 12 years and over. NICE technology appraisal guidance 138 (2008). Omalizumab for severe persistent allergic asthma. NICE technology appraisal guidance 133 (2007). Inhaled corticosteroids for the treatment of chronic asthma in children under the age of 12 years. NICE technology appraisal guidance 131 (2007).# Review of guidance The guidance on this technology is considered for review by the Guidance Executive in March 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveApril 2013# Changes after publication January 2014: minor maintenance.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. It updates and replaces NICE technology appraisal guidance 131 (published November 2007) and NICE technology appraisal guidance 201 (published October 2010). We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0112-8	{'Guidance': 'Omalizumab is recommended as an option for treating severe persistent confirmed allergic IgE‑mediated asthma as an add‑on to optimised standard therapy in people aged 6\xa0years and older:\n\nwho need continuous or frequent treatment with oral corticosteroids (defined as 4\xa0or\xa0more courses in the previous year), and\n\nonly if the manufacturer makes omalizumab available with the discount agreed in the patient access scheme.\n\nOptimised standard therapy is defined as a full trial of and, if tolerated, documented compliance with inhaled high‑dose corticosteroids, long‑acting beta2 agonists, leukotriene receptor antagonists, theophyllines, oral corticosteroids, and smoking cessation if clinically appropriate.\n\nPeople currently receiving omalizumab whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'Clinical need and practice': "Asthma is a long‑term inflammatory disorder of the airways characterised by signs or symptoms including breathlessness, chest tightness, wheezing, sputum production, airflow obstruction, hyper‑responsiveness of airways and cough (particularly at night). Symptoms vary in frequency and severity, from intermittent and mild, to frequent and severe. Allergic and non‑allergic forms of asthma exist. Allergic asthma results from excess immunoglobulin\xa0E (IgE) produced in response to environmental allergens such as house dust mites, pollen and moulds. Non‑allergic asthma can be triggered by factors such as anxiety, stress, exercise, cold air, smoke and infection.\n\nThe Quality and Outcomes Framework (2008) estimated that 5.9% of the UK population receives treatment for asthma. Prevalence is highest in children aged 5 to 15\xa0years, and decreases in adulthood until the age range of 55 to 64\xa0years, when it rises again. In 2008/09, there were over 67,000 emergency hospital visits for asthma in the UK, with more than 40% of these for children aged 15\xa0years or under. People with asthma may have an impaired quality of life, with symptoms leading to fatigue, and absence from school or work. Psychological problems, which can include stress, anxiety and depression, are up to 6\xa0times more common than in the general population, and are particularly common in people with severe and difficult‑to‑control asthma. There are between 1000 and 1200 deaths from asthma each year in the UK, where, in 2008, the rate of premature death from asthma was 1.5\xa0times higher than in the rest of Europe.\n\nThere is no cure for asthma and the aim of treatment is to control symptoms while minimising the adverse reactions to treatment. Current guidelines from the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) recommend a stepwise approach to treatment aligned with the pathway of the Global Initiative for Asthma (GINA). Good control, characterised by no symptoms, normal lung function and no exacerbations, is achieved by stepping up or down treatment as necessary. Severe persistent allergic asthma is defined as poor control despite eliminating environmental allergens and correctly optimising standard care.\n\nStep\xa01 (for mild intermittent asthma) of the GINA pathway recommends using inhaled short‑acting beta2 agonists occasionally, and step\xa02 recommends introducing inhaled corticosteroids at 200–800\xa0micrograms per day in people aged 12\xa0years and over and at 200–400\xa0micrograms per day in children aged 5 to 12\xa0years. Step\xa03 recommends adding an inhaled long‑acting beta2 agonist and, if control remains inadequate, increasing the dosage of inhaled corticosteroids to 800\xa0micrograms per day in adults and adolescents and to 400\xa0micrograms per day in children. If a person's asthma does not respond to an inhaled long‑acting beta2 agonist, a leukotriene receptor antagonist (oral), a theophylline (oral) or a slow‑release beta2 agonist (oral) may be considered instead. Step\xa04 recommends increasing the dosage of inhaled corticosteroids to up to 2000\xa0micrograms per day in adults and adolescents and up to 800\xa0micrograms per day in children. As with step\xa03, adding a leukotriene receptor antagonist, a theophylline or an oral beta2 agonist may also be considered. Before moving to step\xa05, clinicians should refer people whose asthma is inadequately controlled to specialist care. Step\xa05 recommends daily corticosteroid tablets at the lowest dose that provides adequate control, alongside high‑dose inhaled corticosteroids. Treatments that can minimise the use of corticosteroid tablets may also be considered. The adverse effects of long‑term oral corticosteroids are significant and include adrenal suppression, glucose intolerance, decreased bone mineral density, cataracts and glaucoma, and growth failure in children.", 'The technology ': "Omalizumab (Xolair, Novartis) is a monoclonal antibody that binds to IgE. It has a UK marketing authorisation as add‑on therapy to improve control of asthma in adults and adolescents 12\xa0years and over (hereafter referred to as adults and adolescents) and children aged 6 to 11\xa0years (hereafter referred to as children) with severe persistent allergic asthma who have:\n\na positive skin test or in vitro reactivity to a perennial aeroallergen\n\nreduced lung function (forced expiratory volume at 1\xa0second [FEV1] less than 80% in adults and adolescents)\n\nfrequent daytime symptoms or night‑time awakenings\n\nmultiple documented severe exacerbations despite daily high‑dose inhaled corticosteroids plus a long‑acting inhaled beta2 agonist.\n\nThe marketing authorisation states that omalizumab treatment 'should only be considered for patients with convincing IgE (immunoglobulin E) mediated asthma'. It also specifies that, 16\xa0weeks after the start of omalizumab, physicians should assess how effective the treatment is, and should continue omalizumab only in patients whose asthma has markedly improved. It also specifies that omalizumab should be initiated and monitored in a specialist centre by a physician experienced in the diagnosis and treatment of severe persistent asthma.\n\nOmalizumab is given subcutaneously every 2 or 4\xa0weeks. The dosage is determined by the concentration of serum IgE before the start of treatment and body weight. (See the summary of product characteristics.)\n\nThe summary of product characteristics lists injection site pain, swelling, erythema and pruritus, and headaches as the most commonly reported adverse reactions for omalizumab treatment in adults and adolescents. The most commonly reported adverse reactions for omalizumab treatment in children are headaches, pyrexia and upper abdominal pain. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe price of omalizumab is £256.15 for a 150‑mg vial and £128.07 for a 75‑mg vial (excluding VAT; 'British national formulary' [BNF] edition 63). The dosage administered is 75–600\xa0mg every 2 or 4\xa0weeks, up to a maximum dosage of 600\xa0mg every 2\xa0weeks. The cost of omalizumab ranges from approximately £1665 per patient per year (excluding VAT) for a 75\xa0mg dose administered every 4\xa0weeks to approximately £26,640 per patient per year (excluding VAT) for a 600\xa0mg dose (the maximum recommended dose in the summary of product characteristics) administered every 2\xa0weeks. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of omalizumab has agreed a patient access scheme with the Department of Health, which makes omalizumab available with a discount applied to all invoices. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from several sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group focused on 5 specific questions: the efficacy of omalizumab; the long‑term efficacy of omalizumab; the corticosteroid‑sparing effect of omalizumab; the safety of omalizumab; and the adverse effects of oral corticosteroids.\n\nThe Assessment Group identified 11 randomised controlled trials to include in its review on efficacy, which compared omalizumab with placebo or no added treatment. Nine of the randomised controlled trials were relevant only to adults and adolescents, 1\xa0trial was relevant only to children and 1 trial was relevant to both age groups (the trial included people between the ages of 6 and 20\xa0years). Three of the randomised controlled trials had populations that met or closely approximated the criteria in the marketing authorisation for adults and adolescents (INNOVATE [n=419], EXALT [n=404] and a study by Chanez et\xa0al. 2010 [n=31]). Two randomised controlled trials had populations that were broader than those specified in the UK marketing authorisation, but contained relevant subgroups resembling the marketing authorisation (IA‑04 in adults [n=164] and IA‑05 European population subgroup in children [n=235]). The Assessment Group also identified 6 trials as supporting evidence in which an unknown proportion of the population met the criteria in the marketing authorisation (Hanania et\xa0al. 2011 [n=850], Bardelas et\xa0al. 2012 [n=271], Vignola et\xa0al. 2004 [SOLAR, n=405], Hoshino et\xa0al. 2012 [n=30] and Ohta et\xa0al. 2009 [n=327], and the trial by Busse et\xa0al. 2011 [n=419] in children and young adults).\n\nThe 10 randomised controlled trials enrolling adults and adolescents lasted from 16 to 52\xa0weeks. Trials in which the entire population met the criteria in the marketing authorisation lasted from 16\xa0weeks (Chanez et\xa0al.) to 32\xa0weeks (EXALT); INNOVATE ran for 28\xa0weeks. In children, IA‑05 ran for 52\xa0weeks, of which the final 28\xa0weeks was a corticosteroid‑sparing phase. The study by Busse et\xa0al. included in the review by the Assessment Group as supporting evidence ran for 60\xa0weeks.\n\nThe inclusion criteria and treatment regimen varied even among trials in which the whole population or a defined subgroup met the criteria in the marketing authorisation. For example, EXALT included people on a lower dose of inhaled corticosteroids (800\xa0micrograms or more of beclometasone dipropionate or its equivalent) than did the IA‑04 study European population subgroup or INNOVATE (both 1000\xa0micrograms or more of beclometasone dipropionate equivalent). All of the trials in which the whole population or a defined subgroup met marketing authorisation criteria required the use of a long‑acting beta2 agonist, but the concomitant treatments used (such as leukotriene antagonists and theophylline) varied between studies. The proportion of people taking oral corticosteroids was comparable (approximately 20%) between EXALT, INNOVATE and the trial by Chanez et\xa0al.; oral corticosteroid use was not reported in IA‑04. In the European population subgroup in the IA‑05 study, all children took 500\xa0micrograms or more of inhaled fluticasone or the equivalent plus a long‑acting beta2 agonist. The mean dose of inhaled fluticasone was 743\xa0micrograms and 58% took an additional drug; most of the children received a leukotriene antagonist.\n\nThe primary outcomes of the trials selected varied. The primary outcome for INNOVATE was the rate of clinically significant asthma exacerbations. Secondary outcomes included the rate of clinically significant severe exacerbations and the rate of emergency visits for asthma. The IA‑05 trial and Hanania et\xa0al. had clinically significant exacerbations as a primary outcome; in SOLAR it was 1 of the designated primary outcomes together with disease‑related quality of life. In other trials, persistence of response (EXALT), asthma deterioration‑related incidents (IA‑04), Asthma Control Test score, and other measures of symptoms and lung function were the primary outcomes measured.\n\nThe Assessment Group considered that the quality of the included randomised controlled trials was generally high, and that the 5\xa0studies in which the population or a defined subgroup represented the licensed population adequately allocated and concealed randomisation. Eight of the 11 trials included in the review were double blind and placebo controlled and had a low risk of bias. However, the Assessment Group considered that the open‑label EXALT and IA‑04 trials in adults had a higher risk of bias. The Assessment Group therefore did not pool the data from EXALT and IA‑04 with the INNOVATE trial for the base‑case analysis, but did so for EXALT and INNOVATE in the exploratory sensitivity analysis in the economic evaluation.\n\nIn addition to the trial data presented, the Assessment Group used data from observational studies to support evidence from the trials and, in particular, observational studies that provided data on longer‑term response to omalizumab and on corticosteroid sparing. These included open‑label continuation studies, uncontrolled cohort studies (in which all patients took omalizumab) and post‑marketing studies.\n\n## Clinical effectiveness results\n\nFor effectiveness of treatment, 4 of the 10 randomised controlled trials for the adult population (INNOVATE, EXALT, SOLAR and Bardelas et\xa0al.) and 1 randomised controlled trial in children (IA‑05 European population subgroup) reported the global evaluation of treatment effectiveness (GETE). There was a response to treatment in a higher proportion of people randomised to omalizumab compared with the comparator as assessed by the GETE ratings of good or excellent. Response to treatment with omalizumab was higher in the open‑label EXALT trial (70% compared with 28.2% at 16\xa0weeks, relative risk [RR] 2.24, 95% confidence interval [CI] 1.71 to 2.92) than in the double‑blind trials (INNOVATE, 56.5% compared with 41.0% at 28\xa0weeks [RR 1.38, 95%\xa0CI 1.13 to 1.69]; SOLAR, 59.3% compared with 41.3% at 28\xa0weeks [RR 1.44, 95%\xa0CI 1.17 to 1.76]; Bardelas et\xa0al., 55.1% compared with 48.1% at 24 weeks [RR 1.15, 95%\xa0CI 0.91 to 1.44]). Response rates in adults measured by the GETE were also reported in 4 uncontrolled observational studies and were higher than in the double‑blind INNOVATE trial. In the IA‑05 European population subgroup of children, 74% of the omalizumab group responded to treatment as assessed by the GETE ratings of good or excellent at 52\xa0weeks compared with 64.5% in the placebo group, but this was not statistically significant (RR 1.15, 95%\xa0CI 0.95 to 1.39).\n\nFor the outcome of clinically significant exacerbations, all of the 11 randomised controlled trials reported data with the exceptions of Bardelas et\xa0al. and Hoshino et\xa0al. The Assessment Group observed that clinically significant exacerbations were defined differently between trials, but still considered it appropriate to compare these trials. The Assessment Group found a consistent benefit for people randomised to omalizumab compared with the comparator group, both in terms of the rate of exacerbations and the proportion of people who experienced no exacerbations during follow‑up. For example, the rate of total exacerbations in the INNOVATE trial over 28\xa0weeks was 0.68 for omalizumab compared with 0.91 in the placebo arm (rate ratio 0.738, 95%\xa0CI 0.552 to 0.998). In EXALT, the rate of total exacerbations over 32\xa0weeks was 0.55 for omalizumab compared with 0.98 for the comparator (no added treatment; rate ratio 0.570, 95%\xa0CI 0.417 to 0.778) and, in the IA‑04 European population subgroup, the rates over 52\xa0weeks were 1.26 and 3.06 respectively (rate ratio 0.41, 95%\xa0CI 0.288 to 0.583). The trial by Chanez et\xa0al. showed no statistically significant difference between the groups at 16\xa0weeks (RR 0.71, 95%\xa0CI 0.37 to 1.37). For children, the results from the IA‑05 European population subgroup showed a statistically significant benefit in the rate of total exacerbations for omalizumab (0.42 compared with 0.63 in the comparator arm at 24\xa0weeks, rate ratio 0.662, 95%\xa0CI 0.441 to 0.995). In both children and adults, observational studies and trials used to support trial evidence showed that people taking omalizumab had reductions in the exacerbation rate from baseline.\n\nThree of the included trials reported separately the incidence of clinically significant severe exacerbations (defined as an exacerbation in which peak expiratory flow or FEV1 is less than 60% of a patient's personal best) and clinically significant non‑severe exacerbations. For adults, the rate of clinically significant severe exacerbations was statistically significantly lower in patients randomised to omalizumab compared with the comparator (INNOVATE, 0.24 compared with 0.48, rate ratio 0.50, 95%\xa0CI 0.32 to 0.78; EXALT, 0.24 compared with 0.42, rate ratio 0.56, 95%\xa0CI 0.34 to 0.92). For children, the results from the IA‑05 European population subgroup favoured omalizumab, but were not statistically significant (0.14 compared with 0.22 at 24\xa0weeks follow‑up, rate ratio 0.66, 95%\xa0CI 0.30 to 1.42). The Assessment Group commented that this small subgroup lacked power. Evidence from a single non‑comparative observational study (Deschildre et\xa0al. 2010) showed a reduction in severe exacerbations in children (from 4.4 severe exacerbations per year to 0.51 per year (statistical significance not recorded).\n\nThe manufacturer provided rates of exacerbations for the following 5 subgroups defined post hoc in the studies: people who were hospitalised before the onset of the study; people on oral corticosteroids at baseline; people not on oral corticosteroids at baseline; people who had 2 or fewer exacerbations per year at baseline; and people who had 3 or more exacerbations per year at baseline. The Assessment Group commented that data from the INNOVATE trial show that omalizumab may work better in people on maintenance oral corticosteroid therapy than the overall population. The relative risk of total exacerbations in the population taking maintenance oral corticosteroids was 0.662 (compared with 0.74 in the total population) and the relative risk of clinically significant severe exacerbations was 0.36 (compared with 0.50 in the total population), but with no statistical significance reported.\n\nFour trials (INNOVATE, EXALT, the IA‑04 European population subgroup in adults and the IA‑05 European population subgroup in children) reported results on the effectiveness of omalizumab for the 'responder' subgroup (that is, patients randomised to omalizumab whose asthma responded compared with patients randomised to placebo or standard care alone) using GETE ratings or Asthma Quality of Life Questionnaire scores (IA‑04 European population subgroup). In these analyses, the relative risk for total exacerbations was 0.37 (95%\xa0CI 0.27 to 0.52) in INNOVATE, 0.41 (95%\xa0CI 0.31 to 0.55) in EXALT, 0.37 (95%\xa0CI 0.24 to 0.55) in the IA‑04 European population subgroup and 0.38 (95%\xa0CI 0.15 to 0.91) in the IA‑05 European population subgroup, showing a statistically significant advantage for omalizumab. This pattern in the results was similar for the outcome of clinically significant severe exacerbations.\n\nSix randomised controlled trials (INNOVATE, EXALT, IA‑04, Chanez et\xa0al., IA‑05 and Busse et\xa0al.) compared rates of hospitalisation during the studies. The results favoured the omalizumab group but were not statistically significant, apart from in the EXALT study in which randomisation to omalizumab compared with no additional treatment was associated with a rate ratio of\xa00.33 (95%\xa0CI 0.12 to 0.94). Three studies in adults (INNOVATE, EXALT and IA‑04) presented data separately for the outcomes of emergency department visits and unscheduled doctor visits. As with rates of hospitalisation, the only study to show a statistically significant benefit with omalizumab for these outcomes was EXALT. There were, however, statistically significant reductions associated with omalizumab in total emergency visits, including hospital admissions, emergency department and unscheduled visits to the doctor (INNOVATE compared with placebo: risk ratio 0.56, 95%\xa0CI 0.33 to 0.97; EXALT: risk ratio 0.40, 95%\xa0CI 0.24 to 0.65; IA‑04 European population subgroup: risk ratio 0.76, 95%\xa0CI 0.64 to 0.89). For children, the IA‑05 European population subgroup showed no difference between treatment groups for emergency department visits, unscheduled doctor visits or total emergency visits. The Assessment Group commented that limited data from observational studies showed evidence of fewer hospitalisations and unscheduled healthcare visits compared with baseline; when statistical tests were reported, these showed statistically significant benefits of omalizumab treatment relative to baseline or standard care. However, there were no data available for children from observational studies on visits to the doctor or emergency room, or hospitalisations.\n\nAnalyses limited to people receiving omalizumab whose asthma responded compared with people receiving placebo or standard care showed evidence of statistically significant benefit from both INNOVATE and EXALT for hospitalisation and other unscheduled medical care except emergency department visits in INNOVATE. Children in the IA‑05 European population subgroup with a response to omalizumab had a statistically significant reduction in hospitalisation rates compared with children in the placebo arm with a response, but no benefits for other unscheduled healthcare measures.\n\nThe various studies assessed asthma severity differently and used a wide range of scales and measures to assess response to treatment. In INNOVATE, total asthma symptom score improved more at 28\xa0weeks with omalizumab than with placebo (change from baseline −0.66 with omalizumab compared with −0.40 with placebo, p=0.039). In EXALT, people randomised to open‑label omalizumab experienced a greater improvement in total asthma symptom score at 32\xa0weeks than people randomised to standard care without omalizumab using the Asthma Control Questionnaire (change from baseline −0.91 with omalizumab compared with −0.04 without omalizumab, RR 0.87, 95%\xa0CI −1.09 to −0.65) and in the IA‑04 European population subgroup at 52\xa0weeks using the Wasserfallen symptom score (change from baseline −6.7 with omalizumab compared with 0.5 with no additional treatment, p<0.05). For children, no statistically significant benefit for omalizumab compared with placebo was shown in the IA‑05 European population subgroup using the total asthma clinical symptom score and the Wasserfallen symptom score (p>0.05 for both measures at 24\xa0weeks and at 52\xa0weeks). In addition, an observational study in children with severe uncontrolled allergic asthma (Brodlie et\xa0al. 2000) found statistically significant increases in the scores of the Asthma Control Test (measuring asthma symptoms) after treatment with omalizumab (p=0.001). Evidence on the impact of individual symptom measures for children, adolescents and adults was limited and mixed.\n\nThere was limited evidence about whether treatment with omalizumab changed the need for rescue treatment, most commonly salbutamol (albuterol) and terbutaline. In the population that met marketing authorisation criteria, INNOVATE, the IA‑04 European population subgroup and the trial by Chanez et\xa0al. reported data on rescue treatment for adults, and the IA‑05 European population subgroup reported data for children. The IA‑04 European population subgroup was the only trial in the licensed population to show a statistically significant difference between the treatment groups. This trial found that the mean puffs of salbutamol per day per patient over 14\xa0days was 3.91 in the omalizumab group compared with 5.33 in the group not taking omalizumab (p=0.008). Data from Hanania et\xa0al. included by the Assessment Group as supporting data, reported a statistically significant reduction in the use of rescue treatment in people randomised to omalizumab compared with placebo. Observational studies provided limited evidence, with 2 studies reporting reduced use of rescue treatment compared with baseline use, but with no results of statistical tests. In children the IA‑05 European population subgroup initially showed a statistically significant benefit but this lost significance after adjustment for multiple testing. There was no additional evidence from supporting randomised controlled trials or observational studies in children.\n\nRandomised controlled trials of the population reflecting the marketing authorisation showed benefits of omalizumab compared with the comparator arm in improving lung capacity as measured by percentage of predicted FEV1, although these absolute benefits were small. These included INNOVATE at 28\xa0weeks (67.0% with omalizumab compared with 64.2% without omalizumab, p=0.043), EXALT at 32\xa0weeks (68.1% with omalizumab compared with 63.7% with no omalizumab, p=0.007), and the IA‑04 European population subgroup at 52\xa0weeks (71% with omalizumab compared with 60% with no additional treatment, p<0.01). Supporting trials did not show a statistically significant benefit, but the Assessment Group commented that these studies were conducted in people with better lung function. Some observational studies provided additional evidence that omalizumab is associated with statistically significant improvements in lung function in adults with uncontrolled severe asthma. In children, there was no randomised controlled trial evidence for FEV1 for the licensed population. The trial of children and young adults by Busse et\xa0al. included in the Assessment Group's review as supporting evidence and the observational studies in children reported no statistically significant differences between treatment groups.\n\nSix trials in adults (INNOVATE, EXALT and IA‑04 European population subgroup in the licensed population, and SOLAR, Hanania et\xa0al. and Hoshino et\xa0al. among the supporting studies) plus 1 trial in children (the IA‑05 European population subgroup) reported some measure of asthma‑related quality of life. All trials employed either the Asthma Quality of Life Questionnaire or, in the case of the IA‑05 European population subgroup, the paediatric Asthma Quality of Life Questionnaire. EXALT also reported EuroQol 5‑D (EQ‑5D) scores. In INNOVATE, there was a statistically significant improvement at 28\xa0weeks in the Asthma Quality of Life Questionnaire score (ranging from 1 to 7, with a higher score indicative of a better quality of life) in the intention‑to‑treat omalizumab group compared with placebo (change from baseline 0.91 with omalizumab compared with 0.46 with placebo, p<0.001; 61% of people randomised to omalizumab experienced a 0.5‑point or greater increase [0.5 points or more representing a clinically significant difference] compared with 48% with the comparator, p=0.008). Statistically significant improvements favouring omalizumab were also found in EXALT at 31\xa0weeks using the Asthma Quality of Life Questionnaire (change from baseline 1.06 [95%\xa0CI 0.88 to 1.24] with omalizumab compared with −0.07 [95%\xa0CI −0.31 to 0.17] with no omalizumab treatment; 74% of people randomised to omalizumab experienced a 0.5‑point or greater increase compared with 26% with the comparator, p<0.001) and in the IA‑04 European population subgroup at 52\xa0weeks (change from baseline 1.32 with omalizumab compared with 0.17 with no additional treatment, p<0.001; 77% of people randomised to omalizumab experienced a 0.5‑point or greater increase compared with 42% with the comparator, p<0.001). The supporting trials also showed quality‑of‑life benefits associated with omalizumab. In children, the IA‑05 European population subgroup reflecting the licensed indication demonstrated a substantial placebo response and showed no statistically significant evidence of treatment benefit (change from baseline 0.78 with omalizumab compared with 0.70 with the comparator, p=0.566; 62% of people randomised to omalizumab experienced a 0.5‑point or greater increase compared with 58% with the comparator, p=0.654). The Assessment Group stated that the lack of evidence for improvements in symptoms and quality of life in children may reflect the subgroup of the IA‑05 European population being underpowered to detect differences.\n\nThe Assessment Group commented that 3 (APEX, eXpeRience, and PERSIST) of the 5 observational studies that reported a measure of quality of life showed at least a minimally important increase of 0.5 points in score for the Asthma Quality of Life Questionnaire. In the uncontrolled prospective therapeutic trial by Brodlie et\xa0al., there was evidence of statistically significant increases in mini‑Asthma Quality of Life Questionnaire scores associated with taking omalizumab in children dependent on oral corticosteroids in the UK. Statistically significant improvements in scores were observed in children aged under 12\xa0years (change from 2.3 [1.7 to 4.2] at baseline to 5.2 [3.5 to 6.9], p=0.019) and in young people aged 12 to 16\xa0years (change from 3.8 [1.0 to 8.4] at baseline to 6.1 [3.2 to 9.9], p=0.0037). The Assessment Group commented that, although the population for this analysis was small (n=24), it represented the only evidence for children with very severe asthma who need oral corticosteroids.\n\nNine randomised controlled trials reported rates of discontinuing omalizumab or the comparator. The double‑blind randomised controlled trials in adults reported discontinuation rates in the omalizumab arm of between 2.4% and 19.4% compared with 7.7% and 22.2% in the placebo arms. In the open‑label trials the discontinuation rates were much higher in the comparator than the omalizumab arm (EXALT: 19.1% compared with 8.1%; IA‑04: 30.6% compared with 17.4%). In the 1 trial in children (IA‑05 European population subgroup), the discontinuation rate was approximately 20% in both arms.\n\nThe Assessment Group commented that there was very limited evidence relating to the effectiveness of omalizumab beyond 12\xa0months in either adults and adolescents, or children. Three randomised controlled trials and 4 observational studies reported follow‑up data at 52\xa0weeks or longer. Although the PERSIST observational study reported some follow‑up data at 120\xa0weeks, these were limited.\n\nTwo randomised controlled trials provided data on changes in oral corticosteroid use, 1 in the licensed population (EXALT) and 1 in a population with controlled asthma (trial 011). Trial 011, published by Holgate et\xa0al. (2004), was a randomised placebo‑controlled trial evaluating the effect of omalizumab on disease control and oral corticosteroid reduction. The Assessment Group commented that it excluded trial 011 from the other sections of its review because only a few patients received a long‑acting beta2 agonist, but included it in its analysis of corticosteroids because data on changes in oral corticosteroid use were scarce. In the EXALT trial, at 32\xa0weeks, people in the omalizumab group were more likely to have stopped or reduced their use of oral corticosteroids (62.7% compared with 30.4% in the control group, RR 2.06, 95%\xa0CI 1.08 to 3.94) and to have reduced their dose of oral corticosteroid (mean difference\xa06.70\xa0mg/day, 95%\xa0CI 12.93 to 0.47). In contrast, in trial 011, the proportions reducing or stopping oral corticosteroids at 32\xa0weeks follow‑up were similar in both the omalizumab and the placebo groups (74.0% compared with 73.3%, RR 1.01, 95%\xa0CI 0.79 to 1.28). The Assessment Group commented that the EXALT study was unblinded and trial 011 did not sufficiently adjust oral corticosteroid doses during the run‑in phase. Randomised controlled trial data on oral corticosteroid use in children were not available.\n\nTen uncontrolled observational studies reported data on oral corticosteroid use after omalizumab treatment. The Assessment Group commented that all except 1 of these studies were uncontrolled, with greater potential for bias, relatively small, and did not provide data beyond 12\xa0months. For adults on maintenance oral corticosteroids, the proportion of patients reducing or stopping oral corticosteroids ranged from 25.9% to 71.2% after omalizumab treatment. The outcomes for children on oral corticosteroid maintenance were reported in uncontrolled studies by Brodlie et\xa0al. and Kirk et\xa0al. (2011) performed in study populations that may have overlapped. Patients in both studies showed a statistically significant decrease in oral corticosteroid use after 16\xa0weeks of treatment with omalizumab, with the proportion of patients reducing or stopping oral corticosteroids being 13.3% (in the subgroup of children aged 5 to\xa012 years) and 22.2% (in children aged 6 to 11\xa0years). The median baseline daily oral corticosteroid dose in the Brodlie et\xa0al. study was 20\xa0mg (range 5–50\xa0mg), which fell to 5\xa0mg (range 0–40\xa0mg). All patients in the Kirk et\xa0al. study either reduced or stopped oral corticosteroid treatment at follow‑up, with a mean daily oral corticosteroid dose reduction of 14\xa0mg. Those patients who did not stop oral corticosteroids had a mean reduction from 20\xa0mg to 5\xa0mg per day. The Assessment Group included a summary of published systematic reviews of the adverse effects of oral corticosteroids, stating that the reliability of the data was unclear. The reviews included the known adverse effects of bone fracture, diabetes mellitus, peptic ulcer, cardiovascular events including myocardial infarction and stroke, cataract and glaucoma, sleep and mood disturbance, and weight gain and, for children, failure to reach expected adult height.\n\nThe Assessment Group identified 4 reviews of adverse effects associated with omalizumab; these were published between 2007 and 2011 and had a sample size ranging from 3429 to 57,300 people. Two of the reviews included randomised controlled trials and 1 included both randomised controlled trials and open‑label studies. One review included people with severe persistent allergic asthma, the second included people with moderate‑to‑severe persistent allergic asthma, the third included people who had received omalizumab, but in whom the indication was unclear, and the fourth review assessed the incidence of anaphylaxis from the Adverse Event Reporting System in people with asthma who had received omalizumab.\n\nThe key adverse events considered by the Assessment Group were anaphylaxis and arterial thrombotic events. The Assessment Group stated that both occur rarely and have not been conclusively linked to omalizumab. The Assessment Group commented that the evidence that associated omalizumab with cancer is also uncertain. The Assessment Group concluded that, although evidence exists for the short‑term safety of omalizumab, there was insufficient evidence on long‑term safety to draw any conclusion.\n\n# Cost effectiveness\n\nThe Assessment Group identified 6 published studies that evaluated the cost effectiveness of omalizumab for asthma. All studies compared omalizumab with standard care, which differed between studies. For example, Oba and Salzman (2004), Wu et\xa0al. (2007) and Campbell et\xa0al. (2010) considered inhaled corticosteroid plus additional rescue treatment (as needed) as standard care, whereas Dewilde et\xa0al. (2007), Brown et\xa0al. (2007) and Dal Negro et\xa0al. (2011) considered high‑dose inhaled corticosteroids and long‑acting beta2 agonists as standard care. All of the cost‑effectiveness models in these studies assumed that omalizumab conferred benefits, compared with standard care, by reducing clinically significant exacerbations. The studies varied in methodology and conclusions; 5 of 6 studies used quality‑adjusted life years (QALYs) to assess effectiveness for omalizumab compared with standard care, and the resulting incremental cost‑effectiveness ratios (ICERs) ranged from approximately £21,700 to £516,500 per QALY gained. Brown et\xa0al. concluded that omalizumab was cost effective, Oba and Salzman and Dewilde et\xa0al. concluded that omalizumab may be cost effective for people with severe asthma, Wu et\xa0al. concluded that omalizumab was not cost effective unless its acquisition price was reduced substantially, and Campbell et\xa0al. and Dal Negro et\xa0al. concluded that, although omalizumab improves health‑related quality of life, it also increases costs substantially. The Assessment Group commented that the studies had common issues and limitations that precluded reliable conclusions, and included differing populations, differing relative efficacy and adverse effects of omalizumab compared with oral corticosteroids, lacked robust data for asthma‑related mortality and health‑related quality of life, lacked consensus on treatment duration, and differed as to whether treatment persists over time.\n\n## Manufacturer's economic model\n\nThe manufacturer submitted an economic evaluation with a model structure identical to that used in NICE technology appraisals 133 and 201. This compared the costs and health outcomes of omalizumab as an add‑on treatment to standard care compared with standard care alone in people with severe persistent allergic asthma uncontrolled despite daily high‑dose inhaled corticosteroids plus a long‑acting beta2 agonist at BTS/SIGN step\xa04 or 5. The manufacturer used a Markov model that extrapolates the effects of omalizumab treatment for 10\xa0years and follows a hypothetical cohort over a lifetime time horizon (up to age 100\xa0years). People enter the model on either omalizumab in addition to standard care, or standard care alone in a health state characterising day‑to‑day symptoms of asthma. At 16\xa0weeks (the end of the first cycle), asthma in people taking omalizumab either does or does not respond to treatment based on the proportion of response in the trials. People whose asthma responds to omalizumab remain on it for the treatment duration, and the model assumes that they experience exacerbations at the rates observed for people whose asthma has responded in the clinical trials. The model assumes that people whose asthma does not respond stop taking omalizumab revert to standard care alone and have rates of exacerbation experienced by patients in trials randomised to standard care. During each subsequent cycle of the model, people either remain in the day‑to‑day symptom state or can experience an exacerbation. The manufacturer assumed that an asthma‑related death occurs only during a clinically significant severe exacerbation, with each exacerbation being associated with a mortality risk of 0.097% for children under 12\xa0years, 0.319% for those aged 12 to 16\xa0years, 0.383% for those aged 17 to 44\xa0years, and 2.478% for those aged 45\xa0years and over, all of which the manufacturer derived from mortality data for people hospitalised for acute severe asthma from Watson et\xa0al. (2007). The model also assumes that people with asthma can die from non‑asthma related causes. After a non‑fatal exacerbation, a person returns to the day‑to‑day asthma symptoms health state.\n\nThe manufacturer's model includes 2 separate base‑case populations: adults plus adolescents aged 12\xa0years and over (average age approximately 40\xa0years), and children aged 6 to 11\xa0years (average age 9\xa0years) and 2 subgroups: people who are hospitalised in the year before entering the model, and a subgroup of people who receive maintenance oral corticosteroids when entering the model. The model evaluates costs from the perspective of the NHS and personal social services, and discounts costs and health outcomes at a rate of 3.5% per annum, in accordance with the NICE reference case.\n\nThe manufacturer derived the evidence on the clinical effectiveness of omalizumab as add‑on treatment in the model's base case from the results of INNOVATE (adults and adolescents) and IA‑05 (children) and, for the model's scenario analysis in adults and adolescents, from EXALT and APEX. The effectiveness of treatment was based on data from trials on whether or not patients' asthma responded to omalizumab and their rates of clinically significant non‑severe exacerbation and clinically significant severe exacerbation.\n\nThe manufacturer included the costs of acquiring, administering and monitoring omalizumab. Omalizumab dose depends on a patient's baseline serum IgE and weight, and the base‑case model assumes an average dose corresponding to the dose distribution in the populations in INNOVATE, EXALT, APEX and IA‑05. The manufacturer estimated the costs of administration by assuming that it takes a specialist asthma nurse 10\xa0minutes to administer omalizumab, and that specialist asthma nursing care costs the NHS £47 per hour. The manufacturer included costs to monitor for anaphylaxis and for the 16‑week assessment. Standard care costs included 2 routine outpatient appointments per year with a hospital specialist and 2 extra visits for people taking omalizumab. The cost of standard care in the model corresponded to the standard care used in the trials. In addition, the cost of exacerbations, including GP consultations, outpatient appointments, emergency admissions, rehabilitation appointments, general ward stays and intensive care were calculated from the INNOVATE, EXALT, APEX and IA‑05 trials.\n\nThe manufacturer estimated health‑related quality of life (expressed in QALYs) by quality adjusting the period of time the average patient was alive within the model and applying a corresponding utility score. The 2 key elements determining health‑related quality of life were day‑to‑day symptoms and exacerbations (clinically significant non‑severe and severe). For day‑to‑day symptoms in the base‑case analysis, the manufacturer estimated utility values from the Asthma Quality of Life Questionnaire scores collected in INNOVATE and mapped these onto EQ‑5D values; the values were 0.669 for people receiving standard care and 0.779 for people taking omalizumab whose asthma responded to omalizumab (resulting in a difference in EQ‑5D of 0.110). For the subgroup reflecting patients from INNOVATE who were hospitalised in the year before trial entry, the manufacturer used a utility difference of 0.138 and, for the subgroup from INNOVATE who required maintenance oral corticosteroids, the manufacturer used a utility difference of 0.106. To estimate a person's utility decline associated with a clinically significant non‑severe or severe exacerbation, the manufacturer used values from a prospective study conducted in the UK in 4 specialist asthma centres where health‑related quality‑of‑life data were collected (n=112) using the EQ‑5D, mini Asthma Quality of Life Questionnaire, and Asthma Symptom Utility measures (Lloyd et\xa0al. 2007). The mean utility value assigned to a clinically significant non‑severe exacerbation was 0.572, and to a clinically significant severe exacerbation was 0.326, compared with 0.889 for no exacerbations. The manufacturer assumed that children aged 6 to 11 years taking omalizumab did not experience any improvement in health‑related quality of life.\n\n## Results of manufacturer's economic model\n\nThe base‑case deterministic ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone in adults and adolescents was estimated by the manufacturer to be £32,076 per QALY gained, and the probabilistic ICER to be £33,268 per QALY gained. The deterministic base‑case ICER for children was estimated to be £80,747 per QALY gained and the probabilistic ICER to be £88,998 per QALY gained. The manufacturer estimated that the probability that omalizumab is cost effective at £20,000 and £30,000 per QALY gained for adults and adolescents is 0.005 and 0.267 respectively.\n\nThe manufacturer presented cost‑effectiveness results for alternative scenarios based on data from the EXALT study, the best study to provide a scenario for open‑label use of omalizumab, and APEX, the best observational study to provide a scenario relevant to UK practice. The ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone was £61,687 per QALY gained using data from EXALT and £29,773 per QALY gained using data from APEX. The difference in ICER between the INNOVATE base case and the EXALT scenario resulted largely from the lower effect of treatment with omalizumab among people whose asthma responded to omalizumab observed in EXALT compared with INNOVATE, and the difference in improvement in health‑related quality of life for day‑to‑day symptoms estimated in INNOVATE (Asthma Quality of Life Questionnaire mapped to EQ‑5D) being greater than that in EXALT (directly observed EQ‑5D data). Omalizumab reduced the rate of total exacerbations more in INNOVATE (RR 0.373) than in EXALT (RR 0.410), and the health utility improvement was also greater in INNOVATE than in EXALT.\n\nThe manufacturer conducted several deterministic sensitivity analyses on the base‑case populations (INNOVATE and IA‑05 European population). The manufacturer concluded that the results were sensitive to changes in the time horizon, exacerbation rates, asthma‑related mortality, health‑related quality‑of‑life values for day‑to‑day asthma symptoms, omalizumab drug costs and the discount rate. The parameters that had the most effect on the results in the manufacturer's model were asthma‑related mortality and assumptions around health‑related quality of life with omalizumab. The ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone in adults and adolescents increased from £32,076 to £72,113 per QALY gained when asthma‑related mortality risk was set to zero. For children, the effect on the ICER was less pronounced because the asthma‑related risk of dying is much lower in children than in adults and adolescents. For children, treatment duration and the age at which a child starts treatment with omalizumab impacts on the cost effectiveness of omalizumab, reflecting the manufacturer's assumption that treatment with omalizumab does not improve health‑related quality of life until age 12\xa0years or over. Assuming a treatment duration of 2\xa0years instead of 10\xa0years increased the ICER from £80,747 to £662,893 per QALY gained. .Similarly, reducing the age of starting treatment from 9 to 6\xa0years increased the ICER to £130,475 per QALY gained. Assuming a health‑related quality‑of‑life gain with omalizumab in children equal to that seen in adults and adolescents (0.779) reduced the ICER in children to £61,731 per QALY gained.\n\nFor the subgroup reflecting people who had been hospitalised in the year before starting therapy with omalizumab, the ICERs for omalizumab as an add‑on treatment to standard care compared with standard care alone were £27,928, £35,198 and £30,407 per QALY gained for adults and adolescents (based on data from INNOVATE, EXALT and APEX respectively) and £65,100 per QALY gained for children (based on data from the IA‑05 European population). For the subgroup reflecting people who required maintenance oral corticosteroids at the time of starting omalizumab, the ICERs for adults and adolescents were £26,320, £37,604 and £29,685 per QALY gained (based on data from INNOVATE, EXALT and APEX respectively). Data for the maintenance oral corticosteroid subgroup were not available from the IA‑05 European population because only 6 patients were on maintenance oral corticosteroids at baseline.\n\nThe manufacturer conducted a sensitivity analysis, acknowledging the adverse effects of using maintenance oral corticosteroids, and calculated a potential 'oral corticosteroids‑sparing' effect of treatment with omalizumab. The manufacturer conducted these analyses in the subgroup of patients on maintenance oral corticosteroids in EXALT and APEX; the protocol of INNOVATE did not allow investigators to change a patient's ongoing standard care during the study period. In EXALT, 41.9% of people whose asthma responded to omalizumab stopped maintenance oral corticosteroids after 32\xa0weeks, whereas in APEX 45.1% of people whose asthma responded to omalizumab had stopped maintenance oral corticosteroids at follow‑up. For people whose asthma responded to omalizumab and who stopped maintenance oral corticosteroids, the manufacturer applied lower costs and higher QALYs in the model, and the ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone was reduced from £37,604 to £28,319 per QALY gained (using data from EXALT) and from £29,685 to £25,099 per QALY gained (using data from APEX).\n\n## Assessment Group's critique of manufacturer's cost‑effectiveness analysis\n\nThe Assessment Group commented that the manufacturer assumed that the effectiveness of treatment with omalizumab (in people whose asthma had responded to omalizumab by a given time point) did not diminish over time. In contrast, in the EXALT study, 8.6% of patients whose asthma had responded to omalizumab at 16\xa0weeks no longer responded to omalizumab at 32\xa0weeks. The Assessment Group commented that the study's open‑label design may have influenced the results in favour of omalizumab because knowing the patient's treatment may have affected how the investigator assessed response to omalizumab as well as how the patients reported exacerbations.\n\nThe Assessment Group commented that, to estimate the health‑related quality‑of‑life benefit with omalizumab, measuring EQ‑5D directly is more appropriate than the manufacturer's method of mapping Asthma Quality of Life Questionnaire scores (from INNOVATE) onto EQ‑5D values. In addition, the manufacturer assumed that children under 12\xa0years do not experience any improvement in health‑related quality of life with omalizumab until they reach 12\xa0years whereas the Assessment Group considered that the observational study of children by Brodlie suggested that young children also experience an improvement in asthma‑related quality of life.\n\nThe Assessment Group considered that the manufacturer's subgroup sensitivity analyses in people on maintenance oral corticosteroids were generally reasonable, considering the limited evidence. However, to estimate health utility losses from adverse effects related to oral corticosteroids, the manufacturer used disability‑adjusted life‑years (DALYs), which it assumed are equivalent to QALYs, an assumption the Assessment Group considered may not have been appropriate.\n\nThe Assessment Group commented that the manufacturer had addressed some of the uncertainties previously identified in NICE technology appraisals 133 and 201: in particular, the relative efficacy, safety and costs of omalizumab compared with maintenance oral corticosteroids, and a subgroup consisting of people who were hospitalised for asthma in the year before starting omalizumab, but also that several key uncertainties remained. For example, according to the Assessment Group the manufacturer had not adequately addressed the mortality associated with asthma; the relationship between mortality, age and severity of exacerbations; the degree to which omalizumab improves health‑related quality of life; and the influence of age on the cost‑effectiveness results. The Assessment Group commented that the asthma‑related mortality rates applied by the manufacturer in the model may have overestimated the number of asthma deaths because the manufacturer assumed that an individual dies from asthma only when experiencing a clinically significant severe exacerbation (from the health state of 'clinically significant exacerbation'), whether or not hospitalised; however, the manufacturer applied a mortality risk derived only from hospitalised patients. Data from INNOVATE showed that only about 20% of clinically significant severe exacerbations resulted in admission to hospital. In addition, the manufacturer used the mean age at which patients in trials started omalizumab in the model, which made the effect of omalizumab in different age groups difficult to discern. The Assessment Group commented that, because age affects the risk of asthma‑related mortality, the manufacturer should have considered the impact of age at the start of treatment, either by presenting ICERs by subgroups based on age or by combining estimates for different ages into a weighted ICER estimate. The Assessment Group commented that there is uncertainty about the association between clinically significant severe exacerbations and death. The Assessment Group considered that, because the manufacturer only included studies that linked severe exacerbations to asthma deaths in its systematic review on asthma‑related mortality, it may have excluded studies relevant to the appraisal. The Assessment Group also highlighted that, if the asthma‑related mortality rate used by the manufacturer (2.478% in adults aged 45\xa0years and over; derived from Watson et\xa0al.) was applied to the INNOVATE study, 2 or 3 asthma deaths would have been expected out of the 100 observed clinically significant severe exacerbations. In addition, if the same ratio of clinically significant exacerbations to clinically significant severe exacerbations in the INNOVATE study was applied to the APEX study, 3 deaths per year from asthma would have been expected among the 261 observed exacerbations. However, because nobody in these trials died from asthma, the Assessment Group commented that the rates for asthma‑related mortality used in the manufacturer's submission for adults and adolescents were likely to have overestimated mortality.\n\n## Assessment Group's economic model\n\nThe Assessment Group developed an economic model from the perspective of the UK NHS to assess the cost effectiveness of omalizumab as an add‑on treatment to optimised standard care of severe asthma compared with optimised standard care alone. The outcomes of the model are expressed in costs per QALY and costs in UK pound sterling at a 2009/10 price base. The Assessment Group evaluated both costs and outcomes over a lifetime, assuming an omalizumab treatment duration of 10\xa0years and discounting at an annual rate of 3.5%, in accordance with the NICE reference case.\n\nThe evidence of effectiveness of omalizumab compared with not using omalizumab for the base‑case population in the Assessment Group's model came from INNOVATE for adults and adolescents, and from the IA‑05 European population subgroup for children. In addition, the model included a subgroup defined as people admitted to hospital in the year before starting omalizumab (for adults and adolescents, 38.4% of the total INNOVATE trial population at baseline and, for children, 17% of the IA‑05 European population subgroup at baseline), and a subgroup of adults and adolescents who reflect people receiving maintenance oral corticosteroids at the start of treatment with omalizumab (21.7% of the INNOVATE population at trial baseline; for children, data were not available from the IA‑05 trial).\n\nThe model structure used by the Assessment Group was similar to the manufacturer's but differed in the assumptions for asthma‑related mortality and health‑related quality of life. In its model, the manufacturer linked asthma‑related deaths directly to a clinically significant severe exacerbation, whereas the Assessment Group's model assumed that people in the state of day‑to‑day asthma symptoms (and not only the state of clinically significant severe exacerbation) have an elevated risk of asthma‑related death compared with people without asthma. The Assessment Group systematically reviewed the literature for estimates of asthma‑related mortality and considered that the most appropriate data for the base case comes from de Vries et\xa0al. (2010), which used data from the General Practice Research Database from patients without chronic obstructive pulmonary disease registered in general practice in England aged 18\xa0years and over who received a prescription for inhaled short‑acting or long‑acting beta2 agonists. The study followed patients from 1993 and until death, death from asthma or hospitalisation for asthma, and derived incidence rates stratified by treatment steps (1 to 5) of the BTS. In sensitivity analyses, the Assessment Group used alternative mortality rates from Watson et\xa0al., as used in the manufacturer's model. In the base case, the Assessment Group estimated, using the de Vries et\xa0al. data, that the probability of death over a 3‑month period (the cycle length used in the model) was 0.001 for all ages and acknowledged an absence of data for children. The Assessment Group also estimated, using the Watson et\xa0al. data, that the probability of death specifically related to asthma over a 3‑month period was 0.0049 for people 45\xa0years and over, 0.0008 for those 17 to 44\xa0years, 0.0006 for those 12 to 16\xa0years, and 0.0001 for children under 12\xa0years.\n\nAs in the manufacturer's model, the Assessment Group's model considered health‑related quality of life associated with day‑to‑day symptoms of asthma, the degree to which exacerbations worsen the symptoms, and the degree to which treatment with omalizumab improves them. However, to estimate health‑related quality of life for day‑to‑day symptoms, the Assessment Group used EQ‑5D data from EXALT, whereas the manufacturer mapped Asthma Quality of Life Questionnaire scores from INNOVATE onto EQ‑5D values. The Assessment Group assumed that children experience the same improvement in health‑related quality of life from omalizumab treatment as do adults and adolescents, whereas the manufacturer's model assumed no health‑related quality‑of‑life benefit from treatment with omalizumab in children. In the base‑case population, the Assessment Group applied a health utility value for day‑to‑day asthma symptoms for people receiving standard care of 0.719 (compared with 0.669 in the manufacturer's model) and for people taking omalizumab and whose asthma responded to omalizumab at 32\xa0weeks, a utility value of 0.767 (compared with 0.779 in the manufacturer's model). The improvement in utility attributed to omalizumab was smaller in the Assessment Group's model at 0.048 than in the manufacturer's model, with a difference of 0.110. For patients hospitalised in the year before starting (or not starting) omalizumab, the Assessment Group estimated that the difference in utility attributable to omalizumab was 0.130 (compared with 0.138 in the manufacturer's model) and for patients on maintenance oral corticosteroids at the start (or not) of treatment with omalizumab was a difference in utility of 0.105 (compared with 0.106 in the manufacturer's model). To estimate the decrease in utility caused by clinically significant non‑severe and severe exacerbations, the Assessment Group and the manufacturer used data from a prospective study conducted in 4 UK specialist asthma centres, which collected EQ‑5D data (Lloyd et\xa0al.). The Assessment Group commented that exacerbations leading to hospitalisation may have been more severe in the Lloyd et\xa0al. study than in the INNOVATE study, which could have led to overestimation of the effect of an exacerbation on health‑related quality of life. The Assessment Group indicated that the combined impact of these factors is unclear.\n\nThe Assessment Group included in its model the costs of omalizumab and its administration, and costs related to monitoring patients. The costs of omalizumab reflected every 2 to 4\xa0week dosing dependent on serum IgE and body weight. The Assessment Group used the unit price of the 75‑mg syringe (£128.07) to estimate an average annual cost of omalizumab per patient based on the dose distribution used in the trials (INNOVATE for adults and adolescents and IA‑05 European population subgroup for children) obtained from the manufacturer's submission. The Assessment Group assumed 10\xa0minutes of a specialist asthma nurse's time to administer omalizumab, and 15\xa0minutes of nurse's time (both at £47/hour) to monitor the patient up to the third time a patient received omalizumab. From the fourth administration up to the 16‑week assessment, monitoring by the specialist nurse was assumed to take 1\xa0hour. From 16\xa0weeks onwards, no monitoring costs were incurred. The Assessment Group assumed that a patient's 16‑week assessment took place during a routine appointment. This differs from the manufacturer's model, which assumed that clinicians assess the patient during an additional follow‑up appointment. The Assessment Group calculated the annual average cost of omalizumab for adults and adolescents as £8056 plus administration costs of £260 in the first year and £146 in subsequent years; for children, the annual average cost of omalizumab was £8455 plus administration costs of £268 in the first year and £151 in subsequent years. The distribution of the dose of omalizumab for the subgroups (when starting omalizumab when hospitalised in the previous year, or on maintenance corticosteroids) was not available; therefore, the Assessment Group used data from the base‑case patient population for the subgroups. The Assessment Group took the costs of exacerbations and standard care from the manufacturer's submission and applied them to both modelled treatment groups.\n\n## Results of Assessment Group's economic model\n\nFor adults and adolescents, and for children, omalizumab add‑on treatment was more costly and more effective than standard care alone. For adults and adolescents, the mean cost of omalizumab add‑on treatment was £72,938 compared with £33,218 for standard care without omalizumab; the mean QALYs were 14.13 and 13.66 respectively. This resulted in an ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone of £83,822 per QALY gained. For children the mean cost of omalizumab add‑on treatment was £92,497 compared with £40,218 for standard care without omalizumab; the mean QALYs were 17.39 and 16.72 respectively. This resulted in an ICER for omalizumab of £78,009 per QALY gained. The Assessment Group estimated that the probability that omalizumab was cost effective at £30,000 per QALY was zero in both populations.\n\nFor the modelled subgroup reflecting people who had been hospitalised the year before starting treatment, omalizumab add‑on treatment was more costly and more effective than standard care without omalizumab. For adults and adolescents, the mean cost of treatment with omalizumab was £75,826 compared with £36,449 for standard care with mean QALYs of 12.68 and 11.83 respectively. This resulted in an ICER for omalizumab of £46,431 per QALY gained. For children, the mean cost of omalizumab was £83,145 compared with £44,718 for standard care; the mean QALYs were 15.32 and 14.45 respectively. This resulted in an ICER for omalizumab of £44,142 per QALY gained. The Assessment Group estimated that the probability that omalizumab was cost effective at £30,000 per QALY gained was zero in both populations.\n\nFor the modelled subgroup reflecting people who took maintenance oral corticosteroids, omalizumab add‑on treatment was more costly but also more effective than standard care alone. For adults and adolescents, the mean cost of omalizumab add‑on treatment was £68,995 compared with £35,902 for standard care; the mean QALYs were 13.44 and 12.78 respectively. This resulted in an ICER for omalizumab of £50,181 per QALY gained. As with the hospitalisation subgroup, the Assessment Group estimated that the probability that omalizumab was cost effective at £30,000 per QALY was zero.\n\nThe Assessment Group presented results for several scenarios reflecting different assumptions. This included a scenario that took into account the adverse effects of maintenance oral corticosteroids, following a similar approach taken by the manufacturer. The Assessment Group assumed that:\n\npatients who do not receive omalizumab continue maintenance oral corticosteroids for the rest of their lives\n\nthe excess relative risk of developing diseases attributable to use of oral corticosteroids does not persist once an individual has stopped taking oral corticosteroids, and\n\nhealth losses expressed in disability‑adjusted life years (DALYs) are equivalent to health gains expressed in QALYs.\n\nThe Assessment Group commented that the key drivers of cost effectiveness were the asthma‑related mortality rates, the degree to which omalizumab improves health‑related quality of life and, for people who take maintenance oral corticosteroids, whether or not the model included adverse effects from oral corticosteroids. When the model incorporated the higher asthma‑related mortality rates reported by Watson et\xa0al. and adopted by the manufacturer, the ICERs for omalizumab as an add‑on treatment compared with standard care alone for the base‑case populations were £46,029 per QALY gained for adults and adolescents, and £98,688 per QALY gained for children. In the subgroup reflecting patients hospitalised in the year before starting therapy, the ICERs for omalizumab were £31,576 per QALY gained for adults and adolescents and £47,430 per QALY gained for children, and in the subgroup taking maintenance oral corticosteroids, the ICER was £29,657 per QALY gained for adults and adolescents and was not estimated for children. Whether the model included the assumption that omalizumab did or did not improve a child's health‑related quality of life also had a substantial impact on the ICERs. However, the ICER did not fall below £30,000 per QALY gained in children (the lowest ICER was £42,296 per QALY gained in the subgroup of children hospitalised in the previous year). Incorporating the adverse effects of oral corticosteroids in the maintenance oral corticosteroids subgroup reduced the ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone from £50,181 to £44,292.\n\nAn additional subgroup consisting of people experiencing 3 or more exacerbations in the previous year was considered by the Assessment Group. The ICERs for omalizumab in this subgroup were lower than the ICERs for the base‑case populations of adults and adolescents (£77,868 per QALY gained compared with £83,822 per QALY gained) and children (£71,513 per QALY gained compared with £78,009 per QALY gained). The Assessment Group commented that using the health‑related quality‑of‑life data from INNOVATE (EQ‑5D mapped from Asthma Quality of Life Questionnaire scores) reduced the ICERs in this subgroup to £52,236 per QALY gained in adults and adolescents, and to £50,139 per QALY gained in children.\n\n## Additional analyses requested by the Appraisal Committee at the first Appraisal Committee meeting (3 July 2012)\n\nAfter the first appraisal committee meeting, NICE requested on behalf of the Appraisal Committee that the Assessment Group undertake additional analyses in order to model scenarios with alternative assumptions on:\n\nmortality rates for very severe asthma\n\nrates of clinically significant exacerbations for very severe asthma\n\ntreatment duration\n\nadverse effects of oral corticosteroids, and\n\ncarer benefits. The Committee requested additional analyses for 3 scenarios including populations who are covered by the marketing authorisation, whose therapy is optimised and who are followed in a specialist centre:\n\nPopulation 1: people with very severe persistent allergic asthma maintained on oral corticosteroids and who were hospitalised in the year before treatment.\n\nPopulation 2: people with very severe persistent allergic asthma maintained on oral corticosteroids, but who have not necessarily been hospitalised in the year before treatment.\n\nPopulation 3: people with very severe persistent allergic asthma who are on maintenance or frequent courses of oral corticosteroids (for example, 4 or more courses per year), but who have not necessarily been hospitalised in the year before treatment.\n\nThe Assessment Group requested additional data from the manufacturer for populations 1 and 3, and used data for subgroup\xa02 available in the manufacturer's submission. The Assessment Group also received additional information requested from clinical specialists about omalizumab use in the UK. The additional analyses conducted by the Assessment Group were presented for the following: children aged 6 to 11\xa0years; adults and adolescents aged 12\xa0years and over; and the overall population consisting of adults, adolescents and children. For adults and adolescents, and the overall population, the results presented were based on a weighted average of the ICERs for different age cohorts to reflect the mortality risk that differs by age. The weighting was based on the percentage of people at each age in the APEX study.\n\nThe Assessment Group's additional analyses incorporated the following assumptions in the base case: asthma‑related mortality risk from Watson et\xa0al.; adverse effects of oral corticosteroids; 5‑year treatment duration for children, 10‑year treatment duration for adults and adolescents; EQ‑5D utility values from EXALT for the subgroup taking maintenance oral corticosteroids (population 2) used for all populations; and the same exacerbation rates at start of treatment, treatment effectiveness, and health‑related quality of life assumed for children as for adults and adolescents. The ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone for children was £62,945, £61,361 and £61,096 per QALY gained in populations 1, 2 and 3, respectively. The ICER for adults and adolescents was £32,398 and £32,508 per QALY gained in populations 1 and 2 respectively, with the lowest ICER in population 3 (£31,573). The ICER for omalizumab as an add‑on treatment to standard care compared with standard care alone for the overall population (adults, adolescents and children) was £33,077, £33,150 and £32,229 per QALY gained in populations 1, 2 and 3 respectively. The Assessment Group commented that the ICERs for the overall population (adults, adolescents and children), and for adults and adolescents alone, were similar because children represent a small proportion of the overall population (2.2%). The Assessment Group further commented that asthma‑related mortality risk was the main driver of the cost‑effectiveness results and of the differences in the results between the adult and adolescent population and children.\n\nThe Assessment Group presented cost‑effectiveness results for populations 1, 2 and 3 based on alternative scenarios, as requested by the Appraisal Committee. Increasing the clinical effectiveness of omalizumab observed in INNOVATE by 10% in all subgroups reduced the ICERs for omalizumab very slightly across all 3 populations, with all the ICERs remaining above £30,000 per QALY gained. Using the improvement in utility (0.1300) from EXALT for the group hospitalised in the year before starting therapy applied to all populations also reduced the ICERs for omalizumab, though they remained above £30,000 per QALY gained for all 3\xa0populations. Increasing the asthma‑related mortality risk from Watson et\xa0al. by 15% across all age groups also reduced the ICERs slightly. In the overall population, increasing the asthma‑related mortality risk from Watson et\xa0al. by 15% reduced the ICER to £32,047, £32,134 and £31,159 per QALY gained for populations 1, 2 and 3 respectively. Using asthma‑related mortality risk from de Vries et\xa0al. and increasing the risk by 15% reduced the ICERs for children in all 3 populations to approximately £53,000 per QALY gained. For adults and adolescents, the ICERs increased to approximately £42,000 per QALY gained for each population. For the overall population, the ICERs increased to £42,613, £42,634 and £41,868 per QALY gained for populations 1, 2 and 3 respectively. The Assessment Group also incorporated an additional QALY burden from non‑Hodgkin's lymphoma, adrenal insufficiency and sleep disturbance, which resulted in an annual total QALY loss of 0.04978. This reduced the ICERs for omalizumab slightly across all 3 populations, again with all the ICERs remaining above £30,000 per QALY gained.\n\nThe Assessment Group conducted a threshold analysis to estimate the minimum health‑related quality‑of‑life losses associated with oral corticosteroid‑related adverse effects that would be needed to achieve an ICER for omalizumab of less than or equal to £30,000 per QALY gained. The Assessment Group's results showed that the QALY loss associated with oral corticosteroids would need to be at least 0.115 QALYs per patient per year for population 1, at least 0.120 QALYs per patient per year for population 2 and at least 0.095 QALYs per patient per year for population 3. To achieve an ICER of £30,000 per QALY gained, identified health consequences would need to be 2.3, 2.4 and 1.9 times their current values in populations 1, 2 and 3 respectively.\n\nThe Assessment Group was not aware of any evidence to provide adequate estimates on health‑related quality‑of‑life benefits not currently captured in the economic modelling, including in carers. For patients, the model captured the health‑related quality‑of‑life improvements with omalizumab.\n\n## Additional analyses and the patient access scheme submitted by the manufacturer after the second Appraisal Committee meeting (3 October 2012)\n\nIn its response to the appraisal consultation document, the manufacturer provided additional analyses for population 2 (people with very severe persistent allergic asthma who require maintenance oral corticosteroids) and population 3 (people with very severe persistent allergic asthma who require maintenance or frequent courses of oral corticosteroids [4 or more per year]). In contrast to its original analyses, the manufacturer assumed that the utility gain from omalizumab for adolescents and adults applied also to children. The manufacturer calculated an asthma‑related mortality rate midway between the estimates from Watson et\xa0al. and de Vries et\xa0al., and increased the result by 15% to represent those patients with the most severe asthma. The manufacturer varied the proportion of children in the age‑weighted ICER calculations. The 3 proportions were:\n\n%, used in the Assessment Group's weighted average cost‑effectiveness analyses\n\n%, based on mid‑2011 census data for England and Wales; and\n\n%, the midpoint value between 2.2% and 7.3%.\n\nThe manufacturer agreed a patient access scheme with the Department of Health, in which the manufacturer offers a discount on the list price of omalizumab to the NHS. The resulting ICERs for population 2 were £24,183, £24,591 and £25,010 per QALY gained when the proportions of children were assumed to be 2.2%, 4.75% and 7.3% respectively. The resulting ICERs for population 3 were £23,453, £23,902 and £24,370 per QALY gained with the same proportions of children.\n\nThe Assessment Group reviewed the manufacturer's additional analyses and reported that the manufacturer had assumed that the risk of asthma‑related mortality reported in Watson et\xa0al. and de Vries et\xa0al. used the same measure of risk. However, Watson et\xa0al. reported a conditional probability of death after hospitalisation for acute severe asthma, and de Vries et\xa0al. reported an annual mortality rate for patients treated at BTS/SIGN step\xa05. The Assessment Group considered that the probability and the rate should have been converted into the same measure of risk before averaging across risks. The Assessment Group also commented that, by averaging the proportion of patients in the overall population for the different age categories to obtain an average midpoint mortality risk by age, then using this risk to calculate the age‑weighted ICER, the manufacturer had not accurately weighted the proportion of patients in each age category. The Assessment Group corrected these errors and, using the midpoint mortality estimates increased by 15%, estimated ICERs for population 2 of £23,626, £23,817 and £24,008 per QALY gained when the proportions of children were assumed to be 2.2%, 4.75% and 7.3% respectively. The resulting ICERs for population 3 were £23,011, £23,203 and £23,395 per QALY gained with the same proportions of children.\n\n# Innovation\n\nThe manufacturer considered that omalizumab's innovative characteristics included its ability to substantially improve quality of life. The manufacturer highlighted its opinion that omalizumab represents the only significant advance in the management of severe asthma in the past 30\xa0years.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of omalizumab, having considered evidence on the nature of severe persistent allergic asthma and the value placed on the benefits of omalizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n## Management of severe persistent allergic asthma in UK clinical practice\n\nThe Committee discussed the clinical need of people with severe persistent allergic asthma. It heard from the clinical specialists and the patient experts that severe exacerbations have a large impact on people with severe persistent allergic asthma and their families. This may include frequent attendance at accident and emergency departments, emergency GP visits, reduced attendance and poor performance at school or work, limitations to social life and inability to exercise. The Committee also heard that the impact on families and carers may include anxiety, sleep deprivation, and emotional and financial pressures. The Committee accepted that severe uncontrolled asthma can severely reduce quality of life among people with the condition, as well as their families and carers.\n\nThe Committee discussed the role of omalizumab in UK clinical practice. It heard from the clinical specialists that UK clinical practice is based on the 'British guideline on the management of asthma' (BTS/SIGN) and uses a stepped treatment approach, with drugs added or withdrawn depending on symptoms and control. The Committee heard from the clinical specialists and patient experts that, in current UK clinical practice, the population for which omalizumab would be considered was smaller than that covered by the marketing authorisation. Clinicians currently optimise a person's asthma treatment before considering omalizumab; for those whose asthma remains poorly controlled, and affects their quality of life, omalizumab is considered as an add‑on treatment. One clinical specialist estimated that the number of people currently being offered omalizumab in his practice accounts for approximately 1 in 200 people with asthma and approximately 8 in 200 people with asthma are at step\xa05 of the 'British guideline on the management of asthma'. The Committee concluded that only people with the most severe persistent allergic asthma despite optimised treatment would currently be offered omalizumab.\n\nThe Committee was aware that NICE technology appraisal 133 requires a person to have been hospitalised for a clinically significant severe exacerbation in the year before starting omalizumab. The Committee heard from a patient expert that requiring hospitalisation as a prerequisite for treatment with omalizumab provides the perverse incentive to let the condition worsen. The Committee heard from the clinical specialists that there are various reasons why people might choose not to go into hospital, and that some people tolerate respiratory distress better than others. It heard from a patient expert that he chose not to go to hospital even when extremely ill, and heard from the clinical specialists that this behaviour is not unusual for people with severe uncontrolled asthma. The Committee noted that the clinical specialists preferred other ways of identifying candidates for treatment with omalizumab, that is, people with asthma at step\xa05 of the 'British guideline on the management of asthma' (BTS/SIGN) with poorly controlled asthma who are treated with continuous or multiple courses of oral corticosteroids per year, irrespective of whether they had recently been admitted to hospital. The Committee accepted that there are limitations to using the requirement of previous hospitalisation as a criterion for determining clinical need for omalizumab.\n\nThe Committee discussed oral corticosteroid use, including the significant physical and psychiatric long‑term adverse effects associated with frequent use. The Committee noted that these include bone fracture, diabetes mellitus, peptic ulcer, myocardial infarction, stroke, cataracts, glaucoma, sleep and mood disturbance, and weight gain, and, for children, failure to reach expected adult height. It also noted that the patient experts and clinical specialists highly valued any therapy that would help a person with severe asthma taper or stop oral corticosteroid use. The clinical specialists explained that they would offer omalizumab not only to people on maintenance oral corticosteroids, but also to some people who required frequent courses of oral corticosteroids. The Committee heard from the clinical specialists that omalizumab enables people with severe allergic asthma to reduce their use of high‑dose oral corticosteroids, and that patients and their carers are prepared to accept the inconvenience of attending specialist centres to have injections of omalizumab. The Committee accepted that there are significant risks associated with oral corticosteroids, and that frequent use may have a considerable impact on the lives of people with severe asthma.\n\n## Clinical effectiveness\n\nThe Committee considered the evidence on the clinical effectiveness of omalizumab from the manufacturer's submission and the assessment report. The Committee noted that omalizumab as an add‑on to standard care reduced the rate of clinically significant exacerbations and clinically significant severe exacerbations in adults, adolescents and children, although the effect on clinically significant severe exacerbations was not statistically significant in children. The Committee noted that the conclusions from the double‑blind INNOVATE trial were supported by the results from several other clinical trials. The Committee also noted that, in adults, omalizumab reduced total emergency visits (including hospital admissions, emergency department visits and unscheduled visits to the doctor), and reduced hospital admissions in children whose asthma responded to omalizumab compared with children randomised to placebo. The Committee noted that omalizumab treatment resulted in small increases in lung function in adults as measured by percentage of predicted FEV1 but that no FEV1 data were collected in the children's trials. The Committee also noted that there was some evidence that adults and adolescents taking omalizumab used rescue medication less frequently and oral corticosteroids in lower doses. The Committee heard from patient experts and clinical specialists, and again from comments received during consultation, that omalizumab has resulted in life‑changing improvements in reducing the number of asthma‑related clinically significant exacerbations. The Committee concluded that omalizumab as an add‑on to optimised standard care is more clinically effective in treating severe persistent allergic asthma than optimised standard care alone.\n\nThe Committee understood that health‑related quality of life was generally collected using the Asthma Quality of Life Questionnaire, with a paediatric version for children participating in the IA‑05 trial. The Committee noted that EXALT was the only trial that also reported EQ‑5D scores. The Committee also noted that there were statistically significant improvements in health‑related quality of life favouring omalizumab in adults from both INNOVATE and EXALT, but not in children. The Committee agreed with the Assessment Group's suggestion that the IA‑05 trial may have been underpowered to detect differences in health‑related quality of life in children. The Committee heard from a patient expert that treatment with omalizumab resulted in a marked improvement in her child's health‑related quality of life, including the ability to attend school, participate in sports and play in the park. The Committee accepted from the testimonies of the patient experts and the evidence from the clinical studies that omalizumab was likely to improve health‑related quality of life in adults, adolescents and children with severe persistent allergic asthma. The Committee also agreed that there could be additional health‑related benefits for carers as a result of omalizumab use, and that these could be included within NICE's reference case if quantifiable.\n\nThe Committee noted that the clinical trials included people whose asthma was less severe than those currently being treated with omalizumab in the UK. The Committee concluded that the trial evidence may not be fully applicable to people who would be offered omalizumab in the UK, who, having more severe asthma, might receive more benefit from omalizumab treatment, a conclusion supported by the clinical specialists.\n\n## Cost effectiveness\n\nThe Committee considered the cost‑effectiveness results from the manufacturer's submission and the assessment report, and noted that the main differences between the manufacturer's and the Assessment Group's economic models were the assumptions on asthma‑related mortality and how health‑related quality of life improvements from omalizumab were incorporated in the models. The Committee discussed which estimates for asthma‑related mortality risk were most plausible. The manufacturer's model included mortality rates from Watson et\xa0al. for people hospitalised with acute severe asthma, categorised by age. By contrast, the Assessment Group used data from de Vries et\xa0al., which stratified people with asthma aged 18\xa0years and over from the General Practice Research Database according to their GINA stage, with GINA step\xa05 as the Assessment Group's base case. The Committee noted that the mortality rate from de Vries et\xa0al. was constant across all ages, and that the Assessment Group assumed that this mortality rate also applied to children. The Committee heard from the clinical specialists that the asthma‑related mortality risk in children is much lower than in adults, and that in adults mortality risk increases with age. The Committee concluded that it was inappropriate to accept the same mortality risk across all ages because it did not reflect the natural history of the disease. However, the Committee was concerned that the Watson et\xa0al. data were inconsistent with the observation that no deaths attributable to asthma were observed in the APEX trial. On the other hand, the Committee considered that mortality rates may have been underestimated in the de Vries et\xa0al. data, if people offered omalizumab in the UK reflected the more severe end of step\xa05 with higher mortality rates than those reported for people at step\xa05 as a whole. Additionally, the Committee was aware that both studies may have overestimated the true mortality rate from asthma by attributing deaths from chronic obstructive pulmonary disease to asthma, although the de Vries et\xa0al. study tried to exclude people with chronic obstructive pulmonary disease. The Committee concluded that both the Watson et\xa0al. and the de Vries et\xa0al. studies had limitations, that considerable uncertainty remained about the mortality associated with severe persistent asthma, and that neither may reflect mortality among the subgroups of people with very severe persistent asthma, to whom omalizumab is offered in clinical practice. The Committee agreed that the asthma‑related mortality rates applicable to this appraisal were likely to be between the Watson et\xa0al. and de Vries et\xa0al. estimates.\n\nThe Committee considered that assumptions around the utility gain associated with omalizumab also accounted for some of the differences in the results between the Assessment Group's and the manufacturer's models. Firstly, it noted that the Assessment Group assumed that children experienced the same improvement in health‑related quality of life as adults and adolescents, whereas the manufacturer assumed there was no health‑related quality of life improvement from omalizumab treatment in children. The Committee concluded that the evidence presented by a patient expert, and the results from an observational study in children, showed that the utility values used in the manufacturer's economic model did not adequately capture the potential health‑related quality‑of‑life benefits of omalizumab for children. The Committee therefore preferred the Assessment Group's approach in which the same utility gain was assumed for adults, adolescents and children. Secondly, the Committee was aware that the manufacturer and the Assessment Group used different methods of estimating health‑related quality of life for day‑to‑day asthma symptoms. The Committee noted that the Assessment Group's approach, using EQ‑5D values directly collected in the EXALT trial, resulted in a lower quality‑of‑life benefit for people whose asthma responded to omalizumab than did the manufacturer's approach of mapping Asthma Quality of Life Questionnaire scores collected in the INNOVATE trial onto EQ‑5D values. The Committee preferred the direct estimates of EQ‑5D, in line with the NICE reference case.\n\nThe Committee considered which discount rates to use in this appraisal, noting the clarification of the Guide to the methods of technology appraisal issued by the Board of NICE. This states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30\xa0years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. The Committee considered that restoring and sustaining health for a very long period equated to a cure. The Committee heard from the clinical specialists that severe persistent asthma is not considered to be curable. It concluded that it did not have evidence that omalizumab cured asthma and that there was no case to apply differential discounting.\n\nThe Committee noted that the manufacturer's original probabilistic base‑case ICERs (see section 4.2.7) (for omalizumab as an add‑on treatment to standard care compared with standard care alone, and using the Watson et\xa0al. mortality rates) were £33,300 per QALY gained for adults and adolescents and £89,000 per QALY gained for children. By contrast, the Committee noted that the original Assessment Group's base‑case ICERs (using the de Vries et\xa0al. mortality rates) were £83,800 per QALY gained for adults and adolescents and £78,000 per QALY gained for children, and using the Watson et\xa0al. mortality data the Assessment Group's ICERs were £46,000 per QALY gained for adults and adolescents and £98,700 per QALY gained for children. The Committee acknowledged that using the mapped utility values as done in the manufacturer's model would reduce the ICERs from £83,800 to £52,200 per QALY gained for adults and adolescents, but it considered the use of direct EQ‑5D values more appropriate (see section 4.4.10). The Committee concluded that the ICERs for omalizumab for the whole population were higher than what can be considered a cost‑effective use of NHS resources.\n\nThe Committee acknowledged that the analyses carried out for subgroups of people hospitalised in the year before trial entry or on maintenance oral corticosteroids resulted in lower ICERs in both the manufacturer's and Assessment Group's analyses. However, the Committee noted that the Assessment Group's ICERs were still above £30,000 per QALY gained in adults and adolescents even with the use of the more favourable Watson et\xa0al. mortality data. The Committee noted that the Assessment Group's analysis had taken into account the disutility from several long‑term adverse effects including bone fracture, diabetes mellitus, peptic ulcer, myocardial infarction and stroke, cataract and glaucoma, weight gain, non‑Hodgkin's lymphoma, adrenal insufficiency and sleep disturbance. However, the Committee concluded that other adverse effects, such as obesity, hypertension, mood changes, depression, psychosis, thinning skin, delayed wound healing, reduced growth in children and increased risk of infection were additional important factors that had not been captured when calculating the QALY.\n\nThe Committee recognised that omalizumab was an effective therapy, and that the analyses presented may not have been applicable to the population of people with very severe asthma for whom omalizumab is used in clinical practice. The Committee considered whether it was possible to describe more clearly the clinical characteristics of this population and model the use of omalizumab more accurately, thereby identifying people with very severe asthma for whom omalizumab may potentially be cost effective. The Committee requested more information about the clinical characteristics of the population for which omalizumab would be considered, and asked the Assessment Group to carry out additional analysis in 3 high‑risk populations with very severe persistent allergic asthma:\n\npeople who are on maintenance oral corticosteroids and who were hospitalised in the year before treatment\n\npeople who are on maintenance oral corticosteroids but who have not necessarily been hospitalised in the year before treatment\n\npeople who are on maintenance or frequent courses of oral corticosteroids (for example, 4 or more courses per year) but who have not necessarily been hospitalised in the year before treatment. The Committee also asked the Assessment Group to assume higher efficacy for omalizumab and higher asthma‑related mortality estimates to reflect people with very severe uncontrolled asthma, as well as analyses incorporating more adverse effects from oral corticosteroids and carer benefits associated with omalizumab. The Committee also requested pooled analyses for the overall population of children, adolescents and adults for which omalizumab is licensed to explore the possibility of developing a single recommendation for all licensed populations.\n\nThe Committee considered the additional information and analyses provided by clinical specialists and the manufacturer, who provided the Assessment Group with the information necessary to conduct the further analyses requested by the Committee at the first appraisal committee meeting (see section 4.2.28). The Committee was aware that the new analyses incorporated the Watson et\xa0al. asthma‑related mortality data, with a sensitivity analysis using the de Vries et\xa0al. data, and shorter treatment duration for children (5 instead of 10\xa0years in the Assessment Group's original analyses following the advice of the clinical specialists). The Committee noted that the base‑case ICERs were similar across the 3 high‑risk populations, that is, £31,600 to £32,500 per QALY gained for adults and adolescents, £61,100 to £62,900 per QALY gained for children and £32,200 to £33,200 per QALY gained for the overall population. The Committee acknowledged that the ICERs for the overall population and for adults and adolescents were similar because children were assumed to represent only a very small proportion of the overall population treated with omalizumab (2.2%). However, the Committee acknowledged that the lower use of omalizumab in children may reflect the recommendation in NICE technology appraisal 201, and therefore the proportion of children who might otherwise be considered for omalizumab treatment may be underestimated. The Committee concluded that, even assuming 15% higher mortality rates because of the severity of the disease, the ICERs in the overall population were still high at £32,000 and £42,000 per QALY gained using the Watson et\xa0al. or de Vries et\xa0al. data respectively.\n\nThe Committee considered the Assessment Group's additional analysis on the health‑related quality‑of‑life losses associated with oral corticosteroid‑related adverse effects. The Committee noted that the Assessment Group had conducted a threshold analysis to explore the necessary size of the unidentified health effects of oral corticosteroid use, in addition to those already modelled, to reduce the cost per QALY gained of omalizumab to £30,000. The Committee noted that the additional QALYs from unidentified adverse effects of oral corticosteroids would need to be twice or more of those derived from known adverse effects, and was not persuaded that this was a plausible assumption.\n\nThe Committee considered omalizumab to be innovative in its potential to make a significant and substantial impact on health‑related benefits, and explored if any potential significant and substantial health‑related benefits have been identified that were not included in the economic model. The Committee recognised that some benefits of avoiding the adverse effects of oral corticosteroid use had not been fully captured in the QALY measure (see section 4.4.13). The Committee also considered the benefits to carers associated with omalizumab, which may not have been captured in the QALY calculations. The Committee noted that the manufacturer included no empirical and quantifiable evidence relating to potential carer benefits in its submission, and the Assessment Group did not include any carer benefits formally in its additional analyses. The Committee concluded that the potential additional health‑related benefits for carers as a result of omalizumab use could not currently be quantified. The Committee recognised that the approach to estimate utility gain in light of the lack of evidence taken in Pharmalgen for the treatment of bee and wasp venom allergy (NICE technology appraisal 246) was not appropriate to use here, because omalizumab does not provide a cure for asthma.\n\nThe Committee considered the additional analyses, including a patient access scheme, submitted by the manufacturer after consultation on the appraisal consultation document (see section 4.4.14). The Committee noted that the manufacturer calculated an asthma‑related mortality rate midpoint between the conditional probability in Watson et\xa0al. and the mortality risk in de Vries et\xa0al., and increased both by 15% to reflect mortality in people with very severe uncontrolled asthma, acknowledging the Assessment Group's concerns about averaging proportions and rates. The Committee concluded that the 15% increase in mortality risk was an appropriate approximation of the mortality risk in very severe allergic asthma. The Committee also concluded that a more realistic mortality rate likely lay between the midpoint and the estimate from de Vries et\xa0al. and that the average rate as corrected by the Assessment Group was a more plausible mortality rate, though some uncertainty remained.\n\nThe Committee noted the manufacturer's analyses of different proportions of children in the overall population eligible for omalizumab, which were carried out because of concerns that the 2.2% value assumed in the original Assessment Group's weighted average cost‑effectiveness analyses might underestimate the true value (see section 4.4.15). The Committee was aware that increasing the proportion of children from 2.2% to 7.3% in line with 2011 census data did not have a large impact on the ICERs (see section 4.2.35) and it concluded that, given uncertainties in the true value, it would be reasonable to accept the midpoint value of 4.75%. The Committee also concluded that, because the proportion of children used was very small and it did not have a large impact on the ICERs, it was appropriate to use the pooled analyses presented by the Assessment Group as the basis for a recommendation.\n\nThe Committee considered the results of the additional cost‑effective analyses using the asthma‑related mortality rate midpoint between Watson et\xa0al. and de Vries et\xa0al. increased by 15%, the 4.75% proportion of children aged 6 to 11 in the overall population eligible for omalizumab, and incorporating the patient access scheme for omalizumab. The Committee concluded that applying the Assessment Group's corrections to the manufacturer's analysis resulted in a most plausible ICER of £23,200 per QALY gained for the combined population of adults, adolescents and children on maintenance or frequent courses of oral corticosteroids, defined as 4 or more courses in the year before receiving omalizumab.\n\nThe Committee considered the comments received during consultation on the appraisal consultation document indicating the 'life‑changing' effect that omalizumab had on patients' lives and the lives of their families and carers. The Committee noted that many consultees had emphasised the need to acknowledge the uncaptured benefits of reducing dependence on oral corticosteroids and it was persuaded that these uncaptured benefits were sufficient to justify accepting an ICER of £23,200 per QALY gained. The Committee concluded that, with the patient access scheme submitted after consultation on the appraisal consultation document, omalizumab as an add‑on to optimised standard therapy is a cost‑effective use of NHS resources for treating severe persistent confirmed allergic IgE‑mediated asthma in people aged 6\xa0years and over who need continuous or frequent oral corticosteroid treatment (defined as 4 or more courses in the previous year) and should be recommended as an option for treatment in this population.\n\nThe Committee noted that optimised standard therapy was specified in NICE technology appraisal 133, and that oral beta2 agonists were listed as a component of optimised standard therapy but are now rarely used in clinical practice. For the purposes of this guidance, the Committee agreed that optimised standard therapy should be defined as a full trial of, and documented compliance with, inhaled high‑dose corticosteroids, long‑acting beta2 agonists, leukotriene receptor antagonists, theophyllines, oral corticosteroids, and smoking cessation if clinically appropriate.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA278\n\nAppraisal\n title:\n Omalizumab\n for\n treating\n severe\n persistent\n allergic\n asthma\n\nSection\n\nKey\n conclusion\n\nOmalizumab is recommended as an option for treating severe persistent confirmed allergic IgE‑mediated asthma as an add‑on to optimised standard therapy for people aged 6\xa0years and older who need continuous or frequent oral corticosteroid treatment (defined as 4 or more courses in the previous year), and only if the manufacturer makes omalizumab available with the discount agreed in the patient access scheme.\n\n\n\n\n\nThe Committee concluded that, using an asthma‑related mortality rate calculated as the midpoint between Watson et\xa0al. and de Vries et\xa0al. increased by 15% to account for very severe disease; using a proportion of children aged 6 to 11 in the overall population eligible for omalizumab of 4.75%; and incorporating the patient access scheme for omalizumab, resulted in a most plausible ICER of £23,200 per QALY gained for the combined population of adults, adolescents and children on maintenance or frequent courses of oral corticosteroids, defined as 4 or more courses in the year before receiving omalizumab.\n\n\n\nThe Committee acknowledged the uncaptured benefits of reducing dependence on oral corticosteroids and was persuaded that these uncaptured benefits were sufficient to justify accepting an ICER of £23,200 per QALY gained.\n\n\n\nCurrent\n practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee concluded that severe uncontrolled asthma can severely reduce quality of life among people with severe persistent asthma as well as their families and carers.\n\n\n\nThe\n technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee concluded that omalizumab as an add‑on to optimised standard care is more clinically effective in treating severe persistent allergic asthma than optimised standard care alone, leading to a reduction in total emergency visits (including hospital admissions, emergency department visits and unscheduled visits to the doctor) in adults, reduced hospital admissions in children, improved lung function in adults as measured by percentage of predicted FEV1 and a reduction in the frequency and use of rescue medication and oral corticosteroids.\n\n\n\nThe Committee concluded that omalizumab could be considered innovative, but the additional health‑related benefits for carers as a result of omalizumab use cannot currently be quantified.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee concluded that only people with the most severe persistent allergic asthma despite optimised treatment are currently offered omalizumab.\n\n\n\nAdverse reactions\n\nThere was no specific Committee discussion on adverse reactions of omalizumab.\n\nn/a\n\nEvidence\n for\n clinical\n effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted that the conclusions from the pivotal double‑blind INNOVATE trial were supported by the results from several other clinical trials.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee noted that the clinical trials included people whose asthma was less severe than those currently being treated with omalizumab in the UK. The Committee concluded that the trial evidence may not be fully applicable to people who would be offered omalizumab in the UK, who, having more severe asthma, might receive more benefit from omalizumab treatment, a conclusion supported by the clinical specialists.\n\n\n\nUncertainties generated by the evidence\n\nNo other specific uncertainties with respect to the clinical effectiveness of omalizumab were discussed by the Committee.\n\nn/a\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee considered that people with very severe asthma such as people who are on maintenance oral corticosteroids or who have been hospitalised because of asthma in the previous year may benefit the most from omalizumab.\n\n\n\n\n\nThe Committee requested additional analyses for 3 populations covered by the marketing authorisation, whose therapy is optimised, and who are treated in a specialist centre:\n\nPopulation 1: people with very severe persistent allergic asthma maintained on oral corticosteroids and who were hospitalised in the year before treatment.\n\nPopulation 2: people with very severe persistent allergic asthma maintained on oral corticosteroids, but who have not necessarily been hospitalised in the year before treatment.\n\nPopulation 3: people with very severe persistent allergic asthma who are on maintenance or frequent courses of oral corticosteroids (for example, 4 or more courses per year), but who have not necessarily been hospitalised in the year before treatment.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that omalizumab as an add‑on to optimised standard therapy is more clinically effective in treating severe persistent allergic asthma than optimised standard therapy alone.\n\n\n\n\n\nEvidence\n for\n cost\n effectiveness\n\nAvailability and nature of evidence\n\nThere were no specific conclusions made by the Committee about the availability and nature of the cost‑effectiveness evidence.\n\nn/a\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the main differences between the manufacturer's and the Assessment Group's economic models were the assumptions on asthma‑related mortality and how health‑related quality of life improvements from omalizumab treatment were incorporated in the models. The Committee concluded that considerable uncertainty remained about the asthma‑related mortality associated with severe persistent asthma, and that the Watson et\xa0al. and the de Vries et\xa0al. studies may not reflect mortality among the subgroups of people with very severe persistent asthma, to whom omalizumab is offered in clinical practice.\n\n\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee preferred the Assessment Group's approach in which the same utility gain was assumed for adults, adolescents and children.\n\n\n\nThe Committee preferred the Assessment Group's method of using direct estimates of EQ‑5D values, in line with the NICE reference case, to the manufacturer's approach of mapping Asthma Quality of Life Questionnaire scores collected in the INNOVATE trial onto EQ‑5D values.\n\n\n\nThe Committee concluded that some adverse effects of oral corticosteroid use, such as obesity, hypertension, mood changes, depression, psychosis, thinning skin, delayed wound healing, reduced growth in children, and increased risk of infection were additional important factors that had not been captured when calculating the QALY.\n\n\n\nThe Committee concluded that the potential additional health‑related benefits conferred to carers as a result of omalizumab use could not currently be quantified.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee noted that the base‑case ICERs in the overall population of adults, adolescents and children were similar across the 3 high‑risk populations, ranging from £32,200 to £33,200 per QALY gained without incorporating the patient access scheme for omalizumab.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe key drivers of cost effectiveness were the asthma‑related mortality rates, the degree to which omalizumab improves health‑related quality of life, and, for people who take maintenance oral corticosteroids, whether or not the model included adverse effects from oral corticosteroids.\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe Committee concluded that the most plausible ICER was £23,200 per QALY gained for the combined population of adults, adolescents and children on continuous or frequent courses of oral corticosteroids, defined as 4 or more courses in the year before receiving omalizumab incorporating the patient access scheme for omalizumab.\n\n\n\nAdditional\n factors\n taken\n into\n account\n\nPatient access schemes (PPRS)\n\nThe Committee noted that the manufacturer agreed a patient access scheme with the Department of Health including a discount on the list price of omalizumab.\n\n\n\nEnd‑of‑life considerations\n\nNot applicable.\n\nn/a\n\nEqualities, considerations and social value judgements\n\nNo equality issues relevant to the Committees recommendations were raised.\n\nn/a", 'Related NICE guidance': '# Published\n\nBronchial thermoplasty for severe asthma. NICE interventional procedure guidance 419 (2012).\n\nOmalizumab for the treatment of severe persistent allergic asthma in children aged 6 to 11 years. NICE technology appraisal guidance 201 (2010).\n\nInhaled corticosteroids for the treatment of chronic asthma in adults and children aged 12 years and over. NICE technology appraisal guidance 138 (2008).\n\nOmalizumab for severe persistent allergic asthma. NICE technology appraisal guidance 133 (2007).\n\nInhaled corticosteroids for the treatment of chronic asthma in children under the age of 12 years. NICE technology appraisal guidance 131 (2007).', 'Review of guidance': 'The guidance on this technology is considered for review by the Guidance Executive in March\xa02016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveApril 2013', 'Changes after publication': 'January 2014: minor maintenance.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt updates and replaces NICE technology appraisal guidance 131 (published November\xa02007) and NICE technology appraisal guidance 201 (published October\xa02010).\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0112-8'}	https://www.nice.org.uk/guidance/ta278	Evidence-based recommendations on omalizumab (Xolair) for treating severe persistent allergic asthma in people aged 6 and over.
3f321c3d597bd9b0991a5dbaf657be78143ee18c	nice	Percutaneous vertebroplasty and percutaneous balloon kyphoplasty for treating osteoporotic vertebral compression fractures	Percutaneous vertebroplasty and percutaneous balloon kyphoplasty for treating osteoporotic vertebral compression fractures Evidence-based recommendations on percutaneous vertebroplasty and percutaneous balloon kyphoplasty for treating osteoporotic vertebral compression fractures in adults. # Guidance Percutaneous vertebroplasty, and percutaneous balloon kyphoplasty without stenting, are recommended as options for treating osteoporotic vertebral compression fractures only in people: who have severe ongoing pain after a recent, unhealed vertebral fracture despite optimal pain management and in whom the pain has been confirmed to be at the level of the fracture by physical examination and imaging.# Clinical need and practice Vertebral fracture refers to a break in any of the bones (vertebrae) of the spinal column. Vertebral compression fractures usually occur when the front of the vertebral body collapses, and may be caused by trauma, cancer or osteoporosis. Osteoporotic vertebral compression fractures can cause the spine to curve and lose height, and can result in pain, difficulties in breathing, gastrointestinal problems, sleep disturbances and difficulties in performing activities of daily living. High doses of analgesics used to treat such pain can have significant adverse effects. The symptoms and treatment of osteoporotic vertebral compression fractures can worsen quality of life and cause loss of self-esteem. The prevalence of vertebral fractures increases with age and is more common in women. It is estimated that approximately 2.5 million people in England and Wales have osteoporosis. The prevalence of osteoporotic vertebral compression fractures is difficult to estimate because not all fractures come to the attention of clinicians and they are not always recognised on X-rays. Clinically evident osteoporotic vertebral compression fractures are associated with an increase in mortality. Treating vertebral compression fractures aims to restore mobility, reduce pain and minimise the incidence of new fractures. Non‑invasive treatment (such as pain medication, bed rest, and back braces) focuses on alleviating symptoms and supporting the spine. Percutaneous vertebroplasty (NICE interventional procedure guidance 12) and Balloon kyphoplasty for vertebral compression fractures (NICE interventional procedure guidance 166) support the use of percutaneous vertebroplasty and percutaneous balloon kyphoplasty without stenting (hereafter vertebroplasty and kyphoplasty respectively) as options for treating vertebral fractures. These guidance documents note that patients should receive these procedures only after discussion with a specialist multidisciplinary team, and in an appropriately resourced facility that has access to a spinal surgery service. For vertebroplasty, the guidance also states that the procedure should be limited to people whose pain does not respond to more conservative treatment.# The technologies # Percutaneous vertebroplasty Vertebroplasty involves injecting bone cement, typically polymethylmethacrylate, into the vertebral body (the solid part of the vertebra), using local anaesthetic and an analgesic. Vertebroplasty aims to relieve pain in people with painful fractures and to strengthen the bone to prevent future fractures. Several bone cements are available for vertebroplasty. The acquisition cost of the high-viscosity Confidence Spinal Cement System (Johnson and Johnson) is based on the number of vertebrae being treated. The average cost of the kit is £1472. Low-viscosity cements are available and, based on list prices provided by 2 manufacturers (Cook and Stryker); the Assessment Group estimated a cost of £800 per low-viscosity cement vertebroplasty procedure. # Percutaneous balloon kyphoplasty without stenting Kyphoplasty involves inserting a balloon-like device (tamps) into the vertebral body, using local or general anaesthetic. The balloon is slowly inflated until it restores the normal height of the vertebral body or the balloon reaches its highest volume. When the balloon is deflated, the space is filled with bone cement, and a stent may or may not be placed. This document covers kyphoplasty without stenting. Kyphoplasty aims to reduce pain and curvature of the spine. The Kyphon BKP kit (Medtronic) is available in the UK for kyphoplasty. Kyphon BKP is a CE-marked, single-use sterile pack with a list price of £2600.50 and includes 2 Kyphon Xpander inflatable bone tamps, with Kyphon ActivOs bone cement with hydroxyapatite supplied as a separate component. Alternative cements with different costs for use in kyphoplasty are available. # Percutaneous balloon kyphoplasty with stenting Kyphoplasty with stenting involves inserting a small balloon catheter surrounded by a metal stent into the vertebral body using radiographic guidance and either local or general anaesthesia. The balloon catheter is inflated with liquid under pressure to create a space into which the stent is expanded. The balloon catheter is deflated and withdrawn, but the stent remains in the vertebral cavity into which high-viscosity polymethylmethacrylate bone cement is then injected. The stent's function is to prevent the vertebra from losing height after the balloon is deflated. The available vertebral body stenting system (Synthes) consists of a stent catheter, an inflation system, an access kit and a balloon catheter if needed. The manufacturer stated that there is limited clinical evidence available for vertebral body stenting because it has become available only recently. Therefore, balloon kyphoplasty with stenting was not assessed in this appraisal. # Adverse reactions For both vertebroplasty and kyphoplasty, adverse reactions can be caused by: needle insertion (such as local or systemic infection, bleeding and damage to neural or other structures); leakage of bone cement; displacement of bone marrow and other material by the cement; systemic reactions to the cement (such as hypotension and death); and complications related to anaesthesia and patient positioning (such as additional fractures of a rib or the sternum). In addition, there is a small risk that the balloon can rupture in kyphoplasty, which can result in the retention of balloon fragments within the vertebral body.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from several sources (appendix B). # Clinical effectiveness The Assessment Group carried out a systematic review and identified 9 randomised controlled trials that met the inclusion criteria. The Assessment Group adopted the term 'optimal pain management' to encompass comparator treatments in the trials that consisted of optimising pain medication while treating conservatively, or managing without surgery. Two trials (Buchbinder et al. 2009, n=78; INVEST, n=131) compared vertebroplasty with an operative placebo, which included local anaesthetic. Five trials (Farrokhi et al. 2011, n=82; VERTOS, n=46; VERTOS II, n=202; Blasco et al. 2012, n=125; Rousing et al. 2009, n=50) compared vertebroplasty with optimal pain management. One trial (FREE, n=300) compared kyphoplasty with optimal pain management and another study (Liu et al. 2010, n=100) compared vertebroplasty with kyphoplasty. The Assessment Group highlighted that, of the randomised controlled trials, only the Buchbinder and INVEST studies were double blind. In addition, the FREE study included less than 80% of randomised patients in its final analysis and had an imbalance in drop-outs by treatment arm. The quality of the studies comparing vertebroplasty with optimal pain management (Blasco, Farrokhi, Rousing, VERTOS, and VERTOS II) varied, with the Farrokhi study being least at risk of bias. The Blasco and VERTOS II trials had substantial numbers of patients crossing over (changing treatment arms). The only study to compare vertebroplasty with kyphoplasty (Liu) was poorly reported, potentially biased and probably underpowered for its primary end point, as were the other studies, except for the Blasco, FREE, and INVEST trials. The Assessment Group stated that, in the absence of a statistically significant treatment effect in underpowered studies, it should not be assumed that no such difference exists. ## Percutaneous vertebroplasty compared with operative placebo with injected local anaesthesia The outcomes of the Buchbinder and INVEST studies included pain measured on either a numeric rating scale or a visual analogue scale (VAS). The Buchbinder study reported no statistically significant differences in the change from baseline between vertebroplasty and operative placebo with injected local anaesthesia at 1 week, or at 1, 3 or 6 months for the primary outcome of overall pain, with a mean difference adjusted for stratification variables and baselines values of 0.7 (95% confidence interval −0.4 to 1.8) at 1 week, −0.5 (95% CI −1.7 to 0.8) at 1 month, −0.6 (95% CI −1.8 to 0.7) at 3 months and −0.1 (95% CI −1.4 to 1.2) at 6 months (negative numbers indicate less severe pain). The INVEST study reported no statistically significant differences in the change in pain from baseline between groups for overall pain at 3 days, 1 week and 1 month, with an adjusted mean difference of 0.4 (95% CI −0.5 to 1.5, p=0.37) at 3 days, 0.1 (95% CI −0.8 to 1.1, p=0.77) at 1 week, and −0.7 (95%CI −1.7 to 0.3, p=0.19) at 1 month. The INVEST study showed a clinically meaningful improvement in pain (that is, a decrease of 30% or more) with vertebroplasty at 1 month, but this effect was not statistically significantly different from operative placebo with local anaesthesia (64% compared with 48%; p=0.06). In addition, the Assessment Group's meta-analysis of the individual patient data from both studies found no statistically significant improvement in change in pain from baseline between groups at 1 month, with an adjusted mean difference of −0.6 (95% CI −1.4 to 0.2). However, the number of patients taking opioids for pain decreased over time in both groups in both studies. In the Assessment Group's meta-analysis, after adjusting for baseline opioid use, patients randomised to vertebroplasty were statistically significantly more likely to be taking opioids at 1 month than patients randomised to operative placebo with local anaesthesia (relative risk 1.25, 95% CI 1.14 to 1.36, p<0.001). Therefore, the Assessment Group stated that the trend towards a higher proportion of patients in the vertebroplasty group achieving an improvement of 30% or more in pain scores at 1 month may have been influenced by the fact that the vertebroplasty group was more likely to be using opioids than the operative placebo with local anaesthesia group. The Buchbinder study also reported pain as an outcome in terms of QUALEFFO (Quality of Life Questionnaire of the European Foundation for Osteoporosis) pain scores and found no statistically significant differences between groups. Data were also collected on perceived pain, classified as 'better' or 'worse'. There were no statistically significant differences in the proportion of patients in each category at any time point. The INVEST study reported on the frequency with which patients experienced pain, and the impact of pain on their daily lives. For vertebroplasty and operative placebo with local anaesthesia, both pain frequency and pain 'bothersomeness' decreased between baseline and 1 month, with point estimates favouring vertebroplasty. However, the difference between vertebroplasty and operative placebo with local anaesthesia was not statistically significant. The Buchbinder study presented health-related quality-of-life results based on AQoL (Assessment of Quality of Life), EQ-5D and QUALEFFO measures. The INVEST study presented health-related quality-of-life results based on EQ-5D and SF-36. AQoL scores were not different for vertebroplasty and operative placebo with local anaesthesia. EQ-5D scores, available in the Buchbinder study for 79% of patients in the vertebroplasty group and 73% in the operative placebo with local anaesthesia group, were not statistically significant different between groups for short- or medium-term outcomes. The Assessment Group's meta-analysis of individual patient data at 1 month also indicated that the result (with positive numbers indicating better quality of life) was not statistically significant (adjusted mean difference 0.03, 95% CI −0.02 to 0.08). The Assessment Group highlighted that, because 0.08 is the minimum clinically important difference for back pain on the EQ-5D scale, the confidence interval for the pooled data only just included the possibility of a clinically important difference favouring vertebroplasty. Based on QUALEFFO scores in the Buchbinder study, the only statistically significant result was at 1 week, with an adjusted mean difference of −4.0 (95% CI −7.8 to −0.2), but the Assessment Group stated that, because no minimum clinically important difference had been proposed for the QUALEFFO, the clinical significance of this result is not clear. The INVEST study found no statistically significant differences between treatment groups at any point using SF-36 scores. Both the INVEST and Buchbinder studies assessed back-specific functional status using the modified 23-point version of the Roland-Morris Disability Questionnaire (RDQ). However, neither study showed any statistically significant differences for outcomes in the short-term (3 days to 2 weeks) or in the medium-term (1 month to 6 months). In addition, the Assessment Group's meta-analysis of individual patient data from both studies indicated no statistically significant difference between treatment groups at 1 month in terms of mean RDQ scores, with an adjusted mean difference of −0.8 (95% CI −0.9 to 2.4). The INVEST study included a post hoc analysis to identify the proportion of patients who achieved a clinically meaningful (although not defined) improvement in physical disability related to back pain at 1 month. There was no difference between the proportion of patients in each group who achieved a clinically meaningful improvement (40% of the vertebroplasty group and 41% of the operative placebo with local anaesthesia group, p=0.99). The Assessment Group's meta-analysis also found no statistically significant difference in RDQ scores in the proportion of patients improving by at least 3 units or by at least 30%. The INVEST study reported mean Study of Osteoporotic Fractures–Activities of Daily Living (SOF-ADL) scores at baseline and 1 month, with no statistically significant difference between treatment groups in change from baseline with an adjusted mean difference of 0.4 (95% CI −0.8 to 1.6, p=0.51). ## Percutaneous vertebroplasty compared with optimal pain management All studies comparing vertebroplasty with optimal pain management reported pain measured on a numeric rating scale or VAS. The Farrokhi, Rousing and VERTOS II studies showed statistically significant improvements between groups in short- and medium-term changes from baseline in pain after vertebroplasty. However, the Assessment Group highlighted that the favourable result reported by Rousing at 1 month may have been unreliable because these data were collected almost a year after the event. The VERTOS II and Farrokhi studies also found statistically significant improvements in the change from baseline between groups in longer-term outcomes. However, the Assessment Group noted that in the VERTOS II study, when defining a minimum clinically important improvement as 2 or more points, the 95% confidence interval included the possibility that the results were not clinically meaningful. In the study by Blasco, statistical significance in change in pain from baseline was reported at 2 months, when the result favoured vertebroplasty. The proportion of people taking opioids was not statistically significantly different between treatment groups in the Blasco study. However, the Assessment Group found the results from this study difficult to interpret, partly because a higher proportion of patients in the vertebroplasty group needed opioids at baseline. In the VERTOS study, patients in the vertebroplasty group used less analgesia and patients in the control group used more analgesia, resulting in statistically significant differences that favoured vertebroplasty. In VERTOS II, analgesic use fell in the vertebroplasty group compared with the control group at 1 day (p<0.001), 1 week (p<0.001), and 1 month (p=0.033), but not thereafter; the Assessment Group highlighted that the actual figures were not presented. Both the Farrokhi and Blasco studies reported changes in height and deformity of the vertebral body, but the results cannot be compared because it is not clear whether the studies measured height by the same methods. The Blasco study showed no statistically significant or clinically important differences between treatment groups in the change in vertebral body height from baseline at 12 months. In contrast, the Farrokhi study showed that vertebroplasty statistically significantly improved mean vertebral body height throughout the first year but not thereafter, and statistically significantly improved and sustained angular deformity throughout the 36-month follow up period. The VERTOS II study reported data relating to the progression of treated fractures during follow up. At the last follow‑up (median 12.0 months, range 1–24 months), statistically significant moderate or severe height loss was seen in 12% of patients in the vertebroplasty group, compared with 41% of patients in the optimal pain management group (p<0.001). The Rousing study assessed health-related quality of life using the Dallas Pain Questionnaire, which evaluates the impact of chronic pain on a patient's life. Only the score for work and leisure at 3 months reached statistical significance, favouring vertebroplasty compared with optimal pain management, but the score was unadjusted for the difference in scores at baseline. Comparing changes from baseline in each group, rather than directly comparing pain scores at 2 weeks, favoured conservative management. VERTOS II and the Rousing study reported health-related quality of life using EQ-5D. The Rousing study provided EQ-5D utility values for 58% of patients in the vertebroplasty group and 71% in the optimal pain management group. The results, with negative differences indicating a worse outcome with vertebroplasty, indicated a mean group difference of −0.085 (95% CI −0.15 to −0.02) at 3 months and −0.169 (95% CI −0.23 to −0.11) at 12 months, compared with baseline. VERTOS II collected EQ-5D data throughout the study but reported only baseline values. Blasco, VERTOS and VERTOS II reported health-related quality of life using QUALEFFO. Results from the Blasco trial indicated that, in the short and medium term, there was a non‑statistically significant improvement in scores with vertebroplasty compared with optimal pain management at all time points. The VERTOS study found that vertebroplasty was associated with better short-term total QUALEFFO scores than optimal pain management. In VERTOS II, after adjusting for baseline differences, there was a statistically significant difference in QUALEFFO scores at 1 year that favoured vertebroplasty (p<0.0001); however, actual scores were not reported. The Rousing trial reported health-related quality of life using SF-36 and showed no statistically significant differences between treatment groups at any point. The VERTOS and VERTOS II studies used the RDQ (24-point version) to assess back-specific functional status. The VERTOS study reported that the between-group change from baseline to 2 weeks favoured vertebroplasty over optimal pain management, but the Assessment Group could not calculate the statistical significance because the study reported no measure of variability. The VERTOS II study reported a statistically significant difference that favoured vertebroplasty at 1 year compared with optimal pain management (p<0.0001); however, the study did not provide the RDQ scores or indicate what difference would reflect a clinically important difference. The Farrokhi study reported disability using a modified Oswestry Disability Index (ODI) and reported that vertebroplasty was associated with a statistically significant improvement in change from baseline at all times from 1 week to 36 months compared with optimal pain management. The Assessment Group noted that, because 4 points on the ODI is the minimum clinically important difference for back pain, these differences were clinically meaningful throughout. The Farrokhi study also noted that all 40 patients in the vertebroplasty group could walk 1 day after vertebroplasty, but only 1 of the 42 patients (2%) in the optimal pain management group could walk 1 day after optimal pain management, indicating a relative risk of 28.3 (95% CI 5.9 to 136.5, p<0.0001). The Rousing study reported functional outcomes using the Barthel Index, which provided data for a subset of the study population. At 12 months, the absolute score was statistically significantly better in the vertebroplasty group than in the optimal pain management group, but the difference between groups was no longer statistically significant when adjusted for differences at baseline. The Assessment Group stated that the result may indicate a ceiling effect, whereby there is little scope for vertebroplasty to improve functional outcome more than optimal pain management does. The Rousing study also reported 3 tests of physical function for a subset of the population: tandem, timed up and go, and repeated chair tests. No statistically significant differences between groups were noted at 3 or 12 months but, because the trial provided no baseline values, the change from baseline is not known. ## Percutaneous vertebroplasty compared with percutaneous balloon kyphoplasty without stenting The Liu study was the only study to compare vertebroplasty with kyphoplasty, and assessed pain, vertebral body height and angular deformity. It did not assess health-related quality of life. It assessed pain measured on a VAS and reported no statistically significant differences between vertebroplasty and kyphoplasty in the short or medium term, with a mean difference of −0.2 (95% CI −0.43 to 0.03) at 3 days and 0.1 (95% CI −0.28 to 0.48) at 6 months compared with baseline, with negative differences favouring vertebroplasty. However, the Assessment Group highlighted that the trial was likely to have been underpowered. For changes in vertebral body height and angular deformity, the trial reported that kyphoplasty led to statistically significantly greater improvements in both postoperative vertebral body height and angular deformity than did vertebroplasty, but the Assessment Group was not clear at what time points the study measured these outcomes. ## Percutaneous balloon kyphoplasty without stenting compared with optimal pain management The FREE study was the only study to compare kyphoplasty with a non‑operative treatment. For assessing pain as an outcome, the FREE study used SF-36. The results indicated that patients randomised to kyphoplasty improved more than those randomised to optimal pain management, the difference over a period of 12 months being 9.2 points (95% CI 3.9 to 14.6, p=0.0008). The FREE study also reported pain measured on a numeric rating scale and reported statistically significant long-term differences between groups; however, the Assessment Group noted that these differences were unlikely to reflect a clinically meaningful difference. The FREE study reported the use of analgesics. Kyphoplasty statistically significantly reduced the need for opioid medication at 1 month and 6 months, but not at 12 months or 24 months. The Assessment Group highlighted that the FREE study did not report changes in vertebral body height, even though maintenance of vertebral body height was a secondary outcome. The study protocol stated that vertebral body height was measured only in patients having kyphoplasty, making comparison with optimal pain management impossible. The study did show a statistically significant improvement from baseline with kyphoplasty in the kyphotic angle of the fracture at 24 months, but the Assessment Group noted that the clinical significance of this result is not clear. The FREE study used EQ-5D and SF-36 to assess health-related quality of life. Using EQ-5D, statistically significant differences in outcomes favouring kyphoplasty over optimal pain management were reported at 1, 12, and 24 months. However, the Assessment Group highlighted that, at a minimum clinically important difference for back pain of 0.08, the confidence intervals at 3, 6, 12 and 24 months included the possibility of effects that are not considered clinically important. Using the SF-36 physical component summary score, the study reported a statistically significant mean difference of 5.2 (95% CI 2.9 to 7.4, p<0.0001) between groups at 1 month, favouring kyphoplasty. Although the results remained statistically significant at 3 months and 6 months, the confidence intervals included the possibility of achieving a result that may not be considered clinically important and, after 6 months, there was no statistically significant difference between treatment groups. The FREE study also reported psychological wellbeing, which was assessed by the SF-36 mental component summary score, and identified no statistically significant differences between treatment groups, although the confidence intervals included the possibility of potential clinically important treatment effects favouring kyphoplasty compared with optimal pain management at time points up to 12 months. The FREE study assessed back-specific functional status using the original 24-point version of the RDQ. It showed that kyphoplasty was associated with statistically significantly better outcomes compared with optimal pain management at 1 and 12 months, but not at 24 months. Moreover, at 12 months, the confidence intervals included the possibility of not achieving a clinically important outcome. The FREE study also reported that kyphoplasty was associated with a statistically significant reduction in the probability of needing walking aids at 1 month, but not at 12 months. However, the Assessment Group noted the data were not robust because of missing data. The FREE study also recorded the number of patients who reported 1 or more days of bed rest because of back pain in the previous 14 days. At 1 month, patients in the kyphoplasty group reported on average 2.9 fewer days of restricted activity than patients in the optimal pain management group (95% CI 1.3 to 4.6, p<0.001), but at 12 months the difference was no longer statistically significant (1.6 days, 95% CI −0.1 to 3.3, p=0.07). The actual numbers of days of restricted activity in each group were not reported. ## Mortality benefit The Assessment Group stated that the trials were not powered to determine differences in overall mortality, and noted that none of the studies showed any statistically significant differences in overall mortality between treatment groups. The Assessment Group also combined 12 months of mortality data from the Blasco, Rousing and VERTOS II studies comparing vertebroplasty with optimal pain management. The point estimate of the relative risk favoured vertebroplasty, but was not statistically significant (0.68; 95% CI 0.30 to 1.57, p=0.37). Medtronic provided a large observational study (n=858,979) based on US Medicare registry data with follow‑up to 4 years, which showed a mortality benefit with vertebroplasty or kyphoplasty compared with optimal pain management in patients with vertebral compression fractures, with a hazard ratio of 0.76 (95% CI 0.75 to 0.77) for vertebroplasty and 0.56 (95% CI 0.55 to 0.57) for kyphoplasty, adjusting for age, sex, race, Charlson comorbidity index and other coexisting diseases. In addition, kyphoplasty was associated with a greater mortality benefit compared with vertebroplasty, with an adjusted hazard ratio of 0.77 (95% CI 0.75 to 0.78; Edidin 2011). The Assessment Group stated that academic-in-confidence data provided by Medtronic on mortality at 5 years from US Medicare registry data, as well as data from a smaller observational study (n=3607) based on a German health insurance fund, further supported a benefit in mortality associated with the technologies. The Assessment Group stated that, apart from the possibility of uncontrolled confounding, these studies raise the possibility that improvement in biomechanical factors after treatment improves survival. ## Adverse events The Assessment Group presented adverse events reported in the trials supplemented with observational studies and case reports. All but the Liu and INVEST studies reported cement leaks confirmed by imaging, and all had used polymethylmethacrylate cement, presumed by the Assessment Group to be of low viscosity. The Blasco study found that cement leaks did not cause patients immediate complications. However, leaks into the inferior intervertebral disc increased the risk of incident vertebral fracture (odds ratio 7.2, 95% CI 1.7 to 69.3). The Farrokhi study reported 13 asymptomatic leaks and 1 symptomatic leak into the epidural space treated with urgent bilateral laminectomy. The Rousing study stated that none of the cement leaks caused neurological symptoms. In the VERTOS II study, most leaks were discal or into segmental veins, and cement pulmonary emboli were visible on computed tomography scan in 26% (95% CI 16% to 39%) of patients, although the patients did not have symptoms. In the FREE study, most leaks went into the vertebral end-plates or they were intervertebral disc leaks, with 1 leak into the vertebral foramina, no leaks into the spinal canal, and no cement emboli. The Buchbinder, FREE and VERTOS II studies reported postoperative infections potentially related to treatment. In the Buchbinder study, investigators administered the intravenous antibiotic cephalothin prophylactically after cement injection. Osteomyelitis developed in a patient who did not receive an antibiotic because of allergies. In the FREE study, a patient developed spondylitis in the vertebral body 376 days after surgery. Sepsis or septic shock was reported in 1 patient in the kyphoplasty group and in 3 patients in the optimal pain management group. The Assessment Group also noted that 3 patients who underwent kyphoplasty subsequently had pulmonary emboli of venous origin, and the earliest of these occurred 46 days postoperatively. The Farrokhi study reported that no infections occurred, and the Rousing study reported that there were no adverse reactions other than cement leaks. In the remaining 4 studies (Blasco, INVEST, Liu, VERTOS), no postoperative infections were mentioned. The risk of fracturing a vertebra adjacent to the treated vertebra was reported in 4 studies (Buchbinder, Farrokhi, FREE, Rousing), and none identified a statistically significant difference between treatment groups in the proportion of patients who experienced at least 1 clinically important fracture. However, the Blasco study noted that more (71%) of the radiographic fractures in the vertebroplasty group were clinically important compared with fewer (9%) in the optimal pain management group (OR 25.7, 95% CI 3.0 to 216.8, p=0.029); the investigators did not report the number of patients who had incident vertebral fractures. The Assessment Group highlighted the potentially serious complications that can result from managing compression fractures conservatively. Bed rest can result in muscle wasting, deconditioning, deep vein thrombosis and pulmonary emboli. Opioid analgesics can cause undesirable adverse reactions including cognitive impairment, constipation and nausea, and non‑steroidal anti‑inflammatory drugs are associated with gastrointestinal and renal problems. ## Subgroups The Assessment Group stated that no trial data were identified for patients with or without fracture-related vertebral deformity or for inpatients at the time of randomisation. However, some data were available for subgroups based on the severity of pain at randomisation and for the time from fracture to intervention. No data for subgroups were available for kyphoplasty. A meta-analysis by Staples et al. (2011) of individual patient data from the Buchbinder and INVEST studies grouped by baseline pain severity showed no statistically significant differences in RDQ scores, EQ-5D scores, or pain scores between patients with severe pain (score of 8 or more on a 0–10 scale) or mild-to-moderate pain (score of less than 8) at baseline. In both groups (vertebroplasty and operative placebo with local anaesthesia), patients with greater degrees of pain at baseline experienced a greater reduction in pain. The Assessment Group stated that this could reflect a greater potential for improvement. The Assessment Group also stated there were no data to suggest that outcomes would differ between patients who were or were not inpatients before treatment. The INVEST study reported results by duration of pain at baseline in post hoc analyses and found no statistically significant difference between vertebroplasty and operative placebo with local anaesthesia on pain at 1 month, but was underpowered for this analysis. Data from the Staples study combining individual patient data from the INVEST and Buchbinder studies assessed the effectiveness of vertebroplasty in patients with fracture pain of recent onset (6 weeks or less) compared with pain of longer duration. Because the INVEST study allowed crossover after 1 month, the outcomes were compared up to that time point, finding no statistically significant differences in RDQ scores, EQ-5D scores, or pain scores. # Cost effectiveness The Assessment Group conducted a literature review that identified 1 Markov cohort model comparing the cost effectiveness of kyphoplasty with optimal pain management in patients hospitalised in the UK with vertebral compression fractures (Strom et al. 2010). The model simulated the experiences of patients until death or 100 years, with EQ-5D scores taken from the FREE study. The model assumed that the intervention would affect EQ-5D scores up to 3 years after kyphoplasty or optimal pain management, declining linearly between 1 and 3 years. The model incorporated increased risks of future vertebral fracture and increased risks of mortality after vertebral fracture. The base case assumed a cohort of 70-year-old women and men with a T‑score of −2.5 SD (T‑score is defined as the number of standard deviations from the average bone mineral density of healthy young women) and estimated that kyphoplasty would cost an additional £1494 to obtain 0.169 quality-adjusted life years (QALYs), resulting in an incremental cost effectiveness ratio (ICER) of £8840 per QALY gained for kyphoplasty compared with optimal pain management. ## Medtronic model Medtronic submitted a Markov tunnel model adapted from the Strom model (see section 4.2.1) to determine the cost effectiveness of kyphoplasty, vertebroplasty and optimal pain management in patients hospitalised with vertebral compression fractures. The model has a lifetime time horizon, 6-month cycles, and an NHS perspective. Costs and utilities are discounted at 3.5%. In the base case, Medtronic assumed that patients are 70 years old and have a T score of −3.0 SD, similar to patients in the FREE and VERTOS II trials. The model assumes people are either treated with kyphoplasty or an alternative, and remain in their initial treatment health state (progressing through the sub-states) until they die or experience another vertebral fracture that is treated using optimal pain management only. The manufacturer calculated the transition probabilities for further vertebral fractures from equations taking into account a patient's T score, age, number of previous fractures and, because the data were not available, the imputed ratio between the incidence of hip and vertebral fractures at each age, assuming that Swedish values (from Strom) apply to the UK. The transition probabilities to death use data from the Human Mortality Database for patients in the UK and the relative risks of mortality for people with a prior vertebral fracture (from Strom). Medtronic took utility values for kyphoplasty and optimal pain management directly from the FREE trial, and for vertebroplasty indirectly from the VERTOS II trial, estimating values by adding the difference between vertebroplasty and optimal pain management to the scores for optimal pain management in the FREE trial. Because VERTOS II presented data on QALYs at baseline, 1 month and 12 months, Medtronic inferred the average utility across the 1-year period. Medtronic assumed that, unless a patient has a refracture, their utility will improve during the first 2 years and, thereafter, the utility in patients treated with optimal pain management will decline at the rate of the general population. For patients treated with kyphoplasty or vertebroplasty, the utility gain compared with optimal pain management declines linearly during the first year. Consequently after 3 years, unless patients have a refracture, they will have the same health utility, which declines at the same rate as the general population. The model assumes that both kyphoplasty and vertebroplasty improve survival compared with optimal pain management. The hazard ratios for death for kyphoplasty and for vertebroplasty are based on the US Medicare registry data. Medtronic included recurrent vertebral fracture but no other adverse events in the model, citing a lack of data as the reason, although acknowledging potentially substantial consequences of adverse events. The list price of a kyphoplasty kit is £2600.50, and the submission also noted an average selling price of £1900. Medtronic assumed an acquisition cost of vertebroplasty that was commercial in confidence. Medtronic updated the costs of the preparatory, operating and postoperative phases from those in the Strom study. Medtronic obtained data on the length of stay in hospital after treatment from Hospital Episode Statistics 2010/11 data, and the cost per day in hospital from NHS Reference costs 2009–11. The deterministic analyses gave an ICER of £2167 per QALY gained for kyphoplasty compared with optimal pain management and £2053 per QALY gained for vertebroplasty compared with optimal pain management. The deterministic analysis of kyphoplasty compared with vertebroplasty gave an ICER of £2510 per QALY gained, while probabilistic analyses gave ICERs of £2118 (kyphoplasty compared with optimal pain management), £2100 (vertebroplasty compared with optimal pain management) and £2174 (kyphoplasty compared with vertebroplasty) per QALY gained. Medtronic conducted sensitivity analyses to study the impact of changing 1 variable at a time: the time horizon; the discount rate for costs and QALYs; the health utility benefit from the FREE trial; the time at which the utility gain for kyphoplasty and vertebroplasty compared with optimal pain management is offset linearly; mortality rates after a fracture; the price of vertebroplasty compared with kyphoplasty; the unit costs per day in hospital; the assumed T‑score of the cohort; the age of the cohort; whether patients are treated with a bisphosphonate; and the proportion of patients who are male. The ICERs for kyphoplasty compared with optimal pain management and kyphoplasty compared with vertebroplasty remained below £15,000 per QALY gained in all instances. The assumption that vertebroplasty and kyphoplasty cause patients to live longer (greater for kyphoplasty than for vertebroplasty) was a key driver of the cost-effectiveness results and, when the manufacturer assumed no mortality benefit with either vertebroplasty or kyphoplasty, then the ICER for kyphoplasty compared with vertebroplasty was £27,340 per QALY gained. Medtronic noted that the ICERs for both vertebroplasty and kyphoplasty compared with optimal pain management remained low. The sensitivity analysis for changing the length of hospital stay after kyphoplasty also increased the ICER for kyphoplasty compared with vertebroplasty to over £20,000 per QALY gained. ## Johnson and Johnson model Johnson and Johnson's model aimed to determine the cost effectiveness of vertebroplasty, kyphoplasty, optimal pain management and of operative placebo with local anaesthesia using a scenario analysis. The manufacturer developed a treatment-state model with a 1-year time horizon, an NHS perspective, and costs and benefits discounted at 3.5%. To estimate effectiveness measured by pain experienced by patients, Johnson and Johnson performed a network meta-analysis using VAS scores and EQ-5D data from trials. The manufacturer also performed an analysis based on a 'target population', that is, patients with fractures that occur within 3 months who are expected to benefit most from vertebroplasty or kyphoplasty. The model has patients receiving different treatments and assigns values for pain using a VAS score before treatment and then again at 2 weeks depending on the intervention received. The model updates the treatment-dependent VAS score at 1 month, 6 months and 12 months. Johnson and Johnson used a regression analysis to describe the relationship between VAS and EQ-5D, based on data for both outcomes derived from a network meta-analysis. This relationship then allowed the manufacturer to model changes in quality of life from VAS scores that had been reported in trials at multiple time points. The Assessment Group stated that the manufacturer did not attempt in its network meta-analysis to extrapolate or interpolate data from trials that did not report VAS scores at the designated time intervals, and this could be a source of uncertainty when modelling pain scores over time. The Blasco study was published after completion of the manufacturer's systematic review. If the manufacturer had included this trial, which had similar VAS scores for vertebroplasty and optimal pain management (with both values being relatively high), the VAS scores in the model for all treatments would have increased and the relative difference between optimal pain management and both vertebroplasty and kyphoplasty would have diminished. Johnson and Johnson did model procedure-related adverse events. Johnson and Johnson used a bottom-up costing approach based on published data from the Strom study for vertebroplasty and kyphoplasty. The manufacturer did not model costs for optimal pain management because it assumed that all patients, including patients receiving vertebroplasty or kyphoplasty, would receive optimal pain management. The manufacturer determined costs of the preparatory, operating and postoperative phases from the Strom study adjusted for inflation to 2009/10 prices. The costs for vertebroplasty varied according to the number of vertebrae needing treatment, being £1358 for 1 vertebra, £1784 for 2, and £1848 for 3. Based on Dr Foster data, the estimated frequency of treating 1, 2 or 3 fractures resulted in an average weighted cost of £1472. The Assessment Group noted that, in its submission, Johnson and Johnson stated that 11 cm3 of cement was needed to treat 2 fractures but the manufacturer's calculations assume 7 cm3 of cement. If 11 cm3 were used, the average weighted cost would increase to £1546. The cost of the kyphoplasty kit reported in the Strom study was adjusted for inflation by the manufacturer to a 2009/10 cost of £2842. Johnson and Johnson's base-case results indicated that vertebroplasty was both more effective and less costly than kyphoplasty and therefore dominated kyphoplasty. The analysis of vertebroplasty compared with optimal pain management gave an ICER of £4392 per QALY gained and kyphoplasty compared with optimal pain management gave an ICER of £14,643 per QALY gained. The results based on patients with fractures that occur within 3 months who are expected to benefit most from vertebroplasty or kyphoplasty also indicated that vertebroplasty dominated kyphoplasty; the analysis of vertebroplasty compared with optimal pain management gave an ICER of £4755 per QALY gained and kyphoplasty compared with optimal pain management gave an ICER of £15,006 per QALY gained. The scenario analysis including operative placebo with local (injected) anaesthesia resulted in vertebroplasty dominating operative placebo with local anaesthesia, and operative placebo with local anaesthesia dominating kyphoplasty. The comparison of optimal pain management with operative placebo with local anaesthesia gave an ICER of £4853 per QALY gained. Johnson and Johnson performed several other scenario analyses, pooling data from operative placebo with local anaesthesia with data from optimal pain management; extending the time horizon to beyond 1 year for both the base‑case and target population with recent fractures; using an alternative bottom-up costing methodology and payment-by-results tariff for both the base‑case and the target population; and using direct EQ-5D values for both the base‑case and target populations. Vertebroplasty dominated kyphoplasty in all scenarios. The ICER for vertebroplasty compared with optimal pain management ranged from £568–£13,595 per QALY gained in the base case and from £2550–£16,497 per QALY gained in the target population. Johnson and Johnson performed univariate sensitivity analyses comparing vertebroplasty with optimal pain management and vertebroplasty with kyphoplasty. The main drivers of cost effectiveness were the efficacy of the treatment (that is, the VAS score at various time points), and costs (driven by the length of stay, cost per bed day and surgical equipment costs) for both the base case and the population with recent fractures. Results from probabilistic sensitivity analyses (varying parameters simultaneously) were broadly similar to the deterministic results in the base-case analysis; vertebroplasty dominated kyphoplasty for both base-case and target-population analyses. In addition, in the base-case analysis, the probabilistic ICER for vertebroplasty compared with optimal pain management in the model estimated the ICER at £4388 per QALY gained in the base-case analysis and £4711 per QALY gained in the target population analysis. The model estimated the probabilistic ICER for kyphoplasty compared with optimal pain management at £14,718 per QALY gained in the base-case analysis and £15,010 per QALY gained in the target population analysis. In addition, the Assessment Group corrected an error in the manufacturer's mathematical model in which only 10% of patients receiving kyphoplasty consume operating-room resources; the Assessment Group assumed that this value was intended to be 100%. ## Assessment Group model The Assessment Group's model was designed to determine the cost effectiveness of vertebroplasty, kyphoplasty, optimal pain management and operative placebo with local anaesthesia. The Assessment Group presented 6 scenarios rather than a base case. The Assessment Group stated that, given the uncertainty around whether vertebroplasty or kyphoplasty prolonged life, it organised results into 3 categories based on whether: kyphoplasty prolongs life more than vertebroplasty, which prolongs life more than optimal pain management vertebroplasty and kyphoplasty prolong life more than optimal pain management and vertebroplasty and kyphoplasty do not prolong life more than optimal pain management. The Assessment Group also stated that the results differed based on whether it took EQ-5D directly from the trials (INVEST, FREE and Buchbinder) or mapped stable VAS scores (which the Assessment Group defined as VAS scores assumed to occur at 1 month after operation for vertebroplasty or kyphoplasty, and at 3 months after optimal pain management treatment) to EQ-5D. In addition, the Assessment Group produced exploratory analyses assuming the use of high-viscosity cement. The model consisted of 5 health states: the starting state of post-osteoporotic vertebral compression fractures when patients receive kyphoplasty, vertebroplasty, operative placebo with local anaesthesia, or optimal pain management a state in which a patient may experience a subsequent vertebral fracture a state in which a patient may experience a subsequent hip fracture a state in which a patient may experience both a subsequent vertebral and a hip fracture and death. The model allowed a patient to experience only 1 further vertebral fracture and 1 hip fracture. The Assessment Group assumed that a time horizon of 50 years reflects patients' lifetimes and the model employed 36 monthly time cycles followed by 47 yearly time cycles. The Assessment Group's rationale for the different cycle length was that different procedures may lead to different utilities in the period after a procedure, a difference more easily incorporated using monthly time cycles. Both costs and benefits were discounted at 3.5% per year. The model did not include the potential disutility associated with anxiety about the prospect of future fractures, or the potential reduction in bone mineral density associated with prolonged bed rest. The Assessment Group estimated transition probabilities between health states from the literature. Taking into consideration that a patient's bone density is likely to decrease over time, the Assessment Group incorporated a decrease of 0.255 SD per 5‑year age group, assuming that women and men with the same T‑score have the same risks of fracture. If a patient was assumed to be taking a bisphosphonate, the assumed effect on vertebral fractures was based on relative risks reported in the literature. This effect was assumed to last for 5 years, with a linear decline in effect over a 5‑year period, so that the relative risk was 1 after 10 years. The risk of hip fracture or vertebral fracture was assumed to be independent of whether the patient was simulated to have a subsequent vertebral fracture or hip fracture. The Assessment Group estimated the mortality rate associated with hip fracture from Stevenson et al. (2009) and the mortality rate associated with vertebral fracture from a UK study (Jalava et al. 2003). The model assumed that patients are more likely to die in the year in which a subsequent fracture occurs than they are thereafter. The model also assumed that the mortality rate after hip fracture must be equal to or greater than the mortality rates associated with a vertebral fracture in the age- and sex-matched general population. The mortality rate from causes other than fracture was taken from life tables from the Office for National Statistics, and the Assessment Group assumed that all patients die before they reach 101 years. When the Assessment Group assumed that patients who undergo kyphoplasty, vertebroplasty or operative placebo with local anaesthesia live longer than those who receive optimal pain management, mortality benefits were incorporated in the model for a period of 5 years in the base case. It was assumed that mortality benefits would cease immediately after 5 years. The Assessment Group assumed that the relative risks associated with treatment applied to all‑cause mortality and to the mortality rate associated with vertebral fractures, but not to hip fractures. The Assessment Group calculated the hazard ratios within the 3 scenarios used to explore the effects of mortality using US Medicare registry data provided, academic in confidence, by Medtronic. The Assessment Group did not have data about any potential effect of operative placebo with local anaesthesia relative to optimal pain management on mortality, but assumed that the effect is half that observed for vertebroplasty because the effect of operative placebo with local anaesthesia on pain (VAS) was half that observed for vertebroplasty. The Assessment Group assumed that utility values for all health states are a function of: sex; age; which procedure a patient undertakes; the time since the procedure; the time after which the model assumes that the utility values of patients treated with optimal pain management equals those of patients treated with an active intervention; the value of disutility after vertebral fractures that occurred more than 1 year before an intervention; and the mapping of VAS scores onto the EQ-5D. In addition, in the health states in which a patient had an additional vertebral and/or a new hip fracture, the model included a decrease in the utility value reflecting the fracture and, in the following cycles, persistent pain. The Assessment Group's model assumed that adverse events did not increase costs or disutility. However, the Assessment Group conducted a sensitivity analysis assuming that adverse effects led to QALY losses of 0.02 for kyphoplasty and vertebroplasty. Costs within each of the health states were taken largely from the Stevenson study and adjusted for inflation to 2010/11 prices using the Hospital and Community Health Services inflation indices. The Assessment Group took the cost of the high-viscosity Confidence Spinal Cement System from the Johnson and Johnson submission, although it assumed that 7 cm3 of cement was needed to treat 2 vertebral fractures, rather than 11 cm3. This gave an average cost of £1546 per operation. The average estimated value for low-viscosity cement was £697. A clinical specialist advised the Assessment Group that approximately 15% of procedures would use high-viscosity cement or other more expensive cement types. The Assessment Group assumed that these more complex cases would add slightly over £100 to the average cost of an operation, resulting in an assumed cost of £800 per vertebroplasty procedure using low-viscosity cement. In calculating the ICERs, the Assessment Group assumed that vertebroplasty uses low-viscosity cement. The Assessment Group adjusted the list price of £2600.50 per kit for kyphoplasty to acknowledge that a proportion of patients would need kyphoplasty on more than 1 vertebra, which would require an additional pack of Kyphon HV-R bone cement, priced at £62 per pack. This resulted in the average price per patient increasing to £2639 for kyphoplasty. The Assessment Group assumed that the cost of operative placebo with local anaesthesia was equal to vertebroplasty, but varied this assumption in sensitivity analyses. The Assessment Group took costs for all phases of vertebroplasty and kyphoplasty from Johnson and Johnson's submission, estimated to be £540 for the preparatory, £243 for the postoperative and £528 for the operating phases. The Assessment Group chose costs for length of hospital stay data from Medtronic's submission, which used hospital episode statistics data, and chose the value for cost per hospital day of £232 from the Johnson and Johnson submission, noting that this value is an underestimate. The clinical advisers to the Assessment Group stated that most procedures would be performed as day cases and that length of stay would be shorter than suggested by hospital episode statistics data. The Assessment Group performed sensitivity analysis for each scenario, exploring the impact of changes to the following assumptions: assuming a bed day cost of £0; changing the assumed cost of equipment for operative placebo with local anaesthesia and the cost of the procedure; changing the time of convergence (the point at which the pain score in patients undergoing vertebroplasty equals the pain score in patients receiving optimal pain management); and including potential QALY losses associated with adverse events. The Assessment Group summarised that, in scenarios in which the model assumes that patients who undergo kyphoplasty live longer than those who undergo vertebroplasty, results indicated that kyphoplasty provided the most QALYs and gave ICERs below £12,000 per QALY gained, irrespective of whether the utility gain expressed in EQ-5D had been estimated by mapping stable VAS, or measured directly in the trials and even if the cost of kyphoplasty was increased, assuming a separate kit was needed for each level. The ICER for vertebroplasty compared with optimal pain management, when utility gain was estimated directly from EQ-5D in the trials, remained below £7000 per QALY gained, except in 1 instance when it was extendedly dominated, when treatment benefit was assumed to disappear between 12 months and 24 months and the EQ-5D data from the Buchbinder trial were used. In scenarios in which the model assumed that patients who undergo vertebroplasty and kyphoplasty live longer (but by the same degree) than patients who receive optimal pain management, and when the model assumes that patients who receive operative placebo with local anaesthesia also live longer, but only to half the degree as vertebroplasty and kyphoplasty, results indicated that vertebroplasty dominated kyphoplasty because it effectively provided the same QALYs at a higher cost. The ICER for vertebroplasty compared with optimal pain management remained below £10,000 per QALY gained across all assumptions except for the combination of assumptions in which: operative placebo with local anaesthesia was assumed to have an identical mortality benefit to balloon kyphoplasty and vertebroplasty; operative placebo with local anaesthesia was assumed to have a lower cost than vertebroplasty; adverse events for vertebroplasty were included; and the EQ-5D data from the randomised controlled trials were used. In this instance, vertebroplasty was dominated by operative placebo with local anaesthesia. However, it was noted that, if operative placebo with local anaesthesia was not seen to be an appropriate comparator, the ICER of vertebroplasty compared with optimal pain management remained below £10,000 per QALY gained. In the scenarios in which the model assumed that patients who undergo vertebroplasty and kyphoplasty do not live longer than patients who receive optimal pain management, the cost-effectiveness results depend on whether the utility gain is estimated by mapping, but vertebroplasty nonetheless typically provided the most QALYs, and the ICER remained below £16,000 per QALY gained. The exception to this was when the Assessment Group adopted assumptions unfavourable to vertebroplasty, such as hospitalisation stay costs set at £0, reduced cost of operative placebo with local anaesthesia, incorporating adverse events for vertebroplasty, and an earlier convergence over time of EQ-5D scores. When the model estimated utility gained directly from the Buchbinder and INVEST trials, vertebroplasty always dominated kyphoplasty. Vertebroplasty was dominated by operative placebo with local anaesthesia in some cases and had an ICER greater than £20,000 per QALY gained in other cases. If the Assessment Group did not consider operative placebo with local anaesthesia as an appropriate comparator, vertebroplasty compared with optimal pain management had an ICER greater than £20,000 per QALY gained in some cases. The Assessment Group also conducted an exploratory analysis assuming the use of high-viscosity cement for all patients. It stated that, for the cost per QALY gained to be equal to £20,000 per QALY gained, an additional 0.037 QALYs would be needed, a value greater than the value of 0.02 discounted QALYs assumed in the sensitivity analyses. The Assessment Group stated that it was unlikely that the ICER for high-viscosity cement compared with low-viscosity cement would be lower than £20,000 per QALY gained. However, the Assessment Group stated that a patient might need another operation if there was a problem with low-viscosity cement. So the Assessment Group estimated that, if more than 25% of patients needed another procedure on the same vertebra, then a strategy of using high-viscosity cement in all patients for the first procedure would be more cost effective. The Assessment Group stated that it was unlikely that a strategy of using high-viscosity cement in all patients rather than a subset selected by the clinician would have an ICER of less than £20,000 per QALY gained. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of vertebroplasty and kyphoplasty, having considered evidence on the nature of osteoporotic vertebral compression fractures and the value placed on the benefits of vertebroplasty and kyphoplasty by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources. The Committee considered the evidence presented by the patient experts and clinical specialists on the clinical symptoms associated with osteoporotic vertebral compression fractures. The Committee heard that these fractures have a debilitating impact on patients' ability to work and care for themselves, and consequently on their quality of life. The patient expert highlighted that, in addition to the physical pain caused by the fractures, loss of height and a distorted spine have a major impact on the emotional wellbeing and self-image of many patients. The Committee heard from the clinical specialists that people with osteoporotic vertebral compression fractures can experience problems with mobility, digestion and breathing, which may be linked to earlier mortality. The Committee acknowledged the debilitating impact that osteoporotic vertebral compression fractures have on patients' physical and emotional wellbeing. The Committee discussed the clinical management of osteoporotic vertebral compression fractures. The Committee understood from the clinical specialists that vertebroplasty and kyphoplasty are performed by radiologists, anaesthetists or orthopaedic surgeons, some of whom are based in pain clinics, and they work with metabolic bone specialists to assess the need for intervention. The Committee heard that, initially, clinicians treat patients with optimal pain management including analgesics, particularly opioids and non‑steroidal anti‑inflammatory drugs, which are associated with considerable side effects in the older population. The Committee noted comments received during the consultation suggesting that 'optimal pain management', included in the Committee's preliminary recommendations, should be more specifically defined. However, the Committee considered that, because optimal pain management encompasses a broad array of treatments, and it means clinicians individualise therapies, it would be beyond the Committee's remit to define optimal pain management. The Committee heard that vertebroplasty and kyphoplasty are considered as treatment options in patients with recent vertebral fractures (proposed as 6 weeks) who have pain at the level of the fracture (confirmed by physical examination and magnetic resonance imaging) that is ongoing, severe, and does not respond to optimal pain management. The Committee heard that this was because, for many people, the severity of the pain will decline after 2 to 3 weeks and many people will be free of pain in 6 weeks, in line with the natural history of the condition. The clinical specialists stated that kyphoplasty can restore vertebral height to a greater extent than vertebroplasty, but this is possible only if the fracture has not healed. The Committee noted that comments received during the consultation expressed concerns over specifying a time interval of 6 weeks in which to undergo the procedures. The Committee discussed the comments and the impact of stipulating a specific time period. It acknowledged that 6 weeks may not be sufficient to permit an adequate trial of optimal pain management and imaging to confirm an unhealed fracture. The Committee also noted that, although clinicians advocate intervening in patients with recent fractures, a very small number of people with fractures are referred to secondary care with unhealed fractures months after the onset of pain and may benefit from the interventions. The Committee was aware that trials comprising the evidence base included patients with fractures older than 6 weeks. The Committee noted the lack of robust evidence to suggest an association between age of a fracture at the time of intervention and its effectiveness with respect to pain and mortality. The Committee considered that a key factor in determining the timing of vertebroplasty and kyphoplasty was whether the fracture remained unhealed and whether it caused ongoing pain. Although the Committee appreciated the complexities in offering vertebroplasty and kyphoplasty too early (before natural healing has resulted in pain relief) or too late (when there is little chance of restoring vertebral height), it concluded that there were likely to be very few patients for whom these procedures were appropriate more than 12 weeks after fracture, and the appropriate timing in relation to the age of the fracture could be left for clinicians to judge. The Committee considered the evidence for the clinical effectiveness of vertebroplasty and kyphoplasty compared with optimal pain management or operative placebo with local anaesthesia. The Committee was aware that only 2 of the trials were double blind and that results from these trials did not show statistically significant improvements in pain scores, back-specific functional status or health-related quality of life during the duration of the studies. The Committee was aware that the operative placebo that included local anaesthesia may itself reduce pain, and heard that clinicians may treat some patients with local anaesthesia injected into or near the affected vertebrae. However, the Committee agreed that operative placebo could not be considered established clinical practice for the majority of patients. In addition, it noted comments received during consultation indicating that this procedure would not be used to treat any progressive vertebral collapse. The Committee was aware that open-label studies showed that both vertebroplasty and kyphoplasty improved pain compared with optimal pain management. The Committee considered that the open-label trials better reflected 'real life' and included the comparator that would be used in clinical practice. The clinical specialists stated that, although results from the 2 double‑blind trials had raised questions about the value of vertebroplasty and kyphoplasty, in clinical experience, both procedures improved pain and quality of life in people with severe symptoms. The Committee concluded that it could not disregard the results from the open-label trials, and was persuaded that there was sufficient evidence to conclude that vertebroplasty and kyphoplasty are more effective in reducing pain and restoring vertebral body height than optimal pain management in people with recent, painful osteoporotic vertebral compression fractures. The Committee discussed whether vertebroplasty and kyphoplasty prolong life compared with optimal pain management. The Committee noted that the Assessment Group pooled data on mortality at 12 months from 3 trials and found no statistically significant differences between vertebroplasty and optimal pain management (see section 4.1.21), but was aware that the studies were not designed to show a difference in mortality. However, the Committee noted that the point estimate for the mortality benefit was consistent with that estimated from 2 large scale epidemiological studies. Specifically, a large study based on US Medicare registry data that followed patients for up to 4 years reported a statistically significant mortality benefit with narrow confidence intervals, with both vertebroplasty and kyphoplasty compared with optimal pain management. The Committee noted these results, which were substantiated by an additional year of follow‑up from the Medicare registry, as well as by mortality data from a smaller German study. The Committee was aware that the Medicare data had controlled for multiple comorbidities but that the possibility of confounding remained; that is, patients who have the intervention may be healthier, or otherwise different in a way that means they live longer than patients who do not undergo intervention. The Committee discussed that, given the magnitude of the benefit, taking into account further confounding would be likely to diminish, but would be unlikely to abolish, an effect. The Committee discussed the biological plausibility of a mortality benefit with vertebroplasty and kyphoplasty, and heard that improving vertebral height and spinal curvature could improve lung function, digestion and mobility, and consequently have a mortality benefit. The clinical specialists stated that most fractures occur in the thoracic spine making an impact on lung function a plausible effect. The Committee discussed the relationship between chronic pain and mortality, and felt that reducing pain may confer a mortality benefit. The Committee discussed the deleterious effects of analgesia, and the possibility of a beneficial effect on mortality of a reduced intake of opioids and non‑steroidal anti‑inflammatory drugs. The Committee concluded that it was reasonable to assume that both vertebroplasty and kyphoplasty prolong life compared with optimal pain management, but that the precise mechanism or magnitude of such a benefit in clinical practice in the NHS was uncertain. The Committee also noted that, based on both sets of observational data, patients who had kyphoplasty lived longer than patients who had vertebroplasty (see section 4.1.21). The Committee heard that people who had kyphoplasty would, in general, be fitter than people who had vertebroplasty because kyphoplasty normally involves general anaesthesia and is a more technically difficult procedure. However, the Committee was also aware that, in the trial comparing vertebroplasty with kyphoplasty, kyphoplasty was associated with statistically significantly greater improvements in both postoperative vertebral height and angular deformity compared with vertebroplasty. On balance, the Committee concluded that, given the degree of uncertainty, it was plausible that kyphoplasty may be associated with a greater mortality benefit than vertebroplasty, but the Committee would also consider the possibility that kyphoplasty and vertebroplasty had the same degree of mortality benefit. The Committee noted the Assessment Group's comments that adverse reactions from vertebroplasty and kyphoplasty related primarily to cement leakage, particularly for vertebroplasty. Cement leakage was associated with pulmonary embolism, radiculopathy, and temporary or permanent motor deficits. The Committee heard that leakage could be intradiscal or intravascular, with intravascular leaks increasing the risk of cement pulmonary embolism. The Committee heard that, to reduce cement leakage and its complications, high-viscosity cements have been developed as an alternative to low-viscosity cements. The clinical specialists stated that, to reduce leakage of low-viscosity cements, the manufacturers were developing newer methods, and that problems from leakage were rare. The Committee concluded that cement leakage associated with vertebroplasty and kyphoplasty was manageable if the procedure is performed by a skilled clinician with specialised training in these procedures. The Committee was aware that the Assessment Group presented 6 different scenarios based on different assumptions around mortality benefit and whether EQ-5D data were taken directly from trials or were mapped from stable VAS pain scores from a network meta-analysis. The Committee noted that taking EQ-5D data directly from the trials is in line with the NICE reference case and that there was no reason for moving away from this in this appraisal. The Committee concluded that including EQ-5D data directly from the trials was more appropriate. The Committee noted that the Assessment Group presented results based on whether it used EQ-5D data from the FREE trial, the Buchbinder trial or the INVEST trial. For the Buchbinder and INVEST trials, the Assessment Group presented results in which it assumed that the pain in people who had had an intervention declines to a level equal to that in people who had not had an intervention by 12 to 24 months or, alternatively, by 24 to 36 months after the procedure. The Committee agreed that it was not possible to choose only 1 of the trials as a source for the EQ-5D values, but that assuming a later convergence of pain scores, that is between 24 and 36 months, was more plausible. The Committee discussed the ICERs for the scenarios in which kyphoplasty was assumed to prolong life more than vertebroplasty, while also considering the scenario in which kyphoplasty and vertebroplasty prolong life equally, using EQ-5D data included directly from trials and assuming a later convergence of pain scores (see sections 4.3.5, 4.3.8 and 4.3.9). The Committee acknowledged that, in both scenarios related to mortality, operative placebo with injection of local anaesthesia was extendedly dominated or dominated by vertebroplasty and kyphoplasty, and that the ICER for vertebroplasty compared with optimal pain management was below £7000 per QALY gained. When kyphoplasty was assumed to prolong life more than vertebroplasty, the ICER for kyphoplasty compared with vertebroplasty was below £8000 per QALY gained. When kyphoplasty and vertebroplasty were assumed to have the same mortality benefit, kyphoplasty was dominated by vertebroplasty. The Committee noted that the sensitivity analyses carried out by the Assessment Group, which included alternative assumptions on hospitalisation costs, costs of operative placebo and adverse events, changed the results as follows: when kyphoplasty was assumed to prolong life more than vertebroplasty, vertebroplasty was extendedly dominated, and the ICER for kyphoplasty compared with vertebroplasty was below £11,000 per QALY gained; and when kyphoplasty and vertebroplasty were assumed to have the same mortality benefit, the ICER for vertebroplasty was under £10,000 per QALY gained. The Committee concluded that the relative mortality benefits of kyphoplasty and vertebroplasty lie somewhere in between the 2 scenarios modelled by the Assessment Group. The Committee concluded that the ICERs established for both kyphoplasty and vertebroplasty were generally at the lower end of what is usually considered to be a cost-effective use of NHS resources. The Committee noted that the Assessment Group had based the cost of vertebroplasty on the assumption that low-viscosity cement would be used in most procedures, allowing for high-viscosity cement to be used in 15% of procedures. The Committee noted that this assumption halved the cost of vertebroplasty from £1546 to £800 for 85% of procedures, as assumed in the model. The Committee heard that high-viscosity cements are being used increasingly in clinical practice based on concerns around cement leakage with low-viscosity cements, but that clinicians still use low-viscosity cements. The Committee considered that vertebroplasty would no longer be cost effective if high-viscosity cements were used in all vertebroplasty procedures. However, given that new methods are emerging to control leakage associated with use of low-viscosity cements, the Committee considered it unlikely that high-viscosity cements would be used in most vertebroplasty procedures. The Committee therefore based its recommendation on the assumption that clinicians would use low-viscosity cement in most procedures. The Committee discussed whether kyphoplasty and vertebroplasty could be considered cost effective, given the uncertainty around their relative mortality benefits. The Committee noted that the ICERs presented by the Assessment Group were at the lower end of the range usually considered a cost-effective use of NHS resources, assuming that clinicians would use low-viscosity cements in most of the procedures, and discussed the debilitating impact that osteoporotic vertebral compression fractures have on people's physical and emotional wellbeing. On balance, the Committee concluded that both vertebroplasty and kyphoplasty could be considered a cost-effective use of NHS resources and should be recommended as options for treating osteoporotic vertebral compression fractures in people who have severe ongoing pain after a recent, unhealed vertebral fracture, despite optimal pain management, and in whom the pain has been confirmed to be at the level of the fracture by physical examination and imaging. # Summary of Appraisal Committee's key conclusions TA279 Appraisal title: Section Key conclusion Percutaneous vertebroplasty, and percutaneous balloon kyphoplasty without stenting, are recommended as options for treating osteoporotic vertebral compression fractures only in people: who have severe ongoing pain after a recent, unhealed vertebral fracture despite optimal pain management and in whom the pain has been confirmed to be at the level of the fracture by physical examination and imaging. The Committee concluded that the ICERs established for both kyphoplasty and vertebroplasty were generally at the lower end of what is usually considered to be cost effective, assuming that low-viscosity cements would be used in most of the procedures. Current practice Clinical need of patients, including the availability of alternative treatments The Committee acknowledged the debilitating impact that osteoporotic vertebral compression fractures have on patients' physical and emotional wellbeing. The Committee heard that, initially, clinicians treat patients with optimal pain management including analgesics, particularly opioids and non‑steroidal anti‑inflammatory drugs, which are associated with considerable side effects in the older population. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Vertebroplasty and kyphoplasty aim to relieve pain in people with painful fractures and to strengthen the bone to prevent future fractures. In addition, kyphoplasty aims to reduce curvature of the spine. No specific claim of innovation was made. What is the position of the treatment in the pathway of care for the condition? The Committee concluded that vertebroplasty and kyphoplasty can be considered appropriate interventions for people with recent, unhealed osteoporotic vertebral compression fractures in whom the pain is severe and ongoing despite optimal pain management, and has been confirmed to be at the level of the fracture by physical examination and magnetic resonance imaging. The Committee considered that the appropriate timing in relation to the age of the fracture could be left for clinicians to judge. Adverse reactions Adverse reactions from vertebroplasty and kyphoplasty relate primarily to cement leakage, particularly for vertebroplasty. The Committee concluded that cement leakage associated with vertebroplasty and kyphoplasty was manageable if a skilled clinician with specialised training in these procedures performs the operation. Evidence for clinical effectiveness Availability, nature and quality of evidence The Assessment Group identified 9 relevant randomised controlled trials, of which only the Buchbinder and INVEST studies, comparing vertebroplasty with an operative placebo that included local anaesthetic, were double blind. Five open-label trials (Farrokhi, VERTOS, VERTOS II, Blasco, Rousing) compared vertebroplasty with optimal pain management. One open-label trial (FREE) compared kyphoplasty with optimal pain management and another open-label study (Liu) compared vertebroplasty with kyphoplasty. Mortality data available from a large study based on US Medicare registry data, which followed patients for up to 4 years, reported a statistically significant mortality benefit with narrow confidence intervals, with both vertebroplasty and kyphoplasty compared with optimal pain management. These results were substantiated by an additional year of follow‑up from the Medicare registry, as well as by mortality data from a smaller German study. Relevance to general clinical practice in the NHS The Committee heard from the clinical specialists that vertebroplasty and kyphoplasty are performed by radiologists, anaesthetists or orthopaedic surgeons, some based in pain clinics, and they work with metabolic bone specialists to assess the need for intervention. Uncertainties generated by the evidence The Committee was aware that that the results from the blinded trials differed from the results available from open-label studies comparing vertebroplasty or kyphoplasty with optimal pain management. The Committee considered that the open-label trials better reflected 'real life' and included the comparator that would be used in clinical practice. The clinical specialists stated that, although results from the 2 double‑blind trials had raised questions about the value of vertebroplasty and kyphoplasty, in clinical experience, both procedures improved pain and quality of life in people with severe symptoms. The Committee concluded that it could not disregard the results from the open-label trials. The Committee noted that the Assessment Group pooled data on mortality at 12 months from 3 trials and found no statistically significant differences between vertebroplasty and optimal pain management, but was aware that the studies were not designed to show a difference in mortality. However, the Committee noted that the point estimate for the mortality benefit was consistent with that estimated from 2 large-scale epidemiological studies. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No trial data were identified for patients with or without fracture-related vertebral deformity, or for inpatients at the time of randomisation. The clinical specialists stated that it was likely that patients at high risk of future fractures might be even more likely to benefit, but that clinicians find it difficult to identify these patients among all patients with vertebral fractures. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee was persuaded that there was sufficient evidence to conclude that vertebroplasty and kyphoplasty are more effective in reducing pain and restoring vertebral body height than optimal pain management in people with recent, painful, unhealed osteoporotic vertebral compression fractures. The Committee concluded that it was reasonable to assume that both vertebroplasty and kyphoplasty prolong life compared with optimal pain management, but that the precise magnitude of such a benefit in clinical practice in the NHS was uncertain. The Committee considered that it was plausible that kyphoplasty is associated with a greater mortality benefit than vertebroplasty, but the Committee also considered the possibility that kyphoplasty and vertebroplasty had the same degree of mortality benefit. The Committee concluded that the mortality benefits of kyphoplasty and vertebroplasty were somewhere in between the 2 scenarios. Evidence for cost effectiveness Availability and nature of evidence Medtronic submitted a Markov tunnel model adapted from the Strom model to determine the cost effectiveness of kyphoplasty, vertebroplasty and optimal pain management in patients hospitalised with vertebral compression fractures. Johnson and Johnson developed a 1‑year treatment-state model aiming to determine the cost effectiveness of vertebroplasty, kyphoplasty, optimal pain management and operative placebo with local anaesthesia using a scenario analysis. The Assessment Group's model was designed to determine the cost effectiveness of vertebroplasty, kyphoplasty, optimal pain management and operative placebo with local anaesthesia. Uncertainties around and plausibility of assumptions and inputs in the economic model The Assessment Group presented 6 scenarios rather than a base case. Given the uncertainty around whether vertebroplasty or kyphoplasty prolonged life, it organised results into 3 categories based on whether: kyphoplasty prolongs life more than vertebroplasty, which prolongs life more than optimal pain management vertebroplasty and kyphoplasty prolong life more than optimal pain management and vertebroplasty and kyphoplasty do not prolong life more than optimal pain management. The Assessment Group presented results that differed based on whether it took EQ-5D directly from the trials or mapped stable VAS scores to EQ-5D. The Committee considered the scenario in which kyphoplasty was assumed to prolong life more than vertebroplasty, while also considering the scenario in which kyphoplasty and vertebroplasty prolong life equally, using EQ-5D data included directly from trials and assuming a later convergence of pain scores. The Assessment Group had calculated the cost of vertebroplasty in the model assuming that low-viscosity cements would be used in most procedures; this significantly reduced the cost of 85% of procedures in the model. Although high-viscosity cements are being used increasingly in clinical practice because of concerns around cement leakage with low-viscosity cements, the Committee considered it unlikely that high-viscosity cements would be used in most vertebroplasty procedures. The Committee therefore based its recommendation on the Assessment Group's assumption that clinicians would use low-viscosity cement in most procedures. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee concluded that including EQ-5D data directly from the trials was appropriate. The Committee identified no health-related benefits that were excluded from the economic model. Are there specific groups of people for whom the technology is particularly cost effective? See section on subgroups above. What are the key drivers of cost effectiveness? Assumptions about mortality benefits associated with vertebroplasty and kyphoplasty. Most likely cost-effectiveness estimate (given as an ICER) The Committee acknowledged that the results were extremely sensitive to the mortality benefit assumptions. The Committee concluded that the ICERs established for both kyphoplasty and vertebroplasty were generally at the lower end of what is usually considered to be cost effective. Additional factors taken into account Patient access schemes (PPRS) Not applicable End-of-life considerations Not applicable Equalities considerations and social value judgements Potential equality issues raised during the appraisal were outside the remit of NICE technology appraisal guidance or not considered equality issues relevant for the Committee to discuss. No equality issues relevant to the Committees recommendations were raised. # Related NICE guidance Balloon kyphoplasty for vertebral compression fractures. NICE interventional procedure guidance 166 (2006). Percutaneous vertebroplasty. NICE interventional procedure guidance 12 (2003).# Review of guidance The guidance on this technology will be considered for review by the Guidance Executive in November 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveApril 2013# Changes after publication January 2014: minor maintenance.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. It has been incorporated into the NICE pathway on osteoporosis along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN: 978-1-4731-0114-2	{'Guidance': 'Percutaneous vertebroplasty, and percutaneous balloon kyphoplasty without stenting, are recommended as options for treating osteoporotic vertebral compression fractures only in people:\n\nwho have severe ongoing pain after a recent, unhealed vertebral fracture despite optimal pain management and\n\nin whom the pain has been confirmed to be at the level of the fracture by physical examination and imaging.', 'Clinical need and practice': 'Vertebral fracture refers to a break in any of the bones (vertebrae) of the spinal column. Vertebral compression fractures usually occur when the front of the vertebral body collapses, and may be caused by trauma, cancer or osteoporosis. Osteoporotic vertebral compression fractures can cause the spine to curve and lose height, and can result in pain, difficulties in breathing, gastrointestinal problems, sleep disturbances and difficulties in performing activities of daily living. High doses of analgesics used to treat such pain can have significant adverse effects. The symptoms and treatment of osteoporotic vertebral compression fractures can worsen quality of life and cause loss of self-esteem.\n\nThe prevalence of vertebral fractures increases with age and is more common in women. It is estimated that approximately 2.5\xa0million people in England and Wales have osteoporosis. The prevalence of osteoporotic vertebral compression fractures is difficult to estimate because not all fractures come to the attention of clinicians and they are not always recognised on X-rays. Clinically evident osteoporotic vertebral compression fractures are associated with an increase in mortality.\n\nTreating vertebral compression fractures aims to restore mobility, reduce pain and minimise the incidence of new fractures. Non‑invasive treatment (such as pain medication, bed rest, and back braces) focuses on alleviating symptoms and supporting the spine. Percutaneous vertebroplasty (NICE interventional procedure guidance\xa012) and Balloon kyphoplasty for vertebral compression fractures (NICE interventional procedure guidance\xa0166) support the use of percutaneous vertebroplasty and percutaneous balloon kyphoplasty without stenting (hereafter vertebroplasty and kyphoplasty respectively) as options for treating vertebral fractures. These guidance documents note that patients should receive these procedures only after discussion with a specialist multidisciplinary team, and in an appropriately resourced facility that has access to a spinal surgery service. For vertebroplasty, the guidance also states that the procedure should be limited to people whose pain does not respond to more conservative treatment.', 'The technologies': "# Percutaneous vertebroplasty\n\nVertebroplasty involves injecting bone cement, typically polymethylmethacrylate, into the vertebral body (the solid part of the vertebra), using local anaesthetic and an analgesic. Vertebroplasty aims to relieve pain in people with painful fractures and to strengthen the bone to prevent future fractures.\n\nSeveral bone cements are available for vertebroplasty. The acquisition cost of the high-viscosity Confidence Spinal Cement System (Johnson and Johnson) is based on the number of vertebrae being treated. The average cost of the kit is £1472. Low-viscosity cements are available and, based on list prices provided by 2\xa0manufacturers (Cook and Stryker); the Assessment Group estimated a cost of £800 per low-viscosity cement vertebroplasty procedure.\n\n# Percutaneous balloon kyphoplasty without stenting\n\nKyphoplasty involves inserting a balloon-like device (tamps) into the vertebral body, using local or general anaesthetic. The balloon is slowly inflated until it restores the normal height of the vertebral body or the balloon reaches its highest volume. When the balloon is deflated, the space is filled with bone cement, and a stent may or may not be placed. This document covers kyphoplasty without stenting. Kyphoplasty aims to reduce pain and curvature of the spine.\n\nThe Kyphon\xa0BKP kit (Medtronic) is available in the UK for kyphoplasty. Kyphon\xa0BKP is a CE-marked, single-use sterile pack with a list price of £2600.50 and includes 2 Kyphon Xpander inflatable bone tamps, with Kyphon ActivOs bone cement with hydroxyapatite supplied as a separate component. Alternative cements with different costs for use in kyphoplasty are available.\n\n# Percutaneous balloon kyphoplasty with stenting\n\nKyphoplasty with stenting involves inserting a small balloon catheter surrounded by a metal stent into the vertebral body using radiographic guidance and either local or general anaesthesia. The balloon catheter is inflated with liquid under pressure to create a space into which the stent is expanded. The balloon catheter is deflated and withdrawn, but the stent remains in the vertebral cavity into which high-viscosity polymethylmethacrylate bone cement is then injected. The stent's function is to prevent the vertebra from losing height after the balloon is deflated.\n\nThe available vertebral body stenting system (Synthes) consists of a stent catheter, an inflation system, an access kit and a balloon catheter if needed. The manufacturer stated that there is limited clinical evidence available for vertebral body stenting because it has become available only recently. Therefore, balloon kyphoplasty with stenting was not assessed in this appraisal.\n\n# Adverse reactions\n\nFor both vertebroplasty and kyphoplasty, adverse reactions can be caused by: needle insertion (such as local or systemic infection, bleeding and damage to neural or other structures); leakage of bone cement; displacement of bone marrow and other material by the cement; systemic reactions to the cement (such as hypotension and death); and complications related to anaesthesia and patient positioning (such as additional fractures of a rib or the sternum). In addition, there is a small risk that the balloon can rupture in kyphoplasty, which can result in the retention of balloon fragments within the vertebral body.", 'Evidence and interpretation': "The Appraisal Committee (appendix\xa0A) considered evidence from several sources (appendix\xa0B).\n\n# Clinical effectiveness\n\nThe Assessment Group carried out a systematic review and identified 9 randomised controlled trials that met the inclusion criteria. The Assessment Group adopted the term 'optimal pain management' to encompass comparator treatments in the trials that consisted of optimising pain medication while treating conservatively, or managing without surgery. Two trials (Buchbinder\xa0et\xa0al. 2009, n=78; INVEST, n=131) compared vertebroplasty with an operative placebo, which included local anaesthetic. Five trials (Farrokhi\xa0et\xa0al. 2011, n=82; VERTOS, n=46; VERTOS\xa0II, n=202; Blasco\xa0et\xa0al. 2012, n=125; Rousing\xa0et\xa0al. 2009, n=50) compared vertebroplasty with optimal pain management. One trial (FREE, n=300) compared kyphoplasty with optimal pain management and another study (Liu\xa0et\xa0al. 2010, n=100) compared vertebroplasty with kyphoplasty.\n\nThe Assessment Group highlighted that, of the randomised controlled trials, only the Buchbinder and INVEST studies were double blind. In addition, the FREE study included less than 80% of randomised patients in its final analysis and had an imbalance in drop-outs by treatment arm. The quality of the studies comparing vertebroplasty with optimal pain management (Blasco, Farrokhi, Rousing, VERTOS, and VERTOS\xa0II) varied, with the Farrokhi study being least at risk of bias. The Blasco and VERTOS\xa0II trials had substantial numbers of patients crossing over (changing treatment arms). The only study to compare vertebroplasty with kyphoplasty (Liu) was poorly reported, potentially biased and probably underpowered for its primary end point, as were the other studies, except for the Blasco, FREE, and INVEST trials. The Assessment Group stated that, in the absence of a statistically significant treatment effect in underpowered studies, it should not be assumed that no such difference exists.\n\n## Percutaneous vertebroplasty compared with operative placebo with injected local anaesthesia\n\nThe outcomes of the Buchbinder and INVEST studies included pain measured on either a numeric rating scale or a visual analogue scale (VAS). The Buchbinder study reported no statistically significant differences in the change from baseline between vertebroplasty and operative placebo with injected local anaesthesia at 1\xa0week, or at 1, 3 or 6\xa0months for the primary outcome of overall pain, with a mean difference adjusted for stratification variables and baselines values of 0.7 (95% confidence interval [CI] −0.4 to 1.8) at 1\xa0week, −0.5 (95% CI −1.7 to 0.8) at 1\xa0month, −0.6 (95% CI −1.8 to 0.7) at 3\xa0months and −0.1 (95% CI −1.4 to 1.2) at 6\xa0months (negative numbers indicate less severe pain). The INVEST study reported no statistically significant differences in the change in pain from baseline between groups for overall pain at 3\xa0days, 1\xa0week and 1\xa0month, with an adjusted mean difference of 0.4 (95% CI −0.5 to 1.5, p=0.37) at 3\xa0days, 0.1 (95% CI −0.8 to 1.1, p=0.77) at 1\xa0week, and −0.7 (95%CI −1.7 to 0.3, p=0.19) at 1\xa0month. The INVEST study showed a clinically meaningful improvement in pain (that is, a decrease of 30% or more) with vertebroplasty at 1\xa0month, but this effect was not statistically significantly different from operative placebo with local anaesthesia (64% compared with 48%; p=0.06). In addition, the Assessment Group's meta-analysis of the individual patient data from both studies found no statistically significant improvement in change in pain from baseline between groups at 1\xa0month, with an adjusted mean difference of −0.6 (95% CI −1.4 to 0.2). However, the number of patients taking opioids for pain decreased over time in both groups in both studies. In the Assessment Group's meta-analysis, after adjusting for baseline opioid use, patients randomised to vertebroplasty were statistically significantly more likely to be taking opioids at 1\xa0month than patients randomised to operative placebo with local anaesthesia (relative risk [RR] 1.25, 95% CI 1.14 to 1.36, p<0.001). Therefore, the Assessment Group stated that the trend towards a higher proportion of patients in the vertebroplasty group achieving an improvement of 30% or more in pain scores at 1\xa0month may have been influenced by the fact that the vertebroplasty group was more likely to be using opioids than the operative placebo with local anaesthesia group.\n\nThe Buchbinder study also reported pain as an outcome in terms of QUALEFFO (Quality of Life Questionnaire of the European Foundation for Osteoporosis) pain scores and found no statistically significant differences between groups. Data were also collected on perceived pain, classified as 'better' or 'worse'. There were no statistically significant differences in the proportion of patients in each category at any time point. The INVEST study reported on the frequency with which patients experienced pain, and the impact of pain on their daily lives. For vertebroplasty and operative placebo with local anaesthesia, both pain frequency and pain 'bothersomeness' decreased between baseline and 1\xa0month, with point estimates favouring vertebroplasty. However, the difference between vertebroplasty and operative placebo with local anaesthesia was not statistically significant.\n\nThe Buchbinder study presented health-related quality-of-life results based on AQoL (Assessment of Quality of Life), EQ-5D and QUALEFFO measures. The INVEST study presented health-related quality-of-life results based on EQ-5D and SF-36. AQoL scores were not different for vertebroplasty and operative placebo with local anaesthesia. EQ-5D scores, available in the Buchbinder study for 79% of patients in the vertebroplasty group and 73% in the operative placebo with local anaesthesia group, were not statistically significant different between groups for short- or medium-term outcomes. The Assessment Group's meta-analysis of individual patient data at 1\xa0month also indicated that the result (with positive numbers indicating better quality of life) was not statistically significant (adjusted mean difference 0.03, 95% CI −0.02 to 0.08). The Assessment Group highlighted that, because 0.08 is the minimum clinically important difference for back pain on the EQ-5D scale, the confidence interval for the pooled data only just included the possibility of a clinically important difference favouring vertebroplasty. Based on QUALEFFO scores in the Buchbinder study, the only statistically significant result was at 1\xa0week, with an adjusted mean difference of −4.0 (95% CI −7.8 to −0.2), but the Assessment Group stated that, because no minimum clinically important difference had been proposed for the QUALEFFO, the clinical significance of this result is not clear. The INVEST study found no statistically significant differences between treatment groups at any point using SF-36 scores.\n\nBoth the INVEST and Buchbinder studies assessed back-specific functional status using the modified 23-point version of the Roland-Morris Disability Questionnaire (RDQ). However, neither study showed any statistically significant differences for outcomes in the short-term (3\xa0days to 2\xa0weeks) or in the medium-term (1\xa0month to 6\xa0months). In addition, the Assessment Group's meta-analysis of individual patient data from both studies indicated no statistically significant difference between treatment groups at 1\xa0month in terms of mean RDQ scores, with an adjusted mean difference of −0.8 (95% CI −0.9 to 2.4). The INVEST study included a post hoc analysis to identify the proportion of patients who achieved a clinically meaningful (although not defined) improvement in physical disability related to back pain at 1\xa0month. There was no difference between the proportion of patients in each group who achieved a clinically meaningful improvement (40% of the vertebroplasty group and 41% of the operative placebo with local anaesthesia group, p=0.99). The Assessment Group's meta-analysis also found no statistically significant difference in RDQ scores in the proportion of patients improving by at least 3\xa0units or by at least 30%. The INVEST study reported mean Study of Osteoporotic Fractures–Activities of Daily Living (SOF-ADL) scores at baseline and 1\xa0month, with no statistically significant difference between treatment groups in change from baseline with an adjusted mean difference of 0.4 (95% CI −0.8 to 1.6, p=0.51).\n\n## Percutaneous vertebroplasty compared with optimal pain management\n\nAll studies comparing vertebroplasty with optimal pain management reported pain measured on a numeric rating scale or VAS. The Farrokhi, Rousing and VERTOS\xa0II studies showed statistically significant improvements between groups in short- and medium-term changes from baseline in pain after vertebroplasty. However, the Assessment Group highlighted that the favourable result reported by Rousing at 1\xa0month may have been unreliable because these data were collected almost a year after the event. The VERTOS\xa0II and Farrokhi studies also found statistically significant improvements in the change from baseline between groups in longer-term outcomes. However, the Assessment Group noted that in the VERTOS\xa0II study, when defining a minimum clinically important improvement as 2\xa0or more points, the 95% confidence interval included the possibility that the results were not clinically meaningful. In the study by Blasco, statistical significance in change in pain from baseline was reported at 2\xa0months, when the result favoured vertebroplasty.\n\nThe proportion of people taking opioids was not statistically significantly different between treatment groups in the Blasco study. However, the Assessment Group found the results from this study difficult to interpret, partly because a higher proportion of patients in the vertebroplasty group needed opioids at baseline. In the VERTOS study, patients in the vertebroplasty group used less analgesia and patients in the control group used more analgesia, resulting in statistically significant differences that favoured vertebroplasty. In VERTOS\xa0II, analgesic use fell in the vertebroplasty group compared with the control group at 1\xa0day (p<0.001), 1\xa0week (p<0.001), and 1\xa0month (p=0.033), but not thereafter; the Assessment Group highlighted that the actual figures were not presented.\n\nBoth the Farrokhi and Blasco studies reported changes in height and deformity of the vertebral body, but the results cannot be compared because it is not clear whether the studies measured height by the same methods. The Blasco study showed no statistically significant or clinically important differences between treatment groups in the change in vertebral body height from baseline at 12\xa0months. In contrast, the Farrokhi study showed that vertebroplasty statistically significantly improved mean vertebral body height throughout the first year but not thereafter, and statistically significantly improved and sustained angular deformity throughout the 36-month follow\xa0up period. The VERTOS\xa0II study reported data relating to the progression of treated fractures during follow\xa0up. At the last follow‑up (median 12.0\xa0months, range 1–24\xa0months), statistically significant moderate or severe height loss was seen in 12% of patients in the vertebroplasty group, compared with 41% of patients in the optimal pain management group (p<0.001).\n\nThe Rousing study assessed health-related quality of life using the Dallas Pain Questionnaire, which evaluates the impact of chronic pain on a patient's life. Only the score for work and leisure at 3\xa0months reached statistical significance, favouring vertebroplasty compared with optimal pain management, but the score was unadjusted for the difference in scores at baseline. Comparing changes from baseline in each group, rather than directly comparing pain scores at 2\xa0weeks, favoured conservative management.\n\nVERTOS\xa0II and the Rousing study reported health-related quality of life using EQ-5D. The Rousing study provided EQ-5D utility values for 58% of patients in the vertebroplasty group and 71% in the optimal pain management group. The results, with negative differences indicating a worse outcome with vertebroplasty, indicated a mean group difference of −0.085 (95% CI −0.15 to −0.02) at 3\xa0months and −0.169 (95% CI −0.23 to −0.11) at 12\xa0months, compared with baseline. VERTOS\xa0II collected EQ-5D data throughout the study but reported only baseline values.\n\nBlasco, VERTOS and VERTOS\xa0II reported health-related quality of life using QUALEFFO. Results from the Blasco trial indicated that, in the short and medium term, there was a non‑statistically significant improvement in scores with vertebroplasty compared with optimal pain management at all time points. The VERTOS study found that vertebroplasty was associated with better short-term total QUALEFFO scores than optimal pain management. In VERTOS\xa0II, after adjusting for baseline differences, there was a statistically significant difference in QUALEFFO scores at 1\xa0year that favoured vertebroplasty (p<0.0001); however, actual scores were not reported. The Rousing trial reported health-related quality of life using SF-36 and showed no statistically significant differences between treatment groups at any point.\n\nThe VERTOS and VERTOS\xa0II studies used the RDQ (24-point version) to assess back-specific functional status. The VERTOS study reported that the between-group change from baseline to 2\xa0weeks favoured vertebroplasty over optimal pain management, but the Assessment Group could not calculate the statistical significance because the study reported no measure of variability. The VERTOS\xa0II study reported a statistically significant difference that favoured vertebroplasty at 1\xa0year compared with optimal pain management (p<0.0001); however, the study did not provide the RDQ scores or indicate what difference would reflect a clinically important difference.\n\nThe Farrokhi study reported disability using a modified Oswestry Disability Index (ODI) and reported that vertebroplasty was associated with a statistically significant improvement in change from baseline at all times from 1\xa0week to 36\xa0months compared with optimal pain management. The Assessment Group noted that, because 4\xa0points on the ODI is the minimum clinically important difference for back pain, these differences were clinically meaningful throughout. The Farrokhi study also noted that all 40\xa0patients in the vertebroplasty group could walk 1\xa0day after vertebroplasty, but only 1 of the 42\xa0patients (2%) in the optimal pain management group could walk 1\xa0day after optimal pain management, indicating a relative risk of 28.3 (95% CI 5.9 to 136.5, p<0.0001).\n\nThe Rousing study reported functional outcomes using the Barthel Index, which provided data for a subset of the study population. At 12\xa0months, the absolute score was statistically significantly better in the vertebroplasty group than in the optimal pain management group, but the difference between groups was no longer statistically significant when adjusted for differences at baseline. The Assessment Group stated that the result may indicate a ceiling effect, whereby there is little scope for vertebroplasty to improve functional outcome more than optimal pain management does. The Rousing study also reported 3\xa0tests of physical function for a subset of the population: tandem, timed up and go, and repeated chair tests. No statistically significant differences between groups were noted at 3 or 12\xa0months but, because the trial provided no baseline values, the change from baseline is not known.\n\n## Percutaneous vertebroplasty compared with percutaneous balloon kyphoplasty without stenting\n\nThe Liu study was the only study to compare vertebroplasty with kyphoplasty, and assessed pain, vertebral body height and angular deformity. It did not assess health-related quality of life. It assessed pain measured on a VAS and reported no statistically significant differences between vertebroplasty and kyphoplasty in the short or medium term, with a mean difference of −0.2 (95% CI −0.43 to 0.03) at 3\xa0days and 0.1 (95% CI −0.28 to 0.48) at 6\xa0months compared with baseline, with negative differences favouring vertebroplasty. However, the Assessment Group highlighted that the trial was likely to have been underpowered. For changes in vertebral body height and angular deformity, the trial reported that kyphoplasty led to statistically significantly greater improvements in both postoperative vertebral body height and angular deformity than did vertebroplasty, but the Assessment Group was not clear at what time points the study measured these outcomes.\n\n## Percutaneous balloon kyphoplasty without stenting compared with optimal pain management\n\nThe FREE study was the only study to compare kyphoplasty with a non‑operative treatment. For assessing pain as an outcome, the FREE study used SF-36. The results indicated that patients randomised to kyphoplasty improved more than those randomised to optimal pain management, the difference over a period of 12\xa0months being 9.2\xa0points (95% CI 3.9 to 14.6, p=0.0008). The FREE study also reported pain measured on a numeric rating scale and reported statistically significant long-term differences between groups; however, the Assessment Group noted that these differences were unlikely to reflect a clinically meaningful difference.\n\nThe FREE study reported the use of analgesics. Kyphoplasty statistically significantly reduced the need for opioid medication at 1\xa0month and 6\xa0months, but not at 12\xa0months or 24\xa0months. The Assessment Group highlighted that the FREE study did not report changes in vertebral body height, even though maintenance of vertebral body height was a secondary outcome. The study protocol stated that vertebral body height was measured only in patients having kyphoplasty, making comparison with optimal pain management impossible. The study did show a statistically significant improvement from baseline with kyphoplasty in the kyphotic angle of the fracture at 24\xa0months, but the Assessment Group noted that the clinical significance of this result is not clear.\n\nThe FREE study used EQ-5D and SF-36 to assess health-related quality of life. Using EQ-5D, statistically significant differences in outcomes favouring kyphoplasty over optimal pain management were reported at 1, 12, and 24\xa0months. However, the Assessment Group highlighted that, at a minimum clinically important difference for back pain of 0.08, the confidence intervals at 3, 6, 12 and 24\xa0months included the possibility of effects that are not considered clinically important. Using the SF-36 physical component summary score, the study reported a statistically significant mean difference of 5.2 (95% CI 2.9 to 7.4, p<0.0001) between groups at 1\xa0month, favouring kyphoplasty. Although the results remained statistically significant at 3\xa0months and 6\xa0months, the confidence intervals included the possibility of achieving a result that may not be considered clinically important and, after 6\xa0months, there was no statistically significant difference between treatment groups. The FREE study also reported psychological wellbeing, which was assessed by the SF-36 mental component summary score, and identified no statistically significant differences between treatment groups, although the confidence intervals included the possibility of potential clinically important treatment effects favouring kyphoplasty compared with optimal pain management at time points up to 12\xa0months.\n\nThe FREE study assessed back-specific functional status using the original 24-point version of the RDQ. It showed that kyphoplasty was associated with statistically significantly better outcomes compared with optimal pain management at 1 and 12\xa0months, but not at 24\xa0months. Moreover, at 12\xa0months, the confidence intervals included the possibility of not achieving a clinically important outcome. The FREE study also reported that kyphoplasty was associated with a statistically significant reduction in the probability of needing walking aids at 1\xa0month, but not at 12\xa0months. However, the Assessment Group noted the data were not robust because of missing data. The FREE study also recorded the number of patients who reported 1\xa0or more days of bed rest because of back pain in the previous 14\xa0days. At 1\xa0month, patients in the kyphoplasty group reported on average 2.9\xa0fewer days of restricted activity than patients in the optimal pain management group (95% CI 1.3 to 4.6, p<0.001), but at 12\xa0months the difference was no longer statistically significant (1.6\xa0days, 95% CI −0.1 to 3.3, p=0.07). The actual numbers of days of restricted activity in each group were not reported.\n\n## Mortality benefit\n\nThe Assessment Group stated that the trials were not powered to determine differences in overall mortality, and noted that none of the studies showed any statistically significant differences in overall mortality between treatment groups. The Assessment Group also combined 12\xa0months of mortality data from the Blasco, Rousing and VERTOS\xa0II studies comparing vertebroplasty with optimal pain management. The point estimate of the relative risk favoured vertebroplasty, but was not statistically significant (0.68; 95% CI 0.30 to 1.57, p=0.37). Medtronic provided a large observational study (n=858,979) based on US Medicare registry data with follow‑up to 4\xa0years, which showed a mortality benefit with vertebroplasty or kyphoplasty compared with optimal pain management in patients with vertebral compression fractures, with a hazard ratio of 0.76 (95% CI 0.75 to 0.77) for vertebroplasty and 0.56 (95% CI 0.55 to 0.57) for kyphoplasty, adjusting for age, sex, race, Charlson comorbidity index and other coexisting diseases. In addition, kyphoplasty was associated with a greater mortality benefit compared with vertebroplasty, with an adjusted hazard ratio of 0.77 (95% CI 0.75 to 0.78; Edidin 2011). The Assessment Group stated that academic-in-confidence data provided by Medtronic on mortality at 5\xa0years from US Medicare registry data, as well as data from a smaller observational study (n=3607) based on a German health insurance fund, further supported a benefit in mortality associated with the technologies. The Assessment Group stated that, apart from the possibility of uncontrolled confounding, these studies raise the possibility that improvement in biomechanical factors after treatment improves survival.\n\n## Adverse events\n\nThe Assessment Group presented adverse events reported in the trials supplemented with observational studies and case reports.\n\nAll but the Liu and INVEST studies reported cement leaks confirmed by imaging, and all had used polymethylmethacrylate cement, presumed by the Assessment Group to be of low viscosity. The Blasco study found that cement leaks did not cause patients immediate complications. However, leaks into the inferior intervertebral disc increased the risk of incident vertebral fracture (odds ratio [OR] 7.2, 95% CI 1.7 to 69.3). The Farrokhi study reported 13\xa0asymptomatic leaks and 1\xa0symptomatic leak into the epidural space treated with urgent bilateral laminectomy. The Rousing study stated that none of the cement leaks caused neurological symptoms. In the VERTOS\xa0II study, most leaks were discal or into segmental veins, and cement pulmonary emboli were visible on computed tomography scan in 26% (95% CI 16% to 39%) of patients, although the patients did not have symptoms. In the FREE study, most leaks went into the vertebral end-plates or they were intervertebral disc leaks, with 1\xa0leak into the vertebral foramina, no leaks into the spinal canal, and no cement emboli.\n\nThe Buchbinder, FREE and VERTOS\xa0II studies reported postoperative infections potentially related to treatment. In the Buchbinder study, investigators administered the intravenous antibiotic cephalothin prophylactically after cement injection. Osteomyelitis developed in a patient who did not receive an antibiotic because of allergies. In the FREE study, a patient developed spondylitis in the vertebral body 376\xa0days after surgery. Sepsis or septic shock was reported in 1\xa0patient in the kyphoplasty group and in 3\xa0patients in the optimal pain management group. The Assessment Group also noted that 3\xa0patients who underwent kyphoplasty subsequently had pulmonary emboli of venous origin, and the earliest of these occurred 46\xa0days postoperatively. The Farrokhi study reported that no infections occurred, and the Rousing study reported that there were no adverse reactions other than cement leaks. In the remaining 4\xa0studies (Blasco, INVEST, Liu, VERTOS), no postoperative infections were mentioned.\n\nThe risk of fracturing a vertebra adjacent to the treated vertebra was reported in 4\xa0studies (Buchbinder, Farrokhi, FREE, Rousing), and none identified a statistically significant difference between treatment groups in the proportion of patients who experienced at least 1\xa0clinically important fracture. However, the Blasco study noted that more (71%) of the radiographic fractures in the vertebroplasty group were clinically important compared with fewer (9%) in the optimal pain management group (OR 25.7, 95% CI 3.0 to 216.8, p=0.029); the investigators did not report the number of patients who had incident vertebral fractures.\n\nThe Assessment Group highlighted the potentially serious complications that can result from managing compression fractures conservatively. Bed rest can result in muscle wasting, deconditioning, deep vein thrombosis and pulmonary emboli. Opioid analgesics can cause undesirable adverse reactions including cognitive impairment, constipation and nausea, and non‑steroidal anti‑inflammatory drugs are associated with gastrointestinal and renal problems.\n\n## Subgroups\n\nThe Assessment Group stated that no trial data were identified for patients with or without fracture-related vertebral deformity or for inpatients at the time of randomisation. However, some data were available for subgroups based on the severity of pain at randomisation and for the time from fracture to intervention. No data for subgroups were available for kyphoplasty.\n\nA meta-analysis by Staples et al. (2011) of individual patient data from the Buchbinder and INVEST studies grouped by baseline pain severity showed no statistically significant differences in RDQ scores, EQ-5D scores, or pain scores between patients with severe pain (score of 8\xa0or more on a 0–10 scale) or mild-to-moderate pain (score of less than 8) at baseline. In both groups (vertebroplasty and operative placebo with local anaesthesia), patients with greater degrees of pain at baseline experienced a greater reduction in pain. The Assessment Group stated that this could reflect a greater potential for improvement. The Assessment Group also stated there were no data to suggest that outcomes would differ between patients who were or were not inpatients before treatment.\n\nThe INVEST study reported results by duration of pain at baseline in post hoc analyses and found no statistically significant difference between vertebroplasty and operative placebo with local anaesthesia on pain at 1\xa0month, but was underpowered for this analysis. Data from the Staples study combining individual patient data from the INVEST and Buchbinder studies assessed the effectiveness of vertebroplasty in patients with fracture pain of recent onset (6\xa0weeks or less) compared with pain of longer duration. Because the INVEST study allowed crossover after 1\xa0month, the outcomes were compared up to that time point, finding no statistically significant differences in RDQ scores, EQ-5D scores, or pain scores.\n\n# Cost effectiveness\n\nThe Assessment Group conducted a literature review that identified 1\xa0Markov cohort model comparing the cost effectiveness of kyphoplasty with optimal pain management in patients hospitalised in the UK with vertebral compression fractures (Strom\xa0et\xa0al. 2010). The model simulated the experiences of patients until death or 100\xa0years, with EQ-5D scores taken from the FREE study. The model assumed that the intervention would affect EQ-5D scores up to 3\xa0years after kyphoplasty or optimal pain management, declining linearly between 1 and 3\xa0years. The model incorporated increased risks of future vertebral fracture and increased risks of mortality after vertebral fracture. The base case assumed a cohort of 70-year-old women and men with a T‑score of −2.5\xa0SD (T‑score is defined as the number of standard deviations from the average bone mineral density of healthy young women) and estimated that kyphoplasty would cost an additional £1494 to obtain 0.169 quality-adjusted life years (QALYs), resulting in an incremental cost effectiveness ratio (ICER) of £8840 per QALY gained for kyphoplasty compared with optimal pain management.\n\n## Medtronic model\n\nMedtronic submitted a Markov tunnel model adapted from the Strom model (see section 4.2.1) to determine the cost effectiveness of kyphoplasty, vertebroplasty and optimal pain management in patients hospitalised with vertebral compression fractures. The model has a lifetime time horizon, 6-month cycles, and an NHS perspective. Costs and utilities are discounted at 3.5%. In the base case, Medtronic assumed that patients are 70\xa0years old and have a T\xa0score of −3.0\xa0SD, similar to patients in the FREE and VERTOS\xa0II trials. The model assumes people are either treated with kyphoplasty or an alternative, and remain in their initial treatment health state (progressing through the sub-states) until they die or experience another vertebral fracture that is treated using optimal pain management only. The manufacturer calculated the transition probabilities for further vertebral fractures from equations taking into account a patient's T\xa0score, age, number of previous fractures and, because the data were not available, the imputed ratio between the incidence of hip and vertebral fractures at each age, assuming that Swedish values (from Strom) apply to the UK. The transition probabilities to death use data from the Human Mortality Database for patients in the UK and the relative risks of mortality for people with a prior vertebral fracture (from Strom).\n\nMedtronic took utility values for kyphoplasty and optimal pain management directly from the FREE trial, and for vertebroplasty indirectly from the VERTOS\xa0II trial, estimating values by adding the difference between vertebroplasty and optimal pain management to the scores for optimal pain management in the FREE trial. Because VERTOS\xa0II presented data on QALYs at baseline, 1\xa0month and 12\xa0months, Medtronic inferred the average utility across the 1-year period. Medtronic assumed that, unless a patient has a refracture, their utility will improve during the first 2\xa0years and, thereafter, the utility in patients treated with optimal pain management will decline at the rate of the general population. For patients treated with kyphoplasty or vertebroplasty, the utility gain compared with optimal pain management declines linearly during the first year. Consequently after 3\xa0years, unless patients have a refracture, they will have the same health utility, which declines at the same rate as the general population. The model assumes that both kyphoplasty and vertebroplasty improve survival compared with optimal pain management. The hazard ratios for death for kyphoplasty and for vertebroplasty are based on the US Medicare registry data. Medtronic included recurrent vertebral fracture but no other adverse events in the model, citing a lack of data as the reason, although acknowledging potentially substantial consequences of adverse events.\n\nThe list price of a kyphoplasty kit is £2600.50, and the submission also noted an average selling price of £1900. Medtronic assumed an acquisition cost of vertebroplasty that was commercial in confidence. Medtronic updated the costs of the preparatory, operating and postoperative phases from those in the Strom study. Medtronic obtained data on the length of stay in hospital after treatment from Hospital Episode Statistics 2010/11 data, and the cost per day in hospital from NHS Reference costs 2009–11. The deterministic analyses gave an ICER of £2167 per QALY gained for kyphoplasty compared with optimal pain management and £2053 per QALY gained for vertebroplasty compared with optimal pain management. The deterministic analysis of kyphoplasty compared with vertebroplasty gave an ICER of £2510 per QALY gained, while probabilistic analyses gave ICERs of £2118 (kyphoplasty compared with optimal pain management), £2100 (vertebroplasty compared with optimal pain management) and £2174 (kyphoplasty compared with vertebroplasty) per QALY gained.\n\nMedtronic conducted sensitivity analyses to study the impact of changing 1\xa0variable at a time: the time horizon; the discount rate for costs and QALYs; the health utility benefit from the FREE trial; the time at which the utility gain for kyphoplasty and vertebroplasty compared with optimal pain management is offset linearly; mortality rates after a fracture; the price of vertebroplasty compared with kyphoplasty; the unit costs per day in hospital; the assumed T‑score of the cohort; the age of the cohort; whether patients are treated with a bisphosphonate; and the proportion of patients who are male. The ICERs for kyphoplasty compared with optimal pain management and kyphoplasty compared with vertebroplasty remained below £15,000 per QALY gained in all instances. The assumption that vertebroplasty and kyphoplasty cause patients to live longer (greater for kyphoplasty than for vertebroplasty) was a key driver of the cost-effectiveness results and, when the manufacturer assumed no mortality benefit with either vertebroplasty or kyphoplasty, then the ICER for kyphoplasty compared with vertebroplasty was £27,340 per QALY gained. Medtronic noted that the ICERs for both vertebroplasty and kyphoplasty compared with optimal pain management remained low. The sensitivity analysis for changing the length of hospital stay after kyphoplasty also increased the ICER for kyphoplasty compared with vertebroplasty to over £20,000 per QALY gained.\n\n## Johnson and Johnson model\n\nJohnson and Johnson's model aimed to determine the cost effectiveness of vertebroplasty, kyphoplasty, optimal pain management and of operative placebo with local anaesthesia using a scenario analysis. The manufacturer developed a treatment-state model with a 1-year time horizon, an NHS perspective, and costs and benefits discounted at 3.5%. To estimate effectiveness measured by pain experienced by patients, Johnson and Johnson performed a network meta-analysis using VAS scores and EQ-5D data from trials. The manufacturer also performed an analysis based on a 'target population', that is, patients with fractures that occur within 3\xa0months who are expected to benefit most from vertebroplasty or kyphoplasty.\n\nThe model has patients receiving different treatments and assigns values for pain using a VAS score before treatment and then again at 2\xa0weeks depending on the intervention received. The model updates the treatment-dependent VAS score at 1\xa0month, 6\xa0months and 12\xa0months. Johnson and Johnson used a regression analysis to describe the relationship between VAS and EQ-5D, based on data for both outcomes derived from a network meta-analysis. This relationship then allowed the manufacturer to model changes in quality of life from VAS scores that had been reported in trials at multiple time points. The Assessment Group stated that the manufacturer did not attempt in its network meta-analysis to extrapolate or interpolate data from trials that did not report VAS scores at the designated time intervals, and this could be a source of uncertainty when modelling pain scores over time. The Blasco study was published after completion of the manufacturer's systematic review. If the manufacturer had included this trial, which had similar VAS scores for vertebroplasty and optimal pain management (with both values being relatively high), the VAS scores in the model for all treatments would have increased and the relative difference between optimal pain management and both vertebroplasty and kyphoplasty would have diminished. Johnson and Johnson did model procedure-related adverse events.\n\nJohnson and Johnson used a bottom-up costing approach based on published data from the Strom study for vertebroplasty and kyphoplasty. The manufacturer did not model costs for optimal pain management because it assumed that all patients, including patients receiving vertebroplasty or kyphoplasty, would receive optimal pain management. The manufacturer determined costs of the preparatory, operating and postoperative phases from the Strom study adjusted for inflation to 2009/10 prices. The costs for vertebroplasty varied according to the number of vertebrae needing treatment, being £1358 for 1\xa0vertebra, £1784 for 2, and £1848 for 3. Based on Dr Foster data, the estimated frequency of treating 1, 2 or 3\xa0fractures resulted in an average weighted cost of £1472. The Assessment Group noted that, in its submission, Johnson and Johnson stated that 11\xa0cm3 of cement was needed to treat 2\xa0fractures but the manufacturer's calculations assume 7\xa0cm3 of cement. If 11\xa0cm3 were used, the average weighted cost would increase to £1546. The cost of the kyphoplasty kit reported in the Strom study was adjusted for inflation by the manufacturer to a 2009/10 cost of £2842.\n\nJohnson and Johnson's base-case results indicated that vertebroplasty was both more effective and less costly than kyphoplasty and therefore dominated kyphoplasty. The analysis of vertebroplasty compared with optimal pain management gave an ICER of £4392 per QALY gained and kyphoplasty compared with optimal pain management gave an ICER of £14,643 per QALY gained. The results based on patients with fractures that occur within 3\xa0months who are expected to benefit most from vertebroplasty or kyphoplasty also indicated that vertebroplasty dominated kyphoplasty; the analysis of vertebroplasty compared with optimal pain management gave an ICER of £4755 per QALY gained and kyphoplasty compared with optimal pain management gave an ICER of £15,006 per QALY gained. The scenario analysis including operative placebo with local (injected) anaesthesia resulted in vertebroplasty dominating operative placebo with local anaesthesia, and operative placebo with local anaesthesia dominating kyphoplasty. The comparison of optimal pain management with operative placebo with local anaesthesia gave an ICER of £4853 per QALY gained.\n\nJohnson and Johnson performed several other scenario analyses, pooling data from operative placebo with local anaesthesia with data from optimal pain management; extending the time horizon to beyond 1\xa0year for both the base‑case and target population with recent fractures; using an alternative bottom-up costing methodology and payment-by-results tariff for both the base‑case and the target population; and using direct EQ-5D values for both the base‑case and target populations. Vertebroplasty dominated kyphoplasty in all scenarios. The ICER for vertebroplasty compared with optimal pain management ranged from £568–£13,595 per QALY gained in the base case and from £2550–£16,497 per QALY gained in the target population.\n\nJohnson and Johnson performed univariate sensitivity analyses comparing vertebroplasty with optimal pain management and vertebroplasty with kyphoplasty. The main drivers of cost effectiveness were the efficacy of the treatment (that is, the VAS score at various time points), and costs (driven by the length of stay, cost per bed day and surgical equipment costs) for both the base case and the population with recent fractures. Results from probabilistic sensitivity analyses (varying parameters simultaneously) were broadly similar to the deterministic results in the base-case analysis; vertebroplasty dominated kyphoplasty for both base-case and target-population analyses. In addition, in the base-case analysis, the probabilistic ICER for vertebroplasty compared with optimal pain management in the model estimated the ICER at £4388 per QALY gained in the base-case analysis and £4711 per QALY gained in the target population analysis. The model estimated the probabilistic ICER for kyphoplasty compared with optimal pain management at £14,718 per QALY gained in the base-case analysis and £15,010 per QALY gained in the target population analysis. In addition, the Assessment Group corrected an error in the manufacturer's mathematical model in which only 10% of patients receiving kyphoplasty consume operating-room resources; the Assessment Group assumed that this value was intended to be 100%.\n\n## Assessment Group model\n\nThe Assessment Group's model was designed to determine the cost effectiveness of vertebroplasty, kyphoplasty, optimal pain management and operative placebo with local anaesthesia. The Assessment Group presented 6\xa0scenarios rather than a base case. The Assessment Group stated that, given the uncertainty around whether vertebroplasty or kyphoplasty prolonged life, it organised results into 3\xa0categories based on whether:\n\nkyphoplasty prolongs life more than vertebroplasty, which prolongs life more than optimal pain management\n\nvertebroplasty and kyphoplasty prolong life more than optimal pain management and\n\nvertebroplasty and kyphoplasty do not prolong life more than optimal pain management. The Assessment Group also stated that the results differed based on whether it took EQ-5D directly from the trials (INVEST, FREE and Buchbinder) or mapped stable VAS scores (which the Assessment Group defined as VAS scores assumed to occur at 1\xa0month after operation for vertebroplasty or kyphoplasty, and at 3\xa0months after optimal pain management treatment) to EQ-5D. In addition, the Assessment Group produced exploratory analyses assuming the use of high-viscosity cement.\n\nThe model consisted of 5\xa0health states:\n\nthe starting state of post-osteoporotic vertebral compression fractures when patients receive kyphoplasty, vertebroplasty, operative placebo with local anaesthesia, or optimal pain management\n\na state in which a patient may experience a subsequent vertebral fracture\n\na state in which a patient may experience a subsequent hip fracture\n\na state in which a patient may experience both a subsequent vertebral and a hip fracture and\n\ndeath. The model allowed a patient to experience only 1\xa0further vertebral fracture and 1\xa0hip fracture. The Assessment Group assumed that a time horizon of 50\xa0years reflects patients' lifetimes and the model employed 36\xa0monthly time cycles followed by 47\xa0yearly time cycles. The Assessment Group's rationale for the different cycle length was that different procedures may lead to different utilities in the period after a procedure, a difference more easily incorporated using monthly time cycles. Both costs and benefits were discounted at 3.5% per year. The model did not include the potential disutility associated with anxiety about the prospect of future fractures, or the potential reduction in bone mineral density associated with prolonged bed rest.\n\nThe Assessment Group estimated transition probabilities between health states from the literature. Taking into consideration that a patient's bone density is likely to decrease over time, the Assessment Group incorporated a decrease of 0.255\xa0SD per 5‑year age group, assuming that women and men with the same T‑score have the same risks of fracture. If a patient was assumed to be taking a bisphosphonate, the assumed effect on vertebral fractures was based on relative risks reported in the literature. This effect was assumed to last for 5\xa0years, with a linear decline in effect over a 5‑year period, so that the relative risk was 1 after 10\xa0years. The risk of hip fracture or vertebral fracture was assumed to be independent of whether the patient was simulated to have a subsequent vertebral fracture or hip fracture.\n\nThe Assessment Group estimated the mortality rate associated with hip fracture from Stevenson\xa0et\xa0al. (2009) and the mortality rate associated with vertebral fracture from a UK study (Jalava\xa0et\xa0al. 2003). The model assumed that patients are more likely to die in the year in which a subsequent fracture occurs than they are thereafter. The model also assumed that the mortality rate after hip fracture must be equal to or greater than the mortality rates associated with a vertebral fracture in the age- and sex-matched general population. The mortality rate from causes other than fracture was taken from life tables from the Office for National Statistics, and the Assessment Group assumed that all patients die before they reach 101\xa0years. When the Assessment Group assumed that patients who undergo kyphoplasty, vertebroplasty or operative placebo with local anaesthesia live longer than those who receive optimal pain management, mortality benefits were incorporated in the model for a period of 5\xa0years in the base case. It was assumed that mortality benefits would cease immediately after 5\xa0years. The Assessment Group assumed that the relative risks associated with treatment applied to all‑cause mortality and to the mortality rate associated with vertebral fractures, but not to hip fractures.\n\nThe Assessment Group calculated the hazard ratios within the 3\xa0scenarios used to explore the effects of mortality using US Medicare registry data provided, academic in confidence, by Medtronic. The Assessment Group did not have data about any potential effect of operative placebo with local anaesthesia relative to optimal pain management on mortality, but assumed that the effect is half that observed for vertebroplasty because the effect of operative placebo with local anaesthesia on pain (VAS) was half that observed for vertebroplasty.\n\nThe Assessment Group assumed that utility values for all health states are a function of: sex; age; which procedure a patient undertakes; the time since the procedure; the time after which the model assumes that the utility values of patients treated with optimal pain management equals those of patients treated with an active intervention; the value of disutility after vertebral fractures that occurred more than 1\xa0year before an intervention; and the mapping of VAS scores onto the EQ-5D. In addition, in the health states in which a patient had an additional vertebral and/or a new hip fracture, the model included a decrease in the utility value reflecting the fracture and, in the following cycles, persistent pain. The Assessment Group's model assumed that adverse events did not increase costs or disutility. However, the Assessment Group conducted a sensitivity analysis assuming that adverse effects led to QALY losses of 0.02 for kyphoplasty and vertebroplasty.\n\nCosts within each of the health states were taken largely from the Stevenson study and adjusted for inflation to 2010/11 prices using the Hospital and Community Health Services inflation indices. The Assessment Group took the cost of the high-viscosity Confidence Spinal Cement System from the Johnson and Johnson submission, although it assumed that 7\xa0cm3 of cement was needed to treat 2\xa0vertebral fractures, rather than 11\xa0cm3. This gave an average cost of £1546 per operation. The average estimated value for low-viscosity cement was £697. A clinical specialist advised the Assessment Group that approximately 15% of procedures would use high-viscosity cement or other more expensive cement types. The Assessment Group assumed that these more complex cases would add slightly over £100 to the average cost of an operation, resulting in an assumed cost of £800 per vertebroplasty procedure using low-viscosity cement. In calculating the ICERs, the Assessment Group assumed that vertebroplasty uses low-viscosity cement.\n\nThe Assessment Group adjusted the list price of £2600.50 per kit for kyphoplasty to acknowledge that a proportion of patients would need kyphoplasty on more than 1\xa0vertebra, which would require an additional pack of Kyphon HV-R bone cement, priced at £62 per pack. This resulted in the average price per patient increasing to £2639 for kyphoplasty. The Assessment Group assumed that the cost of operative placebo with local anaesthesia was equal to vertebroplasty, but varied this assumption in sensitivity analyses.\n\nThe Assessment Group took costs for all phases of vertebroplasty and kyphoplasty from Johnson and Johnson's submission, estimated to be £540 for the preparatory, £243 for the postoperative and £528 for the operating phases. The Assessment Group chose costs for length of hospital stay data from Medtronic's submission, which used hospital episode statistics data, and chose the value for cost per hospital day of £232 from the Johnson and Johnson submission, noting that this value is an underestimate. The clinical advisers to the Assessment Group stated that most procedures would be performed as day cases and that length of stay would be shorter than suggested by hospital episode statistics data.\n\nThe Assessment Group performed sensitivity analysis for each scenario, exploring the impact of changes to the following assumptions: assuming a bed day cost of £0; changing the assumed cost of equipment for operative placebo with local anaesthesia and the cost of the procedure; changing the time of convergence (the point at which the pain score in patients undergoing vertebroplasty equals the pain score in patients receiving optimal pain management); and including potential QALY losses associated with adverse events.\n\nThe Assessment Group summarised that, in scenarios in which the model assumes that patients who undergo kyphoplasty live longer than those who undergo vertebroplasty, results indicated that kyphoplasty provided the most QALYs and gave ICERs below £12,000 per QALY gained, irrespective of whether the utility gain expressed in EQ-5D had been estimated by mapping stable VAS, or measured directly in the trials and even if the cost of kyphoplasty was increased, assuming a separate kit was needed for each level. The ICER for vertebroplasty compared with optimal pain management, when utility gain was estimated directly from EQ-5D in the trials, remained below £7000 per QALY gained, except in 1\xa0instance when it was extendedly dominated, when treatment benefit was assumed to disappear between 12\xa0months and 24\xa0months and the EQ-5D data from the Buchbinder trial were used.\n\nIn scenarios in which the model assumed that patients who undergo vertebroplasty and kyphoplasty live longer (but by the same degree) than patients who receive optimal pain management, and when the model assumes that patients who receive operative placebo with local anaesthesia also live longer, but only to half the degree as vertebroplasty and kyphoplasty, results indicated that vertebroplasty dominated kyphoplasty because it effectively provided the same QALYs at a higher cost. The ICER for vertebroplasty compared with optimal pain management remained below £10,000 per QALY gained across all assumptions except for the combination of assumptions in which: operative placebo with local anaesthesia was assumed to have an identical mortality benefit to balloon kyphoplasty and vertebroplasty; operative placebo with local anaesthesia was assumed to have a lower cost than vertebroplasty; adverse events for vertebroplasty were included; and the EQ-5D data from the randomised controlled trials were used. In this instance, vertebroplasty was dominated by operative placebo with local anaesthesia. However, it was noted that, if operative placebo with local anaesthesia was not seen to be an appropriate comparator, the ICER of vertebroplasty compared with optimal pain management remained below £10,000 per QALY gained.\n\nIn the scenarios in which the model assumed that patients who undergo vertebroplasty and kyphoplasty do not live longer than patients who receive optimal pain management, the cost-effectiveness results depend on whether the utility gain is estimated by mapping, but vertebroplasty nonetheless typically provided the most QALYs, and the ICER remained below £16,000 per QALY gained. The exception to this was when the Assessment Group adopted assumptions unfavourable to vertebroplasty, such as hospitalisation stay costs set at £0, reduced cost of operative placebo with local anaesthesia, incorporating adverse events for vertebroplasty, and an earlier convergence over time of EQ-5D scores. When the model estimated utility gained directly from the Buchbinder and INVEST trials, vertebroplasty always dominated kyphoplasty. Vertebroplasty was dominated by operative placebo with local anaesthesia in some cases and had an ICER greater than £20,000 per QALY gained in other cases. If the Assessment Group did not consider operative placebo with local anaesthesia as an appropriate comparator, vertebroplasty compared with optimal pain management had an ICER greater than £20,000 per QALY gained in some cases.\n\nThe Assessment Group also conducted an exploratory analysis assuming the use of high-viscosity cement for all patients. It stated that, for the cost per QALY gained to be equal to £20,000 per QALY gained, an additional 0.037 QALYs would be needed, a value greater than the value of 0.02 discounted QALYs assumed in the sensitivity analyses. The Assessment Group stated that it was unlikely that the ICER for high-viscosity cement compared with low-viscosity cement would be lower than £20,000 per QALY gained. However, the Assessment Group stated that a patient might need another operation if there was a problem with low-viscosity cement. So the Assessment Group estimated that, if more than 25% of patients needed another procedure on the same vertebra, then a strategy of using high-viscosity cement in all patients for the first procedure would be more cost effective. The Assessment Group stated that it was unlikely that a strategy of using high-viscosity cement in all patients rather than a subset selected by the clinician would have an ICER of less than £20,000 per QALY gained.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of vertebroplasty and kyphoplasty, having considered evidence on the nature of osteoporotic vertebral compression fractures and the value placed on the benefits of vertebroplasty and kyphoplasty by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the evidence presented by the patient experts and clinical specialists on the clinical symptoms associated with osteoporotic vertebral compression fractures. The Committee heard that these fractures have a debilitating impact on patients' ability to work and care for themselves, and consequently on their quality of life. The patient expert highlighted that, in addition to the physical pain caused by the fractures, loss of height and a distorted spine have a major impact on the emotional wellbeing and self-image of many patients. The Committee heard from the clinical specialists that people with osteoporotic vertebral compression fractures can experience problems with mobility, digestion and breathing, which may be linked to earlier mortality. The Committee acknowledged the debilitating impact that osteoporotic vertebral compression fractures have on patients' physical and emotional wellbeing.\n\nThe Committee discussed the clinical management of osteoporotic vertebral compression fractures. The Committee understood from the clinical specialists that vertebroplasty and kyphoplasty are performed by radiologists, anaesthetists or orthopaedic surgeons, some of whom are based in pain clinics, and they work with metabolic bone specialists to assess the need for intervention. The Committee heard that, initially, clinicians treat patients with optimal pain management including analgesics, particularly opioids and non‑steroidal anti‑inflammatory drugs, which are associated with considerable side effects in the older population. The Committee noted comments received during the consultation suggesting that 'optimal pain management', included in the Committee's preliminary recommendations, should be more specifically defined. However, the Committee considered that, because optimal pain management encompasses a broad array of treatments, and it means clinicians individualise therapies, it would be beyond the Committee's remit to define optimal pain management. The Committee heard that vertebroplasty and kyphoplasty are considered as treatment options in patients with recent vertebral fractures (proposed as 6\xa0weeks) who have pain at the level of the fracture (confirmed by physical examination and magnetic resonance imaging) that is ongoing, severe, and does not respond to optimal pain management. The Committee heard that this was because, for many people, the severity of the pain will decline after 2 to 3\xa0weeks and many people will be free of pain in 6\xa0weeks, in line with the natural history of the condition. The clinical specialists stated that kyphoplasty can restore vertebral height to a greater extent than vertebroplasty, but this is possible only if the fracture has not healed. The Committee noted that comments received during the consultation expressed concerns over specifying a time interval of 6\xa0weeks in which to undergo the procedures. The Committee discussed the comments and the impact of stipulating a specific time period. It acknowledged that 6\xa0weeks may not be sufficient to permit an adequate trial of optimal pain management and imaging to confirm an unhealed fracture. The Committee also noted that, although clinicians advocate intervening in patients with recent fractures, a very small number of people with fractures are referred to secondary care with unhealed fractures months after the onset of pain and may benefit from the interventions. The Committee was aware that trials comprising the evidence base included patients with fractures older than 6\xa0weeks. The Committee noted the lack of robust evidence to suggest an association between age of a fracture at the time of intervention and its effectiveness with respect to pain and mortality. The Committee considered that a key factor in determining the timing of vertebroplasty and kyphoplasty was whether the fracture remained unhealed and whether it caused ongoing pain. Although the Committee appreciated the complexities in offering vertebroplasty and kyphoplasty too early (before natural healing has resulted in pain relief) or too late (when there is little chance of restoring vertebral height), it concluded that there were likely to be very few patients for whom these procedures were appropriate more than 12\xa0weeks after fracture, and the appropriate timing in relation to the age of the fracture could be left for clinicians to judge.\n\nThe Committee considered the evidence for the clinical effectiveness of vertebroplasty and kyphoplasty compared with optimal pain management or operative placebo with local anaesthesia. The Committee was aware that only 2\xa0of the trials were double blind and that results from these trials did not show statistically significant improvements in pain scores, back-specific functional status or health-related quality of life during the duration of the studies. The Committee was aware that the operative placebo that included local anaesthesia may itself reduce pain, and heard that clinicians may treat some patients with local anaesthesia injected into or near the affected vertebrae. However, the Committee agreed that operative placebo could not be considered established clinical practice for the majority of patients. In addition, it noted comments received during consultation indicating that this procedure would not be used to treat any progressive vertebral collapse. The Committee was aware that open-label studies showed that both vertebroplasty and kyphoplasty improved pain compared with optimal pain management. The Committee considered that the open-label trials better reflected 'real life' and included the comparator that would be used in clinical practice. The clinical specialists stated that, although results from the 2 double‑blind trials had raised questions about the value of vertebroplasty and kyphoplasty, in clinical experience, both procedures improved pain and quality of life in people with severe symptoms. The Committee concluded that it could not disregard the results from the open-label trials, and was persuaded that there was sufficient evidence to conclude that vertebroplasty and kyphoplasty are more effective in reducing pain and restoring vertebral body height than optimal pain management in people with recent, painful osteoporotic vertebral compression fractures.\n\nThe Committee discussed whether vertebroplasty and kyphoplasty prolong life compared with optimal pain management. The Committee noted that the Assessment Group pooled data on mortality at 12\xa0months from 3\xa0trials and found no statistically significant differences between vertebroplasty and optimal pain management (see section 4.1.21), but was aware that the studies were not designed to show a difference in mortality. However, the Committee noted that the point estimate for the mortality benefit was consistent with that estimated from 2 large\xa0scale epidemiological studies. Specifically, a large study based on US Medicare registry data that followed patients for up to 4\xa0years reported a statistically significant mortality benefit with narrow confidence intervals, with both vertebroplasty and kyphoplasty compared with optimal pain management. The Committee noted these results, which were substantiated by an additional year of follow‑up from the Medicare registry, as well as by mortality data from a smaller German study. The Committee was aware that the Medicare data had controlled for multiple comorbidities but that the possibility of confounding remained; that is, patients who have the intervention may be healthier, or otherwise different in a way that means they live longer than patients who do not undergo intervention. The Committee discussed that, given the magnitude of the benefit, taking into account further confounding would be likely to diminish, but would be unlikely to abolish, an effect. The Committee discussed the biological plausibility of a mortality benefit with vertebroplasty and kyphoplasty, and heard that improving vertebral height and spinal curvature could improve lung function, digestion and mobility, and consequently have a mortality benefit. The clinical specialists stated that most fractures occur in the thoracic spine making an impact on lung function a plausible effect. The Committee discussed the relationship between chronic pain and mortality, and felt that reducing pain may confer a mortality benefit. The Committee discussed the deleterious effects of analgesia, and the possibility of a beneficial effect on mortality of a reduced intake of opioids and non‑steroidal anti‑inflammatory drugs. The Committee concluded that it was reasonable to assume that both vertebroplasty and kyphoplasty prolong life compared with optimal pain management, but that the precise mechanism or magnitude of such a benefit in clinical practice in the NHS was uncertain.\n\nThe Committee also noted that, based on both sets of observational data, patients who had kyphoplasty lived longer than patients who had vertebroplasty (see section 4.1.21). The Committee heard that people who had kyphoplasty would, in general, be fitter than people who had vertebroplasty because kyphoplasty normally involves general anaesthesia and is a more technically difficult procedure. However, the Committee was also aware that, in the trial comparing vertebroplasty with kyphoplasty, kyphoplasty was associated with statistically significantly greater improvements in both postoperative vertebral height and angular deformity compared with vertebroplasty. On balance, the Committee concluded that, given the degree of uncertainty, it was plausible that kyphoplasty may be associated with a greater mortality benefit than vertebroplasty, but the Committee would also consider the possibility that kyphoplasty and vertebroplasty had the same degree of mortality benefit.\n\nThe Committee noted the Assessment Group's comments that adverse reactions from vertebroplasty and kyphoplasty related primarily to cement leakage, particularly for vertebroplasty. Cement leakage was associated with pulmonary embolism, radiculopathy, and temporary or permanent motor deficits. The Committee heard that leakage could be intradiscal or intravascular, with intravascular leaks increasing the risk of cement pulmonary embolism. The Committee heard that, to reduce cement leakage and its complications, high-viscosity cements have been developed as an alternative to low-viscosity cements. The clinical specialists stated that, to reduce leakage of low-viscosity cements, the manufacturers were developing newer methods, and that problems from leakage were rare. The Committee concluded that cement leakage associated with vertebroplasty and kyphoplasty was manageable if the procedure is performed by a skilled clinician with specialised training in these procedures.\n\nThe Committee was aware that the Assessment Group presented 6\xa0different scenarios based on different assumptions around mortality benefit and whether EQ-5D data were taken directly from trials or were mapped from stable VAS pain scores from a network meta-analysis. The Committee noted that taking EQ-5D data directly from the trials is in line with the NICE reference case and that there was no reason for moving away from this in this appraisal. The Committee concluded that including EQ-5D data directly from the trials was more appropriate.\n\nThe Committee noted that the Assessment Group presented results based on whether it used EQ-5D data from the FREE trial, the Buchbinder trial or the INVEST trial. For the Buchbinder and INVEST trials, the Assessment Group presented results in which it assumed that the pain in people who had had an intervention declines to a level equal to that in people who had not had an intervention by 12 to 24\xa0months or, alternatively, by 24 to 36\xa0months after the procedure. The Committee agreed that it was not possible to choose only 1 of the trials as a source for the EQ-5D values, but that assuming a later convergence of pain scores, that is between 24 and 36\xa0months, was more plausible.\n\nThe Committee discussed the ICERs for the scenarios in which kyphoplasty was assumed to prolong life more than vertebroplasty, while also considering the scenario in which kyphoplasty and vertebroplasty prolong life equally, using EQ-5D data included directly from trials and assuming a later convergence of pain scores (see sections 4.3.5, 4.3.8 and 4.3.9). The Committee acknowledged that, in both scenarios related to mortality, operative placebo with injection of local anaesthesia was extendedly dominated or dominated by vertebroplasty and kyphoplasty, and that the ICER for vertebroplasty compared with optimal pain management was below £7000 per QALY gained. When kyphoplasty was assumed to prolong life more than vertebroplasty, the ICER for kyphoplasty compared with vertebroplasty was below £8000 per QALY gained. When kyphoplasty and vertebroplasty were assumed to have the same mortality benefit, kyphoplasty was dominated by vertebroplasty. The Committee noted that the sensitivity analyses carried out by the Assessment Group, which included alternative assumptions on hospitalisation costs, costs of operative placebo and adverse events, changed the results as follows: when kyphoplasty was assumed to prolong life more than vertebroplasty, vertebroplasty was extendedly dominated, and the ICER for kyphoplasty compared with vertebroplasty was below £11,000 per QALY gained; and when kyphoplasty and vertebroplasty were assumed to have the same mortality benefit, the ICER for vertebroplasty was under £10,000 per QALY gained. The Committee concluded that the relative mortality benefits of kyphoplasty and vertebroplasty lie somewhere in between the 2\xa0scenarios modelled by the Assessment Group. The Committee concluded that the ICERs established for both kyphoplasty and vertebroplasty were generally at the lower end of what is usually considered to be a cost-effective use of NHS resources.\n\nThe Committee noted that the Assessment Group had based the cost of vertebroplasty on the assumption that low-viscosity cement would be used in most procedures, allowing for high-viscosity cement to be used in 15% of procedures. The Committee noted that this assumption halved the cost of vertebroplasty from £1546 to £800 for 85% of procedures, as assumed in the model. The Committee heard that high-viscosity cements are being used increasingly in clinical practice based on concerns around cement leakage with low-viscosity cements, but that clinicians still use low-viscosity cements. The Committee considered that vertebroplasty would no longer be cost effective if high-viscosity cements were used in all vertebroplasty procedures. However, given that new methods are emerging to control leakage associated with use of low-viscosity cements, the Committee considered it unlikely that high-viscosity cements would be used in most vertebroplasty procedures. The Committee therefore based its recommendation on the assumption that clinicians would use low-viscosity cement in most procedures.\n\nThe Committee discussed whether kyphoplasty and vertebroplasty could be considered cost effective, given the uncertainty around their relative mortality benefits. The Committee noted that the ICERs presented by the Assessment Group were at the lower end of the range usually considered a cost-effective use of NHS resources, assuming that clinicians would use low-viscosity cements in most of the procedures, and discussed the debilitating impact that osteoporotic vertebral compression fractures have on people's physical and emotional wellbeing. On balance, the Committee concluded that both vertebroplasty and kyphoplasty could be considered a cost-effective use of NHS resources and should be recommended as options for treating osteoporotic vertebral compression fractures in people who have severe ongoing pain after a recent, unhealed vertebral fracture, despite optimal pain management, and in whom the pain has been confirmed to be at the level of the fracture by physical examination and imaging.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA279\n\nAppraisal title:\n\nSection\n\nKey conclusion\n\nPercutaneous vertebroplasty, and percutaneous balloon kyphoplasty without stenting, are recommended as options for treating osteoporotic vertebral compression fractures only in people:\n\n\n\nwho have severe ongoing pain after a recent, unhealed vertebral fracture despite optimal pain management and\n\nin whom the pain has been confirmed to be at the level of the fracture by physical examination and imaging.\n\n\n\nThe Committee concluded that the ICERs established for both kyphoplasty and vertebroplasty were generally at the lower end of what is usually considered to be cost effective, assuming that low-viscosity cements would be used in most of the procedures.\n\n\n\n\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee acknowledged the debilitating impact that osteoporotic vertebral compression fractures have on patients' physical and emotional wellbeing.\n\n\n\nThe Committee heard that, initially, clinicians treat patients with optimal pain management including analgesics, particularly opioids and non‑steroidal anti‑inflammatory drugs, which are associated with considerable side effects in the older population.\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nVertebroplasty and kyphoplasty aim to relieve pain in people with painful fractures and to strengthen the bone to prevent future fractures. In addition, kyphoplasty aims to reduce curvature of the spine.\n\nNo specific claim of innovation was made.\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee concluded that vertebroplasty and kyphoplasty can be considered appropriate interventions for people with recent, unhealed osteoporotic vertebral compression fractures in whom the pain is severe and ongoing despite optimal pain management, and has been confirmed to be at the level of the fracture by physical examination and magnetic resonance imaging. The Committee considered that the appropriate timing in relation to the age of the fracture could be left for clinicians to judge.\n\n\n\n\n\nAdverse reactions\n\nAdverse reactions from vertebroplasty and kyphoplasty relate primarily to cement leakage, particularly for vertebroplasty. The Committee concluded that cement leakage associated with vertebroplasty and kyphoplasty was manageable if a skilled clinician with specialised training in these procedures performs the operation.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Assessment Group identified 9\xa0relevant randomised controlled trials, of which only the Buchbinder and INVEST studies, comparing vertebroplasty with an operative placebo that included local anaesthetic, were double blind.\n\nFive open-label trials (Farrokhi, VERTOS, VERTOS II, Blasco, Rousing) compared vertebroplasty with optimal pain management. One open-label trial (FREE) compared kyphoplasty with optimal pain management and another open-label study (Liu) compared vertebroplasty with kyphoplasty.\n\n\n\n\n\n\n\nMortality data available from a large study based on US Medicare registry data, which followed patients for up to 4\xa0years, reported a statistically significant mortality benefit with narrow confidence intervals, with both vertebroplasty and kyphoplasty compared with optimal pain management. These results were substantiated by an additional year of follow‑up from the Medicare registry, as well as by mortality data from a smaller German study.\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard from the clinical specialists that vertebroplasty and kyphoplasty are performed by radiologists, anaesthetists or orthopaedic surgeons, some based in pain clinics, and they work with metabolic bone specialists to assess the need for intervention.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee was aware that that the results from the blinded trials differed from the results available from open-label studies comparing vertebroplasty or kyphoplasty with optimal pain management. The Committee considered that the open-label trials better reflected 'real life' and included the comparator that would be used in clinical practice. The clinical specialists stated that, although results from the 2 double‑blind trials had raised questions about the value of vertebroplasty and kyphoplasty, in clinical experience, both procedures improved pain and quality of life in people with severe symptoms. The Committee concluded that it could not disregard the results from the open-label trials.\n\n\n\nThe Committee noted that the Assessment Group pooled data on mortality at 12\xa0months from 3\xa0trials and found no statistically significant differences between vertebroplasty and optimal pain management, but was aware that the studies were not designed to show a difference in mortality. However, the Committee noted that the point estimate for the mortality benefit was consistent with that estimated from 2 large-scale epidemiological studies.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo trial data were identified for patients with or without fracture-related vertebral deformity, or for inpatients at the time of randomisation.\n\n\n\nThe clinical specialists stated that it was likely that patients at high risk of future fractures might be even more likely to benefit, but that clinicians find it difficult to identify these patients among all patients with vertebral fractures.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee was persuaded that there was sufficient evidence to conclude that vertebroplasty and kyphoplasty are more effective in reducing pain and restoring vertebral body height than optimal pain management in people with recent, painful, unhealed osteoporotic vertebral compression fractures.\n\n\n\nThe Committee concluded that it was reasonable to assume that both vertebroplasty and kyphoplasty prolong life compared with optimal pain management, but that the precise magnitude of such a benefit in clinical practice in the NHS was uncertain.\n\n\n\nThe Committee considered that it was plausible that kyphoplasty is associated with a greater mortality benefit than vertebroplasty, but the Committee also considered the possibility that kyphoplasty and vertebroplasty had the same degree of mortality benefit. The Committee concluded that the mortality benefits of kyphoplasty and vertebroplasty were somewhere in between the 2\xa0scenarios.\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nMedtronic submitted a Markov tunnel model adapted from the Strom model to determine the cost effectiveness of kyphoplasty, vertebroplasty and optimal pain management in patients hospitalised with vertebral compression fractures.\n\n\n\nJohnson and Johnson developed a 1‑year treatment-state model aiming to determine the cost effectiveness of vertebroplasty, kyphoplasty, optimal pain management and operative placebo with local anaesthesia using a scenario analysis.\n\n\n\nThe Assessment Group's model was designed to determine the cost effectiveness of vertebroplasty, kyphoplasty, optimal pain management and operative placebo with local anaesthesia.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Assessment Group presented 6\xa0scenarios rather than a base case. Given the uncertainty around whether vertebroplasty or kyphoplasty prolonged life, it organised results into 3\xa0categories based on whether:\n\nkyphoplasty prolongs life more than vertebroplasty, which prolongs life more than optimal pain management\n\nvertebroplasty and kyphoplasty prolong life more than optimal pain management and\n\nvertebroplasty and kyphoplasty do not prolong life more than optimal pain management.\n\nThe Assessment Group presented results that differed based on whether it took EQ-5D directly from the trials or mapped stable VAS scores to EQ-5D. The Committee considered the scenario in which kyphoplasty was assumed to prolong life more than vertebroplasty, while also considering the scenario in which kyphoplasty and vertebroplasty prolong life equally, using EQ-5D data included directly from trials and assuming a later convergence of pain scores.\n\n\n\nThe Assessment Group had calculated the cost of vertebroplasty in the model assuming that low-viscosity cements would be used in most procedures; this significantly reduced the cost of 85% of procedures in the model. Although high-viscosity cements are being used increasingly in clinical practice because of concerns around cement leakage with low-viscosity cements, the Committee considered it unlikely that high-viscosity cements would be used in most vertebroplasty procedures. The Committee therefore based its recommendation on the Assessment Group's assumption that clinicians would use low-viscosity cement in most procedures.\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee concluded that including EQ-5D data directly from the trials was appropriate.\n\nThe Committee identified no health-related benefits that were excluded from the economic model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nSee section on subgroups above.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nAssumptions about mortality benefits associated with vertebroplasty and kyphoplasty.\n\n\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee acknowledged that the results were extremely sensitive to the mortality benefit assumptions. The Committee concluded that the ICERs established for both kyphoplasty and vertebroplasty were generally at the lower end of what is usually considered to be cost effective.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable\n\n\n\nEnd-of-life considerations\n\nNot applicable\n\n\n\nEqualities considerations and social value judgements\n\nPotential equality issues raised during the appraisal were outside the remit of NICE technology appraisal guidance or not considered equality issues relevant for the Committee to discuss. No equality issues relevant to the Committees recommendations were raised.\n\n", 'Related NICE guidance': 'Balloon kyphoplasty for vertebral compression fractures. NICE interventional procedure guidance\xa0166 (2006).\n\nPercutaneous vertebroplasty. NICE interventional procedure guidance\xa012 (2003).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in November\xa02015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveApril 2013', 'Changes after publication': 'January 2014:\n minor maintenance.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt has been incorporated into the NICE pathway on osteoporosis along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-0114-2'}	https://www.nice.org.uk/guidance/ta279	Evidence-based recommendations on percutaneous vertebroplasty and percutaneous balloon kyphoplasty for treating osteoporotic vertebral compression fractures in adults.
3ac25da7b0d188789635e148b7cf4732d63c86aa	nice	Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis	Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis Evidence-based recommendations on colistimethate sodium (Colobreathe) and tobramycin (TOBI Podhaler) dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis in people of 6 years and over. # Guidance Tobramycin dry powder for inhalation (DPI) is recommended as an option for treating chronic pulmonary infection caused by Pseudomonas aeruginosa in people with cystic fibrosis only if: nebulised tobramycin is considered an appropriate treatment, that is, when colistimethate sodium is contraindicated, is not tolerated or has not produced an adequate clinical response and the manufacturer provides tobramycin DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS. Colistimethate sodium DPI is recommended as an option for treating chronic pulmonary infection caused by P. aeruginosa in people with cystic fibrosis only if: they would clinically benefit from continued colistimethate sodium but do not tolerate it in its nebulised form and thus tobramycin therapy would otherwise be considered and the manufacturer provides colistimethate sodium DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS. People currently using tobramycin DPI or colistimethate sodium DPI that is not recommended according to 1.1 or 1.2 should be able to continue treatment until they and their clinician consider it appropriate to stop. For children and young people this decision should be made jointly by the clinician, the child or young person and their parents or carers.# Clinical need and practice Cystic fibrosis is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is characterised by abnormal transport of chloride and sodium across transporting epithelia, leading to thick viscous secretions in the lungs, pancreas, liver, intestine and reproductive tract and to an increased salt content in sweat gland secretions. People with cystic fibrosis have problems with their respiratory system and digestion, including prolonged diarrhoea that can affect growth and body mass index. They are prone to lung infections by a range of pathogens including Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa and Burkholderia cepacia. This is thought to be because the thick mucus makes it difficult for the body to clear inhaled bacteria, and because people with cystic fibrosis have an increased airway inflammatory response to pathogens. Chronic inflammation and progressive lung destruction from chronic infection can lead to bronchiectasis, altered pulmonary function and respiratory failure. Cystic fibrosis affects over 8500 children and young adults in the UK and has an incidence of 1 in 2500 live births. About 1 in 25 people in the UK of white European origin are carriers of an affected CFTR gene. It is much less common in people of African-Caribbean and Asian origin. Cystic fibrosis is a progressive condition that reduces life expectancy. In 2010, the cystic fibrosis registry recorded 103 deaths in UK patients; the median age at death was 29 years. However, prognosis is improving with the treatments now available and around half of the current cystic fibrosis population are expected to have a life expectancy of over 38 years. Management of the pulmonary component of cystic fibrosis includes a range of measures to aid clearance of respiratory secretions and to decrease inflammation and bacterial growth in the respiratory tract, such as chest physiotherapy, inhaled bronchodilators, inhaled mucolytics (such as rhDNase and hypertonic saline) and antibiotic treatment. The aim of treatment is to delay or slow deterioration in lung function, measured by forced expiratory volume in 1 second (FEV1). Ultimately, patients may become eligible for lung transplantation. The care of most patients in the UK is coordinated by a tertiary cystic fibrosis centre with formal shared care with local clinics. Cystic fibrosis treatment can be time-consuming for the patient, with administration of nebulised antibiotics taking up to an hour each day during good health and longer during periods of ill health. The disease also impacts upon carers and needs a considerable commitment of healthcare resources. P. aeruginosa is the most frequent cause of lung infection in people with cystic fibrosis; around 38% of UK patients had a chronic pseudomonas infection in 2010. If recurrent intermittent infections are not controlled, chronic infection can develop in which bacterial microenvironments known as biofilms are formed that are difficult for immune cells and antibiotics to penetrate. The length and quality of life of people with cystic fibrosis are thought to be strongly influenced by the degree to which P. aeruginosa can be eradicated; however, chronic P. aeruginosa infection is rarely completely eradicated. Management of P. aeruginosa lung infection in cystic fibrosis involves treatment with antibiotics, which may be given in hospital, at home or in a combination of these settings. The aims of antibiotic treatment are three-fold: firstly to eradicate intermittent acute P. aeruginosa lung infections; secondly to suppress P. aeruginosa (with long-term treatment) in patients who have become chronically infected; and thirdly to treat acute exacerbations in patients chronically infected with P. aeruginosa. Treatment also aims to maintain lung function and quality of life. Current treatment options include the use of inhaled antibiotics effective against P. aeruginosa (such as nebulised colistimethate sodium or tobramycin) and oral or intravenous antibiotics to eradicate initial or intermittent P. aeruginosa colonisation or acute exacerbations of chronic infection. Azithromycin may be given in combination with these antibiotics to act on the biofilms.# The technologies # Colistimethate sodium DPI Colistimethate sodium DPI (Colobreathe, Forest Laboratories UK ) is a formulation of colistimethate sodium supplied as hard capsules for use with an inhaler. It belongs to the polymixin class of antibacterials and works by disrupting the structure of the bacterial cell membrane, leading to bacterial death. It is active against aerobic gram-negative organisms including P. aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Colistimethate sodium DPI is indicated for the management of chronic pulmonary infections caused by P. aeruginosa in patients with cystic fibrosis aged 6 years and older. The summary of product characteristics lists the following adverse reactions for colistimethate sodium DPI: respiratory disorders (such as dyspnoea, cough and wheezing), ear and labyrinth disorders, thoracic and gastrointestinal disorders, musculoskeletal, connective tissue and bone disorders, general disorders and administration site conditions, and renal and urinary disorders. For full details of adverse reactions and contraindications, see the summary of product characteristics. The recommended dosage for colistimethate sodium DPI is 1 capsule (approximately equal to 125 mg of colistimethate sodium) to be inhaled twice daily using the 'Turbospin' inhaler device (PH&T Pharma) which is a breath-activated, reusable dry powder inhaler. The price for a 28-day pack including 1 Turbospin inhaler is £968 (excluding VAT; price provided by the manufacturer). The list price cost for 56 days of treatment is therefore £1936 excluding VAT. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of colistimethate sodium DPI has agreed a patient access scheme with the Department of Health which makes colistimethate sodium DPI available with a discount applied to all invoices. The size of the discount is commercial in confidence (see section 5.4). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. # Tobramycin DPI Tobramycin DPI (TOBI Podhaler, Novartis) is a formulation of tobramycin supplied as hard capsules for use with an inhaler. It is an aminoglycoside antibiotic that acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope and eventual cell death. Tobramycin inhibits protein synthesis of many gram-negative bacteria and it is active against P. aeruginosa. Tobramycin DPI is indicated for the suppressive treatment of chronic pulmonary infection caused by P. aeruginosa in adults and children aged 6 years and older with cystic fibrosis. The summary of product characteristics lists the following adverse reactions for tobramycin DPI: respiratory, thoracic and mediastinal disorders (such as dyspnoea, productive cough and wheezing), ear and labyrinth disorders, vascular disorders, gastrointestinal disorders, skin and subcutaneous tissue disorders, musculoskeletal, connective tissue and bone disorders, general disorders, and administration site conditions. For full details of adverse reactions and contraindications, see the summary of product characteristics. The recommended dosage for tobramycin DPI is 112 mg tobramycin (4×28-mg capsules), administered twice daily for 28 days using the Podhaler device in alternating cycles of 28 days on treatment followed by 28 days off treatment. The price for a pack of 56×28-mg capsules and 1 Podhaler device is £447.50 (excluding VAT; 'British national formulary' edition 64). The list price cost for 56 days of treatment is therefore £1790 excluding VAT. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of tobramycin DPI (Novartis) has agreed a patient access scheme with the Department of Health which makes tobramycin DPI available with a discount applied to all invoices. The size of the discount is commercial in confidence (see section 5.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). # Clinical effectiveness The Assessment Group identified 3 open-label, multicentre randomised controlled trials in people with cystic fibrosis and chronic P. aeruginosa lung infection for the technologies: 2 for colistimethate sodium DPI (COLO/DPI/02/05 and COLO/DPI/02/06) and 1 for tobramycin DPI (EAGER). The manufacturer of tobramycin DPI included details of 2 randomised controlled trials in their submission: EVOLVE and EAGER. The Assessment Group did not include the EVOLVE trial in its review because the comparator was placebo, which was not in line with the scope provided by NICE. ## Colistimethate sodium DPI COLO/DPI/02/05 was a crossover trial comparing the safety of colistimethate sodium DPI and colistimethate sodium nebuliser solution in children and adults. The trial was carried out at 3 centres in the UK, and the population consisted of 16 people of whom 37.5% were younger than 13 years. The trial compared 1 capsule of colistimethate sodium DPI given twice daily for 4 weeks with 2 million units of colistimethate sodium nebuliser solution given twice daily for 4 weeks. The primary objective was to assess the safety (clinical tolerability and laboratory safety) of 4 weeks' treatment with colistimethate sodium DPI compared with 4 weeks' treatment with nebulised colistimethate sodium. All patients (n=16) receiving the DPI reported treatment-emergent adverse events compared with 9 out of 15 patients (60.0%) receiving the nebuliser solution. The most common treatment-related adverse events were gastrointestinal disorders (87.5% of patients) followed by cough and throat irritation (both in 81.3% of patients) in the DPI group, and cough (46.7% of patients) followed by wheezing (33.3% of patients) in the nebuliser solution group. COLO/DPI/02/06 compared twice-daily doses of 125 mg colistimethate sodium DPI administered by a Turbospin device with twice-daily doses of 300 mg tobramycin nebuliser solution for nebuliser inhalation for 24 weeks. The trial was of a non-inferiority design, that is, it was intended to show that the effect of colistimethate sodium DPI was not statistically significantly worse than that of nebulised tobramycin. It was carried out in 66 centres in the European Union, Russia and the Ukraine. It included 373 people aged 6 to 56 years (mean age 21 years, standard deviation =9.49) with cystic fibrosis who had chronic pseudomonas lung infection (2 or more positive cultures in the previous 6 months) that would normally be treated with inhaled antibiotics. Other inclusion criteria were an FEV1% of between 25 and 75% of predicted and use of tobramycin nebuliser solution for inhalation (a minimum of 2 on/off cycles) before randomisation. The primary end point of the trial was the mean change in FEV1% predicted after 24 weeks of treatment. The trial was powered to detect non-inferiority, that is, a mean change in FEV1% from baseline to week 24 of no less than –3% at the lower end of the two-sided 95% confidence interval (CI) between treatment groups. Secondary outcomes included frequency of and time to exacerbations, adverse events, quality of life and physical changes. Three analyses were performed on the primary efficacy outcome: analysis of co-variance (ANCOVA), log-transformed analysis, and non-parametric analysis. Each of these 3 analyses were performed on 2 populations, the intention to treat (ITT) population (all randomised patients who received at least 1 dose of a study drug) and the per-protocol (PP) population (all randomised patients who received at least 1 dose of the study drug and who could be classified as 'efficacy evaluable'). For each population 2 sets of data were used, one where missing values were replaced using the last observation carried forward (LOCF) method and the other consisting of completers, creating in total 12 sets of results. The manufacturer stated that the primary efficacy analysis was done using LOCF data but that both ITT and PP populations were of equal importance for demonstrating non-inferiority. For the primary end point of mean difference in change in FEV1% predicted after 24 weeks of treatment, the result from the ANCOVA analysis on the ITT population using LOCF data was −1.16% (95% CI −3.15% to 0.84%) suggesting that colistimethate sodium DPI was marginally less efficacious than tobramycin nebuliser solution (because the non-inferiority criterion was not met). The results of the log-transformed and non-parametric ITT population LOCF data analyses were –0.98% (95% CI −2.74% to 0.86%) and −0.56% (95% CI −2.16% to 1.00%) respectively, suggesting in both cases that colistimethate sodium DPI was non-inferior to nebulised tobramycin. For the PP population the ANCOVA, log-transformed and non-parametric analyses using LOCF data indicated that the non-inferiority hypothesis was satisfied for non-parametric analysis only (ANCOVA −1.49% , log-transformed −1.10% and non-parametric −0.67% ). Results for the secondary outcomes reported for the COLO/DPI/02/06 trial indicated that the proportion of people experiencing at least 1 protocol-defined acute exacerbation (at least 4 symptoms of worsening lung function) was higher in the colistimethate sodium DPI group than in the nebulised tobramycin group (31.1% versus 26.1%). The mean time to acute respiratory exacerbation was longer among the colistimethate sodium DPI group than the nebulised tobramycin group (63.7 days compared with 59.4 days). The mean duration of antibiotic administration for acute exacerbations was slightly less for colistimethate sodium DPI than for nebulised tobramycin (13.6 days compared with 14.4 days). Adverse events were more common in the colistimethate sodium DPI group (93.6% of patients) than in the nebulised tobramycin group (89.1% of patients). A total of 27 patients (22/187 patients in the DPI group and 5/193 patients in the nebulised group) were withdrawn from the COLO/DPI/02/06 trial because of an adverse event. Adverse events that appeared to be worse in the colistimethate sodium DPI group compared with the nebulised tobramycin group were cough, throat irritation and dysgeusia. Fewer patients adhered to medication in the colistimethate sodium DPI group than in the nebulised tobramycin group (67% compared with 70% respectively adhered to over 75% of doses). The Assessment Group noted that throughout the 24 weeks, resistance to colistimethate sodium remained low (less than or equal to 1.1%) and resistance to tobramycin at 8 mg/litre breakpoint did not change significantly from baseline during the study. Quality-of-life data using a preference-based measure in line with the NICE reference case were not collected in the COLO/DPI/02/06 trial. Health-related quality of life was evaluated in the trial by the Cystic Fibrosis Questionnaire Revised (CFQ-R) (a disease-specific instrument designed to measure impact on overall health, daily life, perceived wellbeing and symptoms) at several time points. No statistically significant differences in quality of life between baseline and week 24 were seen between the colistimethate sodium DPI and tobramycin nebuliser solution groups. At week 24, quality-of-life assessments were in favour of colistimethate sodium DPI in most CFQ-R domains in the ITT population, but none reached statistical significance. ## Tobramycin DPI The EAGER trial was designed as a non-inferiority trial in which twice-daily doses of 112 mg tobramycin DPI administered via a Podhaler device were compared with twice-daily doses of 300 mg nebulised tobramycin for 24 weeks. The study was powered to detect non-inferiority at a margin of no less than 6% of the lower one-sided 85% confidence limit of the mean difference in relative change in FEV1% between the treatment groups at 20 weeks. The study (n=533) included people aged 6 years or above (DPI group mean age 26 years , nebulised group mean 25 years ) with cystic fibrosis who had chronic pseudomonas lung infection (defined as a positive culture within 6 months of screening and at baseline) and whose FEV1% was between 25 and 75%. Of the study population, 55% were male. The primary end point was the incidence of adverse events; however the trial was powered to detect change in FEV1% predicted from baseline to week 20. Other outcomes included microbiological measures (such as bacterial susceptibility), body mass index changes and laboratory safety end points. The ITT EAGER results were based on complete case analysis and did not incorporate imputation (that is, filling in missing data with possible plausible values). Results indicated that tobramycin DPI was associated with an improved mean FEV1% predicted compared with nebulised tobramycin at 20 weeks of +0.59% (standard error 0.92). The manufacturer reported non-inferiority (supported by least squares mean difference relative change of 1.1% which has a lower limit of the one-sided 85% confidence interval within the predicted 6% margin for non-inferiority). Only limited data were presented for lung function at 24 weeks and the Assessment Group noted that they would expect FEV1% levels to be lower at that stage (following a month without tobramycin). The Assessment Group calculated the mean FEV1% at 24 weeks to be 53.9% for the DPI group and 50.7% for the nebulised tobramycin group indicating a reduction in lung function from 20-week values (55.97% and 55.28% ). In the EAGER trial, pseudomonal resistance (8 mg/litre breakpoint) to tobramycin started at around 20% (the baseline value was at the end of 28 days off previous treatment) and was lower at 24 weeks in both groups (also at the end of 28 days off treatment). P. aeruginosa sputum density data showed a reduction from baseline to week 20 in the tobramycin DPI group (−1.61 log colony-forming units) compared with the nebulised group (−0.77 log colony-forming units). The manufacturer did not provide details on all exacerbations from the EAGER trial; however the measure of lung disorder was used by the Assessment Group as a proxy to give an indication as to the number of participants experiencing an exacerbation. The percentage of patients experiencing lung disorders was greater in the tobramycin DPI group (33.8%) than in the nebulised tobramycin group (30.1%). However, no information was provided on the number of events experienced by patients and therefore it is not known whether some trial participants experienced multiple events. Additionally no information was provided on the time to exacerbation. Mean duration of anti-pseudomonal antibiotic treatment was also slightly shorter in the tobramycin DPI group than in the nebulised tobramycin group (30.9 days compared with 33.4 days). The number of trial participants receiving additional anti-pseudomonal treatments was higher in the tobramycin DPI group. The rate of discontinuation of treatment was higher in the tobramycin DPI group than in the nebulised tobramycin group (83/308 patients compared with 38/309 patients ). Adverse events were more common in the tobramycin DPI group (90.3% of patients) than in the nebulised tobramycin group (84.2% of patients). A total of 57 patients (40 in the DPI group and 17 in the nebulised group) were withdrawn from the EAGER trial because of an adverse event. The most common adverse event in the 2 groups was cough (48.4% in the DPI group and 31.1% in the nebulised group). Adverse events that appeared to be worse in the tobramycin DPI group than in the nebulised group included cough and dysphonia. The EAGER trial did not define the assessment of adherence but stated that it was 'generally high' with over 90% adherence in both groups. Quality-of-life data using a preference-based measure in line with the NICE reference case were not collected in the EAGER trial. The manufacturer reported data from a treatment satisfaction questionnaire for medication results that showed higher values in the tobramycin DPI group than in the nebulised group. Least squares mean difference averages indicated an improvement over visits for effectiveness (9.36 ), for side effects (−0.5 ), for convenience (24.35 ) and for global satisfaction (5.20 ) for tobramycin DPI compared with nebulised tobramycin. The Assessment Group commented that the quality of the included studies for both colistimethate sodium DPI and tobramycin DPI was generally poor to moderate. None of the included trials scored well on all risk of bias items, particularly on the issues of blinding and non-adherence to the current European Medicines Agency (EMA) research guidelines. The Assessment Group judged that this could lead to selection and reporting bias for subjective outcomes such as adverse events, inaccuracies and imprecision in the results, and might limit the generalisability of the studies. The Assessment Group judged that follow-up was not long enough to detect slowing of the rate of decline in respiratory function, according to current EMA research guidelines, nor for any assessment of mortality. The Assessment Group also highlighted that because FEV1% is a surrogate outcome, the EMA recommend that it should be considered alongside microbiological outcomes and 'harder' clinically relevant outcomes such as frequency of exacerbations and antibiotic use. Both tobramycin DPI and colistimethate sodium DPI seemed to result in more exacerbations and more people experiencing exacerbations than nebulised tobramycin, but slightly less time on antibiotics. The incidence of adverse events was similar between groups within the trials except for cough, which had a higher incidence in both DPI groups. More patients in the DPI groups withdrew because of adverse events in both EAGER and COLO/DPI/02/06. The Assessment Group judged that it was not possible to determine whether the changes seen in the colistimethate sodium DPI group were significantly different to the changes seen in the tobramycin DPI group because of different trial designs, a lack of data at 24 weeks, different population analyses of results and uncertain comparability of patient characteristics at baseline. The Assessment Group was unable to draw definite conclusions as to the relative efficacy of any intervention except where there was direct evidence for the dry powder formulations compared with nebulised tobramycin. ## Mixed treatment comparison (tobramycin DPI) The manufacturer of tobramycin DPI performed a literature review followed by a network meta-analysis using data from 7 studies to assess the clinical effectiveness of tobramycin DPI given by Podhaler relative to TOBI (tobramycin nebuliser solution), Bramitob (tobramycin nebuliser solution made by a different manufacturer), nebulised colistimethate sodium, aztreonam nebuliser solution and placebo. Colistimethate sodium DPI was not included in the analysis because study results for this technology were not in the public domain. The manufacturer explained that in the network meta-analysis there were underlying differences in the included trials in terms of trial populations, outcomes used and study design. The Assessment Group did not carry out an evaluation or provide specific comments on the manufacturer's network meta-analysis because it judged that given the available evidence, such an analysis was not feasible. The results of the network meta-analysis found no statistically significant differences between comparators in terms of efficacy at 4 weeks (measured by FEV1% predicted). # Cost effectiveness The cost-effectiveness evidence consisted of: a model by the manufacturer (Forest) for colistimethate sodium DPI; an analysis of the manufacturer's model by the Assessment Group; a de novo model produced by the Assessment Group; and Assessment Group economic analyses in response to the original and revised patient access schemes submitted by the manufacturer of colistimethate sodium DPI and the patient access scheme submitted by the manufacturer of tobramycin DPI. The manufacturer of tobramycin DPI proposed that a cost-minimisation analysis should be undertaken, because their network meta-analysis had found that the included anti-pseudomonal treatments had similar efficacy. The Assessment Group performed a systematic review of published literature and identified 3 economic evaluations: a cost–consequence analysis of home intravenous treatment in people with cystic fibrosis (Wolter et al. 1997); a cost-effectiveness analysis comparing hospital and home care in people with cystic fibrosis (Thornton et al. 2005); and a cost–consequence analysis of inhaled tobramycin nebuliser solution in people with cystic fibrosis (Iles et al. 2003). None of these 3 studies relate to either colistimethate sodium DPI or tobramycin DPI. The Assessment Group judged that these studies provided some information about the costs and outcomes of the comparator therapies and explained some of the key methodological problems surrounding the economic evaluation of treatments for cystic fibrosis, for example, short-term lung function improvements rather than quality-adjusted life year (QALY) gains. ## Manufacturer's model on the cost effectiveness of colistimethate sodium DPI Forest used a cohort-based decision analysis to compare colistimethate sodium DPI with nebulised tobramycin. The population modelled were people aged 6 years or older with documented cystic fibrosis who had chronic pseudomonas lung infection (the same population as the COLO/DPI/02/06 trial). The model had a 24-week time horizon and took a UK NHS perspective. The main assumptions of the model were that FEV1% determines year 1 or 2 mortality risk, utility is fixed at 0.68, there is no reduction in quality of life during an exacerbation or for an adverse event and all patients have a fixed maximum life expectancy of 37.4 years. The COLO/DPI/02/06 trial did not collect health-related quality-of-life data using a preference-based instrument. Utility estimates in the manufacturer's model were obtained from the CFQ used in the COLO/DPI/02/06 study, mapped to EQ-5D tariff values using regression equations with coefficients derived from patient-level data from a published study in people with cystic fibrosis (Eidt-Koch et al. 2009). In this study, data were collected in 2006 across 4 cystic fibrosis centres in Germany. A cohort of 96 patients with cystic fibrosis completed both the German version of the CFQ and the EQ-5D-Y. Patients included in this study were generally young (the mean age was approximately 13 years, range 8 to 17 years) and mean FEV1% predicted was generally high in both the child and adolescent groups (93.6% and 90.7% respectively).The responses to the EQ-5D-Y were valued using the EQ-5D tariff. This mapping exercise produced a single utility value of 0.68 for people with cystic fibrosis with chronic P. aeruginosa lung infection. Costs and QALYs based on treatment, life expectancy and exacerbations were then estimated by a cohort-based decision analysis incorporating an estimated mortality risk and this single utility value of 0.68 for people with cystic fibrosis. Predicted mortality differences between colistimethate sodium DPI and nebulised tobramycin were estimated by regression equations for mortality at 1 and 2 years using reported data from a retrospective analysis of the risk of mortality by Kerem et al. (1992). This study used the patient characteristics of FEV1% predicted, forced vital capacity, partial pressures of oxygen and carbon dioxide, sex, weight and height to predict mortality at 1 and 2 years. The manufacturer fitted several polynomial regression equations to the Kerem et al. data for mortality risk at 1 or 2 years by FEV1% group. The manufacturer then applied the best fit regression equation to patient-level data from COLO/DPI/02/06 to calculate the 1- and 2-year mortality risks for the intervention and comparator groups based on FEV1% predicted only. The manufacturer's model included costs for acquisition of medication and costs associated with exacerbations. Acquisition costs for nebulised tobramycin were taken from BNF edition 61. The model assumed a cost per dose of tobramycin of £21.20 (annual cost of £7738, excluding VAT), corresponding to a regimen in which 2 doses of nebulised tobramycin are used each day, and each 28-day treatment period is followed by 28 days without nebulised tobramycin. The manufacturer's economic analysis priced colistimethate sodium DPI at parity with nebulised tobramycin. Exacerbations were costed from NHS reference costs but as there were no reference costs for cystic fibrosis exacerbations, the reference cost for an asthma admission with major comorbidities and/or complications without intubation was used. The numbers of exacerbations for people receiving colistimethate sodium DPI and nebulised tobramycin were calculated from patient-level data in the pivotal COLO/DPI/02/06 trial. The manufacturer reported results in terms of incremental net benefit with the results indicating that colistimethate sodium DPI dominated nebulised tobramycin, that is, it was more effective and cost less than nebulised tobramycin. ## Assessment Group's analysis of the Forest model The Assessment Group highlighted that there were limitations with the manufacturer's model and that it deviated from the NICE reference case in many ways: no discounting was carried out for costs because of the short time horizon; there were inconsistent time horizons for costs and health outcomes; results were presented as an incremental net benefit rather than an incremental cost per QALY gained; and no probabilistic sensitivity analysis was carried out. The Assessment Group also highlighted that the short study duration of the COLO/DPI/02/06 trial meant a high degree of censoring of mortality estimates. The Assessment Group also expressed substantial concerns in relation to the model using changes in FEV1% predicted measured in the short term to predict long-term mortality benefits. The Assessment Group highlighted the shortcomings of using particular sources of evidence (Kerem et al.) to derive survival estimates, the fixed life expectancy of 37.4 years used in the model, the use of the particular mapping method to produce utility estimates, the potential biases in the modelling of exacerbation rates and omission of relevant costs and health impacts. The Assessment Group carried out a literature search and concluded that FEV1% alone is unlikely to represent a valid independent predictor of survival. It judged that the survival estimated in the manufacturer's model derived from the Kerem et al. data lacked validity because of the potential for confounding from other prognostic factors. The Assessment Group noted that the use of the regression equation to link mortality to lung function was unnecessary and unjustified because it should have been possible to directly apply the Kerem et al. mortality probabilities to the categorical FEV1% predicted bands from the COLO/DPI/02/06 trial. The Assessment Group carried out a re-analysis of the manufacturer's model to try and correct for some of the problems identified with the model. It acknowledged that it could not fully resolve the problems regarding the time horizon, the health impact of adverse events or the uncertainty surrounding the QALY benefits for colistimethate sodium DPI. The results of the revised analysis found that if colistimethate sodium DPI is priced lower than nebulised tobramycin it may dominate because of lower costs from avoided exacerbations and incremental QALY gains. If the price is higher than nebulised tobramycin, the incremental cost per QALY gained ranges from £42,872 to £485,550 depending on assumptions about time horizons and drug acquisition costs. ## Assessment Group de novo model The Assessment Group developed a de novo probabilistic state transition model to compare colistimethate sodium DPI with nebulised tobramycin in people with cystic fibrosis who had chronic P. aeruginosa lung infection. It did not initially include tobramycin DPI in the model because patient-level FEV1 data were not available from the manufacturer at the time the report was produced (this information was subsequently provided by the manufacturer when the patient access scheme for tobramycin DPI was considered) and information on the price of tobramycin DPI was not available until February 2012. Other comparator treatments listed in the scope were not included in the analysis because of lack of data. The model had a lifetime time horizon and a UK NHS perspective. The cycle length was 24 weeks and treatment duration was assumed to be equivalent between the competing treatments. The model assumed that treatments were administered in line with their marketing authorisation. Mean survival for patients in the model was estimated using data from Dodge et al. 2009. This study reported survival data up to the end of 2003 for all people with cystic fibrosis born in the UK between 1968 and 1992 collated by active enquiry of cystic fibrosis clinics and other hospital consultants. The model had 5 health states: FEV1 70–99%, FEV1 40–69%, FEV1 less than 40%, post lung transplant and death. The 24-week probabilities for transition between health states were based on patient-level data from the COL/DPI/02/06 trial. The Assessment Group judged that some people may switch between colistimethate sodium and tobramycin at some point in their lives. However, this feature was not included in the model because clinical-effectiveness data on the effect of treatment switching were not available. Different levels of health-related quality of life were assumed for each health state. Total QALYs were calculated as the total time in each health state weighted by the respective utility for that health state, less any QALY losses resulting from exacerbations. Utility estimates were obtained from the Bradley (2010) study. No mortality gain from improved FEV1% predicted was incorporated into the model. A further assumption was that there was no quality of life reduction with adverse events. Costs in each treatment group included drug acquisition costs and the costs of managing exacerbations (either in hospital or at home). Potential cost savings associated with reduced maintenance of nebulisers were also included in the economic analysis for the DPI group. Costs associated with follow-up and concomitant medications were assumed to be equivalent between treatment groups. The Assessment Group produced a set of analyses that included 5 different pricing scenarios for colistimethate sodium, because at that time the list price for colistimethate sodium DPI was not available. The results of these analyses were superseded by additional analyses which included the confirmed list price and the original and revised patient access schemes (see sections 4.2.15 to 4.2.19). The analyses resulted in an incremental QALY loss (0.13) over a patient's lifetime associated with colistimethate sodium DPI compared with nebulised tobramycin. If colistimethate sodium DPI is priced at £15.98 or above per dose, it is dominated by nebulised tobramycin. If colistimethate sodium DPI is priced at £10.60 per dose, the model suggests an incremental cost-effectiveness ratio (ICER) of £23,788 saved per QALY lost. However, the Assessment Group noted that this ICER lies in the south-west quadrant of the cost-effectiveness plane (that is, less effective and less expensive) and represents a QALY loss and cost savings for colistimethate sodium DPI compared with nebulised tobramycin. The Assessment Group stated that although there is considerable uncertainty surrounding the extrapolation of the COLO/DPI/02/06 trial data, the conclusions of the analysis appear robust. This is because the uncertainty imposed by long-term extrapolation of short-term results has little bearing on the model conclusions because colistimethate sodium DPI remains dominated if its price is set higher than nebulised tobramycin. The Assessment Group highlighted that the deterministic sensitivity analysis (performed on utilities, transition probabilities, utility decrement from exacerbation, cost of hospitalisation and point estimates for parameters) showed that the choice of utility value had the most substantial effect on the cost-effectiveness estimate. The Assessment Group also re-ran the model using a 24-week time horizon. The results indicated an expected tiny decrease (0.002) in QALYs for colistimethate sodium DPI compared with nebulised tobramycin. If priced at £9.11 per dose or £10.60 per dose, colistimethate sodium DPI is expected to be less expensive than nebulised tobramycin and results in ICERs of £276,814 and £49,596 saved per QALY lost respectively. As in the long-term model these positive ICERs are the result of cost savings and QALY reductions. If colistimethate sodium DPI is priced at £15.98 or above per dose, it is dominated by nebulised tobramycin, as in the long-term model. ## Colistimethate sodium DPI patient access schemes The Assessment Group also carried out additional analyses in response to the patient access schemes submitted by the manufacturers of colistimethate sodium (sections 4.2.15 to 4.2.19) and tobramycin DPI (sections 4.2.20 to 4.2.25). With regard to the original colistimethate sodium DPI scheme, only the price of colistimethate sodium DPI was amended; all other assumptions and parameters in the model remained unchanged (sections 4.2.10–4.2.12). The Assessment Group explained that when the list price was modelled (this having been finalised and provided at this stage), colistimethate sodium DPI was dominated by nebulised tobramycin. When the patient access scheme discount was incorporated, the results demonstrated that colistimethate sodium DPI was less effective and less expensive than nebulised tobramycin, the ICER being £52,672 saved per QALY lost. The Assessment Group also carried out a probabilistic sensitivity analysis. The probability of colistimethate sodium DPI (at list price) being more cost effective than nebulised tobramycin (at list price) at a threshold of £20,000 and £30,000 per QALY gained was zero. The results also suggested that when the original patient access scheme is included in the analysis, the probability of colistimethate sodium DPI being more cost effective than nebulised tobramycin is approximately 0.79 at a threshold of £20,000 saved per QALY lost, and 0.66 at a threshold of £30,000 saved per QALY lost. Additionally the Assessment Group carried out a sensitivity analysis using the Commercial Medicines Unit (CMU) Electronic Marketing Information Tool (E-MIT) price rather than the BNF list price for nebulised tobramycin. In September 2012, the estimated price for nebulised tobramycin paid by the NHS was £970.12 rather than the BNF list price of £1187. The results of this analysis suggest that on the basis of the original patient access scheme price for colistimethate sodium DPI and the CMU E-MIT price for nebulised tobramycin, colistimethate sodium DPI is dominated by nebulised tobramycin. The Assessment Group concluded that at its list price, colistimethate sodium DPI is expected to be dominated by nebulised tobramycin (at list price). When the original patient access scheme is included in the analysis, the incremental cost effectiveness of colistimethate sodium DPI compared with nebulised tobramycin (at list price) is expected be around £52,700 saved per QALY lost (that is, colistimethate sodium DPI is less effective but also less expensive than nebulised tobramycin). When the CMU E-MIT price of nebulised tobramycin is compared with both list and original patient access scheme prices of colistimethate sodium DPI, colistimethate sodium DPI is dominated by nebulised tobramycin. The Assessment Group also carried out additional analyses in response to the revised patient access scheme submitted by the manufacturer of colistimethate sodium as part of its response to the appraisal consultation document (ACD) consultation. Only the price of colistimethate sodium DPI was amended in the model; all other assumptions and parameters in the model remained unchanged (sections 4.2.10–4.2.12). When the revised patient access scheme discount was incorporated, the incremental QALY was −0.13, and the incremental cost was −£37,946 compared to nebulised tobramycin (list price). These results demonstrated that colistimethate sodium DPI was less effective and less expensive than nebulised tobramycin, the ICER being £288,563 saved per QALY lost. The probabilistic sensitivity analysis associated with these analyses estimated that with the revised patient access scheme, colistimethate sodium DPI had a probability of 1.0 of being cost effective at the £20,000 and £30,000 per QALY gained thresholds. The Assessment Group again carried out a sensitivity analysis using the CMU E-MIT price rather than the BNF list price for nebulised tobramycin sodium DPI. The results of this analysis suggest that on the basis of the revised patient access scheme price for colistimethate sodium DPI and the CMU E-MIT price for nebulised tobramycin, the resulting ICER was £154,916 saved per QALY lost (incremental cost and QALY of −£20,371 and −0.13 respectively). However, as all these analyses included only a comparison with nebulised tobramycin the cost effectiveness of colistimethate sodium DPI relative to any other comparator is uncertain. ## Tobramycin DPI patient access scheme In response to an agreed patient access scheme for tobramycin DPI, the Assessment Group carried out additional analyses evaluating the cost effectiveness of tobramycin DPI compared with nebulised tobramycin. This analysis used the Assessment Group de novo model (used for colistimethate sodium DPI described above), but transition probabilities between health states and exacerbation parameters were based on those observed in the EAGER trial. The manufacturer provided individual patient-level FEV1% data together with aggregated data on exacerbations from the EAGER trial, which had been previously unavailable to the Assessment Group. All other base-case assumptions in the model were unchanged (see sections 4.2.10–4.2.12). The Assessment Group carried out analyses using 3 sets of FEV1 data from the EAGER trial: 1) pre-dose FEV1% at week 0 to FEV1% at week 24; 2) pre-dose FEV1% at week 0 to pre-dose FEV1% at week 20; 3) post-dose FEV1% at week 0 to post-dose FEV1% at week 20. The Assessment Group highlighted that there was uncertainty around which of these analyses should be considered the most reliable because of the effect of tobramycin on FEV1% soon after administration (rather than off treatment 4 weeks later). The Assessment Group judged that the analysis 'Pre-dose FEV1% at week 0 to FEV1% at week 24' (analysis 1) was the most appropriate and should be considered to be the base-case analysis, but noted that this was not the ITT population because it only included trial participants for whom baseline and week 24 lung function values had been recorded. The Assessment Group highlighted that there was a notable amount of missing data with higher rates of attrition in the tobramycin DPI arm than in the nebulised tobramycin arm and therefore the data may reflect a 'best case scenario' whereby only participants who had a response to the drug are captured in either group. In the Assessment Group model, the incremental QALY gain for tobramycin DPI compared with nebulised tobramycin was 0.34 (pre-dose FEV1% at week 0 to FEV1% at week 24) and the incremental costs were £42,453. The cost-effectiveness results for the base-case analysis of the list prices of tobramycin DPI compared to nebulised tobramycin gave an ICER of £123,563 per QALY gained (without the patient access scheme applied). With the patient access scheme applied, tobramycin DPI dominated nebulised tobramycin (at list price) with incremental cost savings of £19,275. The Assessment Group also carried out a one-way sensitivity analysis on the following parameters: deterministic point estimates of parameters on utility values, transition probabilities, utility decrement for exacerbations and costs of hospitalisation. These analyses indicated that tobramycin DPI dominated nebulised tobramycin when the patient access scheme was included in analysis 1 (pre-dose FEV1% at week 0 to FEV1% at week 24) except for the scenario in which the transition probabilities for nebulised tobramycin were set as equal to those for tobramycin DPI. The Assessment Group also carried out probabilistic sensitivity analyses. The probability of tobramycin DPI (at list price) being more cost effective than nebulised tobramycin (at list price) at thresholds of £20,000 and £30,000 per QALY gained was zero for all 3 ways of interpreting the FEV1 data described in section 4.2.21. The probability of tobramycin DPI (with the inclusion of the patient access scheme) being more cost effective than nebulised tobramycin (at list price) at thresholds of £20,000 and £30,000 per QALY gained was 1.00 for all of the analyses: pre-dose FEV1% at week 0 to FEV1% at week 24; pre-dose FEV1% at week 0 to pre-dose FEV1% at week 20; and post-dose FEV1% at week 0 to post-dose FEV1% at week 20. The Assessment Group also carried out an additional sensitivity analysis using the price of nebulised tobramycin based on estimates from the CMU E-MIT (£970.12) rather than the BNF list price of £1187. The results found that with the introduction of the patient access scheme, tobramycin DPI consistently dominated nebulised tobramycin irrespective of which FEV1% data were used. Probabilistic sensitivity analyses indicated that the probability of tobramycin DPI being more cost effective than nebulised tobramycin was 1.0 at a threshold of £20,000 per QALY gained and 0.99 at a threshold of £30,000 per QALY gained, for the preferred analysis based on pre-dose FEV1% at week 0 to FEV1% at week 24. The Assessment Group concluded that the introduction of the patient access scheme could be expected to result in tobramycin DPI consistently dominating nebulised tobramycin irrespective of which FEV1% data are used. However, the Assessment Group pointed out that uncertainties remained: Because of absence of sufficient evidence relating to any other comparator, the economic analysis of tobramycin DPI is restricted solely to an economic comparison with nebulised tobramycin. Data on minor and major exacerbations were not collected in the EAGER trial. The Assessment Group explained that lung disorder may represent a reasonable proxy for pulmonary or cystic fibrosis exacerbations and hence these data were used to estimate the probability of any exacerbation (minor or major) in each treatment group. The mean probability of exacerbation for tobramycin DPI was estimated to be 0.34 and the mean probability of exacerbation with nebulised tobramycin was 0.30. The manufacturer provided trial data estimates of the number of patients receiving any new antibiotic, total days used, and the number of patients who needed both additional antibiotic treatment and hospitalisation in each treatment group. The estimates of the number of patients who needed both additional antibiotic treatment and hospitalisation, combined with the estimated number of exacerbation events from Konstan et al., were used to produce an estimate of the pooled probability that an exacerbation event was major. The Assessment Group explained that this estimate is very similar in terms of number of exacerbations to that derived from the COLO/DPI/02/06 trial but the validity of this estimate remains questionable. Much of the incremental benefit is driven by the small QALY gains observed within the trial period which are inflated considerably by extrapolating over the patient's remaining lifetime. Over the patient's lifetime this incremental QALY gain is expected to range from 0.04 QALYs (post-dose 0–20 weeks) to 0.34 QALYs (pre-dose 0–24 weeks). Missing data and high attrition rates in the EAGER trial for tobramycin DPI mean that transition data may reflect a best-case scenario in which only responders are captured in either group and therefore cost effectiveness may be less than that estimated. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of colistimethate sodium DPI and tobramycin DPI for treating pseudomonas lung infection in cystic fibrosis, having considered evidence on the nature of chronic pseudomonas lung infection in people with cystic fibrosis and the value placed on the benefits of colistimethate sodium DPI and tobramycin DPI by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee considered the current treatment pathway for people with cystic fibrosis with chronic P. aeruginosa lung infection. The Committee heard from clinical specialists that treatment is generally patient driven and that the most important outcomes for the patient that influence treatment decisions are the person's quality of life, treatment burden, maintaining good lung function and reducing the incidence of exacerbations. The Committee heard from clinical specialists that first-line treatment for chronic P. aeruginosa lung infection routinely starts with nebulised colistimethate sodium (unless it is contraindicated), this choice being largely based on cost. If there is no response, an unacceptable adverse event profile, an excessive number of acute exacerbations or a loss of lung function, then treatment is switched routinely to nebulised tobramycin. Tobramycin is administered in cycles of 28 days on treatment, followed by 28 days off treatment, in accordance with the marketing authorisation. The Committee noted that this was in line with the national guidelines from the Cystic Fibrosis Trust. The clinical specialists advised that having 28 days off treatment was not favoured by some people with cystic fibrosis and some clinicians, and that either nebulised colistimethate sodium during the 28-day off period or continuous half-dose nebulised tobramycin were used in some patients. The Committee noted that the use of colistimethate sodium only in the tobramycin 28-day off period and the use of continuous half-dose tobramycin by some people on nebulised tobramycin were outside the respective marketing authorisations, and heard from the clinical specialists that there was no clinical-effectiveness evidence for such approaches to treatment. The Committee therefore understood that the usual treatment pathway was for nebulised colistimethate sodium to be used first and then nebulised tobramycin second. The Committee discussed the comments received during consultation on the ACD regarding the current treatment pathway. Some indicated that in the majority of adult specialist centres in the UK there has been a move away from offering nebulised colistimethate sodium as initial treatment followed by tobramycin, towards alternating therapy between tobramycin and colistimethate sodium on a monthly basis. Other comments indicated that it was still usual for nebulised colistimethate sodium to be used first and then patients were switched to nebulised tobramycin if there were problems with nebulised colistimethate sodium or if it did not work well enough. The Committee heard from the Assessment Group that information from their clinical experts suggested that less than 25% of people with cystic fibrosis and chronic P. aeruginosa lung infection would receive an alternating therapy regimen. The Committee therefore concluded that some people with cystic fibrosis and chronic pseudomonas lung infection may receive alternating tobramycin and colistimethate sodium treatment in clinical practice. The Committee noted the increased cost of such alternating antibiotic regimens and that it had not been presented with any evidence as to the clinical effectiveness of this approach by the Assessment Group or the manufacturers or during consultation. It concluded that because there was no evidence of the clinical effectiveness of using these antibiotics in an alternating regimen, it could not consider this issue further. The Committee discussed the appropriate comparators for colistimethate sodium and tobramycin DPIs. It heard from the manufacturer of colistimethate sodium DPI that the EMA had indicated that the most appropriate comparator at the time of the study design for its pivotal trial would be nebulised tobramycin because this was the only licensed comparator in all of the study site countries. The Committee agreed that given the current clinical pathway, ideally it would have liked to have seen effectiveness evidence comparing colistimethate sodium DPI with nebulised colistimethate sodium and also whether there was evidence of any clinical benefit of colistimethate sodium DPI in people being switched from nebulised colistimethate sodium because of lack of efficacy. Taking into account the sequence of inhaled antibiotics currently used in the treatment pathway in the UK (see sections 4.3.2 and 4.3.3) and the clinical specialists' opinion that clinicians would switch from one antibiotic to another (whatever the preparation), the Committee concluded that the most appropriate comparator for colistimethate sodium DPI would be nebulised colistimethate sodium and the most appropriate comparator for tobramycin DPI would be nebulised tobramycin. The Committee considered the treatment burden associated with cystic fibrosis. The Committee heard from patient experts how time-consuming all the treatments can be, taking up to 4 hours each day and imposing on other daily activities. The Committee noted that most people with cystic fibrosis use nebulisers for administration of other daily treatments as well as for antibiotics for pseudomonas lung infection. The Committee heard from patient experts how using a nebuliser also involves preparation of the treatment and cleaning of equipment, both of which add to the treatment burden. The Committee recognised that the strict routine and amount of time spent receiving treatment have a significant impact on the daily activities of people with cystic fibrosis and their families. The Committee concluded that reducing the time that people with cystic fibrosis spend receiving treatment would be beneficial in improving the quality of life of people with cystic fibrosis and their families. The Committee discussed the impact of long-term treatment with nebulised antibiotics in people with cystic fibrosis. The Committee heard from clinical specialists and patient experts that adherence to medication was variable and did not just relate to nebulisers but also to inhalers and oral treatments. The Committee heard from clinical specialists that in clinical practice adherence to nebulised treatments was approximately 30–60%. The patient experts commented that out of all of their treatments, the ones they were least likely to adhere to were those administered with a nebuliser. The Committee also heard from the patient experts that older nebulisers are not easily portable, take up a lot of space in the home and involve greater costs to the patient in electricity usage. Additionally, the clinical specialists commented that newer, smaller and faster nebulisers are in common use and these greatly decrease the time of treatment but still involve drug preparation and cleaning. The Committee noted that nebulised colistimethate sodium and tobramycin are not licensed for use with these faster nebulisers but nevertheless accepted that it is usual practice for these types of fast nebulisers to be used, and this was confirmed by the clinical specialists. The Committee concluded that in clinical practice (rather than in clinical trials), people with cystic fibrosis may be more likely to adhere to a dry powder for inhalation treatment than a nebulised treatment in view of the speed and convenience of drug delivery. ## Clinical effectiveness The Committee discussed the clinical-effectiveness evidence for colistimethate sodium and tobramycin DPIs. The Committee noted that there was no clinical trial comparing the effectiveness of colistimethate sodium DPI with that of the preferred comparator, nebulised colistimethate sodium. The Committee discussed the clinical-effectiveness evidence from the COLO/DPI/02/06 trial which compared colistimethate sodium DPI with nebulised tobramycin and the EAGER trial which compared tobramycin DPI with nebulised tobramycin. The Committee noted that both trials were non-inferiority in design and therefore only assessed whether the interventions were not worse than nebulised tobramycin, where non-inferiority was accepted if the lower confidence limit for the difference between treatments in FEV1% was above a fixed percentage (the 95% confidence limit with a difference of –3% was chosen in COLO/DPI/02/06 and the 85% confidence interval with a difference of –6% in EAGER). The Committee noted the different confidence levels and margins of non-inferiority selected for the 2 key trials which it found surprising given it would have expected these to be based on similar clinical considerations. It was also aware that in the case of COLO/DPI/02/06, logarithmic transformations and a non-parametric approach using the median rather than mean values reduced the impact of extreme values and hence made it easier to achieve non-inferiority. The Committee concluded that it only had evidence exploring whether either dry powder formulation was not worse than nebulised tobramycin and no evidence to prove that either was more effective than or equivalent to nebulised tobramycin. The Committee discussed the quality of the 2 key trials. It noted the Assessment Group's critique of the trials, in particular the fact that the manufacturers had not commented in their submissions on the quality of these trials in light of the current EMA research guidelines for the development of medicinal products for the treatment of cystic fibrosis. The Committee supported the Assessment Group's comments on the methodological limitations of both trials, such as lack of blinding, and agreed that this could have introduced selection and reporting bias for subjective outcomes such as adverse events and might limit the generalisability of the findings. The Committee concluded that the evidence base for assessing the clinical effectiveness of colistimethate sodium and tobramycin DPIs was of, at best, modest quality but that it was the best available. The Committee discussed the results for lung function measurements in the 2 key trials and the results of these analyses in the ITT population. The Committee was aware that the primary outcome for the COLO/DPI/02/06 trial was respiratory function as measured by FEV1% predicted at 24 weeks. The Committee noted that the study was powered to detect a minimum change in the difference in FEV1% of −3% (based on the lower bound of a 95% confidence interval for the difference in means). The Committee noted that the non-inferiority criterion was not met in the pre-defined ANCOVA analysis for the ITT population but it acknowledged that in the logarithmic and non-parametric analyses the non-inferiority criterion had been met in the ITT population for the LOCF analyses. The Committee was additionally aware that the manufacturer had stated that both LOCF and completer analyses were of equal importance and that the non-inferiority criterion was only met for the ITT population in the non-parametric analysis using the completer dataset. The Committee noted that the EAGER trial was powered to detect non-inferiority at a margin of no less than 6% difference in the mean FEV1% between tobramycin DPI and nebulised tobramycin at the lower end of the one-sided 85% confidence interval and that results showed that tobramycin DPI was not statistically significantly worse than nebulised tobramycin with respect to change in mean FEV1% at 20 weeks. The Committee heard from the clinical specialists that FEV1% tends to fluctuate over the short term and the clinical specialists therefore agreed that the 24-week follow-up period of the trials was not sufficiently long enough to assess the impact of either colistimethate sodium DPI or tobramycin DPI on FEV1% predicted compared with nebulised tobramycin in the longer term. The Committee noted that both trials had resulted in relatively small changes in FEV1% levels at 24 weeks. Additionally, the Committee heard from the clinical specialists that small changes in FEV1% levels over a short term were not considered clinically meaningful in determining whether chronic P. aeruginosa lung infection was being effectively managed in clinical practice. The Committee discussed the nature of non-inferiority trials compared with trials designed to show equivalence and the short-term nature of both of the DPI versus nebulised tobramycin trials. Whilst it would have much preferred trials that were designed for equivalence and had continued for at least the 12 months specified in the current EMA research guidelines for such agents because of the importance of the clinical outputs for use in the cost-effectiveness analysis, it accepted that the evidence presented in terms of FEV1% was the best available and it had to make its judgements accordingly. Additionally the Committee noted that the results of COLO/DPI/02/06 trial indicated it had failed its primary non-inferiority end point in some analyses, but that it had a stricter definition of non-inferiority than the EAGER trial, which also had a primary end point of 20 not 24 weeks. The Committee concluded that the COLO/DPI/02/06 and EAGER trials may have demonstrated that colistimethate sodium DPI and tobramycin DPI were non-inferior to nebulised tobramycin with respect to change in FEV1% within the populations tested and in the manner conducted within each trial, but remained concerned with the uncertain clinical relevance of these findings given the short-term nature of these trials. The Committee discussed microbiological outcomes and the adverse events reported in the 2 key trials. The Committee noted that the COLO/DPI/02/06 and EAGER trials had both reported improvements in mean sputum density of P. aeruginosa with colistimethate sodium DPI and tobramycin DPI compared to nebulised tobramycin (see sections 4.1.6 and 4.1.10). However, the Committee heard from the clinical specialists that microbiological measurements such as sputum density were not generally carried out in clinical practice. The Committee also observed that both the COLO/DPI/02/06 and EAGER trials reported a higher incidence of adverse events, particularly cough, with both dry powder formulations (see sections 4.1.6 and 4.1.12). Additionally the Committee noted there were higher levels of withdrawal because of adverse events in the dry powder formulation groups of both trials. The Committee was uncertain as to the implications of the adverse event results and it was unsure whether the adverse events associated with either tobramycin DPI or colistimethate sodium DPI were significantly different from those associated with nebulised tobramycin. The Committee considered which outcomes were the most clinically relevant for assessing the effectiveness of a drug for chronic P. aeruginosa lung infection in people with cystic fibrosis. The Committee noted the opinion of clinical specialists that treatment decisions are often informed by the incidence of exacerbations and the quality of life of the person with cystic fibrosis (see section 4.3.2) rather than short-term changes in FEV1%. The Committee understood that the COLO/DPI/02/06 trial had not identified any statistically significant improvement in health-related quality of life with colistimethate sodium DPI compared with nebulised tobramycin (see section 4.1.7). It noted that no health-related quality-of-life data had been collected in the EAGER trial. The Committee heard from clinical specialists that the number of exacerbations was routinely measured in clinical practice to determine whether a particular treatment was working. The Committee noted that the Assessment Group estimated the probability of people experiencing any exacerbation was slightly lower for colistimethate sodium DPI than for nebulised tobramycin in the COLO/DPI/02/06 trial, but that the rate of protocol-defined exacerbations was higher in the colistimethate sodium DPI group than in the nebulised tobramycin group. It also noted the Assessment Group's comments that exacerbation data were not specifically defined and collected in the EAGER trial and that the term 'lung disorder' might be a reasonable proxy for exacerbation of chronic infection. The Committee understood that the Assessment Group had estimated that the probability of any exacerbation was higher with tobramycin DPI than with nebulised tobramycin. The Committee also heard from the patient experts that avoiding exacerbations was considered the most important outcome for people with cystic fibrosis as it meant feeling better and having a better quality of life. The Committee was aware from patient experts that exacerbations can lead to periods of hospitalisation and the need for intravenous drugs which can have a potentially negative impact on quality of life. The Committee acknowledged the importance of exacerbations to patients and the NHS and the fact that the trial evidence for exacerbations was difficult to interpret because of the way it had been reported and the fact it was over such a short time frame. The Committee concluded that the differences observed in the trials may be small and over a short time horizon but they were the only evidence that is available. The Committee concluded that it was uncertain as to how it should interpret the exacerbation results. Because there were limited data on quality of life and uncertainty around the evidence on exacerbations, the Committee could not draw definitive conclusions as to whether either dry powder offered any clinical benefit over nebulised tobramycin for clinically relevant outcomes. The Committee discussed the results of the network meta-analysis by the manufacturer of tobramycin DPI (see section 4.1.15). The Committee noted that both the manufacturer and the Assessment Group had acknowledged the limitations of this analysis because of lack of available trials and comparable populations and outcome datasets. The Committee noted that the network meta-analysis had not included colistimethate sodium DPI, but accepted the manufacturer's explanation that this was because trials of colistimethate sodium DPI were not available as none had been published at the time of the submission. The Committee also heard from the manufacturer of colistimethate sodium DPI that it was not aware of any trials other than the small safety trial COLO/DPI/02/05, which compared colistimethate sodium DPI and nebulised colistimethate sodium. The Committee also noted that the manufacturer of tobramycin DPI considered that the results of the analysis comparing tobramycin DPI with other alternative formulations of nebulised tobramycin (such as Bramitob) should be treated with caution because of the underlying differences in study populations. The Committee agreed that because of the uncertainties surrounding the network meta-analysis it would not consider the results further. The Committee again concluded that it could only draw conclusions based on the evidence described in the 2 key trials and that it had no clinical evidence comparing colistimethate sodium DPI with the appropriate comparator, nebulised colistimethate sodium. The Committee discussed the additional benefits of the mode of delivery of the dry powder formulations over nebulised alternatives. The Committee noted that both technologies aimed to give people with cystic fibrosis and chronic P. aeruginosa lung infection quality-of-life benefits in terms of ease of use and convenience. The Committee considered that it may be plausible that the dry powder formulations could be expected to result in clinical benefits over nebulised solutions because they may increase levels of adherence to treatment. The Committee noted that in the COLO/DPI/02/06 trial levels of adherence to treatment were greater for nebulised tobramycin and it was unclear how adherence was measured in the EAGER trial. However the Committee heard from the patient experts and clinical specialists that people with cystic fibrosis are a heterogeneous population and therefore levels of adherence vary according to individual factors. The Committee heard from clinical specialists that levels of adherence to treatment would be different in clinical practice to those observed under trial conditions. Therefore the Committee agreed that it should not infer too much from these results when evaluating the likely benefit of the technologies in terms of improving adherence to treatment. The Committee acknowledged that both nebulised colistimethate sodium and nebulised tobramycin were embedded as treatment options in current clinical practice and thus judged to be clinically effective in treating chronic P. aeruginosa lung infection. The Committee therefore accepted that a change in the mode of delivery of these drugs would be unlikely to adversely affect their clinical effectiveness compared with nebulised formulations of the drugs, although it only had evidence for the comparison of tobramycin DPI with nebulised tobramycin. The Committee again recognised the limitations of the trial evidence in that this was restricted to a comparison of either DPI with nebulised tobramycin. Despite the limitations in the identified evidence and uncertainties in the interpretation of the trial outcomes, the Committee concluded that on balance it could see an additional benefit for people with cystic fibrosis and chronic pseudomonas lung infection of having the choice of a dry powder formulation of an anti-pseudomonal drug as well as its appropriate nebulised comparator. ## Cost effectiveness The Committee discussed the available cost-effectiveness evidence for colistimethate sodium DPI and tobramycin DPI. It noted that there was no cost-effectiveness evidence comparing colistimethate sodium DPI with nebulised colistimethate sodium. The Committee discussed the model provided by the manufacturer of colistimethate sodium DPI which compared colistimethate sodium DPI with nebulised tobramycin and the critique of the model by the Assessment Group. The Committee noted that the Assessment Group had identified key limitations in the submitted economic model. The Committee had particular concerns about the inconsistent time horizons used in the model for costs and health outcomes and the validity of using mortality benefits associated with 24 weeks of treatment and extrapolating over a lifetime. The Committee noted that the clinical specialists felt that relatively small changes in FEV1% would not be seen as a predictor of 1- or 2-year mortality risk in clinical practice. The Committee also noted that the data used in the regression equations for estimating mortality risk were based on a 20-year-old paper, and the prognosis for people with cystic fibrosis had substantially improved during that time. Additionally, the Committee had concerns about biases in the modelling of exacerbations, which were a major driver of cost savings in the model. The Committee did not accept the validity of the assumption that all patients would have a fixed life expectancy of 37.4 years. The Committee heard from the clinical specialists that it was not unusual to see people aged between 40 and 60 years with cystic fibrosis. The Committee were also concerned about the lack of any preference-based instrument to measure health-related quality of life and the limitation of the method used to map CFQ-R to EQ-5D. Given these uncertainties and others raised by the Assessment Group, the Committee concluded that the manufacturer's (Forest's) model lacked credibility and therefore they would not consider it or its results plausible. The Committee discussed the Assessment Group's de novo model which compared colistimethate sodium DPI with nebulised tobramycin and tobramycin DPI with nebulised tobramycin. The Committee noted that the model had a lifetime time horizon. The Committee agreed that the use of a lifetime horizon was appropriate, but acknowledged the limitation of extrapolating short-term trial results over long time horizons. Additionally the Committee noted other limitations of the Assessment Group model, including the fact that it did not recognise that, in the current treatment pathway, some people would move from one drug to another (for example from colistimethate sodium to tobramycin). The Committee also noted that treatment duration is assumed to be equivalent between the 2 treatments. The Committee agreed that it was also plausible that some people on nebulised tobramycin would receive some form of treatment on a continuous basis (either as continuous nebulised reduced-dose tobramycin or as nebulised colistimethate sodium in off-months from tobramycin) but there was no evidence on which to base any cost-effectiveness estimate. However, the Committee also accepted that other assumptions in the model such as no difference in the rate of adverse events between colistimethate sodium DPI and nebulised tobramycin may bias in terms of favouring colistimethate sodium DPI. It was also aware that no disutility associated with adverse events was included in the model and was aware of the increased rates of cough in the DPI arms of the COLO/DPI/02/06 and EAGER trials and that this could be a factor affecting adherence. The Committee acknowledged comments received during consultation that there are inherent difficulties in quantifying the relationship between FEV1 and quality of life. The Committee concluded, however, that despite these limitations the Assessment Group's de novo model was the best available framework for assessing the cost effectiveness of colistimethate sodium DPI compared with nebulised tobramycin and of tobramycin DPI compared with nebulised tobramycin. The Committee discussed the results from the Assessment Group's de novo model comparing colistimethate sodium with nebulised tobramycin, again noting this was not the appropriate comparator for colistimethate sodium DPI. The Committee noted the approved patient access scheme for colistimethate sodium DPI and based its decisions on the cost-effectiveness results from analyses incorporating the revised patient access scheme price. The Committee considered the sensitivity analysis using the E-MIT price of nebulised tobramycin and recognised that analyses using the list price for nebulised tobramycin may overestimate the cost effectiveness of colistimethate sodium DPI in terms of NHS practice. The Committee discussed the implications of considering a treatment that was less effective and less costly, and the need therefore to have considerable confidence in the clinical-effectiveness results. The Committee concluded that there was a great deal of uncertainty in the modelling of colistimethate sodium DPI and that the most plausible ICERs indicated that with the revised patient access scheme colistimethate sodium DPI resulted in a small QALY loss and a cost saving compared with nebulised tobramycin. The Committee discussed all the uncertainties associated with the clinical- and cost-effectiveness evidence for colistimethate sodium DPI. It acknowledged the difficulties in performing high-quality research in a disease with a heterogenous clinical profile and where treatment options are ultimately based on clinician and patient preferences. However, the Committee was aware of the statements from clinical specialists about current treatment for people with cystic fibrosis and chronic P. aeruginosa lung infection and the treatment pathway of switching from one antibiotic to another. The Committee again confirmed that the most appropriate comparator for colistimethate sodium DPI was nebulised colistimethate sodium and that it would have wished to see the results of such a comparison. The Committee noted again that the manufacturer of colistimethate sodium DPI had confirmed that there was no trial that compared the effectiveness of colistimethate sodium DPI with nebulised colistimethate sodium. The Committee was therefore unable to reach a conclusion on the clinical and cost effectiveness of colistimethate sodium DPI compared with nebulised colistimethate sodium. The Committee discussed the cost-effectiveness evidence for tobramycin DPI. It noted that there was no economic analysis in the manufacturer's submission for tobramycin DPI and that the manufacturer felt that a cost-minimisation approach was appropriate. The Committee did not agree that cost minimisation was appropriate in this instance because the evidence had not proved equivalence between tobramycin DPI and nebulised tobramycin and that cost minimisation would not incorporate any estimate of uncertainty; additionally the Committee was aware that the NICE reference case stated a preference for cost–utility analysis. The Committee therefore based its discussions on the cost-effectiveness analysis carried out by the Assessment Group incorporating the patient access scheme. The Committee noted that the results of this analysis had shown that tobramycin DPI consistently dominated nebulised tobramycin when the patient access scheme was included (incremental cost of –£42,500 and incremental QALY gain of 0.34 in the base case). The Committee also noted the results of the probabilistic sensitivity analysis and one-way sensitivity analysis which indicated that tobramycin DPI consistently dominated nebulised tobramycin. Additionally, the Committee was aware that the analyses were based on the inclusion of aggregate lung disorder data as a proxy measure for exacerbations because data on major and minor exacerbations had not been collected in the EAGER trial. The Committee recognised that the model assumed that the intervention and comparator are used for 28 days followed by 28 days without use of any drug and that this may not be reflective of clinical practice. The Committee accepted that there was no clinical evidence for such an approach and neither the clinical specialists nor the manufacturers knew of any. The Committee acknowledged that the small QALY gain for tobramycin DPI was uncertain because quality-of-life data were not collected in the EAGER trial. However, it agreed it was reasonable to assume that there would be some QALY gain for tobramycin DPI over nebulised tobramycin in clinical practice in view of the reported benefits to patients in terms of ease of use and convenience although it acknowledged that the number of withdrawals from the EAGER trial did not indicate this relationship. The Committee therefore agreed that despite the limitations of all the clinical- and cost-effectiveness evidence and hence the uncertainty inherent in the Assessment Group model, it was reasonable to conclude that tobramycin DPI was a cost-effective use of NHS resources. Therefore the Committee concluded that it could recommend tobramycin DPI (with the associated patient access scheme applied) as a treatment option for chronic P. aeruginosa lung infection in people with cystic fibrosis who would otherwise have been treated with nebulised tobramycin; that is, when colistimethate sodium is contraindicated, is not tolerated, or has not produced an adequate clinical response. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care. The Committee considered whether there were any groups of people for whom the COLO/DPI/02/06 trial (in which the comparator for colistimethate sodium DPI was nebulised tobramycin) provided clinical- or cost-effectiveness evidence for the use of colistimethate sodium. It recognised that the majority of people currently switching to nebulised tobramycin from nebulised colistimethate sodium do so either because of a lack of efficacy of nebulised colistimethate sodium or because colistimethate sodium is contraindicated. The Committee recognised that a potential switch from nebulised colistimethate sodium to colistimethate sodium DPI in these two groups would therefore be inappropriate. However, the Committee considered that there was a group of people who could benefit or were benefiting from nebulised colistimethate sodium but were unable to tolerate it twice daily in its nebulised form. The current treatment option for these people would be nebulised tobramycin and thus the COLO/DPI/02/06 trial did give evidence for the use of colistimethate sodium DPI rather than nebulised tobramycin in such a group of people. The Committee noted the small QALY loss for colistimethate sodium DPI compared with nebulised tobramycin but also the substantial cost saving (£38,000 with the list price for nebulised tobramycin). The Committee further observed that adherence might be greater with the use of a dry powder inhaler in such a population. The Committee also acknowledged comments received during consultation that some people would be sensitive to nebulised aminoglycosides (such as tobramycin) in terms of side effects or be otherwise intolerant of such therapy. However the Committee agreed that its understanding of the treatment pathway was that this group receive colistimethate sodium as first-line treatment, tobramycin as second-line treatment and then an alternative treatment to tobramycin if tobramycin treatment fails or is otherwise contraindicated. The Committee therefore decided that colistimethate sodium DPI did not have a role to play in the treatment of chronic P. aeruginosa in people who were sensitive (in terms of toxicity) to tobramycin or intolerant of tobramycin. It therefore concluded that it could only recommend colistimethate sodium DPI as a treatment option for people who would clinically benefit from continued colistimethate sodium but cannot tolerate it in its nebulised form. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care. The Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. The Committee noted a potential equalities issue in that cystic fibrosis mostly affects people of white European origin; however, the Committee recognised that this reflected the epidemiology of cystic fibrosis rather than being an equalities concern. The Committee was also aware that some patients or carers may have difficulty manipulating an inhaler for dry powder inhalation, but noted that the same may apply to other modes of treatment delivery. The Committee concluded that its recommendations would not affect any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its recommendations. # Summary of Appraisal Committee's key conclusions TA276 Appraisal title: Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis Section Key conclusions The Committee concluded that it could only draw conclusions based on the evidence described in the 2 key trials and that it had no clinical evidence comparing colistimethate sodium DPI with the appropriate comparator, nebulised colistimethate sodium. The Committee agreed that despite the limitations of all the clinical- and cost-effectiveness evidence and hence the uncertainty inherent in the Assessment Group model, it was reasonable to conclude that tobramycin DPI was a cost-effective use of NHS resources. The Committee recommended tobramycin DPI as a treatment option only when nebulised tobramycin is considered an appropriate treatment; that is, when colistimethate sodium is contraindicated, is not tolerated, or has not produced an adequate clinical response. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care. Given the available evidence and the current treatment pathway, the Committee could only recommend colistimethate sodium DPI as a treatment option for people who would clinically benefit from continued colistimethate sodium but cannot tolerate it in its nebulised form. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care. Current practice Clinical need of patients, including the availability of alternative treatments The most important outcomes for the patient that influence treatment decisions are the person's quality of life, treatment burden, maintaining good lung function and reducing the incidence of exacerbations. Current treatment options include the use of inhaled antibiotics effective against P. aeruginosa (such as nebulised colistimethate sodium or tobramycin) and oral or intravenous antibiotics to eradicate initial or intermittent P. aeruginosa colonisation or acute exacerbations of chronic infection. Azithromycin may be given in combination with these antibiotics to act on the biofilms. First-line treatment for chronic P. aeruginosa lung infection routinely starts with nebulised colistimethate sodium (unless it is contraindicated), this choice being largely based on cost. If there is no response, an unacceptable adverse event profile, an excessive number of acute exacerbations or a loss of lung function, then treatment is switched routinely to nebulised tobramycin. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee recognised that the strict routine and amount of time spent receiving treatment have a significant impact on the daily activities of people with cystic fibrosis and their families. The Committee concluded that reducing the time that people with cystic fibrosis spend receiving treatment would be beneficial in improving the quality of life of people with cystic fibrosis and their families. The Committee concluded that in clinical practice (rather than in clinical trials), people with cystic fibrosis may be more likely to adhere to a dry powder for inhalation treatment than a nebulised treatment in view of the speed and convenience of drug delivery. What is the position of the treatment in the pathway of care for the condition? The Committee heard from the manufacturer of colistimethate sodium DPI that the EMA had indicated that the most appropriate comparator at the time of the study design for its pivotal trial would be nebulised tobramycin because this was the only licensed comparator in all of the study site countries. The Committee agreed that given the current clinical pathway, ideally it would have liked to have seen effectiveness evidence comparing colistimethate sodium DPI with nebulised colistimethate sodium and also whether there was evidence of any clinical benefit of colistimethate sodium DPI in people being switched from nebulised colistimethate sodium because of lack of efficacy. Given the current treatment pathway in the UK, the Committee concluded that the most appropriate comparator for colistimethate sodium DPI would be nebulised colistimethate sodium and the most appropriate comparator for tobramycin DPI would be nebulised tobramycin. Adverse reactions The Committee was unsure whether the adverse events associated with either tobramycin DPI or colistimethate sodium DPI were significantly different from those associated with nebulised tobramycin. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee discussed the quality of the 2 key trials that compared colistimethate sodium DPI with nebulised tobramycin and tobramycin DPI with nebulised tobramycin. It noted the Assessment Group's critique of the trials, in particular the fact that the manufacturers had not commented in their submissions on the quality of the trials in light of the current EMA research guidelines for the development of medicinal products for the treatment of cystic fibrosis. The Committee supported the Assessment Group's comments on the methodological limitations of both trials, such as a lack of blinding, and agreed that this could have introduced selection and reporting bias for subjective outcomes such as adverse events and might limit the generalisability of the findings. The Committee concluded that the evidence base for assessing the clinical effectiveness of colistimethate sodium and tobramycin DPIs was of, at best, modest quality but that it was the best available. The Committee noted that there was no clinical trial comparing the effectiveness of colistimethate sodium DPI with that of the preferred comparator, nebulised colistimethate sodium. The Committee noted that both trials were non-inferiority in design and therefore only assessed whether the interventions were not worse than nebulised tobramycin. Relevance to general clinical practice in the NHS The Committee acknowledged that both nebulised colistimethate sodium and nebulised tobramycin were embedded as treatment options in current clinical practice and thus judged to be clinically effective in treating chronic P. aeruginosa lung infection. The Committee therefore accepted that a change in the mode of delivery of these drugs would be unlikely to adversely affect their clinical effectiveness compared with nebulised formulations of the drugs. Uncertainties generated by the evidence There is uncertainty about the clinical relevance of the findings of the 2 key trials given the short-term nature of these trials. The Committee concluded that it was uncertain as to how it should interpret the exacerbation results. Because there were limited data on quality of life and uncertainty around the evidence for exacerbations, the Committee could not draw definitive conclusions as to whether either dry powder offered any clinical benefit over nebulised tobramycin for clinically relevant outcomes. Whilst the Committee would have much preferred trials that were designed for equivalence and had continued for at least the 12 months specified in the current EMA research guidelines for such agents, it accepted that the evidence presented in terms of FEV1% was the best available and it had to make its judgements accordingly. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Not applicable Estimate of the size of the clinical effectiveness including strength of supporting evidence For the primary end point of mean difference in change in FEV1% predicted after 24 weeks of treatment, the result from the ANCOVA analysis on the ITT population using LOCF data was −1.16% (95% CI −3.15% to 0.84%) suggesting that colistimethate sodium DPI was marginally less efficacious than tobramycin nebuliser solution (because the non-inferiority criterion was not met). The results of the log-transformed and non-parametric ITT population LOCF data analyses were −0.98% (95% CI −2.74% to 0.86%) and −0.56% (95% CI −2.16% to 1.00%) respectively, suggesting in both cases that colistimethate sodium DPI was non-inferior to nebulised tobramycin. For the PP population the ANCOVA, log-transformed and non-parametric analyses using LOCF data indicated that the non-inferiority hypothesis was satisfied for non-parametric analysis only (ANCOVA −1.49% , log-transformed −1.10% and non-parametric −0.67% ). Tobramycin DPI was associated with an improved mean FEV1% predicted compared with nebulised tobramycin at 20 weeks of +0.59% (SE 0.92). The manufacturer reported non-inferiority (supported by least squares mean difference relative change of 1.1% which has a lower limit of the one-sided 85% confidence interval within the predicted 6% margin for non-inferiority). The Committee concluded that it only had evidence exploring whether either dry powder formulation was no worse than nebulised tobramycin and no evidence to prove that either was more effective than or equivalent to nebulised tobramycin. The Committee concluded that the COLO/DPI/02/06 and EAGER trials may have demonstrated that colistimethate sodium DPI and tobramycin DPI were non-inferior to nebulised tobramycin with respect to change in FEV1% within the populations tested and in the manner conducted within each trial, but remained concerned with the uncertain clinical relevance of these findings given the short-term nature of these trials. Evidence for cost effectiveness Availability and nature of evidence The manufacturer of colistimethate sodium DPI used a cohort-based decision analysis to compare colistimethate sodium DPI with nebulised tobramycin in people aged 6 years or older with documented cystic fibrosis who had chronic pseudomonas lung infection. The Committee concluded that the manufacturer's (Forest's) model lacked credibility and therefore they would not consider it or its results plausible. The Committee discussed the Assessment Group's de novo model which compared colistimethate sodium DPI with nebulised tobramycin and tobramycin DPI with nebulised tobramycin. The Committee noted that the model had a lifetime time horizon. The Committee agreed that the use of a lifetime horizon was appropriate, but acknowledged the limitation of extrapolating short-term trial results over long time horizons. Additionally the Committee noted other limitations of the Assessment Group model, including the fact that it did not recognise that, in the current treatment pathway, some people would move from one drug to another (for example from colistimethate sodium to tobramycin). The Committee concluded, however, that despite these limitations the Assessment Group's de novo model was the best available framework for assessing the cost effectiveness of colistimethate sodium DPI compared with nebulised tobramycin and of tobramycin DPI compared with nebulised tobramycin. The Assessment Group also carried out additional analyses in response to the patient access schemes submitted by the manufacturers of colistimethate sodium DPI and tobramycin DPI. Uncertainties around and plausibility of assumptions and inputs in the economic model Colistimethate sodium DPI: The Committee had particular concerns about the inconsistent time horizons used in the Forest model for costs and health outcomes and the validity of using mortality benefits associated with 24 weeks of treatment and extrapolating over a lifetime. The Committee had particular concerns about limitations of the Assessment Group's model. The Committee agreed that the use of a lifetime horizon was appropriate, but acknowledged the limitation of extrapolating short-term trial results over long time horizons. Additionally it noted that the model did not recognise that, in the current treatment pathway, some people would move from one drug to another (for example from colistimethate sodium to tobramycin). The Committee also noted that treatment duration is assumed to be equivalent between the 2 treatments. It agreed that it was also plausible that some people on nebulised tobramycin would receive some form of treatment on a continuous basis (either as continuous nebulised reduced-dose tobramycin or as nebulised colistimethate sodium in off-months from tobramycin) but there was no evidence on which to base any cost-effectiveness estimate. Tobramycin DPI: The Committee was aware that for the Assessment Group model for tobramycin DPI uncertainty was generated because the analyses were based on the inclusion of aggregate lung disorder data as a proxy measure for exacerbations because data on major and minor exacerbations had not been collected in the EAGER trial. The QALY gain for tobramycin DPI was uncertain because quality-of-life data were not collected in the EAGER trial. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee discussed the additional benefits of the mode of delivery of the dry powder formulations over nebulised alternatives. The Committee noted that both technologies aimed to give people with cystic fibrosis and chronic P. aeruginosa lung infection quality-of-life benefits in terms of ease of use and convenience. The Committee acknowledged that the small QALY gain for tobramycin DPI was uncertain because quality-of-life data were not collected in the EAGER trial. However, it agreed it was reasonable to assume that there would be some QALY gain for tobramycin DPI over nebulised tobramycin in clinical practice in view of the reported benefits to patients in terms of ease of use and convenience although it acknowledged that the number of withdrawals from the EAGER trial did not indicate this relationship. The Committee noted the small QALY loss for colistimethate sodium DPI compared with nebulised tobramycin but also the substantial saving (£38,000 with the list price for nebulised tobramycin). The Committee further observed that adherence might be greater with the use of a dry powder inhaler in such a population. Are there specific groups of people for whom the technology is particularly cost effective? Not applicable What are the key drivers of cost effectiveness? The key drivers of cost effectiveness were the cost of interventions and comparators when the most recent patient access schemes were included, and the small QALY gains for tobramycin DPI compared with nebulised tobramycin and for colistimethate sodium compared with nebulised tobramycin. Most likely cost-effectiveness estimate (given as an ICER) Tobramycin DPI consistently dominated nebulised tobramycin with inclusion of the patient access scheme, that is, there was a cost saving and QALY gain for tobramycin DPI compared to nebulised tobramycin. The Committee noted the small QALY loss for colistimethate sodium DPI compared with nebulised tobramycin but also the substantial cost saving (£38,000 with the list price for nebulised tobramycin). Additional factors taken into account Patient access schemes (PPRS) A patient access scheme has been agreed with the Department of Health for colistimethate sodium DPI, details of which are confidential. A patient access scheme has been agreed with the Department of Health for tobramycin DPI, details of which are confidential. The Committee noted the approved patient access scheme for colistimethate sodium DPI and based its decisions on the cost-effectiveness results from analyses involving the patient access scheme price. The Committee based its discussions on the cost-effectiveness analysis of tobramycin DPI carried out by the Assessment Group incorporating the patient access scheme. End-of-life considerations Not applicable Equalities considerations and social value judgements The Committee discussed NICE's duties under the equalities legislation and concluded that its recommendations would not affect any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its recommendations. # Related NICE guidance Mannitol dry powder for inhalation for treating cystic fibrosis (2012) NICE technology appraisal guidance 266.	{'Guidance': 'Tobramycin dry powder for inhalation (DPI) is recommended as an option for treating chronic pulmonary infection caused by Pseudomonas aeruginosa in people with cystic fibrosis only if:\n\nnebulised tobramycin is considered an appropriate treatment, that is, when colistimethate sodium is contraindicated, is not tolerated or has not produced an adequate clinical response and\n\nthe manufacturer provides tobramycin DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS.\n\nColistimethate sodium DPI is recommended as an option for treating chronic pulmonary infection caused by P.\xa0aeruginosa in people with cystic fibrosis only if:\n\nthey would clinically benefit from continued colistimethate sodium but do not tolerate it in its nebulised form and thus tobramycin therapy would otherwise be considered and\n\nthe manufacturer provides colistimethate sodium DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS.\n\nPeople currently using tobramycin DPI or colistimethate sodium DPI that is not recommended according to 1.1 or 1.2 should be able to continue treatment until they and their clinician consider it appropriate to stop. For children and young people this decision should be made jointly by the clinician, the child or young person and their parents or carers.', 'Clinical need and practice': 'Cystic fibrosis is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is characterised by abnormal transport of chloride and sodium across transporting epithelia, leading to thick viscous secretions in the lungs, pancreas, liver, intestine and reproductive tract and to an increased salt content in sweat gland secretions. People with cystic fibrosis have problems with their respiratory system and digestion, including prolonged diarrhoea that can affect growth and body mass index. They are prone to lung infections by a range of pathogens including Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa and Burkholderia cepacia. This is thought to be because the thick mucus makes it difficult for the body to clear inhaled bacteria, and because people with cystic fibrosis have an increased airway inflammatory response to pathogens. Chronic inflammation and progressive lung destruction from chronic infection can lead to bronchiectasis, altered pulmonary function and respiratory failure.\n\nCystic fibrosis affects over 8500\xa0children and young adults in the UK and has an incidence of 1 in 2500\xa0live births. About 1 in 25\xa0people in the UK of white European origin are carriers of an affected CFTR gene. It is much less common in people of African-Caribbean and Asian origin. Cystic fibrosis is a progressive condition that reduces life expectancy. In 2010, the cystic fibrosis registry recorded 103\xa0deaths in UK patients; the median age at death was 29\xa0years. However, prognosis is improving with the treatments now available and around half of the current cystic fibrosis population are expected to have a life expectancy of over 38\xa0years.\n\nManagement of the pulmonary component of cystic fibrosis includes a range of measures to aid clearance of respiratory secretions and to decrease inflammation and bacterial growth in the respiratory tract, such as chest physiotherapy, inhaled bronchodilators, inhaled mucolytics (such as rhDNase and hypertonic saline) and antibiotic treatment. The aim of treatment is to delay or slow deterioration in lung function, measured by forced expiratory volume in 1\xa0second (FEV1). Ultimately, patients may become eligible for lung transplantation. The care of most patients in the UK is coordinated by a tertiary cystic fibrosis centre with formal shared care with local clinics. Cystic fibrosis treatment can be time-consuming for the patient, with administration of nebulised antibiotics taking up to an hour each day during good health and longer during periods of ill health. The disease also impacts upon carers and needs a considerable commitment of healthcare resources.\n\nP.\xa0aeruginosa is the most frequent cause of lung infection in people with cystic fibrosis; around 38% of UK patients had a chronic pseudomonas infection in 2010. If recurrent intermittent infections are not controlled, chronic infection can develop in which bacterial microenvironments known as biofilms are formed that are difficult for immune cells and antibiotics to penetrate. The length and quality of life of people with cystic fibrosis are thought to be strongly influenced by the degree to which P.\xa0aeruginosa can be eradicated; however, chronic P.\xa0aeruginosa infection is rarely completely eradicated.\n\nManagement of P.\xa0aeruginosa lung infection in cystic fibrosis involves treatment with antibiotics, which may be given in hospital, at home or in a combination of these settings. The aims of antibiotic treatment are three-fold: firstly to eradicate intermittent acute P.\xa0aeruginosa lung infections; secondly to suppress P.\xa0aeruginosa (with long-term treatment) in patients who have become chronically infected; and thirdly to treat acute exacerbations in patients chronically infected with P.\xa0aeruginosa. Treatment also aims to maintain lung function and quality of life. Current treatment options include the use of inhaled antibiotics effective against P.\xa0aeruginosa (such as nebulised colistimethate sodium or tobramycin) and oral or intravenous antibiotics to eradicate initial or intermittent P.\xa0aeruginosa colonisation or acute exacerbations of chronic infection. Azithromycin may be given in combination with these antibiotics to act on the biofilms.', 'The technologies': "# Colistimethate sodium DPI\n\nColistimethate sodium DPI (Colobreathe, Forest Laboratories UK [in December 2018 NICE was notified that Colobreathe is now owned by Teva UK]) is a formulation of colistimethate sodium supplied as hard capsules for use with an inhaler. It belongs to the polymixin class of antibacterials and works by disrupting the structure of the bacterial cell membrane, leading to bacterial death. It is active against aerobic gram-negative organisms including P. aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Colistimethate sodium DPI is indicated for the management of chronic pulmonary infections caused by P. aeruginosa in patients with cystic fibrosis aged 6\xa0years and older.\n\nThe summary of product characteristics lists the following adverse reactions for colistimethate sodium DPI: respiratory disorders (such as dyspnoea, cough and wheezing), ear and labyrinth disorders, thoracic and gastrointestinal disorders, musculoskeletal, connective tissue and bone disorders, general disorders and administration site conditions, and renal and urinary disorders. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe recommended dosage for colistimethate sodium DPI is 1\xa0capsule (approximately equal to 125\xa0mg of colistimethate sodium) to be inhaled twice daily using the 'Turbospin' inhaler device (PH&T Pharma) which is a breath-activated, reusable dry powder inhaler. The price for a 28-day pack including 1\xa0Turbospin inhaler is £968 (excluding VAT; price provided by the manufacturer). The list price cost for 56\xa0days of treatment is therefore £1936 excluding VAT. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of colistimethate sodium DPI has agreed a patient access scheme with the Department of Health which makes colistimethate sodium DPI available with a discount applied to all invoices. The size of the discount is commercial in confidence (see section 5.4). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n# Tobramycin DPI\n\nTobramycin DPI (TOBI Podhaler, Novartis) is a formulation of tobramycin supplied as hard capsules for use with an inhaler. It is an aminoglycoside antibiotic that acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope and eventual cell death. Tobramycin inhibits protein synthesis of many gram-negative bacteria and it is active against P.\xa0aeruginosa. Tobramycin DPI is indicated for the suppressive treatment of chronic pulmonary infection caused by P.\xa0aeruginosa in adults and children aged 6\xa0years and older with cystic fibrosis.\n\nThe summary of product characteristics lists the following adverse reactions for tobramycin DPI: respiratory, thoracic and mediastinal disorders (such as dyspnoea, productive cough and wheezing), ear and labyrinth disorders, vascular disorders, gastrointestinal disorders, skin and subcutaneous tissue disorders, musculoskeletal, connective tissue and bone disorders, general disorders, and administration site conditions. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe recommended dosage for tobramycin DPI is 112\xa0mg tobramycin (4×28-mg capsules), administered twice daily for 28\xa0days using the Podhaler device in alternating cycles of 28\xa0days on treatment followed by 28\xa0days off treatment. The price for a pack of 56×28-mg capsules and 1\xa0Podhaler device is £447.50 (excluding VAT; 'British national formulary' [BNF] edition 64). The list price cost for 56\xa0days of treatment is therefore £1790 excluding VAT. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of tobramycin DPI (Novartis) has agreed a patient access scheme with the Department of Health which makes tobramycin DPI available with a discount applied to all invoices. The size of the discount is commercial in confidence (see section 5.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence and interpretation': "The Appraisal Committee (appendix\xa0A) considered evidence from a number of sources (appendix\xa0B).\n\n# Clinical effectiveness\n\nThe Assessment Group identified 3\xa0open-label, multicentre randomised controlled trials in people with cystic fibrosis and chronic P.\xa0aeruginosa lung infection for the technologies: 2\xa0for colistimethate sodium DPI (COLO/DPI/02/05 and COLO/DPI/02/06) and 1\xa0for tobramycin DPI (EAGER). The manufacturer of tobramycin DPI included details of 2\xa0randomised controlled trials in their submission: EVOLVE and EAGER. The Assessment Group did not include the EVOLVE trial in its review because the comparator was placebo, which was not in line with the scope provided by NICE.\n\n## Colistimethate sodium DPI\n\nCOLO/DPI/02/05 was a crossover trial comparing the safety of colistimethate sodium DPI and colistimethate sodium nebuliser solution in children and adults. The trial was carried out at 3\xa0centres in the UK, and the population consisted of 16\xa0people of whom 37.5% were younger than 13\xa0years. The trial compared 1\xa0capsule of colistimethate sodium DPI given twice daily for 4\xa0weeks with 2\xa0million units of colistimethate sodium nebuliser solution given twice daily for 4\xa0weeks. The primary objective was to assess the safety (clinical tolerability and laboratory safety) of 4\xa0weeks' treatment with colistimethate sodium DPI compared with 4\xa0weeks' treatment with nebulised colistimethate sodium. All patients (n=16) receiving the DPI reported treatment-emergent adverse events compared with 9 out of 15\xa0patients (60.0%) receiving the nebuliser solution. The most common treatment-related adverse events were gastrointestinal disorders (87.5% of patients) followed by cough and throat irritation (both in 81.3% of patients) in the DPI group, and cough (46.7% of patients) followed by wheezing (33.3% of patients) in the nebuliser solution group.\n\nCOLO/DPI/02/06 compared twice-daily doses of 125\xa0mg colistimethate sodium DPI administered by a Turbospin device with twice-daily doses of 300\xa0mg tobramycin nebuliser solution for nebuliser inhalation for 24\xa0weeks. The trial was of a non-inferiority design, that is, it was intended to show that the effect of colistimethate sodium DPI was not statistically significantly worse than that of nebulised tobramycin. It was carried out in 66\xa0centres in the European Union, Russia and the Ukraine. It included 373\xa0people aged 6 to 56\xa0years (mean age 21\xa0years, standard deviation [SD]=9.49) with cystic fibrosis who had chronic pseudomonas lung infection (2 or more positive cultures in the previous 6\xa0months) that would normally be treated with inhaled antibiotics. Other inclusion criteria were an FEV1% of between 25 and 75% of predicted and use of tobramycin nebuliser solution for inhalation (a minimum of 2\xa0on/off cycles) before randomisation. The primary end point of the trial was the mean change in FEV1% predicted after 24\xa0weeks of treatment. The trial was powered to detect non-inferiority, that is, a mean change in FEV1% from baseline to week\xa024 of no less than –3% at the lower end of the two-sided 95% confidence interval (CI) between treatment groups. Secondary outcomes included frequency of and time to exacerbations, adverse events, quality of life and physical changes. Three analyses were performed on the primary efficacy outcome: analysis of co-variance (ANCOVA), log-transformed analysis, and non-parametric analysis. Each of these 3\xa0analyses were performed on 2\xa0populations, the intention to treat (ITT) population (all randomised patients who received at least 1 dose of a study drug) and the per-protocol (PP) population (all randomised patients who received at least 1\xa0dose of the study drug and who could be classified as 'efficacy evaluable'). For each population 2\xa0sets of data were used, one where missing values were replaced using the last observation carried forward (LOCF) method and the other consisting of completers, creating in total 12\xa0sets of results. The manufacturer stated that the primary efficacy analysis was done using LOCF data but that both ITT and PP populations were of equal importance for demonstrating non-inferiority.\n\nFor the primary end point of mean difference in change in FEV1% predicted after 24\xa0weeks of treatment, the result from the ANCOVA analysis on the ITT population using LOCF data was −1.16% (95% CI −3.15% to 0.84%) suggesting that colistimethate sodium DPI was marginally less efficacious than tobramycin nebuliser solution (because the non-inferiority criterion was not met). The results of the log-transformed and non-parametric ITT population LOCF data analyses were –0.98% (95% CI −2.74% to 0.86%) and −0.56% (95% CI −2.16% to 1.00%) respectively, suggesting in both cases that colistimethate sodium DPI was non-inferior to nebulised tobramycin. For the PP population the ANCOVA, log-transformed and non-parametric analyses using LOCF data indicated that the non-inferiority hypothesis was satisfied for non-parametric analysis only (ANCOVA −1.49% [95% CI −3.79% to 0.81%], log-transformed −1.10% [95% CI –3.08% to 0.97%] and non-parametric −0.67% [95% CI −2.57% to 1.16%]).\n\nResults for the secondary outcomes reported for the COLO/DPI/02/06 trial indicated that the proportion of people experiencing at least 1\xa0protocol-defined acute exacerbation (at least 4\xa0symptoms of worsening lung function) was higher in the colistimethate sodium DPI group than in the nebulised tobramycin group (31.1% versus 26.1%). The mean time to acute respiratory exacerbation was longer among the colistimethate sodium DPI group than the nebulised tobramycin group (63.7\xa0days compared with 59.4\xa0days). The mean duration of antibiotic administration for acute exacerbations was slightly less for colistimethate sodium DPI than for nebulised tobramycin (13.6\xa0days compared with 14.4\xa0days).\n\nAdverse events were more common in the colistimethate sodium DPI group (93.6% of patients) than in the nebulised tobramycin group (89.1% of patients). A total of 27\xa0patients (22/187 patients [11.8%] in the DPI group and 5/193 patients [2.6%] in the nebulised group) were withdrawn from the COLO/DPI/02/06 trial because of an adverse event. Adverse events that appeared to be worse in the colistimethate sodium DPI group compared with the nebulised tobramycin group were cough, throat irritation and dysgeusia. Fewer patients adhered to medication in the colistimethate sodium DPI group than in the nebulised tobramycin group (67% compared with 70% respectively adhered to over 75% of doses). The Assessment Group noted that throughout the 24\xa0weeks, resistance to colistimethate sodium remained low (less than or equal to 1.1%) and resistance to tobramycin at 8\xa0mg/litre breakpoint did not change significantly from baseline during the study.\n\nQuality-of-life data using a preference-based measure in line with the NICE reference case were not collected in the COLO/DPI/02/06 trial. Health-related quality of life was evaluated in the trial by the Cystic Fibrosis Questionnaire Revised (CFQ-R) (a disease-specific instrument designed to measure impact on overall health, daily life, perceived wellbeing and symptoms) at several time points. No statistically significant differences in quality of life between baseline and week\xa024 were seen between the colistimethate sodium DPI and tobramycin nebuliser solution groups. At week\xa024, quality-of-life assessments were in favour of colistimethate sodium DPI in most CFQ-R domains in the ITT population, but none reached statistical significance.\n\n## Tobramycin DPI\n\nThe EAGER trial was designed as a non-inferiority trial in which twice-daily doses of 112\xa0mg tobramycin DPI administered via a Podhaler device were compared with twice-daily doses of 300\xa0mg nebulised tobramycin for 24\xa0weeks. The study was powered to detect non-inferiority at a margin of no less than 6% of the lower one-sided 85% confidence limit of the mean difference in relative change in FEV1% between the treatment groups at 20\xa0weeks. The study (n=533) included people aged 6\xa0years or above (DPI group mean age 26\xa0years [SD=11.4], nebulised group mean 25\xa0years [SD=10.2]) with cystic fibrosis who had chronic pseudomonas lung infection (defined as a positive culture within 6 months of screening and at baseline) and whose FEV1% was between 25 and 75%. Of the study population, 55% were male. The primary end point was the incidence of adverse events; however the trial was powered to detect change in FEV1% predicted from baseline to week\xa020. Other outcomes included microbiological measures (such as bacterial susceptibility), body mass index changes and laboratory safety end points.\n\nThe ITT EAGER results were based on complete case analysis and did not incorporate imputation (that is, filling in missing data with possible plausible values). Results indicated that tobramycin DPI was associated with an improved mean FEV1% predicted compared with nebulised tobramycin at 20\xa0weeks of +0.59% (standard error [SE] 0.92). The manufacturer reported non-inferiority (supported by least squares mean difference relative change of 1.1% [SE 1.75] which has a lower limit of the one-sided 85% confidence interval within the predicted 6% margin for non-inferiority). Only limited data were presented for lung function at 24\xa0weeks and the Assessment Group noted that they would expect FEV1% levels to be lower at that stage (following a month without tobramycin). The Assessment Group calculated the mean FEV1% at 24\xa0weeks to be 53.9% for the DPI group and 50.7% for the nebulised tobramycin group indicating a reduction in lung function from 20-week values (55.97% [DPI] and 55.28% [nebulised tobramycin]).\n\nIn the EAGER trial, pseudomonal resistance (8\xa0mg/litre breakpoint) to tobramycin started at around 20% (the baseline value was at the end of 28\xa0days off previous treatment) and was lower at 24\xa0weeks in both groups (also at the end of 28\xa0days off treatment). P.\xa0aeruginosa sputum density data showed a reduction from baseline to week\xa020 in the tobramycin DPI group (−1.61 log colony-forming units) compared with the nebulised group (−0.77 log colony-forming units).\n\nThe manufacturer did not provide details on all exacerbations from the EAGER trial; however the measure of lung disorder was used by the Assessment Group as a proxy to give an indication as to the number of participants experiencing an exacerbation. The percentage of patients experiencing lung disorders was greater in the tobramycin DPI group (33.8%) than in the nebulised tobramycin group (30.1%). However, no information was provided on the number of events experienced by patients and therefore it is not known whether some trial participants experienced multiple events. Additionally no information was provided on the time to exacerbation. Mean duration of anti-pseudomonal antibiotic treatment was also slightly shorter in the tobramycin DPI group than in the nebulised tobramycin group (30.9\xa0days compared with 33.4\xa0days). The number of trial participants receiving additional anti-pseudomonal treatments was higher in the tobramycin DPI group. The rate of discontinuation of treatment was higher in the tobramycin DPI group than in the nebulised tobramycin group (83/308\xa0patients [26.9%] compared with 38/309\xa0patients [18.2%]).\n\nAdverse events were more common in the tobramycin DPI group (90.3% of patients) than in the nebulised tobramycin group (84.2% of patients). A total of 57\xa0patients (40 [13%] in the DPI group and 17 [8%] in the nebulised group) were withdrawn from the EAGER trial because of an adverse event. The most common adverse event in the 2\xa0groups was cough (48.4% in the DPI group and 31.1% in the nebulised group). Adverse events that appeared to be worse in the tobramycin DPI group than in the nebulised group included cough and dysphonia. The EAGER trial did not define the assessment of adherence but stated that it was 'generally high' with over 90% adherence in both groups.\n\nQuality-of-life data using a preference-based measure in line with the NICE reference case were not collected in the EAGER trial. The manufacturer reported data from a treatment satisfaction questionnaire for medication results that showed higher values in the tobramycin DPI group than in the nebulised group. Least squares mean difference averages indicated an improvement over visits for effectiveness (9.36 [SE\xa01.46]), for side effects (−0.5 [SE\xa01.22]), for convenience (24.35 [SE\xa01.55]) and for global satisfaction (5.20 [SE\xa01.66]) for tobramycin DPI compared with nebulised tobramycin.\n\nThe Assessment Group commented that the quality of the included studies for both colistimethate sodium DPI and tobramycin DPI was generally poor to moderate. None of the included trials scored well on all risk of bias items, particularly on the issues of blinding and non-adherence to the current European Medicines Agency (EMA) research guidelines. The Assessment Group judged that this could lead to selection and reporting bias for subjective outcomes such as adverse events, inaccuracies and imprecision in the results, and might limit the generalisability of the studies. The Assessment Group judged that follow-up was not long enough to detect slowing of the rate of decline in respiratory function, according to current EMA research guidelines, nor for any assessment of mortality. The Assessment Group also highlighted that because FEV1% is a surrogate outcome, the EMA recommend that it should be considered alongside microbiological outcomes and 'harder' clinically relevant outcomes such as frequency of exacerbations and antibiotic use. Both tobramycin DPI and colistimethate sodium DPI seemed to result in more exacerbations and more people experiencing exacerbations than nebulised tobramycin, but slightly less time on antibiotics. The incidence of adverse events was similar between groups within the trials except for cough, which had a higher incidence in both DPI groups. More patients in the DPI groups withdrew because of adverse events in both EAGER and COLO/DPI/02/06. The Assessment Group judged that it was not possible to determine whether the changes seen in the colistimethate sodium DPI group were significantly different to the changes seen in the tobramycin DPI group because of different trial designs, a lack of data at 24\xa0weeks, different population analyses of results and uncertain comparability of patient characteristics at baseline. The Assessment Group was unable to draw definite conclusions as to the relative efficacy of any intervention except where there was direct evidence for the dry powder formulations compared with nebulised tobramycin.\n\n## Mixed treatment comparison (tobramycin DPI)\n\nThe manufacturer of tobramycin DPI performed a literature review followed by a network meta-analysis using data from 7\xa0studies to assess the clinical effectiveness of tobramycin DPI given by Podhaler relative to TOBI (tobramycin nebuliser solution), Bramitob (tobramycin nebuliser solution made by a different manufacturer), nebulised colistimethate sodium, aztreonam nebuliser solution and placebo. Colistimethate sodium DPI was not included in the analysis because study results for this technology were not in the public domain. The manufacturer explained that in the network meta-analysis there were underlying differences in the included trials in terms of trial populations, outcomes used and study design. The Assessment Group did not carry out an evaluation or provide specific comments on the manufacturer's network meta-analysis because it judged that given the available evidence, such an analysis was not feasible. The results of the network meta-analysis found no statistically significant differences between comparators in terms of efficacy at 4\xa0weeks (measured by FEV1% predicted).\n\n# Cost effectiveness\n\nThe cost-effectiveness evidence consisted of: a model by the manufacturer (Forest) for colistimethate sodium DPI; an analysis of the manufacturer's model by the Assessment Group; a de novo model produced by the Assessment Group; and Assessment Group economic analyses in response to the original and revised patient access schemes submitted by the manufacturer of colistimethate sodium DPI and the patient access scheme submitted by the manufacturer of tobramycin DPI. The manufacturer of tobramycin DPI proposed that a cost-minimisation analysis should be undertaken, because their network meta-analysis had found that the included anti-pseudomonal treatments had similar efficacy.\n\nThe Assessment Group performed a systematic review of published literature and identified 3\xa0economic evaluations: a cost–consequence analysis of home intravenous treatment in people with cystic fibrosis (Wolter et al. 1997); a cost-effectiveness analysis comparing hospital and home care in people with cystic fibrosis (Thornton et al. 2005); and a cost–consequence analysis of inhaled tobramycin nebuliser solution in people with cystic fibrosis (Iles et al. 2003). None of these 3\xa0studies relate to either colistimethate sodium DPI or tobramycin DPI. The Assessment Group judged that these studies provided some information about the costs and outcomes of the comparator therapies and explained some of the key methodological problems surrounding the economic evaluation of treatments for cystic fibrosis, for example, short-term lung function improvements rather than quality-adjusted life year (QALY) gains.\n\n## Manufacturer's model on the cost effectiveness of colistimethate sodium DPI\n\nForest used a cohort-based decision analysis to compare colistimethate sodium DPI with nebulised tobramycin. The population modelled were people aged 6\xa0years or older with documented cystic fibrosis who had chronic pseudomonas lung infection (the same population as the COLO/DPI/02/06 trial). The model had a 24-week time horizon and took a UK NHS perspective. The main assumptions of the model were that FEV1% determines year\xa01 or 2 mortality risk, utility is fixed at 0.68, there is no reduction in quality of life during an exacerbation or for an adverse event and all patients have a fixed maximum life expectancy of 37.4\xa0years.\n\nThe COLO/DPI/02/06 trial did not collect health-related quality-of-life data using a preference-based instrument. Utility estimates in the manufacturer's model were obtained from the CFQ used in the COLO/DPI/02/06 study, mapped to EQ-5D tariff values using regression equations with coefficients derived from patient-level data from a published study in people with cystic fibrosis (Eidt-Koch et al. 2009). In this study, data were collected in 2006 across 4\xa0cystic fibrosis centres in Germany. A cohort of 96\xa0patients with cystic fibrosis completed both the German version of the CFQ and the EQ-5D-Y. Patients included in this study were generally young (the mean age was approximately 13\xa0years, range 8 to 17\xa0years) and mean FEV1% predicted was generally high in both the child and adolescent groups (93.6% and 90.7% respectively).The responses to the EQ-5D-Y were valued using the EQ-5D tariff. This mapping exercise produced a single utility value of 0.68 for people with cystic fibrosis with chronic P.\xa0aeruginosa lung infection.\n\nCosts and QALYs based on treatment, life expectancy and exacerbations were then estimated by a cohort-based decision analysis incorporating an estimated mortality risk and this single utility value of 0.68 for people with cystic fibrosis. Predicted mortality differences between colistimethate sodium DPI and nebulised tobramycin were estimated by regression equations for mortality at 1 and 2\xa0years using reported data from a retrospective analysis of the risk of mortality by Kerem et al. (1992). This study used the patient characteristics of FEV1% predicted, forced vital capacity, partial pressures of oxygen and carbon dioxide, sex, weight and height to predict mortality at 1\xa0and 2\xa0years. The manufacturer fitted several polynomial regression equations to the Kerem et al. data for mortality risk at 1\xa0or 2\xa0years by FEV1% group. The manufacturer then applied the best fit regression equation to patient-level data from COLO/DPI/02/06 to calculate the 1- and 2-year mortality risks for the intervention and comparator groups based on FEV1% predicted only.\n\nThe manufacturer's model included costs for acquisition of medication and costs associated with exacerbations. Acquisition costs for nebulised tobramycin were taken from BNF edition 61. The model assumed a cost per dose of tobramycin of £21.20 (annual cost of £7738, excluding VAT), corresponding to a regimen in which 2\xa0doses of nebulised tobramycin are used each day, and each 28-day treatment period is followed by 28\xa0days without nebulised tobramycin. The manufacturer's economic analysis priced colistimethate sodium DPI at parity with nebulised tobramycin. Exacerbations were costed from NHS reference costs but as there were no reference costs for cystic fibrosis exacerbations, the reference cost for an asthma admission with major comorbidities and/or complications without intubation was used. The numbers of exacerbations for people receiving colistimethate sodium DPI and nebulised tobramycin were calculated from patient-level data in the pivotal COLO/DPI/02/06 trial. The manufacturer reported results in terms of incremental net benefit with the results indicating that colistimethate sodium DPI dominated nebulised tobramycin, that is, it was more effective and cost less than nebulised tobramycin.\n\n## Assessment Group's analysis of the Forest model\n\nThe Assessment Group highlighted that there were limitations with the manufacturer's model and that it deviated from the NICE reference case in many ways: no discounting was carried out for costs because of the short time horizon; there were inconsistent time horizons for costs and health outcomes; results were presented as an incremental net benefit rather than an incremental cost per QALY gained; and no probabilistic sensitivity analysis was carried out. The Assessment Group also highlighted that the short study duration of the COLO/DPI/02/06 trial meant a high degree of censoring of mortality estimates. The Assessment Group also expressed substantial concerns in relation to the model using changes in FEV1% predicted measured in the short term to predict long-term mortality benefits. The Assessment Group highlighted the shortcomings of using particular sources of evidence (Kerem et al.) to derive survival estimates, the fixed life expectancy of 37.4\xa0years used in the model, the use of the particular mapping method to produce utility estimates, the potential biases in the modelling of exacerbation rates and omission of relevant costs and health impacts.\n\nThe Assessment Group carried out a literature search and concluded that FEV1% alone is unlikely to represent a valid independent predictor of survival. It judged that the survival estimated in the manufacturer's model derived from the Kerem et al. data lacked validity because of the potential for confounding from other prognostic factors. The Assessment Group noted that the use of the regression equation to link mortality to lung function was unnecessary and unjustified because it should have been possible to directly apply the Kerem et al. mortality probabilities to the categorical FEV1% predicted bands from the COLO/DPI/02/06 trial.\n\nThe Assessment Group carried out a re-analysis of the manufacturer's model to try and correct for some of the problems identified with the model. It acknowledged that it could not fully resolve the problems regarding the time horizon, the health impact of adverse events or the uncertainty surrounding the QALY benefits for colistimethate sodium DPI. The results of the revised analysis found that if colistimethate sodium DPI is priced lower than nebulised tobramycin it may dominate because of lower costs from avoided exacerbations and incremental QALY gains. If the price is higher than nebulised tobramycin, the incremental cost per QALY gained ranges from £42,872 to £485,550 depending on assumptions about time horizons and drug acquisition costs.\n\n## Assessment Group de novo model\n\nThe Assessment Group developed a de novo probabilistic state transition model to compare colistimethate sodium DPI with nebulised tobramycin in people with cystic fibrosis who had chronic P.\xa0aeruginosa lung infection. It did not initially include tobramycin DPI in the model because patient-level FEV1 data were not available from the manufacturer at the time the report was produced (this information was subsequently provided by the manufacturer when the patient access scheme for tobramycin DPI was considered) and information on the price of tobramycin DPI was not available until February 2012. Other comparator treatments listed in the scope were not included in the analysis because of lack of data. The model had a lifetime time horizon and a UK NHS perspective. The cycle length was 24\xa0weeks and treatment duration was assumed to be equivalent between the competing treatments. The model assumed that treatments were administered in line with their marketing authorisation. Mean survival for patients in the model was estimated using data from Dodge et al. 2009. This study reported survival data up to the end of 2003 for all people with cystic fibrosis born in the UK between 1968 and 1992 collated by active enquiry of cystic fibrosis clinics and other hospital consultants. The model had 5\xa0health states: FEV1 70–99%, FEV1 40–69%, FEV1 less than 40%, post lung transplant and death. The 24-week probabilities for transition between health states were based on patient-level data from the COL/DPI/02/06 trial. The Assessment Group judged that some people may switch between colistimethate sodium and tobramycin at some point in their lives. However, this feature was not included in the model because clinical-effectiveness data on the effect of treatment switching were not available.\n\nDifferent levels of health-related quality of life were assumed for each health state. Total QALYs were calculated as the total time in each health state weighted by the respective utility for that health state, less any QALY losses resulting from exacerbations. Utility estimates were obtained from the Bradley (2010) study. No mortality gain from improved FEV1% predicted was incorporated into the model. A further assumption was that there was no quality of life reduction with adverse events.\n\nCosts in each treatment group included drug acquisition costs and the costs of managing exacerbations (either in hospital or at home). Potential cost savings associated with reduced maintenance of nebulisers were also included in the economic analysis for the DPI group. Costs associated with follow-up and concomitant medications were assumed to be equivalent between treatment groups.\n\nThe Assessment Group produced a set of analyses that included 5\xa0different pricing scenarios for colistimethate sodium, because at that time the list price for colistimethate sodium DPI was not available. The results of these analyses were superseded by additional analyses which included the confirmed list price and the original and revised patient access schemes (see sections 4.2.15 to 4.2.19). The analyses resulted in an incremental QALY loss (0.13) over a patient's lifetime associated with colistimethate sodium DPI compared with nebulised tobramycin. If colistimethate sodium DPI is priced at £15.98 or above per dose, it is dominated by nebulised tobramycin. If colistimethate sodium DPI is priced at £10.60 per dose, the model suggests an incremental cost-effectiveness ratio (ICER) of £23,788 saved per QALY lost. However, the Assessment Group noted that this ICER lies in the south-west quadrant of the cost-effectiveness plane (that is, less effective and less expensive) and represents a QALY loss and cost savings for colistimethate sodium DPI compared with nebulised tobramycin.\n\nThe Assessment Group stated that although there is considerable uncertainty surrounding the extrapolation of the COLO/DPI/02/06 trial data, the conclusions of the analysis appear robust. This is because the uncertainty imposed by long-term extrapolation of short-term results has little bearing on the model conclusions because colistimethate sodium DPI remains dominated if its price is set higher than nebulised tobramycin. The Assessment Group highlighted that the deterministic sensitivity analysis (performed on utilities, transition probabilities, utility decrement from exacerbation, cost of hospitalisation and point estimates for parameters) showed that the choice of utility value had the most substantial effect on the cost-effectiveness estimate. The Assessment Group also re-ran the model using a 24-week time horizon. The results indicated an expected tiny decrease (0.002) in QALYs for colistimethate sodium DPI compared with nebulised tobramycin. If priced at £9.11 per dose or £10.60 per dose, colistimethate sodium DPI is expected to be less expensive than nebulised tobramycin and results in ICERs of £276,814 and £49,596 saved per QALY lost respectively. As in the long-term model these positive ICERs are the result of cost savings and QALY reductions. If colistimethate sodium DPI is priced at £15.98 or above per dose, it is dominated by nebulised tobramycin, as in the long-term model.\n\n## Colistimethate sodium DPI patient access schemes\n\nThe Assessment Group also carried out additional analyses in response to the patient access schemes submitted by the manufacturers of colistimethate sodium (sections 4.2.15 to 4.2.19) and tobramycin DPI (sections 4.2.20 to 4.2.25). With regard to the original colistimethate sodium DPI scheme, only the price of colistimethate sodium DPI was amended; all other assumptions and parameters in the model remained unchanged (sections 4.2.10–4.2.12). The Assessment Group explained that when the list price was modelled (this having been finalised and provided at this stage), colistimethate sodium DPI was dominated by nebulised tobramycin. When the patient access scheme discount was incorporated, the results demonstrated that colistimethate sodium DPI was less effective and less expensive than nebulised tobramycin, the ICER being £52,672 saved per QALY lost.\n\nThe Assessment Group also carried out a probabilistic sensitivity analysis. The probability of colistimethate sodium DPI (at list price) being more cost effective than nebulised tobramycin (at list price) at a threshold of £20,000 and £30,000 per QALY gained was zero. The results also suggested that when the original patient access scheme is included in the analysis, the probability of colistimethate sodium DPI being more cost effective than nebulised tobramycin is approximately 0.79 at a threshold of £20,000 saved per QALY lost, and 0.66 at a threshold of £30,000 saved per QALY lost.\n\nAdditionally the Assessment Group carried out a sensitivity analysis using the Commercial Medicines Unit (CMU) Electronic Marketing Information Tool (E-MIT) price rather than the BNF list price for nebulised tobramycin. In September 2012, the estimated price for nebulised tobramycin paid by the NHS was £970.12 rather than the BNF list price of £1187. The results of this analysis suggest that on the basis of the original patient access scheme price for colistimethate sodium DPI and the CMU E-MIT price for nebulised tobramycin, colistimethate sodium DPI is dominated by nebulised tobramycin.\n\nThe Assessment Group concluded that at its list price, colistimethate sodium DPI is expected to be dominated by nebulised tobramycin (at list price). When the original patient access scheme is included in the analysis, the incremental cost effectiveness of colistimethate sodium DPI compared with nebulised tobramycin (at list price) is expected be around £52,700 saved per QALY lost (that is, colistimethate sodium DPI is less effective but also less expensive than nebulised tobramycin). When the CMU E-MIT price of nebulised tobramycin is compared with both list and original patient access scheme prices of colistimethate sodium DPI, colistimethate sodium DPI is dominated by nebulised tobramycin.\n\nThe Assessment Group also carried out additional analyses in response to the revised patient access scheme submitted by the manufacturer of colistimethate sodium as part of its response to the appraisal consultation document (ACD) consultation. Only the price of colistimethate sodium DPI was amended in the model; all other assumptions and parameters in the model remained unchanged (sections 4.2.10–4.2.12). When the revised patient access scheme discount was incorporated, the incremental QALY was −0.13, and the incremental cost was −£37,946 compared to nebulised tobramycin (list price). These results demonstrated that colistimethate sodium DPI was less effective and less expensive than nebulised tobramycin, the ICER being £288,563 saved per QALY lost. The probabilistic sensitivity analysis associated with these analyses estimated that with the revised patient access scheme, colistimethate sodium DPI had a probability of 1.0 of being cost effective at the £20,000 and £30,000 per QALY gained thresholds. The Assessment Group again carried out a sensitivity analysis using the CMU E-MIT price rather than the BNF list price for nebulised tobramycin sodium DPI. The results of this analysis suggest that on the basis of the revised patient access scheme price for colistimethate sodium DPI and the CMU E-MIT price for nebulised tobramycin, the resulting ICER was £154,916 saved per QALY lost (incremental cost and QALY of −£20,371 and −0.13 respectively). However, as all these analyses included only a comparison with nebulised tobramycin the cost effectiveness of colistimethate sodium DPI relative to any other comparator is uncertain.\n\n## Tobramycin DPI patient access scheme\n\nIn response to an agreed patient access scheme for tobramycin DPI, the Assessment Group carried out additional analyses evaluating the cost effectiveness of tobramycin DPI compared with nebulised tobramycin. This analysis used the Assessment Group de novo model (used for colistimethate sodium DPI described above), but transition probabilities between health states and exacerbation parameters were based on those observed in the EAGER trial. The manufacturer provided individual patient-level FEV1% data together with aggregated data on exacerbations from the EAGER trial, which had been previously unavailable to the Assessment Group. All other base-case assumptions in the model were unchanged (see sections 4.2.10–4.2.12).\n\nThe Assessment Group carried out analyses using 3\xa0sets of FEV1 data from the EAGER trial: 1) pre-dose FEV1% at week\xa00 to FEV1% at week\xa024; 2) pre-dose FEV1% at week\xa00 to pre-dose FEV1% at week\xa020; 3) post-dose FEV1% at week\xa00 to post-dose FEV1% at week\xa020. The Assessment Group highlighted that there was uncertainty around which of these analyses should be considered the most reliable because of the effect of tobramycin on FEV1% soon after administration (rather than off treatment 4\xa0weeks later). The Assessment Group judged that the analysis 'Pre-dose FEV1% at week\xa00 to FEV1% at week\xa024' (analysis 1) was the most appropriate and should be considered to be the base-case analysis, but noted that this was not the ITT population because it only included trial participants for whom baseline and week\xa024 lung function values had been recorded. The Assessment Group highlighted that there was a notable amount of missing data with higher rates of attrition in the tobramycin DPI arm than in the nebulised tobramycin arm and therefore the data may reflect a 'best case scenario' whereby only participants who had a response to the drug are captured in either group.\n\nIn the Assessment Group model, the incremental QALY gain for tobramycin DPI compared with nebulised tobramycin was 0.34 (pre-dose FEV1% at week\xa00 to FEV1% at week\xa024) and the incremental costs were £42,453. The cost-effectiveness results for the base-case analysis of the list prices of tobramycin DPI compared to nebulised tobramycin gave an ICER of £123,563 per QALY gained (without the patient access scheme applied). With the patient access scheme applied, tobramycin DPI dominated nebulised tobramycin (at list price) with incremental cost savings of £19,275.\n\nThe Assessment Group also carried out a one-way sensitivity analysis on the following parameters: deterministic point estimates of parameters on utility values, transition probabilities, utility decrement for exacerbations and costs of hospitalisation. These analyses indicated that tobramycin DPI dominated nebulised tobramycin when the patient access scheme was included in analysis 1 (pre-dose FEV1% at week\xa00 to FEV1% at week\xa024) except for the scenario in which the transition probabilities for nebulised tobramycin were set as equal to those for tobramycin DPI.\n\nThe Assessment Group also carried out probabilistic sensitivity analyses. The probability of tobramycin DPI (at list price) being more cost effective than nebulised tobramycin (at list price) at thresholds of £20,000 and £30,000 per QALY gained was zero for all 3\xa0ways of interpreting the FEV1 data described in section 4.2.21. The probability of tobramycin DPI (with the inclusion of the patient access scheme) being more cost effective than nebulised tobramycin (at list price) at thresholds of £20,000 and £30,000 per QALY gained was 1.00 for all of the analyses: pre-dose FEV1% at week\xa00 to FEV1% at week\xa024; pre-dose FEV1% at week\xa00 to pre-dose FEV1% at week\xa020; and post-dose FEV1% at week\xa00 to post-dose FEV1% at week\xa020.\n\nThe Assessment Group also carried out an additional sensitivity analysis using the price of nebulised tobramycin based on estimates from the CMU E-MIT (£970.12) rather than the BNF list price of £1187. The results found that with the introduction of the patient access scheme, tobramycin DPI consistently dominated nebulised tobramycin irrespective of which FEV1% data were used. Probabilistic sensitivity analyses indicated that the probability of tobramycin DPI being more cost effective than nebulised tobramycin was 1.0 at a threshold of £20,000 per QALY gained and 0.99 at a threshold of £30,000 per QALY gained, for the preferred analysis based on pre-dose FEV1% at week\xa00 to FEV1% at week\xa024. The Assessment Group concluded that the introduction of the patient access scheme could be expected to result in tobramycin DPI consistently dominating nebulised tobramycin irrespective of which FEV1% data are used. However, the Assessment Group pointed out that uncertainties remained:\n\nBecause of absence of sufficient evidence relating to any other comparator, the economic analysis of tobramycin DPI is restricted solely to an economic comparison with nebulised tobramycin.\n\nData on minor and major exacerbations were not collected in the EAGER trial. The Assessment Group explained that lung disorder may represent a reasonable proxy for pulmonary or cystic fibrosis exacerbations and hence these data were used to estimate the probability of any exacerbation (minor or major) in each treatment group. The mean probability of exacerbation for tobramycin DPI was estimated to be 0.34 and the mean probability of exacerbation with nebulised tobramycin was 0.30. The manufacturer provided trial data estimates of the number of patients receiving any new antibiotic, total days used, and the number of patients who needed both additional antibiotic treatment and hospitalisation in each treatment group. The estimates of the number of patients who needed both additional antibiotic treatment and hospitalisation, combined with the estimated number of exacerbation events from Konstan et al., were used to produce an estimate of the pooled probability that an exacerbation event was major. The Assessment Group explained that this estimate is very similar in terms of number of exacerbations to that derived from the COLO/DPI/02/06 trial but the validity of this estimate remains questionable.\n\nMuch of the incremental benefit is driven by the small QALY gains observed within the trial period which are inflated considerably by extrapolating over the patient's remaining lifetime. Over the patient's lifetime this incremental QALY gain is expected to range from 0.04\xa0QALYs (post-dose 0–20\xa0weeks) to 0.34\xa0QALYs (pre-dose 0–24\xa0weeks).\n\nMissing data and high attrition rates in the EAGER trial for tobramycin DPI mean that transition data may reflect a best-case scenario in which only responders are captured in either group and therefore cost effectiveness may be less than that estimated.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of colistimethate sodium DPI and tobramycin DPI for treating pseudomonas lung infection in cystic fibrosis, having considered evidence on the nature of chronic pseudomonas lung infection in people with cystic fibrosis and the value placed on the benefits of colistimethate sodium DPI and tobramycin DPI by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the current treatment pathway for people with cystic fibrosis with chronic P.\xa0aeruginosa lung infection. The Committee heard from clinical specialists that treatment is generally patient driven and that the most important outcomes for the patient that influence treatment decisions are the person's quality of life, treatment burden, maintaining good lung function and reducing the incidence of exacerbations. The Committee heard from clinical specialists that first-line treatment for chronic P.\xa0aeruginosa lung infection routinely starts with nebulised colistimethate sodium (unless it is contraindicated), this choice being largely based on cost. If there is no response, an unacceptable adverse event profile, an excessive number of acute exacerbations or a loss of lung function, then treatment is switched routinely to nebulised tobramycin. Tobramycin is administered in cycles of 28\xa0days on treatment, followed by 28\xa0days off treatment, in accordance with the marketing authorisation. The Committee noted that this was in line with the national guidelines from the Cystic Fibrosis Trust. The clinical specialists advised that having 28\xa0days off treatment was not favoured by some people with cystic fibrosis and some clinicians, and that either nebulised colistimethate sodium during the 28-day off period or continuous half-dose nebulised tobramycin were used in some patients. The Committee noted that the use of colistimethate sodium only in the tobramycin 28-day off period and the use of continuous half-dose tobramycin by some people on nebulised tobramycin were outside the respective marketing authorisations, and heard from the clinical specialists that there was no clinical-effectiveness evidence for such approaches to treatment. The Committee therefore understood that the usual treatment pathway was for nebulised colistimethate sodium to be used first and then nebulised tobramycin second.\n\nThe Committee discussed the comments received during consultation on the ACD regarding the current treatment pathway. Some indicated that in the majority of adult specialist centres in the UK there has been a move away from offering nebulised colistimethate sodium as initial treatment followed by tobramycin, towards alternating therapy between tobramycin and colistimethate sodium on a monthly basis. Other comments indicated that it was still usual for nebulised colistimethate sodium to be used first and then patients were switched to nebulised tobramycin if there were problems with nebulised colistimethate sodium or if it did not work well enough. The Committee heard from the Assessment Group that information from their clinical experts suggested that less than 25% of people with cystic fibrosis and chronic P.\xa0aeruginosa lung infection would receive an alternating therapy regimen. The Committee therefore concluded that some people with cystic fibrosis and chronic pseudomonas lung infection may receive alternating tobramycin and colistimethate sodium treatment in clinical practice. The Committee noted the increased cost of such alternating antibiotic regimens and that it had not been presented with any evidence as to the clinical effectiveness of this approach by the Assessment Group or the manufacturers or during consultation. It concluded that because there was no evidence of the clinical effectiveness of using these antibiotics in an alternating regimen, it could not consider this issue further.\n\nThe Committee discussed the appropriate comparators for colistimethate sodium and tobramycin DPIs. It heard from the manufacturer of colistimethate sodium DPI that the EMA had indicated that the most appropriate comparator at the time of the study design for its pivotal trial would be nebulised tobramycin because this was the only licensed comparator in all of the study site countries. The Committee agreed that given the current clinical pathway, ideally it would have liked to have seen effectiveness evidence comparing colistimethate sodium DPI with nebulised colistimethate sodium and also whether there was evidence of any clinical benefit of colistimethate sodium DPI in people being switched from nebulised colistimethate sodium because of lack of efficacy. Taking into account the sequence of inhaled antibiotics currently used in the treatment pathway in the UK (see sections 4.3.2 and 4.3.3) and the clinical specialists' opinion that clinicians would switch from one antibiotic to another (whatever the preparation), the Committee concluded that the most appropriate comparator for colistimethate sodium DPI would be nebulised colistimethate sodium and the most appropriate comparator for tobramycin DPI would be nebulised tobramycin.\n\nThe Committee considered the treatment burden associated with cystic fibrosis. The Committee heard from patient experts how time-consuming all the treatments can be, taking up to 4\xa0hours each day and imposing on other daily activities. The Committee noted that most people with cystic fibrosis use nebulisers for administration of other daily treatments as well as for antibiotics for pseudomonas lung infection. The Committee heard from patient experts how using a nebuliser also involves preparation of the treatment and cleaning of equipment, both of which add to the treatment burden. The Committee recognised that the strict routine and amount of time spent receiving treatment have a significant impact on the daily activities of people with cystic fibrosis and their families. The Committee concluded that reducing the time that people with cystic fibrosis spend receiving treatment would be beneficial in improving the quality of life of people with cystic fibrosis and their families.\n\nThe Committee discussed the impact of long-term treatment with nebulised antibiotics in people with cystic fibrosis. The Committee heard from clinical specialists and patient experts that adherence to medication was variable and did not just relate to nebulisers but also to inhalers and oral treatments. The Committee heard from clinical specialists that in clinical practice adherence to nebulised treatments was approximately 30–60%. The patient experts commented that out of all of their treatments, the ones they were least likely to adhere to were those administered with a nebuliser. The Committee also heard from the patient experts that older nebulisers are not easily portable, take up a lot of space in the home and involve greater costs to the patient in electricity usage. Additionally, the clinical specialists commented that newer, smaller and faster nebulisers are in common use and these greatly decrease the time of treatment but still involve drug preparation and cleaning. The Committee noted that nebulised colistimethate sodium and tobramycin are not licensed for use with these faster nebulisers but nevertheless accepted that it is usual practice for these types of fast nebulisers to be used, and this was confirmed by the clinical specialists. The Committee concluded that in clinical practice (rather than in clinical trials), people with cystic fibrosis may be more likely to adhere to a dry powder for inhalation treatment than a nebulised treatment in view of the speed and convenience of drug delivery.\n\n## Clinical effectiveness\n\nThe Committee discussed the clinical-effectiveness evidence for colistimethate sodium and tobramycin DPIs. The Committee noted that there was no clinical trial comparing the effectiveness of colistimethate sodium DPI with that of the preferred comparator, nebulised colistimethate sodium. The Committee discussed the clinical-effectiveness evidence from the COLO/DPI/02/06 trial which compared colistimethate sodium DPI with nebulised tobramycin and the EAGER trial which compared tobramycin DPI with nebulised tobramycin. The Committee noted that both trials were non-inferiority in design and therefore only assessed whether the interventions were not worse than nebulised tobramycin, where non-inferiority was accepted if the lower confidence limit for the difference between treatments in FEV1% was above a fixed percentage (the 95% confidence limit with a difference of –3% was chosen in COLO/DPI/02/06 and the 85% confidence interval with a difference of –6% in EAGER). The Committee noted the different confidence levels and margins of non-inferiority selected for the 2\xa0key trials which it found surprising given it would have expected these to be based on similar clinical considerations. It was also aware that in the case of COLO/DPI/02/06, logarithmic transformations and a non-parametric approach using the median rather than mean values reduced the impact of extreme values and hence made it easier to achieve non-inferiority. The Committee concluded that it only had evidence exploring whether either dry powder formulation was not worse than nebulised tobramycin and no evidence to prove that either was more effective than or equivalent to nebulised tobramycin.\n\nThe Committee discussed the quality of the 2\xa0key trials. It noted the Assessment Group's critique of the trials, in particular the fact that the manufacturers had not commented in their submissions on the quality of these trials in light of the current EMA research guidelines for the development of medicinal products for the treatment of cystic fibrosis. The Committee supported the Assessment Group's comments on the methodological limitations of both trials, such as lack of blinding, and agreed that this could have introduced selection and reporting bias for subjective outcomes such as adverse events and might limit the generalisability of the findings. The Committee concluded that the evidence base for assessing the clinical effectiveness of colistimethate sodium and tobramycin DPIs was of, at best, modest quality but that it was the best available.\n\nThe Committee discussed the results for lung function measurements in the 2\xa0key trials and the results of these analyses in the ITT population. The Committee was aware that the primary outcome for the COLO/DPI/02/06 trial was respiratory function as measured by FEV1% predicted at 24\xa0weeks. The Committee noted that the study was powered to detect a minimum change in the difference in FEV1% of −3% (based on the lower bound of a 95% confidence interval for the difference in means). The Committee noted that the non-inferiority criterion was not met in the pre-defined ANCOVA analysis for the ITT population but it acknowledged that in the logarithmic and non-parametric analyses the non-inferiority criterion had been met in the ITT population for the LOCF analyses. The Committee was additionally aware that the manufacturer had stated that both LOCF and completer analyses were of equal importance and that the non-inferiority criterion was only met for the ITT population in the non-parametric analysis using the completer dataset. The Committee noted that the EAGER trial was powered to detect non-inferiority at a margin of no less than 6% difference in the mean FEV1% between tobramycin DPI and nebulised tobramycin at the lower end of the one-sided 85% confidence interval and that results showed that tobramycin DPI was not statistically significantly worse than nebulised tobramycin with respect to change in mean FEV1% at 20\xa0weeks. The Committee heard from the clinical specialists that FEV1% tends to fluctuate over the short term and the clinical specialists therefore agreed that the 24-week follow-up period of the trials was not sufficiently long enough to assess the impact of either colistimethate sodium DPI or tobramycin DPI on FEV1% predicted compared with nebulised tobramycin in the longer term. The Committee noted that both trials had resulted in relatively small changes in FEV1% levels at 24\xa0weeks. Additionally, the Committee heard from the clinical specialists that small changes in FEV1% levels over a short term were not considered clinically meaningful in determining whether chronic P.\xa0aeruginosa lung infection was being effectively managed in clinical practice. The Committee discussed the nature of non-inferiority trials compared with trials designed to show equivalence and the short-term nature of both of the DPI versus nebulised tobramycin trials. Whilst it would have much preferred trials that were designed for equivalence and had continued for at least the 12\xa0months specified in the current EMA research guidelines for such agents because of the importance of the clinical outputs for use in the cost-effectiveness analysis, it accepted that the evidence presented in terms of FEV1% was the best available and it had to make its judgements accordingly. Additionally the Committee noted that the results of COLO/DPI/02/06 trial indicated it had failed its primary non-inferiority end point in some analyses, but that it had a stricter definition of non-inferiority than the EAGER trial, which also had a primary end point of 20 not 24\xa0weeks. The Committee concluded that the COLO/DPI/02/06 and EAGER trials may have demonstrated that colistimethate sodium DPI and tobramycin DPI were non-inferior to nebulised tobramycin with respect to change in FEV1% within the populations tested and in the manner conducted within each trial, but remained concerned with the uncertain clinical relevance of these findings given the short-term nature of these trials.\n\nThe Committee discussed microbiological outcomes and the adverse events reported in the 2\xa0key trials. The Committee noted that the COLO/DPI/02/06 and EAGER trials had both reported improvements in mean sputum density of P.\xa0aeruginosa with colistimethate sodium DPI and tobramycin DPI compared to nebulised tobramycin (see sections 4.1.6 and 4.1.10). However, the Committee heard from the clinical specialists that microbiological measurements such as sputum density were not generally carried out in clinical practice. The Committee also observed that both the COLO/DPI/02/06 and EAGER trials reported a higher incidence of adverse events, particularly cough, with both dry powder formulations (see sections 4.1.6 and 4.1.12). Additionally the Committee noted there were higher levels of withdrawal because of adverse events in the dry powder formulation groups of both trials. The Committee was uncertain as to the implications of the adverse event results and it was unsure whether the adverse events associated with either tobramycin DPI or colistimethate sodium DPI were significantly different from those associated with nebulised tobramycin.\n\nThe Committee considered which outcomes were the most clinically relevant for assessing the effectiveness of a drug for chronic P.\xa0aeruginosa lung infection in people with cystic fibrosis. The Committee noted the opinion of clinical specialists that treatment decisions are often informed by the incidence of exacerbations and the quality of life of the person with cystic fibrosis (see section 4.3.2) rather than short-term changes in FEV1%. The Committee understood that the COLO/DPI/02/06 trial had not identified any statistically significant improvement in health-related quality of life with colistimethate sodium DPI compared with nebulised tobramycin (see section 4.1.7). It noted that no health-related quality-of-life data had been collected in the EAGER trial. The Committee heard from clinical specialists that the number of exacerbations was routinely measured in clinical practice to determine whether a particular treatment was working. The Committee noted that the Assessment Group estimated the probability of people experiencing any exacerbation was slightly lower for colistimethate sodium DPI than for nebulised tobramycin in the COLO/DPI/02/06 trial, but that the rate of protocol-defined exacerbations was higher in the colistimethate sodium DPI group than in the nebulised tobramycin group. It also noted the Assessment Group's comments that exacerbation data were not specifically defined and collected in the EAGER trial and that the term 'lung disorder' might be a reasonable proxy for exacerbation of chronic infection. The Committee understood that the Assessment Group had estimated that the probability of any exacerbation was higher with tobramycin DPI than with nebulised tobramycin. The Committee also heard from the patient experts that avoiding exacerbations was considered the most important outcome for people with cystic fibrosis as it meant feeling better and having a better quality of life. The Committee was aware from patient experts that exacerbations can lead to periods of hospitalisation and the need for intravenous drugs which can have a potentially negative impact on quality of life. The Committee acknowledged the importance of exacerbations to patients and the NHS and the fact that the trial evidence for exacerbations was difficult to interpret because of the way it had been reported and the fact it was over such a short time frame. The Committee concluded that the differences observed in the trials may be small and over a short time horizon but they were the only evidence that is available. The Committee concluded that it was uncertain as to how it should interpret the exacerbation results. Because there were limited data on quality of life and uncertainty around the evidence on exacerbations, the Committee could not draw definitive conclusions as to whether either dry powder offered any clinical benefit over nebulised tobramycin for clinically relevant outcomes.\n\nThe Committee discussed the results of the network meta-analysis by the manufacturer of tobramycin DPI (see section 4.1.15). The Committee noted that both the manufacturer and the Assessment Group had acknowledged the limitations of this analysis because of lack of available trials and comparable populations and outcome datasets. The Committee noted that the network meta-analysis had not included colistimethate sodium DPI, but accepted the manufacturer's explanation that this was because trials of colistimethate sodium DPI were not available as none had been published at the time of the submission. The Committee also heard from the manufacturer of colistimethate sodium DPI that it was not aware of any trials other than the small safety trial COLO/DPI/02/05, which compared colistimethate sodium DPI and nebulised colistimethate sodium. The Committee also noted that the manufacturer of tobramycin DPI considered that the results of the analysis comparing tobramycin DPI with other alternative formulations of nebulised tobramycin (such as Bramitob) should be treated with caution because of the underlying differences in study populations. The Committee agreed that because of the uncertainties surrounding the network meta-analysis it would not consider the results further. The Committee again concluded that it could only draw conclusions based on the evidence described in the 2\xa0key trials and that it had no clinical evidence comparing colistimethate sodium DPI with the appropriate comparator, nebulised colistimethate sodium.\n\nThe Committee discussed the additional benefits of the mode of delivery of the dry powder formulations over nebulised alternatives. The Committee noted that both technologies aimed to give people with cystic fibrosis and chronic P.\xa0aeruginosa lung infection quality-of-life benefits in terms of ease of use and convenience. The Committee considered that it may be plausible that the dry powder formulations could be expected to result in clinical benefits over nebulised solutions because they may increase levels of adherence to treatment. The Committee noted that in the COLO/DPI/02/06 trial levels of adherence to treatment were greater for nebulised tobramycin and it was unclear how adherence was measured in the EAGER trial. However the Committee heard from the patient experts and clinical specialists that people with cystic fibrosis are a heterogeneous population and therefore levels of adherence vary according to individual factors. The Committee heard from clinical specialists that levels of adherence to treatment would be different in clinical practice to those observed under trial conditions. Therefore the Committee agreed that it should not infer too much from these results when evaluating the likely benefit of the technologies in terms of improving adherence to treatment. The Committee acknowledged that both nebulised colistimethate sodium and nebulised tobramycin were embedded as treatment options in current clinical practice and thus judged to be clinically effective in treating chronic P.\xa0aeruginosa lung infection. The Committee therefore accepted that a change in the mode of delivery of these drugs would be unlikely to adversely affect their clinical effectiveness compared with nebulised formulations of the drugs, although it only had evidence for the comparison of tobramycin DPI with nebulised tobramycin. The Committee again recognised the limitations of the trial evidence in that this was restricted to a comparison of either DPI with nebulised tobramycin. Despite the limitations in the identified evidence and uncertainties in the interpretation of the trial outcomes, the Committee concluded that on balance it could see an additional benefit for people with cystic fibrosis and chronic pseudomonas lung infection of having the choice of a dry powder formulation of an anti-pseudomonal drug as well as its appropriate nebulised comparator.\n\n## Cost effectiveness\n\nThe Committee discussed the available cost-effectiveness evidence for colistimethate sodium DPI and tobramycin DPI. It noted that there was no cost-effectiveness evidence comparing colistimethate sodium DPI with nebulised colistimethate sodium. The Committee discussed the model provided by the manufacturer of colistimethate sodium DPI which compared colistimethate sodium DPI with nebulised tobramycin and the critique of the model by the Assessment Group. The Committee noted that the Assessment Group had identified key limitations in the submitted economic model. The Committee had particular concerns about the inconsistent time horizons used in the model for costs and health outcomes and the validity of using mortality benefits associated with 24\xa0weeks of treatment and extrapolating over a lifetime. The Committee noted that the clinical specialists felt that relatively small changes in FEV1% would not be seen as a predictor of 1- or 2-year mortality risk in clinical practice. The Committee also noted that the data used in the regression equations for estimating mortality risk were based on a 20-year-old paper, and the prognosis for people with cystic fibrosis had substantially improved during that time. Additionally, the Committee had concerns about biases in the modelling of exacerbations, which were a major driver of cost savings in the model. The Committee did not accept the validity of the assumption that all patients would have a fixed life expectancy of 37.4\xa0years. The Committee heard from the clinical specialists that it was not unusual to see people aged between 40 and 60\xa0years with cystic fibrosis. The Committee were also concerned about the lack of any preference-based instrument to measure health-related quality of life and the limitation of the method used to map CFQ-R to EQ-5D. Given these uncertainties and others raised by the Assessment Group, the Committee concluded that the manufacturer's (Forest's) model lacked credibility and therefore they would not consider it or its results plausible.\n\nThe Committee discussed the Assessment Group's de novo model which compared colistimethate sodium DPI with nebulised tobramycin and tobramycin DPI with nebulised tobramycin. The Committee noted that the model had a lifetime time horizon. The Committee agreed that the use of a lifetime horizon was appropriate, but acknowledged the limitation of extrapolating short-term trial results over long time horizons. Additionally the Committee noted other limitations of the Assessment Group model, including the fact that it did not recognise that, in the current treatment pathway, some people would move from one drug to another (for example from colistimethate sodium to tobramycin). The Committee also noted that treatment duration is assumed to be equivalent between the 2\xa0treatments. The Committee agreed that it was also plausible that some people on nebulised tobramycin would receive some form of treatment on a continuous basis (either as continuous nebulised reduced-dose tobramycin or as nebulised colistimethate sodium in off-months from tobramycin) but there was no evidence on which to base any cost-effectiveness estimate. However, the Committee also accepted that other assumptions in the model such as no difference in the rate of adverse events between colistimethate sodium DPI and nebulised tobramycin may bias in terms of favouring colistimethate sodium DPI. It was also aware that no disutility associated with adverse events was included in the model and was aware of the increased rates of cough in the DPI arms of the COLO/DPI/02/06 and EAGER trials and that this could be a factor affecting adherence. The Committee acknowledged comments received during consultation that there are inherent difficulties in quantifying the relationship between FEV1 and quality of life. The Committee concluded, however, that despite these limitations the Assessment Group's de novo model was the best available framework for assessing the cost effectiveness of colistimethate sodium DPI compared with nebulised tobramycin and of tobramycin DPI compared with nebulised tobramycin.\n\nThe Committee discussed the results from the Assessment Group's de novo model comparing colistimethate sodium with nebulised tobramycin, again noting this was not the appropriate comparator for colistimethate sodium DPI. The Committee noted the approved patient access scheme for colistimethate sodium DPI and based its decisions on the cost-effectiveness results from analyses incorporating the revised patient access scheme price. The Committee considered the sensitivity analysis using the E-MIT price of nebulised tobramycin and recognised that analyses using the list price for nebulised tobramycin may overestimate the cost effectiveness of colistimethate sodium DPI in terms of NHS practice. The Committee discussed the implications of considering a treatment that was less effective and less costly, and the need therefore to have considerable confidence in the clinical-effectiveness results. The Committee concluded that there was a great deal of uncertainty in the modelling of colistimethate sodium DPI and that the most plausible ICERs indicated that with the revised patient access scheme colistimethate sodium DPI resulted in a small QALY loss and a cost saving compared with nebulised tobramycin.\n\nThe Committee discussed all the uncertainties associated with the clinical- and cost-effectiveness evidence for colistimethate sodium DPI. It acknowledged the difficulties in performing high-quality research in a disease with a heterogenous clinical profile and where treatment options are ultimately based on clinician and patient preferences. However, the Committee was aware of the statements from clinical specialists about current treatment for people with cystic fibrosis and chronic P.\xa0aeruginosa lung infection and the treatment pathway of switching from one antibiotic to another. The Committee again confirmed that the most appropriate comparator for colistimethate sodium DPI was nebulised colistimethate sodium and that it would have wished to see the results of such a comparison. The Committee noted again that the manufacturer of colistimethate sodium DPI had confirmed that there was no trial that compared the effectiveness of colistimethate sodium DPI with nebulised colistimethate sodium. The Committee was therefore unable to reach a conclusion on the clinical and cost effectiveness of colistimethate sodium DPI compared with nebulised colistimethate sodium.\n\nThe Committee discussed the cost-effectiveness evidence for tobramycin DPI. It noted that there was no economic analysis in the manufacturer's submission for tobramycin DPI and that the manufacturer felt that a cost-minimisation approach was appropriate. The Committee did not agree that cost minimisation was appropriate in this instance because the evidence had not proved equivalence between tobramycin DPI and nebulised tobramycin and that cost minimisation would not incorporate any estimate of uncertainty; additionally the Committee was aware that the NICE reference case stated a preference for cost–utility analysis. The Committee therefore based its discussions on the cost-effectiveness analysis carried out by the Assessment Group incorporating the patient access scheme. The Committee noted that the results of this analysis had shown that tobramycin DPI consistently dominated nebulised tobramycin when the patient access scheme was included (incremental cost of –£42,500 and incremental QALY gain of 0.34 in the base case). The Committee also noted the results of the probabilistic sensitivity analysis and one-way sensitivity analysis which indicated that tobramycin DPI consistently dominated nebulised tobramycin. Additionally, the Committee was aware that the analyses were based on the inclusion of aggregate lung disorder data as a proxy measure for exacerbations because data on major and minor exacerbations had not been collected in the EAGER trial. The Committee recognised that the model assumed that the intervention and comparator are used for 28\xa0days followed by 28\xa0days without use of any drug and that this may not be reflective of clinical practice. The Committee accepted that there was no clinical evidence for such an approach and neither the clinical specialists nor the manufacturers knew of any. The Committee acknowledged that the small QALY gain for tobramycin DPI was uncertain because quality-of-life data were not collected in the EAGER trial. However, it agreed it was reasonable to assume that there would be some QALY gain for tobramycin DPI over nebulised tobramycin in clinical practice in view of the reported benefits to patients in terms of ease of use and convenience although it acknowledged that the number of withdrawals from the EAGER trial did not indicate this relationship. The Committee therefore agreed that despite the limitations of all the clinical- and cost-effectiveness evidence and hence the uncertainty inherent in the Assessment Group model, it was reasonable to conclude that tobramycin DPI was a cost-effective use of NHS resources. Therefore the Committee concluded that it could recommend tobramycin DPI (with the associated patient access scheme applied) as a treatment option for chronic P.\xa0aeruginosa lung infection in people with cystic fibrosis who would otherwise have been treated with nebulised tobramycin; that is, when colistimethate sodium is contraindicated, is not tolerated, or has not produced an adequate clinical response. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care.\n\nThe Committee considered whether there were any groups of people for whom the COLO/DPI/02/06 trial (in which the comparator for colistimethate sodium DPI was nebulised tobramycin) provided clinical- or cost-effectiveness evidence for the use of colistimethate sodium. It recognised that the majority of people currently switching to nebulised tobramycin from nebulised colistimethate sodium do so either because of a lack of efficacy of nebulised colistimethate sodium or because colistimethate sodium is contraindicated. The Committee recognised that a potential switch from nebulised colistimethate sodium to colistimethate sodium DPI in these two groups would therefore be inappropriate. However, the Committee considered that there was a group of people who could benefit or were benefiting from nebulised colistimethate sodium but were unable to tolerate it twice daily in its nebulised form. The current treatment option for these people would be nebulised tobramycin and thus the COLO/DPI/02/06 trial did give evidence for the use of colistimethate sodium DPI rather than nebulised tobramycin in such a group of people. The Committee noted the small QALY loss for colistimethate sodium DPI compared with nebulised tobramycin but also the substantial cost saving (£38,000 with the list price for nebulised tobramycin). The Committee further observed that adherence might be greater with the use of a dry powder inhaler in such a population. The Committee also acknowledged comments received during consultation that some people would be sensitive to nebulised aminoglycosides (such as tobramycin) in terms of side effects or be otherwise intolerant of such therapy. However the Committee agreed that its understanding of the treatment pathway was that this group receive colistimethate sodium as first-line treatment, tobramycin as second-line treatment and then an alternative treatment to tobramycin if tobramycin treatment fails or is otherwise contraindicated. The Committee therefore decided that colistimethate sodium DPI did not have a role to play in the treatment of chronic P.\xa0aeruginosa in people who were sensitive (in terms of toxicity) to tobramycin or intolerant of tobramycin. It therefore concluded that it could only recommend colistimethate sodium DPI as a treatment option for people who would clinically benefit from continued colistimethate sodium but cannot tolerate it in its nebulised form. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care.\n\nThe Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. The Committee noted a potential equalities issue in that cystic fibrosis mostly affects people of white European origin; however, the Committee recognised that this reflected the epidemiology of cystic fibrosis rather than being an equalities concern. The Committee was also aware that some patients or carers may have difficulty manipulating an inhaler for dry powder inhalation, but noted that the same may apply to other modes of treatment delivery. The Committee concluded that its recommendations would not affect any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its recommendations.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA276\n\nAppraisal title: Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis\n\nSection\n\nKey conclusions\n\nThe Committee concluded that it could only draw conclusions based on the evidence described in the 2\xa0key trials and that it had no clinical evidence comparing colistimethate sodium DPI with the appropriate comparator, nebulised colistimethate sodium.\n\n\n\n\n\nThe Committee agreed that despite the limitations of all the clinical- and cost-effectiveness evidence and hence the uncertainty inherent in the Assessment Group model, it was reasonable to conclude that tobramycin DPI was a cost-effective use of NHS resources. The Committee recommended tobramycin DPI as a treatment option only when nebulised tobramycin is considered an appropriate treatment; that is, when colistimethate sodium is contraindicated, is not tolerated, or has not produced an adequate clinical response. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care.\n\n\n\nGiven the available evidence and the current treatment pathway, the Committee could only recommend colistimethate sodium DPI as a treatment option for people who would clinically benefit from continued colistimethate sodium but cannot tolerate it in its nebulised form. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe most important outcomes for the patient that influence treatment decisions are the person's quality of life, treatment burden, maintaining good lung function and reducing the incidence of exacerbations.\n\n\n\n\n\nCurrent treatment options include the use of inhaled antibiotics effective against P.\xa0aeruginosa (such as nebulised colistimethate sodium or tobramycin) and oral or intravenous antibiotics to eradicate initial or intermittent P.\xa0aeruginosa colonisation or acute exacerbations of chronic infection. Azithromycin may be given in combination with these antibiotics to act on the biofilms.\n\n\n\nFirst-line treatment for chronic P.\xa0aeruginosa lung infection routinely starts with nebulised colistimethate sodium (unless it is contraindicated), this choice being largely based on cost. If there is no response, an unacceptable adverse event profile, an excessive number of acute exacerbations or a loss of lung function, then treatment is switched routinely to nebulised tobramycin.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee recognised that the strict routine and amount of time spent receiving treatment have a significant impact on the daily activities of people with cystic fibrosis and their families. The Committee concluded that reducing the time that people with cystic fibrosis spend receiving treatment would be beneficial in improving the quality of life of people with cystic fibrosis and their families.\n\n\n\n\n\nThe Committee concluded that in clinical practice (rather than in clinical trials), people with cystic fibrosis may be more likely to adhere to a dry powder for inhalation treatment than a nebulised treatment in view of the speed and convenience of drug delivery.\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from the manufacturer of colistimethate sodium DPI that the EMA had indicated that the most appropriate comparator at the time of the study design for its pivotal trial would be nebulised tobramycin because this was the only licensed comparator in all of the study site countries. The Committee agreed that given the current clinical pathway, ideally it would have liked to have seen effectiveness evidence comparing colistimethate sodium DPI with nebulised colistimethate sodium and also whether there was evidence of any clinical benefit of colistimethate sodium DPI in people being switched from nebulised colistimethate sodium because of lack of efficacy. Given the current treatment pathway in the UK, the Committee concluded that the most appropriate comparator for colistimethate sodium DPI would be nebulised colistimethate sodium and the most appropriate comparator for tobramycin DPI would be nebulised tobramycin.\n\n\n\nAdverse reactions\n\nThe Committee was unsure whether the adverse events associated with either tobramycin DPI or colistimethate sodium DPI were significantly different from those associated with nebulised tobramycin.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee discussed the quality of the 2\xa0key trials that compared colistimethate sodium DPI with nebulised tobramycin and tobramycin DPI with nebulised tobramycin. It noted the Assessment Group's critique of the trials, in particular the fact that the manufacturers had not commented in their submissions on the quality of the trials in light of the current EMA research guidelines for the development of medicinal products for the treatment of cystic fibrosis. The Committee supported the Assessment Group's comments on the methodological limitations of both trials, such as a lack of blinding, and agreed that this could have introduced selection and reporting bias for subjective outcomes such as adverse events and might limit the generalisability of the findings. The Committee concluded that the evidence base for assessing the clinical effectiveness of colistimethate sodium and tobramycin DPIs was of, at best, modest quality but that it was the best available.\n\n\n\n\n\nThe Committee noted that there was no clinical trial comparing the effectiveness of colistimethate sodium DPI with that of the preferred comparator, nebulised colistimethate sodium.\n\n\n\nThe Committee noted that both trials were non-inferiority in design and therefore only assessed whether the interventions were not worse than nebulised tobramycin.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee acknowledged that both nebulised colistimethate sodium and nebulised tobramycin were embedded as treatment options in current clinical practice and thus judged to be clinically effective in treating chronic P.\xa0aeruginosa lung infection. The Committee therefore accepted that a change in the mode of delivery of these drugs would be unlikely to adversely affect their clinical effectiveness compared with nebulised formulations of the drugs.\n\n\n\n\n\nUncertainties generated by the evidence\n\nThere is uncertainty about the clinical relevance of the findings of the 2\xa0key trials given the short-term nature of these trials.\n\n\n\n\n\nThe Committee concluded that it was uncertain as to how it should interpret the exacerbation results. Because there were limited data on quality of life and uncertainty around the evidence for exacerbations, the Committee could not draw definitive conclusions as to whether either dry powder offered any clinical benefit over nebulised tobramycin for clinically relevant outcomes.\n\n\n\nWhilst the Committee would have much preferred trials that were designed for equivalence and had continued for at least the 12\xa0months specified in the current EMA research guidelines for such agents, it accepted that the evidence presented in terms of FEV1% was the best available and it had to make its judgements accordingly.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nFor the primary end point of mean difference in change in FEV1% predicted after 24\xa0weeks of treatment, the result from the ANCOVA analysis on the ITT population using LOCF data was −1.16% (95% CI −3.15% to 0.84%) suggesting that colistimethate sodium DPI was marginally less efficacious than tobramycin nebuliser solution (because the non-inferiority criterion was not met). The results of the log-transformed and non-parametric ITT population LOCF data analyses were −0.98% (95% CI −2.74% to 0.86%) and −0.56% (95% CI −2.16% to 1.00%) respectively, suggesting in both cases that colistimethate sodium DPI was non-inferior to nebulised tobramycin. For the PP population the ANCOVA, log-transformed and non-parametric analyses using LOCF data indicated that the non-inferiority hypothesis was satisfied for non-parametric analysis only (ANCOVA −1.49% [95% CI −3.79% to 0.81%], log-transformed −1.10% [95% CI−3.08% to 0.97%] and non-parametric −0.67% [95% CI −2.57% to 1.16%]).\n\n\n\n\n\nTobramycin DPI was associated with an improved mean FEV1% predicted compared with nebulised tobramycin at 20\xa0weeks of +0.59% (SE 0.92). The manufacturer reported non-inferiority (supported by least squares mean difference relative change of 1.1% [SE 1.75] which has a lower limit of the one-sided 85% confidence interval within the predicted 6% margin for non-inferiority).\n\n\n\nThe Committee concluded that it only had evidence exploring whether either dry powder formulation was no worse than nebulised tobramycin and no evidence to prove that either was more effective than or equivalent to nebulised tobramycin.\n\n\n\nThe Committee concluded that the COLO/DPI/02/06 and EAGER trials may have demonstrated that colistimethate sodium DPI and tobramycin DPI were non-inferior to nebulised tobramycin with respect to change in FEV1% within the populations tested and in the manner conducted within each trial, but remained concerned with the uncertain clinical relevance of these findings given the short-term nature of these trials.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer of colistimethate sodium DPI used a cohort-based decision analysis to compare colistimethate sodium DPI with nebulised tobramycin in people aged 6\xa0years or older with documented cystic fibrosis who had chronic pseudomonas lung infection.\n\n\n\n\n\nThe Committee concluded that the manufacturer's (Forest's) model lacked credibility and therefore they would not consider it or its results plausible.\n\n\n\nThe Committee discussed the Assessment Group's de novo model which compared colistimethate sodium DPI with nebulised tobramycin and tobramycin DPI with nebulised tobramycin. The Committee noted that the model had a lifetime time horizon. The Committee agreed that the use of a lifetime horizon was appropriate, but acknowledged the limitation of extrapolating short-term trial results over long time horizons. Additionally the Committee noted other limitations of the Assessment Group model, including the fact that it did not recognise that, in the current treatment pathway, some people would move from one drug to another (for example from colistimethate sodium to tobramycin).\n\n\n\n\n\nThe Committee concluded, however, that despite these limitations the Assessment Group's de novo model was the best available framework for assessing the cost effectiveness of colistimethate sodium DPI compared with nebulised tobramycin and of tobramycin DPI compared with nebulised tobramycin.\n\n\n\n\n\nThe Assessment Group also carried out additional analyses in response to the patient access schemes submitted by the manufacturers of colistimethate sodium DPI and tobramycin DPI.\n\n–4.2.25\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nColistimethate sodium DPI: The Committee had particular concerns about the inconsistent time horizons used in the Forest model for costs and health outcomes and the validity of using mortality benefits associated with 24\xa0weeks of treatment and extrapolating over a lifetime.\n\n\n\n\n\nThe Committee had particular concerns about limitations of the Assessment Group's model. The Committee agreed that the use of a lifetime horizon was appropriate, but acknowledged the limitation of extrapolating short-term trial results over long time horizons. Additionally it noted that the model did not recognise that, in the current treatment pathway, some people would move from one drug to another (for example from colistimethate sodium to tobramycin). The Committee also noted that treatment duration is assumed to be equivalent between the 2\xa0treatments. It agreed that it was also plausible that some people on nebulised tobramycin would receive some form of treatment on a continuous basis (either as continuous nebulised reduced-dose tobramycin or as nebulised colistimethate sodium in off-months from tobramycin) but there was no evidence on which to base any cost-effectiveness estimate.\n\n\n\nTobramycin DPI: The Committee was aware that for the Assessment Group model for tobramycin DPI uncertainty was generated because the analyses were based on the inclusion of aggregate lung disorder data as a proxy measure for exacerbations because data on major and minor exacerbations had not been collected in the EAGER trial.\n\n\n\nThe QALY gain for tobramycin DPI was uncertain because quality-of-life data were not collected in the EAGER trial.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee discussed the additional benefits of the mode of delivery of the dry powder formulations over nebulised alternatives. The Committee noted that both technologies aimed to give people with cystic fibrosis and chronic P.\xa0aeruginosa lung infection quality-of-life benefits in terms of ease of use and convenience.\n\n\n\n\n\nThe Committee acknowledged that the small QALY gain for tobramycin DPI was uncertain because quality-of-life data were not collected in the EAGER trial. However, it agreed it was reasonable to assume that there would be some QALY gain for tobramycin DPI over nebulised tobramycin in clinical practice in view of the reported benefits to patients in terms of ease of use and convenience although it acknowledged that the number of withdrawals from the EAGER trial did not indicate this relationship.\n\n\n\nThe Committee noted the small QALY loss for colistimethate sodium DPI compared with nebulised tobramycin but also the substantial saving (£38,000 with the list price for nebulised tobramycin). The Committee further observed that adherence might be greater with the use of a dry powder inhaler in such a population.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe key drivers of cost effectiveness were the cost of interventions and comparators when the most recent patient access schemes were included, and the small QALY gains for tobramycin DPI compared with nebulised tobramycin and for colistimethate sodium compared with nebulised tobramycin.\n\n, 4.2.25\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nTobramycin DPI consistently dominated nebulised tobramycin with inclusion of the patient access scheme, that is, there was a cost saving and QALY gain for tobramycin DPI compared to nebulised tobramycin.\n\n\n\n\n\nThe Committee noted the small QALY loss for colistimethate sodium DPI compared with nebulised tobramycin but also the substantial cost saving (£38,000 with the list price for nebulised tobramycin).\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nA patient access scheme has been agreed with the Department of Health for colistimethate sodium DPI, details of which are confidential.\n\n\n\n\n\nA patient access scheme has been agreed with the Department of Health for tobramycin DPI, details of which are confidential.\n\n\n\nThe Committee noted the approved patient access scheme for colistimethate sodium DPI and based its decisions on the cost-effectiveness results from analyses involving the patient access scheme price.\n\n\n\nThe Committee based its discussions on the cost-effectiveness analysis of tobramycin DPI carried out by the Assessment Group incorporating the patient access scheme.\n\n\n\nEnd-of-life considerations\n\nNot applicable\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee discussed NICE's duties under the equalities legislation and concluded that its recommendations would not affect any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its recommendations.\n\n", 'Related NICE guidance': 'Mannitol dry powder for inhalation for treating cystic fibrosis\n (2012) NICE technology appraisal guidance 266.'}	https://www.nice.org.uk/guidance/ta276	Evidence-based recommendations on colistimethate sodium (Colobreathe) and tobramycin (TOBI Podhaler) dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis in people of 6 years and over.
079a4887ce8b0a3e6314cdee2b11bfe0383952eb	nice	Methylnaltrexone for treating opioid-induced bowel dysfunction in people with advanced illness receiving palliative care (terminated appraisal)	Methylnaltrexone for treating opioid-induced bowel dysfunction in people with advanced illness receiving palliative care (terminated appraisal) # Background The manufacturer of methylnaltrexone (TMC Pharma Services) was invited to submit evidence for the single technology appraisal of methylnaltrexone for treating opioid-induced bowel dysfunction in people with advanced illness receiving palliative care. In December 2012, TMC Pharma Services informed NICE that it would not be making an evidence submission for this appraisal. The manufacturer stated that it is holding the European marketing authorisation for methylnaltrexone on a temporary basis while the product owner finds a permanent European partner, but timelines for this are not currently known. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of methylnaltrexone for treating opioid-induced bowel dysfunction in people with advanced illness receiving palliative care. If, after doing this, organisations still wish to consider methylnaltrexone for treating opioid-induced bowel dysfunction in people with advanced illness receiving palliative care, they should follow the advice set out in Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable. NICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission. # Related NICE guidance For information about NICE guidance that has been issued or is in development, see the NICE website. ## Published Opioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adults. NICE clinical guideline 140 (2012) Prucalopride for the treatment of chronic constipation in women. NICE technology appraisal guidance 211 (2010) ## Under development NICE is developing the following guidance (details available from the NICE website): Lubiprostone for the treatment of opioid-induced constipation. NICE technology appraisal. Publication date to be confirmed.	{'Background': 'The manufacturer of methylnaltrexone (TMC Pharma Services) was invited to submit evidence for the single technology appraisal of methylnaltrexone for treating opioid-induced bowel dysfunction in people with advanced illness receiving palliative care.\n\nIn December 2012, TMC Pharma Services informed NICE that it would not be making an evidence submission for this appraisal. The manufacturer stated that it is holding the European marketing authorisation for methylnaltrexone on a temporary basis while the product owner finds a permanent European partner, but timelines for this are not currently known.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': 'NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of methylnaltrexone for treating opioid-induced bowel dysfunction in people with advanced illness receiving palliative care. If, after doing this, organisations still wish to consider methylnaltrexone for treating opioid-induced bowel dysfunction in people with advanced illness receiving palliative care, they should follow the advice set out in Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable.\n\nNICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission.\n\n# Related NICE guidance\n\nFor information about NICE guidance that has been issued or is in development, see the NICE website.\n\n## Published\n\nOpioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adults. NICE clinical guideline 140 (2012)\n\nPrucalopride for the treatment of chronic constipation in women. NICE technology appraisal guidance 211 (2010)\n\n## Under development\n\nNICE is developing the following guidance (details available from the NICE website):\n\nLubiprostone for the treatment of opioid-induced constipation. NICE technology appraisal. Publication date to be confirmed.'}	https://www.nice.org.uk/guidance/ta277
fd6d243ca720a5dbe010793333939d51affc1efe	nice	Antisocial personality disorder: prevention and management	Antisocial personality disorder: prevention and management This guideline covers principles for working with people with antisocial personality disorder, including dealing with crises (crisis resolution). It aims to help people with antisocial personality disorder manage feelings of anger, distress, anxiety and depression, and to reduce offending and antisocial behaviour. # Introduction This guideline makes recommendations for the treatment, management and prevention of antisocial personality disorder in primary, secondary and forensic healthcare. This guideline is concerned with the treatment of people with antisocial personality disorder across a wide range of services including those provided within mental health (including substance misuse) services, social care and the criminal justice system. People with antisocial personality disorder exhibit traits of impulsivity, high negative emotionality, low conscientiousness and associated behaviours including irresponsible and exploitative behaviour, recklessness and deceitfulness. This is manifest in unstable interpersonal relationships, disregard for the consequences of one's behaviour, a failure to learn from experience, egocentricity and a disregard for the feelings of others. The condition is associated with a wide range of interpersonal and social disturbance. People with antisocial personality disorder have often grown up in fractured families in which parental conflict is typical and parenting is harsh and inconsistent. As a result of parental inadequacies and/or the child's difficult behaviour, the child's care is often interrupted and transferred to agencies outside the family. This in turn often leads to truancy, having delinquent associates and substance misuse, which frequently result in increased rates of unemployment, poor and unstable housing situations, and inconsistency in relationships in adulthood. Many people with antisocial personality disorder have a criminal conviction and are imprisoned or die prematurely as a result of reckless behaviour. Criminal behaviour is central to the definition of antisocial personality disorder, although it is often the culmination of previous and long-standing difficulties, such as socioeconomic, educational and family problems. Antisocial personality disorder therefore amounts to more than criminal behaviour alone, otherwise everyone convicted of a criminal offence would meet the criteria for antisocial personality disorder and a diagnosis of antisocial personality disorder would be rare in people with no criminal history. This is not the case. The prevalence of antisocial personality disorder among prisoners is slightly less than 50%. It is estimated in epidemiological studies in the community that only 47% of people who meet the criteria for antisocial personality disorder have significant arrest records. A history of aggression, unemployment and promiscuity were more common than serious crimes among people with antisocial personality disorder. The prevalence of antisocial personality disorder in the general population is 3% in men and 1% in women. Under current diagnostic systems, antisocial personality disorder is not formally diagnosed before the age of 18 but the features of the disorder can manifest earlier as conduct disorder. People with conduct disorder typically show antisocial, aggressive or defiant behaviour, which is persistent and repetitive, including aggression to people or animals, destruction of property, deceitfulness, theft and serious rule-breaking. A history of conduct disorder before the age of 15 is a requirement for a diagnosis of antisocial personality disorder in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The course of antisocial personality disorder is variable and although recovery is attainable over time, some people may continue to experience social and interpersonal difficulties. Antisocial personality disorder is often comorbid with depression, anxiety, and alcohol and drug misuse. Families or carers are important in prevention and treatment of antisocial personality disorder. This guideline uses the term 'families or carers' to apply to all family members and other people, such as friends and advocates, who have regular close contact with the person with antisocial personality disorder. This guideline draws on the best available evidence. However, there are significant limitations to the evidence base, notably a relatively small number of randomised controlled trials (RCTs) of interventions with few outcomes in common. Some of the limitations are addressed in the recommendations for research. At the time of publication (January 2009), no drug has UK marketing authorisation for the treatment of antisocial personality disorder. The guideline assumes that prescribers will use a drug's summary of product characteristics to inform their decisions for each person. NICE has also developed a guideline on borderline personality disorder: recognition and management.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. In March 2013, recommendations 1.2.3.1, 1.2.3.2, 1.2.4.1, 1.2.4.2, 1.2.4.4, 1.2.4.5, 1.2.5.1 to 1.2.5.3, 1.2.6.1, 1.2.6.2, 1.2.7.1 to 1.2.7.7 and 1.2.8.1 to 1.2.8.4 were deleted and replaced by the NICE guideline on antisocial behaviour and conduct disorders in children and young people. The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. # General principles for working with people with antisocial personality disorder People with antisocial personality disorder have tended to be excluded from services, the Department of Health's Personality disorder: no longer a diagnosis of exclusion aims to address this. To change the current position, staff need to work actively to engage people with antisocial personality disorder in treatment. Evidence from both clinical trials and scientific studies of antisocial personality disorder shows that positive and reinforcing approaches to the treatment of antisocial personality disorder are more likely to be successful than those that are negative or punitive. ## Access and assessment People with antisocial personality disorder should not be excluded from any health or social care service because of their diagnosis or history of antisocial or offending behaviour. Seek to minimise any disruption to therapeutic interventions for people with antisocial personality disorder by: ensuring that in the initial planning and delivery of treatment, transfers from institutional to community settings take into account the need to continue treatment avoiding unnecessary transfer of care between institutions whenever possible during an intervention, to prevent disruption to the agreed treatment plan. This should be considered at initial planning of treatment. Ensure that people with antisocial personality disorder from black and minority ethnic groups have equal access to culturally appropriate services based on clinical need. When language or literacy is a barrier to accessing or engaging with services for people with antisocial personality disorder, provide: information in their preferred language and in an accessible format psychological or other interventions in their preferred language independent interpreters. When a diagnosis of antisocial personality disorder is made, discuss the implications of it with the person, the family or carers where appropriate, and relevant staff, and: acknowledge the issues around stigma and exclusion that have characterised care for people with antisocial personality disorder emphasise that the diagnosis does not limit access to a range of appropriate treatments for comorbid mental health disorders provide information on and clarify the respective roles of the healthcare, social care and criminal justice services. When working with women with antisocial personality disorder take into account the higher incidences of common comorbid mental health problems and other personality disorders in such women, and: adapt interventions in light of this (for example, extend their duration) ensure that in inpatient and residential settings the increased vulnerability of these women is taken into account. Staff, in particular key workers, working with people with antisocial personality disorder should establish regular one-to-one meetings to review progress, even when the primary mode of treatment is group based. ## People with disabilities and acquired cognitive impairments When a person with learning or physical disabilities or acquired cognitive impairments presents with symptoms and behaviour that suggest antisocial personality disorder, staff involved in assessment and diagnosis should consider consulting with a relevant specialist. Staff providing interventions for people with antisocial personality disorder with learning or physical disabilities or acquired cognitive impairments should, where possible, provide the same interventions as for other people with antisocial personality disorder. Staff might need to adjust the method of delivery or duration of the intervention to take account of the disability or impairment. ## Autonomy and choice Work in partnership with people with antisocial personality disorder to develop their autonomy and promote choice by: ensuring that they remain actively involved in finding solutions to their problems, including during crises encouraging them to consider the different treatment options and life choices available to them, and the consequences of the choices they make. ## Developing an optimistic and trusting relationship Staff working with people with antisocial personality disorder should recognise that a positive and rewarding approach is more likely to be successful than a punitive approach in engaging and retaining people in treatment. Staff should: explore treatment options in an atmosphere of hope and optimism, explaining that recovery is possible and attainable build a trusting relationship, work in an open, engaging and non-judgemental manner, and be consistent and reliable. ## Engagement and motivation When providing interventions for people with antisocial personality disorder, particularly in residential and institutional settings, pay attention to motivating them to attend and engage with treatment. This should happen at initial assessment and be an integral and continuing part of any intervention, as people with antisocial personality disorder are vulnerable to premature withdrawal from treatment and supportive interventions. ## Involving families and carers Ask directly whether the person with antisocial personality disorder wants their family or carers to be involved in their care, and, subject to the person's consent and rights to confidentiality: encourage families or carers to be involved ensure that the involvement of families or carers does not lead to a withdrawal of, or lack of access to, services inform families or carers about local support groups for families or carers. Consider the needs of families and carers of people with antisocial personality disorder and pay particular attention to the: impact of antisocial and offending behaviours on the family consequences of significant drug or alcohol misuse needs of and risks to any children in the family and the safeguarding of their interests. # Prevention of antisocial personality disorder – working with children and young people and their families The evidence for the treatment of antisocial personality disorder in adult life is limited and the outcomes of interventions are modest. The evidence for working with children and young people who are at risk, and their families, points to the potential value of preventative measures. See terms used in this guideline for definitions of the psychological interventions referred to. ## General principles Child and adolescent mental health service (CAMHS) professionals working with young people should: balance the developing autonomy and capacity of the young person with the responsibilities of parents and carers be familiar with the legal framework that applies to young people, including the Mental Capacity Act, the Children Acts and the Mental Health Act. ## Identifying children at risk of developing conduct problems Services should establish robust methods to identify children at risk of developing conduct problems, integrated when possible with the established local assessment system. These should focus on identifying vulnerable parents, where appropriate antenatally, including: parents with other mental health problems, or with significant drug or alcohol problems. mothers younger than 18 years, particularly those with a history of maltreatment in childhood parents with a history of residential care parents with significant previous or current contact with the criminal justice system. When identifying vulnerable parents, take care not to intensify any stigma associated with the intervention or increase the child's problems by labelling them as antisocial or problematic. ## Early interventions for preschool children at risk of developing conduct problems and potentially subsequent antisocial personality disorder This recommendation has been deleted This recommendation has been deleted. ## Interventions for children with conduct problems younger than 12 years and their families This recommendation has been deleted. This recommendation has been deleted. Additional interventions targeted specifically at the parents of children with conduct problems (such as interventions for parental, marital or interpersonal problems) should not be provided routinely alongside parent-training programmes, as they are unlikely to have an impact on the child's conduct problems. This recommendation has been deleted. This recommendation has been deleted. ## How to deliver interventions for children with conduct problems aged younger than 12 years and their families This recommendation has been deleted. This recommendation has been deleted. This recommendation has been deleted. ## Cognitive behavioural interventions for children aged 8 years and older with conduct problems This recommendation has been deleted. This recommendation has been deleted. ## How to deliver interventions for children aged 8 years and older with conduct problems This recommendation has been deleted. This recommendation has been deleted. This recommendation has been deleted. This recommendation has been deleted. This recommendation has been deleted. This recommendation has been deleted. This recommendation has been deleted. ## How to deliver interventions for young people with conduct problems aged between 12 and 17 years and their families This recommendation has been deleted. This recommendation has been deleted. This recommendation has been deleted. This recommendation has been deleted. ## Transition from child and adolescent services to adult services Health and social care services should consider referring vulnerable young people with a history of conduct disorder or contact with youth offending schemes, or those who have been receiving interventions for conduct and related disorders, to appropriate adult services for continuing assessment and/or treatment. # Assessment and risk management of antisocial personality disorder In primary and secondary care services, antisocial personality disorder is under-recognised. When it is identified, significant comorbid disorders such as treatable depression or anxiety are often not detected. In secondary and forensic services there are important concerns about assessing risk of violence and risk of harm to self and others. ## Assessment When assessing a person with possible antisocial personality disorder, healthcare professionals in secondary and forensic mental health services should conduct a full assessment of: antisocial behaviours personality functioning, coping strategies, strengths and vulnerabilities comorbid mental disorders (including depression and anxiety, drug or alcohol misuse, post-traumatic stress disorder and other personality disorders) the need for psychological treatment, social care and support, and occupational rehabilitation or development domestic violence and abuse. Staff involved in the assessment of antisocial personality disorder in secondary and specialist services should use structured assessment methods whenever possible to increase the validity of the assessment. For forensic services, the use of measures such as PCL-R or PCL-SV to assess the severity of antisocial personality disorder should be part of the routine assessment process. Staff working in primary and secondary care services (for example, drug and alcohol services) and community services (for example, the probation service) that include a high proportion of people with antisocial personality disorder should be alert to the possibility of antisocial personality disorder in service users. Where antisocial personality disorder is suspected and the person is seeking help, consider offering a referral to an appropriate forensic mental health service depending on the nature of the presenting complaint. For example, for depression and anxiety this may be to general mental health services; for problems directly relating to the personality disorder it may be to a specialist personality disorder or forensic service. ## Risk assessment and management Risk assessment is part of the overall approach to assessment and care planning as defined in the framework of the Care Programme Approach, and the following recommendations should be regarded in that context. Assessing risk of violence is not routine in primary care, but if such assessment is required consider: current or previous violence, including severity, circumstances, precipitants and victims the presence of comorbid mental disorders and/or substance misuse current life stressors, relationships and life events additional information from written records or families and carers (subject to the person's consent and right to confidentiality), because the person with antisocial personality disorder might not always be a reliable source of information. Healthcare professionals in primary care should consider contact with and/or referral to secondary or forensic services where there is current violence or threats that suggest significant risk and/or a history of serious violence, including predatory offending or targeting of children or other vulnerable people. When assessing the risk of violence in secondary care mental health services, take a detailed history of violence and consider and record: current or previous violence, including severity, circumstances, precipitants and victims contact with the criminal justice system, including convictions and periods of imprisonment the presence of comorbid mental disorder and/or substance misuse current life stressors, relationships and life events additional information from written records or families and carers (subject to the person's consent and right to confidentiality), as the person with antisocial personality disorder might not always be a reliable source of information. The initial risk management should be directed at crisis resolution and ameliorating any acute aggravating factors. The history of previous violence should be an important guide in the development of any future violence risk management plan. Staff in secondary care mental health services should consider a referral to forensic services where there is: current violence or threat that suggests immediate risk or disruption to the operation of the service a history of serious violence, including predatory offending or targeting of children or other vulnerable people. When assessing the risk of violence in forensic, specialist personality disorder or tertiary mental health services, take a detailed history of violence, and consider and record: current and previous violence, including severity, circumstances, precipitants and victims contact with the criminal justice system, including convictions and periods of imprisonment the presence of comorbid mental disorder and/or substance misuse current life stressors, relationships and life events additional information from written records or families and carers (subject to the person's consent and right to confidentiality), as the person with antisocial personality disorder might not always be a reliable source of information. Healthcare professionals in forensic or specialist personality disorder services should consider, as part of a structured clinical assessment, routinely using: a standardised measure of the severity of antisocial personality disorder (for example, PCL-R or PCL-SV) a formal assessment tool such as HCR-20 to develop a risk management strategy. ## Risk management Services should develop a comprehensive risk management plan for people with antisocial personality disorder who are considered to be of high risk. The plan should involve other agencies in health and social care services and the criminal justice system. Probation services should take the lead role when the person is on a community sentence or is on licence from prison with mental health and social care services providing support and liaison. Such cases should routinely be referred to the local Multi-Agency Public Protection Panel. # Treatment and management of antisocial personality disorder and related and comorbid disorders The evidence base for the treatment of antisocial personality disorder is limited. In the development of the recommendations set out below these limitations were addressed by drawing on four related sources of evidence, namely, evidence for: (1) interventions targeted specifically at antisocial personality disorder; (2) the treatment and management of the symptoms and behaviours associated with antisocial personality disorder, such as impulsivity and aggression; (3) the treatment of comorbid disorders such as depression and drug misuse; and (4) the management of offending behaviour. Although the focus of several interventions is offending behaviour, the interventions have the potential to help people with antisocial personality disorder address a wider range of antisocial behaviours with consequent benefits for themselves and others. ## General principles People with antisocial personality disorder should be offered treatment for any comorbid disorders in line with recommendations in the relevant NICE guideline, where available (see the NICE topic page on mental health and behavioural conditions). This should happen regardless of whether the person is receiving treatment for antisocial personality disorder. When providing psychological or pharmacological interventions for antisocial personality disorder, offending behaviour or comorbid disorders to people with antisocial personality disorder, be aware of the potential for and possible impact of: poor concordance high attrition misuse of prescribed medication drug interactions (including with alcohol and illicit drugs). When providing psychological interventions for comorbid disorders to people with antisocial personality disorder, consider lengthening their duration or increasing their intensity. ## The role of psychological interventions For people with antisocial personality disorder, including those with substance misuse problems, in community and mental health services, consider offering group-based cognitive and behavioural interventions, in order to address problems such as impulsivity, interpersonal difficulties and antisocial behaviour. For people with antisocial personality disorder with a history of offending behaviour who are in community and institutional care, consider offering group-based cognitive and behavioural interventions (for example, programmes such as 'reasoning and rehabilitation') focused on reducing offending and other antisocial behaviour. For young offenders aged 17 years or younger with a history of offending behaviour who are in institutional care, offer group-based cognitive and behavioural interventions aimed at young offenders and that are focused on reducing offending and other antisocial behaviour. When providing cognitive and behavioural interventions: assess the level of risk and adjust the duration and intensity of the programme accordingly (participants at all levels of risk may benefit from these interventions) provide support and encouragement to help participants to attend and complete programmes, including people who are legally mandated to do so. ## The role of pharmacological interventions Pharmacological interventions should not be routinely used for the treatment of antisocial personality disorder or associated behaviours of aggression, anger and impulsivity. Pharmacological interventions for comorbid mental disorders, in particular depression and anxiety, should be in line with recommendations in the relevant NICE guideline (see the NICE topic page on mental health and behavioural conditions). When starting and reviewing medication for comorbid mental disorders, pay particular attention to issues of adherence and the risks of misuse or overdose. ## Drug and alcohol misuse Drug and alcohol misuse occurs commonly alongside antisocial personality disorder, and is likely to aggravate risk of harm to self and others and behavioural disturbances in people with antisocial personality disorder. For people with antisocial personality disorder who misuse drugs, in particular opioids or stimulants, offer psychological interventions (in particular, contingency management programmes) in line with recommendations in the relevant NICE guideline (see the NICE topic page on mental health and behavioural conditions). For people with antisocial personality disorder who misuse or are dependent on alcohol, offer psychological and pharmacological interventions in line with existing national guidance for the treatment and management of alcohol disorders. For people with antisocial personality disorder who are in institutional care and who misuse or are dependent on drugs or alcohol, consider referral to a specialist therapeutic community focused on the treatment of drug and alcohol problems. # Psychopathy and dangerous and severe personality disorder People with psychopathy and people who meet criteria for dangerous and severe personality disorder (DSPD) represent a small proportion of people with antisocial personality disorder. However, they present a very high risk of harm to others and consume a significant proportion of the services for people with antisocial personality disorder. In the absence of any high-quality evidence for the treatment of DSPD, the Guideline Development Group drew on the evidence for the treatment of antisocial personality disorder to arrive at their recommendations. Interventions will often need to be adapted for DSPD (for example, a significant extension of the duration of the intervention). People with DSPD can be seen as having a lifelong disability that requires continued input and support over many years. ## Adapting interventions for people who meet criteria for psychopathy or DSPD For people in community and institutional settings who meet criteria for psychopathy or DSPD, consider cognitive and behavioural interventions (for example, programmes such as 'reasoning and rehabilitation') focused on reducing offending and other antisocial behaviour. These interventions should be adapted for this group by extending the nature (for example, concurrent individual and group sessions) and duration of the intervention, and by providing booster sessions, continued follow-up and close monitoring. For people who meet criteria for psychopathy or DSPD, offer treatment for any comorbid disorders in line with existing NICE guidance (see the NICE topic page on mental health and behavioural conditions). This should happen regardless of whether the person is receiving treatment for psychopathy or DSPD because effective treatment of comorbid disorders may reduce the risk associated with psychopathy or DSPD. ## Intensive staff support Staff providing interventions for people who meet criteria for psychopathy or DSPD should receive high levels of support and close supervision, due to increased risk of harm. This may be provided by staff outside the unit. # Organisation and planning of services There has been a considerable expansion of services for people with antisocial personality disorder in recent years involving a wider range of agencies in the health and social care sector, the non-statutory sector and the criminal justice system. If the full benefit of these additional services is to be realised, effective care pathways and specialist networks need to be developed. ## Multi-agency care Provision of services for people with antisocial personality disorder often involves significant inter-agency working. Therefore, services should ensure that there are clear pathways for people with antisocial personality disorder so that the most effective multi-agency care is provided. These pathways should: specify the various interventions that are available at each point enable effective communication among clinicians and organisations at all points and provide the means to resolve differences and disagreements.Clearly agreed local criteria should also be established to facilitate the transfer of people with antisocial personality disorder between services. As far as is possible, shared objective criteria should be developed relating to comprehensive assessment of need and risk. Services should consider establishing antisocial personality disorder networks, where possible linked to other personality disorder networks. (They may be organised at the level of primary care trusts, local authorities, strategic health authorities or government offices.) These networks should be multi-agency, should actively involve people with antisocial personality disorder and should: take a significant role in training staff, including those in primary care, general, secondary and forensic mental health services, and in the criminal justice system have resources to provide specialist support and supervision for staff take a central role in the development of standards for and the coordination of clinical pathways monitor the effective operation of clinical pathways. ## Inpatient services Healthcare professionals should normally only consider admitting people with antisocial personality disorder to inpatient services for crisis management or for the treatment of comorbid disorders. Admission should be brief, where possible set out in a previously agreed crisis plan and have a defined purpose and end point. Admission to inpatient services solely for the treatment of antisocial personality disorder or its associated risks is likely to be a lengthy process and should: be under the care of forensic/specialist personality disorder services not usually be under a hospital order under a section of the Mental Health Act (in the rare instance that this is done, seek advice from a forensic/specialist personality service). ## Staff training, supervision, support Working in services for people with antisocial personality disorder presents a considerable challenge for staff. Effective training and support is crucial so that staff can adhere to the specified treatment programme and manage any emotional pressures arising from their work. Staff competencies All staff working with people with antisocial personality disorder should be familiar with the Department of Health's Ten essential shared capabilities: a framework for the whole of the mental health workforce, and have a knowledge and awareness of antisocial personality disorder that facilitates effective working with service users, families or carers, and colleagues. All staff working with people with antisocial personality disorder should have skills appropriate to the nature and level of contact with service users. These skills include: for all frontline staff, knowledge about antisocial personality disorder and understanding behaviours in context, including awareness of the potential for therapeutic boundary violations (for example, inappropriate relations with service users) for staff with regular and sustained contact with people with antisocial personality disorder, the ability to respond effectively to the needs of service users for staff with direct therapeutic or management roles, competence in the specific treatment interventions and management strategies used in the service. Services should ensure that all staff providing psychosocial or pharmacological interventions for the treatment or prevention of antisocial personality disorder are competent and properly qualified and supervised, and that they adhere closely to the structure and duration of the interventions as set out in the relevant treatment manuals. This should be achieved through: use of competence frameworks based on relevant treatment manuals routine use of sessional outcome measures routine direct monitoring and evaluation of staff adherence, for example through the use of video and audio tapes and external audit and scrutiny where appropriate. Supervision and support Services should ensure that staff supervision is built into the routine working of the service, is properly resourced within local systems and is monitored. Supervision, which may be provided by staff external to the service, should: make use of direct observation (for example, recordings of sessions) and routine outcome measures support adherence to the specific intervention promote general therapeutic consistency and reliability counter negative attitudes among staff. Forensic services should ensure that systems for all staff working with people with antisocial personality disorder are in place that provide: comprehensive induction programmes in which the purpose of the service is made clear a supportive and open environment that encourages reflective practice and honesty about individual difficulties such as the potential for therapeutic boundary violations (such as inappropriate relations with service users) continuing staff support to review and explore the ethical and clinical challenges involved in working in high-intensity environments, thereby building staff capacity and resilience. # Terms used in this guideline ## Anger control Usually offered to children who are aggressive at school, anger control includes a number of cognitive and behavioural techniques similar to cognitive problem-solving skills training (see below). It also includes training of other skills such as relaxation and social skills. ## Brief strategic family therapy An intervention that is systemic in focus and is influenced by other approaches. The main elements include engaging and supporting the family, identifying maladaptive family interactions and seeking to promote new and more adaptive family interactions. ## Cognitive problem-solving skills training An intervention that aims to reduce children's conduct problems by teaching them different responses to interpersonal situations. Using cognitive and behavioural techniques with the child, the training has a focus on thought processes. The training includes: teaching a step-by-step approach to solving interpersonal problems structured tasks such as games and stories to aid the development of skills combining a variety of approaches including modelling and practice, role-playing and reinforcement. ## Functional family therapy A family-based intervention that is behavioural in focus. The main elements include engagement and motivation of the family in treatment, problem-solving and behaviour change through parent-training and communication-training, and seeking to generalise change from specific behaviours to positively influence interactions both within the family and with community agencies such as schools. ## Multidimensional treatment foster care Using strategies from family therapy and behaviour therapy to intervene directly in systems and processes related to antisocial behaviour (for example, parental discipline, family affective relations, peer associations and school performances) for children or young people in foster care and other out-of-home placements. This includes group meetings and other support for the foster parents and family therapy with the child's biological parents. ## Multisystemic therapy Using strategies from family therapy and behaviour therapy to intervene directly in systems and processes related to antisocial behaviour (for example, parental discipline, family affective relations, peer associations and school performances) for children or young people. ## Parent-training programmes An intervention that aims to teach the principles of child behaviour management, to increase parental competence and confidence in raising children and to improve the parent/carer–child relationship by using good communication and positive attention to aid the child's development. Examples of well-developed programmes are the Triple P (Sanders et al. 2000) and Webster-Stratton (Webster-Stratton et al. 1988). ## Self-talk The internal conversation a person has with themselves in response to a situation. Using or changing self-talk is a part of anger control training (see above). ## Social problem skills training A specialist form of cognitive problem-solving training that aims to: modify and expand the child's interpersonal appraisal processes through developing a more sophisticated understanding of beliefs and desires in others improve the child's capacity to regulate his or her own emotional responses.# Recommendations for research The guideline development group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The relatively large number of recommendations made reflects the paucity of research in this area. # Severity as a potential moderator of effect in group-based cognitive and behavioural interventions Does the pre-treatment level of the severity of disorder/problem have an impact on the outcome of group-based cognitive and behavioural interventions for offending behaviour? A meta-analysis of individual participant data should be conducted to determine whether the level of severity assessed at the beginning of the intervention moderates the effect of the intervention. The study (for which there are large data sets that include over 10,000 participants) could inform the design of a large-scale RCT (including potential modifications of cognitive and behavioural interventions) to test the impact of severity on the outcome of cognitive and behavioural interventions. ## Why this is important Research has established the efficacy of cognitive and behavioural interventions in reducing reoffending. However, the effects of these interventions in a range of offending populations are modest. The impact of severity on the outcome of these interventions has not been systematically investigated, and post hoc analyses and meta-regression of risk as a moderating factor have been inconclusive. Expert opinion suggests that severe or high-risk individuals may not benefit from cognitive and behavioural interventions, but if they were to be of benefit then the cost savings could be considerable. # Group-based cognitive and behavioural interventions for populations outside criminal justice settings Are group-based cognitive and behavioural interventions effective in reducing the behaviours associated with antisocial personality disorder (such as impulsivity, rule-breaking, deceitfulness, irritability, aggressiveness and disregard for the safety of self or others)? This should be tested in an RCT that examines medium-term outcomes (including cost effectiveness) over a period of at least 18 months. It should pay particular attention to the modification and development of the interventions to ensure the focus is not just on offending behaviour, but on all aspects of the challenging behaviours associated with antisocial personality disorder. ## Why this is important Not all people with antisocial personality disorder are offenders but they exhibit a wide range of antisocial behaviours. However, the evidence for the treatment of these behaviours outside the criminal justice system is extremely limited. Following publication of the Department of Health's policy guidance, 'Personality disorder: no longer a diagnosis of exclusion' (2003), it is likely that there will be an increased requirement in the NHS to offer treatments for antisocial personality disorder. # Effectiveness of multisystemic therapy versus functional family therapy Is multisystemic therapy or functional family therapy more clinically and cost effective in the treatment of adolescents with conduct disorders? A large-scale RCT comparing the clinical and cost effectiveness of multisystemic therapy and functional family therapy for adolescents with conduct disorders should be conducted. It should examine the medium-term outcomes (for example, offending behaviour, mental state, educational and vocational outcomes and family functioning) over a period of at least 18 months. The study should also be designed to explore the moderators and mediators of treatment effect, which could help to determine the factors associated with benefits or harms of either multisystemic therapy or functional family therapy. ## Why this is important Multisystemic therapy and functional family therapy are two interventions with a relatively strong evidence base in the treatment of adolescents with conduct disorders, but there have been no studies directly comparing their clinical and cost effectiveness. Their use in health and social care services in the UK is increasing. Both interventions target the same population, but although they share some common elements (that is, work with the family), multisystemic therapy is focused on both the family and the wider resources of the school, community and criminal justice systems, and through intensive individual case work seeks to change the pattern of antisocial behaviour. In contrast, functional family therapy focuses more on the immediate family environment and uses the resources of the family to change the pattern of antisocial behaviour. The study should be designed to facilitate the identification of sub-groups within the conduct disorder population who may benefit from either multisystemic therapy or functional family therapy. # Interventions for infants at high risk of developing conduct disorders Do specially designed parent-training programmes focused on sensitivity enhancement (a set of techniques designed to improve secure attachment behaviour between parents and children) reduce the risk of behavioural disorders, including conduct problems and delinquency, in infants at high risk of developing these problems? An RCT comparing parent-training programmes focused on sensitivity enhancement with usual care should be undertaken. It should examine the long-term outcomes over a period of at least 5 years, but with consideration given to the possibility of a further 10-year follow-up. The study should also be designed to explore the moderators and mediators of treatment effect that could help determine the factors associated with benefits or harms of the intervention. ## Why this is important There is limited evidence from non-UK studies that interventions focused on developing better parent–child attachment can have benefits for infants at risk of developing conduct disorder. Determining the criteria and then identifying children at high risk (usually via parental risk factors) is difficult and challenging. Even when these factors are agreed, engaging parents in treatment can be difficult. It is important that a range of effective interventions is developed to increase the treatment choice and opportunities for high-risk groups. Several interventions, such as Nurse–Family Practitioners, are being developed and trialled in the UK. It is important for this group of children to have an alternative, effective intervention. # Treatment of comorbid anxiety disorders in antisocial personality disorder Does the effective treatment of anxiety disorders in antisocial personality disorder improve the long-term outcome for antisocial personality disorder? An RCT of people with antisocial personality disorder and comorbid anxiety disorders that compares a sequenced treatment programme for the anxiety disorder with usual care should be conducted. It should examine, over a period of at least 18 months, the medium-term outcomes for key symptoms and behaviours associated with antisocial personality disorder (including offending behaviour, deceitfulness, irritability and aggressiveness, and disregard for the safety of self or others), as well as drug and alcohol misuse, and anxiety. The study should also be designed to explore the moderators and mediators of treatment effect which could help determine the role of anxiety in the course of antisocial personality disorder. ## Why this is important Comorbidity with Axis I disorders is common in antisocial personality disorder, and chronic anxiety has been identified as a particular disorder that may exacerbate the problems associated with antisocial personality disorder. There are effective treatments (psychological and pharmacological) for anxiety disorders but they are often not offered to people with antisocial personality disorder. Current treatment guidelines set out clear pathways for the stepped or sequenced care of people with anxiety disorders. An RCT to test the benefit of this approach in the treatment of anxiety would potentially lead to a significant reduction in illness burden but a reduction in antisocial behaviour would have wider societal benefits. The study should provide important information on the challenges of delivering these interventions for a population that has typically both rejected and been refused treatment. # Using selective serotonin reuptake inhibitors to increase cooperative behaviour in people with antisocial personality disorder in a prison setting Although there is evidence that selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, increase cooperative behaviour in normal people and do so independently of the level of sub-syndromal depression, this has yet to be tested in other settings. Given that people with antisocial personality disorder are likely to have difficulties cooperating with one another (because of a host of personality traits that include persistent rule-breaking for personal advantage, suspiciousness, grandiosity, etc.). An RCT should be conducted to find out whether these reported changes of behaviour with an SSRI in normal people generalises to clinical populations in different settings. ## Why this is important There is little evidence in the literature on the pharmacotherapy of antisocial personality disorder to justify the use of any particular medication. However, multiple drugs in various combinations are used in this group either to control aberrant behaviour or in the hope that something might work. Current interventions lack a clear rationale. This recommendation has the potential to advance the field in that (a) it is linked to a clear hypothesis (that cooperative behaviour is linked to a dysregulation of the serotonin receptors – for which there is substantial evidence) and (b) that it is feasible to obtain an answer to this question, given that there are a large number of individuals detained in prison settings who would meet ASPD criteria. Constructing an experimental task that requires cooperative activity would not be difficult in such a setting, since all of those who might be willing to participate are already detained. The successful execution of this research would be important in that it (a) would establish the feasibility of conducting such a trial in a prison setting with this group, and (b) provide a clear and sensible outcome measure of antisocial behaviour that might be generalised to other settings. # A therapeutic community approach for antisocial personality disorder in a prison setting Is a therapeutic community approach in a prison setting more clinically and cost effective in the treatment and management of antisocial personality disorder than routine prison care? There should be a large-scale RCT comparing the clinical and cost effectiveness of the therapeutic community approach for adults with antisocial personality disorder with routine care. It should examine the medium-term outcomes (for example, offending behaviour, mental state and vocational outcomes) over a period of at least 18 months following release from prison. The study should also be designed to explore the moderators and mediators of treatment effect, which could help to determine the factors associated with benefits or harms of the therapeutic community approach. ## Why this is important There is evidence from RCTs that the therapeutic community approach is of value with drug and alcohol misusers in a prison setting at reducing the incidence of offending behaviour on release. However, there are no equivalent studies of a programme in the prison system on antisocial personality disorder populations that do not have significant drug or alcohol problems. Data that do exist are from non-UK settings. Answering this question is of importance because outcomes for adults with antisocial personality disorder are poor and there are already considerable resources devoted to a therapeutic community approach in the UK prison system (for example, HMP Grendon Underwood). The study could inform policy and resources decisions about the management of antisocial personality disorder in the criminal justice system.	{'Introduction': "This guideline makes recommendations for the treatment, management and prevention of antisocial personality disorder in primary, secondary and forensic healthcare. This guideline is concerned with the treatment of people with antisocial personality disorder across a wide range of services including those provided within mental health (including substance misuse) services, social care and the criminal justice system.\n\nPeople with antisocial personality disorder exhibit traits of impulsivity, high negative emotionality, low conscientiousness and associated behaviours including irresponsible and exploitative behaviour, recklessness and deceitfulness. This is manifest in unstable interpersonal relationships, disregard for the consequences of one's behaviour, a failure to learn from experience, egocentricity and a disregard for the feelings of others. The condition is associated with a wide range of interpersonal and social disturbance.\n\nPeople with antisocial personality disorder have often grown up in fractured families in which parental conflict is typical and parenting is harsh and inconsistent. As a result of parental inadequacies and/or the child's difficult behaviour, the child's care is often interrupted and transferred to agencies outside the family. This in turn often leads to truancy, having delinquent associates and substance misuse, which frequently result in increased rates of unemployment, poor and unstable housing situations, and inconsistency in relationships in adulthood. Many people with antisocial personality disorder have a criminal conviction and are imprisoned or die prematurely as a result of reckless behaviour.\n\nCriminal behaviour is central to the definition of antisocial personality disorder, although it is often the culmination of previous and long-standing difficulties, such as socioeconomic, educational and family problems. Antisocial personality disorder therefore amounts to more than criminal behaviour alone, otherwise everyone convicted of a criminal offence would meet the criteria for antisocial personality disorder and a diagnosis of antisocial personality disorder would be rare in people with no criminal history. This is not the case. The prevalence of antisocial personality disorder among prisoners is slightly less than 50%. It is estimated in epidemiological studies in the community that only 47% of people who meet the criteria for antisocial personality disorder have significant arrest records. A history of aggression, unemployment and promiscuity were more common than serious crimes among people with antisocial personality disorder. The prevalence of antisocial personality disorder in the general population is 3% in men and 1% in women.\n\nUnder current diagnostic systems, antisocial personality disorder is not formally diagnosed before the age of 18 but the features of the disorder can manifest earlier as conduct disorder. People with conduct disorder typically show antisocial, aggressive or defiant behaviour, which is persistent and repetitive, including aggression to people or animals, destruction of property, deceitfulness, theft and serious rule-breaking. A history of conduct disorder before the age of 15 is a requirement for a diagnosis of antisocial personality disorder in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV).\n\nThe course of antisocial personality disorder is variable and although recovery is attainable over time, some people may continue to experience social and interpersonal difficulties. Antisocial personality disorder is often comorbid with depression, anxiety, and alcohol and drug misuse.\n\nFamilies or carers are important in prevention and treatment of antisocial personality disorder. This guideline uses the term 'families or carers' to apply to all family members and other people, such as friends and advocates, who have regular close contact with the person with antisocial personality disorder.\n\nThis guideline draws on the best available evidence. However, there are significant limitations to the evidence base, notably a relatively small number of randomised controlled trials (RCTs) of interventions with few outcomes in common. Some of the limitations are addressed in the recommendations for research.\n\nAt the time of publication (January\xa02009), no drug has UK marketing authorisation for the treatment of antisocial personality disorder. The guideline assumes that prescribers will use a drug's summary of product characteristics to inform their decisions for each person.\n\nNICE has also developed a guideline on borderline personality disorder: recognition and management.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nIn March 2013, recommendations 1.2.3.1, 1.2.3.2, 1.2.4.1, 1.2.4.2, 1.2.4.4, 1.2.4.5, 1.2.5.1\xa0to\xa01.2.5.3, 1.2.6.1, 1.2.6.2, 1.2.7.1\xa0to\xa01.2.7.7 and 1.2.8.1\xa0to\xa01.2.8.4 were deleted and replaced by the NICE guideline on antisocial behaviour and conduct disorders in children and young people.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# General principles for working with people with antisocial personality disorder\n\nPeople with antisocial personality disorder have tended to be excluded from services, the Department of Health's Personality disorder: no longer a diagnosis of exclusion aims to address this. To change the current position, staff need to work actively to engage people with antisocial personality disorder in treatment. Evidence from both clinical trials and scientific studies of antisocial personality disorder shows that positive and reinforcing approaches to the treatment of antisocial personality disorder are more likely to be successful than those that are negative or punitive.\n\n## Access and assessment\n\nPeople with antisocial personality disorder should not be excluded from any health or social care service because of their diagnosis or history of antisocial or offending behaviour.\n\nSeek to minimise any disruption to therapeutic interventions for people with antisocial personality disorder by:\n\nensuring that in the initial planning and delivery of treatment, transfers from institutional to community settings take into account the need to continue treatment\n\navoiding unnecessary transfer of care between institutions whenever possible during an intervention, to prevent disruption to the agreed treatment plan. This should be considered at initial planning of treatment.\n\nEnsure that people with antisocial personality disorder from black and minority ethnic groups have equal access to culturally appropriate services based on clinical need.\n\nWhen language or literacy is a barrier to accessing or engaging with services for people with antisocial personality disorder, provide:\n\ninformation in their preferred language and in an accessible format\n\npsychological or other interventions in their preferred language\n\nindependent interpreters.\n\nWhen a diagnosis of antisocial personality disorder is made, discuss the implications of it with the person, the family or carers where appropriate, and relevant staff, and:\n\nacknowledge the issues around stigma and exclusion that have characterised care for people with antisocial personality disorder\n\nemphasise that the diagnosis does not limit access to a range of appropriate treatments for comorbid mental health disorders\n\nprovide information on and clarify the respective roles of the healthcare, social care and criminal justice services.\n\nWhen working with women with antisocial personality disorder take into account the higher incidences of common comorbid mental health problems and other personality disorders in such women, and:\n\nadapt interventions in light of this (for example, extend their duration)\n\nensure that in inpatient and residential settings the increased vulnerability of these women is taken into account.\n\nStaff, in particular key workers, working with people with antisocial personality disorder should establish regular one-to-one meetings to review progress, even when the primary mode of treatment is group based.\n\n## People with disabilities and acquired cognitive impairments\n\nWhen a person with learning or physical disabilities or acquired cognitive impairments presents with symptoms and behaviour that suggest antisocial personality disorder, staff involved in assessment and diagnosis should consider consulting with a relevant specialist.\n\nStaff providing interventions for people with antisocial personality disorder with learning or physical disabilities or acquired cognitive impairments should, where possible, provide the same interventions as for other people with antisocial personality disorder. Staff might need to adjust the method of delivery or duration of the intervention to take account of the disability or impairment.\n\n## Autonomy and choice\n\nWork in partnership with people with antisocial personality disorder to develop their autonomy and promote choice by:\n\nensuring that they remain actively involved in finding solutions to their problems, including during crises\n\nencouraging them to consider the different treatment options and life choices available to them, and the consequences of the choices they make.\n\n## Developing an optimistic and trusting relationship\n\nStaff working with people with antisocial personality disorder should recognise that a positive and rewarding approach is more likely to be successful than a punitive approach in engaging and retaining people in treatment. Staff should:\n\nexplore treatment options in an atmosphere of hope and optimism, explaining that recovery is possible and attainable\n\nbuild a trusting relationship, work in an open, engaging and non-judgemental manner, and be consistent and reliable.\n\n## Engagement and motivation\n\nWhen providing interventions for people with antisocial personality disorder, particularly in residential and institutional settings, pay attention to motivating them to attend and engage with treatment. This should happen at initial assessment and be an integral and continuing part of any intervention, as people with antisocial personality disorder are vulnerable to premature withdrawal from treatment and supportive interventions.\n\n## Involving families and carers\n\nAsk directly whether the person with antisocial personality disorder wants their family or carers to be involved in their care, and, subject to the person's consent and rights to confidentiality:\n\nencourage families or carers to be involved\n\nensure that the involvement of families or carers does not lead to a withdrawal of, or lack of access to, services\n\ninform families or carers about local support groups for families or carers.\n\nConsider the needs of families and carers of people with antisocial personality disorder and pay particular attention to the:\n\nimpact of antisocial and offending behaviours on the family\n\nconsequences of significant drug or alcohol misuse\n\nneeds of and risks to any children in the family and the safeguarding of their interests.\n\n# Prevention of antisocial personality disorder – working with children and young people and their families\n\nThe evidence for the treatment of antisocial personality disorder in adult life is limited and the outcomes of interventions are modest. The evidence for working with children and young people who are at risk, and their families, points to the potential value of preventative measures. See terms used in this guideline for definitions of the psychological interventions referred to.\n\n## General principles\n\nChild and adolescent mental health service (CAMHS) professionals working with young people should:\n\nbalance the developing autonomy and capacity of the young person with the responsibilities of parents and carers\n\nbe familiar with the legal framework that applies to young people, including the Mental Capacity Act, the Children Acts and the Mental Health Act.\n\n## Identifying children at risk of developing conduct problems\n\nServices should establish robust methods to identify children at risk of developing conduct problems, integrated when possible with the established local assessment system. These should focus on identifying vulnerable parents, where appropriate antenatally, including:\n\nparents with other mental health problems, or with significant drug or alcohol problems.\n\nmothers younger than 18\xa0years, particularly those with a history of maltreatment in childhood\n\nparents with a history of residential care\n\nparents with significant previous or current contact with the criminal justice system.\n\nWhen identifying vulnerable parents, take care not to intensify any stigma associated with the intervention or increase the child's problems by labelling them as antisocial or problematic.\n\n## Early interventions for preschool children at risk of developing conduct problems and potentially subsequent antisocial personality disorder\n\nThis recommendation has been deleted\n\nThis recommendation has been deleted.\n\n## Interventions for children with conduct problems younger than 12\xa0years and their families\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\nAdditional interventions targeted specifically at the parents of children with conduct problems (such as interventions for parental, marital or interpersonal problems) should not be provided routinely alongside parent-training programmes, as they are unlikely to have an impact on the child's conduct problems.\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\n## How to deliver interventions for children with conduct problems aged younger than 12\xa0years and their families\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\n## Cognitive behavioural interventions for children aged 8\xa0years and older with conduct problems\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\n## How to deliver interventions for children aged 8\xa0years and older with conduct problems\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\n## How to deliver interventions for young people with conduct problems aged between 12 and 17\xa0years and their families\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\nThis recommendation has been deleted.\n\n## Transition from child and adolescent services to adult services\n\nHealth and social care services should consider referring vulnerable young people with a history of conduct disorder or contact with youth offending schemes, or those who have been receiving interventions for conduct and related disorders, to appropriate adult services for continuing assessment and/or treatment.\n\n# Assessment and risk management of antisocial personality disorder\n\nIn primary and secondary care services, antisocial personality disorder is under-recognised. When it is identified, significant comorbid disorders such as treatable depression or anxiety are often not detected. In secondary and forensic services there are important concerns about assessing risk of violence and risk of harm to self and others.\n\n## Assessment\n\nWhen assessing a person with possible antisocial personality disorder, healthcare professionals in secondary and forensic mental health services should conduct a full assessment of:\n\nantisocial behaviours\n\npersonality functioning, coping strategies, strengths and vulnerabilities\n\ncomorbid mental disorders (including depression and anxiety, drug or alcohol misuse, post-traumatic stress disorder and other personality disorders)\n\nthe need for psychological treatment, social care and support, and occupational rehabilitation or development\n\ndomestic violence and abuse.\n\nStaff involved in the assessment of antisocial personality disorder in secondary and specialist services should use structured assessment methods whenever possible to increase the validity of the assessment. For forensic services, the use of measures such as PCL-R or PCL-SV to assess the severity of antisocial personality disorder should be part of the routine assessment process.\n\nStaff working in primary and secondary care services (for example, drug and alcohol services) and community services (for example, the probation service) that include a high proportion of people with antisocial personality disorder should be alert to the possibility of antisocial personality disorder in service users. Where antisocial personality disorder is suspected and the person is seeking help, consider offering a referral to an appropriate forensic mental health service depending on the nature of the presenting complaint. For example, for depression and anxiety this may be to general mental health services; for problems directly relating to the personality disorder it may be to a specialist personality disorder or forensic service.\n\n## Risk assessment and management\n\nRisk assessment is part of the overall approach to assessment and care planning as defined in the framework of the Care Programme Approach, and the following recommendations should be regarded in that context.\n\nAssessing risk of violence is not routine in primary care, but if such assessment is required consider:\n\ncurrent or previous violence, including severity, circumstances, precipitants and victims\n\nthe presence of comorbid mental disorders and/or substance misuse\n\ncurrent life stressors, relationships and life events\n\nadditional information from written records or families and carers (subject to the person's consent and right to confidentiality), because the person with antisocial personality disorder might not always be a reliable source of information.\n\nHealthcare professionals in primary care should consider contact with and/or referral to secondary or forensic services where there is current violence or threats that suggest significant risk and/or a history of serious violence, including predatory offending or targeting of children or other vulnerable people.\n\nWhen assessing the risk of violence in secondary care mental health services, take a detailed history of violence and consider and record:\n\ncurrent or previous violence, including severity, circumstances, precipitants and victims\n\ncontact with the criminal justice system, including convictions and periods of imprisonment\n\nthe presence of comorbid mental disorder and/or substance misuse\n\ncurrent life stressors, relationships and life events\n\nadditional information from written records or families and carers (subject to the person's consent and right to confidentiality), as the person with antisocial personality disorder might not always be a reliable source of information.\n\nThe initial risk management should be directed at crisis resolution and ameliorating any acute aggravating factors. The history of previous violence should be an important guide in the development of any future violence risk management plan.\n\nStaff in secondary care mental health services should consider a referral to forensic services where there is:\n\ncurrent violence or threat that suggests immediate risk or disruption to the operation of the service\n\na history of serious violence, including predatory offending or targeting of children or other vulnerable people.\n\nWhen assessing the risk of violence in forensic, specialist personality disorder or tertiary mental health services, take a detailed history of violence, and consider and record:\n\ncurrent and previous violence, including severity, circumstances, precipitants and victims\n\ncontact with the criminal justice system, including convictions and periods of imprisonment\n\nthe presence of comorbid mental disorder and/or substance misuse\n\ncurrent life stressors, relationships and life events\n\nadditional information from written records or families and carers (subject to the person's consent and right to confidentiality), as the person with antisocial personality disorder might not always be a reliable source of information.\n\nHealthcare professionals in forensic or specialist personality disorder services should consider, as part of a structured clinical assessment, routinely using:\n\na standardised measure of the severity of antisocial personality disorder (for example, PCL-R or PCL-SV)\n\na formal assessment tool such as HCR-20 to develop a risk management strategy.\n\n## Risk management\n\nServices should develop a comprehensive risk management plan for people with antisocial personality disorder who are considered to be of high risk. The plan should involve other agencies in health and social care services and the criminal justice system. Probation services should take the lead role when the person is on a community sentence or is on licence from prison with mental health and social care services providing support and liaison. Such cases should routinely be referred to the local Multi-Agency Public Protection Panel.\n\n# Treatment and management of antisocial personality disorder and related and comorbid disorders\n\nThe evidence base for the treatment of antisocial personality disorder is limited. In the development of the recommendations set out below these limitations were addressed by drawing on four related sources of evidence, namely, evidence for: (1) interventions targeted specifically at antisocial personality disorder; (2) the treatment and management of the symptoms and behaviours associated with antisocial personality disorder, such as impulsivity and aggression; (3) the treatment of comorbid disorders such as depression and drug misuse; and (4) the management of offending behaviour. Although the focus of several interventions is offending behaviour, the interventions have the potential to help people with antisocial personality disorder address a wider range of antisocial behaviours with consequent benefits for themselves and others.\n\n## General principles\n\nPeople with antisocial personality disorder should be offered treatment for any comorbid disorders in line with recommendations in the relevant NICE guideline, where available (see the NICE topic page on mental health and behavioural conditions). This should happen regardless of whether the person is receiving treatment for antisocial personality disorder.\n\nWhen providing psychological or pharmacological interventions for antisocial personality disorder, offending behaviour or comorbid disorders to people with antisocial personality disorder, be aware of the potential for and possible impact of:\n\npoor concordance\n\nhigh attrition\n\nmisuse of prescribed medication\n\ndrug interactions (including with alcohol and illicit drugs).\n\nWhen providing psychological interventions for comorbid disorders to people with antisocial personality disorder, consider lengthening their duration or increasing their intensity.\n\n## The role of psychological interventions\n\nFor people with antisocial personality disorder, including those with substance misuse problems, in community and mental health services, consider offering group-based cognitive and behavioural interventions, in order to address problems such as impulsivity, interpersonal difficulties and antisocial behaviour.\n\nFor people with antisocial personality disorder with a history of offending behaviour who are in community and institutional care, consider offering group-based cognitive and behavioural interventions (for example, programmes such as 'reasoning and rehabilitation') focused on reducing offending and other antisocial behaviour.\n\nFor young offenders aged 17\xa0years or younger with a history of offending behaviour who are in institutional care, offer group-based cognitive and behavioural interventions aimed at young offenders and that are focused on reducing offending and other antisocial behaviour.\n\nWhen providing cognitive and behavioural interventions:\n\nassess the level of risk and adjust the duration and intensity of the programme accordingly (participants at all levels of risk may benefit from these interventions)\n\nprovide support and encouragement to help participants to attend and complete programmes, including people who are legally mandated to do so.\n\n## The role of pharmacological interventions\n\nPharmacological interventions should not be routinely used for the treatment of antisocial personality disorder or associated behaviours of aggression, anger and impulsivity.\n\nPharmacological interventions for comorbid mental disorders, in particular depression and anxiety, should be in line with recommendations in the relevant NICE guideline (see the NICE topic page on mental health and behavioural conditions). When starting and reviewing medication for comorbid mental disorders, pay particular attention to issues of adherence and the risks of misuse or overdose.\n\n## Drug and alcohol misuse\n\nDrug and alcohol misuse occurs commonly alongside antisocial personality disorder, and is likely to aggravate risk of harm to self and others and behavioural disturbances in people with antisocial personality disorder.\n\nFor people with antisocial personality disorder who misuse drugs, in particular opioids or stimulants, offer psychological interventions (in particular, contingency management programmes) in line with recommendations in the relevant NICE guideline (see the NICE topic page on mental health and behavioural conditions).\n\nFor people with antisocial personality disorder who misuse or are dependent on alcohol, offer psychological and pharmacological interventions in line with existing national guidance for the treatment and management of alcohol disorders.\n\nFor people with antisocial personality disorder who are in institutional care and who misuse or are dependent on drugs or alcohol, consider referral to a specialist therapeutic community focused on the treatment of drug and alcohol problems.\n\n# Psychopathy and dangerous and severe personality disorder\n\nPeople with psychopathy and people who meet criteria for dangerous and severe personality disorder (DSPD) represent a small proportion of people with antisocial personality disorder. However, they present a very high risk of harm to others and consume a significant proportion of the services for people with antisocial personality disorder. In the absence of any high-quality evidence for the treatment of DSPD, the Guideline Development Group drew on the evidence for the treatment of antisocial personality disorder to arrive at their recommendations. Interventions will often need to be adapted for DSPD (for example, a significant extension of the duration of the intervention). People with DSPD can be seen as having a lifelong disability that requires continued input and support over many years.\n\n## Adapting interventions for people who meet criteria for psychopathy or DSPD\n\nFor people in community and institutional settings who meet criteria for psychopathy or DSPD, consider cognitive and behavioural interventions (for example, programmes such as 'reasoning and rehabilitation') focused on reducing offending and other antisocial behaviour. These interventions should be adapted for this group by extending the nature (for example, concurrent individual and group sessions) and duration of the intervention, and by providing booster sessions, continued follow-up and close monitoring.\n\nFor people who meet criteria for psychopathy or DSPD, offer treatment for any comorbid disorders in line with existing NICE guidance (see the NICE topic page on mental health and behavioural conditions). This should happen regardless of whether the person is receiving treatment for psychopathy or DSPD because effective treatment of comorbid disorders may reduce the risk associated with psychopathy or DSPD.\n\n## Intensive staff support\n\nStaff providing interventions for people who meet criteria for psychopathy or DSPD should receive high levels of support and close supervision, due to increased risk of harm. This may be provided by staff outside the unit.\n\n# Organisation and planning of services\n\nThere has been a considerable expansion of services for people with antisocial personality disorder in recent years involving a wider range of agencies in the health and social care sector, the non-statutory sector and the criminal justice system. If the full benefit of these additional services is to be realised, effective care pathways and specialist networks need to be developed.\n\n## Multi-agency care\n\nProvision of services for people with antisocial personality disorder often involves significant inter-agency working. Therefore, services should ensure that there are clear pathways for people with antisocial personality disorder so that the most effective multi-agency care is provided. These pathways should:\n\nspecify the various interventions that are available at each point\n\nenable effective communication among clinicians and organisations at all points and provide the means to resolve differences and disagreements.Clearly agreed local criteria should also be established to facilitate the transfer of people with antisocial personality disorder between services. As far as is possible, shared objective criteria should be developed relating to comprehensive assessment of need and risk.\n\nServices should consider establishing antisocial personality disorder networks, where possible linked to other personality disorder networks. (They may be organised at the level of primary care trusts, local authorities, strategic health authorities or government offices.) These networks should be multi-agency, should actively involve people with antisocial personality disorder and should:\n\ntake a significant role in training staff, including those in primary care, general, secondary and forensic mental health services, and in the criminal justice system\n\nhave resources to provide specialist support and supervision for staff\n\ntake a central role in the development of standards for and the coordination of clinical pathways\n\nmonitor the effective operation of clinical pathways.\n\n## Inpatient services\n\nHealthcare professionals should normally only consider admitting people with antisocial personality disorder to inpatient services for crisis management or for the treatment of comorbid disorders. Admission should be brief, where possible set out in a previously agreed crisis plan and have a defined purpose and end point.\n\nAdmission to inpatient services solely for the treatment of antisocial personality disorder or its associated risks is likely to be a lengthy process and should:\n\nbe under the care of forensic/specialist personality disorder services\n\nnot usually be under a hospital order under a section of the Mental Health Act (in the rare instance that this is done, seek advice from a forensic/specialist personality service).\n\n## Staff training, supervision, support\n\nWorking in services for people with antisocial personality disorder presents a considerable challenge for staff. Effective training and support is crucial so that staff can adhere to the specified treatment programme and manage any emotional pressures arising from their work.\n\nStaff competencies\n\nAll staff working with people with antisocial personality disorder should be familiar with the Department of Health's Ten essential shared capabilities: a framework for the whole of the mental health workforce, and have a knowledge and awareness of antisocial personality disorder that facilitates effective working with service users, families or carers, and colleagues.\n\nAll staff working with people with antisocial personality disorder should have skills appropriate to the nature and level of contact with service users. These skills include:\n\nfor all frontline staff, knowledge about antisocial personality disorder and understanding behaviours in context, including awareness of the potential for therapeutic boundary violations (for example, inappropriate relations with service users)\n\nfor staff with regular and sustained contact with people with antisocial personality disorder, the ability to respond effectively to the needs of service users\n\nfor staff with direct therapeutic or management roles, competence in the specific treatment interventions and management strategies used in the service.\n\nServices should ensure that all staff providing psychosocial or pharmacological interventions for the treatment or prevention of antisocial personality disorder are competent and properly qualified and supervised, and that they adhere closely to the structure and duration of the interventions as set out in the relevant treatment manuals. This should be achieved through:\n\nuse of competence frameworks based on relevant treatment manuals\n\nroutine use of sessional outcome measures\n\nroutine direct monitoring and evaluation of staff adherence, for example through the use of video and audio tapes and external audit and scrutiny where appropriate.\n\nSupervision and support\n\nServices should ensure that staff supervision is built into the routine working of the service, is properly resourced within local systems and is monitored. Supervision, which may be provided by staff external to the service, should:\n\nmake use of direct observation (for example, recordings of sessions) and routine outcome measures\n\nsupport adherence to the specific intervention\n\npromote general therapeutic consistency and reliability\n\ncounter negative attitudes among staff.\n\nForensic services should ensure that systems for all staff working with people with antisocial personality disorder are in place that provide:\n\ncomprehensive induction programmes in which the purpose of the service is made clear\n\na supportive and open environment that encourages reflective practice and honesty about individual difficulties such as the potential for therapeutic boundary violations (such as inappropriate relations with service users)\n\ncontinuing staff support to review and explore the ethical and clinical challenges involved in working in high-intensity environments, thereby building staff capacity and resilience.\n\n# Terms used in this guideline\n\n## Anger control\n\nUsually offered to children who are aggressive at school, anger control includes a number of cognitive and behavioural techniques similar to cognitive problem-solving skills training (see below). It also includes training of other skills such as relaxation and social skills.\n\n## Brief strategic family therapy\n\nAn intervention that is systemic in focus and is influenced by other approaches. The main elements include engaging and supporting the family, identifying maladaptive family interactions and seeking to promote new and more adaptive family interactions.\n\n## Cognitive problem-solving skills training\n\nAn intervention that aims to reduce children's conduct problems by teaching them different responses to interpersonal situations. Using cognitive and behavioural techniques with the child, the training has a focus on thought processes. The training includes:\n\nteaching a step-by-step approach to solving interpersonal problems\n\nstructured tasks such as games and stories to aid the development of skills\n\ncombining a variety of approaches including modelling and practice, role-playing and reinforcement.\n\n## Functional family therapy\n\nA family-based intervention that is behavioural in focus. The main elements include engagement and motivation of the family in treatment, problem-solving and behaviour change through parent-training and communication-training, and seeking to generalise change from specific behaviours to positively influence interactions both within the family and with community agencies such as schools.\n\n## Multidimensional treatment foster care\n\nUsing strategies from family therapy and behaviour therapy to intervene directly in systems and processes related to antisocial behaviour (for example, parental discipline, family affective relations, peer associations and school performances) for children or young people in foster care and other out-of-home placements. This includes group meetings and other support for the foster parents and family therapy with the child's biological parents.\n\n## Multisystemic therapy\n\nUsing strategies from family therapy and behaviour therapy to intervene directly in systems and processes related to antisocial behaviour (for example, parental discipline, family affective relations, peer associations and school performances) for children or young people.\n\n## Parent-training programmes\n\nAn intervention that aims to teach the principles of child behaviour management, to increase parental competence and confidence in raising children and to improve the parent/carer–child relationship by using good communication and positive attention to aid the child's development. Examples of well-developed programmes are the Triple P (Sanders et al. 2000) and Webster-Stratton (Webster-Stratton et al. 1988).\n\n## Self-talk\n\nThe internal conversation a person has with themselves in response to a situation. Using or changing self-talk is a part of anger control training (see above).\n\n## Social problem skills training\n\nA specialist form of cognitive problem-solving training that aims to:\n\nmodify and expand the child's interpersonal appraisal processes through developing a more sophisticated understanding of beliefs and desires in others\n\nimprove the child's capacity to regulate his or her own emotional responses.", 'Recommendations for research': "The guideline development group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The relatively large number of recommendations made reflects the paucity of research in this area.\n\n# Severity as a potential moderator of effect in group-based cognitive and behavioural interventions\n\nDoes the pre-treatment level of the severity of disorder/problem have an impact on the outcome of group-based cognitive and behavioural interventions for offending behaviour? A meta-analysis of individual participant data should be conducted to determine whether the level of severity assessed at the beginning of the intervention moderates the effect of the intervention. The study (for which there are large data sets that include over 10,000 participants) could inform the design of a large-scale RCT (including potential modifications of cognitive and behavioural interventions) to test the impact of severity on the outcome of cognitive and behavioural interventions.\n\n## Why this is important\n\nResearch has established the efficacy of cognitive and behavioural interventions in reducing reoffending. However, the effects of these interventions in a range of offending populations are modest. The impact of severity on the outcome of these interventions has not been systematically investigated, and post hoc analyses and meta-regression of risk as a moderating factor have been inconclusive. Expert opinion suggests that severe or high-risk individuals may not benefit from cognitive and behavioural interventions, but if they were to be of benefit then the cost savings could be considerable.\n\n# Group-based cognitive and behavioural interventions for populations outside criminal justice settings\n\nAre group-based cognitive and behavioural interventions effective in reducing the behaviours associated with antisocial personality disorder (such as impulsivity, rule-breaking, deceitfulness, irritability, aggressiveness and disregard for the safety of self or others)? This should be tested in an RCT that examines medium-term outcomes (including cost effectiveness) over a period of at least 18\xa0months. It should pay particular attention to the modification and development of the interventions to ensure the focus is not just on offending behaviour, but on all aspects of the challenging behaviours associated with antisocial personality disorder.\n\n## Why this is important\n\nNot all people with antisocial personality disorder are offenders but they exhibit a wide range of antisocial behaviours. However, the evidence for the treatment of these behaviours outside the criminal justice system is extremely limited. Following publication of the Department of Health's policy guidance, 'Personality disorder: no longer a diagnosis of exclusion' (2003), it is likely that there will be an increased requirement in the NHS to offer treatments for antisocial personality disorder.\n\n# Effectiveness of multisystemic therapy versus functional family therapy\n\nIs multisystemic therapy or functional family therapy more clinically and cost effective in the treatment of adolescents with conduct disorders? A large-scale RCT comparing the clinical and cost effectiveness of multisystemic therapy and functional family therapy for adolescents with conduct disorders should be conducted. It should examine the medium-term outcomes (for example, offending behaviour, mental state, educational and vocational outcomes and family functioning) over a period of at least 18\xa0months. The study should also be designed to explore the moderators and mediators of treatment effect, which could help to determine the factors associated with benefits or harms of either multisystemic therapy or functional family therapy.\n\n## Why this is important\n\nMultisystemic therapy and functional family therapy are two interventions with a relatively strong evidence base in the treatment of adolescents with conduct disorders, but there have been no studies directly comparing their clinical and cost effectiveness. Their use in health and social care services in the UK is increasing. Both interventions target the same population, but although they share some common elements (that is, work with the family), multisystemic therapy is focused on both the family and the wider resources of the school, community and criminal justice systems, and through intensive individual case work seeks to change the pattern of antisocial behaviour. In contrast, functional family therapy focuses more on the immediate family environment and uses the resources of the family to change the pattern of antisocial behaviour. The study should be designed to facilitate the identification of sub-groups within the conduct disorder population who may benefit from either multisystemic therapy or functional family therapy.\n\n# Interventions for infants at high risk of developing conduct disorders\n\nDo specially designed parent-training programmes focused on sensitivity enhancement (a set of techniques designed to improve secure attachment behaviour between parents and children) reduce the risk of behavioural disorders, including conduct problems and delinquency, in infants at high risk of developing these problems? An RCT comparing parent-training programmes focused on sensitivity enhancement with usual care should be undertaken. It should examine the long-term outcomes over a period of at least 5\xa0years, but with consideration given to the possibility of a further 10-year follow-up. The study should also be designed to explore the moderators and mediators of treatment effect that could help determine the factors associated with benefits or harms of the intervention.\n\n## Why this is important\n\nThere is limited evidence from non-UK studies that interventions focused on developing better parent–child attachment can have benefits for infants at risk of developing conduct disorder. Determining the criteria and then identifying children at high risk (usually via parental risk factors) is difficult and challenging. Even when these factors are agreed, engaging parents in treatment can be difficult. It is important that a range of effective interventions is developed to increase the treatment choice and opportunities for high-risk groups. Several interventions, such as Nurse–Family Practitioners, are being developed and trialled in the UK. It is important for this group of children to have an alternative, effective intervention.\n\n# Treatment of comorbid anxiety disorders in antisocial personality disorder\n\nDoes the effective treatment of anxiety disorders in antisocial personality disorder improve the long-term outcome for antisocial personality disorder? An RCT of people with antisocial personality disorder and comorbid anxiety disorders that compares a sequenced treatment programme for the anxiety disorder with usual care should be conducted. It should examine, over a period of at least 18\xa0months, the medium-term outcomes for key symptoms and behaviours associated with antisocial personality disorder (including offending behaviour, deceitfulness, irritability and aggressiveness, and disregard for the safety of self or others), as well as drug and alcohol misuse, and anxiety. The study should also be designed to explore the moderators and mediators of treatment effect which could help determine the role of anxiety in the course of antisocial personality disorder.\n\n## Why this is important\n\nComorbidity with Axis I disorders is common in antisocial personality disorder, and chronic anxiety has been identified as a particular disorder that may exacerbate the problems associated with antisocial personality disorder. There are effective treatments (psychological and pharmacological) for anxiety disorders but they are often not offered to people with antisocial personality disorder. Current treatment guidelines set out clear pathways for the stepped or sequenced care of people with anxiety disorders. An RCT to test the benefit of this approach in the treatment of anxiety would potentially lead to a significant reduction in illness burden but a reduction in antisocial behaviour would have wider societal benefits. The study should provide important information on the challenges of delivering these interventions for a population that has typically both rejected and been refused treatment.\n\n# Using selective serotonin reuptake inhibitors to increase cooperative behaviour in people with antisocial personality disorder in a prison setting\n\nAlthough there is evidence that selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, increase cooperative behaviour in normal people and do so independently of the level of sub-syndromal depression, this has yet to be tested in other settings. Given that people with antisocial personality disorder are likely to have difficulties cooperating with one another (because of a host of personality traits that include persistent rule-breaking for personal advantage, suspiciousness, grandiosity, etc.). An RCT should be conducted to find out whether these reported changes of behaviour with an SSRI in normal people generalises to clinical populations in different settings.\n\n## Why this is important\n\nThere is little evidence in the literature on the pharmacotherapy of antisocial personality disorder to justify the use of any particular medication. However, multiple drugs in various combinations are used in this group either to control aberrant behaviour or in the hope that something might work. Current interventions lack a clear rationale. This recommendation has the potential to advance the field in that (a) it is linked to a clear hypothesis (that cooperative behaviour is linked to a dysregulation of the serotonin receptors – for which there is substantial evidence) and (b) that it is feasible to obtain an answer to this question, given that there are a large number of individuals detained in prison settings who would meet ASPD criteria. Constructing an experimental task that requires cooperative activity would not be difficult in such a setting, since all of those who might be willing to participate are already detained. The successful execution of this research would be important in that it (a) would establish the feasibility of conducting such a trial in a prison setting with this group, and (b) provide a clear and sensible outcome measure of antisocial behaviour that might be generalised to other settings.\n\n# A therapeutic community approach for antisocial personality disorder in a prison setting\n\nIs a therapeutic community approach in a prison setting more clinically and cost effective in the treatment and management of antisocial personality disorder than routine prison care? There should be a large-scale RCT comparing the clinical and cost effectiveness of the therapeutic community approach for adults with antisocial personality disorder with routine care. It should examine the medium-term outcomes (for example, offending behaviour, mental state and vocational outcomes) over a period of at least 18\xa0months following release from prison. The study should also be designed to explore the moderators and mediators of treatment effect, which could help to determine the factors associated with benefits or harms of the therapeutic community approach.\n\n## Why this is important\n\nThere is evidence from RCTs that the therapeutic community approach is of value with drug and alcohol misusers in a prison setting at reducing the incidence of offending behaviour on release. However, there are no equivalent studies of a programme in the prison system on antisocial personality disorder populations that do not have significant drug or alcohol problems. Data that do exist are from non-UK settings. Answering this question is of importance because outcomes for adults with antisocial personality disorder are poor and there are already considerable resources devoted to a therapeutic community approach in the UK prison system (for example, HMP Grendon Underwood). The study could inform policy and resources decisions about the management of antisocial personality disorder in the criminal justice system."}	https://www.nice.org.uk/guidance/cg77	This guideline covers principles for working with people with antisocial personality disorder, including dealing with crises (crisis resolution). It aims to help people with antisocial personality disorder manage feelings of anger, distress, anxiety and depression, and to reduce offending and antisocial behaviour.
e9ebe35da72e0ae2304f6821e091f965178ec0dc	nice	Electrochemotherapy for metastases in the skin from tumours of non-skin origin and melanoma	Electrochemotherapy for metastases in the skin from tumours of non-skin origin and melanoma # Guidance There is sufficient evidence of efficacy of electrochemotherapy for treating metastases in the skin from tumours of non-skin origin and melanoma to support its use as a palliative treatment. There are no major safety concerns. Therefore, in the context of palliative treatment the procedure can be used with normal arrangements for clinical governance, consent and audit. Patient selection should be carried out by an appropriate specialist multidisciplinary team. This procedure should only be carried out by a clinician with specific training in the technique. Clinicians should submit data on all patients undergoing electrochemotherapy (including details of case selection, methods of follow-up and outcomes) to the InspECT register, an international register dedicated to electrochemotherapy, and review clinical outcomes locally.# The procedure # Indications and current treatments Cutaneous and subcutaneous metastases of non-skin origin and melanoma often occur in the setting of disseminated disease and cause significant clinical problems including bleeding, pain and ulceration. The primary aim of treatment is therefore palliative and includes modalities such as regional chemotherapy, curettage, cryotherapy and radiotherapy. # Outline of the procedure Electrochemotherapy aims to enhance the effects of chemotherapy and can be performed as an outpatient procedure. It can be used for local control of cancers that are unsuitable for surgery and resistant to radiotherapy or chemotherapy. The procedure is performed with the patient under general or local anaesthesia with or without sedation. Chemotherapy drugs are given first, either intravenously or directly into the tumour. Drug dose is individualised based on either body surface area or tumour volume. Shortly after drug administration, brief and intense electric pulses are delivered around or directly into the tumour using either surface plates or needle electrodes. This makes the cell membranes more permeable to the chemotherapy drugs so that their cytotoxic effect is increased. Different-shaped electrodes or plates are used depending on the tumour size, extent, shape and location. Treatment duration may vary depending on the number and size of tumours. Larger tumours may need several applications to cover the entire surface. Repeated treatments can be performed if necessary (within the lifetime dose limits of the chemotherapy drugs). Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overviews on electrochemotherapy for metastases in the skin (of non-skin origin) and electrochemotherapy for melanoma metastases in the skin. # Efficacy A randomised controlled trial of 19 patients with melanoma metastases comparing intratumoural electrochemotherapy (in 18 tumours) with intratumoural chemotherapy alone (in 19 tumours) reported complete response in 72% (13/18) of tumours treated with electrochemotherapy at end of follow-up ('average' of 21 months). On an intention-to-treat basis, objective response for electrochemotherapy was significantly greater than for chemotherapy alone (64% versus 29%, p=0.02). A non-randomised comparative study of 61 patients that evaluated electrochemotherapy efficacy in 21 patients (73 tumours) with mixed non-melanoma metastases and 20 patients (98 tumours) with melanoma metastases reported an 85% objective tumour response and a 74% complete tumour response at a median follow-up of 133 days regardless of tumour histology, drug used (bleomycin or cisplatin) or route of drug administration (intravenous or intratumoural). Numbers were not reported. A case series of 35 patients with cutaneous chest wall recurrence from breast cancer reported 54% (19/35) complete response at 2 months follow-up. A non-randomised study of 52 patients (608 tumours) including 18 patients with non-melanoma metastases of mainly breast cancer (95 tumours) and 34 patients with malignant melanoma (171 tumours) reported a significant inverse correlation between maximum tumour diameter and complete response rate: 66% for diameters less than 1.5 cm, 36% for diameters between 1.6 cm and 3 cm and 28% for diameters greater than 3 cm (p=0.0035). The same study of 52 patients reported that 9% (3/34) of patients with melanoma developed recurrence in the areas treated with electrochemotherapy. One patient developed recurrence at 7 months following an initial complete response. A non-randomised comparative study of 6 patients with 26 cutaneous metastases of breast cancer origin, 12 of which were treated with electrochemotherapy, reported a median duration of response of 10 weeks in 33% (4/12) of tumours that had a complete response and 5 weeks in 67% (8/12) of tumours that had a partial response at up to 26 weeks of follow-up. In the randomised controlled trial of 19 patients, 26% (5/19) of patients were alive at follow-up of 37 months. The average survival of the 14 out of 19 patients (74%) who died before this follow-up was 14 months. The study of 52 patients reported improvements in overall quality of life score (assessed in 36 patients) from a mean pretreatment score of 46 to mean scores of 52 and 55 at 1 and 2 months respectively (p<0.005). These were measured using a non-validated questionnaire with scores of 0 to 60, higher scores indicating better quality of life. In the study, 94% (34/36) of responding patients reported an improvement in 1 or more of the 6 parameters assessed in the questionnaire (bleeding, ulceration, aesthetics, activities of daily living, social relations and pain control). The Specialist Advisers listed additional key efficacy outcomes as the number of procedures needed, control of bleeding and reduction in odour from fungating tumours. # Safety Muscle spasms with myoclonus secondary to electric pulses were reported in 25% (3/12) of patients treated by electrochemotherapy in a randomised controlled trial of 12 patients. These stopped immediately after the electric pulses were discontinued. An inflammatory reaction leading to superficial necrosis and an eschar occurred in all tumours treated with electrochemotherapy in the randomised controlled trial of 19 patients. These all healed completely by 16 weeks. Electrode marks and superficial erosions occurred in all patients after electrochemotherapy in the case series of 14 patients. The marks healed within 1 month. A mild injection site rash of grade I–II according to common toxicity criteria was reported in 8% (4/52) of patients treated with electrochemotherapy in the study of 52 patients with metastatic cancer (34 of whom had malignant melanoma). Erythema and oedema at treated areas that resolved in a 'few' days was reported in 2% (3/14) of individuals in the case series of 14 patients. 'Minimal scarring and depigmentation' of the treatment site as a late effect was reported in the non-randomised comparative study of 6 patients. This persisted for the duration of follow-up (up to 26 weeks). No further details were reported. Other side effects attributed to the chemotherapy agent such as slight nausea, transient increase in heart rate and transient dyspnoea were also reported. The Specialist Advisers listed additional key safety outcomes as increase in wound exudate after the procedure and chemotherapy toxicity, specifically pulmonary fibrosis. # Other comments The Committee noted that this procedure might provide palliation and improve quality of life for patients with disease unsuitable for, or resistant to, other treatments. The Committee noted that patients may experience pain and ulceration following treatment.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'There is sufficient evidence of efficacy of electrochemotherapy for treating metastases in the skin from tumours of non-skin origin and melanoma to support its use as a palliative treatment. There are no major safety concerns. Therefore, in the context of palliative treatment the procedure can be used with normal arrangements for clinical governance, consent and audit.\n\nPatient selection should be carried out by an appropriate specialist multidisciplinary team.\n\nThis procedure should only be carried out by a clinician with specific training in the technique.\n\nClinicians should submit data on all patients undergoing electrochemotherapy (including details of case selection, methods of follow-up and outcomes) to the InspECT register, an international register dedicated to electrochemotherapy, and review clinical outcomes locally.', 'The procedure': "# Indications and current treatments\n\nCutaneous and subcutaneous metastases of non-skin origin and melanoma often occur in the setting of disseminated disease and cause significant clinical problems including bleeding, pain and ulceration. The primary aim of treatment is therefore palliative and includes modalities such as regional chemotherapy, curettage, cryotherapy and radiotherapy.\n\n# Outline of the procedure\n\nElectrochemotherapy aims to enhance the effects of chemotherapy and can be performed as an outpatient procedure. It can be used for local control of cancers that are unsuitable for surgery and resistant to radiotherapy or chemotherapy.\n\nThe procedure is performed with the patient under general or local anaesthesia with or without sedation. Chemotherapy drugs are given first, either intravenously or directly into the tumour. Drug dose is individualised based on either body surface area or tumour volume. Shortly after drug administration, brief and intense electric pulses are delivered around or directly into the tumour using either surface plates or needle electrodes. This makes the cell membranes more permeable to the chemotherapy drugs so that their cytotoxic effect is increased. Different-shaped electrodes or plates are used depending on the tumour size, extent, shape and location. Treatment duration may vary depending on the number and size of tumours. Larger tumours may need several applications to cover the entire surface. Repeated treatments can be performed if necessary (within the lifetime dose limits of the chemotherapy drugs).\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overviews on electrochemotherapy for metastases in the skin (of non-skin origin) and electrochemotherapy for melanoma metastases in the skin.\n\n# Efficacy\n\nA randomised controlled trial of 19\xa0patients with melanoma metastases comparing intratumoural electrochemotherapy (in 18\xa0tumours) with intratumoural chemotherapy alone (in 19\xa0tumours) reported complete response in 72% (13/18) of tumours treated with electrochemotherapy at end of follow-up ('average' of 21\xa0months). On an intention-to-treat basis, objective response for electrochemotherapy was significantly greater than for chemotherapy alone (64% versus 29%, p=0.02).\n\nA non-randomised comparative study of 61\xa0patients that evaluated electrochemotherapy efficacy in 21\xa0patients (73\xa0tumours) with mixed non-melanoma metastases and 20\xa0patients (98\xa0tumours) with melanoma metastases reported an 85% objective tumour response and a 74% complete tumour response at a median follow-up of 133\xa0days regardless of tumour histology, drug used (bleomycin or cisplatin) or route of drug administration (intravenous or intratumoural). Numbers were not reported.\n\nA case series of 35\xa0patients with cutaneous chest wall recurrence from breast cancer reported 54% (19/35) complete response at 2\xa0months follow-up.\n\nA non-randomised study of 52\xa0patients (608\xa0tumours) including 18\xa0patients with non-melanoma metastases of mainly breast cancer (95\xa0tumours) and 34\xa0patients with malignant melanoma (171\xa0tumours) reported a significant inverse correlation between maximum tumour diameter and complete response rate: 66% for diameters less than 1.5\xa0cm, 36% for diameters between 1.6\xa0cm and 3\xa0cm and 28% for diameters greater than 3\xa0cm (p=0.0035).\n\nThe same study of 52\xa0patients reported that 9% (3/34) of patients with melanoma developed recurrence in the areas treated with electrochemotherapy. One patient developed recurrence at 7\xa0months following an initial complete response.\n\nA non-randomised comparative study of 6\xa0patients with 26\xa0cutaneous metastases of breast cancer origin, 12\xa0of which were treated with electrochemotherapy, reported a median duration of response of 10\xa0weeks in 33% (4/12) of tumours that had a complete response and 5\xa0weeks in 67% (8/12) of tumours that had a partial response at up to 26\xa0weeks of follow-up.\n\nIn the randomised controlled trial of 19\xa0patients, 26% (5/19) of patients were alive at follow-up of 37\xa0months. The average survival of the 14\xa0out of 19\xa0patients (74%) who died before this follow-up was 14\xa0months.\n\nThe study of 52\xa0patients reported improvements in overall quality of life score (assessed in 36 patients) from a mean pretreatment score of 46 to mean scores of 52 and 55 at 1 and 2\xa0months respectively (p<0.005). These were measured using a non-validated questionnaire with scores of 0 to 60, higher scores indicating better quality of life. In the study, 94% (34/36) of responding patients reported an improvement in 1\xa0or more of the 6\xa0parameters assessed in the questionnaire (bleeding, ulceration, aesthetics, activities of daily living, social relations and pain control).\n\nThe Specialist Advisers listed additional key efficacy outcomes as the number of procedures needed, control of bleeding and reduction in odour from fungating tumours.\n\n# Safety\n\nMuscle spasms with myoclonus secondary to electric pulses were reported in 25% (3/12) of patients treated by electrochemotherapy in a randomised controlled trial of 12\xa0patients. These stopped immediately after the electric pulses were discontinued.\n\nAn inflammatory reaction leading to superficial necrosis and an eschar occurred in all tumours treated with electrochemotherapy in the randomised controlled trial of 19\xa0patients. These all healed completely by 16\xa0weeks.\n\nElectrode marks and superficial erosions occurred in all patients after electrochemotherapy in the case series of 14\xa0patients. The marks healed within 1\xa0month. A mild injection site rash of grade\xa0I–II according to common toxicity criteria was reported in 8% (4/52) of patients treated with electrochemotherapy in the study of 52\xa0patients with metastatic cancer (34\xa0of whom had malignant melanoma).\n\nErythema and oedema at treated areas that resolved in a 'few' days was reported in 2% (3/14) of individuals in the case series of 14\xa0patients.\n\n'Minimal scarring and depigmentation' of the treatment site as a late effect was reported in the non-randomised comparative study of 6\xa0patients. This persisted for the duration of follow-up (up to 26\xa0weeks). No further details were reported.\n\nOther side effects attributed to the chemotherapy agent such as slight nausea, transient increase in heart rate and transient dyspnoea were also reported.\n\nThe Specialist Advisers listed additional key safety outcomes as increase in wound exudate after the procedure and chemotherapy toxicity, specifically pulmonary fibrosis.\n\n# Other comments\n\nThe Committee noted that this procedure might provide palliation and improve quality of life for patients with disease unsuitable for, or resistant to, other treatments.\n\nThe Committee noted that patients may experience pain and ulceration following treatment.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg446
d6cc2efbca06980b16c1d793e66bebd2c242ecaa	nice	Insertion of endobronchial valves for persistent air leaks	Insertion of endobronchial valves for persistent air leaks # Guidance Current evidence on the efficacy and safety of insertion of endobronchial valves for persistent air leaks is limited in both quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake insertion of endobronchial valves for persistent air leaks should take the following actions: Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having insertion of endobronchial valves for persistent air leaks (see section 3.1). Selection of patients for insertion of endobronchial valves for persistent air leaks should be done by a multidisciplinary team including a chest physician and a thoracic surgeon. NICE encourages further reporting about patient selection and outcomes (including long-term outcomes). NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Leakage of air from the lungs into the pleural space can lead to collapse of the lung and difficulty in breathing. Persistent air leaks from the lungs can occur after thoracic operations or trauma, or because of underlying pulmonary disease. Persistent air leaks may initially be treated with a temporary chest drain to remove the air from the pleural space. If air continues to leak from the lung, a surgical repair may be needed. Pleurodesis may be an alternative option. # Outline of the procedure Insertion of endobronchial valves for persistent air leaks aims to reduce or eliminate airflow through the leaks so that the rest of the lung can function normally. It may also allow the tissues around an air leak to heal so that the leak stops. The procedure is done using flexible bronchoscopy with the patient under sedation or general anaesthesia. The area of air leak is identified by occluding suspected segments with a saline-filled balloon and monitoring the air flow. A one-way valve mounted on a flexible catheter is passed through the bronchoscope and inserted into the target airway. More than 1 valve may be inserted during a procedure. Valves may be removed when the defect on the lung surface has sealed. Several different devices are available for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 40 patients treated by insertion of endobronchial valves reported a complete cessation of air leak in 48% (19/40) of patients, partial cessation in 45% (18/40), and no change in 5% (2/40) (range of follow-up 5–1109 days). A case series of 7 patients (8 procedures) reported successful removal of chest drains in 5 patients at a median of 16 days after valve insertion. A case report of 4 patients treated by insertion of endobronchial valves reported a reduction in pneumothorax in 3 patients. Re-expansion of both lungs was reported in 1 patient within 2 days and at 6 months in another patient. Improvement of the pneumothorax in 1 lung was reported in a third patient (timing unclear). In the case series of 7 patients, a 'reduced' air leak returned after valve removal in 1 patient (15 days after the procedure). The Specialist Advisers listed efficacy outcomes as duration of air leak, reduction or resolution of air leak, reduction in hospital stay, reduction in intensive care or high-dependency unit stay, reduction in the use of non-invasive or intermittent positive pressure ventilation, and improvement in health-related quality of life. # Safety Valve migration was reported in a case report (discovered on chest X-ray 2 months after the procedure). The valve was removed 5 months after the procedure. Initial valve malpositioning (needing redeployment) was reported in the case series of 40 patients (numbers of patients not stated and timing of event not described). Expectoration of a valve was reported in the case series of 40 patients (number of patients not stated and timing of event not described). Recurrent chest infection was reported in a case report at 5 months after the initial procedure; the 2 valves were removed. Partial atelectasis of the lower lobe was reported in a case report (timing unclear; no further details). The Specialist Advisers listed anecdotal adverse events as haemoptysis, respiratory failure, distal infection or pneumonia, and granulation tissue formation around valves. They listed death as a theoretical adverse event. The Specialist Advisers also listed recurrence of air leak or pneumothorax. # Other comments The Committee noted that insertion of endobronchial valves for persistent air leaks is typically considered for patients when other treatment options have been exhausted.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), which will be available when the guidance is published. For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the efficacy and safety of insertion of endobronchial valves for persistent air leaks is limited in both quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake insertion of endobronchial valves for persistent air leaks should take the following actions:\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having insertion of endobronchial valves for persistent air leaks (see section 3.1).\n\nSelection of patients for insertion of endobronchial valves for persistent air leaks should be done by a multidisciplinary team including a chest physician and a thoracic surgeon.\n\nNICE encourages further reporting about patient selection and outcomes (including long-term outcomes). NICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nLeakage of air from the lungs into the pleural space can lead to collapse of the lung and difficulty in breathing. Persistent air leaks from the lungs can occur after thoracic operations or trauma, or because of underlying pulmonary disease.\n\nPersistent air leaks may initially be treated with a temporary chest drain to remove the air from the pleural space. If air continues to leak from the lung, a surgical repair may be needed. Pleurodesis may be an alternative option.\n\n# Outline of the procedure\n\nInsertion of endobronchial valves for persistent air leaks aims to reduce or eliminate airflow through the leaks so that the rest of the lung can function normally. It may also allow the tissues around an air leak to heal so that the leak stops.\n\nThe procedure is done using flexible bronchoscopy with the patient under sedation or general anaesthesia. The area of air leak is identified by occluding suspected segments with a saline-filled balloon and monitoring the air flow. A one-way valve mounted on a flexible catheter is passed through the bronchoscope and inserted into the target airway.\n\nMore than 1\xa0valve may be inserted during a procedure. Valves may be removed when the defect on the lung surface has sealed.\n\nSeveral different devices are available for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 40\xa0patients treated by insertion of endobronchial valves reported a complete cessation of air leak in 48% (19/40) of patients, partial cessation in 45% (18/40), and no change in 5% (2/40) (range of follow-up 5–1109\xa0days).\n\nA case series of 7\xa0patients (8\xa0procedures) reported successful removal of chest drains in 5\xa0patients at a median of 16\xa0days after valve insertion.\n\nA case report of 4\xa0patients treated by insertion of endobronchial valves reported a reduction in pneumothorax in 3\xa0patients. Re-expansion of both lungs was reported in 1\xa0patient within 2\xa0days and at 6\xa0months in another patient. Improvement of the pneumothorax in 1\xa0lung was reported in a third patient (timing unclear).\n\nIn the case series of 7\xa0patients, a 'reduced' air leak returned after valve removal in 1\xa0patient (15\xa0days after the procedure).\n\nThe Specialist Advisers listed efficacy outcomes as duration of air leak, reduction or resolution of air leak, reduction in hospital stay, reduction in intensive care or high-dependency unit stay, reduction in the use of non-invasive or intermittent positive pressure ventilation, and improvement in health-related quality of life.\n\n# Safety\n\nValve migration was reported in a case report (discovered on chest X-ray 2\xa0months after the procedure). The valve was removed 5\xa0months after the procedure.\n\nInitial valve malpositioning (needing redeployment) was reported in the case series of 40\xa0patients (numbers of patients not stated and timing of event not described).\n\nExpectoration of a valve was reported in the case series of 40\xa0patients (number of patients not stated and timing of event not described).\n\nRecurrent chest infection was reported in a case report at 5\xa0months after the initial procedure; the 2\xa0valves were removed.\n\nPartial atelectasis of the lower lobe was reported in a case report (timing unclear; no further details).\n\nThe Specialist Advisers listed anecdotal adverse events as haemoptysis, respiratory failure, distal infection or pneumonia, and granulation tissue formation around valves. They listed death as a theoretical adverse event. The Specialist Advisers also listed recurrence of air leak or pneumothorax.\n\n# Other comments\n\nThe Committee noted that insertion of endobronchial valves for persistent air leaks is typically considered for patients when other treatment options have been exhausted.", 'Further information': 'This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), which will be available when the guidance is published.\n\nFor related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg448
ea07ca130ea64ab1859af544cb4755e630794314	nice	Percutaneous electrical nerve stimulation for refractory neuropathic pain	Percutaneous electrical nerve stimulation for refractory neuropathic pain # Guidance Current evidence on the safety of percutaneous electrical nerve stimulation (PENS) for refractory neuropathic pain raises no major safety concerns and there is evidence of efficacy in the short term. Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit. Patient selection and treatment using PENS for refractory neuropathic pain should be carried out by teams specialising in pain management. NICE encourages further research into PENS for refractory neuropathic pain, particularly to provide more information about selection criteria and long-term outcomes, with clear documentation of the indications for treatment.# The procedure # Indications and current treatments Neuropathic pain means pain arising from dysfunction of sensory nerves and pathways in the nervous system. It may occur in a heterogeneous group of disorders: examples include painful diabetic neuropathy, post-herpetic neuralgia and trigeminal neuralgia. People with neuropathic pain may experience altered pain sensation, areas of numbness or burning, and continuous or intermittent evoked or spontaneous pain. Neuropathic pain is an unpleasant sensory and emotional experience that can have a significant impact on a person's quality of life. A range of different drugs are used to manage neuropathic pain, including antidepressants, anti-epileptic (anticonvulsant) drugs, opioids, and topical treatments such as capsaicin and lidocaine (see Neuropathic pain: the pharmacological management of neuropathic pain in adults in non-specialist settings ). Neuropathic pain is often difficult to treat, because it can be refractory to many medications and/or because of the adverse effects associated with some medications. # Outline of the procedure In PENS, 1 or more individual nerves or dermatomes are stimulated using needle probes. A single probe with a grounding pad or pairs of fine-gauge needles are inserted into soft tissue near the targeted nerves or into the affected dermatomes. The needles are connected to a low-voltage pulse generator and an electrical current is then applied. This may generate a sensation of paraesthesia and muscle contraction. The duration of treatment varies but each session of stimulation typically lasts between 15 and 60 minutes. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the systematic review. # Efficacy A crossover randomised controlled trial (RCT) of 64 patients comparing PENS against sham PENS or transcutaneous electrical nerve stimulation (TENS) in patients with pain from sciatica reported a significant reduction in pain after the last treatment session (measured on a visual analogue scale ; 0–10 from best to worse) compared with baseline in both PENS (from 7.2 to 4.1, p<0.05) and TENS (from 7.0 to 5.4, p<0.05) groups, but not in the sham-PENS group (from 6.6 to 6.1, p=not significant). The reduction in the PENS group was significantly greater than the reductions in the TENS and sham-PENS groups (p<0.01). A crossover RCT of 50 patients with diabetic neuropathic pain in the legs comparing PENS with sham PENS reported a significantly greater reduction in pain (measured on a VAS; 0–10 from best to worse) in the PENS group (from 6.2 to 2.6) compared with the sham-PENS group (from 5.2 to 4.8) after the last treatment session (p<0.05). The RCT of 64 patients reported a significant improvement after the last treatment session from baseline in physical activity (measured on a VAS; 0–10 from best to worse) in both the PENS group (from 6.4 to 4.0, p<0.05) and the TENS group (from 5.8 to 4.5, p<0.05) but not in the sham-PENS group (from 6.0 to 5.5, p=not significant). The improvement in the PENS group was significantly greater than in the TENS and sham-PENS groups (p<0.01). The RCT of 50 patients reported baseline physical and mental component SF-36 scores of 31.2 and 41 respectively (mean scores taken 24 hours before the first treatment session). These scores increased to 36.8 (p<0.01) and 43.9 (p<0.01) respectively for the PENS group; and to 32.4 (p<0.05) and 42 (p<0.05) respectively for the sham-PENS group (these were mean scores taken 36 hours after the last treatment session). Improvement was significantly greater for the PENS group (p<0.05). In both RCTs of 64 and 50 patients, the post-intervention scores for PENS groups were still below the normal population score of 50. The RCT of 64 patients reported a 50% reduction over 3 weeks in daily analgesic use with PENS treatment compared with TENS (29%) and sham PENS (8%) (level of significance not reported). The RCT of 64 patients reported a significant improvement from baseline in quality of sleep after the last treatment session (measured on a VAS; 0–10 from best to worse) in both the PENS group (from 5.5 to 3.1, p<0.05) and the TENS group (from 5.0 to 4.0, p<0.05) but not in the sham-PENS group (from 5.2 to 4.9, p=not significant). The improvement in the PENS group was significantly greater than the reductions in the TENS and sham-PENS groups (p<0.01). The RCT of 64 patients reported that most patients (73%) rated PENS as the most desirable treatment, compared with TENS (21%) and sham PENS (6%). The Specialist Advisers listed key efficacy outcomes as reduction in pain (alleviation of localised neuropathic pain, relief of allodynia and hyperpathia, reduction in the frequency of sharp shooting pains, reduction in the burning sensation) and its associated functional and emotional improvements. # Safety The RCT of 64 patients did not report safety findings. The RCT of 50 patients and an RCT of 31 patients stated that no adverse events were reported. The Specialist Advisers listed exacerbation of pain, bruising and bleeding as anecdotal adverse events. They listed theoretical adverse events as vascular damage; damage to local nerves with sequelae, depending on which nerve was damaged; pneumothorax; possible interaction with a cardiac pacemaker if used above the waistline; possible epileptogenic effect if used near the head; possible effects if used in pregnancy; dislodgement (with loss of effect); unpleasant paraesthesias; and local bruising or haematoma. # Other comments The Committee noted that clinical response to treatment with PENS may differ according to the indication treated. The Committee recognised that the numbers of patients in the RCTs were relatively small, but the evidence of efficacy in relieving pain was consistent. No major safety concerns were raised by the trials or the Specialist Advisors, or in the Committee's judgement of likely risks. Patients being considered for this procedure are often distressed by chronic pain that has been refractory to other treatments. The Committee therefore considered that the balance of benefits and risks justified a recommendation for use of this procedure with normal arrangements for clinical governance, consent and audit, in the context of patient selection by teams specialising in pain management.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety of percutaneous electrical nerve stimulation (PENS) for refractory neuropathic pain raises no major safety concerns and there is evidence of efficacy in the short term. Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit.\n\nPatient selection and treatment using PENS for refractory neuropathic pain should be carried out by teams specialising in pain management.\n\nNICE encourages further research into PENS for refractory neuropathic pain, particularly to provide more information about selection criteria and long-term outcomes, with clear documentation of the indications for treatment.', 'The procedure': "# Indications and current treatments\n\nNeuropathic pain means pain arising from dysfunction of sensory nerves and pathways in the nervous system. It may occur in a heterogeneous group of disorders: examples include painful diabetic neuropathy, post-herpetic neuralgia and trigeminal neuralgia. People with neuropathic pain may experience altered pain sensation, areas of numbness or burning, and continuous or intermittent evoked or spontaneous pain. Neuropathic pain is an unpleasant sensory and emotional experience that can have a significant impact on a person's quality of life.\n\nA range of different drugs are used to manage neuropathic pain, including antidepressants, anti-epileptic (anticonvulsant) drugs, opioids, and topical treatments such as capsaicin and lidocaine (see Neuropathic pain: the pharmacological management of neuropathic pain in adults in non-specialist settings [NICE clinical guideline\xa096]). Neuropathic pain is often difficult to treat, because it can be refractory to many medications and/or because of the adverse effects associated with some medications.\n\n# Outline of the procedure\n\nIn PENS, 1\xa0or more individual nerves or dermatomes are stimulated using needle probes. A single probe with a grounding pad or pairs of fine-gauge needles are inserted into soft tissue near the targeted nerves or into the affected dermatomes. The needles are connected to a low-voltage pulse generator and an electrical current is then applied. This may generate a sensation of paraesthesia and muscle contraction. The duration of treatment varies but each session of stimulation typically lasts between 15 and 60\xa0minutes.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the systematic review.\n\n# Efficacy\n\nA crossover randomised controlled trial (RCT) of 64\xa0patients comparing PENS against sham PENS or transcutaneous electrical nerve stimulation (TENS) in patients with pain from sciatica reported a significant reduction in pain after the last treatment session (measured on a visual analogue scale [VAS]; 0–10 from best to worse) compared with baseline in both PENS (from 7.2 to 4.1, p<0.05) and TENS (from 7.0 to 5.4, p<0.05) groups, but not in the sham-PENS group (from 6.6 to 6.1, p=not significant). The reduction in the PENS group was significantly greater than the reductions in the TENS and sham-PENS groups (p<0.01).\n\nA crossover RCT of 50\xa0patients with diabetic neuropathic pain in the legs comparing PENS with sham PENS reported a significantly greater reduction in pain (measured on a VAS; 0–10 from best to worse) in the PENS group (from 6.2 to 2.6) compared with the sham-PENS group (from 5.2 to 4.8) after the last treatment session (p<0.05).\n\nThe RCT of 64\xa0patients reported a significant improvement after the last treatment session from baseline in physical activity (measured on a VAS; 0–10 from best to worse) in both the PENS group (from 6.4 to 4.0, p<0.05) and the TENS group (from 5.8 to 4.5, p<0.05) but not in the sham-PENS group (from 6.0 to 5.5, p=not significant). The improvement in the PENS group was significantly greater than in the TENS and sham-PENS groups (p<0.01).\n\nThe RCT of 50\xa0patients reported baseline physical and mental component SF-36 scores of 31.2 and 41 respectively (mean scores taken 24\xa0hours before the first treatment session). These scores increased to 36.8 (p<0.01) and 43.9 (p<0.01) respectively for the PENS group; and to 32.4 (p<0.05) and 42 (p<0.05) respectively for the sham-PENS group (these were mean scores taken 36\xa0hours after the last treatment session). Improvement was significantly greater for the PENS group (p<0.05). In both RCTs of 64 and 50\xa0patients, the post-intervention scores for PENS groups were still below the normal population score of 50.\n\nThe RCT of 64\xa0patients reported a 50% reduction over 3\xa0weeks in daily analgesic use with PENS treatment compared with TENS (29%) and sham PENS (8%) (level of significance not reported).\n\nThe RCT of 64\xa0patients reported a significant improvement from baseline in quality of sleep after the last treatment session (measured on a VAS; 0–10 from best to worse) in both the PENS group (from 5.5 to 3.1, p<0.05) and the TENS group (from 5.0 to 4.0, p<0.05) but not in the sham-PENS group (from 5.2 to 4.9, p=not significant). The improvement in the PENS group was significantly greater than the reductions in the TENS and sham-PENS groups (p<0.01). The RCT of 64\xa0patients reported that most patients (73%) rated PENS as the most desirable treatment, compared with TENS (21%) and sham PENS (6%).\n\nThe Specialist Advisers listed key efficacy outcomes as reduction in pain (alleviation of localised neuropathic pain, relief of allodynia and hyperpathia, reduction in the frequency of sharp shooting pains, reduction in the burning sensation) and its associated functional and emotional improvements.\n\n# Safety\n\nThe RCT of 64\xa0patients did not report safety findings.\n\nThe RCT of 50\xa0patients and an RCT of 31\xa0patients stated that no adverse events were reported.\n\nThe Specialist Advisers listed exacerbation of pain, bruising and bleeding as anecdotal adverse events. They listed theoretical adverse events as vascular damage; damage to local nerves with sequelae, depending on which nerve was damaged; pneumothorax; possible interaction with a cardiac pacemaker if used above the waistline; possible epileptogenic effect if used near the head; possible effects if used in pregnancy; dislodgement (with loss of effect); unpleasant paraesthesias; and local bruising or haematoma.\n\n# Other comments\n\nThe Committee noted that clinical response to treatment with PENS may differ according to the indication treated.\n\nThe Committee recognised that the numbers of patients in the RCTs were relatively small, but the evidence of efficacy in relieving pain was consistent. No major safety concerns were raised by the trials or the Specialist Advisors, or in the Committee's judgement of likely risks. Patients being considered for this procedure are often distressed by chronic pain that has been refractory to other treatments. The Committee therefore considered that the balance of benefits and risks justified a recommendation for use of this procedure with normal arrangements for clinical governance, consent and audit, in the context of patient selection by teams specialising in pain management.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg450
8585571d35b76d848408cd376ef717065149b09e	nice	Peripheral nerve-field stimulation for chronic low back pain	Peripheral nerve-field stimulation for chronic low back pain # Guidance Current evidence on the efficacy of peripheral nerve-field stimulation (PNFS) for chronic low back pain is limited in both quantity and quality, and duration of follow-up is limited. Evidence on safety is also limited and there is a risk of complications from any implanted device. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake PNFS for chronic low back pain should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Patient selection for treatment using PNFS for chronic low back pain should be done by a multidisciplinary team, including specialists in pain management and neurosurgery. Clinicians should enter details about all patients undergoing PNFS for chronic low back pain onto the UK Neuromodulation Register when it is available. They should audit and review clinical outcomes locally. NICE encourages collaborative data collection and publication of comparative studies on PNFS for chronic low back pain. Outcomes should include measures of pain, function and quality of life, particularly in the long term. Full details of any complications and adjunctive or subsequent treatments should be recorded.# The procedure # Indications and current treatments Chronic low back pain is a common condition with a number of contributing and/or causative factors. In some people the pain can resolve spontaneously. Conservative treatments include advice and education, posture and exercise training, manual therapies, analgesics, non-steroidal anti-inflammatory drugs and acupuncture. For patients with severe chronic low back pain that is refractory to conservative interventions, surgery such as spinal fusion or insertion of prosthetic intervertebral discs may be done. # Outline of the procedure PNFS for chronic low back pain is less invasive than spinal cord stimulation or spinal fusion and offers a reversible method of pain control for those with severe refractory pain. The procedure is usually done in 2 stages. First, electrodes are implanted and connected to a neurostimulator. If this produces benefit over a trial of several days then the patient receives a fully implanted system, at a second operation. The procedure is done using local anaesthesia. One or more lead(s) are introduced percutaneously into the subcutaneous tissues of the lower back. Depending on the patient's pain pattern, areas of pain and anticipated changes in the patient's condition, it may be appropriate to implant several leads. Implanting several leads may provide greater flexibility for covering the patient's pain pattern with paraesthesia. Intra-operative stimulation is used to verify that the electrodes have been correctly placed. The lead(s) are tunnelled under the skin to a distant exit site and connected by an external extension lead to a hand-held neurostimulator. The patient is able to change the stimulation settings within limits set by the clinician. The second stage is carried out if the trial is successful. Local anaesthesia is used (sometimes with sedation). A subcutaneous pouch is formed for the implantable neurostimulator, which is connected to the already implanted trial electrodes. The patient has a hand-held remote control that permits stimulation within set parameters. The system can be removed if desired. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the systematic review. # Efficacy A case series of 100 patients reported a significant reduction in pain scores (in 44 patients who received treatment at the lumbosacral region) (measured on a visual analogue scale ; 0–10; higher score indicating greater pain) from 7.0 to 3.7 at a mean follow-up of 7 months (p<0.001). A case series of 18 patients reported that all patients had greater than 50% reduction in pain (measured on a VAS; 0–10; higher score indicating greater pain) at 12 months, from a baseline pain score of 7.4. A case series of 13 patients reported a reduction in pain (measured on a VAS; 0–10; higher score indicating greater pain) from a mean score of 7.4 (standard deviation 1.2) before PNFS to a mean score of 3.9 (SD 1.7) at a mean follow-up of 7 months (p<0.05). Pain relief was rated by the patients as excellent (improvement of 75% or more) in 15% (2/13) of patients, good (improvement 50–74%) in 38% (5/13), fair (improvement 25–49%) in 38% (5/13), and poor (improvement less than 24%) in 8% (1/13) of patients. A case series of 119 patients with mixed types of pain (including 37 with failed back surgery syndrome and 29 with low back pain) reported a reduction in mean pain intensity score (measured on a numerical rating scale; lower score indicating less pain). The scores improved from 8.0 (SD 1.4) before the procedure to 3.3 (SD 2.1) in the FBSS group (p<0.0001) (3 months after implantation) and from 8.3 (SD 0.9) before the procedure to 4.2 (SD 2.2) in the low back pain group (p<0.0001) (3 months after implantation). The case series of 18 patients reported that 89% (16/18) of patients had reduced or stopped opioid analgesic use at 12-month follow-up. The case series of 13 patients reported that 54% (7/13) of patients reported a reduction in analgesic use (exact timing of reporting unclear). The case series of 13 patients reported that 69% (9/13) of patients were 'satisfied' or 'very satisfied' with treatment (exact timing of reporting unclear). The Specialist Advisers listed key efficacy outcomes as pain reduction measured on a VAS; improvement in function as measured by the Oswestry Disability Index; improvement in quality of life as measured on the EQ-5D; reduction in concomitant medication for pain relief including neuropathic agents, opioids and non-steroidal anti-inflammatory drugs; and early mobilisation and rehabilitation. # Safety Postoperative infection requiring removal of the stimulation system was reported in 1 patient in the case series of 18 patients (timing unclear). The stimulation system was later re-implanted. Electrode migration requiring repositioning was reported in 1 patient in a case series of 10 patients (3 weeks after implantation). Device reprogramming was needed in 67% (12/18) of patients within the first 6 weeks (no further details provided) and additional education about device recharging was needed in 17% (3/18) of patients in the case series of 18 patients. In addition to the above, the Specialist Advisers listed lead fracture and postoperative bleeding as anecdotal adverse events. They listed theoretical adverse events as skin erosion, visceral damage (very rare, but not impossible, particularly in very thin patients) and haematoma. # Other comments The Committee recognised that patients being considered for PNFS for chronic low back pain commonly have very distressing and chronic symptoms, which other methods of treatment may have failed to control effectively, and who might otherwise need spinal cord stimulation. The Committee recognised research in this area is difficult because of the complex and heterogeneous nature of chronic low back pain. Currently there are not enough good-quality comparative studies to be able to confidently evaluate the procedure's efficacy. This underpinned the recommendations in section 1.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the efficacy of peripheral nerve-field stimulation (PNFS) for chronic low back pain is limited in both quantity and quality, and duration of follow-up is limited. Evidence on safety is also limited and there is a risk of complications from any implanted device. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake PNFS for chronic low back pain should take the following actions.\n\n\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\n\n\nPatient selection for treatment using PNFS for chronic low back pain should be done by a multidisciplinary team, including specialists in pain management and neurosurgery.\n\nClinicians should enter details about all patients undergoing PNFS for chronic low back pain onto the UK Neuromodulation Register when it is available. They should audit and review clinical outcomes locally.\n\nNICE encourages collaborative data collection and publication of comparative studies on PNFS for chronic low back pain. Outcomes should include measures of pain, function and quality of life, particularly in the long term. Full details of any complications and adjunctive or subsequent treatments should be recorded.", 'The procedure': "# Indications and current treatments\n\nChronic low back pain is a common condition with a number of contributing and/or causative factors. In some people the pain can resolve spontaneously.\n\nConservative treatments include advice and education, posture and exercise training, manual therapies, analgesics, non-steroidal anti-inflammatory drugs and acupuncture. For patients with severe chronic low back pain that is refractory to conservative interventions, surgery such as spinal fusion or insertion of prosthetic intervertebral discs may be done.\n\n# Outline of the procedure\n\nPNFS for chronic low back pain is less invasive than spinal cord stimulation or spinal fusion and offers a reversible method of pain control for those with severe refractory pain. The procedure is usually done in 2\xa0stages. First, electrodes are implanted and connected to a neurostimulator. If this produces benefit over a trial of several days then the patient receives a fully implanted system, at a second operation.\n\nThe procedure is done using local anaesthesia. One or more lead(s) are introduced percutaneously into the subcutaneous tissues of the lower back. Depending on the patient's pain pattern, areas of pain and anticipated changes in the patient's condition, it may be appropriate to implant several leads. Implanting several leads may provide greater flexibility for covering the patient's pain pattern with paraesthesia. Intra-operative stimulation is used to verify that the electrodes have been correctly placed. The lead(s) are tunnelled under the skin to a distant exit site and connected by an external extension lead to a hand-held neurostimulator. The patient is able to change the stimulation settings within limits set by the clinician.\n\nThe second stage is carried out if the trial is successful. Local anaesthesia is used (sometimes with sedation). A subcutaneous pouch is formed for the implantable neurostimulator, which is connected to the already implanted trial electrodes. The patient has a hand-held remote control that permits stimulation within set parameters. The system can be removed if desired.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the systematic review.\n\n# Efficacy\n\nA case series of 100\xa0patients reported a significant reduction in pain scores (in 44\xa0patients who received treatment at the lumbosacral region) (measured on a visual analogue scale [VAS]; 0–10; higher score indicating greater pain) from 7.0 to 3.7 at a mean follow-up of 7\xa0months (p<0.001).\n\nA case series of 18\xa0patients reported that all patients had greater than 50% reduction in pain (measured on a VAS; 0–10; higher score indicating greater pain) at 12\xa0months, from a baseline pain score of 7.4.\n\nA case series of 13\xa0patients reported a reduction in pain (measured on a VAS; 0–10; higher score indicating greater pain) from a mean score of 7.4 (standard deviation [SD]\xa01.2) before PNFS to a mean score of 3.9 (SD\xa01.7) at a mean follow-up of 7\xa0months (p<0.05). Pain relief was rated by the patients as excellent (improvement of 75% or more) in 15% (2/13) of patients, good (improvement 50–74%) in 38% (5/13), fair (improvement 25–49%) in 38% (5/13), and poor (improvement less than 24%) in 8% (1/13) of patients.\n\nA case series of 119\xa0patients with mixed types of pain (including 37\xa0with failed back surgery syndrome [FBSS] and 29\xa0with low back pain) reported a reduction in mean pain intensity score (measured on a numerical rating scale; lower score indicating less pain). The scores improved from 8.0 (SD\xa01.4) before the procedure to 3.3 (SD\xa02.1) in the FBSS group (p<0.0001) (3\xa0months after implantation) and from 8.3 (SD\xa00.9) before the procedure to 4.2 (SD\xa02.2) in the low back pain group (p<0.0001) (3\xa0months after implantation).\n\nThe case series of 18\xa0patients reported that 89% (16/18) of patients had reduced or stopped opioid analgesic use at 12-month follow-up. The case series of 13\xa0patients reported that 54% (7/13) of patients reported a reduction in analgesic use (exact timing of reporting unclear).\n\nThe case series of 13\xa0patients reported that 69% (9/13) of patients were 'satisfied' or 'very satisfied' with treatment (exact timing of reporting unclear).\n\nThe Specialist Advisers listed key efficacy outcomes as pain reduction measured on a VAS; improvement in function as measured by the Oswestry Disability Index; improvement in quality of life as measured on the EQ-5D; reduction in concomitant medication for pain relief including neuropathic agents, opioids and non-steroidal anti-inflammatory drugs; and early mobilisation and rehabilitation.\n\n# Safety\n\nPostoperative infection requiring removal of the stimulation system was reported in 1\xa0patient in the case series of 18\xa0patients (timing unclear). The stimulation system was later re-implanted.\n\nElectrode migration requiring repositioning was reported in 1\xa0patient in a case series of 10\xa0patients (3\xa0weeks after implantation).\n\nDevice reprogramming was needed in 67% (12/18) of patients within the first 6\xa0weeks (no further details provided) and additional education about device recharging was needed in 17% (3/18) of patients in the case series of 18\xa0patients.\n\nIn addition to the above, the Specialist Advisers listed lead fracture and postoperative bleeding as anecdotal adverse events. They listed theoretical adverse events as skin erosion, visceral damage (very rare, but not impossible, particularly in very thin patients) and haematoma.\n\n# Other comments\n\nThe Committee recognised that patients being considered for PNFS for chronic low back pain commonly have very distressing and chronic symptoms, which other methods of treatment may have failed to control effectively, and who might otherwise need spinal cord stimulation.\n\nThe Committee recognised research in this area is difficult because of the complex and heterogeneous nature of chronic low back pain. Currently there are not enough good-quality comparative studies to be able to confidently evaluate the procedure's efficacy. This underpinned the recommendations in section\xa01.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg451
1041dd2303d3ffed9501e5db1cc5246a2fd92485	nice	Hepatitis B and C testing: people at risk of infection	Hepatitis B and C testing: people at risk of infection This guideline covers raising awareness of and testing for hepatitis B and C infection. It aims to ensure that people at increased risk of hepatitis B and C infection are tested. # Introduction: scope and purpose of this guidance # What is this guidance about? This guidance aims to ensure more people at increased risk of hepatitis B and C infection are tested. The recommendations cover: Awareness-raising among: the general population people at increased risk of hepatitis B and C infection. Developing the knowledge and skills of healthcare professionals and others providing services for people at increased risk of hepatitis B or C infection. Testing: in primary care in prisons and youth offender institutions in immigration removal centres in drugs services in genitourinary medicine and sexual health clinics. Contact tracing. Providing and auditing neonatal hepatitis B vaccination. Commissioning hepatitis B and C testing and treatment services. Laboratory services for hepatitis B and C testing. This guidance does not provide detail on treatments for hepatitis B or C. (For treatment recommendations see other NICE guidance listed in section 7.) # Who is this guidance for? The guidance is for: Commissioners and providers of public health services, hepatitis testing and treatment services and laboratory services for hepatitis B and C testing. Local organisations providing services for children and adults at increased risk of hepatitis B and C infection, including those in the NHS, local authorities, prisons, immigration removal centres and drugs services. It is also for voluntary sector and community organisations working with people at increased risk. The guidance may also be of interest to groups at increased risk of viral hepatitis, for example, migrant populations from countries with an intermediate or high prevalence of hepatitis B or hepatitis C infection or people who inject drugs and their families. In addition, other members of the public may have an interest in this guidance. # Why is this guidance being produced? The Department of Health (DH) asked the National Institute for Health and Clinical Excellence (NICE) to produce this guidance. The guidance should be implemented alongside other guidance and regulations (for more details, see sections 4 and 7 on implementation and related NICE guidance respectively). # How was this guidance developed? The recommendations are based on the best available evidence. They were developed by the Programme Development Group (PDG). Members of the PDG are listed in appendix A. The guidance was developed using the NICE public health programme process. See appendix B for details. Supporting documents used to prepare this document are listed in appendix E. # What evidence is the guidance based on? The evidence that the PDG considered included: reviews of the evidence, economic modelling, the testimony of expert witnesses and stakeholder comments. Further detail on the evidence is given in the considerations section (section 3) and appendices B and C. In some cases the evidence was insufficient and the PDG has made recommendations for future research. More details on the evidence on which this guidance is based, and NICE's processes for developing public health guidance, are on the NICE website. # Status of this guidance This is final guidance. The guidance complements but does not replace other NICE guidance on hepatitis B and C (for further details, see section 7).# Recommendations # Introduction There has been a change in recommendation 7. See Changes after publication for details. The evidence statements underpinning the recommendations are listed in appendix C. The Programme Development Group (PDG) considers that the recommended measures and approaches are cost effective. For the research recommendations and gaps in research, see section 5 and appendix D respectively. # Pre-requisites The recommendations are based on the assumption that hepatitis B and C tests are provided according to current best practice and are offered as part of a care pathway covering diagnosis, treatment and immunisation. ## Testing The recommendations assume that: Testing facilities are equipped with sharps bins and follow advice on infection control and appropriate testing methods, particularly if testing is done outside healthcare settings. People being tested for hepatitis B and C are offered pre- and post-test discussions (see Box 1). Testing is undertaken with the person's consent. Standards for local surveillance are followed, including laboratory reporting to Public Health England centres and follow-up of hepatitis B and C. Have issues of confidentiality and anxiety been addressed? Has the offer been accompanied by an agreed mechanism for providing the result to the person being tested? Has the offer been phrased in a way that suits the person's age, culture and literacy level and is respectful and non-judgemental? Has the offer taken into account potential barriers to testing such as the stigma associated with hepatitis B and C or lack of access to services? Has the offer included information to enable people to make informed choices about their care should they test positive, and to reduce their risk of hepatitis B and C infection should they test negative? Has the offer been accompanied by details of support available for clinical and non-clinical needs, both while waiting for test results and following diagnosis? ## Treatment NICE has recommended a number of drugs to treat hepatitis B and C and also has clinical guidelines in development on the diagnosis and management of hepatitis B and C (see section 7 for details). Guidance on managing co-infection with HIV-1 and hepatitis B or C is available from the British HIV Association. The European Association for the Study of the Liver (EASL) has published best practice guidelines on managing hepatitis B and hepatitis C. ## Immunisation Guidance on hepatitis B vaccination is available in the Green book: immunisation against infectious disease and the Hepatitis B antenatal screening and newborn immunisation programme, both published by the Department of Health, and in the NICE guidance on Reducing the differences in the uptake of immunisations. # Whose health will benefit? In the UK, the majority (95%) of new chronic hepatitis B infections occur in migrant populations, having been acquired perinatally in the country of birth. In contrast, approximately 90% of chronic hepatitis C infections are seen in people who inject drugs or have done so in the past. Groups at increased risk of hepatitis B compared with the general UK population include: People born or brought up in a country with an intermediate or high prevalence (2% or greater) of chronic hepatitis B. This includes all countries in Africa, Asia, the Caribbean, Central and South America, Eastern and Southern Europe, the Middle East and the Pacific islands. Babies born to mothers infected with hepatitis B. People who have ever injected drugs. Men who have sex with men. Anyone who has had unprotected sex, particularly: people who have had multiple sexual partners people reporting unprotected sexual contact in areas of intermediate and high prevalence) people presenting at sexual health and genitourinary medicine clinics people diagnosed with a sexually transmitted disease commercial sex workers. Looked-after children and young people, including those living in care homes. Prisoners, including young offenders. Immigration detainees. Close contacts of someone known to be chronically infected with hepatitis B. For hepatitis C, groups at increased risk include: People who have ever injected drugs. People who received a blood transfusion before 1991 or blood products before 1986, when screening of blood donors for hepatitis C infection, or heat treatment for inactivation of viruses were introduced. People born or brought up in a country with an intermediate or high prevalence (2% or greater) of chronic hepatitis C. Although data are not available for all countries, for practical purposes this includes all countries in Africa, Asia, the Caribbean, Central and South America, Eastern and Southern Europe, the Middle East and the Pacific islands. Babies born to mothers infected with hepatitis C. Prisoners, including young offenders. Looked-after children and young people, including those living in care homes. People living in hostels for the homeless or sleeping on the streets. HIV-positive men who have sex with men. Close contacts of someone known to be chronically infected with hepatitis C. # Recommendation 1 Awareness-raising about hepatitis B and C among the general population ## Who should take action? Commissioners and providers of national public health services, for example Public Health England, working in partnership with: -ther government departments allied to health local commissioners and providers of public health services, including local authorities and health and wellbeing boards primary and secondary care including genitourinary medicine and sexual health clinics the commercial sector, national and local voluntary sector, not-for-profit and non-governmental organisations. ## What action should they take? Conduct awareness-raising campaigns, using campaign material and resources on hepatitis B and C. These should include up-to-date information on: the main routes of infection and transmission hepatitis B vaccination the benefits of early testing and treatment, including the role of earlier treatment in preventing serious illness such as chronic liver disease and liver cancer the potential for chronic infection to be asymptomatic, particularly in the early stages. Ensure national and local awareness-raising campaigns address common misconceptions about the risk of hepatitis B and C that can act as a barrier to testing. This includes the belief that treatments are not effective, or that treatment is not needed until the illness is advanced. Campaigns should also make it clear that testing and treatment is confidential and address the stigma surrounding these infections. Ensure messages to raise awareness of hepatitis B and C are coordinated and integrated within other health promotion campaigns, where possible or appropriate. Ensure national and local awareness-raising activities take into account age, culture and religious beliefs of groups at increased risk, and their needs in relation to format and the language used. For example, the needs of people with low literacy level and learning disabilities, and people with little interaction with statutory services should be considered. # Recommendation 2 Awareness-raising for people at increased risk of hepatitis B or C infection ## Who should take action? Commissioners and providers of national public health services, for example Public Health England and the NHS Commissioning Board. Local authorities, in particular directors of public health. Local organisations providing services for children and adults at increased risk of hepatitis B or C infection. Other local and national organisations that raise awareness of hepatitis, promote testing or provide treatment. ## What action should they take? Public Health England, the NHS Commissioning Board and directors of public health should facilitate partnership working to ensure there is a coordinated national and local programme of awareness-raising about hepatitis B and C among groups at increased risk. Directors of public health should promote local testing and hepatitis B vaccination services. Local and national organisations should provide awareness-raising material tailored to the needs of groups at increased risk. In addition to the information outlined in recommendation 1, this should: inform people how and where to access local testing and hepatitis B vaccination services describe what testing for hepatitis B and C involves explain how a positive diagnosis can affect lifestyle. Material should: address the needs of non-English-speaking groups at increased risk, for example, by providing translated information or information in audio or visual formats. be culturally and age appropriate address the needs of people with low literacy levels or learning disabilities. Local organisations should encourage and support people from groups at increased risk who have been diagnosed with hepatitis B or C to contribute to awareness-raising activities (for further information see NICE guidance on Community engagement). Local organisations should run awareness-raising sessions to promote hepatitis B and C testing in venues and at events popular among groups at increased risk. Examples of possible venues include: faith and cultural centres, NHS and non-NHS drugs services, GP surgeries, sexual health and genitourinary medicine services, immigration centres, hostels for the homeless, prisons and youth offender institutions. Local and national organisations should consider offering testing for hepatitis B and C at awareness-raising sessions. If this is not possible, information on where and how to access testing locally should be provided. # Recommendation 3 Developing the knowledge and skills of healthcare professionals and others providing services for people at increased risk of hepatitis B or C infection ## Who should take action? Health Education England. Public Health England. Royal medical and nursing colleges. Local authorities, in particular directors of public health. Clinical commissioning groups. Local education and training boards. ## What action should they take? Ensure there is an ongoing education programme for professionals providing health and social care services for people at increased risk of hepatitis B or C infection. This includes: clinical and non-clinical staff in primary and secondary care including nurses, health visitors, midwives, healthcare assistants and support workers as well as staff in sexual health, genitourinary medicine and HIV clinics people working in drugs services staff in community-based criminal justice services social workers working with people at increased risk of hepatitis B or C infection statutory and non-statutory staff working with looked-after children prison, youth offender and immigration removal centre staff staff in voluntary and community organisations that care for or support migrant populations, people who inject drugs, people with HIV, or men who have sex with men people working in hostels for the homeless and providing outreach services to homeless people. Ensure education programmes address the following core topics and are designed to meet the needs of the target group: incorporating the recommendations in national guidance to improve identification and testing of people at increased risk of hepatitis B and C infection -vercoming social and cultural barriers and improving access to testing and treatment for people at increased risk of hepatitis B and C infection reducing morbidity and mortality associated with hepatitis B and C through early detection and diagnosis improving clinical management and quality of life for people diagnosed with hepatitis B and C infection and reducing the number of people admitted to secondary and tertiary care with hepatitis B- and C-related morbidity, for example, liver disease. Ensure training programme content is accurate and up-to-date, reflecting advances in testing, diagnosis and treatment of hepatitis B and C. Think about linking awareness-raising activities with existing education for health and social care professionals. This could take a variety of forms, for example, it could be offered as a taught or an electronic learning module. Local education and training boards in each region should ensure that people involved in testing for hepatitis B and C take part in a programme of continuing professional development. Directors of public health should ensure all healthcare and public health managers, in collaboration with the local education and training board, use staff annual appraisals and personal development plans to reinforce training and education on hepatitis B and C. # Recommendation 4 Testing for hepatitis B and C in primary care ## Who should take action? GPs and practice nurses. Antenatal services. Local community services serving migrant populations. ## What action should they take? GPs and practice nurses should offer testing for hepatitis B and C to adults and children at increased risk of infection, particularly migrants from medium- or high-prevalence countries and people who inject or have injected drugs (see Whose health will benefit?). GPs and practice nurses should offer testing for hepatitis B and C to people who are newly registered with the practice and belong to a group at increased risk of infection (see Whose health will benefit?). GPs and practice nurses should ask newly registered adults if they have ever injected drugs, including image and performance enhancement substances at their first consultation. GPs and practice nurses should offer hepatitis B testing and vaccination to men who have sex with men who are offered a test for HIV and have not previously tested positive for hepatitis B antibodies (see NICE guidance on Increasing the uptake of HIV testing among men who have sex with men). GPs and practice nurses should offer hepatitis B vaccination to people who test negative for hepatitis B but remain at increased risk of infection (see the Green book). GPs and practice nurses should offer annual testing for hepatitis C to people who test negative for hepatitis C but remain at increased risk of infection. GPs and practice nurses should ensure people diagnosed with hepatitis B or C are referred to specialist care. Local community services serving migrant populations should work in partnership with primary care practitioners to promote testing of adults and children at increased risk of infection. This should include raising awareness of hepatitis B and C, promoting the availability of primary care testing facilities and providing support to access these services. Staff providing antenatal services, including midwives, obstetricians, practice nurses and GPs, should ask about risk factors for hepatitis C during pregnancy and offer testing for hepatitis C to women at increased risk. Women who are diagnosed with hepatitis C should be offered hepatitis A and B vaccination in line with the Green book. # Recommendation 5 Testing for hepatitis B and C in prisons and immigration removal centres ## Who should take action? Prison healthcare services, including services for young offenders. Immigration removal centre healthcare services. Secondary care services that provide treatment for hepatitis B and C. Public Health England centres. ## What action should they take? Prison and immigration removal centre healthcare services should develop a policy on testing for hepatitis B and C with local partners, including secondary care services that provide treatment, the Public Health England centre, and commissioners of prison and immigration removal centre healthcare services. Prison and immigration removal centre healthcare services should designate a member of staff as the hepatitis lead in every prison, young offender service and immigration removal centre. The lead should have the knowledge and skills to promote hepatitis B and C testing and treatment and hepatitis B vaccination. Consideration should be given to training peer mentors and health champions from the prison and immigration removal centre populations to support this work. The NHS lead for hepatitis treatment (for example, a community hepatitis nurse) should develop a care pathway for prisoners and immigration detainees with diagnosed hepatitis B or C. This should be developed in conjunction with prison or immigration removal centre healthcare services (including commissioners), local drugs services and the Public Health England centre. The care pathway should ensure: people with diagnosed hepatitis B and C should be referred to, and managed by, the local hepatitis treatment services, in liaison with prison or immigration removal centre healthcare services investigations and follow-up should be undertaken in the prison or immigration removal centre, if possible prisoners and immigration detainees with hepatitis B and C should be treated in the prison or immigration removal centre, using in-reach services involving local specialist secondary care providers or the prison or immigration removal centre healthcare team. The prison or immigration removal centre should support this, for example, by giving security clearance to healthcare staff. Prison and immigration removal centre healthcare services (coordinated with and supported by the NHS lead for hepatitis) should ensure that: all prisoners and immigration detainees are offered hepatitis B vaccination when entering prison or an immigration removal centre (for the vaccination schedule, refer to the Green book) all prisoners and immigration detainees are offered access to confidential testing for hepatitis B and C when entering prison or an immigration removal centre and during their detention prisoners and immigration detainees who test for hepatitis B or C receive the results of the test, regardless of their location when the test results become available results from hepatitis B and C testing are provided to the prisoner's community-based GP, if consent is given all prison and immigration removal centre staff are trained to promote hepatitis B and C testing and treatment and hepatitis B vaccination (see recommendation 3). Prison services should have access to dried blood spot testing for hepatitis B and C for people for whom venous access is difficult. The NHS lead for hepatitis treatment in prisons should ensure continuity of hepatitis treatment through contingency, liaison and handover arrangements before the prisoner release date, or before any prisoner or immigration detainee receiving hepatitis treatment is transferred between prisons or removal centres. Once a prisoner has started treatment, it may be helpful to put them on medical hold to ensure continuity of care (which might be compromised by transfer between prisons). Planning should involve NHS, prison and immigration removal centre healthcare services and other agencies working with prisoners or detainees. # Recommendation 6 Testing for hepatitis B and C in drugs services ## Who should take action? Drugs services, including drug and alcohol action teams. Commissioners of hepatitis testing and treatment services, including local authorities and clinical commissioning groups. Secondary care services that provide treatment for hepatitis B and C. Public Health England centres. ## What action should they take? Commissioners of hepatitis testing and treatment services should agree local care pathways for people with hepatitis B and C who use drugs services. If possible, the pathway should include provision of hepatitis C treatment services in the community. Drugs services should designate a hepatitis lead for the service. The lead should have the knowledge and skills to promote hepatitis B and C testing and treatment and hepatitis B vaccination. Consideration should be given to training peer mentors and health champions from the drugs service to support this work (for further information see NICE guidance on Community engagement). Drugs services should have access to: dried blood spot testing for hepatitis B and C for people for whom venous access is difficult specialist phlebotomy services in order to encourage hepatitis C treatment in the community, particularly for people who inject drugs. Drugs services should: -ffer hepatitis B vaccination to all service users in line with the Green book. -ffer and promote hepatitis B and C testing to all service users -ffer annual testing for hepatitis C to people who test negative for hepatitis C but remain at risk of infection ensure people diagnosed with hepatitis B and C are referred for specialist care; for hepatitis C this may involve offering hepatitis C treatment in the community for people who are unwilling or unlikely to attend hospital appointments, and whose hepatitis C treatment could be integrated with ongoing drug treatment (such as opiate substitution treatment) ensure staff have the knowledge and skills to promote hepatitis B and C testing and treatment (see recommendation 3) ensure staff who undertake pre- and post-test discussions and dried blood spot testing are trained and competent to do so provide information to women with hepatitis C about the importance of testing in babies and children born after the woman acquired infection provide information to injecting drug users about the importance of hepatitis B vaccination for sexual partners and children (see the Green book). # Recommendation 7 Testing for hepatitis B and C in sexual health and genitourinary medicine clinics ## Who should take action? Commissioners of hepatitis testing and treatment services, including local authorities and clinical commissioning groups. Sexual health and genitourinary medicine clinics. ## What action should they take? Commissioners of hepatitis testing and treatment services should agree local care pathways for people with hepatitis B and C who use sexual health and genitourinary medicine clinics. Sexual health and genitourinary medicine clinics should: -ffer hepatitis B vaccination to all service users in line with the Green book -ffer and promote hepatitis B and C testing to all service users at increased risk of infection, including people younger than 18 ensure people diagnosed with hepatitis B or C are referred for specialist care ensure staff have the knowledge and skills to promote hepatitis B and C testing and treatment (see recommendation 3) ensure staff who undertake pre- and post-test discussions are trained and competent to do so. # Recommendation 8 Contact tracing ## Who should take action? Public Health England centres. Primary care practitioners. ## What action should they take? Public Health England centres should: take overall responsibility for tracing the close contacts of people with confirmed acute and chronic hepatitis B infection advise and oversee the activities of other local organisations undertaking contact tracing, such as GP surgeries and genitourinary medicine clinics, to ensure the national standards for local surveillance and follow-up of hepatitis B and C are met. For example, GPs may need to offer close contacts hepatitis B vaccination and refer for treatment. Primary care practitioners should promote the importance of hepatitis C testing for children who may have been exposed to hepatitis C at birth or during childhood. # Recommendation 9 Effective delivery and auditing of neonatal hepatitis B vaccination ## Who should take action? Directors of public health. Public Health England. ## What action should they take? Directors of public health should ensure existing recommendations on hepatitis B prophylaxis for babies born to mothers with chronic hepatitis B infection are implemented locally by general practitioners, as described in the Green book. Public Health England should audit the hepatitis B vaccination programme for babies. The audit should note how many children received vaccines, whether vaccinated children were given all doses and if not how many doses they received, whether doses were given on schedule, whether babies were tested after completing the vaccination course and the rate of vaccination failure. This audit should be carried out annually and deficiencies addressed. # Recommendation 10 Commissioning locally appropriate integrated services for hepatitis B and C testing and treatment ## Who should take action? Local authorities, in particular directors of public health and clinical commissioning groups Commissioners of hepatitis testing and treatment services. ## What action should they take? Local authorities, in particular directors of public health and clinical commissioning groups should ensure the inclusion of hepatitis B and C in the health and wellbeing board's joint strategic needs assessment. This should provide information on local prevalence of chronic hepatitis B and C and groups at increased risk, including by country of origin or risk behaviour. Commissioners should encourage the development of locally enhanced services for hepatitis B and C in areas where there is a higher than average number of people at increased risk (especially areas with a large migrant population or high prevalence of people who inject drugs). Commissioners should regularly undertake a health needs assessment, health equity audit and an audit of hepatitis B and C services as part of the agreed local care pathway and commission testing and treatment services accordingly. Commissioners should ensure mechanisms are in place for following up patients who defer treatment. Commissioners should audit the uptake of testing and outcomes, including: the number of people tested for hepatitis B and C the number of people diagnosed with hepatitis B and C the number of people with chronic infection who: are referred to a treatment service attend a treatment service are receiving treatment in accordance with treatment guidelines the number of people with hepatitis C who obtain a sustained virological response on antiviral therapy. Commissioners should develop and commission a fully integrated care pathway, working with services that provide hepatitis B and C testing and treatment in primary and secondary care (in the community or specialist services in hospital). This should: take into account the needs of people who test positive for hepatitis B or C infection and are assessed for treatment, including their broader health and psychosocial needs consider all venues where testing and treatment services are, or could be offered that can also ensure continuity of care and onward referral to specialist treatment for people who test positive (such as pharmacy testing and outreach testing and treatment) ensure primary and secondary care staff are educated and trained in hepatitis B and C testing and treatment (see recommendation 3). # Recommendation 11 Laboratory services for hepatitis B and C testing ## Who should take action? Commissioners of laboratory services for hepatitis B and C testing. ## What action should they take? Ensure that samples are transported from patients to laboratories within 24 hours (adjusted for weekends and bank holidays as necessary) Ensure service specifications specify that laboratory services providing hepatitis B and C testing: have Clinical Pathology Accreditation (UK) can support the range of samples used for hepatitis B and C testing (for example, dried blood-spot or venepuncture samples) or can refer the sample to a laboratory which can perform these tests automatically test samples that are positive for hepatitis C antibody for the presence of hepatitis C virus (for example, using a polymerase chain reaction assay), or refer the sample to a laboratory which can perform this test can deliver results within 2 weeks of the sample being received ensure local Public Health England centres are notified of cases of hepatitis B and C infection, in line with national public health legislation provide the organisation or professional requesting a test with an accurate interpretation of the laboratory results and guidance on future management of confirmed cases, such as onward referral to specialist care. Ensure laboratory services provide accurate data on the following: the number of people tested and the type of test performed the referral source of samples (for example, primary care, secondary care, drug and alcohol services, prisons) exposure category, if provided the number of people testing positive: for hepatitis B, this should include acute, chronic and past infection for hepatitis C, this should include PCR positive/current and PCR negative/resolved. NICE has accredited the process used by the British HIV Association to produce UK national guidelines. Accreditation is valid for 5 years from 12 July 2012 and is applicable to guidance produced since 2011. The NICE Accreditation Scheme recognises organisations that demonstrate high standards in producing health or social care guidance. Users of the accredited guidance can therefore have high confidence in the quality of the information. Guidance produced by EASL has not been reviewed by the NICE Accreditation Scheme. EASL guidelines may assist healthcare providers in the clinical decision-making process by describing a range of generally accepted approaches for diagnosing, treating and preventing hepatitis B and C. However, it should be ensured that action taken is in line with NICE guidance.# Public health need and practice Chronic hepatitis B and C are the leading cause of liver disease worldwide (Perz 2006), and the second most common cause of liver disease in the UK, after alcohol. # Hepatitis B The hepatitis B virus is transmitted perinatally from mother to child and through contact with infected blood. Some individuals clear hepatitis B infection naturally, whereas others develop a chronic infection that can result in severe liver disease. Rates of progression from acute to chronic infection vary according to age at the time of exposure. About 85% of hepatitis B infections in newborns become chronic compared with 4% in adults (Edmunds et al. 1993). It has been estimated that 95% of people with new chronic hepatitis B in the UK are migrants, most of whom acquired the infection in early childhood in the country of their birth (Hahné et al. 2004). The remaining 5% of people with chronic hepatitis B acquired the infection in the UK, either through vertical transmission from mother to child or through exposure between adults. Migrant populations are therefore the main focus for hepatitis B case-finding in the UK, and infection in childhood is the major route of transmission. Other key risk groups for hepatitis B infection are described in Whose health will benefit? There is considerable uncertainty about the number of people with chronic hepatitis B in the UK. In 2002 the Department of Health estimated that chronic hepatitis B affects 180,000 people in the UK (Department of Health 2002). Information on the burden of hepatitis B in England and Wales is derived from a number of sources: laboratory reports of confirmed acute and chronic infections serological studies of populations covered by screening programmes (that is, pregnant women and blood donors) serological studies of populations at high risk (for example, people who inject drugs) sentinel laboratory surveillance of people being tested estimates of the size of the migrant population. In 2011, 589 acute or probable acute cases of hepatitis B were reported in England (Health Protection Agency 2012). The total number of acute infections will be greater than the number reported. The most recent study to estimate the annual incidence of hepatitis B in England and Wales was conducted between 1995 and 2000 (Health Protection Agency, Hahné et al. 2004). It estimated the annual incidence of hepatitis B, from laboratory reports, to be around 7.4 per 100,000 people. This translates into around 3700 acute infections per year and around 270 cases of chronic hepatitis B per year. Information about risk factors was available for about 50% of the acute cases. The most common reported risk was heterosexual exposure, followed by homosexual exposure. In comparison, fewer than 5% of cases were attributed to injecting drug use. The decline in the number of cases linked to injecting drug use is supported by the 2011 Unlinked Anonymous Monitoring (UAM) survey, which reported a fall in the proportion of injecting drug users who had ever been infected with hepatitis B, from 28% in 2001 to 16% in 2011 (Health Protection Agency 2011c). This decrease is probably associated with an increase in the uptake of hepatitis B vaccination (Judd et al. 2007; Hope et al. 2007). According to the UAM survey, self-reported rates of hepatitis B vaccination increased from 35% in 2000 to 76% in 2011 (Health Protection Agency 2011c). ## Antenatal screening A national antenatal screening programme for hepatitis B surface antigen (HBsAg) began in 2000 (Health Protection Agency 2011a). Uptake of screening during pregnancy has increased over time (up to 97% in 2011), but the proportion of women who test positive has remained stable (0.42% in 2011). The sentinel surveillance programme identified that 28.5% (73,290) of women who had been tested for HBsAg in 2011 were tested through antenatal screening. Overall, 0.5% of the women tested in the antenatal programme tested positive. Most of the 73,290 women in the study were white or white-British. More black or black-British women (3.9%) and women from 'other' or mixed ethnicity (3.8%) tested positive for HBsAg compared with their Asian/Asian-British (0.5%) and white counterparts (0.3%). # Hepatitis C Hepatitis C is a blood-borne viral infection transmitted through contact with infected blood. In the UK, hepatitis C is primarily acquired through injecting drug use. Approximately 70–75% of people who are infected with acute hepatitis C develop a chronic condition that can result in liver failure and liver cancer. The most recent national estimate suggests that around 216,000 people in the UK have chronic hepatitis C (Health Protection Agency 2012; Scottish Executive 2008). Of these, around 160,000 live in England (Harris 2012a). Injecting drug use is the main route of hepatitis C infection in England. Of the estimated number of people who are chronically infected, around 87% are current or past injection drug users. Of the remaining 13%, 6% are of South Asian descent and the other 7% are of white/other ethnicity (Harris et al. 2012a). Similarly, 90% of the total laboratory reports including risk information in the UK in 2010 attributed infection to injecting drug use (Health Protection Agency 2011c). The main focus for hepatitis C case-finding is therefore people who inject or have injected drugs. There is good evidence that HIV-positive men who have sex with men are at increased risk of hepatitis C infection, and British HIV Association guidelines recommend regular hepatitis C testing in this group. Emerging evidence suggests that people who inject image- and performance-enhancing drugs are also at increased risk of hepatitis C infection. In England, more than 95,000 individuals had been diagnosed with hepatitis C by the end of 2011, suggesting that a significant number of infections remain undiagnosed. Hospitalisations, registrations for liver transplant and deaths from liver cancer due to hepatitis C are steadily increasing throughout the UK. In England, rates of end-stage liver disease caused by hepatitis C are likely to increase if diagnosis and treatment rates do not improve (Health Protection Agency 2012). The prevalence of chronic disease in current and past drug users varies by region, and is highest in London and the North West (Harris et al. 2012). An analysis of the 2010 UAM survey of people who inject drugs and attend specialist services estimated the overall prevalence of hepatitis C antibodies (indicating exposure to the virus) to be 43%, but ranging from 14% to 82% in different geographical sites (Harris et al. 2012b). Data from the UAM survey also suggest that over 83% of people surveyed had a voluntary test for hepatitis C in 2010, compared with 40% in 2000. However, only about half were aware they were hepatitis C antibody positive when comparing self-reported data with anonymous test results (Health Protection Agency 2011b). # National recommendations The national hepatitis B immunisation programme recommends that people from at-risk groups are immunised against hepatitis B. Post-exposure immunisation (which may include hepatitis B immunoglobulin as well as hepatitis B vaccine) is also recommended for babies born to chronically infected mothers (Department of Health 2006). NICE recommends a number of treatments for hepatitis B and hepatitis C (see section 7). Early diagnosis and treatment can clear infection and reduce the risk of long-term complications, such as cirrhosis and liver cancer. For people with chronic hepatitis C, early therapy is associated with increased and sustained virological response rates (Foster et al. 2010).# Considerations The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations. # Awareness-raising The PDG felt that awareness-raising in the general population was a very important issue. While it was always intended that the guidance would make specific recommendations for awareness-raising in professionals and in populations at increased risk, the group decided that it would also be helpful to raise awareness generally. The PDG was aware of the potential benefit of educating all healthcare professionals about hepatitis B and C but was pragmatic in its approach, focusing on those who were likely to be providing services to people at increased risk of infection. Recent developments in the treatment of hepatitis B and C are not reflected in the qualitative literature on the barriers and facilitators to testing. This is because much of the research was undertaken before the newer drugs (see section 7) were available. The Group felt that awareness of more effective treatments may have a positive impact on the uptake of testing. The need for awareness-raising and training on hepatitis C for healthcare professionals was a key theme in the qualitative review, and was in accord with PDG members' experiences. The Group heard reports of people with hepatitis C having to ask for testing for viral hepatitis and liver function and being left with misinformation and confusion about their diagnosis, its consequences and treatment pathways. The Group felt it important that professionals working in this area had the ability to help people make informed choices. The PDG considered there was a need for targeted education programmes for health and social care professionals, such as those produced by Hepatitis Scotland and the Royal College of General Practitioners (RCGP). An outline of requirements on Hepatitis C workforce education development (NHS Education for Scotland 2010) has been produced as part of the Hepatitis C Action Plan for Scotland (Scottish Executive 2006, 2008). The RCGP programme is aimed at generalist clinicians such as GPs and nurses working in primary care, and covers detection, diagnosis and management of hepatitis B and C in primary care. The PDG felt education programmes might cover, depending on the role of the health and social care professional, some or all of the following: epidemiology, public health impact and clinical consequences of hepatitis B and C infection risk factors for hepatitis B and C and population groups at increased risk of infection detection and diagnosis of hepatitis B and C factors to consider in a pre- and post-test discussion and how these discussions should be conducted the importance of repeat testing and harm reduction interventions for people who remain at risk of infection, including hepatitis B vaccination social and cultural barriers to testing and treatment (for example, stigma) local testing, treatment and referral pathways the main features of treatment for hepatitis B and C, in line with current best practice guidelines tests used to monitor liver health the benefits and risks of current treatment options, including their effectiveness, adverse events and barriers and facilitators to treatment adherence. # Barriers and facilitators There are many barriers to testing for hepatitis B and C for groups at increased risk of infection and many are similar for both infections. They include: Fear of being stigmatised, whether by healthcare professionals, sexual partners, family or friends. Knowledge and awareness in relation to the transmission of infection and the treatments available. The PDG was aware of a general lack of knowledge about hepatitis B and C, including among people promoting tests for these infections. Members felt that this contributed to the low uptake of testing among people at increased risk of infection and to the stigma surrounding these infections. It was noted that lack of awareness among people at increased risk of infection may result from lack of access to statutory services. Parental fears that they will not be able to cope with the issues their child may face if the child is found to have hepatitis B or C. (This is especially the case if appropriate information and care pathways have not been discussed with parents.) People who have injected drugs in the past may not want to disclose drug-using history. This may be a barrier to hepatitis B and C testing and treatment. The PDG felt that positive messages about the effectiveness of treatment and attempts to 'normalise' testing might help reach these people. The PDG was keen for the guidance to convey the improvement in health outcomes associated with early identification of hepatitis C in people for whom treatment is indicated. However, they acknowledged that personal circumstances may influence the timing of testing, and that economic, social or other health needs may be a higher priority for some people. The PDG recognised the important role that family, partners and friends may play in encouraging people to get tested and complete treatment. The Group also recognised a role for the peers of people at increased risk in promoting hepatitis B and C testing and supporting people who are diagnosed positive. The PDG noted that it was important to ensure people are not stigmatised by the way information on hepatitis B and C is delivered. The PDG was mindful that combining awareness-raising campaigns for hepatitis B and C with other health promotion campaigns, such as those for HIV, may risk alienating some populations at increased risk. For example, the PDG was made aware that some migrant populations are unlikely to engage with a campaign that associates hepatitis B with sexually transmitted infection. The need to target awareness-raising campaigns to different audiences was felt to be of considerable importance to the PDG. Transmission of hepatitis B from mother to child may be considered normal among some minority ethnic communities. Although this suggests there is less stigma associated with infection among these communities, the Group felt that acceptance of infection may adversely impact on the uptake of testing and treatment. It noted a lack of qualitative evidence about this route of transmission, suggesting a lack of awareness and the need for preventive education. Employment-based screening and subsequent discrimination against workers who test positive for hepatitis B in countries where there is a high prevalence of hepatitis B may discourage voluntary testing among migrants from those countries. The PDG noted that people who inject drugs and have hepatitis C could be stigmatised by the injecting drug community, as a diagnosis of hepatitis C suggests a history of sharing injecting equipment. The PDG was mindful that offering universal testing in certain settings may help reduce the stigma associated with hepatitis B and C. Access to dried blood spot testing or a specialist phlebotomist can reduce pain and embarrassment associated with the difficulties of taking blood samples from people with poor vascular access – typically associated with long-term injecting or poor injecting technique. The PDG discussed the need to train all healthcare staff who are involved in hepatitis testing to carry out pre- and post-test discussions with people at increased risk of hepatitis B and C infection. The PDG were mindful of the sensitivities of discussing people's sexuality and potential sexual exposure to hepatitis B or C. # Testing The PDG noted the importance of all blood samples that test positive for hepatitis C antibody being routinely tested for hepatitis C virus, for example, by PCR. In addition, further consideration of and research on the use of PCR for initial testing in current injecting drug users, with follow-up antibody testing for people who test PCR positive, may be warranted to enable rapid diagnosis of recent infections. While venepuncture samples remain the gold standard, the PDG noted that dried blood spot tests for hepatitis B and C have a high test sensitivity and specificity and can be useful in certain settings for people with poor venous access and where there may be no facilities or expertise to take venous blood samples (for example, in specialist drug treatment services or prisons). The PDG recognised that the use of dried blood spot testing for diagnosis may be more acceptable to some of the target populations than taking a blood sample from a vein, especially if there is poor venous access or the person is needle phobic. In addition, more staff would probably be able to carry out such tests, so helping to increase the number of people who are tested. The PDG noted the success of the Scottish Hepatitis C Action Plan in place since 2008 (Scottish Executive 2006, 2008). Preliminary evidence from this programme suggests that hepatitis C testing in specialist drug clinics increased after the introduction of dried blood spot testing and wide-scale training of healthcare workers in hepatitis C. The PDG recognised that oral fluid testing may be more acceptable to some people because it is less invasive than taking blood from a vein, but that oral fluid testing has a lower sensitivity and specificity than tests for hepatitis B and C performed on blood. If an oral fluid sample was used, a blood sample would then be needed to confirm the initial positive results, and for PCR testing to diagnose chronic hepatitis C. The PDG acknowledged that different populations are at increased risk of hepatitis B and C. However, there is some overlap between them, and it would simplify delivery if testing for both infections at the same time was recommended in people who are at increased risk of either. The PDG felt that the point of entry into a hepatitis B vaccination programme also provides an opportunity to offer testing to people considered to be at increased risk for hepatitis B and C infection. The Group was aware of cases where people had repeatedly been vaccinated against hepatitis B (for example in the prison setting) but not tested for infection, and had later been found to have chronic infection and subsequent liver damage. Nonetheless, the PDG felt that it is important for testing to be offered after vaccination, so as not to impede the success of the vaccination programme. In line with the Green book, the PDG felt that drug services should offer hepatitis B vaccination to all service users who inject or have injected drugs and people with a risk of progression to injecting, for example people who are currently smoking heroin and/or crack cocaine, and heavily dependent amphetamine users, as well as non-injecting users who are living with current injectors. The PDG felt that despite the focus of this guidance on primary and secondary care there may be a role for routine testing for hepatitis B and C in some tertiary clinical services (such as liver clinics, haemodialysis, rheumatology, cancer and fertility services) and as such staff should have access to appropriate training and a role in awareness-raising. The PDG was aware that evidence regarding the effectiveness of routine testing in tertiary clinical services has not been adequately considered in the development of this guidance, but felt this area should be acknowledged. The PDG felt that there may be merit in commissioners considering a range of venues for hepatitis B and C testing in order to improve accessibility. Mechanisms would need to be in place to ensure access to laboratory testing services, delivery of results and referral of people who test positive into the care pathway. In addition, venues would need to ensure adequate measures were taken to ensure infection control and privacy. The PDG acknowledged that there is encouraging evidence from pilot schemes where community pharmacists provide dried blood spot testing for hepatitis. Although the evidence is not strong enough to uniformly recommend that all community pharmacists provide this service, the PDG felt that it would be worthwhile considering extending pilot programmes. This extension could be considered for pharmacists already engaged with people at increased risk of hepatitis B and C, such as pharmacists providing needle exchange and NHS health checks. The PDG noted that abnormal liver function tests, such as raised ALT (alanine aminotransferase) can occur for a variety of reasons (for example, as a consequence of alcohol consumption and fatty liver, or use of statins). In primary care there is a requirement to investigate the cause of an abnormal liver function test, including testing for hepatitis. In secondary care, however, hepatitis tests should only be conducted if the cause of an abnormal liver function test is not known. Active contact tracing for people who test positive for hepatitis C is not recommended, given low transmission rates to both sexual and household contacts. The PDG acknowledged that it would be sensible to discuss with people who test positive whether any of their contacts may have been exposed to infection, including the children of mothers with hepatitis C infection. Testing of identified contacts would be offered at clinical discretion. # Limitations of the evidence There was little published evidence on effective or cost-effective interventions to promote and offer testing to people at increased risk of hepatitis B. There was also a lack of corresponding evidence for interventions addressing hepatitis C testing among migrants. The PDG, therefore, largely drew on economic modelling and other evidence presented to the PDG in order to formulate the recommendations. The PDG was concerned about people who have previously injected drugs but are no longer doing so, and other groups at increased risk, because there was limited evidence on how to reach them effectively. This includes, for example, commercial sex workers and men who have sex with men. The group felt that the principles of the recommendations may apply to these groups. The mapping review provided limited evidence of existing good practice on testing among people at increased risk of hepatitis B and C in England. The Hepatitis C Action Plan for Scotland, however, does provide a model for improving testing and treatment for hepatitis C (Scottish Executive 2006, 2008). The PDG recognised the potential risk of hepatitis C transmission among people who inject performance and image-enhancing drugs (PIEDs) such as anabolic steroids (for non-medical reasons). However, there is a lack of published evidence on the extent of risk in this group or on their contribution to overall hepatitis C prevalence. The PDG recognised and understood the potential risks associated with the transmission of hepatitis C via sharing straws to snort drugs (in theory, if nasal passages were bleeding a straw could transfer infected blood to others using the same straw), but there was a lack of strong biological evidence on which to base recommendations. The key risk was considered to be through sharing injecting equipment. The PDG noted a lack of evidence specific to the role of peer support in promoting the uptake of testing and treatment for hepatitis B and C. Evidence of its positive effect on attitudes, knowledge and behavioural practices relating to prisoners' sexual health was considered. Based on this evidence, the PDG considered it logical that peer support could be beneficial for the groups of interest identified in the guidance. # Economic modelling The way hepatitis B and C are transmitted among different groups at greatest risk varies by group. For example, in the UK 90% of hepatitis C infections are attributed to sharing injecting equipment among people who inject drugs. Among migrant groups from medium- and high-prevalence countries, adult-to-adult transmission of hepatitis B within the UK is responsible for only about 5–10% of chronic cases. The main transmission routes for hepatitis B are from mother to baby and between children through exposure to contaminated blood. The majority of chronic infections of hepatitis B are acquired in the country of origin. The modelling analyses took these differences into account. There was a lack of data on interventions to increase rates of case-finding and treatment in prison, and on continuity of treatment from prison into the community. This meant it was difficult to judge the cost effectiveness of such interventions and treatment rates following diagnosis. Modelling showed that if continuity of treatment (for a prisoner deemed appropriate for treatment) between prisons, from outside to inside prison, or from inside prison to release is at least 40% of the treatment rate of people diagnosed in the community then the treatment would be estimated to be cost effective. The migration modelling was also severely hampered by lack of data on the prevalence of chronic hepatitis B among minority ethnic groups, the cost of finding infected people within these groups and treatment rates. Nevertheless, modelling showed that provided that the prevalence of chronic hepatitis B in migrants from minority ethnic groups was at least 2%, then it was estimated that it would be cost effective to find, test and treat within such communities. The cost effectiveness of primary care interventions to promote testing for hepatitis B and hepatitis C among men who have sex with men was not formally evaluated. The PDG acknowledged the existence of other NICE guidance promoting testing for HIV among this group. Modelling for that guidance showed that, where there is a reasonably high prevalence of undiagnosed cases of hepatitis B and C, adding a test for these infections when testing for HIV would be cost effective. The PDG discussed the possibility of testing all people between the ages of 40 and 65 or 70 for hepatitis C infection. Three recent studies have been carried out in the USA to estimate the cost effectiveness of hepatitis C screening in several different cohorts of people born between 1945 and 1975 (that is, people who were between 37 and 67 years of age in 2012). These studies estimate that such testing would be cost effective, and have led to a recommendation for cohort testing in the USA. The PDG was aware that it was not possible in the time available to carry out modelling for an equivalent cohort in England. The PDG does note, however, that the estimated prevalence of chronic hepatitis C infection in England for that part of the population that does not currently inject drugs would be substantially lower than the 1.6% assumed for the US cohort (Harris et al. 2012). This suggests that a comprehensive testing programme for people born between 1945 and 1975 is unlikely to be cost effective if it were carried out independently of other programmes. The PDG discussed the possibility of linking a cohort testing programme for hepatitis C to the Health Check programme currently being introduced for people between 40 and 70 years in England. However, given that a potential extension of the Health Check programme had not been mentioned in the draft guidance sent for consultation, and that there was uncertainty about whether cohort testing offered as part of the Health Check programme would be cost effective, the PDG believed that it would be preferable to wait for more information before making a substantive recommendation in this area. # Prisons The PDG noted a lack of evidence on interventions to promote testing for hepatitis B and C in specific settings, for example, prisons. Expert testimony was sought to address these gaps. Given the prevalence of hepatitis B and the history of injecting drug use among the prison population, the PDG recognised the importance of prison as a setting for promoting and offering hepatitis B and C vaccination and testing. It also acknowledged that the established hepatitis B vaccination programme in prisons provides an opportunity for discussing the benefits of testing. The PDG felt testing should be offered in prisons after vaccination, so as not to hamper the success of the vaccination programme. The PDG was aware of problems with transferring medical records and information between prison and community settings. However, it was beyond the remit of this guidance to make recommendations about sharing health data between custodial and community providers. The PDG recognised the barriers to continuity of care when someone enters or is released from prison. However, the Group felt that these barriers should not prevent testing for hepatitis B and C being offered to prisoners. Testing for hepatitis C in prisons, with prisoners' informed consent, is cost effective if there is continuity of care when someone who is infected is referred to, from or between prisons and treatment is at least 40% of the treatment rate of people diagnosed in the community. The PDG felt that prison testing would also help ensure that prisoners' right to the same access to healthcare as the general population would be met, and so address health inequalities. The PDG was aware that a key factor affecting treatment outcomes was the length of someone's remaining stay in prison following diagnosis – many prisoners only live at one site for short periods of time, for example when on remand. The PDG was aware that treatment success rates are greater when treatment is based on an 'in-reach' model of care in prisons (where healthcare services are brought into the prison rather than providing escorted outpatient treatment). However, the Group acknowledged that the necessary security arrangements in prison could act as a barrier to this approach. # Immigration Removal Centres The PDG recognised the importance of immigration removal centres as a setting for promoting and offering hepatitis B and C testing. Many of the people detained in these centres originate from medium and high prevalence countries and so are at increased risk of hepatitis B and C infection. In 2011, approximately 27,000 migrants entered detention. Although the majority of immigration detainees are held for less than 2 months, many are held for 2 to 6 months, and some are held for more than 1 year. # Data The PDG acknowledged the limitations and challenges of current surveillance systems for hepatitis B and C (for example, data on the number of people completing treatment successfully are not available). The Group considered that the collection and collation of robust, service-level data on testing and treatment services was important for both monitoring and developing services. The PDG discussed the need for hepatitis B and C databases holding details on people who have been tested and treated. The importance of collecting data on treatment uptake and the need for this data collection to be built into the pathway at every point was noted. It considered that an integrated system, bridging different healthcare providers and capturing a range of data, was the ideal. However, it was felt that there needed to be a balance between the burden of collecting data and the value of those data. The Group acknowledged that it would be resource-intensive. # Other issues It may not always be easy to identify people from groups at increased risk of hepatitis B or C infection. Examples include: children born to parents who inject drugs, and who may later be placed in care or adopted, or children who have been adopted from a country with a medium or high background prevalence. Other smaller groups at increased risk of hepatitis B and C infection include people who: have received medical or dental procedures, including renal dialysis, in countries where infection control may be inadequate have been exposed to unsterile needles (for example, by having non-professional tattoos, body or ear piercing, or acupuncture, or through vaccination in a developing country) are jaundiced or have abnormal liver function tests. The PDG was aware of the need to test candidates for chemotherapy or immunosuppressive therapy for hepatitis B prior to treatment. In people with hepatitis B, chemotherapy or immunosuppressive therapy can result in a flare-up of liver disease and death by fulminant liver failure. To increase testing in primary care the PDG considered recommending that GPs review patient notes to identify people at increased risk and invite them in for discussion and testing. However, there was insufficient evidence on which to decide whether such an approach would be effective or cost effective. The PDG noted the importance of verifying the identity of people testing for hepatitis B and C. Members were made aware of instances where NHS cards have been passed on or sold to illegal migrant workers. In some cases medical information had, as a result, been linked to the wrong people. The PDG emphasised existing hepatitis B vaccination recommendations (as detailed in the Green book) because although hepatitis B vaccination was beyond the scope of this guidance, case-finding may identify contacts of infected individuals who should be offered vaccination. In addition, the Group was aware of the complexities and the importance of the hepatitis B vaccination schedule for babies born to infected mothers. Adherence to the vaccination schedule provides an opportunity to prevent chronic infection in babies. The Group was aware that the current system is failing to ensure babies receive a full course of vaccination and are tested for hepatitis B surface antigen (HBsAg) at 12 months to exclude infection. Staff working in drugs services have a diverse mix of skills. As a result, it would not be possible to adopt a universal approach to training them in hepatitis B and C testing. However, the PDG felt that all staff should be capable of encouraging people to be vaccinated against hepatitis B and test for hepatitis B and C infection. The PDG focused on people who inject drugs and migrants from medium- and high-prevalence countries. The Group noted that effective vaccination and testing for hepatitis B has already been implemented for other groups at increased risk, including men who have sex with men and people with multiple sexual partners. For example, see the Royal College of General Practitioners' Guidance for the prevention, testing, treatment and management of hepatitis C in primary care (Appendix 5) for information on hepatitis B vaccination in men who have sex with men and other groups at increased risk. For other populations at increased risk there was no evidence that infection rates were sufficiently high to warrant a recommendation for case-finding amongst these groups. (These groups include people who have been exposed to unsterile needles, for example, by having non-professional tattoos, body or ear piercing, or acupuncture.)# Recommendations for research # Intervention development and promotion How can case-finding for hepatitis B and C be improved? What modifiable factors influence whether or not specific groups at increased risk of hepatitis B and hepatitis C infection are identified and tested? How can the uptake of hepatitis C treatment be improved? What factors influence whether or not specific groups at increased risk will begin and complete hepatitis C treatment? What cost-effective interventions can be used to increase hepatitis B case-finding among migrant populations in primary and secondary care? What cost-effective interventions ensure continuity of care for prisoners who are diagnosed with chronic hepatitis B or C in prison? How cost effective are alternative testing sites, such as community pharmacist programmes, for increasing the number of people who are tested and treated for hepatitis B and C? What are the most effective ways of involving people from groups at increased risk in awareness-raising about, and promoting testing and treatment for, hepatitis B and C infection? Specifically, how cost effective are peer mentor programmes at increasing the number of people at increased risk who are tested and treated for hepatitis B and C? What impact does increased knowledge and awareness of hepatitis B and C among the general public have on the uptake of testing and treatment? Which interventions for other communicable diseases could be used to encourage people at increased risk of hepatitis B and C infection to take up the offer of testing and treatment? # Epidemiology How many children in the UK are infected with chronic hepatitis B and C and which subgroups of the population do they come from? How many people in the UK are infected with chronic hepatitis B and C and which subgroups of the population do they come from? How cost effective are cohort testing programmes: as a stand-alone programme, or as an extension of the NHS Health Check programme?More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.# Updating the recommendations This guidance will be reviewed 3 years after publication to determine whether all or part of it should be updated. Information on the progress of any update will be posted at the NICE website.# Related NICE guidance # Published Patient experience in adult NHS services. NICE clinical guidance 138 (2012) Hepatitis C (genotype 1) – boceprevir. NICE technology appraisal 253 (2012) Hepatitis C (genotype 1) – telaprevir. NICE technology appraisal 252 (2012) Tuberculosis – hard-to-reach groups. NICE public health guidance 37 (2012) Increasing the uptake of HIV testing among men who have sex with men. NICE public health guidance 34 (2011) Increasing the uptake of HIV testing among black Africans in England. NICE public health guidance 33 (2011) Looked-after children and young people. NICE public health guidance 28 (2011) Hepatitis C – peginterferon alfa and ribavirin. NICE technology appraisal 200 (2010) Hepatitis B – tenofovir disoproxil fumarate. NICE technology appraisal 173 (2009) Reducing differences in the uptake of immunisations. NICE public health guidance 21 (2009) Needle and syringe programmes. NICE public health guidance 18 (2009) Community engagement. NICE public health guidance 9 (2008) Antenatal care. NICE clinical guideline 62 (2008) Hepatitis B – telbivudine. NICE technology appraisal 154 (2008) Hepatitis B – entecavir. NICE technology appraisal 153 (2008) Prevention of sexually transmitted infections and under-18 conceptions. NICE public health guidance 3 (2007) Hepatitis C – peginterferon alfa and ribavirin. NICE technology appraisal 106 (2006) Hepatitis B (chronic) – adefovir dipivoxil and pegylated interferon alpha-2a. NICE technology appraisal 96 (2006) Hepatitis C – pegylated interferons, ribavirin and alfa interferon. NICE technology appraisal 75 (2004) # Under development Hepatitis B: diagnosis and management. NICE clinical guideline (publication expected June 2013) Hepatitis C (children and young people) – peginterferon alfa and ribavirin. NICE technology appraisal (publication expected August 2013) Hepatitis C. NICE clinical guideline (publication date to be confirmed)# Glossary # Close contacts The people in close contact with someone infected with hepatitis B or C, where there is a risk of transmitting the infection (through blood or body fluids). This could include their family members, close friends, household contacts or sexual partners. # Continuity of care Continuation of treatment and referral for people moving in, out or between prisons. # Household contacts People sharing a bedroom, kitchen, bathroom or sitting room with a person infected with hepatitis B or C. # Immigration removal centres In addition to housing people who remain in the UK illegally, immigration removal centres house people who are waiting for their immigration claims to be resolved or to have their identities established. Detainees are entitled to primary healthcare facilities during their stay, equivalent to those available in the community. # In-reach model A model of prison-based healthcare provision in which healthcare services are brought into the prison, instead of the prisoner being taken out to the healthcare service (for example, to a hospital outpatient unit). # Joint strategic needs assessment A process that identifies the current and future health and wellbeing needs of a local population, leading to agreed commissioning priorities that aim to improve outcomes and reduce health inequalities. # Locally enhanced services Additional services provided by GPs, designed to meet specific local health needs. # Medical hold A process to ensure prisoners are not transferred until they are medically fit. # Past infection Hepatitis B and C can be cleared by the body's own immune system. An antibody test determines whether a person has ever been infected with hepatitis in the past. If the test is positive further tests are carried out to establish whether the virus is still present in the body. # Peers Peers are members of the target population who have been diagnosed with hepatitis B or C. They may be recruited and supported to communicate health messages, including promoting testing and treatment, assist with contact tracing or testing, and to offer people support during testing and treatment. # Prison Her Majesty's prison establishments, including young offender institutions. # Sexual contact Intimate contact with others, including kissing and oral, anal, and vaginal intercourse. Hepatitis B is transmitted by direct contact with infected blood. However, it can also be transmitted by contact with semen, vaginal fluids and other body fluids. Hepatitis C is primarily transmitted by contact with infected blood.# References Department of Health (2006) Immunisation against infectious disease – the green book. London: Department of Health. Department of Health (2002) Getting ahead of the curve: a strategy for combating infectious diseases (including other aspects of health protection). London: Department of Health. Edmunds WJ, Medley GF, Nokes DJ et al. (1993) The influence of age on the development of the hepatitis B carrier state. Proceedings B 253: 197–201. Foster GR, Fried MW, Hadziyannis SJ et al. (2007) Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin. Scandinavian Journal of Gastroenterology 42 (2): 247–55. Hahné S, Ramsay M, Balogun K et al. (2004) Incidence and routes of transmission of hepatitis B virus in England and Wales, 1995–2000: implications for immunisation policy. Journal of Clinical Virology 29: 211–20. Harris RJ, Ramsay M, Hope V et al. (2012a) Hepatitis C prevalence in England remains low and varies by ethnicity: an updated evidence synthesis. European Journal of Public Health 22 (2): 187–92. Harris RJ, Hope V, Marongiou A (2012b) Spatial mapping of hepatitis C prevalence in recent injecting drug users in contact with services. Epidemiology and Infection 140 (6): 1054–63. Health Protection Agency (2012) Acute hepatitis B (England): annual report for 2011 Infections report, 6 (34). London: Health Protection Agency Centre for Infections. Health Protection Agency (2011a) Health protection report weekly report 4 (34). London: Health Protection Agency Centre for Infections. Health Protection Agency (2011b) Hepatitis C in the UK 2011. London: Health Protection Agency Centre for Infections. Health Protection Agency (2011c) Shooting up: Infections among people who inject drugs in the UK 2010. An update: November 2011. London: Health Protection Agency. Health Protection Agency (2011d) Sentinel surveillance of hepatitis testing in England. Hepatitis B and D 2010 report. Analysis of testing between 2007 and 2010. London: Health Protection. Hickman M, McDonald T, Judd A et al. (2008) Increasing the uptake of hepatitis C virus testing among injecting drug users in specialist drug treatment and prison settings by using dried blood spots for diagnostic testing: a cluster randomised controlled trial. Journal of Viral Hepatitis 15: 250–4. Hope V, Ncube F, Hickman M et al. (2007) Hepatitis B vaccine uptake among injecting drug users in England 1998 to 2004: is the prison vaccination programme driving recent improvements? Journal of Viral Hepatitis 14 (9): 653–60. Judd A, Hickman M, Hope V et al. (2007) Twenty years of selective hepatitis B vaccination: is hepatitis B declining among injecting drug users in England and Wales? Journal of Viral Hepatitis 14 (8): 584–9. NHS Education for Scotland (2010) Hepatitis C workforce education development: an outline of requirements. Edinburgh: NHS Education for Scotland. Perz JF, Armstrong GL, Farrington LA, et al. (2006) The contribution of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. Journal of Hepatology 45: 529–38. Scottish Executive (2008) Hepatitis C Action Plan for Scotland: phase II: May 2008 – March 2011. Edinburgh: Scottish Executive. Scottish Executive (2006) Hepatitis C Action Plan for Scotland – phase I: September 2006 – August 2008. Edinburgh: Scottish Executive.# Appendix B Summary of the methods used to develop this guidance # Introduction The reviews and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations. All supporting documents are listed in appendix E and are available at the NICE website. # Guidance development The stages involved in developing public health programme guidance are outlined in the box below. . Draft scope released for consultation . Stakeholder meeting about the draft scope . Stakeholder comments used to revise the scope . Final scope and responses to comments published on website . Evidence reviews and economic modelling undertaken and submitted to PDG . PDG produces draft recommendations . Draft guidance (and evidence) released for consultation and for field testing . PDG amends recommendations . Final guidance published on website . Responses to comments published on website # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were: Which interventions are effective and cost effective in encouraging people from high-risk groups to use services that currently (or potentially could) offer hepatitis B or C testing? What prevents people in high-risk groups from seeking and accepting a hepatitis B or hepatitis C test? How do these factors differ for each group – and what factors increase the likelihood that they will seek and accept a test? Which interventions are effective and cost effective at overcoming the barriers to hepatitis B or C testing faced by high-risk groups and professionals? What type of services and activities need to be commissioned to encourage people who have tested positive to continue to seek support? These questions were made more specific for each review (see reviews for further details). # Reviewing the evidence ## Qualitative review One qualitative review was conducted (review 1). A number of databases were searched in March/April 2011 for qualitative studies exploring the views on, and experiences of, hepatitis B and C testing and treatment among people at greatest risk. Five journals with the highest yield of references were selected as follows: Australian Health Review Gastroenterology Nursing International Journal of Drug Policy Journal of Community Health Journal of Viral Hepatitis. All journal issues (113) and supplements published between 2008 and 2011 were hand-searched. A number of websites were also searched. For details, see the review. Studies were included in review 1 if they considered: Groups at an increased risk of hepatitis B and C infection, their close contacts and practitioners who treat them or are involved in preventive activities. Mixed 'low'- and 'high'-risk populations where it was possible to attribute the findings to particular high-risk populations. The views and experiences of groups at increased risk in relation to case-finding, testing, communication of test results or subsequent treatment. Patient and practitioner perspectives on the barriers to, and opportunities for, changing behaviour in relation to hepatitis B and C testing and subsequent care and treatment. Studies were excluded if they: Focused solely on general population groups or groups at low risk of hepatitis B or C. Used structured questionnaires as the sole method of data collection. Only reported quantitative data not elicited from the patients or providers themselves. ## Effectiveness review One review of effectiveness was conducted (review 2). A number of databases were searched in July 2011 for studies from 1990 onwards. Studies were included in the effectiveness review if they: Targeted groups at increased risk of hepatitis B and C infection. Targeted healthcare professionals involved in hepatitis B and C testing and treatment. Aimed to raise awareness of hepatitis B and C testing services among people from high-risk groups. Encouraged people from high-risk groups and their 'close contacts' to use hepatitis B and C testing services. Improved access to testing services. Studies were excluded if they focused on changing the behaviour of people who inject drugs (in relation to injecting or sharing practices but without reference to case-finding or testing). See each review for details of the inclusion and exclusion criteria. ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual Methods for the development of NICE public health guidance (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. – Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. The evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable). ## Summarising the evidence and making evidence statements The review data were summarised in evidence tables (see full reviews). The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope. ## Mapping review The mapping review comprised a survey of awareness-raising and other activities to encourage groups at increased risk of hepatitis B and C to seek support. Telephone interviews and an online questionnaire were used with healthcare professionals and representatives of voluntary and community sector organisations who work with people at increased risk of hepatitis B and C infection. See the review for details. # Cost effectiveness There was a review of economic evaluations and two economic modelling exercises. ## Review of economic evaluations There was a review of economic evaluations as part of the effectiveness review (review 2). Studies were included if they reported both costs (regardless of how estimated) and outcomes (regardless of how specified). ## Economic modelling Three economic models were constructed to incorporate data from the reviews of effectiveness and cost effectiveness. A dynamic model was developed to estimate the cost effectiveness of interventions to promote hepatitis testing among people who inject drugs. The model had to be dynamic to account for the ongoing transmission of hepatitis C between people who inject drugs. Two static models were developed to evaluate interventions aimed at migrant groups. (Hepatitis B and C case finding and treatment in the UK will have an effect on morbidity among people tested, but little impact on the incidence of chronic infection, because most new cases have not been caused by infection within the UK.) The results are reported in: 'An economic evaluation of finding cases of hepatitis B and C infection in UK migrant populations'; and 'Assessing the cost-effectiveness of interventions aimed at promoting and offering hepatitis C testing to injecting drug users: An economic modelling report'. # How the PDG formulated the recommendations At its meetings in May, July, September, November and December 2011 and February, March and April 2012, the Programme Development Group (PDG) considered the evidence and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guidance. The PDG developed draft recommendations through informal consensus, based on the following criteria: Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. Where possible, recommendations were linked to an evidence statement(s) (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence). The draft guidance, including the recommendations, was released for consultation in June 2012. At its meeting in September 2012, the PDG amended the guidance in light of comments from stakeholders and experts. The guidance was signed off by the NICE Guidance Executive in November 2012.# Appendix C The evidence This appendix lists the evidence statements from two reviews, provided by external contractors (see appendix A and appendix E) and links them to the relevant recommendations. See appendix B for the meaning of the (++), (+) and (-) quality assessments referred to in the evidence statements. The two reviews are: Review 1: 'A systematic review of qualitative research on the views, perspectives and experiences of hepatitis B and C testing among practitioners and people at greatest risk of infection'. Review 2: 'A systematic review of the effectiveness and cost effectiveness of interventions aimed at raising awareness and engaging with groups who are at increased risk of hepatitis B and C infection'. The evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letter(s) in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document. Evidence statement Q1 indicates that the linked statement is numbered 1 in review 1. Evidence statement E3 indicates that the linked statement is numbered 3 in review 2. The reviews and economic analysis are available online. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Where the Programme Development Group (PDG) has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix. Recommendation 1: evidence statements: Q1, Q2, Q3, Q4, Q5, Q8, Q9, Q10, E1; IDE Recommendation 2: evidence statements: Q1, Q2, Q3, Q4, Q5, Q8, Q9, Q10, Q14, Q15, Q16, Q23, Q28, Q29, E1; IDE Recommendation 3: evidence statements: Q2, Q18, Q20, Q21, Q28, Q29, Q30, E2, E5, E8; IDE Recommendation 4: evidence statements: Q28, E5, E6, E11 Recommendation 5: evidence statements: Q16, Q27, Q28, E1, E6; IDE Recommendation 6: evidence statements: Q18, Q20, Q21, Q24, Q25, Q28, Q29, Q30, E1, E4, E5, E6, E7, E8, E9; IDE Recommendation 7: IDE Recommendation 8: IDE Recommendation 9: IDE Recommendation 10: Q7, E5; IDE Recommendation 11: evidence statements: IDE # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the evidence review(s) to make them more consistent with each other and NICE's standard house style. The superscript numbers refer to the studies cited beneath each statement. The full references for those studies can be found in the reviews. ## Evidence statement Q1 Understanding and awareness of hepatitis B among people born in countries with intermediate and high endemicity may be strongly influenced by their personal experiences and cultural beliefs (two , one )1,2,3. Burke et al. 2004. Burke et al. 2011. Wallace et al. 2011. ## Evidence statement Q2 People born in countries with intermediate and high endemicity for hepatitis B may confuse the various forms of hepatitis and the relationship between hepatitis and HIV, and they may commonly hold inaccurate beliefs about transmission risks (two , one )1,2,3. The lack of, or gaps in, knowledge about hepatitis B identified among some healthcare professionals (two )3,4 may contribute to or compound inadequate knowledge about hepatitis B among groups at a high risk of infection. Burke et al. 2011. van der Veen et al. 2009. Wallace et al. 2011. Hwang et al. 2010. ## Evidence statement Q3 People born in countries with intermediate and high endemicity for hepatitis B may commonly cite access to or contamination of food, or cultural practices associated with sharing food and communal eating, as the main cause of hepatitis B transmission (three and one )1,2,3,4. Although vertical transmission of hepatitis B was acknowledged in some studies, sexual transmission of hepatitis B was infrequently mentioned; overall, the evidence suggests that groups at a high risk of infection do not perceive hepatitis B as a sexually transmitted infection (three )4,5,6. Burke et al. 2004. Burke et al. 2011. Chen et al. 2006. Choe et al. 2005. van der Veen et al. 2009. Wallace et al. 2011. ## Evidence statement Q4 As with their beliefs about the causes and prevention of hepatitis B, people born in countries with intermediate and high endemicity may express beliefs about prevention that are influenced by their personal experiences and cultural background (four )1,2,3,4. Among people originating from East and South East Asia, prevention strategies may commonly reflect the practice of traditional medicine and vaccination may not generally be considered as a primary means of prevention(five and one )1,2,5,6,7,8. Religious influences on preventive health strategies may also be apparent, for example among Muslim men (one )3. Choe et al. 2005. Chen et al. 2006. van der Veen et al. 2009. Wallace et al. 2011. Burke et al. 2004. Burke et al. 2011. Chang et al. 2008. Hwang et al. 2010. ## Evidence statement Q5 Despite some participants expressing generally positive attitudes towards hepatitis B vaccination and people at high risk being receptive to vaccination (one and one )1,2 some studies (two and one )1,3,4 indicated that there is significant confusion and uncertainty surrounding vaccination among groups at a high risk of infection. Buck et al. 2006. van der Veen et al. 2009. Chen et al. 2006. Chang et al. 2008. ## Evidence statement Q7 Barriers to testing for hepatitis B include an absence of clear symptoms of infection, practical obstacles such as inconvenience and time constraints, and language and cultural barriers, all of which may discourage some people from seeking care and may limit the role that healthcare providers play in providing education and outreach to immigrant communities (one )1. van der Veen et al. 2009. ## Evidence statement Q8 The perception of hepatitis B as a 'liver' or 'blood' illness rather than a sexually transmitted infection (STI) appears to play an important role in tempering stigma associated with hepatitis B. Increasing awareness of hepatitis B as a sexually transmitted infection was viewed by one study ()1as potentially contributing to increased stigma. van der Veen et al. 2009. ## Evidence statement Q9 One study ()1 reported that people with a diagnosis of chronic hepatitis B, including first- and second-generation immigrants, had little recollection of providing consent to test and did not receive adequate information at diagnosis. This lack of information and knowledge was perceived as impacting negatively on their health and preventing opportunities for behaviour change. Both patients and community workers expressed concerns about a lack of provider knowledge with regards to hepatitis B. Wallace et al. 2011. ## Evidence statement Q10 There was evidence that safe and responsible injecting practices are employed by injecting drug users (IDUs) to avoid the transmission of hepatitis C from 6 studies (5 and 1 1,2,3,4,5,6. There was a lack of consensus as to whether safe practices are strictly adhered to in relation to the sharing of drug related paraphernalia3,5,7. Davis et al. 2004. Ellard 2007. Rhodes et al. 2004. Southgate et al. 2005. Wright et al. 2005. Fraser 2004. Coupland et al. 2009. ## Evidence statement Q14 There is strong evidence from 18 studies (eleven , five , one and one not rated )1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 that IDUs have an uncertain and incomplete knowledge of hepatitis C. Studies showed that IDUs are confused over what the disease is, how it differs from other forms of hepatitis, how the infection is transmitted and what symptoms are involved. This confusion was reinforced by the perception that expert and scientific knowledge on hepatitis C is shifting and uncertain (three and one )4,11,12,17. There is evidence that some IDUs are aware of their limited knowledge of hepatitis C (three )3,4,12. Copeland 2004. Coupland et al. 2009. Davis and Rhodes 2004. Davis et al. 2004. Ellard 2007. Fraser 2004. Fraser 2010. Gyarmathy et al. 2006. Harris 2009a. Munoz-Plaza et al. 2004. Rhodes and Treloar 2008. Rhodes et al. 2004. Sosman et al. 2005. Southgate et al. 2005. Sutton and Treloar 2007. Swan et al. 2010. Tompkins et al. 2005. Wright et al. 2005. ## Evidence statement Q15 Hepatitis C is often understood in relation to HIV in a way that trivialises the seriousness of contracting hepatitis C and may have implications for the use of safe injecting practices and the uptake of hepatitis C services (eleven , two and two )1,2,3,4,5,6,7,8,9,10,11,12,13,14,15. Copeland 2004. Davis and Rhodes 2004. Davis et al. 2004. Ellard 2007. Faye and Irurita 2003. Harris 2009a. Munoz-Plaza et al. 2010. Rhodes et al. 2004. Roy et al. 2007. Southgate et al. 2005. Sutton and Treloar 2007. Swan et al. 2010. Rhodes and Treloar 2008. Treloar and Rhodes 2009. Wozniak et al. 2007. ## Evidence statement Q16 A number of barriers to hepatitis C testing among IDUs were identified. People perceiving themselves to be at low risk of hepatitis C infection, a lack of visible symptoms of hepatitis C infection, fear of a positive test result, the use of needles and fear of disclosure were found to prevent the uptake of hepatitis C testing among IDUs (seven , eight , one and one )1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17. Three studies (two and one )7,18,19 reported barriers to testing specific to the prison setting including long waiting times, lack of information provision, prioritisation of detoxification and withdrawal, and movement between prisons. Craine et al. 2004. Davis et al. 2004. Fraser 2004. Fraser 2010. Gyarmathy et al. 2006. Harris 2009a. Khaw et al. 2007. Lally et al. 2008. Perry et al. 2003. Rhodes and Treloar 2008. Rhodes et al. 2004. Temple-Smith et al. 2004. Sosman et al. 2005. Southgate et al. 2005. Strauss et al. 2008. Sutton and Treloar 2007. Swan et al. 2010. Dyer and Tolliday 2009. Munoz-Plaza et al. 2005b. ## Evidence statement Q18 Convenient and opportunistic testing and a 'one-stop shop' approach for all hepatitis C services was regarded as a convenient approach among IDUs (three and five )1,2,3,4,5,6,7,8. There is evidence (two and two )3,9,10,11 that some IDUs were unaware that they had been tested for hepatitis C and concern over informed consent to testing was noted by a number of authors. Although an opportunistic approach can increase testing compliance, a lack of informed consent may also contribute towards uncertain knowledge of hepatitis C among IDUs and limit the impact of testing on behaviour. Gyarmathy et al. 2006. Munoz-Plaza et al. 2004. Rhodes et al. 2004. Roy et al. 2007. Sosman et al. 2005. Swan et al. 2010. Strauss et al. 2008. Temple-Smith et al. 2004. Munoz-Plaza et al. 2005b. Perry and Chew-Graham 2003. Tompkins et al. 2005. ## Evidence statement Q20 Trust and rapport with healthcare professionals and drug treatment staff motivated people to get tested. Support and encouragement from healthcare professionals also facilitated testing among IDUs (four )1,2,3,4. Munoz-Plaza et al. 2004. Perry et al. 2003. Sosman et al. 2005. Strauss et al. 2008. ## Evidence statement Q21 Studies showed that the experience of being informed about the outcome of hepatitis C testing can be highly confusing (nine , two , one and one )1,2,3,4,5,6,7,8,9,10,11,12,13. Limited and inadequate information provision by healthcare professionals can lead to confusion over the meaning of a positive diagnosis and substantial gaps in knowledge. Copeland 2004. Cullen et al. 2005. Faye and Irurita 2003. Khaw et al. 2007. Kinder 2009. Lally et al. 2008. Rhodes and Treloar 2008. Rhodes et al. 2004. Southgate et al. 2005. Strauss et al. 2008. Sutton and Treloar 2007. Swan et al. 2010. Tompkins et al. 2005. ## Evidence statement Q23 Fear of the adverse effects associated with hepatitis C treatment and the circulation of 'horror stories' and unsuccessful treatment cases among peers discouraged IDUs from engaging with treatment (three , one and two )1,2,3,4,5,6. A fear of needles was also common and using needles during the treatment process was a challenge to overcome when considering treatment (two and one )3,5,7. In contrast, anxiety over hepatitis C, witnessing peers suffer from symptoms of hepatitis C infection and hearing stories of successful treatment cases among peers encouraged treatment uptake (two and one )3,5,8. Cullen et al. 2005. Fraser 2010. Kinder 2009. Munoz-Plaza et al. 2008. Swan et al. 2010. Treloar and Holt 2008. Strauss et al. 2008. Munoz-Plaza et al. 2004. ## Evidence statement Q24 Socioeconomic and family circumstances can lead to treatment being de-prioritised among IDUs (three and one )1,2,3,4. Studies have shown that a preoccupation with drug use, chaotic lifestyles, long waiting times between appointments and employment contributed towards IDUs missing and forgetting treatment appointments, thus increasing the possibility of treatment dropout (three )1,3,5. The assumption of abstinence as a requirement for hepatitis C treatment and continued substance use among IDUs acted as a barrier to treatment (six and one )1,3,5,6,7,8,9. Coupland et al. 2009. Fraser 2010. Swan et al. 2010. Treloar et al. 2010. Lally et al. 2008. Cullen et al. 2005. Roy et al. 2007. Wozniak et al. 2007. Wright et al. 2005. ## Evidence statement Q25 Receiving support from family, partners and peers, starting family life and concerns over the impact of hepatitis C on significant others (for example partners and children) motivated IDUs to engage with hepatitis C treatment (three )1,2,3. Faye and Irurita 2003. Kinder 2009. Swan et al. 2010. ## Evidence statement Q27 One study ()1 found that being in prison was viewed by healthcare professionals as both a barrier and a facilitator for hepatitis C treatment. Transportation of prisoners between prisons and short sentences were viewed as interfering with the treatment process whereas the structured environment of prison and availability of peer support during treatment were regarded as beneficial. Dyer and Tolliday 2009. ## Evidence statement Q28 Two studies found that a lack of access to treatment and a lack of information on treatment options act as barriers to hepatitis C treatment (two )1,2. Increasing knowledge of hepatitis C through the provision of information by healthcare professionals encouraged IDUs to consider their treatment options (one , two and one )1,3,4,5. Swan et al. 2010. Treloar et al. 2010. Cullen et al. 2005. Munoz-Plaza et al. 2004. Munoz-Plaza et al. 2008. ## Evidence statement Q29 The experience of stigma prevented IDUs from seeking hepatitis C testing because of fear of disclosure, and prevented IDUs from disclosing a positive hepatitis C status because of fear of a negative reaction, isolation and social exclusion (eight , three , one and one )1,2,3,4,5,6,7,8,9,10,11,12,13. Stigma also prevented engagement with further prevention education, investigations and treatment and resulted in IDUs receiving inadequate and judgemental care by healthcare professionals (seven , six , one and two )5,6,7,9,12,14,15,16,17,18,19,20,21,22,23,24. Craine et al. 2004. Ellard 2007. Harris 2009b. Khaw et al. 2007. Lally et al. 2008. McCreaddie et al. 2011. Roy et al. 2007. Sosman et al. 2005. Strauss et al. 2008. Sutton and Treloar 2007. Tompkins et al. 2005. Treloar and Rhodes 2009. Wright et al. 2005. Carrier et al. 2005. Coupland et al. 2009. Faye and Irurita 2003. Habib and Adorjany 2003. Munoz-Plaza et al. 2004. Paterson et al. 2007. Perry et al. 2003. Swan et al. 2010. Temple-Smith et al. 2004. Treloar and Hopwood 2004. Treloar et al. 2010. ## Evidence statement Q30 Perceiving health care professionals to be supportive, concerned and caring, and being encouraged to undertake treatment by healthcare professionals was found to motivate IDUs to engage in hepatitis C treatment (four , one and one )1,2,3,4,5,6. There was evidence across a number of studies that IDUs preferred hepatitis C services, including treatment, to be situated in one setting such as drug treatment programmes and methadone substitution settings (two and one )5,7,6. These services were also seen as useful in providing information on hepatitis C treatment (one and three )5,6,8,9. Fraser 2010. Coupland et al. 2009. Kinder 2009. McCreaddie et al. 2011. Munoz-Plaza et al. 2004. Swan et al. 2010. Treloar et al. 2010. Munoz-Plaza et al. 2005a. Munoz-Plaza et al. 2006. ## Evidence statement E1 There is moderate evidence from three randomised controlled trials (RCTs) (one and two )1,2,3 and one uncontrolled before and after (UBA) study (-)4 to suggest that providing information and education on hepatitis B to migrant populations may improve their knowledge about risk, screening and prevention; moderate evidence from three RCTs (one and two )1,2,3 to suggest that providing information and education on hepatitis B to migrant populations does not improve testing uptake; and weak evidence from one case series (-)5 to suggest that testing supplemented with culturally appropriate education may encourage the uptake of follow-up care among migrant populations. Taylor et al. 2009a. Taylor et al. 2009b. Taylor et al. 2011. Hsu et al. 2007; 2010. Chao et al. 2009. ## Evidence statement E2 There is moderate evidence from one RCT (+)1 to suggest that a strategy to promote cancer prevention activities among doctors serving migrant populations does not improve their practices in relation to hepatitis B testing. There is weak evidence from one UBA study (-)2 to suggest that providing information and education on hepatitis B to complementary and alternative medicine practitioners (including those practising traditional Chinese medicine and acupuncture) may improve their knowledge about risk, screening and prevention. However, the wider impact of this change in knowledge on their practices regarding referral for testing is not clear. Nguyen et al. 2000. Chang et al. 2007. ## Evidence statement E4 There is moderate evidence from one RCT (+)1 and one controlled before and after (CBA) study (-)2 to suggest that offering dried blood spot testing to IDUs attending substance misuse services may increase uptake of hepatitis C testing compared to venepuncture alone being offered. The increase in uptake may reflect an increase in testing availability, as more staff can be trained to deliver dried blood spot testing than venepuncture, as well as higher acceptability to IDUs. There is weak evidence from one case series (CS) study (-)3 to suggest that providing high-risk groups with access to dried blood spot testing kits via a telephone hotline is not an effective use of resources compared to testing via state laboratories. Hickman et al. 2008. Craine et al. 2009. Rainey et al. 2005. ## Evidence statement E5 There is moderate evidence from one RCT (+)1 to suggest that although providing GPs with both training and assistance with screening (through the use of patient-targeted materials) may increase patient requests for testing, it does not impact upon the number of patients tested for hepatitis C overall. There is moderate evidence from two non-randomised controlled trials (two )2,3 to suggest that targeted case finding in primary care for patients with a history of injecting drug use may have a positive impact on the number of patients who are offered and accept a hepatitis C test. Although the level of referral of patients identified with infection was relatively high, the number of subsequent dropouts prior to treatment indicates that there is a need for further support beyond the intervention offered in these studies. Roudot-Thoraval et al. 2000. Anderson et al. 2009. Cullen et al. 2012. ## Evidence statement E6 There is moderate evidence from one RCT (+) and two case series (two )1,2,3 to suggest that providing hepatitis C services in community settings may have a positive impact on testing acceptance and uptake. In particular, there is weak evidence from two case series (two )4,5 to suggest that a multidisciplinary or shared care approach to hepatitis C testing and treatment for IDUs is associated with high uptake of follow-up services and treatment outcomes comparable with non-drug-using populations. In two studies conducted in the USA (two )6,7, hepatitis testing was added to routine blood work undertaken on entry to drugs services and therefore a high testing rate was inevitable. There is moderate evidence from one RCT (+)8 to suggest that the provision of testing services via outreach may have a positive impact on testing acceptance and uptake. The impact may be greatest when testing is offered on-site rather than by referral. There is weak evidence from one UBA study (-)9 to suggest that the provision of hepatitis C outreach services for new prisoners may lead to relatively low uptake of testing. Rosenberg et al. 2010. Lindenberg et al. 2011. Jack et al. 2009. Lindenberg et al. 2011. Jack et al. 2009. Harris et al. 2010. Hagedorn et al. 2007. Sahajian et al. 2011. Skipper et al. 2003. ## Evidence statement E7 There is weak evidence from one case series (-)1 to suggest that offering a non-invasive liver evaluation technique in outreach settings provides an opportunity to subsequently test IDUs for hepatitis C. There is weak evidence from one case series (-)2 that education by a peer outreach worker may improve short-term knowledge about hepatitis C transmission among IDUs. Foucher et al. 2009. Aitken et al. 2002. ## Evidence statement E8 There is moderate evidence from one RCT (++)1, one non-randomised controlled trial (+)2 and one UBA study (-)3 to suggest that complex interventions that provide support to primary care professionals when offering hepatitis C testing may have a positive impact on testing acceptance and uptake. One repeated cross-sectional study (+)4 demonstrated that without support, offers of testing may increase, but not within the desired high-risk groups. There is weak evidence from three UBA studies (three )1,5,6 to suggest that educational interventions aimed at healthcare professionals may have short-term benefits on knowledge about hepatitis C. However, there is no clear evidence that an increase in knowledge leads to an increase in testing. Weak evidence from one UBA study (-)4 suggested that a continuing medical education programme had a limited impact on testing uptake. There is mixed evidence from two studies (one and one)7 that examined the effectiveness of interventions aimed at professionals on treatment initiation. There is moderate evidence from a repeated cross-sectional study (+)4 that a national campaign had no impact on the management of drug users following a positive hepatitis C test. However, there is strong evidence from one RCT (++)1 that a complex intervention providing support in primary care had a positive impact on number of referrals and attendance at follow-up appointments after testing. Cullen et al. 2006. Helsper et al. 2010. Sahajian et al. 2004. Defossez et al. 2008. D'Souza et al. 2004. Fischer et al. 2000. Garrard et al. 2006. ## Evidence statement E9 There is weak evidence from one controlled before and after (CBA) study (-)1 and one case series (-)2 to suggest that the provision of hepatitis C treatment in community settings for IDUs had a positive effect on treatment initiation and outcomes. There is weak evidence from two case series (both )3,4 that attendance at a support group for hepatitis C may have a positive effect on treatment initiation. However, it was unclear due to the study design used whether attendance at the support group was higher among more highly motivated individuals who may have been more likely to initiate treatment regardless of their attendance at the group. There is weak evidence from one cohort study (-)5 to suggest that allowing patients, such as those who have not been referred by their doctor, to self-refer to speciality liver clinics for assessment was associated with treatment uptake and completion at rates similar to those referred by healthcare professionals. There is weak evidence from a CBA study (-)6 to suggest that ensuring patients receive education about hepatitis C prior to referral appointments may have a positive effect on attendance at follow-up appointments, and on short to medium-term knowledge. Moussalli et al. 2010. Wilkinson et al. 2008. Grebely et al. 2007. Grebely et al. 2010. Doucette et al. 2009. Surjadi et al. 2011. ## Evidence statement E11 There is moderate evidence from one cost utility analysis (+)1 to suggest that community-based screening and treatment for hepatitis B among migrant populations is cost effective. Veldhuijzen et al. 2010. # Additional evidence A mapping review was also carried out. This was a practice survey of activities and interventions that aim to raise awareness among, and/or engage with, groups who are at an increased risk of hepatitis B and C infection. # Economic modelling There were three models. One model looked at three scenarios for increasing testing for hepatitis C among people who inject drugs and people who used to inject drugs, with the emphasis on training and education: Training specialist addiction services in the community to undertake dried blood-spot testing for hepatitis C infection. Educating and supporting GPs to identify patients at risk of the infection. Training prison nurses to undertake dried blood-spot testing for hepatitis C infection. Training for dried blood-spot testing in the community resulted in a substantially greater proportion of cases of hepatitis C infection being identified, compared with not offering this blood sampling method. This led to an estimated cost per quality-adjusted life year (QALY) gained of £15,000, which is below the threshold of £20,000 generally accepted by NICE as cost effective. Educating GPs about hepatitis C infection and targeted paid testing also resulted in an increase in testing and was also cost effective, yielding an estimated cost per QALY of £14,000. (Clinical administration systems were reviewed to identify registered patients aged 30-54 who had indicators of past injecting drug use. These individuals were offered testing for hepatitis C when they attended the practice for a non-urgent consultation. Practices received £100 remuneration for each test offered). Training prison nurses to undertake dried blood spot testing also increased the proportion of hepatitis C cases found, compared with not offering this sampling method. However, the cost effectiveness of this training depended on whether the resulting treatment was completed. The baseline scenario considered no continuity of care between prison and the community – in which case the cost per QALY of finding a new case was estimated to be £59,000 per QALY and therefore was not cost effective. The estimated cost per QALY of case-finding in prison will be less than £20,000 per QALY gained if there is continuity of care between prison and the community and the treatment rate of people diagnosed in prison is at least 40% of the treatment rate of people diagnosed in the community. Higher treatment rates in the community make prison case-finding more cost effective as long as there is continuity of care. A second model looked at finding and testing UK migrants for hepatitis C infection. This was found to be cost effective if 2% of the migrant group were infected and it cost no more than £20 to find and test each person. In such a case, the cost per QALY gained was estimated to be £10,000. If the cost of finding and testing someone was £50, the estimated cost per QALY was £18,000. For a given cost of testing, it became more cost effective to find and test people if more than 2% of the population group were infected. A third model looked at finding and testing UK migrants for chronic hepatitis B. If there was a 2% prevalence within the population group and it cost £20 to find and test each infected person, the estimated cost per QALY gained would be £21,000, marginally above the NICE £20,000 threshold for cost effectiveness. However, it would be cost effective if the prevalence of infection was 3% or higher. At 20% prevalence, as is believed to be the case among some migrant groups, the estimated cost per QALY of finding and testing people falls to £12,000 and was, therefore, deemed cost effective. Based on the modelling, the PDG considered that it would be cost effective to simultaneously find and test people at risk for both hepatitis B and C, provided there was a 2% prevalence of both infections and it cost up to £75 to find and test each person.# Appendix D Gaps in the evidence The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence. These gaps are set out below. . There is a lack of robust, quantitative studies on identifying, testing and treating hepatitis B and C (that is, studies that are applicable to the UK context). In particular there is a lack of reliable data on: a) the number of people in the UK with chronic hepatitis B and C. In particular, there is no national information on the number of children infected. b) local information on the number of people with chronic hepatitis B and C. c) interventions to increase hepatitis B and C testing among migrant populations. d) interventions to increase hepatitis B and C testing in non-health settings, for example, prisons. . There is a lack of qualitative studies on hepatitis B and C, including studies focused on: a) cultural issues which may act as a barrier to testing and treatment. b) knowledge of, barriers against, and facilitators for hepatitis C testing and treatment among migrant populations. c) knowledge of, barriers against, and facilitators for preventing hepatitis B and C among men who have sex with men. d) knowledge of, barriers against, and facilitators for improving the prevention of maternal transmission of hepatitis B. e) knowledge of, barriers against, and facilitators for preventing hepatitis B among injecting drug users. f) how former drug users, both from a service user and provider perspective, regard testing for hepatitis. g) the views, perspectives and experiences of hepatitis B and C testing among people whose past behaviour has put them at risk but who choose not to disclose this information. This includes people who have previously injected drugs or worked as commercial sex workers. h) the views, perspectives and experiences of hepatitis B and C testing among practitioners and people at increased risk of infection, according to the practitioner's level and type of knowledge. i) prisoners' views of hepatitis testing and treatment and the views of those working with them. j) the acceptability of different sampling methods for testing for hepatitis. k) factors which encourage people to have a liver biopsy or discourage them from this. l) the knowledge GPs have regarding identification of at-risk patients. m) why people referred by GPs for a hepatitis test drop out of appropriate care pathways and whether or not an integrated services/one-stop-shop approach would improve uptake rates. n) understanding of hepatitis B and C care pathways. . There is a lack of evidence on the role of the voluntary sector in promoting and offering tests for hepatitis B and C. . There is a lack of evidence on what is happening in the 'real world'. This includes the views of people: a) at risk of hepatitis B and C. b) who have been identified and/or tested and/or treated. c) who have dropped out at different stages of the care pathway. . There is a lack of qualitative and quantitative evidence on the acceptability of dried blood spot testing among different communities. . There is a lack of evidence on how hepatitis B and C status could be assessed when testing for other diseases and blood-borne viruses. The Group made 12 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in section 5.# Appendix E Supporting documents Supporting documents include the following (see supporting evidence). Evidence reviews: Review 1: 'A systematic review of qualitative research on the views, perspectives and experiences of hepatitis B and C testing among practitioners and people at greatest risk of infection' Review 2: 'A systematic review of the effectiveness and cost effectiveness of interventions aimed at raising awareness and engaging with groups who are at increased risk of hepatitis B and C infection' Mapping review: 'A practice survey of activities and interventions that aim to raise awareness among, and/or engage with, groups who are at an increased risk of hepatitis B and C infection'. Economic modelling: 'An economic evaluation of finding cases of hepatitis B and C infection in UK migrant populations' 'Assessing the cost-effectiveness of interventions aimed at promoting and offering hepatitis C testing to injecting drug users: An economic modelling report'. Expert testimony: Presentation 1: 'UK National Screening Committee and case finding versus screening' Presentation 2: 'Hepatitis B vaccination in England and Wales' Presentation 3: 'Hepatitis testing in prisons' Presentation 4: 'Paediatric hepatitis testing and treatment' Presentation 5: 'The role of GPs in promoting hepatitis B and C testing among at risk populations' Presentation 6: 'Perspective on barriers to hepatitis testing and treatment for people who inject drugs'. For information on how NICE public health guidance is developed, see: Methods for development of NICE public health guidance (third edition, 2012) The NICE public health guidance development process (third edition, 2012)# About this guidance NICE public health guidance makes recommendations on the promotion of good health and the prevention of ill health. This guidance was developed using the NICE public health programme guidance process. The recommendations from this guidance have been incorporated into a NICE Pathway. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of the Institute and was arrived at after careful consideration of the evidence available. Those working in the NHS, local authorities, the wider public, voluntary and community sectors and the private sector should take it into account when carrying out their professional, managerial or voluntary duties. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity, and foster good relations. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk 033 7780# Changes after publication March 2013: recommendation 7 has been clarified by adding the text: 'at increased risk of infection' to the sentence 'offer and promote hepatitis B and C testing to all service users at increased risk of infection, including people younger than 18'. April 2013: minor maintenance.	{'Introduction: scope and purpose of this guidance': "# What is this guidance about?\n\nThis guidance aims to ensure more people at increased risk of hepatitis B and C infection are tested.\n\nThe recommendations cover:\n\nAwareness-raising among:\n\n\n\nthe general population\n\npeople at increased risk of hepatitis B and C infection.\n\n\n\nDeveloping the knowledge and skills of healthcare professionals and others providing services for people at increased risk of hepatitis B or C infection.\n\nTesting:\n\n\n\nin primary care\n\nin prisons and youth offender institutions\n\nin immigration removal centres\n\nin drugs services\n\nin genitourinary medicine and sexual health clinics.\n\n\n\nContact tracing.\n\nProviding and auditing neonatal hepatitis B vaccination.\n\nCommissioning hepatitis B and C testing and treatment services.\n\nLaboratory services for hepatitis B and C testing.\n\nThis guidance does not provide detail on treatments for hepatitis B or C. (For treatment recommendations see other NICE guidance listed in section 7.)\n\n# Who is this guidance for?\n\nThe guidance is for:\n\nCommissioners and providers of public health services, hepatitis testing and treatment services and laboratory services for hepatitis B and C testing.\n\nLocal organisations providing services for children and adults at increased risk of hepatitis B and C infection, including those in the NHS, local authorities, prisons, immigration removal centres and drugs services. It is also for voluntary sector and community organisations working with people at increased risk.\n\nThe guidance may also be of interest to groups at increased risk of viral hepatitis, for example, migrant populations from countries with an intermediate or high prevalence of hepatitis B or hepatitis C infection or people who inject drugs and their families. In addition, other members of the public may have an interest in this guidance.\n\n# Why is this guidance being produced?\n\nThe Department of Health (DH) asked the National Institute for Health and Clinical Excellence (NICE) to produce this guidance.\n\nThe guidance should be implemented alongside other guidance and regulations (for more details, see sections 4 and 7 on implementation and related NICE guidance respectively).\n\n# How was this guidance developed?\n\nThe recommendations are based on the best available evidence. They were developed by the Programme Development Group (PDG).\n\nMembers of the PDG are listed in appendix A.\n\nThe guidance was developed using the NICE public health programme process. See appendix B for details.\n\nSupporting documents used to prepare this document are listed in appendix E.\n\n# What evidence is the guidance based on?\n\nThe evidence that the PDG considered included: reviews of the evidence, economic modelling, the testimony of expert witnesses and stakeholder comments. Further detail on the evidence is given in the considerations section (section 3) and appendices B and C.\n\nIn some cases the evidence was insufficient and the PDG has made recommendations for future research.\n\nMore details on the evidence on which this guidance is based, and NICE's processes for developing public health guidance, are on the NICE website.\n\n# Status of this guidance\n\nThis is final guidance.\n\nThe guidance complements but does not replace other NICE guidance on hepatitis B and C (for further details, see section 7).", 'Recommendations ': "# Introduction\n\nThere has been a change in recommendation 7. See Changes after publication for details.\n\nThe evidence statements underpinning the recommendations are listed in appendix C.\n\nThe Programme Development Group (PDG) considers that the recommended measures and approaches are cost effective.\n\nFor the research recommendations and gaps in research, see section 5 and appendix D respectively.\n\n# Pre-requisites\n\nThe recommendations are based on the assumption that hepatitis B and C tests are provided according to current best practice and are offered as part of a care pathway covering diagnosis, treatment and immunisation.\n\n## Testing\n\nThe recommendations assume that:\n\nTesting facilities are equipped with sharps bins and follow advice on infection control and appropriate testing methods, particularly if testing is done outside healthcare settings.\n\nPeople being tested for hepatitis B and C are offered pre- and post-test discussions (see Box 1).\n\nTesting is undertaken with the person's consent.\n\nStandards for local surveillance are followed, including laboratory reporting to Public Health England centres and follow-up of hepatitis B and C.\n\nHave issues of confidentiality and anxiety been addressed?\n\nHas the offer been accompanied by an agreed mechanism for providing the result to the person being tested?\n\nHas the offer been phrased in a way that suits the person's age, culture and literacy level and is respectful and non-judgemental?\n\nHas the offer taken into account potential barriers to testing such as the stigma associated with hepatitis B and C or lack of access to services?\n\nHas the offer included information to enable people to make informed choices about their care should they test positive, and to reduce their risk of hepatitis B and C infection should they test negative?\n\nHas the offer been accompanied by details of support available for clinical and non-clinical needs, both while waiting for test results and following diagnosis?\n\n## Treatment\n\nNICE has recommended a number of drugs to treat hepatitis B and C and also has clinical guidelines in development on the diagnosis and management of hepatitis B and C (see section 7 for details). Guidance on managing co-infection with HIV-1 and hepatitis B or C is available from the British HIV Association. The European Association for the Study of the Liver (EASL) has published best practice guidelines on managing hepatitis B and hepatitis C.\n\n## Immunisation\n\nGuidance on hepatitis B vaccination is available in the Green book: immunisation against infectious disease and the Hepatitis B antenatal screening and newborn immunisation programme, both published by the Department of Health, and in the NICE guidance on Reducing the differences in the uptake of immunisations.\n\n# Whose health will benefit?\n\nIn the UK, the majority (95%) of new chronic hepatitis B infections occur in migrant populations, having been acquired perinatally in the country of birth. In contrast, approximately 90% of chronic hepatitis C infections are seen in people who inject drugs or have done so in the past.\n\nGroups at increased risk of hepatitis B compared with the general UK population include:\n\nPeople born or brought up in a country with an intermediate or high prevalence (2% or greater) of chronic hepatitis B. This includes all countries in Africa, Asia, the Caribbean, Central and South America, Eastern and Southern Europe, the Middle East and the Pacific islands.\n\nBabies born to mothers infected with hepatitis B.\n\nPeople who have ever injected drugs.\n\nMen who have sex with men.\n\nAnyone who has had unprotected sex, particularly:\n\n\n\npeople who have had multiple sexual partners\n\npeople reporting unprotected sexual contact in areas of intermediate and high prevalence)\n\npeople presenting at sexual health and genitourinary medicine clinics\n\npeople diagnosed with a sexually transmitted disease\n\ncommercial sex workers.\n\n\n\nLooked-after children and young people, including those living in care homes.\n\nPrisoners, including young offenders.\n\nImmigration detainees.\n\nClose contacts of someone known to be chronically infected with hepatitis B.\n\nFor hepatitis C, groups at increased risk include:\n\nPeople who have ever injected drugs.\n\nPeople who received a blood transfusion before 1991 or blood products before 1986, when screening of blood donors for hepatitis C infection, or heat treatment for inactivation of viruses were introduced.\n\nPeople born or brought up in a country with an intermediate or high prevalence (2% or greater) of chronic hepatitis C. Although data are not available for all countries, for practical purposes this includes all countries in Africa, Asia, the Caribbean, Central and South America, Eastern and Southern Europe, the Middle East and the Pacific islands.\n\nBabies born to mothers infected with hepatitis C.\n\nPrisoners, including young offenders.\n\nLooked-after children and young people, including those living in care homes.\n\nPeople living in hostels for the homeless or sleeping on the streets.\n\nHIV-positive men who have sex with men.\n\nClose contacts of someone known to be chronically infected with hepatitis C.\n\n# Recommendation 1 Awareness-raising about hepatitis B and C among the general population\n\n## Who should take action?\n\nCommissioners and providers of national public health services, for example Public Health England, working in partnership with:\n\nother government departments allied to health\n\nlocal commissioners and providers of public health services, including local authorities and health and wellbeing boards\n\nprimary and secondary care including genitourinary medicine and sexual health clinics\n\nthe commercial sector, national and local voluntary sector, not-for-profit and non-governmental organisations.\n\n## What action should they take?\n\nConduct awareness-raising campaigns, using campaign material and resources on hepatitis B and C. These should include up-to-date information on:\n\n\n\nthe main routes of infection and transmission\n\nhepatitis B vaccination\n\nthe benefits of early testing and treatment, including the role of earlier treatment in preventing serious illness such as chronic liver disease and liver cancer\n\nthe potential for chronic infection to be asymptomatic, particularly in the early stages.\n\n\n\nEnsure national and local awareness-raising campaigns address common misconceptions about the risk of hepatitis B and C that can act as a barrier to testing. This includes the belief that treatments are not effective, or that treatment is not needed until the illness is advanced. Campaigns should also make it clear that testing and treatment is confidential and address the stigma surrounding these infections.\n\nEnsure messages to raise awareness of hepatitis B and C are coordinated and integrated within other health promotion campaigns, where possible or appropriate.\n\nEnsure national and local awareness-raising activities take into account age, culture and religious beliefs of groups at increased risk, and their needs in relation to format and the language used. For example, the needs of people with low literacy level and learning disabilities, and people with little interaction with statutory services should be considered.\n\n# Recommendation 2 Awareness-raising for people at increased risk of hepatitis B or C infection\n\n## Who should take action?\n\nCommissioners and providers of national public health services, for example Public Health England and the NHS Commissioning Board.\n\nLocal authorities, in particular directors of public health.\n\nLocal organisations providing services for children and adults at increased risk of hepatitis B or C infection.\n\nOther local and national organisations that raise awareness of hepatitis, promote testing or provide treatment.\n\n## What action should they take?\n\nPublic Health England, the NHS Commissioning Board and directors of public health should facilitate partnership working to ensure there is a coordinated national and local programme of awareness-raising about hepatitis B and C among groups at increased risk.\n\nDirectors of public health should promote local testing and hepatitis B vaccination services.\n\nLocal and national organisations should provide awareness-raising material tailored to the needs of groups at increased risk. In addition to the information outlined in recommendation 1, this should:\n\n\n\ninform people how and where to access local testing and hepatitis B vaccination services\n\ndescribe what testing for hepatitis B and C involves\n\nexplain how a positive diagnosis can affect lifestyle.\n\n\n\nMaterial should:\n\n\n\naddress the needs of non-English-speaking groups at increased risk, for example, by providing translated information or information in audio or visual formats.\n\nbe culturally and age appropriate\n\naddress the needs of people with low literacy levels or learning disabilities.\n\n\n\nLocal organisations should encourage and support people from groups at increased risk who have been diagnosed with hepatitis B or C to contribute to awareness-raising activities (for further information see NICE guidance on Community engagement).\n\nLocal organisations should run awareness-raising sessions to promote hepatitis B and C testing in venues and at events popular among groups at increased risk. Examples of possible venues include: faith and cultural centres, NHS and non-NHS drugs services, GP surgeries, sexual health and genitourinary medicine services, immigration centres, hostels for the homeless, prisons and youth offender institutions.\n\nLocal and national organisations should consider offering testing for hepatitis B and C at awareness-raising sessions. If this is not possible, information on where and how to access testing locally should be provided.\n\n# Recommendation 3 Developing the knowledge and skills of healthcare professionals and others providing services for people at increased risk of hepatitis B or C infection\n\n## Who should take action?\n\nHealth Education England.\n\nPublic Health England.\n\nRoyal medical and nursing colleges.\n\nLocal authorities, in particular directors of public health.\n\nClinical commissioning groups.\n\nLocal education and training boards.\n\n## What action should they take?\n\nEnsure there is an ongoing education programme for professionals providing health and social care services for people at increased risk of hepatitis B or C infection. This includes:\n\n\n\nclinical and non-clinical staff in primary and secondary care including nurses, health visitors, midwives, healthcare assistants and support workers as well as staff in sexual health, genitourinary medicine and HIV clinics\n\npeople working in drugs services\n\nstaff in community-based criminal justice services\n\nsocial workers working with people at increased risk of hepatitis B or C infection\n\nstatutory and non-statutory staff working with looked-after children\n\nprison, youth offender and immigration removal centre staff\n\nstaff in voluntary and community organisations that care for or support migrant populations, people who inject drugs, people with HIV, or men who have sex with men\n\npeople working in hostels for the homeless and providing outreach services to homeless people.\n\n\n\nEnsure education programmes address the following core topics and are designed to meet the needs of the target group:\n\n\n\nincorporating the recommendations in national guidance to improve identification and testing of people at increased risk of hepatitis B and C infection\n\novercoming social and cultural barriers and improving access to testing and treatment for people at increased risk of hepatitis B and C infection\n\nreducing morbidity and mortality associated with hepatitis B and C through early detection and diagnosis\n\nimproving clinical management and quality of life for people diagnosed with hepatitis B and C infection and reducing the number of people admitted to secondary and tertiary care with hepatitis B- and C-related morbidity, for example, liver disease.\n\n\n\nEnsure training programme content is accurate and up-to-date, reflecting advances in testing, diagnosis and treatment of hepatitis B and C.\n\nThink about linking awareness-raising activities with existing education for health and social care professionals. This could take a variety of forms, for example, it could be offered as a taught or an electronic learning module.\n\nLocal education and training boards in each region should ensure that people involved in testing for hepatitis B and C take part in a programme of continuing professional development.\n\nDirectors of public health should ensure all healthcare and public health managers, in collaboration with the local education and training board, use staff annual appraisals and personal development plans to reinforce training and education on hepatitis B and C.\n\n# Recommendation 4 Testing for hepatitis B and C in primary care\n\n## Who should take action?\n\nGPs and practice nurses.\n\nAntenatal services.\n\nLocal community services serving migrant populations.\n\n## What action should they take?\n\nGPs and practice nurses should offer testing for hepatitis B and C to adults and children at increased risk of infection, particularly migrants from medium- or high-prevalence countries and people who inject or have injected drugs (see Whose health will benefit?).\n\nGPs and practice nurses should offer testing for hepatitis B and C to people who are newly registered with the practice and belong to a group at increased risk of infection (see Whose health will benefit?).\n\nGPs and practice nurses should ask newly registered adults if they have ever injected drugs, including image and performance enhancement substances at their first consultation.\n\nGPs and practice nurses should offer hepatitis B testing and vaccination to men who have sex with men who are offered a test for HIV and have not previously tested positive for hepatitis B antibodies (see NICE guidance on Increasing the uptake of HIV testing among men who have sex with men).\n\nGPs and practice nurses should offer hepatitis B vaccination to people who test negative for hepatitis B but remain at increased risk of infection (see the Green book).\n\nGPs and practice nurses should offer annual testing for hepatitis C to people who test negative for hepatitis C but remain at increased risk of infection.\n\nGPs and practice nurses should ensure people diagnosed with hepatitis B or C are referred to specialist care.\n\nLocal community services serving migrant populations should work in partnership with primary care practitioners to promote testing of adults and children at increased risk of infection. This should include raising awareness of hepatitis B and C, promoting the availability of primary care testing facilities and providing support to access these services.\n\nStaff providing antenatal services, including midwives, obstetricians, practice nurses and GPs, should ask about risk factors for hepatitis C during pregnancy and offer testing for hepatitis C to women at increased risk. Women who are diagnosed with hepatitis C should be offered hepatitis A and B vaccination in line with the Green book.\n\n# Recommendation 5 Testing for hepatitis B and C in prisons and immigration removal centres\n\n## Who should take action?\n\nPrison healthcare services, including services for young offenders.\n\nImmigration removal centre healthcare services.\n\nSecondary care services that provide treatment for hepatitis B and C.\n\nPublic Health England centres.\n\n## What action should they take?\n\nPrison and immigration removal centre healthcare services should develop a policy on testing for hepatitis B and C with local partners, including secondary care services that provide treatment, the Public Health England centre, and commissioners of prison and immigration removal centre healthcare services.\n\nPrison and immigration removal centre healthcare services should designate a member of staff as the hepatitis lead in every prison, young offender service and immigration removal centre. The lead should have the knowledge and skills to promote hepatitis B and C testing and treatment and hepatitis B vaccination. Consideration should be given to training peer mentors and health champions from the prison and immigration removal centre populations to support this work.\n\nThe NHS lead for hepatitis treatment (for example, a community hepatitis nurse) should develop a care pathway for prisoners and immigration detainees with diagnosed hepatitis B or C. This should be developed in conjunction with prison or immigration removal centre healthcare services (including commissioners), local drugs services and the Public Health England centre. The care pathway should ensure:\n\n\n\npeople with diagnosed hepatitis B and C should be referred to, and managed by, the local hepatitis treatment services, in liaison with prison or immigration removal centre healthcare services\n\ninvestigations and follow-up should be undertaken in the prison or immigration removal centre, if possible\n\nprisoners and immigration detainees with hepatitis B and C should be treated in the prison or immigration removal centre, using in-reach services involving local specialist secondary care providers or the prison or immigration removal centre healthcare team. The prison or immigration removal centre should support this, for example, by giving security clearance to healthcare staff.\n\n\n\nPrison and immigration removal centre healthcare services (coordinated with and supported by the NHS lead for hepatitis) should ensure that:\n\n\n\nall prisoners and immigration detainees are offered hepatitis B vaccination when entering prison or an immigration removal centre (for the vaccination schedule, refer to the Green book)\n\nall prisoners and immigration detainees are offered access to confidential testing for hepatitis B and C when entering prison or an immigration removal centre and during their detention\n\nprisoners and immigration detainees who test for hepatitis B or C receive the results of the test, regardless of their location when the test results become available\n\nresults from hepatitis B and C testing are provided to the prisoner's community-based GP, if consent is given\n\nall prison and immigration removal centre staff are trained to promote hepatitis B and C testing and treatment and hepatitis B vaccination (see recommendation 3).\n\n\n\nPrison services should have access to dried blood spot testing for hepatitis B and C for people for whom venous access is difficult.\n\nThe NHS lead for hepatitis treatment in prisons should ensure continuity of hepatitis treatment through contingency, liaison and handover arrangements before the prisoner release date, or before any prisoner or immigration detainee receiving hepatitis treatment is transferred between prisons or removal centres. Once a prisoner has started treatment, it may be helpful to put them on medical hold to ensure continuity of care (which might be compromised by transfer between prisons). Planning should involve NHS, prison and immigration removal centre healthcare services and other agencies working with prisoners or detainees.\n\n# Recommendation 6 Testing for hepatitis B and C in drugs services\n\n## Who should take action?\n\nDrugs services, including drug and alcohol action teams.\n\nCommissioners of hepatitis testing and treatment services, including local authorities and clinical commissioning groups.\n\nSecondary care services that provide treatment for hepatitis B and C.\n\nPublic Health England centres.\n\n## What action should they take?\n\nCommissioners of hepatitis testing and treatment services should agree local care pathways for people with hepatitis B and C who use drugs services. If possible, the pathway should include provision of hepatitis C treatment services in the community.\n\nDrugs services should designate a hepatitis lead for the service. The lead should have the knowledge and skills to promote hepatitis B and C testing and treatment and hepatitis B vaccination. Consideration should be given to training peer mentors and health champions from the drugs service to support this work (for further information see NICE guidance on Community engagement).\n\nDrugs services should have access to:\n\n\n\ndried blood spot testing for hepatitis B and C for people for whom venous access is difficult\n\nspecialist phlebotomy services in order to encourage hepatitis C treatment in the community, particularly for people who inject drugs.\n\n\n\nDrugs services should:\n\n\n\noffer hepatitis B vaccination to all service users in line with the Green book.\n\noffer and promote hepatitis B and C testing to all service users\n\noffer annual testing for hepatitis C to people who test negative for hepatitis C but remain at risk of infection\n\nensure people diagnosed with hepatitis B and C are referred for specialist care; for hepatitis C this may involve offering hepatitis C treatment in the community for people who are unwilling or unlikely to attend hospital appointments, and whose hepatitis C treatment could be integrated with ongoing drug treatment (such as opiate substitution treatment)\n\nensure staff have the knowledge and skills to promote hepatitis B and C testing and treatment (see recommendation 3)\n\nensure staff who undertake pre- and post-test discussions and dried blood spot testing are trained and competent to do so\n\nprovide information to women with hepatitis C about the importance of testing in babies and children born after the woman acquired infection\n\nprovide information to injecting drug users about the importance of hepatitis B vaccination for sexual partners and children (see the Green book).\n\n\n\n# Recommendation 7 Testing for hepatitis B and C in sexual health and genitourinary medicine clinics\n\n## Who should take action?\n\nCommissioners of hepatitis testing and treatment services, including local authorities and clinical commissioning groups.\n\nSexual health and genitourinary medicine clinics.\n\n## What action should they take?\n\nCommissioners of hepatitis testing and treatment services should agree local care pathways for people with hepatitis B and C who use sexual health and genitourinary medicine clinics.\n\nSexual health and genitourinary medicine clinics should:\n\n\n\noffer hepatitis B vaccination to all service users in line with the Green book\n\noffer and promote hepatitis B and C testing to all service users at increased risk of infection, including people younger than 18\n\nensure people diagnosed with hepatitis B or C are referred for specialist care\n\nensure staff have the knowledge and skills to promote hepatitis B and C testing and treatment (see recommendation 3)\n\nensure staff who undertake pre- and post-test discussions are trained and competent to do so.\n\n\n\n# Recommendation 8 Contact tracing\n\n## Who should take action?\n\nPublic Health England centres.\n\nPrimary care practitioners.\n\n## What action should they take?\n\nPublic Health England centres should:\n\n\n\ntake overall responsibility for tracing the close contacts of people with confirmed acute and chronic hepatitis B infection\n\nadvise and oversee the activities of other local organisations undertaking contact tracing, such as GP surgeries and genitourinary medicine clinics, to ensure the national standards for local surveillance and follow-up of hepatitis B and C are met. For example, GPs may need to offer close contacts hepatitis B vaccination and refer for treatment.\n\n\n\nPrimary care practitioners should promote the importance of hepatitis C testing for children who may have been exposed to hepatitis C at birth or during childhood.\n\n# Recommendation 9 Effective delivery and auditing of neonatal hepatitis B vaccination\n\n## Who should take action?\n\nDirectors of public health.\n\nPublic Health England.\n\n## What action should they take?\n\nDirectors of public health should ensure existing recommendations on hepatitis B prophylaxis for babies born to mothers with chronic hepatitis B infection are implemented locally by general practitioners, as described in the Green book.\n\nPublic Health England should audit the hepatitis B vaccination programme for babies. The audit should note how many children received vaccines, whether vaccinated children were given all doses and if not how many doses they received, whether doses were given on schedule, whether babies were tested after completing the vaccination course and the rate of vaccination failure. This audit should be carried out annually and deficiencies addressed.\n\n# Recommendation 10 Commissioning locally appropriate integrated services for hepatitis B and C testing and treatment\n\n## Who should take action?\n\nLocal authorities, in particular directors of public health and clinical commissioning groups\n\nCommissioners of hepatitis testing and treatment services.\n\n## What action should they take?\n\nLocal authorities, in particular directors of public health and clinical commissioning groups should ensure the inclusion of hepatitis B and C in the health and wellbeing board's joint strategic needs assessment. This should provide information on local prevalence of chronic hepatitis B and C and groups at increased risk, including by country of origin or risk behaviour.\n\nCommissioners should encourage the development of locally enhanced services for hepatitis B and C in areas where there is a higher than average number of people at increased risk (especially areas with a large migrant population or high prevalence of people who inject drugs).\n\nCommissioners should regularly undertake a health needs assessment, health equity audit and an audit of hepatitis B and C services as part of the agreed local care pathway and commission testing and treatment services accordingly.\n\nCommissioners should ensure mechanisms are in place for following up patients who defer treatment.\n\nCommissioners should audit the uptake of testing and outcomes, including:\n\n\n\nthe number of people tested for hepatitis B and C\n\nthe number of people diagnosed with hepatitis B and C\n\nthe number of people with chronic infection who:\n\n\n\nare referred to a treatment service\n\nattend a treatment service\n\nare receiving treatment in accordance with treatment guidelines\n\n\n\nthe number of people with hepatitis C who obtain a sustained virological response on antiviral therapy.\n\n\n\nCommissioners should develop and commission a fully integrated care pathway, working with services that provide hepatitis B and C testing and treatment in primary and secondary care (in the community or specialist services in hospital). This should:\n\n\n\ntake into account the needs of people who test positive for hepatitis B or C infection and are assessed for treatment, including their broader health and psychosocial needs\n\nconsider all venues where testing and treatment services are, or could be offered that can also ensure continuity of care and onward referral to specialist treatment for people who test positive (such as pharmacy testing and outreach testing and treatment)\n\nensure primary and secondary care staff are educated and trained in hepatitis B and C testing and treatment (see recommendation 3).\n\n\n\n# Recommendation 11 Laboratory services for hepatitis B and C testing\n\n## Who should take action?\n\nCommissioners of laboratory services for hepatitis B and C testing.\n\n## What action should they take?\n\nEnsure that samples are transported from patients to laboratories within 24 hours (adjusted for weekends and bank holidays as necessary)\n\nEnsure service specifications specify that laboratory services providing hepatitis B and C testing:\n\n\n\nhave Clinical Pathology Accreditation (UK)\n\ncan support the range of samples used for hepatitis B and C testing (for example, dried blood-spot or venepuncture samples) or can refer the sample to a laboratory which can perform these tests\n\nautomatically test samples that are positive for hepatitis C antibody for the presence of hepatitis C virus (for example, using a polymerase chain reaction [PCR] assay), or refer the sample to a laboratory which can perform this test\n\ncan deliver results within 2 weeks of the sample being received\n\nensure local Public Health England centres are notified of cases of hepatitis B and C infection, in line with national public health legislation\n\nprovide the organisation or professional requesting a test with an accurate interpretation of the laboratory results and guidance on future management of confirmed cases, such as onward referral to specialist care.\n\n\n\nEnsure laboratory services provide accurate data on the following:\n\n\n\nthe number of people tested and the type of test performed\n\nthe referral source of samples (for example, primary care, secondary care, drug and alcohol services, prisons)\n\nexposure category, if provided\n\nthe number of people testing positive:\n\n\n\nfor hepatitis B, this should include acute, chronic and past infection\n\nfor hepatitis C, this should include PCR positive/current and PCR negative/resolved.\n\n\n\n\n\n NICE has accredited the process used by the British HIV Association to produce UK national guidelines. Accreditation is valid for 5 years from 12 July 2012 and is applicable to guidance produced since 2011. The NICE Accreditation Scheme recognises organisations that demonstrate high standards in producing health or social care guidance. Users of the accredited guidance can therefore have high confidence in the quality of the information.\n\n Guidance produced by EASL has not been reviewed by the NICE Accreditation Scheme. EASL guidelines may assist healthcare providers in the clinical decision-making process by describing a range of generally accepted approaches for diagnosing, treating and preventing hepatitis B and C. However, it should be ensured that action taken is in line with NICE guidance.", 'Public health need and practice': "Chronic hepatitis B and C are the leading cause of liver disease worldwide (Perz 2006), and the second most common cause of liver disease in the UK, after alcohol.\n\n# Hepatitis B\n\nThe hepatitis B virus is transmitted perinatally from mother to child and through contact with infected blood. Some individuals clear hepatitis B infection naturally, whereas others develop a chronic infection that can result in severe liver disease. Rates of progression from acute to chronic infection vary according to age at the time of exposure. About 85% of hepatitis B infections in newborns become chronic compared with 4% in adults (Edmunds et al. 1993).\n\nIt has been estimated that 95% of people with new chronic hepatitis B in the UK are migrants, most of whom acquired the infection in early childhood in the country of their birth (Hahné et al. 2004). The remaining 5% of people with chronic hepatitis B acquired the infection in the UK, either through vertical transmission from mother to child or through exposure between adults. Migrant populations are therefore the main focus for hepatitis B case-finding in the UK, and infection in childhood is the major route of transmission. Other key risk groups for hepatitis B infection are described in Whose health will benefit?\n\nThere is considerable uncertainty about the number of people with chronic hepatitis B in the UK. In 2002 the Department of Health estimated that chronic hepatitis B affects 180,000 people in the UK (Department of Health 2002). Information on the burden of hepatitis B in England and Wales is derived from a number of sources:\n\nlaboratory reports of confirmed acute and chronic infections\n\nserological studies of populations covered by screening programmes (that is, pregnant women and blood donors)\n\nserological studies of populations at high risk (for example, people who inject drugs)\n\nsentinel laboratory surveillance of people being tested\n\nestimates of the size of the migrant population.\n\nIn 2011, 589 acute or probable acute cases of hepatitis B were reported in England (Health Protection Agency 2012). The total number of acute infections will be greater than the number reported. The most recent study to estimate the annual incidence of hepatitis B in England and Wales was conducted between 1995 and 2000 (Health Protection Agency, Hahné et al. 2004). It estimated the annual incidence of hepatitis B, from laboratory reports, to be around 7.4 per 100,000 people. This translates into around 3700 acute infections per year and around 270 cases of chronic hepatitis B per year. Information about risk factors was available for about 50% of the acute cases. The most common reported risk was heterosexual exposure, followed by homosexual exposure. In comparison, fewer than 5% of cases were attributed to injecting drug use. The decline in the number of cases linked to injecting drug use is supported by the 2011 Unlinked Anonymous Monitoring (UAM) survey, which reported a fall in the proportion of injecting drug users who had ever been infected with hepatitis B, from 28% in 2001 to 16% in 2011 (Health Protection Agency 2011c). This decrease is probably associated with an increase in the uptake of hepatitis B vaccination (Judd et al. 2007; Hope et al. 2007). According to the UAM survey, self-reported rates of hepatitis B vaccination increased from 35% in 2000 to 76% in 2011 (Health Protection Agency 2011c).\n\n## Antenatal screening\n\nA national antenatal screening programme for hepatitis B surface antigen (HBsAg) began in 2000 (Health Protection Agency 2011a). Uptake of screening during pregnancy has increased over time (up to 97% in 2011), but the proportion of women who test positive has remained stable (0.42% in 2011).\n\nThe sentinel surveillance programme identified that 28.5% (73,290) of women who had been tested for HBsAg in 2011 were tested through antenatal screening. Overall, 0.5% of the women tested in the antenatal programme tested positive. Most of the 73,290 women in the study were white or white-British. More black or black-British women (3.9%) and women from 'other' or mixed ethnicity (3.8%) tested positive for HBsAg compared with their Asian/Asian-British (0.5%) and white counterparts (0.3%).\n\n# Hepatitis C\n\nHepatitis C is a blood-borne viral infection transmitted through contact with infected blood. In the UK, hepatitis C is primarily acquired through injecting drug use. Approximately 70–75% of people who are infected with acute hepatitis C develop a chronic condition that can result in liver failure and liver cancer.\n\nThe most recent national estimate suggests that around 216,000 people in the UK have chronic hepatitis C (Health Protection Agency 2012; Scottish Executive 2008). Of these, around 160,000 live in England (Harris 2012a). Injecting drug use is the main route of hepatitis C infection in England. Of the estimated number of people who are chronically infected, around 87% are current or past injection drug users. Of the remaining 13%, 6% are of South Asian descent and the other 7% are of white/other ethnicity (Harris et al. 2012a). Similarly, 90% of the total laboratory reports including risk information in the UK in 2010 attributed infection to injecting drug use (Health Protection Agency 2011c). The main focus for hepatitis C case-finding is therefore people who inject or have injected drugs. There is good evidence that HIV-positive men who have sex with men are at increased risk of hepatitis C infection, and British HIV Association guidelines recommend regular hepatitis C testing in this group. Emerging evidence suggests that people who inject image- and performance-enhancing drugs are also at increased risk of hepatitis C infection.\n\nIn England, more than 95,000 individuals had been diagnosed with hepatitis C by the end of 2011, suggesting that a significant number of infections remain undiagnosed. Hospitalisations, registrations for liver transplant and deaths from liver cancer due to hepatitis C are steadily increasing throughout the UK. In England, rates of end-stage liver disease caused by hepatitis C are likely to increase if diagnosis and treatment rates do not improve (Health Protection Agency 2012).\n\nThe prevalence of chronic disease in current and past drug users varies by region, and is highest in London and the North West (Harris et al. 2012). An analysis of the 2010 UAM survey of people who inject drugs and attend specialist services estimated the overall prevalence of hepatitis C antibodies (indicating exposure to the virus) to be 43%, but ranging from 14% to 82% in different geographical sites (Harris et al. 2012b). Data from the UAM survey also suggest that over 83% of people surveyed had a voluntary test for hepatitis C in 2010, compared with 40% in 2000. However, only about half were aware they were hepatitis C antibody positive when comparing self-reported data with anonymous test results (Health Protection Agency 2011b).\n\n# National recommendations\n\nThe national hepatitis B immunisation programme recommends that people from at-risk groups are immunised against hepatitis B. Post-exposure immunisation (which may include hepatitis B immunoglobulin as well as hepatitis B vaccine) is also recommended for babies born to chronically infected mothers (Department of Health 2006).\n\nNICE recommends a number of treatments for hepatitis B and hepatitis C (see section 7). Early diagnosis and treatment can clear infection and reduce the risk of long-term complications, such as cirrhosis and liver cancer. For people with chronic hepatitis C, early therapy is associated with increased and sustained virological response rates (Foster et al. 2010).", 'Considerations': "The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.\n\n# Awareness-raising\n\nThe PDG felt that awareness-raising in the general population was a very important issue. While it was always intended that the guidance would make specific recommendations for awareness-raising in professionals and in populations at increased risk, the group decided that it would also be helpful to raise awareness generally.\n\nThe PDG was aware of the potential benefit of educating all healthcare professionals about hepatitis B and C but was pragmatic in its approach, focusing on those who were likely to be providing services to people at increased risk of infection.\n\nRecent developments in the treatment of hepatitis B and C are not reflected in the qualitative literature on the barriers and facilitators to testing. This is because much of the research was undertaken before the newer drugs (see section 7) were available. The Group felt that awareness of more effective treatments may have a positive impact on the uptake of testing.\n\nThe need for awareness-raising and training on hepatitis C for healthcare professionals was a key theme in the qualitative review, and was in accord with PDG members' experiences. The Group heard reports of people with hepatitis C having to ask for testing for viral hepatitis and liver function and being left with misinformation and confusion about their diagnosis, its consequences and treatment pathways. The Group felt it important that professionals working in this area had the ability to help people make informed choices.\n\nThe PDG considered there was a need for targeted education programmes for health and social care professionals, such as those produced by Hepatitis Scotland and the Royal College of General Practitioners (RCGP). An outline of requirements on Hepatitis C workforce education development (NHS Education for Scotland 2010) has been produced as part of the Hepatitis C Action Plan for Scotland (Scottish Executive 2006, 2008). The RCGP programme is aimed at generalist clinicians such as GPs and nurses working in primary care, and covers detection, diagnosis and management of hepatitis B and C in primary care.\n\nThe PDG felt education programmes might cover, depending on the role of the health and social care professional, some or all of the following:\n\nepidemiology, public health impact and clinical consequences of hepatitis B and C infection\n\nrisk factors for hepatitis B and C and population groups at increased risk of infection\n\ndetection and diagnosis of hepatitis B and C\n\nfactors to consider in a pre- and post-test discussion and how these discussions should be conducted\n\nthe importance of repeat testing and harm reduction interventions for people who remain at risk of infection, including hepatitis B vaccination\n\nsocial and cultural barriers to testing and treatment (for example, stigma)\n\nlocal testing, treatment and referral pathways\n\nthe main features of treatment for hepatitis B and C, in line with current best practice guidelines\n\ntests used to monitor liver health\n\nthe benefits and risks of current treatment options, including their effectiveness, adverse events and barriers and facilitators to treatment adherence.\n\n# Barriers and facilitators\n\nThere are many barriers to testing for hepatitis B and C for groups at increased risk of infection and many are similar for both infections. They include:\n\nFear of being stigmatised, whether by healthcare professionals, sexual partners, family or friends.\n\nKnowledge and awareness in relation to the transmission of infection and the treatments available. The PDG was aware of a general lack of knowledge about hepatitis B and C, including among people promoting tests for these infections. Members felt that this contributed to the low uptake of testing among people at increased risk of infection and to the stigma surrounding these infections. It was noted that lack of awareness among people at increased risk of infection may result from lack of access to statutory services.\n\nParental fears that they will not be able to cope with the issues their child may face if the child is found to have hepatitis B or C. (This is especially the case if appropriate information and care pathways have not been discussed with parents.)\n\nPeople who have injected drugs in the past may not want to disclose drug-using history. This may be a barrier to hepatitis B and C testing and treatment. The PDG felt that positive messages about the effectiveness of treatment and attempts to 'normalise' testing might help reach these people.\n\nThe PDG was keen for the guidance to convey the improvement in health outcomes associated with early identification of hepatitis C in people for whom treatment is indicated. However, they acknowledged that personal circumstances may influence the timing of testing, and that economic, social or other health needs may be a higher priority for some people.\n\nThe PDG recognised the important role that family, partners and friends may play in encouraging people to get tested and complete treatment. The Group also recognised a role for the peers of people at increased risk in promoting hepatitis B and C testing and supporting people who are diagnosed positive.\n\nThe PDG noted that it was important to ensure people are not stigmatised by the way information on hepatitis B and C is delivered.\n\nThe PDG was mindful that combining awareness-raising\xa0campaigns for hepatitis B and C with other health promotion campaigns, such as those for HIV, may risk\xa0alienating some populations at increased risk. For example, the PDG was made aware that some migrant populations are unlikely to engage with a campaign that associates hepatitis B with sexually transmitted infection. The need to target awareness-raising campaigns to different audiences was felt to be of considerable importance to the PDG.\n\nTransmission of hepatitis B from mother to child may be considered normal among some minority ethnic communities. Although this suggests there is less stigma associated with infection among these communities, the Group felt that acceptance of infection may adversely impact on the uptake of testing and treatment. It noted a lack of qualitative evidence about this route of transmission, suggesting a lack of awareness and the need for preventive education.\n\nEmployment-based screening and subsequent discrimination against workers who test positive for hepatitis B in countries where there is a high prevalence of hepatitis B may discourage voluntary testing among migrants from those countries.\n\nThe PDG noted that people who inject drugs and have hepatitis C could be stigmatised by the injecting drug community, as a diagnosis of hepatitis C suggests a history of sharing injecting equipment.\n\nThe PDG was mindful that offering universal testing in certain settings may help reduce the stigma associated with hepatitis B and C.\n\nAccess to dried blood spot testing or a specialist phlebotomist can reduce pain and embarrassment associated with the difficulties of taking blood samples from people with poor vascular access – typically associated with long-term injecting or poor injecting technique.\n\nThe PDG discussed the need to train all healthcare staff who are involved in hepatitis testing to carry out pre- and post-test discussions with people at increased risk of hepatitis B and C infection.\n\nThe PDG were mindful of the sensitivities of discussing people's sexuality and potential sexual exposure to hepatitis B or C.\n\n# Testing\n\nThe PDG noted the importance of all blood samples that test positive for hepatitis C antibody being routinely tested for hepatitis C virus, for example, by PCR. In addition, further consideration of and research on the use of PCR for initial testing in current injecting drug users, with follow-up antibody testing for people who test PCR positive, may be warranted to enable rapid diagnosis of recent infections.\n\nWhile venepuncture samples remain the gold standard, the PDG noted that dried blood spot tests for hepatitis B and C have a high test sensitivity and specificity and can be useful in certain settings for people with poor venous access and where there may be no facilities or expertise to take venous blood samples (for example, in specialist drug treatment services or prisons).\n\nThe PDG recognised that the use of dried blood spot testing for diagnosis may be more acceptable to some of the target populations than taking a blood sample from a vein, especially if there is poor venous access or the person is needle phobic. In addition, more staff would probably be able to carry out such tests, so helping to increase the number of people who are tested. The PDG noted the success of the Scottish Hepatitis C Action Plan\xa0in place since 2008 (Scottish Executive 2006, 2008). Preliminary evidence from this programme suggests that hepatitis C testing in specialist drug clinics increased after the introduction of dried blood spot testing and wide-scale training of healthcare workers in hepatitis C.\n\nThe PDG recognised that oral fluid testing may be more acceptable to some people because it is less invasive than taking blood from a vein, but that oral fluid testing has a lower sensitivity and specificity than tests for hepatitis B and C performed on blood. If an oral fluid sample was used, a blood sample would then be needed to confirm the initial positive results, and for PCR testing to diagnose chronic hepatitis C.\n\nThe PDG acknowledged that different populations are at increased risk of hepatitis B and C. However, there is some overlap between them, and it would simplify delivery if testing for both infections at the same time was recommended in people who are at increased risk of either.\n\nThe PDG felt that the point of entry into a hepatitis B vaccination programme also provides an opportunity to offer testing to people considered to be at increased risk for hepatitis B and C infection.\n\nThe Group was aware of cases where people had repeatedly been vaccinated against hepatitis B (for example in the prison setting) but not tested for infection, and had later been found to have chronic infection and subsequent liver damage. Nonetheless, the PDG felt that it is important for testing to be offered after vaccination, so as not to impede the success of the vaccination programme.\n\nIn line with the Green book, the PDG felt that drug services should offer hepatitis B vaccination to all service users who inject or have injected drugs and people with a risk of progression to injecting, for example people who are currently smoking heroin and/or crack cocaine, and heavily dependent amphetamine users, as well as non-injecting users who are living with current injectors.\n\nThe PDG felt that despite the focus of this guidance on primary and secondary care there may be a role for routine testing for hepatitis B and C in some tertiary clinical services (such as liver clinics, haemodialysis, rheumatology, cancer and fertility services) and as such staff should have access to appropriate training and a role in awareness-raising. The PDG was aware that evidence regarding the effectiveness of routine testing in tertiary clinical services has not been adequately considered in the development of this guidance, but felt this area should be acknowledged.\n\nThe PDG felt that there may be merit in commissioners considering a range of venues for hepatitis B and C testing in order to improve accessibility. Mechanisms would need to be in place to ensure access to laboratory testing services, delivery of results and referral of people who test positive into the care pathway. In addition, venues would need to ensure adequate measures were taken to ensure infection control and privacy. The PDG acknowledged that there is encouraging evidence from pilot schemes where community pharmacists provide dried blood spot testing for hepatitis. Although the evidence is not strong enough to uniformly recommend that all community pharmacists provide this service, the PDG felt that it would be worthwhile considering extending pilot programmes. This extension could be considered for pharmacists already engaged with people at increased risk of hepatitis B and C, such as pharmacists providing needle exchange and NHS health checks.\n\nThe PDG noted that abnormal liver function tests, such as raised ALT (alanine aminotransferase) can occur for a variety of reasons (for example, as a consequence of alcohol consumption and fatty liver, or use of statins). In primary care there is a requirement to investigate the cause of an abnormal liver function test, including testing for hepatitis. In secondary care, however, hepatitis tests should only be conducted if the cause of an abnormal liver function test is not known.\n\nActive contact tracing for people who test positive for hepatitis C is not recommended, given low transmission rates to both sexual and household contacts. The PDG acknowledged that it would be sensible to discuss with people who test positive whether any of their contacts may have been exposed to infection, including the children of mothers with hepatitis C infection. Testing of identified contacts would be offered at clinical discretion.\n\n# Limitations of the evidence\n\nThere was little published evidence on effective or cost-effective interventions to promote and offer testing to people at increased risk of hepatitis B. There was also a lack of corresponding evidence for interventions addressing hepatitis C testing among migrants. The PDG, therefore, largely drew on economic modelling and other evidence presented to the PDG in order to formulate the recommendations.\n\nThe PDG was concerned about people who have previously injected drugs but are no longer doing so, and other groups at increased risk, because there was limited evidence on how to reach them effectively. This includes, for example, commercial sex workers and men who have sex with men. The group felt that the principles of the recommendations may apply to these groups.\n\nThe mapping review provided limited evidence of existing good practice on testing among people at increased risk of hepatitis B and C in England. The Hepatitis C Action Plan for Scotland, however, does provide a model for improving testing and treatment for hepatitis C (Scottish Executive 2006, 2008).\n\nThe PDG recognised the potential risk of hepatitis C transmission among people who inject performance and image-enhancing drugs (PIEDs) such as anabolic steroids (for non-medical reasons). However, there is a lack of published evidence on the extent of risk in this group or on their contribution to overall hepatitis C prevalence.\n\nThe PDG recognised and understood the potential risks associated with the transmission of hepatitis C via sharing straws to snort drugs (in theory, if nasal passages were bleeding a straw could transfer infected blood to others using the same straw), but there was a lack of strong biological evidence on which to base recommendations. The key risk was considered to be through sharing injecting equipment.\n\nThe PDG noted a lack of evidence specific to the role of peer support in promoting the uptake of testing and treatment for hepatitis B and C. Evidence of its positive effect on attitudes, knowledge and behavioural practices relating to prisoners' sexual health was considered. Based on this evidence, the PDG considered it logical that peer support could be beneficial for the groups of interest identified in the guidance.\n\n# Economic modelling\n\nThe way hepatitis B and C are transmitted among different groups at greatest risk varies by group. For example, in the UK 90% of hepatitis C infections are attributed to sharing injecting equipment among people who inject drugs. Among migrant groups from medium- and high-prevalence countries, adult-to-adult transmission of hepatitis B within the UK is responsible for only about 5–10% of chronic cases. The main transmission routes for hepatitis B are from mother to baby and between children through exposure to contaminated blood. The majority of chronic infections of hepatitis B are acquired in the country of origin. The modelling analyses took these differences into account.\n\nThere was a lack of data on interventions to increase rates of case-finding and treatment in prison, and on continuity of treatment from prison into the community. This meant it was difficult to judge the cost effectiveness of such interventions and treatment rates following diagnosis. Modelling showed that if continuity of treatment (for a prisoner deemed appropriate for treatment) between prisons, from outside to inside prison, or from inside prison to release is at least 40% of the treatment rate of people diagnosed in the community then the treatment would be estimated to be cost effective.\n\nThe migration modelling was also severely hampered by lack of data on the prevalence of chronic hepatitis B among minority ethnic groups, the cost of finding infected people within these groups and treatment rates. Nevertheless, modelling showed that provided that the prevalence of chronic hepatitis B in migrants from minority ethnic groups was at least 2%, then it was estimated that it would be cost effective to find, test and treat within such communities.\n\nThe cost effectiveness of primary care interventions to promote testing for hepatitis B and hepatitis C among men who have sex with men was not formally evaluated.\xa0The PDG acknowledged the existence of other NICE guidance promoting testing for HIV among this group. Modelling for that guidance showed that, where there is a reasonably high prevalence of undiagnosed cases of hepatitis B and C, adding a test for these infections when testing for HIV would be cost effective.\n\nThe PDG discussed the possibility of testing all people between the ages of 40 and 65 or 70 for hepatitis C infection. Three recent studies have been carried out in the USA to estimate the cost effectiveness of hepatitis C screening in several different cohorts of people born between 1945 and 1975 (that is, people who were between 37 and 67 years of age in 2012). These studies estimate that such testing would be cost effective, and have led to a recommendation for cohort testing in the USA. The PDG was aware that it was not possible in the time available to carry out modelling for an equivalent cohort in England. The PDG does note, however, that the estimated prevalence of chronic hepatitis C infection in England for that part of the population that does not currently inject drugs would be substantially lower than the 1.6% assumed for the US cohort (Harris et al. 2012). This suggests that a comprehensive testing programme for people born between 1945 and 1975 is unlikely to be cost effective if it were carried out independently of other programmes.\n\nThe PDG discussed the possibility of linking a cohort testing programme for hepatitis C to the Health Check programme currently being introduced for people between 40 and 70 years in England. However, given that a potential extension of the Health Check programme had not been mentioned in the draft guidance sent for consultation, and that there was uncertainty about whether cohort testing offered as part of the Health Check programme would be cost effective, the PDG believed that it would be preferable to wait for more information before making a substantive recommendation in this area.\n\n# Prisons\n\nThe PDG noted a lack of evidence on interventions to promote testing for hepatitis B and C in specific settings, for example, prisons. Expert testimony was sought to address these gaps.\n\nGiven the prevalence of hepatitis B and the history of injecting drug use among the prison population, the PDG recognised the importance of prison as a setting for promoting and offering hepatitis B and C vaccination and testing. It also acknowledged that the established hepatitis B vaccination programme in prisons provides an opportunity for discussing the benefits of testing. The PDG felt testing should be offered in prisons after vaccination, so as not to hamper the success of the vaccination programme.\n\nThe PDG was aware of problems with transferring medical records and information between prison and community settings. However, it was beyond the remit of this guidance to make recommendations about sharing health data between custodial and community providers.\n\nThe PDG recognised the barriers to continuity of care when someone enters or is released from prison. However, the Group felt that these barriers should not prevent testing for hepatitis B and C being offered to prisoners.\n\nTesting for hepatitis C in prisons, with prisoners' informed consent, is cost effective if there is continuity of care when someone who is infected is referred to, from or between prisons and treatment is at least 40% of the treatment rate of people diagnosed in the community. The PDG felt that prison testing would also help ensure that prisoners' right to the same access to healthcare as the general population would be met, and so address health inequalities.\n\nThe PDG was aware that a key factor affecting treatment outcomes was the length of someone's remaining stay in prison following diagnosis – many prisoners only live at one site for short periods of time, for example when on remand.\n\nThe PDG was aware that treatment success rates are greater when treatment is based on an 'in-reach' model of care in prisons (where healthcare services are brought into the prison rather than providing escorted outpatient treatment). However, the Group acknowledged that the necessary security arrangements in prison could act as a barrier to this approach.\n\n# Immigration Removal Centres\n\nThe PDG recognised the importance of immigration removal centres as a setting for promoting and offering hepatitis B and C testing. Many of the people detained in these centres originate from medium and high prevalence countries and so are at increased risk of hepatitis B and C infection. In 2011, approximately 27,000 migrants entered detention. Although the majority of immigration detainees are held for less than 2 months, many are held for 2 to 6 months, and some are held for more than 1 year.\n\n# Data\n\nThe PDG acknowledged the limitations and challenges of current surveillance systems for hepatitis B and C (for example, data on the number of people completing treatment successfully are not available). The Group considered that the collection and collation of robust, service-level data on testing and treatment services was important for both monitoring and developing services.\n\nThe PDG discussed the need for hepatitis B and C databases holding details on people who have been tested and treated. The importance of collecting data on treatment uptake and the need for this data collection to be built into the pathway at every point was noted. It considered that an integrated system, bridging different healthcare providers and capturing a range of data, was the ideal. However, it was felt that there needed to be a balance between the burden of collecting data and the value of those data. The Group acknowledged that it would be resource-intensive.\n\n# Other issues\n\nIt may not always be easy to identify people from groups at increased risk of hepatitis B or C infection. Examples include: children born to parents who inject drugs, and who may later be placed in care or adopted, or children who have been adopted from a country with a medium or high background prevalence.\n\nOther smaller groups at increased risk of hepatitis B and C infection include people who:\n\nhave received medical or dental procedures, including renal dialysis, in countries where infection control may be inadequate\n\nhave been exposed to unsterile needles (for example, by having non-professional tattoos, body or ear piercing, or acupuncture, or through vaccination in a developing country)\n\nare jaundiced or have abnormal liver function tests.\n\nThe PDG was aware of the need to test candidates for chemotherapy or immunosuppressive therapy for hepatitis B prior to treatment. In people with hepatitis B, chemotherapy or immunosuppressive therapy can result in a flare-up of liver disease and death by fulminant liver failure.\n\nTo increase testing in primary care the PDG considered recommending that GPs review patient notes to identify people at increased risk and invite them in for discussion and testing. However, there was insufficient evidence on which to decide whether such an approach would be effective or cost effective.\n\nThe PDG noted the importance of verifying the identity of people testing for hepatitis B and C. Members were made aware of instances where NHS cards have been passed on or sold to illegal migrant workers. In some cases medical information had, as a result, been linked to the wrong people.\n\nThe PDG emphasised existing hepatitis B vaccination recommendations (as detailed in the Green book) because although hepatitis B vaccination was beyond the scope of this guidance, case-finding may identify contacts of infected individuals who should be offered vaccination.\n\nIn addition, the Group was aware of the complexities and the importance of the hepatitis B vaccination schedule for babies born to infected mothers. Adherence to the vaccination schedule provides an opportunity to prevent chronic infection in babies. The Group was aware that the current system is failing to ensure babies receive a full course of vaccination and are tested for hepatitis B surface antigen (HBsAg) at 12 months to exclude infection.\n\nStaff working in drugs services have a diverse mix of skills. As a result, it would not be possible to adopt a universal approach to training them in hepatitis B and C testing. However, the PDG felt that all staff should be capable of encouraging people to be vaccinated against hepatitis B and test for hepatitis B and C infection.\n\nThe PDG focused on people who inject drugs and migrants from medium- and high-prevalence countries. The Group noted that effective vaccination and testing for hepatitis B has already been implemented for other groups at increased risk, including men who have sex with men and people with multiple sexual partners. For example, see the Royal College of General Practitioners' Guidance for the prevention, testing, treatment and management of hepatitis C in primary care (Appendix 5) for information on hepatitis B vaccination in men who have sex with men and other groups at increased risk. For other populations at increased risk there was no evidence that infection rates were sufficiently high to warrant a recommendation for case-finding amongst these groups. (These groups include people who have been exposed to unsterile needles, for example, by having non-professional tattoos, body or ear piercing, or acupuncture.)", 'Recommendations for research ': '# Intervention development and promotion\n\nHow can case-finding for hepatitis B and C be improved? What modifiable factors influence whether or not specific groups at increased risk of hepatitis B and hepatitis C infection are identified and tested?\n\nHow can the uptake of hepatitis C treatment be improved? What factors influence whether or not specific groups at increased risk will begin and complete hepatitis C treatment?\n\nWhat cost-effective interventions can be used to increase hepatitis B case-finding among migrant populations in primary and secondary care?\n\nWhat cost-effective interventions ensure continuity of care for prisoners who are diagnosed with chronic hepatitis B or C in prison?\n\nHow cost effective are alternative testing sites, such as community pharmacist programmes, for increasing the number of people who are tested and treated for hepatitis B and C?\n\nWhat are the most effective ways of involving people from groups at increased risk in awareness-raising about, and promoting testing and treatment for, hepatitis B and C infection? Specifically, how cost effective are peer mentor programmes at increasing the number of people at increased risk who are tested and treated for hepatitis B and C?\n\nWhat impact does increased knowledge and awareness of hepatitis B and C among the general public have on the uptake of testing and treatment?\n\nWhich interventions for other communicable diseases could be used to encourage people at increased risk of hepatitis B and C infection to take up the offer of testing and treatment?\n\n# Epidemiology\n\nHow many children in the UK are infected with chronic hepatitis B and C and which subgroups of the population do they come from?\n\nHow many people in the UK are infected with chronic hepatitis B and C and which subgroups of the population do they come from?\n\nHow cost effective are cohort testing programmes:\n\nas a stand-alone programme, or\n\nas an extension of the NHS Health Check programme?More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.', 'Updating the recommendations ': 'This guidance will be reviewed 3 years after publication to determine whether all or part of it should be updated. Information on the progress of any update will be posted at the NICE website.', 'Related NICE guidance': '# Published\n\nPatient experience in adult NHS services. NICE clinical guidance 138 (2012)\n\nHepatitis C (genotype 1) – boceprevir. NICE technology appraisal 253 (2012)\n\nHepatitis C (genotype 1) – telaprevir. NICE technology appraisal 252 (2012)\n\nTuberculosis – hard-to-reach groups. NICE public health guidance 37 (2012)\n\nIncreasing the uptake of HIV testing among men who have sex with men. NICE public health guidance 34 (2011)\n\nIncreasing the uptake of HIV testing among black Africans in England. NICE public health guidance 33 (2011)\n\nLooked-after children and young people. NICE public health guidance 28 (2011)\n\nHepatitis C – peginterferon alfa and ribavirin. NICE technology appraisal 200 (2010)\n\nHepatitis B – tenofovir disoproxil fumarate. NICE technology appraisal 173 (2009)\n\nReducing differences in the uptake of immunisations. NICE public health guidance 21 (2009)\n\nNeedle and syringe programmes. NICE public health guidance 18 (2009)\n\nCommunity engagement. NICE public health guidance 9 (2008)\n\nAntenatal care. NICE clinical guideline 62 (2008)\n\nHepatitis B – telbivudine. NICE technology appraisal 154 (2008)\n\nHepatitis B – entecavir. NICE technology appraisal 153 (2008)\n\nPrevention of sexually transmitted infections and under-18 conceptions. NICE public health guidance 3 (2007)\n\nHepatitis C – peginterferon alfa and ribavirin. NICE technology appraisal 106 (2006)\n\nHepatitis B (chronic) – adefovir dipivoxil and pegylated interferon alpha-2a. NICE technology appraisal 96 (2006)\n\nHepatitis C – pegylated interferons, ribavirin and alfa interferon. NICE technology appraisal 75 (2004)\n\n# Under development\n\nHepatitis B: diagnosis and management. NICE clinical guideline (publication expected June 2013)\n\nHepatitis C (children and young people) – peginterferon alfa and ribavirin. NICE technology appraisal (publication expected August 2013)\n\nHepatitis C. NICE clinical guideline (publication date to be confirmed)', 'Glossary ': "# Close contacts\n\nThe people in close contact with someone infected with hepatitis B or C, where there is a risk of transmitting the infection (through blood or body fluids). This could include their family members, close friends, household contacts or sexual partners.\n\n# Continuity of care\n\nContinuation of treatment and referral for people moving in, out or between prisons.\n\n# Household contacts\n\nPeople sharing a bedroom, kitchen, bathroom or sitting room with a person infected with hepatitis B or C.\n\n# Immigration removal centres\n\nIn addition to housing people who remain in the UK illegally, immigration removal centres house people who are waiting for their immigration claims to be resolved or to have their identities established. Detainees are entitled to primary healthcare facilities during their stay, equivalent to those available in the community.\n\n# In-reach model\n\nA model of prison-based healthcare provision in which healthcare services are brought into the prison, instead of the prisoner being taken out to the healthcare service (for example, to a hospital outpatient unit).\n\n# Joint strategic needs assessment\n\nA process that identifies the current and future health and wellbeing needs of a local population, leading to agreed commissioning priorities that aim to improve outcomes and reduce health inequalities.\n\n# Locally enhanced services\n\nAdditional services provided by GPs, designed to meet specific local health needs.\n\n# Medical hold\n\nA process to ensure prisoners are not transferred until they are medically fit.\n\n# Past infection\n\nHepatitis B and C can be cleared by the body's own immune system. An antibody test determines whether a person has ever been infected with hepatitis in the past. If the test is positive further tests are carried out to establish whether the virus is still present in the body.\n\n# Peers\n\nPeers are members of the target population who have been diagnosed with hepatitis B or C.\xa0They may be recruited and supported to communicate health messages, including promoting testing and treatment, assist with contact tracing or testing, and to offer people support during testing and treatment.\n\n# Prison\n\nHer Majesty's prison establishments, including young offender institutions.\n\n# Sexual contact\n\nIntimate contact with others, including kissing and oral, anal, and vaginal intercourse. Hepatitis B is transmitted by direct contact with infected blood. However, it can also be transmitted by contact with semen, vaginal fluids and other body fluids. Hepatitis C is primarily transmitted by contact with infected blood.", 'References': 'Department of Health (2006) Immunisation against infectious disease – the green book. London: Department of Health.\n\nDepartment of Health (2002) Getting ahead of the curve: a strategy for combating infectious diseases (including other aspects of health protection). London: Department of Health.\n\nEdmunds WJ, Medley GF, Nokes DJ et al. (1993) The influence of age on the development of the hepatitis B carrier state. Proceedings B 253: 197–201.\n\nFoster GR, Fried MW, Hadziyannis SJ et al. (2007) Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin. Scandinavian Journal of Gastroenterology 42 (2): 247–55.\n\nHahné S, Ramsay M, Balogun K et al. (2004) Incidence and routes of transmission of hepatitis B virus in England and Wales, 1995–2000: implications for immunisation policy. Journal of Clinical Virology 29: 211–20.\n\nHarris RJ, Ramsay M, Hope V et al. (2012a) Hepatitis C prevalence in England remains low and varies by ethnicity: an updated evidence synthesis. European Journal of Public Health 22 (2): 187–92.\n\nHarris RJ, Hope V, Marongiou A (2012b) Spatial mapping of hepatitis C prevalence in recent injecting drug users in contact with services. Epidemiology and Infection 140 (6): 1054–63.\n\nHealth Protection Agency (2012) Acute hepatitis B (England): annual report for 2011 Infections report, 6 (34). London: Health Protection Agency Centre for Infections.\n\nHealth Protection Agency (2011a) Health protection report weekly report 4 (34). London: Health Protection Agency Centre for Infections.\n\nHealth Protection Agency (2011b) Hepatitis C in the UK 2011. London: Health Protection Agency Centre for Infections.\n\nHealth Protection Agency (2011c) Shooting up: Infections among people who inject drugs in the UK 2010. An update: November 2011. London: Health Protection Agency.\n\nHealth Protection Agency (2011d) Sentinel surveillance of hepatitis testing in England. Hepatitis B and D 2010 report. Analysis of testing between 2007 and 2010. London: Health Protection.\n\nHickman M, McDonald T, Judd A et al. (2008) Increasing the uptake of hepatitis C virus testing among injecting drug users in specialist drug treatment and prison settings by using dried blood spots for diagnostic testing: a cluster randomised controlled trial. Journal of Viral Hepatitis 15: 250–4.\n\nHope V, Ncube F, Hickman M et al. (2007) Hepatitis B vaccine uptake among injecting drug users in England 1998 to 2004: is the prison vaccination programme driving recent improvements? Journal of Viral Hepatitis 14 (9): 653–60.\n\nJudd A, Hickman M, Hope V et al. (2007) Twenty years of selective hepatitis B vaccination: is hepatitis B declining among injecting drug users in England and Wales? Journal of Viral Hepatitis 14 (8): 584–9.\n\nNHS Education for Scotland (2010) Hepatitis C workforce education development: an outline of requirements. Edinburgh: NHS Education for Scotland.\n\nPerz JF, Armstrong GL, Farrington LA, et al. (2006) The contribution of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. Journal of Hepatology 45: 529–38.\n\nScottish Executive (2008) Hepatitis C Action Plan for Scotland: phase II: May 2008 – March 2011. Edinburgh: Scottish Executive.\n\nScottish Executive (2006) Hepatitis C Action Plan for Scotland – phase I: September 2006 – August 2008. Edinburgh: Scottish Executive.', 'Appendix B Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E and are available at the NICE website.\n\n# Guidance development\n\nThe stages involved in developing public health programme guidance are outlined in the box below.\n\n. Draft scope released for consultation\n\n. Stakeholder meeting about the draft scope\n\n. Stakeholder comments used to revise the scope\n\n. Final scope and responses to comments published on website\n\n. Evidence reviews and economic modelling undertaken and submitted to PDG\n\n. PDG produces draft recommendations\n\n. Draft guidance (and evidence) released for consultation and for field testing\n\n. PDG amends recommendations\n\n. Final guidance published on website\n\n. Responses to comments published on website\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were:\n\nWhich interventions are effective and cost effective in encouraging people from high-risk groups to use services that currently (or potentially could) offer hepatitis B or C testing?\n\nWhat prevents people in high-risk groups from seeking and accepting a hepatitis B or hepatitis C test? How do these factors differ for each group – and what factors increase the likelihood that they will seek and accept a test?\n\nWhich interventions are effective and cost effective at overcoming the barriers to hepatitis B or C testing faced by high-risk groups and professionals?\n\nWhat type of services and activities need to be commissioned to encourage people who have tested positive to continue to seek support?\n\nThese questions were made more specific for each review (see reviews for further details).\n\n# Reviewing the evidence\n\n## Qualitative review\n\nOne qualitative review was conducted (review 1).\n\nA number of databases were searched in March/April 2011 for qualitative studies exploring the views on, and experiences of, hepatitis B and C testing and treatment among people at greatest risk. Five journals with the highest yield of references were selected as follows:\n\nAustralian Health Review\n\nGastroenterology Nursing\n\nInternational Journal of Drug Policy\n\nJournal of Community Health\n\nJournal of Viral Hepatitis.\n\nAll journal issues (113) and supplements published between 2008 and 2011 were hand-searched. A number of websites were also searched. For details, see the review.\n\nStudies were included in review 1 if they considered:\n\nGroups at an increased risk of hepatitis B and C infection, their close contacts and practitioners who treat them or are involved in preventive activities.\n\nMixed 'low'- and 'high'-risk populations where it was possible to attribute the findings to particular high-risk populations.\n\nThe views and experiences of groups at increased risk in relation to case-finding, testing, communication of test results or subsequent treatment.\n\nPatient and practitioner perspectives on the barriers to, and opportunities for, changing behaviour in relation to hepatitis B and C testing and subsequent care and treatment.\n\nStudies were excluded if they:\n\nFocused solely on general population groups or groups at low risk of hepatitis B or C.\n\nUsed structured questionnaires as the sole method of data collection.\n\nOnly reported quantitative data not elicited from the patients or providers themselves.\n\n## Effectiveness review\n\nOne review of effectiveness was conducted (review 2).\n\nA number of databases were searched in July 2011 for studies from 1990 onwards.\n\nStudies were included in the effectiveness review if they:\n\nTargeted groups at increased risk of hepatitis B and C infection.\n\nTargeted healthcare professionals involved in hepatitis B and C testing and treatment.\n\nAimed to raise awareness of hepatitis B and C testing services among people from high-risk groups.\n\nEncouraged people from high-risk groups and their 'close contacts' to use hepatitis B and C testing services.\n\nImproved access to testing services.\n\nStudies were excluded if they focused on changing the behaviour of people who inject drugs (in relation to injecting or sharing practices but without reference to case-finding or testing).\n\nSee each review for details of the inclusion and exclusion criteria.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual Methods for the development of NICE public health guidance (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nThe evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable).\n\n## Summarising the evidence and making evidence statements\n\nThe review data were summarised in evidence tables (see full reviews).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n## Mapping review\n\nThe mapping review comprised a survey of awareness-raising and other activities to encourage groups at increased risk of hepatitis B and C to seek support.\n\nTelephone interviews and an online questionnaire were used with healthcare professionals and representatives of voluntary and community sector organisations who work with people at increased risk of hepatitis B and C infection. See the review for details.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and two economic modelling exercises.\n\n## Review of economic evaluations\n\nThere was a review of economic evaluations as part of the effectiveness review (review 2). Studies were included if they reported both costs (regardless of how estimated) and outcomes (regardless of how specified).\n\n## Economic modelling\n\nThree economic models were constructed to incorporate data from the reviews of effectiveness and cost effectiveness.\n\nA dynamic model was developed to estimate the cost effectiveness of interventions to promote hepatitis testing among people who inject drugs. The model had to be dynamic to account for the ongoing transmission of hepatitis C between people who inject drugs.\n\nTwo static models were developed to evaluate interventions aimed at migrant groups. (Hepatitis B and C case finding and treatment in the UK will have an effect on morbidity among people tested, but little impact on the incidence of chronic infection, because most new cases have not been caused by infection within the UK.)\n\nThe results are reported in: 'An economic evaluation of finding cases of hepatitis B and C infection in UK migrant populations'; and 'Assessing the cost-effectiveness of interventions aimed at promoting and offering hepatitis C testing to injecting drug users: An economic modelling report'.\n\n# How the PDG formulated the recommendations\n\nAt its meetings in May, July, September, November and December 2011 and February, March and April 2012, the Programme Development Group (PDG) considered the evidence and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to an evidence statement(s) (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in June 2012. At its meeting in September 2012, the PDG amended the guidance in light of comments from stakeholders and experts. The guidance was signed off by the NICE Guidance Executive in November 2012.", 'Appendix C The evidence ': "This appendix lists the evidence statements from two reviews, provided by external contractors (see appendix A and appendix E) and links them to the relevant recommendations. See appendix B for the meaning of the (++), (+) and (-) quality assessments referred to in the evidence statements.\n\nThe two reviews are:\n\nReview 1: 'A systematic review of qualitative research on the views, perspectives and experiences of hepatitis B and C testing among practitioners and people at greatest risk of infection'.\n\nReview 2: 'A systematic review of the effectiveness and cost effectiveness of interventions aimed at raising awareness and engaging with groups who are at increased risk of hepatitis B and C infection'.\n\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letter(s) in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document.\n\nEvidence\n statement\n Q1 indicates that the linked statement is numbered 1 in review 1. Evidence statement E3 indicates that the linked statement is numbered 3 in review 2.\n\nThe reviews and economic analysis are available online. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nWhere the Programme Development Group (PDG) has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix.\n\nRecommendation\n 1: evidence statements: Q1, Q2, Q3, Q4, Q5, Q8, Q9, Q10, E1; IDE\n\nRecommendation\n 2: evidence statements: Q1, Q2, Q3, Q4, Q5, Q8, Q9, Q10, Q14, Q15, Q16, Q23, Q28, Q29, E1; IDE\n\nRecommendation\n 3: evidence statements: Q2, Q18, Q20, Q21, Q28, Q29, Q30, E2, E5, E8; IDE\n\nRecommendation\n 4: evidence statements: Q28, E5, E6, E11\n\nRecommendation\n 5: evidence statements: Q16, Q27, Q28, E1, E6; IDE\n\nRecommendation\n 6: evidence statements: Q18, Q20, Q21, Q24, Q25, Q28, Q29, Q30, E1, E4, E5, E6, E7, E8, E9; IDE\n\nRecommendation\n 7: IDE\n\nRecommendation\n 8: IDE\n\nRecommendation\n 9: IDE\n\nRecommendation\n 10: Q7, E5; IDE\n\nRecommendation\n 11: evidence statements: IDE\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence review(s) to make them more consistent with each other and NICE's standard house style. The superscript numbers refer to the studies cited beneath each statement. The full references for those studies can be found in the reviews.\n\n## Evidence statement Q1\n\nUnderstanding and awareness of hepatitis B among people born in countries with intermediate and high endemicity may be strongly influenced by their personal experiences and cultural beliefs (two [++], one [+])1,2,3.\n\nBurke et al. 2004.\n\nBurke et al. 2011.\n\nWallace et al. 2011.\n\n## Evidence statement Q2\n\nPeople born in countries with intermediate and high endemicity for hepatitis B may confuse the various forms of hepatitis and the relationship between hepatitis and HIV, and they may commonly hold inaccurate beliefs about transmission risks (two [++], one [+])1,2,3. The lack of, or gaps in, knowledge about hepatitis B identified among some healthcare professionals (two [++])3,4 may contribute to or compound inadequate knowledge about hepatitis B among groups at a high risk of infection.\n\nBurke et al. 2011.\n\nvan der Veen et al. 2009.\n\nWallace et al. 2011.\n\nHwang et al. 2010.\n\n## Evidence statement Q3\n\nPeople born in countries with intermediate and high endemicity for hepatitis B may commonly cite access to or contamination of food, or cultural practices associated with sharing food and communal eating, as the main cause of hepatitis B transmission (three [++] and one [+])1,2,3,4. Although vertical transmission of hepatitis B was acknowledged in some studies, sexual transmission of hepatitis B was infrequently mentioned; overall, the evidence suggests that groups at a high risk of infection do not perceive hepatitis B as a sexually transmitted infection (three [++])4,5,6.\n\nBurke et al. 2004.\n\nBurke et al. 2011.\n\nChen et al. 2006.\n\nChoe et al. 2005.\n\nvan der Veen et al. 2009.\n\nWallace et al. 2011.\n\n## Evidence statement Q4\n\nAs with their beliefs about the causes and prevention of hepatitis B, people born in countries with intermediate and high endemicity may express beliefs about prevention that are influenced by their personal experiences and cultural background (four [++])1,2,3,4. Among people originating from East and South East Asia, prevention strategies may commonly reflect the practice of traditional medicine and vaccination may not generally be considered as a primary means of prevention(five [++] and one [+])1,2,5,6,7,8. Religious influences on preventive health strategies may also be apparent, for example among Muslim men (one [++])3.\n\nChoe et al. 2005.\n\nChen et al. 2006.\n\nvan der Veen et al. 2009.\n\nWallace et al. 2011.\n\nBurke et al. 2004.\n\nBurke et al. 2011.\n\nChang et al. 2008.\n\nHwang et al. 2010.\n\n## Evidence statement Q5\n\nDespite some participants expressing generally positive attitudes towards hepatitis B vaccination and people at high risk being receptive to vaccination (one [++] and one [+])1,2 some studies (two [++] and one [+])1,3,4 indicated that there is significant confusion and uncertainty surrounding vaccination among groups at a high risk of infection.\n\nBuck et al. 2006.\n\nvan der Veen et al. 2009.\n\nChen et al. 2006.\n\nChang et al. 2008.\n\n## Evidence statement Q7\n\nBarriers to testing for hepatitis B include an absence of clear symptoms of infection, practical obstacles such as inconvenience and time constraints, and language and cultural barriers, all of which may discourage some people from seeking care and may limit the role that healthcare providers play in providing education and outreach to immigrant communities (one [++])1.\n\nvan der Veen et al. 2009.\n\n## Evidence statement Q8\n\nThe perception of hepatitis B as a 'liver' or 'blood' illness rather than a sexually transmitted infection (STI) appears to play an important role in tempering stigma associated with hepatitis B. Increasing awareness of hepatitis B as a sexually transmitted infection was viewed by one study ([++])1as potentially contributing to increased stigma.\n\nvan der Veen et al. 2009.\n\n## Evidence statement Q9\n\nOne study ([++])1 reported that people with a diagnosis of chronic hepatitis B, including first- and second-generation immigrants, had little recollection of providing consent to test and did not receive adequate information at diagnosis. This lack of information and knowledge was perceived as impacting negatively on their health and preventing opportunities for behaviour change. Both patients and community workers expressed concerns about a lack of provider knowledge with regards to hepatitis B.\n\nWallace et al. 2011.\n\n## Evidence statement Q10\n\nThere was evidence that safe and responsible injecting practices are employed by injecting drug users (IDUs) to avoid the transmission of hepatitis C from 6 studies (5 [++] and 1 [+]1,2,3,4,5,6. There was a lack of consensus as to whether safe practices are strictly adhered to in relation to the sharing of drug related paraphernalia3,5,7.\n\nDavis et al. 2004.\n\nEllard 2007.\n\nRhodes et al. 2004.\n\nSouthgate et al. 2005.\n\nWright et al. 2005.\n\nFraser 2004.\n\nCoupland et al. 2009.\n\n## Evidence statement Q14\n\nThere is strong evidence from 18 studies (eleven [++], five [+], one [-] and one not rated [NR])1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 that IDUs have an uncertain and incomplete knowledge of hepatitis C. Studies showed that IDUs are confused over what the disease is, how it differs from other forms of hepatitis, how the infection is transmitted and what symptoms are involved. This confusion was reinforced by the perception that expert and scientific knowledge on hepatitis C is shifting and uncertain (three [++] and one [NR])4,11,12,17. There is evidence that some IDUs are aware of their limited knowledge of hepatitis C (three [++])3,4,12.\n\nCopeland 2004.\n\nCoupland et al. 2009.\n\nDavis and Rhodes 2004.\n\nDavis et al. 2004.\n\nEllard 2007.\n\nFraser 2004.\n\nFraser 2010.\n\nGyarmathy et al. 2006.\n\nHarris 2009a.\n\nMunoz-Plaza et al. 2004.\n\nRhodes and Treloar 2008.\n\nRhodes et al. 2004.\n\nSosman et al. 2005.\n\nSouthgate et al. 2005.\n\nSutton and Treloar 2007.\n\nSwan et al. 2010.\n\nTompkins et al. 2005.\n\nWright et al. 2005.\n\n## Evidence statement Q15\n\nHepatitis C is often understood in relation to HIV in a way that trivialises the seriousness of contracting hepatitis C and may have implications for the use of safe injecting practices and the uptake of hepatitis C services (eleven [++], two [+] and two [NR])1,2,3,4,5,6,7,8,9,10,11,12,13,14,15.\n\nCopeland 2004.\n\nDavis and Rhodes 2004.\n\nDavis et al. 2004.\n\nEllard 2007.\n\nFaye and Irurita 2003.\n\nHarris 2009a.\n\nMunoz-Plaza et al. 2010.\n\nRhodes et al. 2004.\n\nRoy et al. 2007.\n\nSouthgate et al. 2005.\n\nSutton and Treloar 2007.\n\nSwan et al. 2010.\n\nRhodes and Treloar 2008.\n\nTreloar and Rhodes 2009.\n\nWozniak et al. 2007.\n\n## Evidence statement Q16\n\nA number of barriers to hepatitis C testing among IDUs were identified. People perceiving themselves to be at low risk of hepatitis C infection, a lack of visible symptoms of hepatitis C infection, fear of a positive test result, the use of needles and fear of disclosure were found to prevent the uptake of hepatitis C testing among IDUs (seven [++], eight [+], one [-] and one [NR])1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17. Three studies (two [+] and one [-])7,18,19 reported barriers to testing specific to the prison setting including long waiting times, lack of information provision, prioritisation of detoxification and withdrawal, and movement between prisons.\n\nCraine et al. 2004.\n\nDavis et al. 2004.\n\nFraser 2004.\n\nFraser 2010.\n\nGyarmathy et al. 2006.\n\nHarris 2009a.\n\nKhaw et al. 2007.\n\nLally et al. 2008.\n\nPerry et al. 2003.\n\nRhodes and Treloar 2008.\n\nRhodes et al. 2004.\n\nTemple-Smith et al. 2004.\n\nSosman et al. 2005.\n\nSouthgate et al. 2005.\n\nStrauss et al. 2008.\n\nSutton and Treloar 2007.\n\nSwan et al. 2010.\n\nDyer and Tolliday 2009.\n\nMunoz-Plaza et al. 2005b.\n\n## Evidence statement Q18\n\nConvenient and opportunistic testing and a 'one-stop shop' approach for all hepatitis C services was regarded as a convenient approach among IDUs (three [++] and five [+])1,2,3,4,5,6,7,8. There is evidence (two [++] and two [+])3,9,10,11 that some IDUs were unaware that they had been tested for hepatitis C and concern over informed consent to testing was noted by a number of authors. Although an opportunistic approach can increase testing compliance, a lack of informed consent may also contribute towards uncertain knowledge of hepatitis C among IDUs and limit the impact of testing on behaviour.\n\nGyarmathy et al. 2006.\n\nMunoz-Plaza et al. 2004.\n\nRhodes et al. 2004.\n\nRoy et al. 2007.\n\nSosman et al. 2005.\n\nSwan et al. 2010.\n\nStrauss et al. 2008.\n\nTemple-Smith et al. 2004.\n\nMunoz-Plaza et al. 2005b.\n\nPerry and Chew-Graham 2003.\n\nTompkins et al. 2005.\n\n## Evidence statement Q20\n\nTrust and rapport with healthcare professionals and drug treatment staff motivated people to get tested. Support and encouragement from healthcare professionals also facilitated testing among IDUs (four [+])1,2,3,4.\n\nMunoz-Plaza et al. 2004.\n\nPerry et al. 2003.\n\nSosman et al. 2005.\n\nStrauss et al. 2008.\n\n## Evidence statement Q21\n\nStudies showed that the experience of being informed about the outcome of hepatitis C testing can be highly confusing (nine [++], two [+], one [-] and one [NR])1,2,3,4,5,6,7,8,9,10,11,12,13. Limited and inadequate information provision by healthcare professionals can lead to confusion over the meaning of a positive diagnosis and substantial gaps in knowledge.\n\nCopeland 2004.\n\nCullen et al. 2005.\n\nFaye and Irurita 2003.\n\nKhaw et al. 2007.\n\nKinder 2009.\n\nLally et al. 2008.\n\nRhodes and Treloar 2008.\n\nRhodes et al. 2004.\n\nSouthgate et al. 2005.\n\nStrauss et al. 2008.\n\nSutton and Treloar 2007.\n\nSwan et al. 2010.\n\nTompkins et al. 2005.\n\n## Evidence statement Q23\n\nFear of the adverse effects associated with hepatitis C treatment and the circulation of 'horror stories' and unsuccessful treatment cases among peers discouraged IDUs from engaging with treatment (three [++], one [+] and two [-])1,2,3,4,5,6. A fear of needles was also common and using needles during the treatment process was a challenge to overcome when considering treatment (two [++] and one [+])3,5,7. In contrast, anxiety over hepatitis C, witnessing peers suffer from symptoms of hepatitis C infection and hearing stories of successful treatment cases among peers encouraged treatment uptake (two [++] and one [+])3,5,8.\n\nCullen et al. 2005.\n\nFraser 2010.\n\nKinder 2009.\n\nMunoz-Plaza et al. 2008.\n\nSwan et al. 2010.\n\nTreloar and Holt 2008.\n\nStrauss et al. 2008.\n\nMunoz-Plaza et al. 2004.\n\n## Evidence statement Q24\n\nSocioeconomic and family circumstances can lead to treatment being de-prioritised among IDUs (three[++] and one [-])1,2,3,4. Studies have shown that a preoccupation with drug use, chaotic lifestyles, long waiting times between appointments and employment contributed towards IDUs missing and forgetting treatment appointments, thus increasing the possibility of treatment dropout (three [++])1,3,5. The assumption of abstinence as a requirement for hepatitis C treatment and continued substance use among IDUs acted as a barrier to treatment (six [++] and one [-])1,3,5,6,7,8,9.\n\nCoupland et al. 2009.\n\nFraser 2010.\n\nSwan et al. 2010.\n\nTreloar et al. 2010.\n\nLally et al. 2008.\n\nCullen et al. 2005.\n\nRoy et al. 2007.\n\nWozniak et al. 2007.\n\nWright et al. 2005.\n\n## Evidence statement Q25\n\nReceiving support from family, partners and peers, starting family life and concerns over the impact of hepatitis C on significant others (for example partners and children) motivated IDUs to engage with hepatitis C treatment (three [++])1,2,3.\n\nFaye and Irurita 2003.\n\nKinder 2009.\n\nSwan et al. 2010.\n\n## Evidence statement Q27\n\nOne study ([-])1 found that being in prison was viewed by healthcare professionals as both a barrier and a facilitator for hepatitis C treatment. Transportation of prisoners between prisons and short sentences were viewed as interfering with the treatment process whereas the structured environment of prison and availability of peer support during treatment were regarded as beneficial.\n\nDyer and Tolliday 2009.\n\n## Evidence statement Q28\n\nTwo studies found that a lack of access to treatment and a lack of information on treatment options act as barriers to hepatitis C treatment (two [++])1,2. Increasing knowledge of hepatitis C through the provision of information by healthcare professionals encouraged IDUs to consider their treatment options (one [++], two [+] and one [-])1,3,4,5.\n\nSwan et al. 2010.\n\nTreloar et al. 2010.\n\nCullen et al. 2005.\n\nMunoz-Plaza et al. 2004.\n\nMunoz-Plaza et al. 2008.\n\n## Evidence statement Q29\n\nThe experience of stigma prevented IDUs from seeking hepatitis C testing because of fear of disclosure, and prevented IDUs from disclosing a positive hepatitis C status because of fear of a negative reaction, isolation and social exclusion (eight [++], three [+], one [-] and one [NR])1,2,3,4,5,6,7,8,9,10,11,12,13. Stigma also prevented engagement with further prevention education, investigations and treatment and resulted in IDUs receiving inadequate and judgemental care by healthcare professionals (seven [++], six [+], one [-] and two [NR])5,6,7,9,12,14,15,16,17,18,19,20,21,22,23,24.\n\nCraine et al. 2004.\n\nEllard 2007.\n\nHarris 2009b.\n\nKhaw et al. 2007.\n\nLally et al. 2008.\n\nMcCreaddie et al. 2011.\n\nRoy et al. 2007.\n\nSosman et al. 2005.\n\nStrauss et al. 2008.\n\nSutton and Treloar 2007.\n\nTompkins et al. 2005.\n\nTreloar and Rhodes 2009.\n\nWright et al. 2005.\n\nCarrier et al. 2005.\n\nCoupland et al. 2009.\n\nFaye and Irurita 2003.\n\nHabib and Adorjany 2003.\n\nMunoz-Plaza et al. 2004.\n\nPaterson et al. 2007.\n\nPerry et al. 2003.\n\nSwan et al. 2010.\n\nTemple-Smith et al. 2004.\n\nTreloar and Hopwood 2004.\n\nTreloar et al. 2010.\n\n## Evidence statement Q30\n\nPerceiving health care professionals to be supportive, concerned and caring, and being encouraged to undertake treatment by healthcare professionals was found to motivate IDUs to engage in hepatitis C treatment (four [++], one [+] and one [-])1,2,3,4,5,6. There was evidence across a number of studies that IDUs preferred hepatitis C services, including treatment, to be situated in one setting such as drug treatment programmes and methadone substitution settings (two [++] and one [+])5,7,6. These services were also seen as useful in providing information on hepatitis C treatment (one [++] and three [+])5,6,8,9.\n\nFraser 2010.\n\nCoupland et al. 2009.\n\nKinder 2009.\n\nMcCreaddie et al. 2011.\n\nMunoz-Plaza et al. 2004.\n\nSwan et al. 2010.\n\nTreloar et al. 2010.\n\nMunoz-Plaza et al. 2005a.\n\nMunoz-Plaza et al. 2006.\n\n## Evidence statement E1\n\nThere is moderate evidence from three randomised controlled trials (RCTs) (one [++] and two [+])1,2,3 and one uncontrolled before and after (UBA) study (-)4 to suggest that providing information and education on hepatitis B to migrant populations may improve their knowledge about risk, screening and prevention; moderate evidence from three RCTs (one [++] and two [+])1,2,3 to suggest that providing information and education on hepatitis B to migrant populations does not improve testing uptake; and weak evidence from one case series (-)5 to suggest that testing supplemented with culturally appropriate education may encourage the uptake of follow-up care among migrant populations.\n\nTaylor et al. 2009a.\n\nTaylor et al. 2009b.\n\nTaylor et al. 2011.\n\nHsu et al. 2007; 2010.\n\nChao et al. 2009.\n\n## Evidence statement E2\n\nThere is moderate evidence from one RCT (+)1 to suggest that a strategy to promote cancer prevention activities among doctors serving migrant populations does not improve their practices in relation to hepatitis B testing. There is weak evidence from one UBA study (-)2 to suggest that providing information and education on hepatitis B to complementary and alternative medicine practitioners (including those practising traditional Chinese medicine and acupuncture) may improve their knowledge about risk, screening and prevention. However, the wider impact of this change in knowledge on their practices regarding referral for testing is not clear.\n\nNguyen et al. 2000.\n\nChang et al. 2007.\n\n## Evidence statement E4\n\nThere is moderate evidence from one RCT (+)1 and one controlled before and after (CBA) study (-)2 to suggest that offering dried blood spot testing to IDUs attending substance misuse services may increase uptake of hepatitis C testing compared to venepuncture alone being offered. The increase in uptake may reflect an increase in testing availability, as more staff can be trained to deliver dried blood spot testing than venepuncture, as well as higher acceptability to IDUs. There is weak evidence from one case series (CS) study (-)3 to suggest that providing high-risk groups with access to dried blood spot testing kits via a telephone hotline is not an effective use of resources compared to testing via state laboratories.\n\nHickman et al. 2008.\n\nCraine et al. 2009.\n\nRainey et al. 2005.\n\n## Evidence statement E5\n\nThere is moderate evidence from one RCT (+)1 to suggest that although providing GPs with both training and assistance with screening (through the use of patient-targeted materials) may increase patient requests for testing, it does not impact upon the number of patients tested for hepatitis C overall. There is moderate evidence from two non-randomised controlled trials (two [+])2,3 to suggest that targeted case finding in primary care for patients with a history of injecting drug use may have a positive impact on the number of patients who are offered and accept a hepatitis C test. Although the level of referral of patients identified with infection was relatively high, the number of subsequent dropouts prior to treatment indicates that there is a need for further support beyond the intervention offered in these studies.\n\nRoudot-Thoraval et al. 2000.\n\nAnderson et al. 2009.\n\nCullen et al. 2012.\n\n## Evidence statement E6\n\nThere is moderate evidence from one RCT (+) and two case series (two [-])1,2,3 to suggest that providing hepatitis C services in community settings may have a positive impact on testing acceptance and uptake. In particular, there is weak evidence from two case series (two [-])4,5 to suggest that a multidisciplinary or shared care approach to hepatitis C testing and treatment for IDUs is associated with high uptake of follow-up services and treatment outcomes comparable with non-drug-using populations. In two studies conducted in the USA (two [-])6,7, hepatitis testing was added to routine blood work undertaken on entry to drugs services and therefore a high testing rate was inevitable. There is moderate evidence from one RCT (+)8 to suggest that the provision of testing services via outreach may have a positive impact on testing acceptance and uptake. The impact may be greatest when testing is offered on-site rather than by referral. There is weak evidence from one UBA study (-)9 to suggest that the provision of hepatitis C outreach services for new prisoners may lead to relatively low uptake of testing.\n\nRosenberg et al. 2010.\n\nLindenberg et al. 2011.\n\nJack et al. 2009.\n\nLindenberg et al. 2011.\n\nJack et al. 2009.\n\nHarris et al. 2010.\n\nHagedorn et al. 2007.\n\nSahajian et al. 2011.\n\nSkipper et al. 2003.\n\n## Evidence statement E7\n\nThere is weak evidence from one case series (-)1 to suggest that offering a non-invasive liver evaluation technique in outreach settings provides an opportunity to subsequently test IDUs for hepatitis C. There is weak evidence from one case series (-)2 that education by a peer outreach worker may improve short-term knowledge about hepatitis C transmission among IDUs.\n\nFoucher et al. 2009.\n\nAitken et al. 2002.\n\n## Evidence statement E8\n\nThere is moderate evidence from one RCT (++)1, one non-randomised controlled trial (+)2 and one UBA study (-)3 to suggest that complex interventions that provide support to primary care professionals when offering hepatitis C testing may have a positive impact on testing acceptance and uptake. One repeated cross-sectional study (+)4 demonstrated that without support, offers of testing may increase, but not within the desired high-risk groups. There is weak evidence from three UBA studies (three [-])1,5,6 to suggest that educational interventions aimed at healthcare professionals may have short-term benefits on knowledge about hepatitis C. However, there is no clear evidence that an increase in knowledge leads to an increase in testing. Weak evidence from one UBA study (-)4 suggested that a continuing medical education programme had a limited impact on testing uptake. There is mixed evidence from two studies (one [++] and one[+])7 that examined the effectiveness of interventions aimed at professionals on treatment initiation. There is moderate evidence from a repeated cross-sectional study (+)4 that a national campaign had no impact on the management of drug users following a positive hepatitis C test. However, there is strong evidence from one RCT (++)1 that a complex intervention providing support in primary care had a positive impact on number of referrals and attendance at follow-up appointments after testing.\n\nCullen et al. 2006.\n\nHelsper et al. 2010.\n\nSahajian et al. 2004.\n\nDefossez et al. 2008.\n\nD'Souza et al. 2004.\n\nFischer et al. 2000.\n\nGarrard et al. 2006.\n\n## Evidence statement E9\n\nThere is weak evidence from one controlled before and after (CBA) study (-)1 and one case series (-)2 to suggest that the provision of hepatitis C treatment in community settings for IDUs had a positive effect on treatment initiation and outcomes. There is weak evidence from two case series (both [-])3,4 that attendance at a support group for hepatitis C may have a positive effect on treatment initiation. However, it was unclear due to the study design used whether attendance at the support group was higher among more highly motivated individuals who may have been more likely to initiate treatment regardless of their attendance at the group. There is weak evidence from one cohort study (-)5 to suggest that allowing patients, such as those who have not been referred by their doctor, to self-refer to speciality liver clinics for assessment was associated with treatment uptake and completion at rates similar to those referred by healthcare professionals. There is weak evidence from a CBA study (-)6 to suggest that ensuring patients receive education about hepatitis C prior to referral appointments may have a positive effect on attendance at follow-up appointments, and on short to medium-term knowledge.\n\nMoussalli et al. 2010.\n\nWilkinson et al. 2008.\n\nGrebely et al. 2007.\n\nGrebely et al. 2010.\n\nDoucette et al. 2009.\n\nSurjadi et al. 2011.\n\n## Evidence statement E11\n\nThere is moderate evidence from one cost utility analysis (+)1 to suggest that community-based screening and treatment for hepatitis B among migrant populations is cost effective.\n\nVeldhuijzen et al. 2010.\n\n# Additional evidence\n\nA mapping review was also carried out. This was a practice survey of activities and interventions that aim to raise awareness among, and/or engage with, groups who are at an increased risk of hepatitis B and C infection.\n\n# Economic modelling\n\nThere were three models. One model looked at three scenarios for increasing testing for hepatitis C among people who inject drugs and people who used to inject drugs, with the emphasis on training and education:\n\nTraining specialist addiction services in the community to undertake dried blood-spot testing for hepatitis C infection.\n\nEducating and supporting GPs to identify patients at risk of the infection.\n\nTraining prison nurses to undertake dried blood-spot testing for hepatitis C infection.\n\nTraining for dried blood-spot testing in the community resulted in a substantially greater proportion of cases of hepatitis C infection being identified, compared with not offering this blood sampling method. This led to an estimated cost per quality-adjusted life year (QALY) gained of £15,000, which is below the threshold of £20,000 generally accepted by NICE as cost effective.\n\nEducating GPs about hepatitis C infection and targeted paid testing also resulted in an increase in testing and was also cost effective, yielding an estimated cost per QALY of £14,000. (Clinical administration systems were reviewed to identify registered patients aged 30-54 who had indicators of past injecting drug use. These individuals were offered testing for hepatitis C when they attended the practice for a non-urgent consultation. Practices received £100 remuneration for each test offered). Training prison nurses to undertake dried blood spot testing also increased the proportion of hepatitis C cases found, compared with not offering this sampling method. However, the cost effectiveness of this training depended on whether the resulting treatment was completed. The baseline scenario considered no continuity of care between prison and the community – in which case the cost per QALY of finding a new case was estimated to be £59,000 per QALY and therefore was not cost effective. The estimated cost per QALY of case-finding in prison will be less than £20,000 per QALY gained if there is continuity of care between prison and the community and the treatment rate of people diagnosed in prison is at least 40% of the treatment rate of people diagnosed in the community. Higher treatment rates in the community make prison case-finding more cost effective as long as there is continuity of care.\n\nA second model looked at finding and testing UK migrants for hepatitis C infection. This was found to be cost effective if 2% of the migrant group were infected and it cost no more than £20 to find and test each person. In such a case, the cost per QALY gained was estimated to be £10,000. If the cost of finding and testing someone was £50, the estimated cost per QALY was £18,000. For a given cost of testing, it became more cost effective to find and test people if more than 2% of the population group were infected.\n\nA third model looked at finding and testing UK migrants for chronic hepatitis B. If there was a 2% prevalence within the population group and it cost £20 to find and test each infected person, the estimated cost per QALY gained would be £21,000, marginally above the NICE £20,000 threshold for cost effectiveness. However, it would be cost effective if the prevalence of infection was 3% or higher. At 20% prevalence, as is believed to be the case among some migrant groups, the estimated cost per QALY of finding and testing people falls to £12,000 and was, therefore, deemed cost effective.\n\nBased on the modelling, the PDG considered that it would be cost effective to simultaneously find and test people at risk for both hepatitis B and C, provided there was a 2% prevalence of both infections and it cost up to £75 to find and test each person.", 'Appendix D Gaps in the evidence': "The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence. These gaps are set out below.\n\n. There is a lack of robust, quantitative studies on identifying, testing and treating hepatitis B and C (that is, studies that are applicable to the UK context). In particular there is a lack of reliable data on:\n\na) the number of people in the UK with chronic hepatitis B and C. In particular, there is no national information on the number of children infected.\n\nb) local information on the number of people with chronic hepatitis B and C.\n\nc) interventions to increase hepatitis B and C testing among migrant populations.\n\nd) interventions to increase hepatitis B and C testing in non-health settings, for example, prisons.\n\n. There is a lack of qualitative studies on hepatitis B and C, including studies focused on:\n\na) cultural issues which may act as a barrier to testing and treatment.\n\nb) knowledge of, barriers against, and facilitators for hepatitis C testing and treatment among migrant populations.\n\nc) knowledge of, barriers against, and facilitators for preventing hepatitis B and C among men who have sex with men.\n\nd) knowledge of, barriers against, and facilitators for improving the prevention of maternal transmission of hepatitis B.\n\ne) knowledge of, barriers against, and facilitators for preventing hepatitis B among injecting drug users.\n\nf) how former drug users, both from a service user and provider perspective, regard testing for hepatitis.\n\ng) the views, perspectives and experiences of hepatitis B and C testing among people whose past behaviour has put them at risk but who choose not to disclose this information. This includes people who have previously injected drugs or worked as commercial sex workers.\n\nh) the views, perspectives and experiences of hepatitis B and C testing among practitioners and people at increased risk of infection, according to the practitioner's level and type of knowledge.\n\ni) prisoners' views of hepatitis testing and treatment and the views of those working with them.\n\nj) the acceptability of different sampling methods for testing for hepatitis.\n\nk) factors which encourage people to have a liver biopsy or discourage them from this.\n\nl) the knowledge GPs have regarding identification of at-risk patients.\n\nm) why people referred by GPs for a hepatitis test drop out of appropriate care pathways and whether or not an integrated services/one-stop-shop approach would improve uptake rates.\n\nn) understanding of hepatitis B and C care pathways.\n\n. There is a lack of evidence on the role of the voluntary sector in promoting and offering tests for hepatitis B and C.\n\n. There is a lack of evidence on what is happening in the 'real world'. This includes the views of people:\n\na) at risk of hepatitis B and C.\n\nb) who have been identified and/or tested and/or treated.\n\nc) who have dropped out at different stages of the care pathway.\n\n. There is a lack of qualitative and quantitative evidence on the acceptability of dried blood spot testing among different communities.\n\n. There is a lack of evidence on how hepatitis B and C status could be assessed when testing for other diseases and blood-borne viruses.\n\nThe Group made 12 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in section 5.", 'Appendix E Supporting documents': "Supporting documents include the following (see supporting evidence).\n\nEvidence reviews:\n\n\n\nReview 1: 'A systematic review of qualitative research on the views, perspectives and experiences of hepatitis B and C testing among practitioners and people at greatest risk of infection'\n\nReview 2: 'A systematic review of the effectiveness and cost effectiveness of interventions aimed at raising awareness and engaging with groups who are at increased risk of hepatitis B and C infection'\n\nMapping review: 'A practice survey of activities and interventions that aim to raise awareness among, and/or engage with, groups who are at an increased risk of hepatitis B and C infection'.\n\n\n\nEconomic modelling:\n\n\n\n'An economic evaluation of finding cases of hepatitis B and C infection in UK migrant populations'\n\n'Assessing the cost-effectiveness of interventions aimed at promoting and offering hepatitis C testing to injecting drug users: An economic modelling report'.\n\n\n\nExpert testimony:\n\n\n\nPresentation 1: 'UK National Screening Committee and case finding versus screening'\n\nPresentation 2: 'Hepatitis B vaccination in England and Wales'\n\nPresentation 3: 'Hepatitis testing in prisons'\n\nPresentation 4: 'Paediatric hepatitis testing and treatment'\n\nPresentation 5: 'The role of GPs in promoting hepatitis B and C testing among at risk populations'\n\nPresentation 6: 'Perspective on barriers to hepatitis testing and treatment for people who inject drugs'.\n\n\n\nFor information on how NICE public health guidance is developed, see:\n\nMethods for development of NICE public health guidance (third edition, 2012)\n\nThe NICE public health guidance development process (third edition, 2012)", 'About this guidance': 'NICE public health guidance makes recommendations on the promotion of good health and the prevention of ill health.\n\nThis guidance was developed using the NICE public health programme guidance process.\n\nThe recommendations from this guidance have been incorporated into a NICE Pathway. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibility\n This guidance represents the views of the Institute and was arrived at after careful consideration of the evidence available. Those working in the NHS, local authorities, the wider public, voluntary and community sectors and the private sector should take it into account when carrying out their professional, managerial or voluntary duties.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity, and foster good relations. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780', 'Changes after publication': "March 2013: recommendation 7 has been clarified by adding the text: 'at increased risk of infection' to the sentence 'offer and promote hepatitis B and C testing to all service users at increased risk of infection, including people younger than 18'.\n\nApril 2013: minor maintenance."}	https://www.nice.org.uk/guidance/ph43	This guideline covers raising awareness of and testing for hepatitis B and C infection. It aims to ensure that people at increased risk of hepatitis B and C infection are tested.
bdeb022ee2901bf23a6e725f4e5c384b3cf7e7e4	nice	Ranibizumab for treating diabetic macular oedema	Ranibizumab for treating diabetic macular oedema Evidence-based recommendations on ranibizumab (Lucentis) for treating diabetic macular oedema in adults. # Guidance This guidance replaces NICE technology appraisal guidance 237 (published in November 2011). For details see About this guidance. Ranibizumab is recommended as an option for treating visual impairment due to diabetic macular oedema only if: the eye has a central retinal thickness of 400 micrometres or more at the start of treatment and the manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of this appraisal. People currently receiving ranibizumab for treating visual impairment due to diabetic macular oedema whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology Ranibizumab (Lucentis, Novartis) belongs to a class of drugs that blocks the action of vascular endothelial growth factor A (VEGF-A). In diabetic macular oedema, VEGF-A causes blood vessels to leak in the macula, the area of the retina responsible for the clearest vision. The accumulated fluid causes swelling, or oedema, which impairs vision. By inhibiting the action of VEGF-A, ranibizumab reduces oedema and limits visual loss or improves vision. Ranibizumab has a marketing authorisation for 'the treatment of visual impairment due to diabetic macular oedema in adults'. The summary of product characteristics states that treatment should be given monthly and continued until maximum visual acuity is reached – that is, until visual acuity has been stable for 3 consecutive months. Thereafter, visual acuity should be monitored monthly. Treatment is resumed if monitoring indicates a loss of visual acuity caused by diabetic macular oedema, and continued until visual acuity has remained stable for 3 consecutive months. The interval between doses should not be shorter than 1 month. Contraindications to ranibizumab include known hypersensitivity to the active substance or to any of its excipients, active or suspected ocular or periocular infections and active severe intraocular inflammation. Adverse reactions of treatment are mostly limited to the eye. Those commonly reported in clinical trials include vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, sensation of a foreign body in the eye, increased production of tears, blepharitis, dry eye, ocular hyperaemia, itching of the eye and increased intraocular pressure. Nasopharyngitis, arthralgia and headaches are also reported as common adverse reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics. Ranibizumab is administered as a single intravitreal injection of 0.5 mg. Each vial of ranibizumab contains 2.3 mg in 0.23 ml; overfilling is considered necessary to achieve an injectable dose of 0.5 mg. The list price of ranibizumab is £742.17 per vial (excluding VAT; 'British national formulary' edition 64). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of ranibizumab (Novartis) has agreed a patient access scheme with the Department of Health which makes ranibizumab available with a discount applied to all invoices. The size of the discount is commercial in confidence (see section 5.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.# The manufacturer's original submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ranibizumab and a review of this submission by the Evidence Review Group (ERG; appendix B). This document refers to an original submission and a revised submission (made during development of NICE technology appraisal guidance 237) and a rapid review submission, described for the first time in this document. The manufacturer submitted evidence on the clinical effectiveness and cost effectiveness of ranibizumab monotherapy and ranibizumab plus laser photocoagulation compared with laser photocoagulation alone in its original submission. The manufacturer did not provide a comparison with bevacizumab, which the appraisal scope lists as a comparator. The manufacturer explained that this was because it believed that there is no robust evidence base for the clinical effectiveness or safety of bevacizumab in the treatment of diabetic macular oedema, bevacizumab has not been in long-term use in the NHS and there is no widely accepted dosage. # Clinical effectiveness The manufacturer performed a systematic review of the evidence on the clinical effectiveness of ranibizumab. The review identified 4 randomised controlled trials (RCTs) that included ranibizumab in people with diabetic macular oedema – RESTORE, Diabetic Retinopathy Clinical Research Network Protocol I (DRCR.net), RESOLVE and READ-2. The manufacturer focused its submission on RESTORE and DRCR.net. The 2 other RCTs did not receive detailed attention, because the manufacturer judged them to be of less direct relevance to the decision problem. It stated that RESOLVE had limited application to the appraisal because it did not present a comparison with laser photocoagulation, which the manufacturer believed to be the most relevant comparator for an analysis concentrating on practice in the UK. The manufacturer stated that READ-2 did not provide high-quality evidence because follow-up was of shorter duration than in other included studies, the schedule for treatment differed from that in the summary of product characteristics for ranibizumab and the manufacturer believed the trial may have had methodological shortcomings. RESTORE was an industry-sponsored, multicentre (73 centres in 13 countries), sham-controlled randomised trial that compared ranibizumab plus sham laser photocoagulation (n=116) with ranibizumab plus laser photocoagulation (n=118) and laser photocoagulation plus sham injections (n=111). The trial lasted for 1 year, and participants were followed beyond 1 year, but did not necessarily remain on the treatment to which they had been randomised. RESTORE included people aged over 18 years with type 1 or type 2 diabetes and haemoglobin A1c (HbA1c) lower than 10% (86 mmol/mol). The trial protocol stated that, for each participant, only 1 eye should be treated, even if both eyes had disease. The eye with the worse vision was treated unless the investigator deemed it appropriate to treat the eye with the better vision. According to the trial protocol, 20% of participants had their better-seeing eye treated. Best corrected visual acuity (hereafter, 'visual acuity') was measured using 'ETDRS (Early Treatment Diabetic Retinopathy Study)-like' charts, in which a score of 85 letters corresponds to normal visual acuity ('20/20 vision'). An eye was eligible for randomisation if visual acuity was between 78 and 39 letters. Participants who had previous laser photocoagulation were included in the trial. Ranibizumab or sham injections were administered monthly in months 1 to 3; after this, they continued on a monthly basis until vision was stabilised for 2 visits or visual acuity reached 85 letters or more. Treatment with monthly injections was restarted if there was a decrease in visual acuity caused by progression of diabetic macular oedema and continued until the same criteria were fulfilled. Laser photocoagulation or sham laser photocoagulation was administered on day 1 and repeated at intervals of at least 13 weeks, if deemed necessary by the treating clinician. RESTORE was judged to satisfy all methodological quality criteria assessed by the manufacturer. At the time of the original submission, full details of RESTORE had not been published. DRCR.net, an RCT funded by the US National Institutes of Health, was conducted at 52 clinical sites in the United States. The trial protocol stipulated that the trial would last for 3 years; however, at the time of submission for NICE technology appraisal 237, only 12-month follow-up data were available. Participants were aged over 18 years and had type 1 or type 2 diabetes. An eye was eligible for randomisation if it had centre-involving macular oedema and a visual acuity of between 78 and 24 letters using the Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test (again, a score of 85 letters corresponds to normal visual acuity). People who had previous laser photocoagulation were included in the trial. Randomisation was by eye (rather than by participant) and a participant could have both eyes involved in the study. Each eligible eye was randomised to receive either a sham injection plus laser photocoagulation (n=293 eyes), ranibizumab plus prompt laser photocoagulation (within 3–10 days of first ranibizumab injection; n=187 eyes) or ranibizumab with the possibility of subsequent (deferred) laser photocoagulation (at least 24 weeks after the first ranibizumab injection; n=188 eyes). In practice, only 28% of the ranibizumab plus deferred laser arm received laser treatment at any time during the first study year. A fourth group in DRCR.net received triamcinolone; this group is not included in this appraisal because triamcinolone is not currently used in clinical practice in the UK for diabetic macular oedema and was not in the scope for this appraisal. The randomisation protocol specified that, in participants with 2 eligible eyes, 1 eye would receive pharmacological treatment (plus prompt or deferred laser photocoagulation) and the other eye would receive prompt laser photocoagulation alone. Investigators administered ranibizumab or sham injections every 4 weeks until the fourth study visit (that is, after 12 weeks of treatment). At subsequent 4-weekly visits, the decision to give another injection depended on visual acuity and retinal thickness of the treated eye. Investigators repeated laser photocoagulation or sham laser photocoagulation, if needed, at intervals of at least 13 weeks (3-monthly). The manufacturer judged that DRCR.net satisfied all the methodological quality criteria it assessed (although it noted that participants randomised to ranibizumab plus deferred laser were aware of their allocated treatment). The primary outcome measure of both RESTORE and DRCR.net was mean change in visual acuity in the treated eye after 12 monthly follow-up visits. The RESTORE analysis was based on the average of changes in visual acuity from baseline, measured monthly over the period from month 1 to month 12 ('mean average change'), whereas DRCR.net compared the visual acuity measured at baseline with that measured at 12 months ('mean change'). In RESTORE, the visual acuity of eyes randomised to ranibizumab monotherapy rose by a mean average of 6.1 letters, and eyes randomised to ranibizumab plus laser photocoagulation gained a mean average of 5.9 letters. In RESTORE, eyes randomised to laser photocoagulation alone gained fewer letters (0.8) than eyes randomised to either ranibizumab-containing arm (p<0.001). In DRCR.net, visual acuity rose by an average of 9 letters after 12 months in eyes randomised to ranibizumab plus either prompt or deferred laser photocoagulation compared with an average of 3 letters in eyes randomised to laser photocoagulation alone (p<0.001 for either ranibizumab-containing arm compared with laser photocoagulation alone). The manufacturer provided a meta-analysis of mean changes from baseline visual acuity at 12 months combining results from RESTORE and DRCR.net. This suggested that the visual acuity of eyes treated with ranibizumab plus laser photocoagulation gained an average of 5.83 more letters than the visual acuity of eyes treated with laser photocoagulation alone (95% confidence interval 4.07 to 7.59, p<0.001; fixed-effects and random-effects models estimate identical results). In both RESTORE and DRCR.net, a series of subgroup analyses examined the primary outcome measure in participants categorised according to baseline characteristics. In all subgroups analysed in both trials, the visual acuity of participants randomised to ranibizumab-containing treatment improved more than the visual acuity of those randomised to laser photocoagulation. The manufacturer's submission noted that, in RESTORE, gains in visual acuity associated with ranibizumab were greatest in participants with baseline central retinal thickness of 300 micrometres or more and participants with a baseline visual acuity of fewer than 74 letters; the manufacturer presented no evidence on the statistical significance of these differences. An alternative approach to presenting the results of visual acuity testing reports the proportion of participants in whom the treated eye improved or worsened by an amount reflecting a clinically significant change in vision, usually a gain or loss of 10 letters. The manufacturer's submission reported that, in RESTORE, the proportions of participants gaining 10 letters in visual acuity in their treated eye after 12 months of treatment were 37% in those randomised to ranibizumab monotherapy, 43% in those randomised to ranibizumab plus laser photocoagulation and 15% in those randomised to laser photocoagulation alone (p<0.001 for either ranibizumab-containing arm compared with laser photocoagulation alone; p-values taken from European Medicines Agency Assessment Report). The proportions of participants who lost 10 letters of visual acuity in their treated eye after 12 months were 3%, 4% and 13% respectively (p<0.05 for either ranibizumab-containing arm compared with laser photocoagulation alone; p values calculated by the NICE technical team). In DRCR.net, after 12 months of treatment a gain of 10 letters in visual acuity was reported in 47% of eyes treated with ranibizumab plus deferred laser photocoagulation, 51% of eyes treated with ranibizumab plus prompt laser photocoagulation and 28% of eyes treated with laser photocoagulation alone (p<0.001 for either ranibizumab-containing arm compared with laser monotherapy). After 12 months a loss of 10 letters in the treated eye was reported in 3%, 3% and 13% of eyes respectively (p≤0.001 for either ranibizumab-containing arm compared with laser photocoagulation alone). The manufacturer provided a meta-analysis of categorical visual acuity data from RESTORE and DRCR.net after 12 months of treatment. This suggested that the visual acuity of eyes randomised to ranibizumab plus laser photocoagulation was approximately twice as likely to improve by 10 letters than the visual acuity of eyes randomised to laser photocoagulation alone (relative risk=2.15, 95% CI 1.43 to 3.22, p<0.001; random-effects model; fixed-effects model produced similar results). Eyes treated with ranibizumab plus laser photocoagulation were over 3 times less likely to lose 10 letters in visual acuity (relative risk=0.28, 95% CI 0.15 to 0.53, p<0.001; random-effects model; fixed-effects model produced similar results). RESTORE measured vision-related quality of life using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), which has 25 questions designed to measure the effect of visual impairment on daily functioning and quality of life. The mean changes from baseline in the composite score and in subscales related directly to vision were in favour of ranibizumab compared with laser photocoagulation alone (p0.05). The RESTORE investigators also administered assessments of health-related quality of life, including EuroQol-5D (EQ-5D). The manufacturer did not report the results directly, although its economic model relied on an analysis incorporating the EQ-5D data (see section 3.12). The manufacturer stated that ranibizumab has a favourable safety profile, emphasising that extensive evidence is available from the use of ranibizumab in the treatment of wet age-related macular degeneration. Although none of the RCTs of ranibizumab in diabetic macular oedema were designed primarily to assess safety outcomes, no significant differences were observed between arms in the frequency of ocular and non-ocular adverse events. None of the studies reported death rates. # Cost effectiveness The economic evidence provided by the manufacturer in its original submission comprised a brief literature review (identifying no relevant published analyses) and a de novo cost–utility analysis. The cost–utility analysis used a Markov model simulating cohorts of people with diabetic macular oedema receiving ranibizumab monotherapy, ranibizumab plus laser photocoagulation, or laser photocoagulation alone. The model had 3-monthly cycles and a base-case time horizon of 15 years. It assumed (simulated) a starting population with diabetic macular oedema with a mean age of 63 years and visual acuity scores of between 75 and 36 letters. Health states were defined by visual acuity in the treated eye, rather than both eyes, and used 10-letter categories (with the exception of the best and worst states), resulting in 8 health states excluding death: 0–25 letters, 26–35 letters, 36–45 letters, 46–55 letters, 56–65 letters, 66–75 letters, 76–85 letters and 86–100 letters. Based on the average number of injections received in RESTORE, the manufacturer's original model included 7 ranibizumab injections in the first year for both the ranibizumab monotherapy arm and the combination therapy arm. The manufacturer included an additional stopping rule, assuming that people with a visual acuity of 76 letters or more in the treated eye would not receive active treatment and would incur no treatment costs. In the second year of the model, based on data from DRCR.net, the manufacturer assumed 3 further ranibizumab injections in the ranibizumab monotherapy arm and 2 further ranibizumab injections in the combination therapy arm. For both the combination therapy arm and the laser photocoagulation alone arm, the model assumed 2 laser photocoagulation treatments in the first year and 1 additional laser treatment in the second year. The original model did not simulate any ranibizumab treatment or laser photocoagulation after the second year. The manufacturer accepted that, in practice, additional laser photocoagulation would take place after the second year, but assumed that there would be no difference between the modelled arms in this respect and therefore any costs and effects would cancel each other out. To estimate the health-related quality of life associated with each health state corresponding to vision in the model, EQ-5D data from RESTORE were transformed to utility values using standard social tariffs and then related to visual acuity in the treated eye using linear regression. In this way, a mathematical relationship was assumed between visual acuity in the treated eye and the health-related quality of life of people with diabetic macular oedema. Tests of interaction demonstrated that neither treatment allocation nor duration of treatment at the time of measurement had a significant impact on the relationship between utility and visual acuity category. Therefore, the utility value was derived for each visual acuity category using the whole data set, without any adjustment variables. The results of the regression suggested that, depending on visual acuity in the treated eye, the utility value ranged from 0.860 to 0.547. The utility value for the best health state (visual acuity 86–100 letters) resulting from the regression was 0.831; however, this result was considered anomalous, because it was based on relatively few data points and it was thought unrealistic that utility should be worse than in the next-best state, in which vision is inferior. Therefore, the manufacturer set the utility value for a visual acuity of 86–100 letters to be equal to the utility value for a visual acuity of 75–85 letters (that is, 0.860). The manufacturer did not apply any treatment-specific utilities and specifically did not apply a decrement in utility value to reflect adverse effects associated with the treatments. Depending on the period of follow-up being simulated, the model used 3 different sets of data and assumptions to estimate the probability of changing between visual acuity states (transition probabilities). The first phase of the model reflected the first year of treatment, for which the manufacturer drew transition probabilities directly from changes in visual acuity observed among individual participants in RESTORE. In the original model, this data set included a proportion of treated eyes with a visual acuity of more than 75 letters at baseline, although eyes with equivalent vision were not simulated in the model. In the second and third phases of the model, the manufacturer based the transition probabilities on a 3-way matrix that reflected the estimated likelihood of improvement, deterioration or no change in the visual acuity of a given eye. The manufacturer assumed that the same probabilities applied to all states (with the exception of assuming that an eye with the best possible visual acuity could not improve and that an eye with the worst possible visual acuity could not worsen). The second phase of treatment reflected a period during which visual acuity was assumed to remain constant. This was based on the DRCR.net study, which the manufacturer interpreted as showing that average visual acuity was maintained between 12 months and 24 months for all treatments. Therefore, the manufacturer assumed equal probabilities of improving or worsening in all model arms. In the original model, this phase comprised the second year of treatment only. In the third phase, the model assumed no treatment effect: based on an informal review of epidemiological literature, the manufacturer assumed quarterly probabilities of 0.025 for improvement and 0.035 for deterioration in all arms (implying that the probability of visual acuity staying the same was 0.94 in any quarter). In the original model, this final phase began at the start of year 3, and continued until the end of the model. According to this approach, the relative difference in treatment effect observed at the end of the initial treatment phase (year 1) was preserved for the remainder of the model. Thus, beyond 1 year, the visual acuities of participants previously treated with ranibizumab remained constant during the second year and after that declined at the same rate as the visual acuities of participants previously treated with laser photocoagulation. As a result, the relative difference in vision between treatments estimated at the end of the first year was preserved for the remainder of the model (that is, for the next 14 years). In its model, the manufacturer assumed that the probability of dying is the same for all health states (so no additional risk of death was associated with worsening vision). Mortality rates were derived from life tables for England and Wales, modified by a relative risk representing the additional hazard of death for the modelled cohort when compared with the general population. In the original model, the manufacturer used a relative risk of 1.27, drawn from published literature comparing the risk of death for people with clinically significant diabetic macular oedema with the risk of death for people with diabetes, but without diabetic macular oedema. The manufacturer modelled adverse events on the basis of observed, treatment-specific rates of 4 events (cataract, endophthalmitis, retinal detachment and vitreous haemorrhage) in a pooled analysis of RESTORE and DRCR.net. The manufacturer included only the costs associated with these complications; it did not assume that the presence of these adverse events lowers quality of life (utility). The cost of ranibizumab included in the original model was £761.20 per injection (this was before the manufacturer submitted a patient access scheme; the manufacturer submitted the patient access scheme after publication of the appraisal consultation document for NICE technology appraisal guidance 237, and revised it for the rapid review submission). Unit costs of a visit to an eye clinic for a check-up and/or treatment were based on NHS reference costs (2008/09). The manufacturer assumed that treatment with both ranibizumab and laser photocoagulation occurs on an outpatient basis, and costs £150 per visit. For combination therapy, the manufacturer assumed that ranibizumab injections and laser photocoagulation would occur at the same visit, and cost £184 per visit. The manufacturer assumed that the full cost of laser photocoagulation is encompassed within the NHS reference cost for the clinic visit and included no additional costs for buying and maintaining the equipment. The costs (£126 each) of visits to monitor people (for vision and recurrence of disease) were also included: in the original model, people receiving ranibizumab monotherapy had 12 visits in the first year and 10 visits in the second year; people receiving combination therapy had 12 visits in the first year and 8 visits in the second year; those receiving laser photocoagulation alone in the first and second years, and all people from the third year onwards, had 4 visits per year. For the ranibizumab-containing arms, a visit for treatment was assumed to include monitoring as well. The same assumption was not applied for people receiving laser photocoagulation alone; that is, people receiving laser photocoagulation needed separate visits for treatment and monitoring. In the model, the manufacturer applied estimated costs associated with severe vision loss for people with the lowest visual acuity in the treated eye (0–25 or 26–35 letters), regardless of vision in the non-treated eye. These costs reflected the additional resource use associated with people who are eligible to register as severely sight impaired (blind). The costs accounted for a range of items including low-vision aids, rehabilitation, residential care, district nursing, community care and the cost of treating complications including depression and falls. The manufacturer drew cost data largely from a published costing study of blindness in the UK that focused on people with age-related macular degeneration (Meads and Hyde 2003), with costs updated or adjusted for inflation as appropriate. The total cost applied was £6067 in the first year and £5936 in subsequent years. In its deterministic base case, the manufacturer's original model estimated an incremental cost-effectiveness ratio (ICER) of £19,075 per quality-adjusted life year (QALY) gained for ranibizumab monotherapy compared with laser photocoagulation alone. The model predicted that combining laser photocoagulation with ranibizumab would be more expensive and less effective than ranibizumab alone; that is, ranibizumab alone dominated combination therapy. The manufacturer also presented a series of deterministic sensitivity analyses in which single parameters (or related groups of parameters) were varied across plausible ranges. These analyses suggested that the model was most sensitive to the time horizon: when the time horizon was limited to 10 years, the estimated ICERs for ranibizumab monotherapy compared with laser photocoagulation alone rose by approximately 50%, to £30,367 per QALY gained. Most sensitivity analyses repeated the base-case finding that ranibizumab monotherapy dominates combination therapy with ranibizumab plus laser photocoagulation. Probabilistic sensitivity analysis (based on 10,000 Monte-Carlo simulations) suggested that the probability of ranibizumab monotherapy providing best cost–utility compared with laser alone was 49.3% and 76.8% at thresholds of £20,000 and £30,000 per QALY gained respectively. The probability of combination therapy providing best cost–utility compared with ranibizumab monotherapy was 19.4% and 17.8% at the same thresholds (these estimates have been corrected from the manufacturer's submission for NICE technology appraisal guidance 237 by the NICE technical team and verified by the ERG). The manufacturer also presented a series of deterministic subgroup analyses in which first-year transition probabilities were derived from analyses of the RESTORE trial limited to participants with the characteristic(s) in question. The manufacturer changed no other parameters in the model. The manufacturer noted that several of the analyses were based on small numbers of participants. There were large variations between the results of some subgroups: Limiting the analysis to people with good glycaemic control (HbA1c less than 8%) produced an ICER of £13,196 per QALY gained for ranibizumab monotherapy compared with laser photocoagulation. In people with poorer glycaemic control (HbA1c 8% or more) ranibizumab monotherapy had an ICER of £36,383 per QALY gained when compared with laser photocoagulation. In people who previously had laser photocoagulation, ranibizumab monotherapy was associated with an ICER of £29,660 per QALY gained compared with laser photocoagulation. The equivalent figure for the subgroup who had not previously had laser photocoagulation was £12,675 per QALY gained. The ICERs for ranibizumab monotherapy compared with laser photocoagulation in people with baseline visual acuity of 36–45 letters, 46–55 letters, 56–65 letters and 66–75 letters were £52,704, £7645, £42,477 and £12,198 per QALY gained respectively.However, the manufacturer considered that in light of the limitations related to the small number of trial participants in some of the subgroups, the relative cost effectiveness of ranibizumab monotherapy in these subgroups is uncertain and should be interpreted with caution. ## Evidence Review Group comments on the manufacturer's original submission The ERG noted that the manufacturer's original submission did not contain a comparison of ranibizumab with bevacizumab, which the appraisal scope lists as a comparator. The ERG report stated that, although it does not have a marketing authorisation for use in diabetic macular oedema in the UK, bevacizumab is used by ophthalmologists in some NHS centres if laser photocoagulation has failed to produce a response or as an alternative treatment if long-term treatment with laser photocoagulation is considered a risk. The ERG questioned the manufacturer's argument that there is a lack of robust evidence on clinical effectiveness or safety of bevacizumab in the treatment of diabetic macular oedema. In its report, the ERG provided details of 29 published studies it considered relevant to the use of intraocular bevacizumab in diabetic macular oedema, including 7 randomised comparisons with laser photocoagulation and/or sham injections. The ERG noted that some of the evidence evaluates the long-term effects of bevacizumab and some compares different dosages. The ERG stated that the manufacturer's view of bevacizumab was 'unjustifiably negative' and expressed the opinion that the evidence base should have been sufficient to enable an indirect comparison of ranibizumab with bevacizumab. # Additional evidence to the original submission submitted by the manufacturer during consultation for NICE technology appraisal guidance 237 In response to consultation on the original appraisal consultation document, the manufacturer submitted a revised cost–utility analysis, addressing reservations the Committee had expressed about the original model and submitted a first patient access scheme. Several consultees and commentators, including patient and professional groups, agreed with the Committee that the manufacturer's original economic model had given an unrealistic representation of likely clinical practice in some respects. The manufacturer stated that the revised model should be 'considered a better-seeing eye model' – that is, it should be thought of as simulating a treatment strategy in which people with diabetic macular oedema received treatment in their better-seeing eye only. This was a change from the manufacturer's original economic analysis, in which the modelled treatment strategy assumed that people would largely receive treatment in their worse-seeing eye. The manufacturer observed that cost–utility models produce lower ICERs when simulating treatment in the better-seeing eye of people with diabetic macular oedema than when simulating treatment in the worse-seeing eye. This is partly because the health-related quality of life of people with visual impairment is associated primarily with vision in the better-seeing eye and partly because the costs of severe visual impairment depend on vision in the better-seeing eye. Thus, in general, treatments that maintain or improve vision in the better-seeing eye will be favoured in economic analyses. The manufacturer cited the precedent of NICE technology appraisal guidance 155 (Ranibizumab and pegaptanib for the treatment of age-related macular degeneration) in which the Assessment Group's model had explicitly assumed that only the better-seeing eye was treated, but the Committee had made recommendations on the assumption that treatment would be given to the first eye to present clinically, be it the better- or worse-seeing eye. For these reasons, the manufacturer felt it would be helpful to present the Committee with a model that explicitly assumed treatment of the better-seeing eye, although the data on which the model was based were drawn predominantly from people whose worse-seeing eye had been treated, and it did not otherwise change the way the model associated vision in the worse-seeing eye with quality of life. The manufacturer accepted the view the Committee had expressed in the appraisal consultation document that its original model had underestimated the hazard of death associated with diabetic macular oedema by not including the hazard associated with diabetes itself. Its revised model used a higher relative risk of death of 2.45 for people with diabetic macular oedema compared with the general population. The manufacturer derived this value by combining an estimate of the additional hazard of death associated with diabetes (1.93 compared with the general population, from an English epidemiological study by Mulnier et al. 2006) with an estimate of the additional hazard of death independently associated with macular oedema among people with diabetes in Wisconsin, USA (1.27, as reported by Hirai et al. 2008). The manufacturer stated that the revised relative risk of 2.45 was more plausible, although it might overestimate the true hazard associated with diabetic macular oedema. It noted that the revised model predicted that 43% of the cohort would remain alive after 15 years (at age 78), whereas the original model had suggested that 65% of people would be alive at that time. In NICE technology appraisal guidance 237 the Committee considered at its first meeting that, by assuming people whose visual acuity rose to 76 letters or higher would stop receiving ranibizumab, the manufacturer's original model had not reflected likely clinical practice. Acknowledging this view, the manufacturer removed the stopping rule from the base case of its revised model. For related reasons, the manufacturer also revised the effectiveness evidence used to simulate the first year of treatment. The original model drew transitions between visual acuity states from those observed in the whole population in RESTORE, including participants whose visual acuity had been higher than 75 letters at the start of treatment. In its revised model, the manufacturer calculated visual acuity state transitions in the first year of treatment using only participants whose visual acuities matched those of the assumed starting population in the model (that is, only people with baseline visual acuities of 36–75 letters). The manufacturer accepted that there were uncertainties around the assumption in its original model that people would need only 2 years of treatment with ranibizumab. Its revised model assumed that people receiving ranibizumab would receive an average of 2 injections in a third year of treatment and 1 injection in a fourth year of treatment. In the laser photocoagulation arm, the model assumed once-yearly treatments for years 3 and 4. To reflect the benefit that would accrue from these additional treatments, the manufacturer extended its original assumption that visual acuity would be maintained in all arms in year 2 of the model to encompass years 3 and 4 – that is, vision remained stable from years 2 to 4 and then declined equally in the group treated with ranibizumab and the group treated with laser photocoagulation. When considering the manufacturer's original model, the Committee had expressed concern that it did not account for the need to treat both eyes in a significant proportion of people. The manufacturer did not alter its base case to address this issue. However, it provided a scenario analysis, using its revised model, which simulated treatment in both eyes for 35% of people. This analysis assumed that, in people with bilateral disease, both eyes would be treated and monitored at the same visit, with ranibizumab drug and treatment costs doubled. The analysis applied reduced costs associated with severe visual impairment because fewer people would go blind in both eyes. The analysis assumed that treating the second eye would result in utility gains a quarter the magnitude of those achieved by treating the first eye; this is because the health-related quality of life of people who can see well with both eyes is only a little better than the health-related quality of life of people who can see well with 1 eye. The model calculated this figure by applying a 25% uplift to the QALYs generated by ranibizumab. In NICE technology appraisal guidance 237, the Committee had noted that the range of utility values used in the manufacturer's original model was broader than would be expected according to the assumptions of the model. The Committee had suggested that 1 possible explanation for this was that the regression model used to define the relationship between visual acuity and utility (see section 3.12) had not accounted for confounding variables reflecting the effect of diabetic comorbidities on health-related quality of life. To address this point, the manufacturer's consultation comments included an 'extended' analysis, which re-estimated the relationship between visual acuity and utility using a model containing additional covariates: age, sex, duration of diabetes, blood pressure control at baseline (categorised dichotomously), baseline HbA1c and a variable indicating whether each treated eye was the participant's better- or worse-seeing one. This analysis suggested that, apart from visual acuity, only sex was a significant predictor of utility (p<0.05). The manufacturer concluded that the utility function used in the original model had not been confounded by factors relating to diabetic comorbidities and retained the same utility values in its revised base case. However, the manufacturer also presented a scenario analysis that used the utility values estimated in the extended regression analysis, including all non-significant covariates. When considering the manufacturer's original model, the Committee had questioned the validity of assuming that the relative improvement in vision achieved in the first year would persist for the duration of the model (see section 3.13), that is, that vision would deteriorate equally in the groups. The manufacturer responded to this point in its consultation comments, arguing that there was no evidence to suggest that gains in visual acuity would diminish at different rates depending on the treatment. It also cited the precedent of NICE technology appraisal guidance 155, in which the Committee had accepted an analogous approach, as a reasonable basis for decision-making. In NICE technology appraisal guidance 237, the Committee had expressed concern that the unit cost of injection procedures used in the manufacturer's original model (£150; see section 3.15) might underestimate the true costs of administering ranibizumab. In its response to consultation, the manufacturer provided a 'bottom-up' estimate of the cost of an intravitreal injection visit, compiling separate estimates of the costs associated with consulting individual members of an ophthalmology clinic team and including overheads. This resulted in an estimated unit cost of £142.91, which the manufacturer took as evidence that the value used in the original model had accurately reflected the administration costs of ranibizumab. The manufacturer emphasised that charges applied to visits for ranibizumab injections are subject to local agreements between commissioners and providers, and may not always reflect the true costs of service delivery. In NICE technology appraisal guidance 237, the Committee had initially concluded that the manufacturer's original model overestimated the cost savings of ranibizumab-based therapy that would be achieved by avoiding or delaying severe vision loss. The model drew the costs of severe vision loss from visual acuities that fell below 35 letters in treated eyes, but the data sources from which the manufacturer drew these costs used visual acuity in the better-seeing eye. By stating that its revised model should be considered to simulate treatment in the better-seeing eye, the manufacturer suggested it had removed this problem. The results of the manufacturer's revised model in NICE technology appraisal guidance 237 included a subgroup analysis estimating the cost–utility of ranibizumab in people with the greatest degree of macular oedema (central foveal thickness greater than 400 micrometres). The manufacturer provided this analysis in response to comments from clinical specialists, reported in the original appraisal consultation document, suggesting that laser photocoagulation may be less effective in a thicker, more oedematous retina. For this reason, the manufacturer stated that such people represented a 'clinically plausible' subgroup in which ranibizumab could be expected to have a greater relative effect when compared with laser photocoagulation. The manufacturer confirmed that the trial protocol for RESTORE had pre-specified subgroup analyses according to 3 categories of central foveal thickness: less than 300 micrometres, 300–400 micrometres and greater than 400 micrometres. In its response to consultation, the manufacturer stated that it had carried out tests of the statistical significance of differences in clinical outcome according to baseline central foveal thickness category. However, the results of these tests were not presented in the submitted documentation. The manufacturer's revised model also included a patient access scheme reflecting its agreement with the Department of Health in 2011 that ranibizumab will be made available to the NHS at a discounted price (level of discount confidential; see section 2.4). The manufacturer's revised base case focused solely on the comparison of ranibizumab monotherapy with laser photocoagulation. It estimated that ranibizumab is associated with an ICER of £30,277 per QALY gained (disaggregated cost and QALY estimates are unavailable because of the confidentiality of the patient access scheme). In the subgroup of people with central foveal thickness greater than 400 micrometres, the equivalent ICER was £21,418 per QALY gained. The manufacturer's scenario analysis simulating treatment in both eyes for 35% of people resulted in an ICER of £44,355 per QALY gained for ranibizumab monotherapy compared with laser photocoagulation. In the subgroup of people with central foveal thickness greater than 400 micrometres, the equivalent ICER was £35,719 per QALY gained. The manufacturer provided a scenario analysis adopting utilities re-estimated from RESTORE data using an extended model with additional covariates reflecting baseline characteristics of participants and factors relating to diabetic comorbidities (see section 3.26). This resulted in an increase in the ICER from its base case of £30,277 per QALY gained to £33,857 per QALY gained for ranibizumab monotherapy compared with laser photocoagulation. A further series of scenario analyses adopted alternative estimates of utility drawn from various published sources. When utility values from the better-seeing eye study by Lloyd et al. were used, the ICER was £24,779 per QALY gained. When utility was estimated according to an equation published by Sharma et al., associating visual acuity in the better-seeing eye with health-related quality of life, the ICER was between £12,312 and £12,610 per QALY gained, depending on the version of the equation used. A final analysis adopted utility values estimated in a study by Czoski-Murray et al. (referred to as Brazier et al. in NICE technology appraisal guidance 237), in which members of the general public valued levels of visual impairment that were simulated by custom-made contact lenses, using the time trade-off method. Participants wore the same lenses in both eyes, so the resulting utility values reflected bilateral impairment of vision. This was the source of utility values the Committee had judged most accurately reflected the health-related quality of life associated with visual impairment in NICE technology appraisal guidance 155. When these values were used in the revised ranibizumab model, the ICER was £23,664 per QALY gained. In its response to consultation on the appraisal consultation document for NICE technology appraisal guidance 237, the manufacturer provided additional arguments on the suitability of bevacizumab as a comparator. The manufacturer stated that bevacizumab could not be considered routine or best practice, because NHS experience is 'limited to experimental or compassionate use' and 'there are no robust data to demonstrate the safety, effectiveness and quality of the product'. The manufacturer argued that the optimum dose of bevacizumab for intraocular use is not established. It summarised 'emerging safety signals for the use of unlicensed intravitreal bevacizumab', and emphasised that any cost–utility analysis including bevacizumab would have to include the costs of an NHS pharmacovigilance programme. The manufacturer also reviewed the evidence that might be used to perform an indirect comparison of ranibizumab with bevacizumab. It concluded that significant methodological and clinical differences between studies precluded a valid analysis. ## Evidence Review Group's comments on the manufacturer's revised model during NICE technology appraisal guidance 237 The ERG reviewed the manufacturer's consultation comments and revised economic model. It stated that the revised model's updated estimate of the relative risk of death for people with diabetic macular oedema compared with the general population (relative risk 2.45; see section 3.22) was reasonable. It agreed with the manufacturer that this figure may be an overestimate of the true additional hazard associated with diabetic macular oedema, but emphasised that it was a more realistic figure than that used in the original model. The ERG noted the modified assumptions about duration of treatment in the manufacturer's revised model (see section 3.24). It had no comments about the manufacturer's new assumptions about additional treatments in years 3 and 4 of the model. However, the ERG emphasised that significant uncertainty remained about whether people with diabetic macular oedema would need injections of ranibizumab beyond the fourth year of treatment. The ERG reviewed the manufacturer's scenario analysis as part of its revised model, which assumed that 35% of people with diabetic macular oedema would need treatment in both eyes (see section 3.25). It noted that the assumed benefit of treatment in the second eye (a 25% uplift in incremental QALY gain) did not appear to be evidence-based. It also expressed the view that, in people in whom the better-seeing eye is treated, the other eye would receive the same therapy unless it had already suffered irreparable visual loss. As a result, the ERG suggested that an ophthalmologist is likely to offer treatment in both eyes or only the worse-seeing eye. The ERG reviewed the manufacturer's comments about the utility values used to estimate health-related quality of life in its revised model, and its additional analyses exploring alternative assumptions. The ERG expressed continuing concern that the analyses did not account for the covariance between visual acuity in the treated and untreated eyes of participants at baseline – that is, it was possible that health-related quality-of-life measurement was strongly influenced by vision in the untreated eye, which was unlikely to be similar to vision in the treated eye. The ERG suggested that it would have been possible to avoid this problem by basing the regression model on the impact over time of treatment on utility – that is, by modelling the relationship between changes in visual acuity and changes in health-related quality of life, rather than modelling absolute levels of both. The ERG stated that the bottom-up costing exercise carried out by the manufacturer to validate the unit cost of ranibizumab injection procedures (see section 3.28) was reasonable and useful. It noted that, if the additional cost of consumables (instruments, cotton wool, a drape and a syringe) were included, the total estimate would reach the £150 unit cost used in the model. The ERG expressed support for the manufacturer's assumption that all ranibizumab injections would take place on an outpatient basis. The ERG reviewed the manufacturer's subgroup analysis presenting the cost–utility of ranibizumab in people with central foveal thickness greater than 400 micrometres. It accepted the theoretical basis of the subgroup, agreeing that laser photocoagulation is expected to be less effective in a very thick retina. Because it noted that the manufacturer had presented subgroup results only for people with the thickest retinas, the ERG provided equivalent data for the other categories of retinal thickness analysed in RESTORE. For people with central foveal thickness less than 300 micrometres (49 trial participants), the ICER for ranibizumab compared with laser photocoagulation was £27,496 per QALY gained. For people with central foveal thickness of 300–400 micrometres (62 trial participants), the ICER for ranibizumab compared with laser photocoagulation was £386,321 per QALY gained. The ERG noted that this pattern of cost-effectiveness estimates was erratic and should be interpreted with caution. It commented that the calculations were based on small sample sizes, although it noted that the subgroup presented by the manufacturer – people with central foveal thickness greater than 400 micrometres (see section 3.32) – represented around half of the population recruited in RESTORE (114 of 217 participants randomised to ranibizumab monotherapy or laser photocoagulation). The ERG noted that the manufacturer's model (in both its original and revised versions) assumed that an administration visit for a ranibizumab injection can double as a monitoring visit but an administration visit for laser photocoagulation cannot. The ERG provided analyses removing this difference. When it was assumed that people receiving ranibizumab need additional monitoring visits (as for laser photocoagulation), the ICER rose to £37,673 per QALY gained; when it was assumed that people receiving laser photocoagulation do not need additional monitoring visits (as for ranibizumab), the ICER was £33,074 per QALY gained. The ERG responded to the manufacturer's comments on the suitability of bevacizumab as a comparator. It disagreed with the manufacturer's suggestion that the optimum dose of bevacizumab is unknown, suggesting that the standard dose is 1.25 mg. The ERG reiterated its view that safety data are available on the use of bevacizumab. It emphasised that the incidence of adverse events is low with both ranibizumab and bevacizumab. The ERG noted that a recent head-to-head trial of ranibizumab and bevacizumab for age-related macular degeneration (CATT ) showed equivalent efficacy between the 2 technologies. # Rapid review of NICE technology appraisal guidance 237 patient access scheme NICE technology appraisal guidance 237 did not recommend ranibizumab for the treatment of visual impairment due to diabetic macular oedema. After publication of NICE technology appraisal guidance 237, the manufacturer submitted a revised patient access scheme in which it applied a revised discount to ranibizumab for all indications (see section 2.4) to be considered as a rapid review of the original guidance. As this was a rapid review, the manufacturer did not submit any additional clinical effectiveness data. However, in addition to the revised patient access scheme, the manufacturer submitted an amended economic model that attempted to address 6 specific concerns that were raised by the Committee in section 4.29 of NICE technology appraisal guidance 237 as follows: By not accounting for the need to treat both eyes in a large proportion of people with diabetic macular oedema, the manufacturer's revised base-case model underestimated the benefits and – to a greater degree – the costs of treatments. The manufacturer's scenario analysis simulating treatment in both eyes for 35% of people provided a more realistic reflection of likely clinical practice. The range of utility values used in the manufacturer's revised base case was broader than would be expected according to the assumptions of the model. The Committee preferred the manufacturer's scenario analysis adjusting for factors that may influence the relationship between visual acuity and health-related quality of life. The model underestimated the amount of ranibizumab that people with diabetic macular oedema were likely to need over time. Basing the number of injections for year 2 of the model's ranibizumab monotherapy arm on experience in DRCR.net overlooks the fact that the participants in the trial also received laser photocoagulation, which clinicians believe may have a ranibizumab-sparing effect. The declining number of ranibizumab injections assumed in years 3 and 4 is not evidence-based, and is unlikely to lead to stable vision during that period, as assumed. It may also have been unrealistic to assume that ranibizumab treatment will not continue beyond 4 years. The model's assumption that the relative benefit achieved during the treatment phase lasts indefinitely was unrealistic. If NICE technology appraisal guidance 155 is considered as a precedent, then it should be noted that the model in that appraisal had a shorter time horizon, which limited the Committee's uncertainty about extrapolating treatment effects into the future. The model applied unequal assumptions about treatment and monitoring visits for people treated with ranibizumab and those treated with laser photocoagulation. The manufacturer's model overestimated the degree of glycaemic control that would be expected in people treated in clinical practice in the UK. In response to the Committee's concerns, the manufacturer amended its economic model with the following revisions: To approximate an ICER for treating both eyes, the manufacturer multiplied the ICER from the revised model, considered by the manufacturer to represent a better-seeing eye model, by a factor of 1.5. The manufacturer noted that this approach was consistent with that taken by the Committee in NICE technology appraisal guidance 155, when it observed that a policy of treating the first eye to come to clinical attention would result in substantially higher costs, but fewer savings and lower utility gains, than a policy of treating only the better-seeing affected eye. The manufacturer did not make any additional changes to the model to address this issue. To address the Committee's concerns about utility, the manufacturer considered that the utility values estimated in a study by Czoski-Murray et al. (2009) were those preferred by the Committee. In this study, the investigators developed a regression model that estimated the contribution of visual acuity (measured by the LogMAR scale) to health-related quality of life, adjusting for age. The regression model was subsequently used by the manufacturer to estimate utility values for each of the 8 visual acuity health states (defined by the ETDRS scale) after converting the upper and lower limits of the ETDRS scale to its LogMAR equivalent. Based on a mean age of 65 years, the estimated utility values used in the manufacturer's new base-case analysis ranged from 0.869 for the best health state to 0.353 for the worst health state. To address the Committee's concerns about the number of ranibizumab injections people with diabetic macular oedema would need, the manufacturer assumed that people receiving ranibizumab alone would need a total of 14 ranibizumab injections over 4 years: 7 injections in the first year, 4 injections in the second year, and 3 injections in the third year. These assumptions were based on a 2-year extension of the RESTORE study, which showed that trial participants needed a decreasing number of ranibizumab injections from the first year to the third year. The manufacturer assumed that no injections were needed in the fourth year. The manufacturer also carried out a threshold analysis to estimate the maximum number of ranibizumab injections that could be administered over the time horizon of the model while maintaining an ICER below £30,000 per QALY gained. To address the Committee's concerns about extrapolating the relative benefit of treatment with ranibizumab beyond the initial treatment phase, the manufacturer reduced the time horizon of the model from 15 years to 10 years. The manufacturer also conducted a threshold analysis to explore the highest rate at which vision could worsen in people treated with ranibizumab and maintain an ICER below £30,000 per QALY gained. To do this, the manufacturer assumed from the fourth year onwards, quarterly probabilities of 0.025 for improvement and 0.055 for deterioration for people receiving ranibizumab monotherapy and quarterly probabilities of 0.025 for improvement and 0.035 for deterioration for people receiving laser photocoagulation alone. To address the Committee's concerns about care provided during visits to the eye clinic, the manufacturer assumed that for people receiving either ranibizumab monotherapy or laser alone, a visit for treatment also included monitoring. People receiving ranibizumab monotherapy visited the eye clinic 12 times in the first year, 8 times in the second year and 6 times in the third year; those receiving laser photocoagulation alone had 4 visits per year in the first, second and third years, and people on either treatment had 2 visits per year in the fourth year. Despite the Committee's concerns that the ICER for ranibizumab monotherapy compared with laser photocoagulation would be higher in people with poor glycaemic control, the manufacturer did not present further subgroup analyses according to the degree of glycaemic control. The manufacturer noted the Committee's considerations in NICE technology appraisal guidance 237 that analyses restricted to people with good glycaemic control (HbA1c less than 8%) and poor glycaemic control (HbA1c 8% or more) were 'exploratory'. The manufacturer also suggested that these subgroup analyses need careful interpretation because of the small sample sizes, which resulted in a very small number of people in extreme health states influencing the results. The manufacturer's model for the rapid review submission, including the revised patient access scheme, compared ranibizumab monotherapy with laser photocoagulation. The manufacturer presented separate ICERs for treating the better-seeing eye and for treating both eyes. In the base case, the manufacturer estimated that treating the better-seeing eye with ranibizumab was associated with an ICER of £14,137 per QALY gained and that treating both eyes with ranibizumab was associated with an ICER of £21,205 per QALY gained. The manufacturer estimated that an additional 4 injections of ranibizumab can be given in years 4 to 9 (resulting in a total of 18 injections) for the ICER when treating both eyes to remain below £30,000 per QALY gained. The manufacturer also estimated that the rate of deterioration in vision (visual acuity) for people treated with ranibizumab in both eyes from year 4 onwards would need to be more than 1.5 times higher than that for people treated with laser photocoagulation for the ICER to increase to £30,000 per QALY gained. The manufacturer conducted one-way sensitivity analyses that suggested that the model was most sensitive to changes to the time horizon and to utility values. When the time horizon was limited to 5 years the ICER associated with treating both eyes was £41,568 per QALY gained. When the manufacturer instead used utility values from the study by Lloyd et al. (representing the contribution to utility from the better-seeing eye), the ICER associated with treating both eyes was £43,716 per QALY gained. The manufacturer provided no probabilistic sensitivity analyses in its rapid review submission. To address the Committee's concerns about the validity of the manufacturer's previous subgroup analyses (submitted in response to the consultation on the original appraisal consultation document for NICE technology appraisal guidance 237) according to retinal thickness and the inconsistent relationship between retinal thickness and cost effectiveness, the manufacturer presented additional subgroup analyses according to the degree of retinal thickness. For the rapid review, the manufacturer presented subgroup analyses based on central retinal (rather than foveal) thickness, arguing that this more reliably measures retinal thickness than central foveal thickness. The manufacturer acknowledged that the pattern of cost-effectiveness estimates for the 3 subgroups defined by central foveal thickness had been erratic, and may have been influenced by small sample sizes (see section 3.42). Therefore, the manufacturer combined the 2 subgroups with lower values of central retinal thickness to create 2 subgroups (less than 400 micrometres and 400 micrometres or greater) of similar size. The manufacturer presented post hoc tests of the statistical significance of differences in clinical outcome according to baseline central retinal thickness, which suggested that laser photocoagulation was less effective in people with central retinal thickness of 400 micrometres or more (p<0.01) than in people with thicker retinas. In response to Committee comments in NICE technology appraisal guidance 237 that the manufacturer should explore subgroup-specific parameters for all model inputs, and not only effectiveness, the manufacturer also adjusted other model parameters according to the 2 subgroups, including distribution of visual acuity at baseline and treatment frequency in the first year. For people with central retinal thickness of 400 micrometres or more, the ICER associated with treating only the better-seeing eye was £8881 per QALY gained and the ICER associated with treating both eyes was £13,322 per QALY gained. For people with central retinal thickness of less than 400 micrometres, the ICER associated with treating the better-seeing eye was £28,861 per QALY gained and the ICER associated with treating both eyes was £43,292 per QALY gained. ## ERG comments on the manufacturer's rapid review submission The ERG reviewed whether the manufacturer had correctly implemented the revised patient access scheme in their cost-effectiveness analysis. Additionally, the ERG checked that the Committee's concerns about the manufacturer's revised model from the guidance on ranibizumab for diabetic macular oedema (NICE technology appraisal guidance 237) had been addressed in the economic analysis. The ERG reported that the manufacturer addressed most of the issues raised by the Committee in NICE technology appraisal guidance 237. However the ERG raised the following concerns about the manufacturer's analyses: It was unclear why the manufacturer had reduced the number of injections from 1 to 0 in the fourth year of the model when it had increased the number of ranibizumab injections from 2 to 3 in the third year. The ERG agreed with the manufacturer that the results of the manufacturer's subgroup analyses by degree of glycaemic control may have been influenced by small sample sizes. However, the ERG suggested that the manufacturer could have addressed this issue in a probabilistic model rather than a deterministic analysis. When the ERG ran a probabilistic version of the manufacturer's model, for people with good glycaemic control (HbA1c less than 8%) it produced an ICER associated with the better-seeing eye of £12,895 per QALY gained for ranibizumab monotherapy compared with laser photocoagulation. In people with poorer glycaemic control (HbA1c 8% or more) ranibizumab monotherapy had an ICER associated with the better-seeing eye of £21,560 per QALY gained when compared with laser photocoagulation. The ERG commented that the manufacturer may have incorrectly converted the ETDRS scale to the LogMAR scale to establish utility values for 3 of the 8 visual acuity health states in the model. The ERG instead estimated utility values ranging from 0.850 for the best health state to 0.353 for the worst health state which, when applied in the manufacturer's model, slightly increased the ICERs for treating the better-seeing eye and both eyes to £14,473 and £21,710 per QALY gained respectively. The ERG conducted exploratory analyses to determine whether the utility values used by the manufacturer were appropriate for people who only have their better-seeing eye treated. The ERG identified a study (Brown 1999) that measured vision-related utility values using the time trade-off method in 325 people from the USA with impaired vision (Snellen scale 20/40) in at least 1 eye. This study produced utility values reflecting the contribution of vision in the better-seeing eye to health-related quality of life that ranged from 0.920 to 0.540 for the 8 health states defined by visual acuity, a range the ERG noted was narrower than in the Czoski-Murray et al. study. The ERG noted that both studies showed a linear relationship between vision and utility. The ERG also noted from the Brown study that, among people who had good vision in their better-seeing eye, the worse-seeing eye contributed little to health-related quality of life. To explore the impact of treating only the worse-seeing eye on health-related quality of life, the ERG presented 6 scenario analyses. The 2 extreme scenarios assumed that, at one extreme, treating only the worse-seeing eye and improving vision did not improve health-related quality of life, to the other extreme where treating only the worse-seeing eye improves health-related quality of life to the same degree as would treating the better-seeing eye. The remaining 4 scenarios provided intermediate assumptions. The ERG used the range of utility values for the better-seeing eye from its own adjusted values estimated from Czoski-Murray et al. for the 8 health states reflecting the best to worst vision for the worse-seeing eye (a range of 0.497). The 6 scenarios explored the impact of vision in the worse-seeing eye on health-related quality of life using the following assumptions: Scenario analysis 1: A flat health-related quality-of-life function in which improvements in vision in the treated worse-seeing eye have no impact, that is, health-related quality of life is determined solely by vision in the untreated better-seeing eye. Scenario analysis 2: A health-related quality-of-life function in which treating only the worse-seeing eye results in 15% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, a range of (15% of 0.497)=0.075. Scenario analysis 3: A health-related quality-of-life function in which treating only the worse-seeing eye results in 30% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, a range of (30% of 0.497)=0.149. Scenario analysis 4: A health-related quality-of-life function in which treating only the worse-seeing eye results in 50% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, a range of (50% of 0.497)=0.248. Scenario analysis 5: A health-related quality-of-life function in which treating only the worse-seeing eye results in 75% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, a range of (75% of 0.497)=0.373. Scenario analysis 6: A health-related quality-of-life function in treating only the worse-seeing eye results in 100% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, vision in the worse-seeing eye influences health-related quality of life to the same extent as vision in the better-seeing eye (range of 0.497). The ERG also presented an alternative approach to estimating the costs and QALYs associated with treating both eyes. This differed from the manufacturer's approach of multiplying the ICER associated with treating the better-seeing eye by 1.5 to estimate the ICER associated with treating both eyes. The ERG made a number of assumptions about the proportion of people who would be treated in their better-seeing eye only, their worse-seeing eye only, or in both eyes and the associated costs and QALYs: To estimate the proportion of people who have only their better-seeing eye treated, the ERG based their estimate on the RESTORE trial, in which 20% of people had their better-seeing eye treated at baseline. The utility values used by the ERG were those associated with the better-seeing eye (from Czoski-Murray et al.). The ERG assumed that if vision in the better-seeing eye deteriorated to the point at which the person became severely visually impaired, the person incurs the costs associated with blindness. To estimate the proportion of people who have only their worse-seeing eye treated, the ERG based their estimate on the remainder of people who are treated only in their better-seeing eye or in both eyes (100%−20%−35%=45%). The utility values used by the ERG were those associated with the health-related quality-of-life functions for treating the worse-seeing eye, as described in section 3.53. The ERG assumed that if vision in the worse-seeing eye deteriorated and the person became severely visually impaired, the person would not incur the costs associated with blindness, because the better-seeing eye continues to provide vision. The ERG assumed that 35% of people have both eyes treated based on figures presented by the manufacturer as part of its original submission for NICE technology appraisal guidance 237. The ERG assumed that changes in the vision of the worse-seeing eye contribute the same amount to health-related quality of life whether it is treated alongside the better-seeing eye or treated alone; that is, the 2 health-related quality-of-life functions resulting from changes in vision of the better-seeing eye or worse-seeing eye are independent. Therefore, the ERG calculated the total QALYs gained with ranibizumab treatment in both eyes as the total QALYs gained for improving vision of the better-seeing eye combined with the total QALYs gained for improving vision of the worse-seeing eye for each of the 6 scenarios described in section 3.53. The ERG assumed that treatment costs of ranibizumab were doubled, and included the costs of blindness in the model. However, the ERG assumed that the costs of visits for treatment and for monitoring did not increase from the scenarios that considered treating only the better-seeing eye or worse-seeing eye. The ERG then combined the total costs and QALYs for people treated in the better-seeing eye, the worse-seeing eye, or both eyes as a weighted average and calculated the resultant pooled ICERs for each of the 6 scenario analyses described in section 3.53. The ERG did not present subgroup analyses according to retinal thickness when using this approach to estimating the costs and QALYs associated with treating both eyes. In these exploratory analyses, the ICERs ranged from £16,585 per QALY gained in scenario analysis 6 (changes in the vision of the worse-seeing eye have exactly the same impact on health-related quality of life as changes in the vision of the better-seeing eye) to £39,712 per QALY gained in scenario analysis 1 (changes in the vision of the worse-seeing eye were assumed to have no impact on health-related quality of life). The ERG repeated these analyses but replaced the utility values estimated from Czoski-Murray et al. with those from the study by Brown. This resulted in ICERs that ranged from £21,054 per QALY gained in scenario 6 to £50,879 per QALY gained in scenario 1. The ERG also repeated these exploratory analyses but increased the proportion of people receiving treatment in both eyes to 62% on the basis of the proportion of participants in the RESTORE trial with a best corrected visual acuity of 78 letters or fewer at baseline (the modelled threshold below which ranibizumab would be offered) in the second eye. When the ERG used utility values estimated from Czoski-Murray et al., the ICERs ranged from £15,433 to £29,868 per QALY gained; when the ERG used utility values from Brown, the ICERs ranged from £19,970 to £38,267 per QALY gained. The ERG commented that based on the Brown study, which suggested that vision of the worse-seeing eye has minimal impact on a person's health-related quality of life, the ICERs from scenarios 4 to 6 (suggesting that vision in the worse-seeing eye contributes 50 to 100% to health-related quality of life) were less plausible than scenarios 1 to 3 (suggesting that vision in the worse-seeing eye contributes 0 to 30% to health-related quality of life). The ERG proposed that scenario 1 was implausible, because it was unlikely that vision in the worse-seeing eye would have no impact on health-related quality of life. In scenarios 2 and 3, the ICERs ranged from £32,843 to £27,999 per QALY gained when utility values estimated from Czoski-Murray et al. were used and from £42,227 to £36,089 per QALY gained when utility values from Brown were used. The ERG also commented that the scenarios that considered treating only the worse-seeing eye did not account for a gain in health-related quality of life from reducing the fear of blindness in the worse-seeing eye. ## Additional analyses submitted by the manufacturer during consultation on the appraisal consultation document for the rapid review of NICE technology appraisal guidance 237 In response to the appraisal consultation document for the rapid review of NICE technology appraisal guidance 237, the manufacturer presented cost-effectiveness analyses based on the approach taken by the ERG when estimating the costs and QALYs associated with treating both eyes (see sections 3.53–3.54). The manufacturer presented alternative estimates, based on baseline data from RESTORE, of the proportion of people who would be treated in their better-seeing eye only, their worse-seeing eye only, or in both eyes. In addition, the manufacturer suggested that some patients in RESTORE were treated in an eye with the same vision as the other eye, defined as the same-seeing eye. The manufacturer defined a same-seeing eye as one with a difference in visual acuity between eyes of fewer than 5 letters on the ETDRS scale for patients with visual acuity of 50 letters or more in both eyes at baseline, or a difference in visual acuity of fewer than 10 letters for patients with visual acuity of fewer than 50 letters in both eyes at baseline. Based on these criteria, approximately 22% of patients from RESTORE were defined as being treated in the same-seeing eye, 22% were defined as being treated in the better-seeing eye and 56% were defined as being treated in the worse-seeing eye. The manufacturer presented 3 separate analyses, which varied the proportion of people who might be treated in their better-seeing eye only, their worse-seeing only, or in both eyes, to incorporate assumptions about treatment of same-seeing eyes: In the first analysis, the manufacturer assumed that treating the same-seeing eye improves health-related quality of life to the same degree as treating only the better-seeing eye. A total of 44% of people in RESTORE were treated in either the better-seeing eye or the same-seeing eye. Of the remaining 56% of people, the manufacturer assumed that 35% were treated in both eyes and the remaining 21% were treated in the worse-seeing eye only. In the second analysis, the manufacturer defined the better-seeing eye as having a visual acuity of only 1 letter or more than the other eye, which suggested that the same-seeing eye had a visual acuity within 1 letter of the other eye. This resulted in 32% of people being treated in their better-seeing eye only, 35% treated in both eyes and the remaining 33% treated in their worse-seeing eye only. In the third analysis, the manufacturer assumed that the 22% of people defined as being treated in the same-seeing eye (based on a difference in visual acuity between eyes of fewer than 5 letters on the ETDRS scale for patients with visual acuity of 50 letters or more in both eyes at baseline, or a difference in visual acuity of fewer than 10 letters for patients with visual acuity of fewer than 50 letters in both eyes at baseline) would need treatment in both eyes in addition to the 35% of people already assumed to be treated in both eyes, resulting in 57% of people treated in both eyes. The manufacturer noted that this estimate was close to the proportion of participants in RESTORE with a visual acuity of 78 letters or fewer at baseline in both eyes. The manufacturer assumed that 32% of people would receive treatment only in their better-seeing eye on the basis of the better-seeing eye having a visual acuity better than the other eye by at least 1 letter. The remaining 11% were treated only in their worse-seeing eye. For these 3 analyses, the manufacturer used utility values estimated from Czoski-Murray et al. and presented ICERs for scenarios 2 to 5 as defined by the ERG (see section 3.53), corresponding to an increasing impact on health-related quality of life from improved vision as a result of treating the worse-seeing eye. In analysis 1, the ICERs ranged from £17,332 per QALY gained in scenario 5 to £23,735 per QALY gained in scenario 2. In analysis 2, the ICERs ranged from £18,337 per QALY gained in scenario 5 to £27,679 per QALY gained in scenario 2. In analysis 3, the ICERs ranged from £16,978 per QALY gained in scenario 5 to £23,701 per QALY gained in scenario 2. The ERG reviewed the new analyses provided by the manufacturer in response to the appraisal consultation document. The ERG commented that analysis 1, which assumed that 22% of people would be treated in their same-seeing eye only, appeared to be unrealistic because if a patient had a same-seeing eye that needed treatment, then it was very likely that the other eye would also need treatment. The ERG also noted that in analysis 3, the manufacturer applied the criterion that defined what it assumed to be a minimum clinically relevant difference in visual acuity of fewer than 5 letters on the ETDRS scale when estimating the proportion of people treated in their same-seeing eye (22%), but did not apply this criterion when estimating the proportion of people treated only in the better-seeing eye (32%). Therefore, the ERG suggested that analysis 2, which did not include a minimum clinically relevant difference in visual acuity to define the same-seeing eye, defining it instead as an eye with vision equal within 1 letter, to be the most plausible of the 3 analyses presented by the manufacturer. The ERG repeated analysis 2, but replaced the utility values estimated from Czoski-Murray et al. with those from the study by Brown. This resulted in ICERs that ranged from £35,555 to £31,602 per QALY gained in scenarios 2 and 3, proposed as the 2 most plausible scenarios by the ERG. Full details of all the evidence are in the manufacturer's submission and the ERG report. This ICER has been amended from the ICER given in the manufacturer's consultation comments to correct an error in the utility values used (identified by the NICE technical team and confirmed by the manufacturer in correspondence).# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of diabetic macular oedema and the value placed on the benefits of ranibizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee understood from patient experts that visual impairment has a substantial negative impact on quality of life and activities of daily living in people with diabetic macular oedema. The patient experts placed particular emphasis on loss of independence and its implications for employment. They emphasised that diabetes is usually managed with self-care, and that visual impairment can affect a person's ability to manage their own condition (for example, checking their blood glucose level with a meter, administering medication, caring for their feet and managing their diet). The patient experts described a significant impact of visual impairment on emotional wellbeing, which can lead to depression and, in some instances, suicidal thoughts. The Committee understood that any relief from these problems would have a positive impact on the lives of people with diabetic macular oedema. The Committee heard from the clinical specialists that the current standard treatment for diabetic macular oedema is focal and/or grid laser photocoagulation. The clinical specialists stated that an eye's response to laser photocoagulation is hard to predict but, in their experience, the people who benefit most tend to be those who have less visual impairment at the onset of treatment. People whose vision worsens despite laser photocoagulation are more likely to have thicker, more oedematous retinas. The clinical specialists explained that there are national screening programmes for diabetic retinopathy in England and Wales to identify people who need diagnosis and treatment. The Committee discussed the likely place of ranibizumab in the treatment of diabetic macular oedema. It heard from the clinical specialists that they would consider using ranibizumab either on its own or in a treatment strategy including laser photocoagulation given before, after or at the same time as ranibizumab. The clinical specialists explained that they would be likely to start ranibizumab treatment with a 'loading' period of monthly injections for at least 3 months. After this, they would monitor people on a regular basis, providing repeat monthly injections for as long as visual acuity improved and/or retinal thickness reduced (as measured using optical coherence tomography). The clinical specialists anticipated that people with diabetic macular oedema would need between 7 and 9 treatments in the first year. The Committee heard from the clinical specialists that treatment would not be for a predefined period. Instead, clinicians would discontinue treatment if a person's vision stopped improving, and would restart treatment in the event that the person's vision worsened. The clinical specialists stated that this phase would continue until it was evident that the person was deriving no additional benefit from treatment. The clinical specialists advised that they would carry out monthly follow-up in the first year of treatment, extending the interval to 6–8 weeks for people whose diabetic macular oedema stabilised. The clinical specialists gave the opinion that the RESTORE trial provided an accurate picture of likely clinical practice in this respect because it had followed a similar approach to treatment and monitoring (3-month loading followed by repeat injection at monthly intervals as deemed appropriate by the treating clinician). However, because people with diabetic macular oedema in clinical practice are likely to have more advanced visual impairment than those in clinical trials, they may also need more frequent treatment than observed in clinical trials. The Committee heard from the clinical specialists that a clinically significant gain in visual acuity is 10–15 letters. However, the clinical specialists also stated that smaller gains could be significant – for example, if a gain were sufficient to allow a person to meet the legal requirements for driving. In general, the clinical specialists thought that a gain of 10–15 letters would benefit a person with worse vision more than a person with moderate visual impairment. The Committee understood from the clinical specialists that, because diabetes is a systemic metabolic condition, diabetic macular oedema is more often seen in both eyes than maculopathy from other causes. The clinical specialists estimated that at least 25–30% of people with diabetic macular oedema need treatment in both eyes. The clinical specialists said that, for these people, they would aim to provide treatment in both eyes at the same visit. They explained that, through experience gained in treating wet age-related macular degeneration, many NHS units are now well equipped to treat people with ranibizumab. The clinical specialists suggested that ranibizumab treatment would need an ophthalmologist (rather than a nurse) and would be provided on an outpatient basis. The Committee heard from the clinical specialists that, if using visual acuity as part of a fixed algorithm for deciding whether and when to treat and re-treat, it would be vital to correct sight optimally before measuring visual acuity, and this would entail comprehensive refraction (correcting sight with lenses) on each occasion visual acuity was measured. In addition, clinics would need to use the same vision charts as used to test vision in the trials, which take considerably longer to administer than routine tests of visual acuity. The clinical specialists explained that both these factors would extend the time and resources needed for routine follow-up of people with diabetic macular oedema beyond what is needed in current clinical practice. The Committee understood from the clinical specialists and patient experts that ranibizumab is generally well tolerated, and that people usually use antibiotic eye drops for a few days after treatment with ranibizumab to prevent infection. # Clinical effectiveness The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. It agreed that, of the 4 RCTs identified, it was appropriate to concentrate on the 2 larger, more directly relevant trials, RESTORE and DRCR.net. It noted that both trials were judged to be of high methodological quality by the manufacturer, and that the ERG agreed with this assessment. The Committee was aware that the studies were of relatively short duration, providing treatment for up to 3 years, and did not include long-term follow-up. The Committee concluded that the quality of the clinical-effectiveness evidence for ranibizumab was acceptable. The Committee noted that, based on the results of the RESTORE study, ranibizumab (alone or in combination with laser photocoagulation) is associated with immediate and sustained gains in visual acuity in the treated eye, whereas improvement with laser photocoagulation alone is significantly less marked. The Committee understood from the clinical trial evidence that adding laser photocoagulation to ranibizumab does not appear to provide any additional improvement in vision over 2 years. However, it was aware of the clinical specialists' belief that laser photocoagulation is more likely than ranibizumab to have long-term benefits, and that this could reduce the number of injections of ranibizumab needed after 2 years, although this cannot be confirmed using current evidence. The Committee concluded that, when compared with laser photocoagulation alone, treatment regimens that include ranibizumab are effective in improving visual acuity in the treated eye over 2 years, but that there is no evidence of additional benefit in adding laser photocoagulation to ranibizumab. The Committee was aware that this is inconsistent with the expectations of the clinical specialists. The Committee noted that initial subgroup analyses in both RESTORE and DRCR.net had shown little evidence of differences in clinical effectiveness by subgroup. It understood from the manufacturer's evidence that, in RESTORE, gains in visual acuity associated with ranibizumab were greatest in participants with thicker retinas and more severe visual impairment at baseline. In particular, it noted the manufacturer's suggestion that ranibizumab could be expected to have a superior relative effect among people with thicker retinas (see section 3.30). The Committee was aware that the manufacturer had provided evidence in its rapid review submission to confirm this subgroup effect by testing for interaction between retinal thickness and treatment allocation. The Committee noted that the manufacturer's revised subgroup analyses according to retinal thickness relied on different categories of retinal thickness to those presented in NICE technology appraisal guidance 237 and also differed from those specified in the methods for subgroup analyses of the RESTORE study. The Committee also noted that changing these categories led to different results. However, the Committee acknowledged the clinical specialists' suggestion that laser photocoagulation would be less clinically effective in people with a thicker retina. Therefore, the Committee concluded that it had received sufficient evidence of biological plausibility for a clinically relevant subgroup in which ranibizumab has a significantly greater relative effect. The Committee considered the generalisability of the results of the RESTORE study to people with diabetic macular oedema in clinical practice. The Committee heard from the clinical specialists that glycaemic control as reflected by HbA1c varies more in clinical practice than in trials, because the RESTORE trial excluded people with HbA1c values of 10% or more. The Committee also noted the comments on the use and effects of laser photocoagulation from the clinical specialists (see section 4.10), and discussed whether the trials accurately reflect the way in which ranibizumab would be combined with laser therapy in clinical practice. The Committee concluded that the generalisability of trial results to the population with diabetic macular oedema seen in clinical practice is uncertain. The Committee also expressed concerns about whether the proportion of people who were treated in both eyes in the RESTORE study reflected clinical practice. The Committee concluded that the lack of evidence on vision in both eyes, as presented by the manufacturer in its original submission for NICE technology appraisal guidance 237, increased its uncertainty about how the effects of ranibizumab demonstrated in the trials would translate into benefits for people with diabetic macular oedema in clinical practice. # Cost effectiveness The Committee discussed the appropriate approach for determining the cost effectiveness of ranibizumab. The Committee noted that the manufacturer's original base case and all additional original analyses performed by the manufacturer and the ERG suggest that combination therapy is more expensive and little or no more effective than ranibizumab alone. As a consequence, the Committee concluded that ranibizumab and laser photocoagulation as part of a simultaneous treatment strategy could not be recommended as an effective use of NHS resources. However, the Committee also heard from the clinical specialists that people currently treated with ranibizumab are likely to have had laser photocoagulation, which the clinical specialists believed is more likely to be associated with a long-term decrease in the recurrence of diabetic macular oedema than treatment with ranibizumab. The Committee agreed with the ERG's suggestion and consultation comments from retinal specialists that it is possible that ranibizumab and laser photocoagulation in a sequential treatment algorithm could provide a valuable treatment option. However, because no evidence to support this was available, the Committee concluded that it could not make separate recommendations on the sequential use of ranibizumab and laser photocoagulation. When it reviewed the manufacturer's revised model submitted in NICE technology appraisal guidance 237, the Committee concluded that the model did not reflect likely clinical practice in at least 6 respects, as described in section 3.46. The manufacturer addressed these issues in its rapid review submission, and offered a revised patient access scheme (see sections 3.47–3.49). The Committee discussed the manufacturer's approach to estimating the cost effectiveness of treating both eyes, in which it multiplied the ICERs generated in its better-seeing eye model by a factor of 1.5. The Committee was aware that this approach was consistent with that adopted by the Committee in NICE technology appraisal guidance 155 and that the same approach was used by the Committee when estimating the most plausible ICER in NICE technology appraisal guidance 237. The Committee also considered the new, alternative approach taken by the ERG in its 6 scenario analyses, which made explicit assumptions about the impact on costs and outcomes associated with treating only the worse-seeing eye, only the better-seeing eye or both eyes. The Committee noted that the ERG's 6 scenario analyses varied both the health-related quality of life impact of changes in the vision of the worse-seeing eye and the resultant QALYs associated with treatment of the worse-seeing eye or both eyes. The Committee agreed that, without available data on health-related quality of life associated with vision in both eyes, these scenarios fully explored the impact of treating both eyes on the relative cost effectiveness of ranibizumab. The Committee noted that, although there is little evidence of the impact of vision in the worse-seeing eye on health-related quality of life, the Brown study suggested that among people who had good vision in their better-seeing eye, the worse-seeing-eye contributed little to health-related quality of life. The Committee therefore considered scenario analysis 3 to be consistent with previous appraisals, which suggested that changes in vision for people treated in their worse-seeing eye had 30% of the health-related quality of life impact of the same change in vision from treating the better-seeing eye. In response to the rapid review appraisal consultation document, the Royal College of Ophthalmologists commented that the ERG's approach seemed logical, but that scenario 4 might be more appropriate. However, in the absence of new empirical evidence to suggest otherwise, the Committee accepted that scenario 3 reasonably reflected the clinical situation for people with diabetic macular oedema. The Committee concluded that the ERG's more comprehensive approach to modelling treatment of both eyes was likely to be more valid than multiplying the ICER associated with treating the better-seeing eye by 1.5 because it explored more explicitly the impact on costs and outcomes associated with treating only 1 or both eyes. The Committee considered the cost-effectiveness analyses presented by the manufacturer in its response to the appraisal consultation document for the rapid review of NICE technology appraisal guidance 237, which adopted the approach taken by the ERG (see sections 3.58–3.60). The Committee discussed the manufacturer's approach to estimating the proportion of people who would be treated in the better-seeing eye only, worse-seeing eye only or both eyes. The Committee noted that, as part of these 3 new analyses, the manufacturer presented data on the proportion of patients in RESTORE whom the manufacturer considered as having the same vision in both eyes at the start of treatment. The Committee was surprised that the manufacturer had not presented these data earlier in the appraisal. However, the Committee acknowledged that, although the manufacturer had originally proposed that patients would need treatment in only 1 eye despite bilateral disease, it had subsequently attempted to consider the cost effectiveness of treating both eyes in its rapid review submission. The Committee heard from the manufacturer that it considered the same-seeing eye pertinent only after the Committee had expressed its preference for the ERG's approach to estimating the costs and QALYs associated with treating both eyes. The Committee also heard from the manufacturer that it chose its definition of a same-seeing eye from a single study, that it was aware that other definitions existed, and that it had not taken a systematic approach to assessing other possible definitions. The Committee noted that the ICERs did not vary substantially between the 3 analyses presented by the manufacturer. The Committee concluded, given its concerns around the definition of same-seeing eyes, that analysis 2 (which suggested that the same-seeing eye has a visual acuity within 1 letter of the other eye) was the most plausible of the 3 new analyses presented by the manufacturer. The Committee considered the utility values that quantified the changes in health-related quality of life attributed to vision in the manufacturer's new model in its rapid review submission. It was aware that the manufacturer used utility values estimated from the study by Czoski-Murray et al., in which members of the UK general public valued levels of visual impairment simulated by wearing vision-worsening contact lenses in both eyes. The Committee noted that this study resulted in a broader range of utility values between best and worst health states in the model than those used in the manufacturer's original submission in NICE technology appraisal guidance 237, which were estimated from the RESTORE study and which the Committee considered to be unrealistically large (see section 3.26). The Committee also noted that participants in the Czoski-Murray study wore the lenses simulating bilateral visual impairment for a short period of time (between 1.5 and 2 hours). Therefore, the Committee considered that the participants may have overstated the detrimental impact on health-related quality of life of visual impairment in both eyes because they had little time to adjust to it. The Committee was aware that the Brown study identified by the ERG measured health-related quality of life directly from patients with impaired vision in at least 1 eye, and that this produced a narrower range of utility values than the study by Czoski-Murray et al. In consideration of a comment from the manufacturer who suggested that the utility values from the Brown study were not in line with the NICE reference case, the Committee noted that neither set of utility values was in line with the NICE reference case for measuring and valuing health effects. The Committee concluded that there was uncertainty about which utility data were most appropriate to include in the model. However, the Committee agreed that, in the absence of further evidence, it was reasonable to assume that the range of utility values would probably lie somewhere in between those estimated from the Czoski-Murray and Brown studies. The Committee discussed the manufacturer's assumptions about how often people would receive ranibizumab in clinical practice. The Committee noted that, on the basis of the results from an extension to the RESTORE study available at the time of the rapid review submission, the manufacturer assumed that people would need 4 injections in year 2 and 3 injections in year 3 and no more injections from year 4 onwards. The Committee commented that it was unlikely that people who received 3 injections in year 3 would receive no further injections in year 4, especially if vision was assumed to remain stable during this period. The Committee was aware that some consultees had suggested that people with diabetic macular oedema would need more frequent treatment with ranibizumab than was assumed by the manufacturer. The Committee also noted that uncertainty remained about whether people would need ranibizumab beyond 4 years and, if they did, what the costs of ongoing treatment would be. However, the Committee acknowledged that the manufacturer had attempted to address this uncertainty by conducting a threshold analysis to assess the maximum number of injections per person that could be administered while maintaining an ICER below £30,000 per QALY gained. The Committee was aware that these analyses allowed for only 4 additional injections in the first 3 years of the model. The Committee concluded that, without longer-term clinical data, significant uncertainty remained about the number of ranibizumab injections that people with diabetic macular oedema are likely to need. The Committee considered the manufacturer's assumptions about how vision in the treated eye improved and deteriorated beyond the third year of the model, when the model assumes that ranibizumab treatment finishes. It understood that, although vision deteriorated over time in the model, it did so at the same rate in people previously treated with ranibizumab as in people who had previously been treated with laser photocoagulation. The Committee was aware of the opinion of clinical specialists that the most important effect of ranibizumab is to reduce the permeability of blood vessels and oedema in the eye, and heard from the clinical specialists that it is implausible that this effect would persist in the long term. By contrast, the benefits to vision from laser photocoagulation, although not as great as those of ranibizumab, are believed to last longer. The Committee noted that the manufacturer reduced uncertainty about the projected effects of ranibizumab treatment by following the approach discussed by the Committee in NICE technology appraisal guidance 237 and adopting a 10-year time horizon. The Committee also noted that this approach was consistent with previous appraisals. The Committee was aware of the new clinical evidence submitted by consultees in their response to the rapid review appraisal consultation document. The Committee understood that the consideration of such new clinical evidence on the long-term clinical benefits of the comparator treatment laser photocoagulation is beyond the remit of a rapid review, and would require a full review of the appraisal. Therefore the Committee concluded that, although significant uncertainty remains about the long-term benefit of ranibizumab treatment, compared with the manufacturer's original submission, the rapid review model more accurately reflects the duration of benefit that could be expected from treatment with ranibizumab. The Committee considered the manufacturer's assumptions about the number of treatment and monitoring visits for people treated with ranibizumab and those treated with laser photocoagulation. The Committee was aware that in its original submission in NICE technology appraisal guidance 237, the manufacturer had assumed that a visit for treatment with ranibizumab would double as a monitoring visit and that people treated with laser photocoagulation would need a separate monitoring visit. The Committee was unaware of any clinical evidence to justify this difference, and the manufacturer had not explained the difference in its original submission or in consultation comments. The Committee noted that the manufacturer had addressed this issue in its rapid review submission by assuming that a treatment visit for people receiving ranibizumab or laser photocoagulation doubles as a monitoring visit. The Committee concluded that, compared with the manufacturer's original submission, the rapid review model provided a more plausible reflection of the number of treatment and monitoring visits that people receiving ranibizumab treatment or laser photocoagulation would need. The Committee considered whether the revised base-case model applies to the population with diabetic macular oedema in England and Wales. It noted the clinical specialists' advice that glycaemic control as reflected by HbA1c is likely to be worse in clinical practice than in the RESTORE trial, which excluded people with HbA1c levels of 10% or more (see section 4.12). The Committee observed that a subgroup analysis provided as part of the manufacturer's original submission for NICE technology appraisal guidance 237 suggested that restricting the analysis to people with good glycaemic control (HbA1c less than 8%) produced a much lower ICER than the ICER based on the group of people with poor control (HbA1c 8% or more; see section 3.18). The Committee noted that the manufacturer did not provide further analyses for these subgroups in its rapid review submission because of the relatively small sample sizes, which may have resulted in a small number of people in the extreme health states influencing the results. The Committee was aware of the new clinical evidence submitted by the manufacturer in response to the consultation on the rapid review appraisal consultation document. The Committee understood that submission of such further evidence would not normally be expected in the context of a rapid review, and accepted that this evidence could not be considered without formal review by the ERG. The Committee acknowledged that the issue of glycaemic control had been considered in NICE technology appraisal guidance 237, and that the Committee's considerations had been upheld at appeal. Based on the evidence provided in the manufacturer's original submission, the Committee agreed that uncertainty remained about the cost effectiveness of ranibizumab in people with poorer glycaemic control. Therefore, the Committee concluded that the manufacturer's model would probably generate a higher ICER if it was more reflective of the population seen in routine clinical practice. The Committee discussed what could be considered as the most plausible ICERs. In the Committee's view, ICERs reflecting the possibility of treating both eyes were the most useful starting points for considering the cost effectiveness of ranibizumab for treating diabetic macular oedema. The Committee was aware that the manufacturer's rapid review base-case model produced an ICER of £21,200 per QALY gained for treating both eyes by multiplying the ICER for the better-seeing eye model by a factor of 1.5. The Committee agreed that this ICER was from a model that relied on a more plausible set of assumptions than those used in the manufacturer's original submission for NICE technology appraisal guidance 237. However, the Committee also acknowledged the ERG's technically more comprehensive approach of accounting for treatment in both eyes and noted that the manufacturer acknowledged the advantages of this approach. The Committee noted that this approach was subsequently adopted by the manufacturer in its response to the rapid review appraisal consultation document and led to ICERs in the range of £24,600 to £31,600 per QALY gained depending on the utility values used in the model for the Committee's preferred analysis. The Committee agreed that these ICERs would increase if the model accounted for people needing more than 4 treatments with ranibizumab beyond the third year, if people who had laser photocoagulation maintained any improvements in vision after treatment for longer than people treated with ranibizumab, and if the model better reflected the population with poorer glycaemic control seen in routine clinical practice. The Committee concluded that the most plausible ICER was likely to be above £30,000 per QALY gained, and that it therefore could not recommend ranibizumab as an effective use of NHS resources for the treatment of all people with diabetic macular oedema. The Committee discussed whether it had received evidence of any groups of people for whom ranibizumab could be considered an effective use of NHS resources. It noted that, in its rapid review submission, the manufacturer provided additional subgroup analyses that showed that ranibizumab has a lower ICER in people with thicker retinas (central retinal thickness of 400 micrometres or more) than in people with thinner retinas (central retinal thickness of less than 400 micrometres) at the start of treatment. The Committee recognised the clinical plausibility of a greater relative efficacy of ranibizumab in people with a central retinal thickness of 400 micrometres or more, because it understood that laser photocoagulation may be less effective when used on a thicker retina. The Committee noted that the manufacturer had presented statistical evidence of greater clinical effectiveness in this predefined group. The Committee also noted that the manufacturer had reduced the impact of small sample sizes, which had been raised as a concern in NICE technology appraisal guidance 237, by combining groups of people with thinner retinas (central retinal thickness less than 300 micrometres and 300–400 micrometres) into 1 larger group (people with central retinal thickness greater than 400 micrometres). This also produced more plausible cost-effectiveness results across the 2 groups. The Committee also acknowledged that the manufacturer had adequately accounted for differences in costs and outcomes for these subgroups by making adjustments to subgroup‑specific parameters for other important model inputs. The Committee therefore concluded that the manufacturer had provided robust evidence demonstrating a subgroup effect in favour of people with thicker retinas. The Committee considered the most plausible ICERs for people with thicker retinas (central retinal thickness of 400 micrometres or more) at the start of treatment. The Committee noted that the manufacturer's rapid review model produced an ICER of £13,300 per QALY gained for treating both eyes in this group by multiplying the ICER for the better-seeing eye model by a factor of 1.5. The Committee agreed that this ICER would increase if the model accounted for people needing more frequent treatment with ranibizumab beyond the third year, if people who had laser photocoagulation maintained any improvements in vision after treatment for longer than people who had ranibizumab, if the model better reflected the population with poorer glycaemic control seen in routine clinical practice, and if people with thicker retinas had higher rates of mortality than people with thinner retinas. The Committee also noted that neither the ERG nor the manufacturer provided exploratory scenario analyses for people with central retinal thickness of 400 micrometres or more. However, the Committee agreed that the ICER would likely increase if the ERG's approach of adapting the manufacturer's model to consider treating both eyes was used along with the Committee's preferred assumptions. The Committee therefore concluded that the most plausible ICER for the subgroup of people with thicker retinas was likely to be higher than the manufacturer's estimate, but would be under £25,000 per QALY gained. The Committee also considered the manufacturer's suggestion in response to the rapid review appraisal consultation document that ranibizumab would be cost effective for the whole population. However, the Committee noted that the ICER for treating people with thinner retinas (central retinal thickness of less than 400 micrometres) was £43,300 per QALY gained in the manufacturer's rapid review model and that ranibizumab would therefore not be an effective use of NHS resources in this group. Therefore the Committee recommended ranibizumab as an option for treating visual impairment due to diabetic macular oedema only if the eye has a central retinal thickness of 400 micrometres or more at the start of treatment. The Committee noted that the scope for the appraisal included bevacizumab as a comparator. It was also aware of its previous conclusions on bevacizumab in NICE technology appraisal guidance 237, that ranibizumab at that time did not represent an effective use of NHS resources when compared with laser photocoagulation, and that therefore the Committee did not believe that considering evidence for bevacizumab would have altered its decision. However, because the Committee had concluded after the rapid review that ranibizumab represents a cost-effective use of NHS resources when compared with laser photocoagulation for people with a central retinal thickness of 400 micrometres or more, it discussed the comparison of ranibizumab with bevacizumab. The Committee noted and reviewed information from the regulatory authorities to prescribers in which the use of bevacizumab as an intravitreal injection in people with diabetic macular oedema is considered 'unlicensed'. Also, the Committee heard conflicting evidence about the extent to which bevacizumab is currently used to treat diabetic macular oedema in England and Wales. It concluded that bevacizumab is adopted by some clinicians and funded by some NHS trusts, but is not in use throughout the NHS. The Committee was aware that some consultees and commentators supported a comparison with bevacizumab and others opposed it. The Committee discussed whether a cost-effectiveness analysis of ranibizumab compared with bevacizumab was possible. The Committee recognised that a formal comparison of the 2 drugs would need evidence not only of all aspects of clinical effectiveness and safety, but also of the costs associated with preparing and administering bevacizumab, including the dose and number of injections needed. The Committee agreed that such evidence, in particular about the balance of harms and benefits associated with bevacizumab, was not readily available for people with diabetic macular oedema. The Committee also noted that it was unaware of any evidence of the effectiveness of intravitreal bevacizumab compared with ranibizumab in the subgroup of patients with thicker retinas. The Committee agreed that, taking into account all these uncertainties, it could not consider a comparison of ranibizumab with bevacizumab. The Committee also concluded that further research directly comparing the clinical and cost effectiveness of ranibizumab and bevacizumab in people with diabetic macular oedema would reduce some of these uncertainties. The Committee discussed whether ranibizumab should be considered an innovative treatment. It considered that, in terms of both pharmacological progress and potential benefits for people with diabetic macular oedema, the development of the anti-angiogenic drugs pegaptanib sodium and bevacizumab preceded that of ranibizumab. Therefore, the Committee concluded that ranibizumab itself could not properly be considered to provide distinctive pharmacological innovation. The Committee further noted that the analyses of the incremental health benefit of ranibizumab were based on a comparison with laser photocoagulation, and that the Committee had not been alerted to any benefits that were not already captured in the QALY measure. The Committee was also aware that, before NICE technology appraisal guidance 237 was published, the Committee's conclusions on innovation as described above were upheld by the Appeal Panel. It therefore concluded that the incremental value of ranibizumab for people with diabetic macular oedema had been appropriately captured. The Committee discussed the proposed date for review of the guidance. The Committee was aware of the emerging evidence on the effectiveness and safety of bevacizumab as a treatment option for diabetic macular oedema, including work undertaken by NICE's Decision Support Unit and ongoing clinical trials comparing bevacizumab with ranibizumab in diabetic macular oedema and other eye diseases. The Committee was also aware that additional clinical data, including 3-year results from the DRCR.net study, had become available since the publication of NICE technology appraisal guidance 237, but that these data could not be considered as part of the rapid review process. The Committee heard that some commentators suggested that the proposed date for review should be earlier than February 2016, because the guidance would exclude ranibizumab as a treatment option for a significant proportion of people with diabetic macular oedema. Therefore, the Committee agreed that the proposed date for review of the guidance should be brought forward to February 2015. The Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. During the scoping phase of the appraisal, NICE had received evidence that some people in full-time residential care had restricted access to treatment for diabetic macular oedema. However, consultees suggested that the national screening programmes for diabetic retinopathy in England and Wales has reduced this inequality across the NHS. In submissions, the Committee had been made aware that there is a higher prevalence of diabetes in people of South Asian, African and African–Caribbean family origin and that, among people with diabetes, sight-threatening eye disease is more common in people of African and African–Caribbean family origin than in white Europeans. However, the Committee agreed that this was an issue that could not be addressed in a technology appraisal. # Summary of Appraisal Committee's key conclusions TA274 Appraisal title: Ranibizumab for treating diabetic macular oedema (rapid review of technology appraisal guidance Section Key conclusion Ranibizumab is recommended as an option for treating visual impairment due to diabetic macular oedema only if: the eye has a central retinal thickness of 400 micrometres or more at the start of treatment and the manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of this appraisal. The Committee concluded that the most plausible ICER for the treatment of all people with diabetic macular oedema was likely to be above £30,000 per QALY gained, and that it therefore could not recommend ranibizumab as an effective use of NHS resources. The Committee concluded that the most plausible ICER for the subgroup of people with thicker retinas was likely to be under £25,000 per QALY gained. Therefore the Committee recommended ranibizumab as an option for treating diabetic macular oedema only for people with a central retinal thickness of 400 micrometres or more at the start of treatment. Current practice Clinical need of patients, including the availability of alternative treatments The Committee understood from patient experts that visual impairment has a substantial negative impact on quality of life and activities of daily living in people with diabetic macular oedema. The Committee heard from the clinical specialists that the current standard treatment for diabetic macular oedema is focal and/or grid laser photocoagulation. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee considered that, in terms of both pharmacological progress and potential benefits for people with diabetic macular oedema, the development of the anti-angiogenic drugs pegaptanib sodium and bevacizumab preceded that of ranibizumab. Therefore, the Committee concluded that ranibizumab itself could not properly be considered to provide distinctive pharmacological innovation. What is the position of the treatment in the pathway of care for the condition? The Committee heard from the clinical specialists that they would consider using ranibizumab either on its own or in a treatment strategy including laser photocoagulation given before, after or at the same time as ranibizumab. Adverse reactions The Committee understood from the clinical specialists and patient experts that ranibizumab is generally well tolerated. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee agreed that, of the 4 RCTs identified, it was appropriate to concentrate on the 2 larger, more directly relevant trials, RESTORE and DRCR.net. It noted that both trials were judged to be of high methodological quality by the manufacturer, and that the ERG agreed with this assessment. Relevance to general clinical practice in the NHS The Committee heard from the clinical specialists that glycaemic control as reflected by HbA1c varies more in clinical practice than in trials, because the RESTORE trial excluded people with HbA1c values of 10% or more. The Committee also noted the comments on the use and effects of laser photocoagulation from the clinical specialists, and discussed whether the trials accurately reflect the way in which ranibizumab would be combined with laser therapy in clinical practice. The Committee concluded that the generalisability of trial results to the population with diabetic macular oedema seen in clinical practice is uncertain. Uncertainties generated by the evidence The Committee concluded that there is no evidence of additional benefit in adding laser photocoagulation to ranibizumab, but that this is inconsistent with the expectations of the clinical specialists. The Committee concluded that the lack of evidence on vision in both eyes increased its uncertainty about how the effects of ranibizumab demonstrated in the trials would translate into benefits for people with diabetic macular oedema in clinical practice. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee understood from the manufacturer's evidence that, in RESTORE, gains in visual acuity associated with ranibizumab were greatest in participants with thicker retinas and more severe visual impairment at baseline. In particular, it noted the manufacturer's suggestion that ranibizumab could be expected to have a superior relative effect among people with thicker retinas. The Committee was aware that the manufacturer had provided evidence in its rapid review submission to confirm this subgroup effect by testing for interaction between retinal thickness and treatment allocation. Therefore, the Committee concluded that it had received evidence of a clinically relevant subgroup in which ranibizumab has a significantly greater relative effect. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that, when compared with laser photocoagulation alone, treatment regimens that include ranibizumab are effective in improving visual acuity in the treated eye over 2 years, but that there is no evidence of additional benefit in adding laser photocoagulation to ranibizumab. Evidence for cost effectiveness Availability and nature of evidence When it reviewed the manufacturer's revised model submitted in NICE technology appraisal guidance 237, the Committee concluded that the model did not reflect likely clinical practice in at least 6 respects. The manufacturer addressed these issues in its rapid review submission, and offered a revised patient access scheme. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee was aware that the manufacturer's base-case model produced an ICER of £21,200 per QALY gained for treating both eyes by multiplying the ICER for the better-seeing eye model by a factor of 1.5. The Committee agreed that this ICER was from a model that relied on a more plausible set of assumptions than those used in the manufacturer's original submission for NICE technology appraisal guidance 237. However, the Committee also acknowledged the ERG's technically more comprehensive approach of accounting for treatment in both eyes explored by the ERG and noted that the manufacturer acknowledged the advantages of this approach. The Committee noted that this approach was subsequently adopted by the manufacturer in its response to the rapid review appraisal consultation document and led to ICERs in the range of £24,600 to £31,600 per QALY gained depending on the utility values used in the model for the Committee's preferred analysis. The Committee agreed that these ICERs would increase if the model accounted for people needing more than 4 treatments with ranibizumab beyond the third year, if people who had laser photocoagulation maintained any improvements in vision after treatment longer than people treated with ranibizumab, and if the model better reflected the population with poorer glycaemic control seen in routine clinical practice. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee concluded that there was uncertainty about which utility data were most appropriate to include in the model. However, the Committee agreed that, in the absence of further evidence, it was reasonable to assume that the range of utility values would probably lie somewhere in between those estimated from the Czoski-Murray and Brown studies. Are there specific groups of people for whom the technology is particularly cost effective? The Committee concluded that the manufacturer had provided robust evidence demonstrating a subgroup effect in favour of people with thicker retinas. The Committee concluded that the most plausible ICER for the subgroup of people with thicker retinas was likely to be higher than the manufacturer's estimate, but would be under £25,000 per QALY gained. What are the key drivers of cost effectiveness? The Committee concluded that the cost-effectiveness results were driven by the manufacturer's assumptions about: the need to treat both eyes of people with diabetic macular oedema, the utility associated with changes in vision of the treated eye, likely frequency of ranibizumab injections, the expected duration of benefit from ranibizumab treatment, the number of treatment visits and monitoring visits needed, and the generalisability of the economic evidence, especially about glycaemic control in the treated population. Most likely cost-effectiveness estimate (given as an ICER) The Committee concluded that the most plausible ICER for the treatment of all people with diabetic macular oedema was likely to be above £30,000 per QALY gained, and that it therefore could not recommend ranibizumab as an effective use of NHS resources. The Committee concluded that the most plausible ICER for the subgroup of people with thicker retinas was likely to be higher than the manufacturer's estimate, but would be under £25,000 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) The manufacturer has agreed a patient access scheme with the Department of Health which makes ranibizumab available with a discount applied to all invoices. The size of the discount is commercial in confidence. End-of-life considerations Not applicable. Equalities considerations and social value judgements NICE had received evidence that some people in full-time residential care had restricted access to treatment for diabetic macular oedema. However, consultees suggested that the national screening programme for diabetic retinopathy in England and Wales has reduced this inequality across the NHS. The Committee had been made aware that there is a higher prevalence of diabetes in people of South Asian, African and African–Caribbean family origin and that, among people with diabetes, sight-threatening eye disease is more common in people of African and African–Caribbean family origin than in white Europeans. However, the Committee agreed that this was an issue that could not be addressed in a technology appraisal. # Recommendations for further research The Committee concluded that further research directly comparing the clinical and cost effectiveness of ranibizumab and bevacizumab in people with diabetic macular oedema should be conducted.# Related NICE guidance # Published Fluocinolone acetonide intravitreal implant for the treatment of diabetic macular oedema.NICE technology appraisal guidance 271 (2013). Dexamethasone for the treatment of retinal vein occlusion in macular oedema. NICE technology appraisal guidance 229 (2011). Type 2 diabetes: the management of type 2 diabetes. NICE clinical guideline 87 (2009). Ranibizumab and pegaptanib for the treatment of age-related macular degeneration.NICE technology appraisal guidance 155 (2008). Type 1 diabetes. NICE clinical guideline 15 (2004). # Under development NICE is developing the following guidance (details available from the NICE website): Pegaptanib sodium for the treatment of diabetic macular oedema.NICE technology appraisal. Publication date to be confirmed.# Review of guidance The guidance on this technology will be considered for review in February 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief executiveFebruary 2013# Changes after publication January 2014: minor maintenance. April 2013: The wording of the recommendation describing the patient access scheme (see section 1.1) has been amended to make it clear which scheme is being referred to.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It updates and replaces NICE technology appraisal guidance 237 (published November 2011). We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. ISBN 978-1-4731-0043-5	{'Guidance': 'This guidance replaces NICE technology appraisal guidance 237 (published in November 2011). For details see About this guidance.\n\nRanibizumab is recommended as an option for treating visual impairment due to diabetic macular oedema only if:\n\nthe eye has a central retinal thickness of 400\xa0micrometres or more at the start of treatment and\n\nthe manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of this appraisal.\n\nPeople currently receiving ranibizumab for treating visual impairment due to diabetic macular oedema whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology': "Ranibizumab (Lucentis, Novartis) belongs to a class of drugs that blocks the action of vascular endothelial growth factor A (VEGF-A). In diabetic macular oedema, VEGF-A causes blood vessels to leak in the macula, the area of the retina responsible for the clearest vision. The accumulated fluid causes swelling, or oedema, which impairs vision. By inhibiting the action of VEGF-A, ranibizumab reduces oedema and limits visual loss or improves vision. Ranibizumab has a marketing authorisation for 'the treatment of visual impairment due to diabetic macular oedema in adults'.\n\nThe summary of product characteristics states that treatment should be given monthly and continued until maximum visual acuity is reached – that is, until visual acuity has been stable for 3\xa0consecutive months. Thereafter, visual acuity should be monitored monthly. Treatment is resumed if monitoring indicates a loss of visual acuity caused by diabetic macular oedema, and continued until visual acuity has remained stable for 3\xa0consecutive months. The interval between doses should not be shorter than 1\xa0month.\n\nContraindications to ranibizumab include known hypersensitivity to the active substance or to any of its excipients, active or suspected ocular or periocular infections and active severe intraocular inflammation. Adverse reactions of treatment are mostly limited to the eye. Those commonly reported in clinical trials include vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, sensation of a foreign body in the eye, increased production of tears, blepharitis, dry eye, ocular hyperaemia, itching of the eye and increased intraocular pressure. Nasopharyngitis, arthralgia and headaches are also reported as common adverse reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRanibizumab is administered as a single intravitreal injection of 0.5\xa0mg. Each vial of ranibizumab contains 2.3\xa0mg in 0.23\xa0ml; overfilling is considered necessary to achieve an injectable dose of 0.5\xa0mg. The list price of ranibizumab is £742.17 per vial (excluding VAT; 'British national formulary' [BNF] edition\xa064). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of ranibizumab (Novartis) has agreed a patient access scheme with the Department of Health which makes ranibizumab available with a discount applied to all invoices. The size of the discount is commercial in confidence (see section\xa05.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.", "The manufacturer's original submission": "The Appraisal Committee (appendix\xa0A) considered evidence submitted by the manufacturer of ranibizumab and a review of this submission by the Evidence Review Group (ERG; appendix\xa0B). This document refers to an original submission and a revised submission (made during development of NICE technology appraisal guidance 237) and a rapid review submission, described for the first time in this document.\n\nThe manufacturer submitted evidence on the clinical effectiveness and cost effectiveness of ranibizumab monotherapy and ranibizumab plus laser photocoagulation compared with laser photocoagulation alone in its original submission. The manufacturer did not provide a comparison with bevacizumab, which the appraisal scope lists as a comparator. The manufacturer explained that this was because it believed that there is no robust evidence base for the clinical effectiveness or safety of bevacizumab in the treatment of diabetic macular oedema, bevacizumab has not been in long-term use in the NHS and there is no widely accepted dosage.\n\n# Clinical effectiveness\n\nThe manufacturer performed a systematic review of the evidence on the clinical effectiveness of ranibizumab. The review identified 4\xa0randomised controlled trials (RCTs) that included ranibizumab in people with diabetic macular oedema – RESTORE, Diabetic Retinopathy Clinical Research Network Protocol\xa0I (DRCR.net), RESOLVE and READ-2. The manufacturer focused its submission on RESTORE and DRCR.net. The 2 other RCTs did not receive detailed attention, because the manufacturer judged them to be of less direct relevance to the decision problem. It stated that RESOLVE had limited application to the appraisal because it did not present a comparison with laser photocoagulation, which the manufacturer believed to be the most relevant comparator for an analysis concentrating on practice in the UK. The manufacturer stated that READ-2 did not provide high-quality evidence because follow-up was of shorter duration than in other included studies, the schedule for treatment differed from that in the summary of product characteristics for ranibizumab and the manufacturer believed the trial may have had methodological shortcomings.\n\nRESTORE was an industry-sponsored, multicentre (73\xa0centres in 13\xa0countries), sham-controlled randomised trial that compared ranibizumab plus sham laser photocoagulation (n=116) with ranibizumab plus laser photocoagulation (n=118) and laser photocoagulation plus sham injections (n=111). The trial lasted for 1\xa0year, and participants were followed beyond 1\xa0year, but did not necessarily remain on the treatment to which they had been randomised. RESTORE included people aged over 18\xa0years with type\xa01 or type\xa02 diabetes and haemoglobin A1c (HbA1c) lower than 10% (86\xa0mmol/mol). The trial protocol stated that, for each participant, only 1\xa0eye should be treated, even if both eyes had disease. The eye with the worse vision was treated unless the investigator deemed it appropriate to treat the eye with the better vision. According to the trial protocol, 20% of participants had their better-seeing eye treated. Best corrected visual acuity (hereafter, 'visual acuity') was measured using 'ETDRS (Early Treatment Diabetic Retinopathy Study)-like' charts, in which a score of 85\xa0letters corresponds to normal visual acuity ('20/20\xa0vision'). An eye was eligible for randomisation if visual acuity was between 78 and 39\xa0letters. Participants who had previous laser photocoagulation were included in the trial. Ranibizumab or sham injections were administered monthly in months\xa01 to 3; after this, they continued on a monthly basis until vision was stabilised for 2\xa0visits or visual acuity reached 85\xa0letters or more. Treatment with monthly injections was restarted if there was a decrease in visual acuity caused by progression of diabetic macular oedema and continued until the same criteria were fulfilled. Laser photocoagulation or sham laser photocoagulation was administered on day\xa01 and repeated at intervals of at least 13\xa0weeks, if deemed necessary by the treating clinician. RESTORE was judged to satisfy all methodological quality criteria assessed by the manufacturer. At the time of the original submission, full details of RESTORE had not been published.\n\nDRCR.net, an RCT funded by the US National Institutes of Health, was conducted at 52\xa0clinical sites in the United States. The trial protocol stipulated that the trial would last for 3\xa0years; however, at the time of submission for NICE technology appraisal 237, only 12-month follow-up data were available. Participants were aged over 18\xa0years and had type\xa01 or type\xa02\xa0diabetes. An eye was eligible for randomisation if it had centre-involving macular oedema and a visual acuity of between 78 and 24\xa0letters using the Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test (again, a score of 85\xa0letters corresponds to normal visual acuity). People who had previous laser photocoagulation were included in the trial. Randomisation was by eye (rather than by participant) and a participant could have both eyes involved in the study. Each eligible eye was randomised to receive either a sham injection plus laser photocoagulation (n=293 eyes), ranibizumab plus prompt laser photocoagulation (within 3–10\xa0days of first ranibizumab injection; n=187\xa0eyes) or ranibizumab with the possibility of subsequent (deferred) laser photocoagulation (at least 24\xa0weeks after the first ranibizumab injection; n=188\xa0eyes). In practice, only 28% of the ranibizumab plus deferred laser arm received laser treatment at any time during the first study year. A fourth group in DRCR.net received triamcinolone; this group is not included in this appraisal because triamcinolone is not currently used in clinical practice in the UK for diabetic macular oedema and was not in the scope for this appraisal. The randomisation protocol specified that, in participants with 2\xa0eligible eyes, 1\xa0eye would receive pharmacological treatment (plus prompt or deferred laser photocoagulation) and the other eye would receive prompt laser photocoagulation alone. Investigators administered ranibizumab or sham injections every 4\xa0weeks until the fourth study visit (that is, after 12\xa0weeks of treatment). At subsequent 4-weekly visits, the decision to give another injection depended on visual acuity and retinal thickness of the treated eye. Investigators repeated laser photocoagulation or sham laser photocoagulation, if needed, at intervals of at least 13\xa0weeks (3-monthly). The manufacturer judged that DRCR.net satisfied all the methodological quality criteria it assessed (although it noted that participants randomised to ranibizumab plus deferred laser were aware of their allocated treatment).\n\nThe primary outcome measure of both RESTORE and DRCR.net was mean change in visual acuity in the treated eye after 12\xa0monthly follow-up visits. The RESTORE analysis was based on the average of changes in visual acuity from baseline, measured monthly over the period from month\xa01 to month\xa012 ('mean average change'), whereas DRCR.net compared the visual acuity measured at baseline with that measured at 12\xa0months ('mean change'). In RESTORE, the visual acuity of eyes randomised to ranibizumab monotherapy rose by a mean average of 6.1\xa0letters, and eyes randomised to ranibizumab plus laser photocoagulation gained a mean average of 5.9\xa0letters. In RESTORE, eyes randomised to laser photocoagulation alone gained fewer letters (0.8) than eyes randomised to either ranibizumab-containing arm (p<0.001). In DRCR.net, visual acuity rose by an average of 9\xa0letters after 12\xa0months in eyes randomised to ranibizumab plus either prompt or deferred laser photocoagulation compared with an average of 3\xa0letters in eyes randomised to laser photocoagulation alone (p<0.001 for either ranibizumab-containing arm compared with laser photocoagulation alone). The manufacturer provided a meta-analysis of mean changes from baseline visual acuity at 12\xa0months combining results from RESTORE and DRCR.net. This suggested that the visual acuity of eyes treated with ranibizumab plus laser photocoagulation gained an average of 5.83\xa0more letters than the visual acuity of eyes treated with laser photocoagulation alone (95%\xa0confidence interval [CI]\xa04.07 to 7.59, p<0.001; fixed-effects and random-effects models estimate identical results).\n\nIn both RESTORE and DRCR.net, a series of subgroup analyses examined the primary outcome measure in participants categorised according to baseline characteristics. In all subgroups analysed in both trials, the visual acuity of participants randomised to ranibizumab-containing treatment improved more than the visual acuity of those randomised to laser photocoagulation. The manufacturer's submission noted that, in RESTORE, gains in visual acuity associated with ranibizumab were greatest in participants with baseline central retinal thickness of 300\xa0micrometres or more and participants with a baseline visual acuity of fewer than 74\xa0letters; the manufacturer presented no evidence on the statistical significance of these differences.\n\nAn alternative approach to presenting the results of visual acuity testing reports the proportion of participants in whom the treated eye improved or worsened by an amount reflecting a clinically significant change in vision, usually a gain or loss of 10\xa0letters. The manufacturer's submission reported that, in RESTORE, the proportions of participants gaining 10\xa0letters in visual acuity in their treated eye after 12\xa0months of treatment were 37% in those randomised to ranibizumab monotherapy, 43% in those randomised to ranibizumab plus laser photocoagulation and 15% in those randomised to laser photocoagulation alone (p<0.001 for either ranibizumab-containing arm compared with laser photocoagulation alone; p-values taken from European Medicines Agency Assessment Report). The proportions of participants who lost 10\xa0letters of visual acuity in their treated eye after 12\xa0months were 3%, 4% and 13% respectively (p<0.05 for either ranibizumab-containing arm compared with laser photocoagulation alone; p\xa0values calculated by the NICE technical team). In DRCR.net, after 12\xa0months of treatment a gain of 10\xa0letters in visual acuity was reported in 47% of eyes treated with ranibizumab plus deferred laser photocoagulation, 51% of eyes treated with ranibizumab plus prompt laser photocoagulation and 28% of eyes treated with laser photocoagulation alone (p<0.001 for either ranibizumab-containing arm compared with laser monotherapy). After 12\xa0months a loss of 10\xa0letters in the treated eye was reported in 3%, 3% and 13% of eyes respectively (p≤0.001 for either ranibizumab-containing arm compared with laser photocoagulation alone). The manufacturer provided a meta-analysis of categorical visual acuity data from RESTORE and DRCR.net after 12\xa0months of treatment. This suggested that the visual acuity of eyes randomised to ranibizumab plus laser photocoagulation was approximately twice as likely to improve by 10\xa0letters than the visual acuity of eyes randomised to laser photocoagulation alone (relative risk=2.15, 95% CI 1.43 to 3.22, p<0.001; random-effects model; fixed-effects model produced similar results). Eyes treated with ranibizumab plus laser photocoagulation were over 3 times less likely to lose 10\xa0letters in visual acuity (relative risk=0.28, 95% CI 0.15 to 0.53, p<0.001; random-effects model; fixed-effects model produced similar results).\n\nRESTORE measured vision-related quality of life using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), which has 25\xa0questions designed to measure the effect of visual impairment on daily functioning and quality of life. The mean changes from baseline in the composite score and in subscales related directly to vision were in favour of ranibizumab compared with laser photocoagulation alone (p<0.05), but benefit was not demonstrated in subscales addressing dependency and driving (p>0.05). The RESTORE investigators also administered assessments of health-related quality of life, including EuroQol-5D (EQ-5D). The manufacturer did not report the results directly, although its economic model relied on an analysis incorporating the EQ-5D data (see section\xa03.12).\n\nThe manufacturer stated that ranibizumab has a favourable safety profile, emphasising that extensive evidence is available from the use of ranibizumab in the treatment of wet age-related macular degeneration. Although none of the RCTs of ranibizumab in diabetic macular oedema were designed primarily to assess safety outcomes, no significant differences were observed between arms in the frequency of ocular and non-ocular adverse events. None of the studies reported death rates.\n\n# Cost effectiveness\n\nThe economic evidence provided by the manufacturer in its original submission comprised a brief literature review (identifying no relevant published analyses) and a de novo cost–utility analysis. The cost–utility analysis used a Markov model simulating cohorts of people with diabetic macular oedema receiving ranibizumab monotherapy, ranibizumab plus laser photocoagulation, or laser photocoagulation alone. The model had 3-monthly cycles and a base-case time horizon of 15\xa0years. It assumed (simulated) a starting population with diabetic macular oedema with a mean age of 63\xa0years and visual acuity scores of between 75 and 36\xa0letters. Health states were defined by visual acuity in the treated eye, rather than both eyes, and used 10-letter categories (with the exception of the best and worst states), resulting in 8 health states excluding death: 0–25\xa0letters, 26–35\xa0letters, 36–45\xa0letters, 46–55\xa0letters, 56–65\xa0letters, 66–75\xa0letters, 76–85\xa0letters and 86–100\xa0letters.\n\nBased on the average number of injections received in RESTORE, the manufacturer's original model included 7 ranibizumab injections in the first year for both the ranibizumab monotherapy arm and the combination therapy arm. The manufacturer included an additional stopping rule, assuming that people with a visual acuity of 76\xa0letters or more in the treated eye would not receive active treatment and would incur no treatment costs. In the second year of the model, based on data from DRCR.net, the manufacturer assumed 3 further ranibizumab injections in the ranibizumab monotherapy arm and 2 further ranibizumab injections in the combination therapy arm. For both the combination therapy arm and the laser photocoagulation alone arm, the model assumed 2 laser photocoagulation treatments in the first year and 1 additional laser treatment in the second year. The original model did not simulate any ranibizumab treatment or laser photocoagulation after the second year. The manufacturer accepted that, in practice, additional laser photocoagulation would take place after the second year, but assumed that there would be no difference between the modelled arms in this respect and therefore any costs and effects would cancel each other out.\n\nTo estimate the health-related quality of life associated with each health state corresponding to vision in the model, EQ-5D data from RESTORE were transformed to utility values using standard social tariffs and then related to visual acuity in the treated eye using linear regression. In this way, a mathematical relationship was assumed between visual acuity in the treated eye and the health-related quality of life of people with diabetic macular oedema. Tests of interaction demonstrated that neither treatment allocation nor duration of treatment at the time of measurement had a significant impact on the relationship between utility and visual acuity category. Therefore, the utility value was derived for each visual acuity category using the whole data set, without any adjustment variables. The results of the regression suggested that, depending on visual acuity in the treated eye, the utility value ranged from 0.860 to 0.547. The utility value for the best health state (visual acuity 86–100\xa0letters) resulting from the regression was 0.831; however, this result was considered anomalous, because it was based on relatively few data points and it was thought unrealistic that utility should be worse than in the next-best state, in which vision is inferior. Therefore, the manufacturer set the utility value for a visual acuity of 86–100\xa0letters to be equal to the utility value for a visual acuity of 75–85\xa0letters (that is,\xa00.860). The manufacturer did not apply any treatment-specific utilities and specifically did not apply a decrement in utility value to reflect adverse effects associated with the treatments.\n\nDepending on the period of follow-up being simulated, the model used 3\xa0different sets of data and assumptions to estimate the probability of changing between visual acuity states (transition probabilities). The first phase of the model reflected the first year of treatment, for which the manufacturer drew transition probabilities directly from changes in visual acuity observed among individual participants in RESTORE. In the original model, this data set included a proportion of treated eyes with a visual acuity of more than 75\xa0letters at baseline, although eyes with equivalent vision were not simulated in the model. In the second and third phases of the model, the manufacturer based the transition probabilities on a 3-way matrix that reflected the estimated likelihood of improvement, deterioration or no change in the visual acuity of a given eye. The manufacturer assumed that the same probabilities applied to all states (with the exception of assuming that an eye with the best possible visual acuity could not improve and that an eye with the worst possible visual acuity could not worsen). The second phase of treatment reflected a period during which visual acuity was assumed to remain constant. This was based on the DRCR.net study, which the manufacturer interpreted as showing that average visual acuity was maintained between 12\xa0months and 24\xa0months for all treatments. Therefore, the manufacturer assumed equal probabilities of improving or worsening in all model arms. In the original model, this phase comprised the second year of treatment only. In the third phase, the model assumed no treatment effect: based on an informal review of epidemiological literature, the manufacturer assumed quarterly probabilities of 0.025 for improvement and 0.035 for deterioration in all arms (implying that the probability of visual acuity staying the same was 0.94 in any quarter). In the original model, this final phase began at the start of year\xa03, and continued until the end of the model. According to this approach, the relative difference in treatment effect observed at the end of the initial treatment phase (year\xa01) was preserved for the remainder of the model. Thus, beyond 1\xa0year, the visual acuities of participants previously treated with ranibizumab remained constant during the second year and after that declined at the same rate as the visual acuities of participants previously treated with laser photocoagulation. As a result, the relative difference in vision between treatments estimated at the end of the first year was preserved for the remainder of the model (that is, for the next 14\xa0years).\n\nIn its model, the manufacturer assumed that the probability of dying is the same for all health states (so no additional risk of death was associated with worsening vision). Mortality rates were derived from life tables for England and Wales, modified by a relative risk representing the additional hazard of death for the modelled cohort when compared with the general population. In the original model, the manufacturer used a relative risk of 1.27, drawn from published literature comparing the risk of death for people with clinically significant diabetic macular oedema with the risk of death for people with diabetes, but without diabetic macular oedema. The manufacturer modelled adverse events on the basis of observed, treatment-specific rates of 4\xa0events (cataract, endophthalmitis, retinal detachment and vitreous haemorrhage) in a pooled analysis of RESTORE and DRCR.net. The manufacturer included only the costs associated with these complications; it did not assume that the presence of these adverse events lowers quality of life (utility).\n\nThe cost of ranibizumab included in the original model was £761.20 per injection (this was before the manufacturer submitted a patient access scheme; the manufacturer submitted the patient access scheme after publication of the appraisal consultation document for NICE technology appraisal guidance 237, and revised it for the rapid review submission). Unit costs of a visit to an eye clinic for a check-up and/or treatment were based on NHS reference costs (2008/09). The manufacturer assumed that treatment with both ranibizumab and laser photocoagulation occurs on an outpatient basis, and costs £150 per visit. For combination therapy, the manufacturer assumed that ranibizumab injections and laser photocoagulation would occur at the same visit, and cost £184 per visit. The manufacturer assumed that the full cost of laser photocoagulation is encompassed within the NHS reference cost for the clinic visit and included no additional costs for buying and maintaining the equipment. The costs (£126\xa0each) of visits to monitor people (for vision and recurrence of disease) were also included: in the original model, people receiving ranibizumab monotherapy had 12\xa0visits in the first year and 10\xa0visits in the second year; people receiving combination therapy had 12\xa0visits in the first year and 8\xa0visits in the second year; those receiving laser photocoagulation alone in the first and second years, and all people from the third year onwards, had 4\xa0visits per year. For the ranibizumab-containing arms, a visit for treatment was assumed to include monitoring as well. The same assumption was not applied for people receiving laser photocoagulation alone; that is, people receiving laser photocoagulation needed separate visits for treatment and monitoring.\n\nIn the model, the manufacturer applied estimated costs associated with severe vision loss for people with the lowest visual acuity in the treated eye (0–25 or 26–35\xa0letters), regardless of vision in the non-treated eye. These costs reflected the additional resource use associated with people who are eligible to register as severely sight impaired (blind). The costs accounted for a range of items including low-vision aids, rehabilitation, residential care, district nursing, community care and the cost of treating complications including depression and falls. The manufacturer drew cost data largely from a published costing study of blindness in the UK that focused on people with age-related macular degeneration (Meads and Hyde 2003), with costs updated or adjusted for inflation as appropriate. The total cost applied was £6067 in the first year and £5936 in subsequent years.\n\nIn its deterministic base case, the manufacturer's original model estimated an incremental cost-effectiveness ratio (ICER) of £19,075 per quality-adjusted life year (QALY) gained for ranibizumab monotherapy compared with laser photocoagulation alone. The model predicted that combining laser photocoagulation with ranibizumab would be more expensive and less effective than ranibizumab alone; that is, ranibizumab alone dominated combination therapy. The manufacturer also presented a series of deterministic sensitivity analyses in which single parameters (or related groups of parameters) were varied across plausible ranges. These analyses suggested that the model was most sensitive to the time horizon: when the time horizon was limited to 10\xa0years, the estimated ICERs for ranibizumab monotherapy compared with laser photocoagulation alone rose by approximately 50%, to £30,367 per QALY gained. Most sensitivity analyses repeated the base-case finding that ranibizumab monotherapy dominates combination therapy with ranibizumab plus laser photocoagulation. Probabilistic sensitivity analysis (based on 10,000 Monte-Carlo simulations) suggested that the probability of ranibizumab monotherapy providing best cost–utility compared with laser alone was 49.3% and 76.8% at thresholds of £20,000 and £30,000 per QALY gained respectively. The probability of combination therapy providing best cost–utility compared with ranibizumab monotherapy was 19.4% and 17.8% at the same thresholds (these estimates have been corrected from the manufacturer's submission for NICE technology appraisal guidance 237 by the NICE technical team and verified by the ERG).\n\nThe manufacturer also presented a series of deterministic subgroup analyses in which first-year transition probabilities were derived from analyses of the RESTORE trial limited to participants with the characteristic(s) in question. The manufacturer changed no other parameters in the model. The manufacturer noted that several of the analyses were based on small numbers of participants. There were large variations between the results of some subgroups:\n\nLimiting the analysis to people with good glycaemic control (HbA1c less than 8%) produced an ICER of £13,196 per QALY gained for ranibizumab monotherapy compared with laser photocoagulation. In people with poorer glycaemic control (HbA1c 8% or more) ranibizumab monotherapy had an ICER of £36,383 per QALY gained when compared with laser photocoagulation.\n\nIn people who previously had laser photocoagulation, ranibizumab monotherapy was associated with an ICER of £29,660 per QALY gained compared with laser photocoagulation. The equivalent figure for the subgroup who had not previously had laser photocoagulation was £12,675 per QALY gained.\n\nThe ICERs for ranibizumab monotherapy compared with laser photocoagulation in people with baseline visual acuity of 36–45\xa0letters, 46–55 letters, 56–65\xa0letters and 66–75\xa0letters were £52,704, £7645, £42,477 and £12,198 per QALY gained respectively.However, the manufacturer considered that in light of the limitations related to the small number of trial participants in some of the subgroups, the relative cost effectiveness of ranibizumab monotherapy in these subgroups is uncertain and should be interpreted with caution.\n\n## Evidence Review Group comments on the manufacturer's original submission\n\nThe ERG noted that the manufacturer's original submission did not contain a comparison of ranibizumab with bevacizumab, which the appraisal scope lists as a comparator. The ERG report stated that, although it does not have a marketing authorisation for use in diabetic macular oedema in the UK, bevacizumab is used by ophthalmologists in some NHS centres if laser photocoagulation has failed to produce a response or as an alternative treatment if long-term treatment with laser photocoagulation is considered a risk. The ERG questioned the manufacturer's argument that there is a lack of robust evidence on clinical effectiveness or safety of bevacizumab in the treatment of diabetic macular oedema. In its report, the ERG provided details of 29\xa0published studies it considered relevant to the use of intraocular bevacizumab in diabetic macular oedema, including 7\xa0randomised comparisons with laser photocoagulation and/or sham injections. The ERG noted that some of the evidence evaluates the long-term effects of bevacizumab and some compares different dosages. The ERG stated that the manufacturer's view of bevacizumab was 'unjustifiably negative' and expressed the opinion that the evidence base should have been sufficient to enable an indirect comparison of ranibizumab with bevacizumab.\n\n# Additional evidence to the original submission submitted by the manufacturer during consultation for NICE technology appraisal guidance 237\n\nIn response to consultation on the original appraisal consultation document, the manufacturer submitted a revised cost–utility analysis, addressing reservations the Committee had expressed about the original model and submitted a first patient access scheme. Several consultees and commentators, including patient and professional groups, agreed with the Committee that the manufacturer's original economic model had given an unrealistic representation of likely clinical practice in some respects.\n\nThe manufacturer stated that the revised model should be 'considered a better-seeing eye model' – that is, it should be thought of as simulating a treatment strategy in which people with diabetic macular oedema received treatment in their better-seeing eye only. This was a change from the manufacturer's original economic analysis, in which the modelled treatment strategy assumed that people would largely receive treatment in their worse-seeing eye. The manufacturer observed that cost–utility models produce lower ICERs when simulating treatment in the better-seeing eye of people with diabetic macular oedema than when simulating treatment in the worse-seeing eye. This is partly because the health-related quality of life of people with visual impairment is associated primarily with vision in the better-seeing eye and partly because the costs of severe visual impairment depend on vision in the better-seeing eye. Thus, in general, treatments that maintain or improve vision in the better-seeing eye will be favoured in economic analyses. The manufacturer cited the precedent of NICE technology appraisal guidance\xa0155 (Ranibizumab and pegaptanib for the treatment of age-related macular degeneration) in which the Assessment Group's model had explicitly assumed that only the better-seeing eye was treated, but the Committee had made recommendations on the assumption that treatment would be given to the first eye to present clinically, be it the better- or worse-seeing eye. For these reasons, the manufacturer felt it would be helpful to present the Committee with a model that explicitly assumed treatment of the better-seeing eye, although the data on which the model was based were drawn predominantly from people whose worse-seeing eye had been treated, and it did not otherwise change the way the model associated vision in the worse-seeing eye with quality of life.\n\nThe manufacturer accepted the view the Committee had expressed in the appraisal consultation document that its original model had underestimated the hazard of death associated with diabetic macular oedema by not including the hazard associated with diabetes itself. Its revised model used a higher relative risk of death of 2.45 for people with diabetic macular oedema compared with the general population. The manufacturer derived this value by combining an estimate of the additional hazard of death associated with diabetes (1.93 compared with the general population, from an English epidemiological study by Mulnier\xa0et\xa0al. 2006) with an estimate of the additional hazard of death independently associated with macular oedema among people with diabetes in Wisconsin, USA (1.27, as reported by Hirai\xa0et\xa0al. 2008). The manufacturer stated that the revised relative risk of 2.45 was more plausible, although it might overestimate the true hazard associated with diabetic macular oedema. It noted that the revised model predicted that 43% of the cohort would remain alive after 15\xa0years (at age\xa078), whereas the original model had suggested that 65% of people would be alive at that time.\n\nIn NICE technology appraisal guidance 237 the Committee considered at its first meeting that, by assuming people whose visual acuity rose to 76\xa0letters or higher would stop receiving ranibizumab, the manufacturer's original model had not reflected likely clinical practice. Acknowledging this view, the manufacturer removed the stopping rule from the base case of its revised model. For related reasons, the manufacturer also revised the effectiveness evidence used to simulate the first year of treatment. The original model drew transitions between visual acuity states from those observed in the whole population in RESTORE, including participants whose visual acuity had been higher than 75\xa0letters at the start of treatment. In its revised model, the manufacturer calculated visual acuity state transitions in the first year of treatment using only participants whose visual acuities matched those of the assumed starting population in the model (that is, only people with baseline visual acuities of 36–75\xa0letters).\n\nThe manufacturer accepted that there were uncertainties around the assumption in its original model that people would need only 2\xa0years of treatment with ranibizumab. Its revised model assumed that people receiving ranibizumab would receive an average of 2\xa0injections in a third year of treatment and 1\xa0injection in a fourth year of treatment. In the laser photocoagulation arm, the model assumed once-yearly treatments for years\xa03 and 4. To reflect the benefit that would accrue from these additional treatments, the manufacturer extended its original assumption that visual acuity would be maintained in all arms in year\xa02 of the model to encompass years\xa03 and 4 – that is, vision remained stable from years\xa02 to 4 and then declined equally in the group treated with ranibizumab and the group treated with laser photocoagulation.\n\nWhen considering the manufacturer's original model, the Committee had expressed concern that it did not account for the need to treat both eyes in a significant proportion of people. The manufacturer did not alter its base case to address this issue. However, it provided a scenario analysis, using its revised model, which simulated treatment in both eyes for 35% of people. This analysis assumed that, in people with bilateral disease, both eyes would be treated and monitored at the same visit, with ranibizumab drug and treatment costs doubled. The analysis applied reduced costs associated with severe visual impairment because fewer people would go blind in both eyes. The analysis assumed that treating the second eye would result in utility gains a quarter the magnitude of those achieved by treating the first eye; this is because the health-related quality of life of people who can see well with both eyes is only a little better than the health-related quality of life of people who can see well with 1\xa0eye. The model calculated this figure by applying a 25% uplift to the QALYs generated by ranibizumab.\n\nIn NICE technology appraisal guidance 237, the Committee had noted that the range of utility values used in the manufacturer's original model was broader than would be expected according to the assumptions of the model. The Committee had suggested that 1 possible explanation for this was that the regression model used to define the relationship between visual acuity and utility (see section\xa03.12) had not accounted for confounding variables reflecting the effect of diabetic comorbidities on health-related quality of life. To address this point, the manufacturer's consultation comments included an 'extended' analysis, which re-estimated the relationship between visual acuity and utility using a model containing additional covariates: age, sex, duration of diabetes, blood pressure control at baseline (categorised dichotomously), baseline HbA1c and a variable indicating whether each treated eye was the participant's better- or worse-seeing one. This analysis suggested that, apart from visual acuity, only sex was a significant predictor of utility (p<0.05). The manufacturer concluded that the utility function used in the original model had not been confounded by factors relating to diabetic comorbidities and retained the same utility values in its revised base case. However, the manufacturer also presented a scenario analysis that used the utility values estimated in the extended regression analysis, including all non-significant covariates.\n\nWhen considering the manufacturer's original model, the Committee had questioned the validity of assuming that the relative improvement in vision achieved in the first year would persist for the duration of the model (see section\xa03.13), that is, that vision would deteriorate equally in the groups. The manufacturer responded to this point in its consultation comments, arguing that there was no evidence to suggest that gains in visual acuity would diminish at different rates depending on the treatment. It also cited the precedent of NICE technology appraisal guidance 155, in which the Committee had accepted an analogous approach, as a reasonable basis for decision-making.\n\nIn NICE technology appraisal guidance 237, the Committee had expressed concern that the unit cost of injection procedures used in the manufacturer's original model (£150; see section\xa03.15) might underestimate the true costs of administering ranibizumab. In its response to consultation, the manufacturer provided a 'bottom-up' estimate of the cost of an intravitreal injection visit, compiling separate estimates of the costs associated with consulting individual members of an ophthalmology clinic team and including overheads. This resulted in an estimated unit cost of £142.91, which the manufacturer took as evidence that the value used in the original model had accurately reflected the administration costs of ranibizumab. The manufacturer emphasised that charges applied to visits for ranibizumab injections are subject to local agreements between commissioners and providers, and may not always reflect the true costs of service delivery.\n\nIn NICE technology appraisal guidance 237, the Committee had initially concluded that the manufacturer's original model overestimated the cost savings of ranibizumab-based therapy that would be achieved by avoiding or delaying severe vision loss. The model drew the costs of severe vision loss from visual acuities that fell below 35\xa0letters in treated eyes, but the data sources from which the manufacturer drew these costs used visual acuity in the better-seeing eye. By stating that its revised model should be considered to simulate treatment in the better-seeing eye, the manufacturer suggested it had removed this problem.\n\nThe results of the manufacturer's revised model in NICE technology appraisal guidance 237 included a subgroup analysis estimating the cost–utility of ranibizumab in people with the greatest degree of macular oedema (central foveal thickness greater than 400\xa0micrometres). The manufacturer provided this analysis in response to comments from clinical specialists, reported in the original appraisal consultation document, suggesting that laser photocoagulation may be less effective in a thicker, more oedematous retina. For this reason, the manufacturer stated that such people represented a 'clinically plausible' subgroup in which ranibizumab could be expected to have a greater relative effect when compared with laser photocoagulation. The manufacturer confirmed that the trial protocol for RESTORE had pre-specified subgroup analyses according to 3 categories of central foveal thickness: less than 300\xa0micrometres, 300–400\xa0micrometres and greater than 400\xa0micrometres. In its response to consultation, the manufacturer stated that it had carried out tests of the statistical significance of differences in clinical outcome according to baseline central foveal thickness category. However, the results of these tests were not presented in the submitted documentation.\n\nThe manufacturer's revised model also included a patient access scheme reflecting its agreement with the Department of Health in 2011 that ranibizumab will be made available to the NHS at a discounted price (level of discount confidential; see section\xa02.4).\n\nThe manufacturer's revised base case focused solely on the comparison of ranibizumab monotherapy with laser photocoagulation. It estimated that ranibizumab is associated with an ICER of £30,277 per QALY gained (disaggregated cost and QALY estimates are unavailable because of the confidentiality of the patient access scheme). In the subgroup of people with central foveal thickness greater than 400\xa0micrometres, the equivalent ICER was £21,418 per QALY gained.\n\nThe manufacturer's scenario analysis simulating treatment in both eyes for 35% of people resulted in an ICER of £44,355 per QALY gained for ranibizumab monotherapy compared with laser photocoagulation. In the subgroup of people with central foveal thickness greater than 400\xa0micrometres, the equivalent ICER was £35,719 per QALY gained.\n\nThe manufacturer provided a scenario analysis adopting utilities re-estimated from RESTORE data using an extended model with additional covariates reflecting baseline characteristics of participants and factors relating to diabetic comorbidities (see section\xa03.26). This resulted in an increase in the ICER from its base case of £30,277 per QALY gained to £33,857 per QALY gained for ranibizumab monotherapy compared with laser photocoagulation.\n\nA further series of scenario analyses adopted alternative estimates of utility drawn from various published sources. When utility values from the better-seeing eye study by Lloyd\xa0et\xa0al. were used, the ICER was £24,779 per QALY gained. When utility was estimated according to an equation published by Sharma\xa0et\xa0al., associating visual acuity in the better-seeing eye with health-related quality of life, the ICER was between £12,312 and £12,610 per QALY gained, depending on the version of the equation used. A final analysis adopted utility values estimated in a study by Czoski-Murray\xa0et\xa0al. (referred to as Brazier\xa0et\xa0al. in NICE technology appraisal guidance 237), in which members of the general public valued levels of visual impairment that were simulated by custom-made contact lenses, using the time trade-off method. Participants wore the same lenses in both eyes, so the resulting utility values reflected bilateral impairment of vision. This was the source of utility values the Committee had judged most accurately reflected the health-related quality of life associated with visual impairment in NICE technology appraisal guidance 155. When these values were used in the revised ranibizumab model, the ICER was £23,664 per QALY gained.\n\nIn its response to consultation on the appraisal consultation document for NICE technology appraisal guidance 237, the manufacturer provided additional arguments on the suitability of bevacizumab as a comparator. The manufacturer stated that bevacizumab could not be considered routine or best practice, because NHS experience is 'limited to experimental or compassionate use' and 'there are no robust data to demonstrate the safety, effectiveness and quality of the product'. The manufacturer argued that the optimum dose of bevacizumab for intraocular use is not established. It summarised 'emerging safety signals for the use of unlicensed intravitreal bevacizumab', and emphasised that any cost–utility analysis including bevacizumab would have to include the costs of an NHS pharmacovigilance programme. The manufacturer also reviewed the evidence that might be used to perform an indirect comparison of ranibizumab with bevacizumab. It concluded that significant methodological and clinical differences between studies precluded a valid analysis.\n\n## Evidence Review Group's comments on the manufacturer's revised model during NICE technology appraisal guidance 237\n\nThe ERG reviewed the manufacturer's consultation comments and revised economic model. It stated that the revised model's updated estimate of the relative risk of death for people with diabetic macular oedema compared with the general population (relative risk\xa02.45; see section\xa03.22) was reasonable. It agreed with the manufacturer that this figure may be an overestimate of the true additional hazard associated with diabetic macular oedema, but emphasised that it was a more realistic figure than that used in the original model.\n\nThe ERG noted the modified assumptions about duration of treatment in the manufacturer's revised model (see section\xa03.24). It had no comments about the manufacturer's new assumptions about additional treatments in years\xa03 and 4 of the model. However, the ERG emphasised that significant uncertainty remained about whether people with diabetic macular oedema would need injections of ranibizumab beyond the fourth year of treatment.\n\nThe ERG reviewed the manufacturer's scenario analysis as part of its revised model, which assumed that 35% of people with diabetic macular oedema would need treatment in both eyes (see section\xa03.25). It noted that the assumed benefit of treatment in the second eye (a 25% uplift in incremental QALY gain) did not appear to be evidence-based. It also expressed the view that, in people in whom the better-seeing eye is treated, the other eye would receive the same therapy unless it had already suffered irreparable visual loss. As a result, the ERG suggested that an ophthalmologist is likely to offer treatment in both eyes or only the worse-seeing eye.\n\nThe ERG reviewed the manufacturer's comments about the utility values used to estimate health-related quality of life in its revised model, and its additional analyses exploring alternative assumptions. The ERG expressed continuing concern that the analyses did not account for the covariance between visual acuity in the treated and untreated eyes of participants at baseline – that is, it was possible that health-related quality-of-life measurement was strongly influenced by vision in the untreated eye, which was unlikely to be similar to vision in the treated eye. The ERG suggested that it would have been possible to avoid this problem by basing the regression model on the impact over time of treatment on utility – that is, by modelling the relationship between changes in visual acuity and changes in health-related quality of life, rather than modelling absolute levels of both.\n\nThe ERG stated that the bottom-up costing exercise carried out by the manufacturer to validate the unit cost of ranibizumab injection procedures (see section\xa03.28) was reasonable and useful. It noted that, if the additional cost of consumables (instruments, cotton wool, a drape and a syringe) were included, the total estimate would reach the £150 unit cost used in the model. The ERG expressed support for the manufacturer's assumption that all ranibizumab injections would take place on an outpatient basis.\n\nThe ERG reviewed the manufacturer's subgroup analysis presenting the cost–utility of ranibizumab in people with central foveal thickness greater than 400\xa0micrometres. It accepted the theoretical basis of the subgroup, agreeing that laser photocoagulation is expected to be less effective in a very thick retina. Because it noted that the manufacturer had presented subgroup results only for people with the thickest retinas, the ERG provided equivalent data for the other categories of retinal thickness analysed in RESTORE. For people with central foveal thickness less than 300\xa0micrometres (49\xa0trial participants), the ICER for ranibizumab compared with laser photocoagulation was £27,496 per QALY gained. For people with central foveal thickness of 300–400\xa0micrometres (62\xa0trial participants), the ICER for ranibizumab compared with laser photocoagulation was £386,321 per QALY gained. The ERG noted that this pattern of cost-effectiveness estimates was erratic and should be interpreted with caution. It commented that the calculations were based on small sample sizes, although it noted that the subgroup presented by the manufacturer – people with central foveal thickness greater than 400\xa0micrometres (see section\xa03.32) – represented around half of the population recruited in RESTORE (114 of 217\xa0participants randomised to ranibizumab monotherapy or laser photocoagulation).\n\nThe ERG noted that the manufacturer's model (in both its original and revised versions) assumed that an administration visit for a ranibizumab injection can double as a monitoring visit but an administration visit for laser photocoagulation cannot. The ERG provided analyses removing this difference. When it was assumed that people receiving ranibizumab need additional monitoring visits (as for laser photocoagulation), the ICER rose to £37,673 per QALY gained; when it was assumed that people receiving laser photocoagulation do not need additional monitoring visits (as for ranibizumab), the ICER was £33,074 per QALY gained.\n\nThe ERG responded to the manufacturer's comments on the suitability of bevacizumab as a comparator. It disagreed with the manufacturer's suggestion that the optimum dose of bevacizumab is unknown, suggesting that the standard dose is 1.25\xa0mg. The ERG reiterated its view that safety data are available on the use of bevacizumab. It emphasised that the incidence of adverse events is low with both ranibizumab and bevacizumab. The ERG noted that a recent head-to-head trial of ranibizumab and bevacizumab for age-related macular degeneration (CATT [Comparison of Age-related Macular Degeneration Treatments Trial]) showed equivalent efficacy between the 2 technologies.\n\n# Rapid review of NICE technology appraisal guidance 237 patient access scheme\n\nNICE technology appraisal guidance 237 did not recommend ranibizumab for the treatment of visual impairment due to diabetic macular oedema. After publication of NICE technology appraisal guidance 237, the manufacturer submitted a revised patient access scheme in which it applied a revised discount to ranibizumab for all indications (see section\xa02.4) to be considered as a rapid review of the original guidance.\n\nAs this was a rapid review, the manufacturer did not submit any additional clinical effectiveness data. However, in addition to the revised patient access scheme, the manufacturer submitted an amended economic model that attempted to address 6\xa0specific concerns that were raised by the Committee in section\xa04.29 of NICE technology appraisal guidance 237 as follows:\n\nBy not accounting for the need to treat both eyes in a large proportion of people with diabetic macular oedema, the manufacturer's revised base-case model underestimated the benefits and – to a greater degree – the costs of treatments. The manufacturer's scenario analysis simulating treatment in both eyes for 35% of people provided a more realistic reflection of likely clinical practice.\n\nThe range of utility values used in the manufacturer's revised base case was broader than would be expected according to the assumptions of the model. The Committee preferred the manufacturer's scenario analysis adjusting for factors that may influence the relationship between visual acuity and health-related quality of life.\n\nThe model underestimated the amount of ranibizumab that people with diabetic macular oedema were likely to need over time. Basing the number of injections for year\xa02 of the model's ranibizumab monotherapy arm on experience in DRCR.net overlooks the fact that the participants in the trial also received laser photocoagulation, which clinicians believe may have a ranibizumab-sparing effect. The declining number of ranibizumab injections assumed in years\xa03 and 4 is not evidence-based, and is unlikely to lead to stable vision during that period, as assumed. It may also have been unrealistic to assume that ranibizumab treatment will not continue beyond 4\xa0years.\n\nThe model's assumption that the relative benefit achieved during the treatment phase lasts indefinitely was unrealistic. If NICE technology appraisal guidance 155 is considered as a precedent, then it should be noted that the model in that appraisal had a shorter time horizon, which limited the Committee's uncertainty about extrapolating treatment effects into the future.\n\nThe model applied unequal assumptions about treatment and monitoring visits for people treated with ranibizumab and those treated with laser photocoagulation.\n\nThe manufacturer's model overestimated the degree of glycaemic control that would be expected in people treated in clinical practice in the UK.\n\nIn response to the Committee's concerns, the manufacturer amended its economic model with the following revisions:\n\nTo approximate an ICER for treating both eyes, the manufacturer multiplied the ICER from the revised model, considered by the manufacturer to represent a better-seeing eye model, by a factor of 1.5. The manufacturer noted that this approach was consistent with that taken by the Committee in NICE technology appraisal guidance 155, when it observed that a policy of treating the first eye to come to clinical attention would result in substantially higher costs, but fewer savings and lower utility gains, than a policy of treating only the better-seeing affected eye. The manufacturer did not make any additional changes to the model to address this issue.\n\nTo address the Committee's concerns about utility, the manufacturer considered that the utility values estimated in a study by Czoski-Murray\xa0et\xa0al. (2009) were those preferred by the Committee. In this study, the investigators developed a regression model that estimated the contribution of visual acuity (measured by the LogMAR [logarithm as the minimal angle of resolution] scale) to health-related quality of life, adjusting for age. The regression model was subsequently used by the manufacturer to estimate utility values for each of the 8\xa0visual acuity health states (defined by the ETDRS scale) after converting the upper and lower limits of the ETDRS scale to its LogMAR equivalent. Based on a mean age of 65\xa0years, the estimated utility values used in the manufacturer's new base-case analysis ranged from 0.869 for the best health state to 0.353 for the worst health state.\n\nTo address the Committee's concerns about the number of ranibizumab injections people with diabetic macular oedema would need, the manufacturer assumed that people receiving ranibizumab alone would need a total of 14\xa0ranibizumab injections over 4\xa0years: 7\xa0injections in the first year, 4\xa0injections in the second year, and 3\xa0injections in the third year. These assumptions were based on a 2-year extension of the RESTORE study, which showed that trial participants needed a decreasing number of ranibizumab injections from the first year to the third year. The manufacturer assumed that no injections were needed in the fourth year. The manufacturer also carried out a threshold analysis to estimate the maximum number of ranibizumab injections that could be administered over the time horizon of the model while maintaining an ICER below £30,000 per QALY gained.\n\nTo address the Committee's concerns about extrapolating the relative benefit of treatment with ranibizumab beyond the initial treatment phase, the manufacturer reduced the time horizon of the model from 15\xa0years to 10\xa0years. The manufacturer also conducted a threshold analysis to explore the highest rate at which vision could worsen in people treated with ranibizumab and maintain an ICER below £30,000 per QALY gained. To do this, the manufacturer assumed from the fourth year onwards, quarterly probabilities of 0.025 for improvement and 0.055 for deterioration for people receiving ranibizumab monotherapy and quarterly probabilities of 0.025 for improvement and 0.035 for deterioration for people receiving laser photocoagulation alone.\n\nTo address the Committee's concerns about care provided during visits to the eye clinic, the manufacturer assumed that for people receiving either ranibizumab monotherapy or laser alone, a visit for treatment also included monitoring. People receiving ranibizumab monotherapy visited the eye clinic 12\xa0times in the first year, 8\xa0times in the second year and 6\xa0times in the third year; those receiving laser photocoagulation alone had 4\xa0visits per year in the first, second and third years, and people on either treatment had 2\xa0visits per year in the fourth year.\n\nDespite the Committee's concerns that the ICER for ranibizumab monotherapy compared with laser photocoagulation would be higher in people with poor glycaemic control, the manufacturer did not present further subgroup analyses according to the degree of glycaemic control. The manufacturer noted the Committee's considerations in NICE technology appraisal guidance 237 that analyses restricted to people with good glycaemic control (HbA1c less than 8%) and poor glycaemic control (HbA1c 8% or more) were 'exploratory'. The manufacturer also suggested that these subgroup analyses need careful interpretation because of the small sample sizes, which resulted in a very small number of people in extreme health states influencing the results.\n\nThe manufacturer's model for the rapid review submission, including the revised patient access scheme, compared ranibizumab monotherapy with laser photocoagulation. The manufacturer presented separate ICERs for treating the better-seeing eye and for treating both eyes. In the base case, the manufacturer estimated that treating the better-seeing eye with ranibizumab was associated with an ICER of £14,137 per QALY gained and that treating both eyes with ranibizumab was associated with an ICER of £21,205 per QALY gained. The manufacturer estimated that an additional 4\xa0injections of ranibizumab can be given in years 4 to 9 (resulting in a total of 18\xa0injections) for the ICER when treating both eyes to remain below £30,000 per QALY gained. The manufacturer also estimated that the rate of deterioration in vision (visual acuity) for people treated with ranibizumab in both eyes from year\xa04 onwards would need to be more than 1.5\xa0times higher than that for people treated with laser photocoagulation for the ICER to increase to £30,000 per QALY gained. The manufacturer conducted one-way sensitivity analyses that suggested that the model was most sensitive to changes to the time horizon and to utility values. When the time horizon was limited to 5\xa0years the ICER associated with treating both eyes was £41,568 per QALY gained. When the manufacturer instead used utility values from the study by Lloyd\xa0et\xa0al. (representing the contribution to utility from the better-seeing eye), the ICER associated with treating both eyes was £43,716 per QALY gained. The manufacturer provided no probabilistic sensitivity analyses in its rapid review submission.\n\nTo address the Committee's concerns about the validity of the manufacturer's previous subgroup analyses (submitted in response to the consultation on the original appraisal consultation document for NICE technology appraisal guidance 237) according to retinal thickness and the inconsistent relationship between retinal thickness and cost effectiveness, the manufacturer presented additional subgroup analyses according to the degree of retinal thickness. For the rapid review, the manufacturer presented subgroup analyses based on central retinal (rather than foveal) thickness, arguing that this more reliably measures retinal thickness than central foveal thickness. The manufacturer acknowledged that the pattern of cost-effectiveness estimates for the 3\xa0subgroups defined by central foveal thickness had been erratic, and may have been influenced by small sample sizes (see section\xa03.42). Therefore, the manufacturer combined the 2\xa0subgroups with lower values of central retinal thickness to create 2\xa0subgroups (less than 400\xa0micrometres and 400\xa0micrometres or greater) of similar size. The manufacturer presented post hoc tests of the statistical significance of differences in clinical outcome according to baseline central retinal thickness, which suggested that laser photocoagulation was less effective in people with central retinal thickness of 400\xa0micrometres or more (p<0.01) than in people with thicker retinas. In response to Committee comments in NICE technology appraisal guidance 237 that the manufacturer should explore subgroup-specific parameters for all model inputs, and not only effectiveness, the manufacturer also adjusted other model parameters according to the 2\xa0subgroups, including distribution of visual acuity at baseline and treatment frequency in the first year. For people with central retinal thickness of 400\xa0micrometres or more, the ICER associated with treating only the better-seeing eye was £8881 per QALY gained and the ICER associated with treating both eyes was £13,322 per QALY gained. For people with central retinal thickness of less than 400\xa0micrometres, the ICER associated with treating the better-seeing eye was £28,861 per QALY gained and the ICER associated with treating both eyes was £43,292 per QALY gained.\n\n## ERG comments on the manufacturer's rapid review submission\n\nThe ERG reviewed whether the manufacturer had correctly implemented the revised patient access scheme in their cost-effectiveness analysis. Additionally, the ERG checked that the Committee's concerns about the manufacturer's revised model from the guidance on ranibizumab for diabetic macular oedema (NICE technology appraisal guidance 237) had been addressed in the economic analysis.\n\nThe ERG reported that the manufacturer addressed most of the issues raised by the Committee in NICE technology appraisal guidance 237. However the ERG raised the following concerns about the manufacturer's analyses:\n\nIt was unclear why the manufacturer had reduced the number of injections from 1 to 0 in the fourth\xa0year of the model when it had increased the number of ranibizumab injections from 2 to 3 in the third\xa0year.\n\nThe ERG agreed with the manufacturer that the results of the manufacturer's subgroup analyses by degree of glycaemic control may have been influenced by small sample sizes. However, the ERG suggested that the manufacturer could have addressed this issue in a probabilistic model rather than a deterministic analysis. When the ERG ran a probabilistic version of the manufacturer's model, for people with good glycaemic control (HbA1c less than 8%) it produced an ICER associated with the better-seeing eye of £12,895 per QALY gained for ranibizumab monotherapy compared with laser photocoagulation. In people with poorer glycaemic control (HbA1c 8% or more) ranibizumab monotherapy had an ICER associated with the better-seeing eye of £21,560 per QALY gained when compared with laser photocoagulation.\n\nThe ERG commented that the manufacturer may have incorrectly converted the ETDRS scale to the LogMAR scale to establish utility values for 3 of the 8\xa0visual acuity health states in the model. The ERG instead estimated utility values ranging from 0.850 for the best health state to 0.353 for the worst health state which, when applied in the manufacturer's model, slightly increased the ICERs for treating the better-seeing eye and both eyes to £14,473 and £21,710 per QALY gained respectively.\n\nThe ERG conducted exploratory analyses to determine whether the utility values used by the manufacturer were appropriate for people who only have their better-seeing eye treated. The ERG identified a study (Brown\xa01999) that measured vision-related utility values using the time trade-off method in 325 people from the USA with impaired vision (Snellen scale\xa020/40) in at least 1\xa0eye. This study produced utility values reflecting the contribution of vision in the better-seeing eye to health-related quality of life that ranged from 0.920 to 0.540 for the 8\xa0health states defined by visual acuity, a range the ERG noted was narrower than in the Czoski-Murray\xa0et\xa0al. study. The ERG noted that both studies showed a linear relationship between vision and utility. The ERG also noted from the Brown study that, among people who had good vision in their better-seeing eye, the worse-seeing eye contributed little to health-related quality of life.\n\nTo explore the impact of treating only the worse-seeing eye on health-related quality of life, the ERG presented 6\xa0scenario analyses. The 2\xa0extreme scenarios assumed that, at one\xa0extreme, treating only the worse-seeing eye and improving vision did not improve health-related quality of life, to the other extreme where treating only the worse-seeing eye improves health-related quality of life to the same degree as would treating the better-seeing eye. The remaining 4\xa0scenarios provided intermediate assumptions. The ERG used the range of utility values for the better-seeing eye from its own adjusted values estimated from Czoski-Murray\xa0et\xa0al. for the 8\xa0health states reflecting the best to worst vision for the worse-seeing eye (a range of 0.497). The 6\xa0scenarios explored the impact of vision in the worse-seeing eye on health-related quality of life using the following assumptions:\n\nScenario analysis 1: A flat health-related quality-of-life function in which improvements in vision in the treated worse-seeing eye have no impact, that is, health-related quality of life is determined solely by vision in the untreated better-seeing eye.\n\nScenario analysis 2: A health-related quality-of-life function in which treating only the worse-seeing eye results in 15% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, a range of (15% of 0.497)=0.075.\n\nScenario analysis 3: A health-related quality-of-life function in which treating only the worse-seeing eye results in 30% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, a range of (30% of 0.497)=0.149.\n\nScenario analysis 4: A health-related quality-of-life function in which treating only the worse-seeing eye results in 50% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, a range of (50% of 0.497)=0.248.\n\nScenario analysis 5: A health-related quality-of-life function in which treating only the worse-seeing eye results in 75% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, a range of (75% of 0.497)=0.373.\n\nScenario analysis 6: A health-related quality-of-life function in treating only the worse-seeing eye results in 100% of the range of improvements in vision that would have been achieved by treating only the better-seeing eye, that is, vision in the worse-seeing eye influences health-related quality of life to the same extent as vision in the better-seeing eye (range of 0.497).\n\nThe ERG also presented an alternative approach to estimating the costs and QALYs associated with treating both eyes. This differed from the manufacturer's approach of multiplying the ICER associated with treating the better-seeing eye by 1.5 to estimate the ICER associated with treating both eyes. The ERG made a number of assumptions about the proportion of people who would be treated in their better-seeing eye only, their worse-seeing eye only, or in both eyes and the associated costs and QALYs:\n\nTo estimate the proportion of people who have only their better-seeing eye treated, the ERG based their estimate on the RESTORE trial, in which 20% of people had their better-seeing eye treated at baseline. The utility values used by the ERG were those associated with the better-seeing eye (from Czoski-Murray\xa0et\xa0al.). The ERG assumed that if vision in the better-seeing eye deteriorated to the point at which the person became severely visually impaired, the person incurs the costs associated with blindness.\n\nTo estimate the proportion of people who have only their worse-seeing eye treated, the ERG based their estimate on the remainder of people who are treated only in their better-seeing eye or in both eyes (100%−20%−35%=45%). The utility values used by the ERG were those associated with the health-related quality-of-life functions for treating the worse-seeing eye, as described in section\xa03.53. The ERG assumed that if vision in the worse-seeing eye deteriorated and the person became severely visually impaired, the person would not incur the costs associated with blindness, because the better-seeing eye continues to provide vision.\n\nThe ERG assumed that 35% of people have both eyes treated based on figures presented by the manufacturer as part of its original submission for NICE technology appraisal guidance 237. The ERG assumed that changes in the vision of the worse-seeing eye contribute the same amount to health-related quality of life whether it is treated alongside the better-seeing eye or treated alone; that is, the 2 health-related quality-of-life functions resulting from changes in vision of the better-seeing eye or worse-seeing eye are independent. Therefore, the ERG calculated the total QALYs gained with ranibizumab treatment in both eyes as the total QALYs gained for improving vision of the better-seeing eye combined with the total QALYs gained for improving vision of the worse-seeing eye for each of the 6\xa0scenarios described in section\xa03.53. The ERG assumed that treatment costs of ranibizumab were doubled, and included the costs of blindness in the model. However, the ERG assumed that the costs of visits for treatment and for monitoring did not increase from the scenarios that considered treating only the better-seeing eye or worse-seeing eye.\n\nThe ERG then combined the total costs and QALYs for people treated in the better-seeing eye, the worse-seeing eye, or both eyes as a weighted average and calculated the resultant pooled ICERs for each of the 6\xa0scenario analyses described in section\xa03.53. The ERG did not present subgroup analyses according to retinal thickness when using this approach to estimating the costs and QALYs associated with treating both eyes.\n\nIn these exploratory analyses, the ICERs ranged from £16,585 per QALY gained in scenario analysis\xa06 (changes in the vision of the worse-seeing eye have exactly the same impact on health-related quality of life as changes in the vision of the better-seeing eye) to £39,712 per QALY gained in scenario analysis\xa01 (changes in the vision of the worse-seeing eye were assumed to have no impact on health-related quality of life). The ERG repeated these analyses but replaced the utility values estimated from Czoski-Murray\xa0et\xa0al. with those from the study by Brown. This resulted in ICERs that ranged from £21,054 per QALY gained in scenario\xa06 to £50,879 per QALY gained in scenario\xa01. The ERG also repeated these exploratory analyses but increased the proportion of people receiving treatment in both eyes to 62% on the basis of the proportion of participants in the RESTORE trial with a best corrected visual acuity of 78\xa0letters or fewer at baseline (the modelled threshold below which ranibizumab would be offered) in the second eye. When the ERG used utility values estimated from Czoski-Murray\xa0et\xa0al., the ICERs ranged from £15,433 to £29,868 per QALY gained; when the ERG used utility values from Brown, the ICERs ranged from £19,970 to £38,267 per QALY gained.\n\nThe ERG commented that based on the Brown study, which suggested that vision of the worse-seeing eye has minimal impact on a person's health-related quality of life, the ICERs from scenarios\xa04 to 6 (suggesting that vision in the worse-seeing eye contributes 50 to 100% to health-related quality of life) were less plausible than scenarios\xa01 to 3 (suggesting that vision in the worse-seeing eye contributes 0 to 30% to health-related quality of life). The ERG proposed that scenario\xa01 was implausible, because it was unlikely that vision in the worse-seeing eye would have no impact on health-related quality of life. In scenarios\xa02 and 3, the ICERs ranged from £32,843 to £27,999 per QALY gained when utility values estimated from Czoski-Murray\xa0et\xa0al. were used and from £42,227 to £36,089 per QALY gained when utility values from Brown were used. The ERG also commented that the scenarios that considered treating only the worse-seeing eye did not account for a gain in health-related quality of life from reducing the fear of blindness in the worse-seeing eye.\n\n## Additional analyses submitted by the manufacturer during consultation on the appraisal consultation document for the rapid review of NICE technology appraisal guidance 237\n\nIn response to the appraisal consultation document for the rapid review of NICE technology appraisal guidance 237, the manufacturer presented cost-effectiveness analyses based on the approach taken by the ERG when estimating the costs and QALYs associated with treating both eyes (see sections 3.53–3.54). The manufacturer presented alternative estimates, based on baseline data from RESTORE, of the proportion of people who would be treated in their better-seeing eye only, their worse-seeing eye only, or in both eyes. In addition, the manufacturer suggested that some patients in RESTORE were treated in an eye with the same vision as the other eye, defined as the same-seeing eye. The manufacturer defined a same-seeing eye as one with a difference in visual acuity between eyes of fewer than 5\xa0letters on the ETDRS scale for patients with visual acuity of 50\xa0letters or more in both eyes at baseline, or a difference in visual acuity of fewer than 10\xa0letters for patients with visual acuity of fewer than 50\xa0letters in both eyes at baseline. Based on these criteria, approximately 22% of patients from RESTORE were defined as being treated in the same-seeing eye, 22% were defined as being treated in the better-seeing eye and 56% were defined as being treated in the worse-seeing eye. The manufacturer presented 3 separate analyses, which varied the proportion of people who might be treated in their better-seeing eye only, their worse-seeing only, or in both eyes, to incorporate assumptions about treatment of same-seeing eyes:\n\nIn the first analysis, the manufacturer assumed that treating the same-seeing eye improves health-related quality of life to the same degree as treating only the better-seeing eye. A total of 44% of people in RESTORE were treated in either the better-seeing eye or the same-seeing eye. Of the remaining 56% of people, the manufacturer assumed that 35% were treated in both eyes and the remaining 21% were treated in the worse-seeing eye only.\n\nIn the second analysis, the manufacturer defined the better-seeing eye as having a visual acuity of only 1\xa0letter or more than the other eye, which suggested that the same-seeing eye had a visual acuity within 1\xa0letter of the other eye. This resulted in 32% of people being treated in their better-seeing eye only, 35% treated in both eyes and the remaining 33% treated in their worse-seeing eye only.\n\nIn the third analysis, the manufacturer assumed that the 22% of people defined as being treated in the same-seeing eye (based on a difference in visual acuity between eyes of fewer than 5\xa0letters on the ETDRS scale for patients with visual acuity of 50\xa0letters or more in both eyes at baseline, or a difference in visual acuity of fewer than 10\xa0letters for patients with visual acuity of fewer than 50\xa0letters in both eyes at baseline) would need treatment in both eyes in addition to the 35% of people already assumed to be treated in both eyes, resulting in 57% of people treated in both eyes. The manufacturer noted that this estimate was close to the proportion of participants in RESTORE with a visual acuity of 78\xa0letters or fewer at baseline in both eyes. The manufacturer assumed that 32% of people would receive treatment only in their better-seeing eye on the basis of the better-seeing eye having a visual acuity better than the other eye by at least 1\xa0letter. The remaining 11% were treated only in their worse-seeing eye.\n\nFor these 3\xa0analyses, the manufacturer used utility values estimated from Czoski-Murray\xa0et\xa0al. and presented ICERs for scenarios\xa02 to 5 as defined by the ERG (see section 3.53), corresponding to an increasing impact on health-related quality of life from improved vision as a result of treating the worse-seeing eye. In analysis\xa01, the ICERs ranged from £17,332 per QALY gained in scenario\xa05 to £23,735 per QALY gained in scenario\xa02. In analysis\xa02, the ICERs ranged from £18,337 per QALY gained in scenario\xa05 to £27,679 per QALY gained in scenario\xa02. In analysis\xa03, the ICERs ranged from £16,978 per QALY gained in scenario 5 to £23,701 per QALY gained in scenario\xa02.\n\nThe ERG reviewed the new analyses provided by the manufacturer in response to the appraisal consultation document. The ERG commented that analysis\xa01, which assumed that 22% of people would be treated in their same-seeing eye only, appeared to be unrealistic because if a patient had a same-seeing eye that needed treatment, then it was very likely that the other eye would also need treatment. The ERG also noted that in analysis\xa03, the manufacturer applied the criterion that defined what it assumed to be a minimum clinically relevant difference in visual acuity of fewer than 5\xa0letters on the ETDRS scale when estimating the proportion of people treated in their same-seeing eye (22%), but did not apply this criterion when estimating the proportion of people treated only in the better-seeing eye (32%). Therefore, the ERG suggested that analysis\xa02, which did not include a minimum clinically relevant difference in visual acuity to define the same-seeing eye, defining it instead as an eye with vision equal within 1\xa0letter, to be the most plausible of the 3\xa0analyses presented by the manufacturer. The ERG repeated analysis\xa02, but replaced the utility values estimated from Czoski-Murray\xa0et\xa0al. with those from the study by Brown. This resulted in ICERs that ranged from £35,555 to £31,602 per QALY gained in scenarios\xa02 and 3, proposed as the 2 most plausible scenarios by the ERG.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.\n\n This ICER has been amended from the ICER given in the manufacturer's consultation comments to correct an error in the utility values used (identified by the NICE technical team and confirmed by the manufacturer in correspondence).", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of diabetic macular oedema and the value placed on the benefits of ranibizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee understood from patient experts that visual impairment has a substantial negative impact on quality of life and activities of daily living in people with diabetic macular oedema. The patient experts placed particular emphasis on loss of independence and its implications for employment. They emphasised that diabetes is usually managed with self-care, and that visual impairment can affect a person's ability to manage their own condition (for example, checking their blood glucose level with a meter, administering medication, caring for their feet and managing their diet). The patient experts described a significant impact of visual impairment on emotional wellbeing, which can lead to depression and, in some instances, suicidal thoughts. The Committee understood that any relief from these problems would have a positive impact on the lives of people with diabetic macular oedema.\n\nThe Committee heard from the clinical specialists that the current standard treatment for diabetic macular oedema is focal and/or grid laser photocoagulation. The clinical specialists stated that an eye's response to laser photocoagulation is hard to predict but, in their experience, the people who benefit most tend to be those who have less visual impairment at the onset of treatment. People whose vision worsens despite laser photocoagulation are more likely to have thicker, more oedematous retinas. The clinical specialists explained that there are national screening programmes for diabetic retinopathy in England and Wales to identify people who need diagnosis and treatment.\n\nThe Committee discussed the likely place of ranibizumab in the treatment of diabetic macular oedema. It heard from the clinical specialists that they would consider using ranibizumab either on its own or in a treatment strategy including laser photocoagulation given before, after or at the same time as ranibizumab. The clinical specialists explained that they would be likely to start ranibizumab treatment with a 'loading' period of monthly injections for at least 3\xa0months. After this, they would monitor people on a regular basis, providing repeat monthly injections for as long as visual acuity improved and/or retinal thickness reduced (as measured using optical coherence tomography). The clinical specialists anticipated that people with diabetic macular oedema would need between 7 and 9\xa0treatments in the first year. The Committee heard from the clinical specialists that treatment would not be for a predefined period. Instead, clinicians would discontinue treatment if a person's vision stopped improving, and would restart treatment in the event that the person's vision worsened. The clinical specialists stated that this phase would continue until it was evident that the person was deriving no additional benefit from treatment. The clinical specialists advised that they would carry out monthly follow-up in the first year of treatment, extending the interval to 6–8\xa0weeks for people whose diabetic macular oedema stabilised. The clinical specialists gave the opinion that the RESTORE trial provided an accurate picture of likely clinical practice in this respect because it had followed a similar approach to treatment and monitoring (3-month loading followed by repeat injection at monthly intervals as deemed appropriate by the treating clinician). However, because people with diabetic macular oedema in clinical practice are likely to have more advanced visual impairment than those in clinical trials, they may also need more frequent treatment than observed in clinical trials.\n\nThe Committee heard from the clinical specialists that a clinically significant gain in visual acuity is 10–15\xa0letters. However, the clinical specialists also stated that smaller gains could be significant – for example, if a gain were sufficient to allow a person to meet the legal requirements for driving. In general, the clinical specialists thought that a gain of 10–15\xa0letters would benefit a person with worse vision more than a person with moderate visual impairment.\n\nThe Committee understood from the clinical specialists that, because diabetes is a systemic metabolic condition, diabetic macular oedema is more often seen in both eyes than maculopathy from other causes. The clinical specialists estimated that at least 25–30% of people with diabetic macular oedema need treatment in both eyes. The clinical specialists said that, for these people, they would aim to provide treatment in both eyes at the same visit. They explained that, through experience gained in treating wet age-related macular degeneration, many NHS units are now well equipped to treat people with ranibizumab. The clinical specialists suggested that ranibizumab treatment would need an ophthalmologist (rather than a nurse) and would be provided on an outpatient basis.\n\nThe Committee heard from the clinical specialists that, if using visual acuity as part of a fixed algorithm for deciding whether and when to treat and re-treat, it would be vital to correct sight optimally before measuring visual acuity, and this would entail comprehensive refraction (correcting sight with lenses) on each occasion visual acuity was measured. In addition, clinics would need to use the same vision charts as used to test vision in the trials, which take considerably longer to administer than routine tests of visual acuity. The clinical specialists explained that both these factors would extend the time and resources needed for routine follow-up of people with diabetic macular oedema beyond what is needed in current clinical practice.\n\nThe Committee understood from the clinical specialists and patient experts that ranibizumab is generally well tolerated, and that people usually use antibiotic eye drops for a few days after treatment with ranibizumab to prevent infection.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. It agreed that, of the 4\xa0RCTs identified, it was appropriate to concentrate on the 2\xa0larger, more directly relevant trials, RESTORE and DRCR.net. It noted that both trials were judged to be of high methodological quality by the manufacturer, and that the ERG agreed with this assessment. The Committee was aware that the studies were of relatively short duration, providing treatment for up to 3\xa0years, and did not include long-term follow-up. The Committee concluded that the quality of the clinical-effectiveness evidence for ranibizumab was acceptable.\n\nThe Committee noted that, based on the results of the RESTORE study, ranibizumab (alone or in combination with laser photocoagulation) is associated with immediate and sustained gains in visual acuity in the treated eye, whereas improvement with laser photocoagulation alone is significantly less marked. The Committee understood from the clinical trial evidence that adding laser photocoagulation to ranibizumab does not appear to provide any additional improvement in vision over 2\xa0years. However, it was aware of the clinical specialists' belief that laser photocoagulation is more likely than ranibizumab to have long-term benefits, and that this could reduce the number of injections of ranibizumab needed after 2\xa0years, although this cannot be confirmed using current evidence. The Committee concluded that, when compared with laser photocoagulation alone, treatment regimens that include ranibizumab are effective in improving visual acuity in the treated eye over 2\xa0years, but that there is no evidence of additional benefit in adding laser photocoagulation to ranibizumab. The Committee was aware that this is inconsistent with the expectations of the clinical specialists.\n\nThe Committee noted that initial subgroup analyses in both RESTORE and DRCR.net had shown little evidence of differences in clinical effectiveness by subgroup. It understood from the manufacturer's evidence that, in RESTORE, gains in visual acuity associated with ranibizumab were greatest in participants with thicker retinas and more severe visual impairment at baseline. In particular, it noted the manufacturer's suggestion that ranibizumab could be expected to have a superior relative effect among people with thicker retinas (see section\xa03.30). The Committee was aware that the manufacturer had provided evidence in its rapid review submission to confirm this subgroup effect by testing for interaction between retinal thickness and treatment allocation. The Committee noted that the manufacturer's revised subgroup analyses according to retinal thickness relied on different categories of retinal thickness to those presented in NICE technology appraisal guidance 237 and also differed from those specified in the methods for subgroup analyses of the RESTORE study. The Committee also noted that changing these categories led to different results. However, the Committee acknowledged the clinical specialists' suggestion that laser photocoagulation would be less clinically effective in people with a thicker retina. Therefore, the Committee concluded that it had received sufficient evidence of biological plausibility for a clinically relevant subgroup in which ranibizumab has a significantly greater relative effect.\n\nThe Committee considered the generalisability of the results of the RESTORE study to people with diabetic macular oedema in clinical practice. The Committee heard from the clinical specialists that glycaemic control as reflected by HbA1c varies more in clinical practice than in trials, because the RESTORE trial excluded people with HbA1c values of 10% or more. The Committee also noted the comments on the use and effects of laser photocoagulation from the clinical specialists (see section\xa04.10), and discussed whether the trials accurately reflect the way in which ranibizumab would be combined with laser therapy in clinical practice. The Committee concluded that the generalisability of trial results to the population with diabetic macular oedema seen in clinical practice is uncertain. The Committee also expressed concerns about whether the proportion of people who were treated in both eyes in the RESTORE study reflected clinical practice. The Committee concluded that the lack of evidence on vision in both eyes, as presented by the manufacturer in its original submission for NICE technology appraisal guidance 237, increased its uncertainty about how the effects of ranibizumab demonstrated in the trials would translate into benefits for people with diabetic macular oedema in clinical practice.\n\n# Cost effectiveness\n\nThe Committee discussed the appropriate approach for determining the cost effectiveness of ranibizumab. The Committee noted that the manufacturer's original base case and all additional original analyses performed by the manufacturer and the ERG suggest that combination therapy is more expensive and little or no more effective than ranibizumab alone. As a consequence, the Committee concluded that ranibizumab and laser photocoagulation as part of a simultaneous treatment strategy could not be recommended as an effective use of NHS resources. However, the Committee also heard from the clinical specialists that people currently treated with ranibizumab are likely to have had laser photocoagulation, which the clinical specialists believed is more likely to be associated with a long-term decrease in the recurrence of diabetic macular oedema than treatment with ranibizumab. The Committee agreed with the ERG's suggestion and consultation comments from retinal specialists that it is possible that ranibizumab and laser photocoagulation in a sequential treatment algorithm could provide a valuable treatment option. However, because no evidence to support this was available, the Committee concluded that it could not make separate recommendations on the sequential use of ranibizumab and laser photocoagulation.\n\nWhen it reviewed the manufacturer's revised model submitted in NICE technology appraisal guidance 237, the Committee concluded that the model did not reflect likely clinical practice in at least 6\xa0respects, as described in section\xa03.46. The manufacturer addressed these issues in its rapid review submission, and offered a revised patient access scheme (see sections 3.47–3.49).\n\nThe Committee discussed the manufacturer's approach to estimating the cost effectiveness of treating both eyes, in which it multiplied the ICERs generated in its better-seeing eye model by a factor of 1.5. The Committee was aware that this approach was consistent with that adopted by the Committee in NICE technology appraisal guidance 155 and that the same approach was used by the Committee when estimating the most plausible ICER in NICE technology appraisal guidance 237. The Committee also considered the new, alternative approach taken by the ERG in its 6\xa0scenario analyses, which made explicit assumptions about the impact on costs and outcomes associated with treating only the worse-seeing eye, only the better-seeing eye or both eyes. The Committee noted that the ERG's 6\xa0scenario analyses varied both the health-related quality of life impact of changes in the vision of the worse-seeing eye and the resultant QALYs associated with treatment of the worse-seeing eye or both eyes. The Committee agreed that, without available data on health-related quality of life associated with vision in both eyes, these scenarios fully explored the impact of treating both eyes on the relative cost effectiveness of ranibizumab. The Committee noted that, although there is little evidence of the impact of vision in the worse-seeing eye on health-related quality of life, the Brown study suggested that among people who had good vision in their better-seeing eye, the worse-seeing-eye contributed little to health-related quality of life. The Committee therefore considered scenario analysis\xa03 to be consistent with previous appraisals, which suggested that changes in vision for people treated in their worse-seeing eye had 30% of the health-related quality of life impact of the same change in vision from treating the better-seeing eye. In response to the rapid review appraisal consultation document, the Royal College of Ophthalmologists commented that the ERG's approach seemed logical, but that scenario\xa04 might be more appropriate. However, in the absence of new empirical evidence to suggest otherwise, the Committee accepted that scenario\xa03 reasonably reflected the clinical situation for people with diabetic macular oedema. The Committee concluded that the ERG's more comprehensive approach to modelling treatment of both eyes was likely to be more valid than multiplying the ICER associated with treating the better-seeing eye by 1.5 because it explored more explicitly the impact on costs and outcomes associated with treating only 1 or both eyes.\n\nThe Committee considered the cost-effectiveness analyses presented by the manufacturer in its response to the appraisal consultation document for the rapid review of NICE technology appraisal guidance 237, which adopted the approach taken by the ERG (see sections 3.58–3.60). The Committee discussed the manufacturer's approach to estimating the proportion of people who would be treated in the better-seeing eye only, worse-seeing eye only or both eyes. The Committee noted that, as part of these 3\xa0new analyses, the manufacturer presented data on the proportion of patients in RESTORE whom the manufacturer considered as having the same vision in both eyes at the start of treatment. The Committee was surprised that the manufacturer had not presented these data earlier in the appraisal. However, the Committee acknowledged that, although the manufacturer had originally proposed that patients would need treatment in only 1\xa0eye despite bilateral disease, it had subsequently attempted to consider the cost effectiveness of treating both eyes in its rapid review submission. The Committee heard from the manufacturer that it considered the same-seeing eye pertinent only after the Committee had expressed its preference for the ERG's approach to estimating the costs and QALYs associated with treating both eyes. The Committee also heard from the manufacturer that it chose its definition of a same-seeing eye from a single study, that it was aware that other definitions existed, and that it had not taken a systematic approach to assessing other possible definitions. The Committee noted that the ICERs did not vary substantially between the 3\xa0analyses presented by the manufacturer. The Committee concluded, given its concerns around the definition of same-seeing eyes, that analysis\xa02 (which suggested that the same-seeing eye has a visual acuity within 1\xa0letter of the other eye) was the most plausible of the 3\xa0new analyses presented by the manufacturer.\n\nThe Committee considered the utility values that quantified the changes in health-related quality of life attributed to vision in the manufacturer's new model in its rapid review submission. It was aware that the manufacturer used utility values estimated from the study by Czoski-Murray\xa0et\xa0al., in which members of the UK general public valued levels of visual impairment simulated by wearing vision-worsening contact lenses in both eyes. The Committee noted that this study resulted in a broader range of utility values between best and worst health states in the model than those used in the manufacturer's original submission in NICE technology appraisal guidance 237, which were estimated from the RESTORE study and which the Committee considered to be unrealistically large (see section\xa03.26). The Committee also noted that participants in the Czoski-Murray study wore the lenses simulating bilateral visual impairment for a short period of time (between 1.5 and 2\xa0hours). Therefore, the Committee considered that the participants may have overstated the detrimental impact on health-related quality of life of visual impairment in both eyes because they had little time to adjust to it. The Committee was aware that the Brown study identified by the ERG measured health-related quality of life directly from patients with impaired vision in at least 1\xa0eye, and that this produced a narrower range of utility values than the study by Czoski-Murray\xa0et\xa0al. In consideration of a comment from the manufacturer who suggested that the utility values from the Brown study were not in line with the NICE reference case, the Committee noted that neither set of utility values was in line with the NICE reference case for measuring and valuing health effects. The Committee concluded that there was uncertainty about which utility data were most appropriate to include in the model. However, the Committee agreed that, in the absence of further evidence, it was reasonable to assume that the range of utility values would probably lie somewhere in between those estimated from the Czoski-Murray and Brown studies.\n\nThe Committee discussed the manufacturer's assumptions about how often people would receive ranibizumab in clinical practice. The Committee noted that, on the basis of the results from an extension to the RESTORE study available at the time of the rapid review submission, the manufacturer assumed that people would need 4\xa0injections in year\xa02 and 3\xa0injections in year\xa03 and no more injections from year\xa04 onwards. The Committee commented that it was unlikely that people who received 3\xa0injections in year\xa03 would receive no further injections in year\xa04, especially if vision was assumed to remain stable during this period. The Committee was aware that some consultees had suggested that people with diabetic macular oedema would need more frequent treatment with ranibizumab than was assumed by the manufacturer. The Committee also noted that uncertainty remained about whether people would need ranibizumab beyond 4\xa0years and, if they did, what the costs of ongoing treatment would be. However, the Committee acknowledged that the manufacturer had attempted to address this uncertainty by conducting a threshold analysis to assess the maximum number of injections per person that could be administered while maintaining an ICER below £30,000 per QALY gained. The Committee was aware that these analyses allowed for only 4\xa0additional injections in the first 3\xa0years of the model. The Committee concluded that, without longer-term clinical data, significant uncertainty remained about the number of ranibizumab injections that people with diabetic macular oedema are likely to need.\n\nThe Committee considered the manufacturer's assumptions about how vision in the treated eye improved and deteriorated beyond the third year of the model, when the model assumes that ranibizumab treatment finishes. It understood that, although vision deteriorated over time in the model, it did so at the same rate in people previously treated with ranibizumab as in people who had previously been treated with laser photocoagulation. The Committee was aware of the opinion of clinical specialists that the most important effect of ranibizumab is to reduce the permeability of blood vessels and oedema in the eye, and heard from the clinical specialists that it is implausible that this effect would persist in the long term. By contrast, the benefits to vision from laser photocoagulation, although not as great as those of ranibizumab, are believed to last longer. The Committee noted that the manufacturer reduced uncertainty about the projected effects of ranibizumab treatment by following the approach discussed by the Committee in NICE technology appraisal guidance 237 and adopting a 10-year time horizon. The Committee also noted that this approach was consistent with previous appraisals. The Committee was aware of the new clinical evidence submitted by consultees in their response to the rapid review appraisal consultation document. The Committee understood that the consideration of such new clinical evidence on the long-term clinical benefits of the comparator treatment laser photocoagulation is beyond the remit of a rapid review, and would require a full review of the appraisal. Therefore the Committee concluded that, although significant uncertainty remains about the long-term benefit of ranibizumab treatment, compared with the manufacturer's original submission, the rapid review model more accurately reflects the duration of benefit that could be expected from treatment with ranibizumab.\n\nThe Committee considered the manufacturer's assumptions about the number of treatment and monitoring visits for people treated with ranibizumab and those treated with laser photocoagulation. The Committee was aware that in its original submission in NICE technology appraisal guidance 237, the manufacturer had assumed that a visit for treatment with ranibizumab would double as a monitoring visit and that people treated with laser photocoagulation would need a separate monitoring visit. The Committee was unaware of any clinical evidence to justify this difference, and the manufacturer had not explained the difference in its original submission or in consultation comments. The Committee noted that the manufacturer had addressed this issue in its rapid review submission by assuming that a treatment visit for people receiving ranibizumab or laser photocoagulation doubles as a monitoring visit. The Committee concluded that, compared with the manufacturer's original submission, the rapid review model provided a more plausible reflection of the number of treatment and monitoring visits that people receiving ranibizumab treatment or laser photocoagulation would need.\n\nThe Committee considered whether the revised base-case model applies to the population with diabetic macular oedema in England and Wales. It noted the clinical specialists' advice that glycaemic control as reflected by HbA1c is likely to be worse in clinical practice than in the RESTORE trial, which excluded people with HbA1c levels of 10% or more (see section\xa04.12). The Committee observed that a subgroup analysis provided as part of the manufacturer's original submission for NICE technology appraisal guidance\xa0237 suggested that restricting the analysis to people with good glycaemic control (HbA1c less than 8%) produced a much lower ICER than the ICER based on the group of people with poor control (HbA1c 8% or more; see section\xa03.18). The Committee noted that the manufacturer did not provide further analyses for these subgroups in its rapid review submission because of the relatively small sample sizes, which may have resulted in a small number of people in the extreme health states influencing the results. The Committee was aware of the new clinical evidence submitted by the manufacturer in response to the consultation on the rapid review appraisal consultation document. The Committee understood that submission of such further evidence would not normally be expected in the context of a rapid review, and accepted that this evidence could not be considered without formal review by the ERG. The Committee acknowledged that the issue of glycaemic control had been considered in NICE technology appraisal guidance 237, and that the Committee's considerations had been upheld at appeal. Based on the evidence provided in the manufacturer's original submission, the Committee agreed that uncertainty remained about the cost effectiveness of ranibizumab in people with poorer glycaemic control. Therefore, the Committee concluded that the manufacturer's model would probably generate a higher ICER if it was more reflective of the population seen in routine clinical practice.\n\nThe Committee discussed what could be considered as the most plausible ICERs. In the Committee's view, ICERs reflecting the possibility of treating both eyes were the most useful starting points for considering the cost effectiveness of ranibizumab for treating diabetic macular oedema. The Committee was aware that the manufacturer's rapid review base-case model produced an ICER of £21,200 per QALY gained for treating both eyes by multiplying the ICER for the better-seeing eye model by a factor of 1.5. The Committee agreed that this ICER was from a model that relied on a more plausible set of assumptions than those used in the manufacturer's original submission for NICE technology appraisal guidance 237. However, the Committee also acknowledged the ERG's technically more comprehensive approach of accounting for treatment in both eyes and noted that the manufacturer acknowledged the advantages of this approach. The Committee noted that this approach was subsequently adopted by the manufacturer in its response to the rapid review appraisal consultation document and led to ICERs in the range of £24,600 to £31,600 per QALY gained depending on the utility values used in the model for the Committee's preferred analysis. The Committee agreed that these ICERs would increase if the model accounted for people needing more than 4\xa0treatments with ranibizumab beyond the third year, if people who had laser photocoagulation maintained any improvements in vision after treatment for longer than people treated with ranibizumab, and if the model better reflected the population with poorer glycaemic control seen in routine clinical practice. The Committee concluded that the most plausible ICER was likely to be above £30,000 per QALY gained, and that it therefore could not recommend ranibizumab as an effective use of NHS resources for the treatment of all people with diabetic macular oedema.\n\nThe Committee discussed whether it had received evidence of any groups of people for whom ranibizumab could be considered an effective use of NHS resources. It noted that, in its rapid review submission, the manufacturer provided additional subgroup analyses that showed that ranibizumab has a lower ICER in people with thicker retinas (central retinal thickness of 400\xa0micrometres or more) than in people with thinner retinas (central retinal thickness of less than 400\xa0micrometres) at the start of treatment. The Committee recognised the clinical plausibility of a greater relative efficacy of ranibizumab in people with a central retinal thickness of 400\xa0micrometres or more, because it understood that laser photocoagulation may be less effective when used on a thicker retina. The Committee noted that the manufacturer had presented statistical evidence of greater clinical effectiveness in this predefined group. The Committee also noted that the manufacturer had reduced the impact of small sample sizes, which had been raised as a concern in NICE technology appraisal guidance 237, by combining groups of people with thinner retinas (central retinal thickness less than 300\xa0micrometres and 300–400\xa0micrometres) into 1\xa0larger group (people with central retinal thickness greater than 400\xa0micrometres). This also produced more plausible cost-effectiveness results across the 2\xa0groups. The Committee also acknowledged that the manufacturer had adequately accounted for differences in costs and outcomes for these subgroups by making adjustments to subgroup‑specific parameters for other important model inputs. The Committee therefore concluded that the manufacturer had provided robust evidence demonstrating a subgroup effect in favour of people with thicker retinas.\n\nThe Committee considered the most plausible ICERs for people with thicker retinas (central retinal thickness of 400\xa0micrometres or more) at the start of treatment. The Committee noted that the manufacturer's rapid review model produced an ICER of £13,300 per QALY gained for treating both eyes in this group by multiplying the ICER for the better-seeing eye model by a factor of 1.5. The Committee agreed that this ICER would increase if the model accounted for people needing more frequent treatment with ranibizumab beyond the third year, if people who had laser photocoagulation maintained any improvements in vision after treatment for longer than people who had ranibizumab, if the model better reflected the population with poorer glycaemic control seen in routine clinical practice, and if people with thicker retinas had higher rates of mortality than people with thinner retinas. The Committee also noted that neither the ERG nor the manufacturer provided exploratory scenario analyses for people with central retinal thickness of 400\xa0micrometres or more. However, the Committee agreed that the ICER would likely increase if the ERG's approach of adapting the manufacturer's model to consider treating both eyes was used along with the Committee's preferred assumptions. The Committee therefore concluded that the most plausible ICER for the subgroup of people with thicker retinas was likely to be higher than the manufacturer's estimate, but would be under £25,000 per QALY gained. The Committee also considered the manufacturer's suggestion in response to the rapid review appraisal consultation document that ranibizumab would be cost effective for the whole population. However, the Committee noted that the ICER for treating people with thinner retinas (central retinal thickness of less than 400\xa0micrometres) was £43,300 per QALY gained in the manufacturer's rapid review model and that ranibizumab would therefore not be an effective use of NHS resources in this group. Therefore the Committee recommended ranibizumab as an option for treating visual impairment due to diabetic macular oedema only if the eye has a central retinal thickness of 400\xa0micrometres or more at the start of treatment.\n\nThe Committee noted that the scope for the appraisal included bevacizumab as a comparator. It was also aware of its previous conclusions on bevacizumab in NICE technology appraisal guidance 237, that ranibizumab at that time did not represent an effective use of NHS resources when compared with laser photocoagulation, and that therefore the Committee did not believe that considering evidence for bevacizumab would have altered its decision. However, because the Committee had concluded after the rapid review that ranibizumab represents a cost-effective use of NHS resources when compared with laser photocoagulation for people with a central retinal thickness of 400\xa0micrometres or more, it discussed the comparison of ranibizumab with bevacizumab. The Committee noted and reviewed information from the regulatory authorities to prescribers in which the use of bevacizumab as an intravitreal injection in people with diabetic macular oedema is considered 'unlicensed'. Also, the Committee heard conflicting evidence about the extent to which bevacizumab is currently used to treat diabetic macular oedema in England and Wales. It concluded that bevacizumab is adopted by some clinicians and funded by some NHS trusts, but is not in use throughout the NHS. The Committee was aware that some consultees and commentators supported a comparison with bevacizumab and others opposed it. The Committee discussed whether a cost-effectiveness analysis of ranibizumab compared with bevacizumab was possible. The Committee recognised that a formal comparison of the 2\xa0drugs would need evidence not only of all aspects of clinical effectiveness and safety, but also of the costs associated with preparing and administering bevacizumab, including the dose and number of injections needed. The Committee agreed that such evidence, in particular about the balance of harms and benefits associated with bevacizumab, was not readily available for people with diabetic macular oedema. The Committee also noted that it was unaware of any evidence of the effectiveness of intravitreal bevacizumab compared with ranibizumab in the subgroup of patients with thicker retinas. The Committee agreed that, taking into account all these uncertainties, it could not consider a comparison of ranibizumab with bevacizumab. The Committee also concluded that further research directly comparing the clinical and cost effectiveness of ranibizumab and bevacizumab in people with diabetic macular oedema would reduce some of these uncertainties.\n\nThe Committee discussed whether ranibizumab should be considered an innovative treatment. It considered that, in terms of both pharmacological progress and potential benefits for people with diabetic macular oedema, the development of the anti-angiogenic drugs pegaptanib sodium and bevacizumab preceded that of ranibizumab. Therefore, the Committee concluded that ranibizumab itself could not properly be considered to provide distinctive pharmacological innovation. The Committee further noted that the analyses of the incremental health benefit of ranibizumab were based on a comparison with laser photocoagulation, and that the Committee had not been alerted to any benefits that were not already captured in the QALY measure. The Committee was also aware that, before NICE technology appraisal guidance 237 was published, the Committee's conclusions on innovation as described above were upheld by the Appeal Panel. It therefore concluded that the incremental value of ranibizumab for people with diabetic macular oedema had been appropriately captured.\n\nThe Committee discussed the proposed date for review of the guidance. The Committee was aware of the emerging evidence on the effectiveness and safety of bevacizumab as a treatment option for diabetic macular oedema, including work undertaken by NICE's Decision Support Unit and ongoing clinical trials comparing bevacizumab with ranibizumab in diabetic macular oedema and other eye diseases. The Committee was also aware that additional clinical data, including 3-year results from the DRCR.net study, had become available since the publication of NICE technology appraisal guidance 237, but that these data could not be considered as part of the rapid review process. The Committee heard that some commentators suggested that the proposed date for review should be earlier than February\xa02016, because the guidance would exclude ranibizumab as a treatment option for a significant proportion of people with diabetic macular oedema. Therefore, the Committee agreed that the proposed date for review of the guidance should be brought forward to February\xa02015.\n\nThe Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. During the scoping phase of the appraisal, NICE had received evidence that some people in full-time residential care had restricted access to treatment for diabetic macular oedema. However, consultees suggested that the national screening programmes for diabetic retinopathy in England and Wales has reduced this inequality across the NHS. In submissions, the Committee had been made aware that there is a higher prevalence of diabetes in people of South Asian, African and African–Caribbean family origin and that, among people with diabetes, sight-threatening eye disease is more common in people of African and African–Caribbean family origin than in white Europeans. However, the Committee agreed that this was an issue that could not be addressed in a technology appraisal.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA274\n\nAppraisal\n title:\n Ranibizumab\n for\n treating\n diabetic\n macular\n oedema\n (rapid\n review\n of\n technology\n appraisal\n guidance\n 237)\n\nSection\n\nKey\n conclusion\n\nRanibizumab is recommended as an option for treating visual impairment due to diabetic macular oedema only if:\n\nthe eye has a central retinal thickness of 400\xa0micrometres or more at the start of treatment and\n\nthe manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of this appraisal.\n\n\n\nThe Committee concluded that the most plausible ICER for the treatment of all people with diabetic macular oedema was likely to be above £30,000 per QALY gained, and that it therefore could not recommend ranibizumab as an effective use of NHS resources.\n\n\n\nThe Committee concluded that the most plausible ICER for the subgroup of people with thicker retinas was likely to be under £25,000 per QALY gained. Therefore the Committee recommended ranibizumab as an option for treating diabetic macular oedema only for people with a central retinal thickness of 400\xa0micrometres or more at the start of treatment.\n\n\n\nCurrent\n practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee understood from patient experts that visual impairment has a substantial negative impact on quality of life and activities of daily living in people with diabetic macular oedema. The Committee heard from the clinical specialists that the current standard treatment for diabetic macular oedema is focal and/or grid laser photocoagulation.\n\n–4.3\n\nThe\n technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee considered that, in terms of both pharmacological progress and potential benefits for people with diabetic macular oedema, the development of the anti-angiogenic drugs pegaptanib sodium and bevacizumab preceded that of ranibizumab. Therefore, the Committee concluded that ranibizumab itself could not properly be considered to provide distinctive pharmacological innovation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from the clinical specialists that they would consider using ranibizumab either on its own or in a treatment strategy including laser photocoagulation given before, after or at the same time as ranibizumab.\n\n\n\nAdverse reactions\n\nThe Committee understood from the clinical specialists and patient experts that ranibizumab is generally well tolerated.\n\n\n\nEvidence\n for\n clinical\n effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee agreed that, of the 4 RCTs identified, it was appropriate to concentrate on the 2 larger, more directly relevant trials, RESTORE and DRCR.net. It noted that both trials were judged to be of high methodological quality by the manufacturer, and that the ERG agreed with this assessment.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard from the clinical specialists that glycaemic control as reflected by HbA1c varies more in clinical practice than in trials, because the RESTORE trial excluded people with HbA1c values of 10% or more. The Committee also noted the comments on the use and effects of laser photocoagulation from the clinical specialists, and discussed whether the trials accurately reflect the way in which ranibizumab would be combined with laser therapy in clinical practice. The Committee concluded that the generalisability of trial results to the population with diabetic macular oedema seen in clinical practice is uncertain.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that there is no evidence of additional benefit in adding laser photocoagulation to ranibizumab, but that this is inconsistent with the expectations of the clinical specialists.\n\nThe Committee concluded that the lack of evidence on vision in both eyes increased its uncertainty about how the effects of ranibizumab demonstrated in the trials would translate into benefits for people with diabetic macular oedema in clinical practice.\n\n, 4.12\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee understood from the manufacturer's evidence that, in RESTORE, gains in visual acuity associated with ranibizumab were greatest in participants with thicker retinas and more severe visual impairment at baseline. In particular, it noted the manufacturer's suggestion that ranibizumab could be expected to have a superior relative effect among people with thicker retinas. The Committee was aware that the manufacturer had provided evidence in its rapid review submission to confirm this subgroup effect by testing for interaction between retinal thickness and treatment allocation. Therefore, the Committee concluded that it had received evidence of a clinically relevant subgroup in which ranibizumab has a significantly greater relative effect.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that, when compared with laser photocoagulation alone, treatment regimens that include ranibizumab are effective in improving visual acuity in the treated eye over 2\xa0years, but that there is no evidence of additional benefit in adding laser photocoagulation to ranibizumab.\n\n\n\nEvidence\n for\n cost\n effectiveness\n\nAvailability and nature of evidence\n\nWhen it reviewed the manufacturer's revised model submitted in NICE technology appraisal guidance 237, the Committee concluded that the model did not reflect likely clinical practice in at least 6\xa0respects. The manufacturer addressed these issues in its rapid review submission, and offered a revised patient access scheme.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee was aware that the manufacturer's base-case model produced an ICER of £21,200 per QALY gained for treating both eyes by multiplying the ICER for the better-seeing eye model by a factor of 1.5. The Committee agreed that this ICER was from a model that relied on a more plausible set of assumptions than those used in the manufacturer's original submission for NICE technology appraisal guidance 237. However, the Committee also acknowledged the ERG's technically more comprehensive approach of accounting for treatment in both eyes explored by the ERG and noted that the manufacturer acknowledged the advantages of this approach. The Committee noted that this approach was subsequently adopted by the manufacturer in its response to the rapid review appraisal consultation document and led to ICERs in the range of £24,600 to £31,600 per QALY gained depending on the utility values used in the model for the Committee's preferred analysis. The Committee agreed that these ICERs would increase if the model accounted for people needing more than 4 treatments with ranibizumab beyond the third year, if people who had laser photocoagulation maintained any improvements in vision after treatment longer than people treated with ranibizumab, and if the model better reflected the population with poorer glycaemic control seen in routine clinical practice.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee concluded that there was uncertainty about which utility data were most appropriate to include in the model. However, the Committee agreed that, in the absence of further evidence, it was reasonable to assume that the range of utility values would probably lie somewhere in between those estimated from the Czoski-Murray and Brown studies.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee concluded that the manufacturer had provided robust evidence demonstrating a subgroup effect in favour of people with thicker retinas.\n\nThe Committee concluded that the most plausible ICER for the subgroup of people with thicker retinas was likely to be higher than the manufacturer's estimate, but would be under £25,000 per QALY gained.\n\n– 4.24\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee concluded that the cost-effectiveness results were driven by the manufacturer's assumptions about: the need to treat both eyes of people with diabetic macular oedema, the utility associated with changes in vision of the treated eye, likely frequency of ranibizumab injections, the expected duration of benefit from ranibizumab treatment, the number of treatment visits and monitoring visits needed, and the generalisability of the economic evidence, especially about glycaemic control in the treated population.\n\n–4.21\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that the most plausible ICER for the treatment of all people with diabetic macular oedema was likely to be above £30,000 per QALY gained, and that it therefore could not recommend ranibizumab as an effective use of NHS resources.\n\n\n\n\n\nThe Committee concluded that the most plausible ICER for the subgroup of people with thicker retinas was likely to be higher than the manufacturer's estimate, but would be under £25,000 per QALY gained.\n\n\n\nAdditional\n factors\n taken\n into\n account\n\nPatient access schemes (PPRS)\n\nThe manufacturer has agreed a patient access scheme with the Department of Health which makes ranibizumab available with a discount applied to all invoices. The size of the discount is commercial in confidence.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n-\n\nEqualities considerations and social value judgements\n\nNICE had received evidence that some people in full-time residential care had restricted access to treatment for diabetic macular oedema. However, consultees suggested that the national screening programme for diabetic retinopathy in England and Wales has reduced this inequality across the NHS. The Committee had been made aware that there is a higher prevalence of diabetes in people of South Asian, African and African–Caribbean family origin and that, among people with diabetes, sight-threatening eye disease is more common in people of African and African–Caribbean family origin than in white Europeans. However, the Committee agreed that this was an issue that could not be addressed in a technology appraisal.\n\n", 'Recommendations for further research': 'The Committee concluded that further research directly comparing the clinical and cost effectiveness of ranibizumab and bevacizumab in people with diabetic macular oedema should be conducted.', 'Related NICE guidance': '# Published\n\nFluocinolone acetonide intravitreal implant for the treatment of diabetic macular oedema.NICE technology appraisal guidance 271 (2013).\n\nDexamethasone for the treatment of retinal vein occlusion in macular oedema. NICE technology appraisal guidance 229 (2011).\n\nType\xa02 diabetes: the management of type\xa02 diabetes. NICE clinical guideline 87 (2009).\n\nRanibizumab and pegaptanib for the treatment of age-related macular degeneration.NICE technology appraisal guidance 155 (2008).\n\nType\xa01 diabetes. NICE clinical guideline 15 (2004).\n\n# Under development\n\nNICE is developing the following guidance (details available from the NICE website):\n\nPegaptanib sodium for the treatment of diabetic macular oedema.NICE technology appraisal. Publication date to be confirmed.', 'Review of guidance': 'The guidance on this technology will be considered for review in February\xa02015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief executiveFebruary 2013', 'Changes after publication': 'January 2014: minor maintenance.\n\nApril 2013: The wording of the recommendation describing the patient access scheme (see section 1.1) has been amended to make it clear which scheme is being referred to.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt updates and replaces NICE technology appraisal guidance 237 (published November 2011).\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN 978-1-4731-0043-5'}	https://www.nice.org.uk/guidance/ta274	Evidence-based recommendations on ranibizumab (Lucentis) for treating diabetic macular oedema in adults.
d4b4df07e39f1e665b159acf9cbc5284157a0bc8	nice	Irreversible electroporation for treating liver metastases	Irreversible electroporation for treating liver metastases # Guidance Current evidence on the safety and efficacy of irreversible electroporation for treating liver metastases is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. In particular, studies should report the effect of the procedure on local tumour control and patient survival.# The procedure # Indications and current treatments Liver metastases are most commonly caused by colorectal cancer but may also result from other malignancies, such as lung and gastric cancer. Treatment of liver metastases depends on their extent and location. Treatment options include surgical resection, thermal ablation, chemotherapy, different types of arterial embolisation, external beam radiotherapy and selective internal radiation therapy. Irreversible electroporation is a non-thermal cell-destruction technique, which is claimed to allow targeted destruction of cancerous cells with less damage to surrounding supporting connective tissue (such as nearby blood vessels and nerves) than other types of treatment. # Outline of the procedure The aim of irreversible electroporation is to destroy cancerous cells by subjecting them to a series of short electrical pulses using high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell's homeostasis mechanisms and leading to cell death. The procedure is performed with the patient under general anaesthesia. A neuromuscular blocking agent is essential to prevent uncontrolled severe muscle contractions caused by the electric current. Bipolar or unipolar electrode needles are introduced percutaneously (or by open surgical or laparoscopic approaches) and guided into place in and adjacent to the target tumour using imaging guidance. A series of very short electrical pulses is delivered over several minutes to ablate the tumour. The electrodes may then be repositioned to extend the zone of electroporation until the entire tumour and an appropriate margin have been ablated. Cardiac synchronisation is used to time delivery of the electrical pulse within the refractory period of the heart cycle, minimising the risk of arrhythmia. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of 38 patients (including 69 procedures for tumours in the liver, lung and kidney), a response rate of 50% was reported in 45 procedures to treat liver metastases (number of patients not reported; response rate was not defined; exact timing of assessment unclear). Liver metastases larger than 5 cm in any dimension showed no response in terms of tumour control and all patients with liver metastases had other tumours that progressed. A case series of 44 patients (including 30 with liver metastases) reported local recurrence-free survival of 95% at 6 months and 60% at 12 months. A case series of 28 patients with hepatic tumours (including 21 patients with colorectal liver metastases) reported local recurrence in 6% (3/54) of tumours and 1 tumour with persistent disease at a median follow-up of 6 months. The Specialist Advisers listed key efficacy outcomes as survival (including progression-free survival and overall survival), local tumour control and/or tumour recurrence rate, and preservation of vascular and biliary structures. # Safety The case series of 38 patients reported transient cardiac arrhythmia in 6 patients (4 patients had ventricular tachycardia, 1 patient had supraventricular tachycardia and 1 patient had atrial fibrillation). Two of these patients had cardiac synchronisation and 4 did not. All the arrhythmias resolved without treatment except for atrial fibrillation in 1 patient, which was treated by cardioversion. A case series of 21 patients with primary or metastatic cancer (liver, kidney and lung) reported transient ventricular tachycardia in 25% (7/28) of procedures. In 4 of the 7 procedures, arterial blood pressure was 'markedly decreased' (not defined). A case series of 18 procedures reported ventricular tachycardia associated with a fall in blood pressure in 1 patient (cardiac synchronisation was not used in this patient). A case series of 9 patients reported sustained intraoperative new-onset atrial fibrillation in 1 patient. This was treated medically and the atrial fibrillation resolved before the patient was discharged. A case series of 45 patients (with different types of tumours) reported pneumothorax in 14% (7/50) of procedures. It was treated with small-calibre thoracostomy tubes in 6 cases; it was not stated whether patients were treated for tumours in the liver. The case series of 38 and 21 patients reported treatment of 12 liver metastases and 17 liver tumours respectively; pneumothorax occurred after 1 of these cases in each series (an incidence of 8% and 6% respectively). The case series of 28 patients reported 1 patient with postoperative portal vein thrombosis (there was no associated biliary dilatation). The case series of 44 patients reported 1 patient with neurogenic bladder within 90 days of the procedure; this resolved within 30 days. The case series of 38 patients reported increases in alanine aminotransferase (ALT) level of between 19 and 1747 international units per litre 24 hours after 95% (40/42) of procedures (ALT levels available for 42 of 49 liver tumour ablation procedures). Levels returned to normal or baseline at 1-month follow-up after 98% (39/40) of the procedures. The same case series reported transient increases in bilirubin level, which returned to normal or baseline levels at 1-month follow-up, in 18% (9/49) of liver tumour ablation procedures. The Specialist Advisers reported an anecdotal adverse event of post-ablation syndrome (flu-like symptoms, tiredness and lethargy lasting for 2–3 days). They listed theoretical adverse events as puncture or damage of non-target organs, sepsis, tumour seeding in needle tracks and bleeding.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk ISBN 978-1-4731-0041-1	{'Guidance': 'Current evidence on the safety and efficacy of irreversible electroporation for treating liver metastases is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. In particular, studies should report the effect of the procedure on local tumour control and patient survival.', 'The procedure': "# Indications and current treatments\n\nLiver metastases are most commonly caused by colorectal cancer but may also result from other malignancies, such as lung and gastric cancer.\n\nTreatment of liver metastases depends on their extent and location. Treatment options include surgical resection, thermal ablation, chemotherapy, different types of arterial embolisation, external beam radiotherapy and selective internal radiation therapy. Irreversible electroporation is a non-thermal cell-destruction technique, which is claimed to allow targeted destruction of cancerous cells with less damage to surrounding supporting connective tissue (such as nearby blood vessels and nerves) than other types of treatment.\n\n# Outline of the procedure\n\nThe aim of irreversible electroporation is to destroy cancerous cells by subjecting them to a series of short electrical pulses using high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell's homeostasis mechanisms and leading to cell death.\n\nThe procedure is performed with the patient under general anaesthesia. A neuromuscular blocking agent is essential to prevent uncontrolled severe muscle contractions caused by the electric current. Bipolar or unipolar electrode needles are introduced percutaneously (or by open surgical or laparoscopic approaches) and guided into place in and adjacent to the target tumour using imaging guidance. A series of very short electrical pulses is delivered over several minutes to ablate the tumour. The electrodes may then be repositioned to extend the zone of electroporation until the entire tumour and an appropriate margin have been ablated. Cardiac synchronisation is used to time delivery of the electrical pulse within the refractory period of the heart cycle, minimising the risk of arrhythmia.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 38\xa0patients (including 69\xa0procedures for tumours in the liver, lung and kidney), a response rate of 50% was reported in 45\xa0procedures to treat liver metastases (number of patients not reported; response rate was not defined; exact timing of assessment unclear). Liver metastases larger than 5\xa0cm in any dimension showed no response in terms of tumour control and all patients with liver metastases had other tumours that progressed.\n\nA case series of 44\xa0patients (including 30 with liver metastases) reported local recurrence-free survival of 95% at 6\xa0months and 60% at 12\xa0months. A case series of 28\xa0patients with hepatic tumours (including 21\xa0patients with colorectal liver metastases) reported local recurrence in 6% (3/54) of tumours and 1\xa0tumour with persistent disease at a median follow-up of 6\xa0months.\n\nThe Specialist Advisers listed key efficacy outcomes as survival (including progression-free survival and overall survival), local tumour control and/or tumour recurrence rate, and preservation of vascular and biliary structures.\n\n# Safety\n\nThe case series of 38\xa0patients reported transient cardiac arrhythmia in 6\xa0patients (4\xa0patients had ventricular tachycardia, 1\xa0patient had supraventricular tachycardia and 1\xa0patient had atrial fibrillation). Two of these patients had cardiac synchronisation and 4\xa0did not. All the arrhythmias resolved without treatment except for atrial fibrillation in 1\xa0patient, which was treated by cardioversion.\n\nA case series of 21\xa0patients with primary or metastatic cancer (liver, kidney and lung) reported transient ventricular tachycardia in 25% (7/28) of procedures. In 4 of the 7\xa0procedures, arterial blood pressure was 'markedly decreased' (not defined). A case series of 18\xa0procedures reported ventricular tachycardia associated with a fall in blood pressure in 1\xa0patient (cardiac synchronisation was not used in this patient). A case series of 9\xa0patients reported sustained intraoperative new-onset atrial fibrillation in 1\xa0patient. This was treated medically and the atrial fibrillation resolved before the patient was discharged.\n\nA case series of 45\xa0patients (with different types of tumours) reported pneumothorax in 14% (7/50) of procedures. It was treated with small-calibre thoracostomy tubes in 6\xa0cases; it was not stated whether patients were treated for tumours in the liver. The case series of 38 and 21\xa0patients reported treatment of 12\xa0liver metastases and 17\xa0liver tumours respectively; pneumothorax occurred after 1 of these cases in each series (an incidence of 8% and 6% respectively).\n\nThe case series of 28\xa0patients reported 1\xa0patient with postoperative portal vein thrombosis (there was no associated biliary dilatation).\n\nThe case series of 44\xa0patients reported 1\xa0patient with neurogenic bladder within 90\xa0days of the procedure; this resolved within 30\xa0days.\n\nThe case series of 38\xa0patients reported increases in alanine aminotransferase (ALT) level of between 19 and 1747\xa0international units per litre 24\xa0hours after 95% (40/42) of procedures (ALT levels available for 42 of 49\xa0liver tumour ablation procedures). Levels returned to normal or baseline at 1-month follow-up after 98% (39/40) of the procedures. The same case series reported transient increases in bilirubin level, which returned to normal or baseline levels at 1-month follow-up, in 18% (9/49) of liver tumour ablation procedures.\n\nThe Specialist Advisers reported an anecdotal adverse event of post-ablation syndrome (flu-like symptoms, tiredness and lethargy lasting for 2–3\xa0days). They listed theoretical adverse events as puncture or damage of non-target organs, sepsis, tumour seeding in needle tracks and bleeding.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780\n\nISBN 978-1-4731-0041-1'}	https://www.nice.org.uk/guidance/ipg445
8650fb13936d5f10b5ab8cc6cd9b62434e906199	nice	Ultrasound-guided foam sclerotherapy for varicose veins	Ultrasound-guided foam sclerotherapy for varicose veins # Guidance This document replaces previous guidance on ultrasound-guided foam sclerotherapy for varicose veins (interventional procedure guidance 314). Current evidence on the efficacy of ultrasound-guided foam sclerotherapy for varicose veins is adequate. The evidence on safety is adequate, and provided that patients are warned of the small but significant risks of foam embolisation (see section 1.2), this procedure may be used with normal arrangements for clinical governance, consent and audit. During the consent process, clinicians should inform patients that there are reports of temporary chest tightness, dry cough, headaches and visual disturbance, and rare but significant complications including myocardial infarction, seizures, transient ischaemic attacks and stroke.# The procedure # Indications and current treatments Varicose veins are enlarged tortuous veins with deficient valves. Venous insufficiency occurs when blood collects in them rather than being pumped back to the heart. Most people with varicose veins have no symptoms, but venous insufficiency may cause fatigue, heaviness, aching, throbbing, itching and cramps in the legs. Chronic venous insufficiency can lead to skin discolouration, inflammatory dermatitis and ulceration. Great saphenous vein insufficiency is the most common form of venous insufficiency in people presenting with symptoms. Conservative methods such as compression hosiery (support stockings or tights) may help people with symptomatic varicose veins. If symptoms are severe the main treatment options include surgery (ligation and stripping of the great saphenous veins or ligation with or without stripping of the small saphenous veins, and phlebectomy), endovenous laser treatment and radiofrequency ablation. # Outline of the procedure The aim of ultrasound-guided foam sclerotherapy for varicose veins is to damage the endothelial surface of the vein causing scarring and leading to blockage of the treated varicose veins. Sclerosant, in the form of a foam, is intended to have good surface area contact with the vein walls. The procedure may be carried out with local anaesthesia. Sclerosant foam is injected into the affected veins using ultrasound guidance. The foam causes an inflammatory reaction in the vein wall, blocking the vein. Compression bandages are applied after the procedure and are typically worn for between a week and a month. More than 1 vein may be treated during the same session. If any vein is incompletely treated, further injections may be given in the same or subsequent sessions. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 73 patients (82 legs), in which foam sclerotherapy plus saphenofemoral ligation (n=39) was compared with standard surgery (n=43), reported above-the-knee vein obliteration in 58% (19/33) of legs in patients treated in the foam plus saphenofemoral ligation group and 54% (14/26) of legs in patients treated by standard surgery alone at 5-year follow-up (p=0.19). Below-the-knee vein obliteration was reported in 24% (8/33) of legs in patients treated by foam plus saphenofemoral ligation and 39% (10/26) of legs in patients treated by standard surgery alone at 5-year follow-up (p=0.34). A meta-analysis of 2 RCTs (included in a systematic review) with 340 patients reported that foam sclerotherapy was not significantly more efficacious (n=174) than liquid (n=166) in occluding the vein (relative risk 1.5; 95% confidence interval 0.6 to 3.6, I2=95%, indicating significant heterogeneity), with follow-up ranging from 1 to 10 years. In a case series of 146 patients (203 limbs), the clinical recurrence rate (reported in 23 patients) with significant venous symptoms (visible or palpable varices, aching, oedema or venous skin changes) was 4%, the clinical recurrence rate with minimal venous symptoms was 22%, and recurrence with no venous symptoms was 74% at 5-year follow-up. In the RCT of 73 patients the median Venous Clinical Severity scores (graded from 0 to 3 ; maximum score 30) decreased from 5 to 1 in patients treated by foam sclerotherapy plus saphenofemoral ligation and decreased from 5 to 3 in patients treated by surgery alone at 5-year follow-up (p=0.35 between groups; p values for change within groups not reported). The RCT of 73 patients reported that the median Aberdeen Varicose Vein Questionnaire scores (range 0–100, with higher scores indicating more severe effects) decreased from 12 at baseline to 7 in patients treated by foam sclerotherapy plus saphenofemoral ligation, and from 16 at baseline to 6 in patients treated by surgery. The difference between the groups was statistically significant but not considered 'clinically significant' at 5-year follow-up (p=0.02). The Specialist Advisers listed additional key efficacy outcomes as mobility and recurrence of leg ulceration. # Safety Stroke was reported in a case report of 3 patients, all of whom were subsequently diagnosed with a patent foramen ovale. In 1 patient treated by foam sclerotherapy and ambulatory phlebectomy, middle cerebral arterial bubbles were detected immediately after the procedure (treated with tissue plasminogen activator), and in the other 2 patients middle cerebral arterial ischaemic change was confirmed (1 day after the procedure in 1 patient and 2 days after the procedure in the other patient). All 3 patients recovered completely with no further neurological or thrombotic events reported at follow-up ranging from 3 months to 2 years. A transient ischaemic attack after injection was reported in 1 patient in a case series of 1025 patients. Complete clinical recovery occurred in 30 minutes. Myocardial infarction was reported in 1 patient 30 minutes after injection (unpublished report included in the systematic review; no further details available). A grand mal epileptic seizure was reported in 1 patient 40 minutes after injection (based on an unpublished report included in the systematic review; no further details available). Bubble embolisation was reported in 73% (60/82) of patients in a case series of 82 patients with right-to-left shunts. 'Most' bubbles were detected within 15 minutes of the foam injection and no new neurological symptoms were detected at follow-up (assessed at 1, 7 and/or 28 days). Transient visual disturbance was reported in 5 patients, during or shortly after treatment, in a case series of 977 patients treated by foam sclerotherapy. Headache was reported in 3 patients immediately after the procedure in the case series of 977 patients (resolved in 24 hours after treatment by analgesia). Pulmonary embolism (treated by an anticoagulant) was reported in 1 patient in the case series of 977 patients 5 weeks after the procedure. Thrombophlebitis was reported in 7% (17/230) of patients treated by foam sclerotherapy within 1 week of the procedure compared with 0% of 200 patients treated by surgery in an RCT of 430 patients (p<0.001). Skin pigmentation was reported in 6% (12/213) of patients treated by foam sclerotherapy compared with 1% (2/177) of patients treated by surgery in the RCT of 430 patients at 2-year follow-up. Complications including coughing, chest tightness/heaviness, panic attack, malaise and vasovagal fainting occurred at a rate of 0–3% across the studies in the systematic review (follow-up ranged between 1 month and 5 years). The Specialist Advisers listed an additional theoretical adverse event to be extravasation.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. It updates and replaces NICE interventional procedure guidance 314. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on ultrasound-guided foam sclerotherapy for varicose veins (interventional procedure guidance 314).\n\nCurrent evidence on the efficacy of ultrasound-guided foam sclerotherapy for varicose veins is adequate. The evidence on safety is adequate, and provided that patients are warned of the small but significant risks of foam embolisation (see section 1.2), this procedure may be used with normal arrangements for clinical governance, consent and audit.\n\nDuring the consent process, clinicians should inform patients that there are reports of temporary chest tightness, dry cough, headaches and visual disturbance, and rare but significant complications including myocardial infarction, seizures, transient ischaemic attacks and stroke.', 'The procedure': "# Indications and current treatments\n\nVaricose veins are enlarged tortuous veins with deficient valves. Venous insufficiency occurs when blood collects in them rather than being pumped back to the heart. Most people with varicose veins have no symptoms, but venous insufficiency may cause fatigue, heaviness, aching, throbbing, itching and cramps in the legs. Chronic venous insufficiency can lead to skin discolouration, inflammatory dermatitis and ulceration. Great saphenous vein insufficiency is the most common form of venous insufficiency in people presenting with symptoms.\n\nConservative methods such as compression hosiery (support stockings or tights) may help people with symptomatic varicose veins. If symptoms are severe the main treatment options include surgery (ligation and stripping of the great saphenous veins or ligation with or without stripping of the small saphenous veins, and phlebectomy), endovenous laser treatment and radiofrequency ablation.\n\n# Outline of the procedure\n\nThe aim of ultrasound-guided foam sclerotherapy for varicose veins is to damage the endothelial surface of the vein causing scarring and leading to blockage of the treated varicose veins. Sclerosant, in the form of a foam, is intended to have good surface area contact with the vein walls.\n\nThe procedure may be carried out with local anaesthesia. Sclerosant foam is injected into the affected veins using ultrasound guidance. The foam causes an inflammatory reaction in the vein wall, blocking the vein. Compression bandages are applied after the procedure and are typically worn for between a week and a month.\n\nMore than 1\xa0vein may be treated during the same session. If any vein is incompletely treated, further injections may be given in the same or subsequent sessions.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 73\xa0patients (82\xa0legs), in which foam sclerotherapy plus saphenofemoral ligation (n=39) was compared with standard surgery (n=43), reported above-the-knee vein obliteration in 58% (19/33) of legs in patients treated in the foam plus saphenofemoral ligation group and 54% (14/26) of legs in patients treated by standard surgery alone at 5-year follow-up (p=0.19). Below-the-knee vein obliteration was reported in 24% (8/33) of legs in patients treated by foam plus saphenofemoral ligation and 39% (10/26) of legs in patients treated by standard surgery alone at 5-year follow-up (p=0.34).\n\nA meta-analysis of 2\xa0RCTs (included in a systematic review) with 340\xa0patients reported that foam sclerotherapy was not significantly more efficacious (n=174) than liquid (n=166) in occluding the vein (relative risk [RR] 1.5; 95% confidence interval [CI] 0.6 to 3.6, I2=95%, indicating significant heterogeneity), with follow-up ranging from 1 to 10\xa0years.\n\nIn a case series of 146\xa0patients (203\xa0limbs), the clinical recurrence rate (reported in 23\xa0patients) with significant venous symptoms (visible or palpable varices, aching, oedema or venous skin changes) was 4%, the clinical recurrence rate with minimal venous symptoms was 22%, and recurrence with no venous symptoms was 74% at 5-year follow-up.\n\nIn the RCT of 73\xa0patients the median Venous Clinical Severity scores (graded from 0 [absent] to 3 [severe]; maximum score 30) decreased from 5\xa0to\xa01 in patients treated by foam sclerotherapy plus saphenofemoral ligation and decreased from 5\xa0to\xa03 in patients treated by surgery alone at 5-year follow-up (p=0.35 between groups; p values for change within groups not reported).\n\nThe RCT of 73\xa0patients reported that the median Aberdeen Varicose Vein Questionnaire scores (range 0–100, with higher scores indicating more severe effects) decreased from 12 at baseline to 7 in patients treated by foam sclerotherapy plus saphenofemoral ligation, and from 16 at baseline to 6 in patients treated by surgery. The difference between the groups was statistically significant but not considered 'clinically significant' at 5-year follow-up (p=0.02).\n\nThe Specialist Advisers listed additional key efficacy outcomes as mobility and recurrence of leg ulceration.\n\n# Safety\n\nStroke was reported in a case report of 3\xa0patients, all of whom were subsequently diagnosed with a patent foramen ovale. In 1\xa0patient treated by foam sclerotherapy and ambulatory phlebectomy, middle cerebral arterial bubbles were detected immediately after the procedure (treated with tissue plasminogen activator), and in the other 2\xa0patients middle cerebral arterial ischaemic change was confirmed (1\xa0day after the procedure in 1\xa0patient and 2\xa0days after the procedure in the other patient). All 3\xa0patients recovered completely with no further neurological or thrombotic events reported at follow-up ranging from 3\xa0months to 2\xa0years. A transient ischaemic attack after injection was reported in 1\xa0patient in a case series of 1025\xa0patients. Complete clinical recovery occurred in 30\xa0minutes.\n\nMyocardial infarction was reported in 1\xa0patient 30\xa0minutes after injection (unpublished report included in the systematic review; no further details available).\n\nA grand mal epileptic seizure was reported in 1\xa0patient 40\xa0minutes after injection (based on an unpublished report included in the systematic review; no further details available).\n\nBubble embolisation was reported in 73% (60/82) of patients in a case series of 82\xa0patients with right-to-left shunts. 'Most' bubbles were detected within 15\xa0minutes of the foam injection and no new neurological symptoms were detected at follow-up (assessed at 1, 7 and/or 28\xa0days).\n\nTransient visual disturbance was reported in 5\xa0patients, during or shortly after treatment, in a case series of 977\xa0patients treated by foam sclerotherapy.\n\nHeadache was reported in 3\xa0patients immediately after the procedure in the case series of 977\xa0patients (resolved in 24\xa0hours after treatment by analgesia).\n\nPulmonary embolism (treated by an anticoagulant) was reported in 1\xa0patient in the case series of 977\xa0patients 5\xa0weeks after the procedure.\n\nThrombophlebitis was reported in 7% (17/230) of patients treated by foam sclerotherapy within 1\xa0week of the procedure compared with 0% of 200\xa0patients treated by surgery in an RCT of 430\xa0patients (p<0.001).\n\nSkin pigmentation was reported in 6% (12/213) of patients treated by foam sclerotherapy compared with 1% (2/177) of patients treated by surgery in the RCT of 430\xa0patients at 2-year follow-up.\n\nComplications including coughing, chest tightness/heaviness, panic attack, malaise and vasovagal fainting occurred at a rate of 0–3% across the studies in the systematic review (follow-up ranged between 1\xa0month and 5\xa0years).\n\nThe Specialist Advisers listed an additional theoretical adverse event to be extravasation.", 'Further information': 'For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 314.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg440
40a19fe7a81dc50dc99ffec5a0daedbdf41dbb8e	nice	Irreversible electroporation for treating primary lung cancer and metastases in the lung	Irreversible electroporation for treating primary lung cancer and metastases in the lung # Guidance Current evidence on the safety and efficacy of irreversible electroporation for treating primary lung cancer and metastases in the lung is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. In particular, studies should report the effect of the procedure on local tumour control and patient survival.# The procedure # Indications and current treatments Lung cancer is one of the most common cancers in the UK. The symptoms often do not appear until the disease is at an advanced stage, and the prognosis is generally poor. The lung is also a common site for metastases from other primary cancers, such as breast and colon cancer. The choice of treatment for primary lung cancer and metastases in the lung is influenced primarily by the type of tumour and stage of the disease. Treatments include surgical resection (open or thoracoscopic), chemotherapy, radiotherapy, photodynamic therapy or thermal ablation, or a combination of these. If the tumour protrudes into the major airways, interventional bronchoscopic treatments including diathermy, laser therapy, cryotherapy, brachytherapy or photodynamic therapy may be used. Irreversible electroporation is a non-thermal cell-destruction technique, which is claimed to allow targeted destruction of cancerous cells with less damage to supporting connective tissue (such as nearby blood vessels and nerves) than with other types of treatment. # Outline of the procedure The aim of irreversible electroporation is to destroy cancerous cells by subjecting them to a series of short electrical pulses using high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell's homeostasis mechanisms and leading to cell death. The procedure is performed with the patient under general anaesthesia. A neuromuscular blocking agent is essential to prevent uncontrolled severe muscle contractions caused by the electric current. Bipolar or unipolar electrode needles are introduced percutaneously (or by open surgical or laparoscopic approaches) and guided into place in and adjacent to the target tumour using imaging guidance. A series of very short electrical pulses is delivered over several minutes to ablate the tumour. The electrodes may then be repositioned to extend the zone of electroporation until the entire tumour and an appropriate margin have been ablated. Cardiac synchronisation is used to time delivery of the electrical pulse within the refractory period of the heart cycle, minimising the risk of arrhythmia. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 38 patients with a variety of tumours reported no satisfactory tumour response in any of the 4 patients treated for lung tumours, and all 4 patients had progressive disease when assessed by the modified 'Response Evaluation Criteria in Solid Tumors' at 3 months. A case report of 2 patients with primary and metastatic lung tumours reported progression of disease (at 2 months after the procedure in 1 patient and at 6 months in the other patient). The Specialist Advisers listed key efficacy outcomes as patient survival, tumour response on follow-up imaging, local tumour control, time to disease progression, improvement in health-related quality of life and reduction in tumour-related symptoms. # Safety The case series of 38 patients reported cardiac arrhythmia in 6 patients (4 patients had ventricular tachycardia, 1 patient had supraventricular tachycardia and 1 patient had atrial fibrillation). Two of these patients had arrhythmias despite the use of cardiac synchronisation. All the arrhythmias resolved spontaneously except for the atrial fibrillation, which was treated by cardioversion. A case series of 21 patients with primary or metastatic cancer (liver, kidney and lung) reported transient ventricular tachycardia during 2 out of 3 procedures in patients with lung tumours. A case series of 45 patients (12 lung lesions) reported pneumothorax in 14% (7/50) of procedures. The case series of 38 patients (4 patients with lung cancer) reported 2 cases of pneumothorax (50% incidence). The case series of 21 patients (3 patients with lung cancer) reported 2 cases of pneumothorax (67% incidence). The case series of 38 patients reported collapse of the right upper lobe in 1 patient with advanced lung cancer: the lobe re-expanded spontaneously. The case report of 2 patients reported moderate parenchymal haemorrhage at the time of the procedure in 1 patient. One Specialist Adviser reported an anecdotal adverse event of sepsis. The Specialist Advisers listed theoretical adverse events as tumour seeding, bronchopleural fistula, residual necrotic tissue and changes such as fibrosis. # Other comments The Committee noted that most of the published studies included patients with a variety of different types of tumour, among whom there were few with primary lung cancer or metastases in the lung. The Committee noted the claim that this procedure may cause less damage to surrounding structures (such as major blood vessels) than other types of ablative treatment for lung cancer, but considered that more evidence is needed to support this.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk ISBN 978-1-4731-0033-6	{'Guidance': 'Current evidence on the safety and efficacy of irreversible electroporation for treating primary lung cancer and metastases in the lung is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. In particular, studies should report the effect of the procedure on local tumour control and patient survival.', 'The procedure': "# Indications and current treatments\n\nLung cancer is one of the most common cancers in the UK. The symptoms often do not appear until the disease is at an advanced stage, and the prognosis is generally poor. The lung is also a common site for metastases from other primary cancers, such as breast and colon cancer.\n\nThe choice of treatment for primary lung cancer and metastases in the lung is influenced primarily by the type of tumour and stage of the disease. Treatments include surgical resection (open or thoracoscopic), chemotherapy, radiotherapy, photodynamic therapy or thermal ablation, or a combination of these. If the tumour protrudes into the major airways, interventional bronchoscopic treatments including diathermy, laser therapy, cryotherapy, brachytherapy or photodynamic therapy may be used. Irreversible electroporation is a non-thermal cell-destruction technique, which is claimed to allow targeted destruction of cancerous cells with less damage to supporting connective tissue (such as nearby blood vessels and nerves) than with other types of treatment.\n\n# Outline of the procedure\n\nThe aim of irreversible electroporation is to destroy cancerous cells by subjecting them to a series of short electrical pulses using high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell's homeostasis mechanisms and leading to cell death.\n\nThe procedure is performed with the patient under general anaesthesia. A neuromuscular blocking agent is essential to prevent uncontrolled severe muscle contractions caused by the electric current. Bipolar or unipolar electrode needles are introduced percutaneously (or by open surgical or laparoscopic approaches) and guided into place in and adjacent to the target tumour using imaging guidance. A series of very short electrical pulses is delivered over several minutes to ablate the tumour. The electrodes may then be repositioned to extend the zone of electroporation until the entire tumour and an appropriate margin have been ablated. Cardiac synchronisation is used to time delivery of the electrical pulse within the refractory period of the heart cycle, minimising the risk of arrhythmia.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 38\xa0patients with a variety of tumours reported no satisfactory tumour response in any of the 4\xa0patients treated for lung tumours, and all 4\xa0patients had progressive disease when assessed by the modified 'Response Evaluation Criteria in Solid Tumors' at 3\xa0months.\n\nA case report of 2\xa0patients with primary and metastatic lung tumours reported progression of disease (at 2\xa0months after the procedure in 1\xa0patient and at 6\xa0months in the other patient).\n\nThe Specialist Advisers listed key efficacy outcomes as patient survival, tumour response on follow-up imaging, local tumour control, time to disease progression, improvement in health-related quality of life and reduction in tumour-related symptoms.\n\n# Safety\n\nThe case series of 38\xa0patients reported cardiac arrhythmia in 6\xa0patients (4\xa0patients had ventricular tachycardia, 1\xa0patient had supraventricular tachycardia and 1\xa0patient had atrial fibrillation). Two of these patients had arrhythmias despite the use of cardiac synchronisation. All the arrhythmias resolved spontaneously except for the atrial fibrillation, which was treated by cardioversion.\n\nA case series of 21\xa0patients with primary or metastatic cancer (liver, kidney and lung) reported transient ventricular tachycardia during 2 out of 3\xa0procedures in patients with lung tumours.\n\nA case series of 45\xa0patients (12\xa0lung lesions) reported pneumothorax in 14% (7/50) of procedures. The case series of 38\xa0patients (4\xa0patients with lung cancer) reported 2\xa0cases of pneumothorax (50% incidence). The case series of 21\xa0patients (3\xa0patients with lung cancer) reported 2\xa0cases of pneumothorax (67% incidence).\n\nThe case series of 38\xa0patients reported collapse of the right upper lobe in 1\xa0patient with advanced lung cancer: the lobe re-expanded spontaneously.\n\nThe case report of 2\xa0patients reported moderate parenchymal haemorrhage at the time of the procedure in 1\xa0patient.\n\nOne Specialist Adviser reported an anecdotal adverse event of sepsis. The Specialist Advisers listed theoretical adverse events as tumour seeding, bronchopleural fistula, residual necrotic tissue and changes such as fibrosis.\n\n# Other comments\n\nThe Committee noted that most of the published studies included patients with a variety of different types of tumour, among whom there were few with primary lung cancer or metastases in the lung.\n\nThe Committee noted the claim that this procedure may cause less damage to surrounding structures (such as major blood vessels) than other types of ablative treatment for lung cancer, but considered that more evidence is needed to support this.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780\n\nISBN 978-1-4731-0033-6'}	https://www.nice.org.uk/guidance/ipg441
0cd3b4d6c5e875f7b32c9a1cb37b89fff32cec40	nice	Irreversible electroporation for treating renal cancer	Irreversible electroporation for treating renal cancer # Guidance Current evidence on the safety and efficacy of irreversible electroporation for treating renal cancer is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. In particular, studies should report the effect of the procedure on local tumour control and patient survival.# The procedure # Indications and current treatments The most common type of renal cancer in adults is renal cell carcinoma. Symptoms and signs may include pain and haematuria. Some patients are diagnosed during investigation with imaging for other disorders. Patients with certain genetic syndromes that predispose them to kidney tumours may be diagnosed during routine imaging surveillance. Establishing the diagnosis and assessing the prognosis of some renal tumours can be difficult, and not all are actively treated. Treatment options include laparoscopic (or open) partial or total nephrectomy, and ablation techniques including radiofrequency ablation and cryoablation. Drug therapy is commonly used for advanced renal cancer. Irreversible electroporation is a non-thermal cell-destruction technique, which is claimed to allow targeted destruction of cancerous cells with less damage to surrounding structures (such as major blood vessels and ducts). # Outline of the procedure The aim of irreversible electroporation is to destroy cancerous cells by subjecting them to a series of short electrical pulses using high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell's homeostasis mechanisms and leading to cell death. The procedure is performed with the patient under general anaesthesia. A neuromuscular blocking agent is essential to prevent uncontrolled severe muscle contractions caused by the electric current. Bipolar or unipolar electrode needles are introduced percutaneously (or by open surgical or laparoscopic approaches) and guided into place in and adjacent to the target tumour using imaging guidance. A series of very short electrical pulses is delivered over several minutes to ablate the tumour. The electrodes may then be repositioned to extend the zone of electroporation until the entire tumour and an appropriate margin have been ablated. Cardiac synchronisation is used to time delivery of the electrical pulse within the refractory period of the heart cycle, minimising the risk of arrhythmia. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 38 patients including 7 patients with renal cancer (10 tumours) reported a complete response in 5 tumours and progressive disease in 5 tumours at 3-month follow-up, assessed by modified 'Response Evaluation Criteria in Solid Tumors' (modified RECIST). Computed tomography follow-up at 3 months confirmed ablation of the tumour in 5 of the 7 patients, although 2 patients needed a second irreversible electroporation procedure. The Specialist Advisers listed key efficacy outcomes as local tumour control, time to progression, and patient survival. # Safety The case series of 38 patients reported transient cardiac arrhythmia in 6 patients (4 patients had ventricular tachycardia, 1 patient had supraventricular tachycardia and 1 patient had atrial fibrillation). Two of these patients had cardiac synchronisation and 4 did not. All of the arrhythmias resolved without treatment except for the atrial fibrillation in 1 patient, which was treated by cardioversion. A case series of 21 patients with primary or metastatic cancer (liver, kidney or lung) reported transient ventricular tachycardia during 25% (7/28) of procedures. In 4 of the 7 procedures, arterial blood pressure was 'markedly decreased' (not defined). The authors noted that a synchronisation device was used from early in the trial, but they had variable success with synchronisation. Intraoperative supraventricular extrasystole was reported in 1 patient in a case series of 6 patients. No electrocardiography-related changes were detected after the procedure or at follow-up (after 12 weeks). The case series of 38 patients reported partial ureteric obstruction and increasing creatinine level in 1 patient with renal cancer (timing not reported). The patient's ureter had been damaged previously by radiofrequency ablation. The obstruction was treated by inserting a ureteric stent. The case series of 21 patients with tumours in the liver, kidney or lung reported extreme increases in blood pressure during the procedure (up to 200/100 mmHg from a baseline of 140/60 mmHg) in 7% (2/28) of procedures (both patients were being treated for renal cancer). In 1 patient, the blood pressure increase lasted for more than a few minutes and medical treatment was needed. The position of the electrodes was subsequently checked, and thought to be in the adrenal gland. Transient increases in systolic blood pressure of approximately 20 to 30 mmHg after treatment cycles were reported for all patients in the same study. The Specialist Advisers listed additional theoretical adverse effects as damage to surrounding organs, minor bleeding, sepsis and ureteric stricture. # Other comments The Committee noted the claim that this procedure may cause less damage to surrounding structures (such as major blood vessels) than other types of ablative treatment for renal cancer, but considered that more evidence is needed to support this.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk ISBN 978-1-4731-0037-4	{'Guidance': 'Current evidence on the safety and efficacy of irreversible electroporation for treating renal cancer is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. In particular, studies should report the effect of the procedure on local tumour control and patient survival.', 'The procedure': "# Indications and current treatments\n\nThe most common type of renal cancer in adults is renal cell carcinoma. Symptoms and signs may include pain and haematuria. Some patients are diagnosed during investigation with imaging for other disorders. Patients with certain genetic syndromes that predispose them to kidney tumours may be diagnosed during routine imaging surveillance. Establishing the diagnosis and assessing the prognosis of some renal tumours can be difficult, and not all are actively treated.\n\nTreatment options include laparoscopic (or open) partial or total nephrectomy, and ablation techniques including radiofrequency ablation and cryoablation. Drug therapy is commonly used for advanced renal cancer. Irreversible electroporation is a non-thermal cell-destruction technique, which is claimed to allow targeted destruction of cancerous cells with less damage to surrounding structures (such as major blood vessels and ducts).\n\n# Outline of the procedure\n\nThe aim of irreversible electroporation is to destroy cancerous cells by subjecting them to a series of short electrical pulses using high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell's homeostasis mechanisms and leading to cell death.\n\nThe procedure is performed with the patient under general anaesthesia. A neuromuscular blocking agent is essential to prevent uncontrolled severe muscle contractions caused by the electric current. Bipolar or unipolar electrode needles are introduced percutaneously (or by open surgical or laparoscopic approaches) and guided into place in and adjacent to the target tumour using imaging guidance. A series of very short electrical pulses is delivered over several minutes to ablate the tumour. The electrodes may then be repositioned to extend the zone of electroporation until the entire tumour and an appropriate margin have been ablated. Cardiac synchronisation is used to time delivery of the electrical pulse within the refractory period of the heart cycle, minimising the risk of arrhythmia.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 38\xa0patients including 7\xa0patients with renal cancer (10\xa0tumours) reported a complete response in 5\xa0tumours and progressive disease in 5\xa0tumours at 3-month follow-up, assessed by modified 'Response Evaluation Criteria in Solid Tumors' (modified RECIST). Computed tomography follow-up at 3\xa0months confirmed ablation of the tumour in 5 of the 7\xa0patients, although 2\xa0patients needed a second irreversible electroporation procedure.\n\nThe Specialist Advisers listed key efficacy outcomes as local tumour control, time to progression, and patient survival.\n\n# Safety\n\nThe case series of 38\xa0patients reported transient cardiac arrhythmia in 6\xa0patients (4\xa0patients had ventricular tachycardia, 1\xa0patient had supraventricular tachycardia and 1\xa0patient had atrial fibrillation). Two of these patients had cardiac synchronisation and 4\xa0did not. All of the arrhythmias resolved without treatment except for the atrial fibrillation in 1\xa0patient, which was treated by cardioversion.\n\nA case series of 21\xa0patients with primary or metastatic cancer (liver, kidney or lung) reported transient ventricular tachycardia during 25% (7/28) of procedures. In 4 of the 7\xa0procedures, arterial blood pressure was 'markedly decreased' (not defined). The authors noted that a synchronisation device was used from early in the trial, but they had variable success with synchronisation. Intraoperative supraventricular extrasystole was reported in 1\xa0patient in a case series of 6\xa0patients. No electrocardiography-related changes were detected after the procedure or at follow-up (after 12\xa0weeks).\n\nThe case series of 38\xa0patients reported partial ureteric obstruction and increasing creatinine level in 1\xa0patient with renal cancer (timing not reported). The patient's ureter had been damaged previously by radiofrequency ablation. The obstruction was treated by inserting a ureteric stent.\n\nThe case series of 21\xa0patients with tumours in the liver, kidney or lung reported extreme increases in blood pressure during the procedure (up to 200/100\xa0mmHg from a baseline of 140/60\xa0mmHg) in 7% (2/28) of procedures (both patients were being treated for renal cancer). In 1\xa0patient, the blood pressure increase lasted for more than a few minutes and medical treatment was needed. The position of the electrodes was subsequently checked, and thought to be in the adrenal gland. Transient increases in systolic blood pressure of approximately 20 to 30\xa0mmHg after treatment cycles were reported for all patients in the same study.\n\nThe Specialist Advisers listed additional theoretical adverse effects as damage to surrounding organs, minor bleeding, sepsis and ureteric stricture.\n\n# Other comments\n\nThe Committee noted the claim that this procedure may cause less damage to surrounding structures (such as major blood vessels) than other types of ablative treatment for renal cancer, but considered that more evidence is needed to support this.", 'Further information': 'For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780\n\nISBN 978-1-4731-0037-4'}	https://www.nice.org.uk/guidance/ipg443
5a72fa857ddbaa9d6e204c5bc77572b450d0b915	nice	Vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract	Vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract Evidence-based recommendations on vinflunine (Javlor) for treating advanced transitional cell carcinoma of the urothelial tract in adults. # Guidance Vinflunine is not recommended within its marketing authorisation for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy. People currently receiving vinflunine that is not recommended according to 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology Vinflunine (Javlor, Pierre Fabre) is a chemotherapeutic agent belonging to the vinca-alkaloid class of drugs. Vinflunine has a marketing authorisation for use as 'monotherapy for the treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen'. The summary of product characteristics (SPC) notes that vinflunine has not been studied in patients with a performance status of 2 or more. According to the SPC, common undesirable effects associated with vinflunine include haematological disorders (neutropenia and anaemia), gastrointestinal disorders (constipation, nausea, stomatitis, vomiting, abdominal pain and diarrhoea), and general disorders (asthenia/fatigue). For full details of side effects and contraindications, see the SPC. The SPC states that the recommended dosage of vinflunine is 320 mg/m2 as a 20-minute intravenous infusion every 3 weeks. The SPC also states that in patients with a World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 1 or of 0 who have had pelvic irradiation, treatment should be started at a dose of 280 mg/m2; in the absence of any haematological toxicity during the first cycle causing treatment delay or dose reduction, the dosage can be increased to 320 mg/m2 every 3 weeks for the subsequent cycles. The SPC states that monitoring of complete blood counts should be conducted before each treatment cycle, and that oral hydration and laxatives should be given during each cycle. Vinflunine is available in 50 mg and 250 mg vials, costing £212.50 and £1062.50 respectively (excluding VAT; 'British National Formulary' edition 64). The acquisition cost of vinflunine for an entire course of treatment is £9817.50, assuming an average of 4.2 cycles, a dose of 287 mg/m2 and a body surface area of 1.85 m2 (see section 3.10). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of vinflunine and a review of this submission by the Evidence Review Group (ERG; appendix B). The main evidence for the clinical effectiveness of vinflunine was from 1 open-label, phase III, randomised controlled trial (study 302, the registration trial) that compared vinflunine plus best supportive care with best supportive care alone in patients with advanced or metastatic transitional cell carcinoma of the urothelial tract whose disease had progressed after platinum-based chemotherapy. Results from 2 open-label, single-arm, phase II studies (study 202 and CA001) were also provided. The manufacturer's submission highlighted issues around using best supportive care alone as the control arm in study 302. In particular, patients had to be fit enough to receive chemotherapy but willing to accept randomisation to best supportive care. The manufacturer stated that patients in the trial had a poorer prognosis, as indicated by the high percentage (approximately 74%) of patients with visceral involvement in both groups in the trial. The manufacturer also highlighted that there is currently no standard chemotherapy regimen for patients with advanced transitional cell carcinoma of the urothelial tract whose disease has progressed after a prior platinum-containing chemotherapy, and there is a lack of trial evidence of survival advantage from chemotherapy in this clinical situation. Therefore no standard active treatments were available to use as a control, and best supportive care was considered the most appropriate comparator for vinflunine. Patients were included in study 302 if they had progressive disease after at least 2 cycles of platinum-based first-line chemotherapy (or after 1 cycle if there was clear evidence of disease progression at this point), an ECOG performance status of 0 or 1, and an estimated life expectancy of at least 12 weeks. Previous systemic chemotherapy must have been stopped at least 30 days before randomisation. Patients were excluded if they had received more than 1 previous systemic chemotherapy for advanced or metastatic disease, or if they had been treated with neoadjuvant or adjuvant chemotherapy. Patients were randomised on a 2:1 basis to vinflunine plus best supportive care (hereafter called the vinflunine arm) or best supportive care alone (hereafter called the best supportive care arm). Patients in the vinflunine arm initially received 320 mg/m2 every 21 days via infusion, but the protocol was subsequently amended to allow a lower starting dose (280 mg/m2) in patients at greater risk of haematological toxicity. Best supportive care included palliative radiotherapy, antibiotics, analgesics, corticosteroids and blood transfusions. A total of 370 patients were enrolled into the study (253 in the vinflunine arm and 117 in the best supportive care arm). The median age of study participants was 64 years, and 79% were male. Most baseline characteristics were similar across the 2 treatment arms. However, a greater proportion of patients in the vinflunine arm had an ECOG performance status of 1 compared with the best supportive care arm (72% and 62% respectively) although this difference was not statistically significant. Cisplatin was the most common first-line platinum treatment and had been received by more patients in the best supportive care arm than in the vinflunine arm (73% and 65% respectively), although this difference was not statistically significant. More patients in the vinflunine arm than in the best supportive care arm had received carboplatin as first-line platinum treatment (30% and 20% respectively; p=0.044). Study results were provided for 4 study populations, only 2 of which are presented here: the intention-to-treat (ITT) population, which included all randomised patients, and the 'eligible ITT population'. The latter excluded 13 patients who were found, upon retrospective review of the patient inclusion criteria, not to have progressive disease at the time of entry into the study, and who therefore should not have been randomised (4 patients in the vinflunine arm and 9 in the best supportive care arm; 3 of the 4 excluded patients in the vinflunine arm and 6 of the 9 excluded patients in the best supportive care arm were also ineligible because they had received neoadjuvant or adjuvant chemotherapy). The primary outcome of study 302 was median overall survival. For the ITT population, this was 6.9 months in the vinflunine arm compared with 4.6 months in the best supportive care arm (hazard ratio 0.88, 95% confidence interval 0.69 to 1.12, p=0.2868). A pre-planned multivariate analysis, adjusting for a number of prognostic factors (performance status, visceral invasion, alkaline phosphatase, haemoglobin and prior pelvic irradiation), showed a statistically significant overall survival benefit for vinflunine (HR 0.77, 95% CI 0.61 to 0.98, p=0.036). For the eligible ITT population, median overall survival was 6.9 months in the vinflunine arm and 4.3 months in the best supportive care arm (HR 0.78, 95% CI 0.61 to 0.99, p=0.0403). An extended multivariate analysis was also done, adjusting for the same prognostic factors outlined above plus additional baseline characteristics such as age, sex and disease stage at diagnosis. This analysis also showed a statistically significant overall survival benefit for vinflunine (HR 0.68, 95% CI 0.52 to 0.88, p=0.0035). Progression-free survival for the ITT population was 3.0 months in the vinflunine arm compared with 1.5 months in the best supportive care arm (HR 0.68, 95% CI 0.54 to 0.86, p=0.0012). In the vinflunine arm, 46.5% of patients had stable disease after second-line treatment, 44.9% had progressive disease, and 8.6% had a partial or complete response. In the best supportive care arm, 27% of patients had stable disease, 73% had progressive disease, and none had a partial or complete response. These outcomes were not reported for the eligible ITT population. After disease progression, 29% of patients in the vinflunine arm and 34% of patients in the best supportive care arm received palliative chemotherapy; 60% of these re-treated patients received multi-agent chemotherapy. Quality of life was assessed using the cancer-specific European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire. This was done at study entry and at the end of cycles 1, 2, 4 and 6 for both arms. There were no statistically significant differences in overall EORTC QLQ-C30 global health status score between the 2 arms (p=0.658). In the 2 phase II, single-arm trials (study 202 and CA001), vinflunine was given every 21 days at a dose of 320 or 280 mg/m2. In study 202 (n=58), the overall response rate (partial or complete response) was 18%, median progression-free survival was 3 months (95% CI 2.4 to 3.8 months) and median overall survival was 6.6 months (95% CI 4.8 to 7.6 months). In CA001 (n=151), the overall response rate was 14.6% (95% CI 9.4% to 21.2%), median progression-free survival was 2.8 months (95% CI 2.6 to 3.8 months) and median overall survival was 7.9 months (95% CI 6.7 to 9.7 months). The most common adverse events (any grade) associated with vinflunine across the 3 phase II and phase III studies (n=450) were constipation (55%), nausea (41%), infusion-site reactions (28%), stomatitis/mucositis (27%) and vomiting (27%). Overall, there were 6 deaths related to treatment (1.3%), of which 4 were a result of myelotoxicity. Four treatment-related deaths occurred in the vinflunine arm of study 302. Grade 3 or 4 toxicities relating to neutropenia, anaemia and constipation occurred in 50%, 19% and 16% respectively of patients in the vinflunine arm of study 302, compared with 1%, 8% and 1% of patients respectively in the best supportive care arm. Febrile neutropenia occurred in 6% of patients receiving vinflunine (none in the best supportive care arm). The manufacturer submitted an economic analysis comparing vinflunine plus best supportive care with best supportive care alone. The manufacturer's model was similar to a Markov cohort model in that it included 3 health states: pre-progression, post-progression and dead. The model calculated the proportion of patients expected to be in each health state, based on the estimated survival curves for the eligible ITT population from study 302. The model assumed that treatment is administered in cycles of 21 days until disease progression, major toxicity or other reason for treatment discontinuation, or death (if occurring before progression). All patients are assumed to be in a pre-progression health state at model entry (baseline). Patients who experience disease progression are assumed to stop treatment with vinflunine and remain in the post-progression state until death. The cycle length of the model was 1 day and the time horizon was 5 years. Costs of vinflunine were based on the mean dose (287 mg/m2), the mean body surface area (1.85 m2) and the mean number of treatment cycles (4.2) in study 302. Other treatment costs included administration for intravenous infusion every 21 days in an outpatient setting, complete blood count before drug administration and constipation prophylaxis. Drug wastage was assumed to be zero in the base-case analysis. The total per-patient cost of treatment with vinflunine included in the model was £10,207. Costs for 3 common adverse events were included in the model: constipation (£39; based on 1 GP consultation and 1 pack of laxatives), febrile neutropenia resulting in hospitalisation (£3538; NHS HRG costs) and abdominal pain resulting in hospitalisation (£557; NHS HRG costs). Costs for best supportive care were calculated for the pre-progression and post-progression health states. For the pre-progression health state, best supportive care included: home visits by a GP, community nurse, health home visitor and dietician, an oncologist follow-up visit (assumed to be the same for each treatment group) and palliative radiation therapy (which differed by treatment group). For the post-progression health state, best supportive care included home visits by a GP, community nurse, health home visitor and dietician, a non-consultant oncologist follow-up visit, hospice care, pain medication (assumed to be the same for each treatment group), and palliative radiation therapy and palliative chemotherapy (which differed by treatment group). The pre-progression utility values used in the manufacturer's submission were based on responses to 1 item from the EORTC QLQ-C30 questionnaire used in study 302, which asked patients to rate their overall quality of life in the previous week. Responses were transformed to health-state utilities using a published regression model relating this measure to utility values from a time-trade-off analysis in a sample of US cancer patients and their relatives. Post-progression utility values were taken from a study reporting EQ-5D values in 1270 terminally ill cancer patients with painful bone metastases or poor-prognosis non-small-cell lung cancer. Disutility values associated with treatment-related adverse events were not included in the model. In the manufacturer's base case, the incremental cost-effectiveness ratio (ICER) for vinflunine plus best supportive care compared with best supportive care alone was £100,144 per quality-adjusted life year (QALY) gained (incremental cost of £13,071 and incremental benefit of 0.131 QALYs). The manufacturer's deterministic sensitivity analyses showed that vial price and pre-progression utility values had the greatest impact on the base-case ICER. When a vial price of £0 was used, the ICER was £27,478 per QALY gained. When a pre-progression utility of 0.4 was used (instead of 0.65), the ICER was £133,094 per QALY gained. The ICER was also sensitive to assumptions about the number of vinflunine treatment cycles (£70,233 per QALY gained when 3 cycles were costed) and vial wastage (£121,095 per QALY gained when wastage was accounted for). The manufacturer's probabilistic sensitivity analysis suggested that vinflunine had a 6% probability of being cost effective at a threshold of £30,000 per QALY gained when compared with best supportive care alone. The ERG considered the modelling approach and model structure used by the manufacturer to be appropriate and reasonable; however, it commented on a number of areas of uncertainty. The ERG stated that the modelled population reflected that of the pivotal trial (study 302) but may not be representative of the majority of patients whose disease progresses after first-line therapy. This was because patients who had received prior neoadjuvant or adjuvant platinum-based chemotherapy had been excluded from the trial. The ERG commented that best supportive care may not be the most appropriate comparator because alternative second-line treatments are available in UK clinical practice. However, the ERG noted that best supportive care was the comparator specified in the scope for the appraisal, and that there are no randomised controlled trials of relevant comparators for the population of interest. The ERG stated that data from the ITT population of study 302 may have been a more appropriate basis for the economic model than the data from the eligible ITT population that were used by the manufacturer. It also stated that the utility values used did not fit with the preferred NICE reference case, and that there is considerable uncertainty around these estimates because standard methods were not used. The ERG also compared the overall survival curve for vinflunine used in the manufacturer's economic model with that obtained using Kaplan–Meier estimates. It concluded that the most realistic results were those obtained using the Kaplan–Meier estimates, although it noted that the choice of survival curve did not have a significant impact on the cost effectiveness of vinflunine in the manufacturer's sensitivity analysis. The ERG conducted an exploratory analysis using the confidence intervals around the modelled estimates of overall survival and progression-free survival. This resulted in ICERs ranging from £87,871 to £117,938 per QALY gained. In a separate exploratory analysis the ERG used estimates of progression-free survival and overall survival from the ITT population of study 302 (rather than the eligible ITT population) and corrected an error in the manufacturer's model in which the vinflunine vial cost was entered incorrectly. The resulting ICER was £99,792 per QALY gained when the manufacturer's method of estimating survival was used, and £126,422 per QALY gained when Kaplan–Meier estimates based on trial data for the ITT population were used. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of vinflunine, having considered evidence on the nature of transitional cell carcinoma of the urothelial tract and the value placed on the benefits of vinflunine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee considered current UK practice for the treatment of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. It heard from clinical specialists that patients with localised muscle-invasive disease who are fit enough usually undergo either radical surgery (frequently preceded by neoadjuvant chemotherapy) or radical radiotherapy with concurrent chemotherapy. For patients whose disease progresses after radical treatment, platinum-based chemotherapy may be given to improve survival and quality of life. The clinical specialists stated that there is currently no standard treatment for patients whose disease relapses after first-line chemotherapy for advanced disease and who are fit enough to receive further treatment, although a number of agents may be used. They commented that there is general agreement that this patient group can benefit from second-line treatment, particularly if their disease has shown a good response to previous chemotherapy, and therefore would not usually receive palliative care alone. The clinical specialists stated that there was no comparative evidence on the use of any agents for the second-line chemotherapy of advanced or metastatic transitional cell carcinoma of the urothelial tract and that studies in this setting would be welcomed. The Committee was aware that the lack of research on second-line treatments for advanced or metastatic transitional cell carcinoma of the urothelial tract meant there was a significant unmet need for evidence on the treatment of patients whose disease has progressed after platinum-based chemotherapy. It welcomed study 302 as the first randomised controlled trial of a second-line treatment for advanced or metastatic transitional cell carcinoma of the urothelial tract. # Clinical effectiveness The Committee considered the clinical evidence on the use of vinflunine for the second-line chemotherapy of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. It noted there was only 1 randomised clinical trial (study 302), and that this compared vinflunine with best supportive care alone. The Committee was aware that best supportive care was the only comparator listed in the scope for the appraisal. It was also aware that there are no proven standard agents for second-line chemotherapy (see section 4.2). For these reasons, the Committee concluded that best supportive care was the appropriate comparator for vinflunine. The Committee discussed whether the population in study 302 was representative of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract who would receive vinflunine in UK clinical practice. It heard from the clinical specialists that the study population was younger, fitter and had better renal function than the general population of UK patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. The Committee was also aware that neoadjuvant chemotherapy, adjuvant chemotherapy and concurrent chemotherapy and radiotherapy are all used as part of radical treatment for localised muscle-invasive transitional cell carcinoma of the urothelial tract. The Committee noted that patients treated in this way had been excluded from study 302. The Committee heard from the clinical specialists that many patients in the UK who are eligible to receive second-line palliative chemotherapy will already have received 2 lines of treatment (that is, neoadjuvant chemotherapy, adjuvant chemotherapy or concurrent chemotherapy and radiotherapy, plus first-line palliative chemotherapy). Finally, the Committee noted that the manufacturer considered the trial population to be only people with a poor prognosis. The Committee understood that this was because 74% of people in the trial had visceral involvement, and because it was unlikely that people with a better prognosis would be willing to be randomised to a trial in which one of the treatment options was best supportive care. The Committee noted that the marketing authorisation for vinflunine is for all patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen. The manufacturer was invited to submit further evidence for vinflunine in the whole licensed patient population compared with best supportive care, but no data were submitted for the Committee to consider. The Committee considered whether the evidence from study 302 might be generalisable to the full licensed population. It was mindful of clinical specialists' comments regarding the differences in the characteristics and treatment pathway of patients in the trial compared with patients in UK clinical practice. The Committee was not persuaded that the evidence for the effectiveness of vinflunine would be generalisable to the whole population who might receive vinflunine in UK clinical practice, compared with best supportive care. However the Committee was aware that study 302 was the only available evidence on which a decision could be based. The Committee concluded that the nature and availability of the evidence base would result in significant uncertainty regarding the effectiveness of vinflunine for the whole licensed population compared with best supportive care. The Committee discussed the results of study 302. It noted that vinflunine was associated with improved progression-free survival and a higher disease control rate (defined as the percentage of patients with a complete response, a partial response or stable disease) compared with best supportive care alone. The Committee also noted that the difference in overall survival between the study arms was not statistically significant for the ITT population, but was significant for the eligible ITT population. The Committee was aware that the difference between the 2 analyses resulted from the exclusion of 13 patients from the ITT analysis because they had not been shown to have progressive disease after prior therapy. A greater proportion of ineligible patients came from the best supportive care arm than from the vinflunine arm (8% versus 2%) and this lowered the overall survival in the best supportive care arm in the eligible ITT analysis. The Committee considered that the results from the ITT population were the most appropriate basis for its deliberations because randomisation had not been broken. It also noted that there were no significant differences in health-related quality of life between patients receiving vinflunine and those receiving best supportive care alone. The Committee concluded that the extent of the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated because of the uncertainty in the overall survival results. The Committee discussed the most common adverse events associated with vinflunine, namely constipation, anaemia, stomatitis and infusion-site reactions. It noted that grade 3 or 4 constipation occurred in 16% of patients receiving vinflunine. It was aware that grade 4 constipation can lead to intestinal obstruction or acute abdominal distension requiring hospitalisation. The Committee also noted the 6% incidence of febrile neutropenia in the vinflunine arm of the study. The clinical specialists stated that the safety profile of second-line chemotherapy in this setting needed to be predictable, acceptable to patients and manageable, and that they had concerns about vinflunine in this regard. The Committee concluded that there were concerns about the tolerability of vinflunine. # Cost effectiveness The Committee reviewed the economic model submitted by the manufacturer and the ERG's critique of the model. The Committee was aware that the costs for the intravenous administration of vinflunine included in the manufacturer's model were based on out-of-date NHS HRG figures which were lower than current estimates. The Committee considered the manufacturer's lack of inclusion of vial wastage in the model to be inappropriate because of the small number of patients who would be treated with vinflunine at any one centre and time. The Committee concluded that the costs of treatment with vinflunine had been underestimated in the manufacturer's model. The Committee discussed the utility values used in the manufacturer's model. It noted that different methods of estimating utilities were used for the post-progression and pre-progression health states. It noted that the utility for the post-progression health state was taken from a study of patients with lung cancer. The pre-progression utility was based on answers to 1 of the 30 questions in the EORTC questionnaire, which asked patients to rate their overall quality of life during the past week. The questionnaire was administered at the end of each treatment cycle. The Committee noted clinical specialist opinion that quality of life varies considerably between 2 consecutive clinic visits. It therefore considered that this question may have to be interpreted with caution because a patient's quality of life in the last week of a treatment cycle may not reflect their quality of life for the whole period before disease progression. It also noted that established algorithms for mapping EORTC responses to EQ-5D exist but were not used by the manufacturer. The Committee noted that neither utility used in the economic model conformed to the preferred NICE reference case and concluded that the lack of appropriate utility data contributed to uncertainty in the model. The Committee discussed the data on clinical effectiveness used in the model. It was aware that various hazard ratios of overall survival had been reported depending on the population analysed and the type of analysis used (multivariate analysis or extended multivariate analysis). The Committee noted that the modelled hazard ratios were based on the multivariate analysis of the results for the eligible ITT population and that these results were more favourable for vinflunine than those obtained from the ITT population. The Committee had previously concluded (see section 4.5) that the results from the ITT population were the most appropriate for this appraisal. It therefore concluded that the survival benefit of vinflunine compared with best supportive care alone was likely to be overestimated in the manufacturer's model. The Committee discussed the inclusion of adverse events in the model and noted that although the costs of adverse events were included, the disutility associated with them was not. It discussed the costs for grade 3 and 4 constipation, and considered that these were likely to be significantly higher than the cost for constipation used in the model (£39). The Committee discussed the manufacturer's base-case ICER of £100,100 per QALY gained (incremental cost of £13,100 and incremental QALYs of 0.131). It noted that in the manufacturer's sensitivity analyses the inclusion of vial wastage and the use of a lower pre-progression utility value increased the ICER significantly from the base case (to £121,100 and £133,100 per QALY gained respectively). It also noted that in the ERG's exploratory analysis, based on Kaplan–Meier estimates of survival from the ITT population rather than the eligible ITT population, the ICER was £126,400 per QALY gained. The Committee considered the most plausible ICER to be above £120,000 per QALY gained. It further considered that additional uncertainties around the costs of adverse events and the modelling of survival data would increase the ICER. The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The Committee considered that the life expectancy of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract whose disease has progressed after first-line chemotherapy is usually less than 6 months. It discussed the number of UK patients for whom vinflunine is licensed, estimated by the manufacturer to be about 800–1500, and concluded that this could be considered a small patient population. The Committee discussed the extension to life offered by vinflunine in the study populations. In the manufacturer's model, the overall survival benefit of vinflunine was 3.2 months. However, the overall survival benefit based on the trial results was 2.3 months in the ITT population (not statistically significant) and 2.6 months in the eligible ITT population. The Committee was not persuaded that an extension to life of at least 3 months had been proven, and therefore concluded that the end-of-life advice did not apply to this appraisal. The Committee further noted that even if the end-of-life considerations were taken into account, the most plausible ICER for vinflunine compared with best supportive care (above £120,000 per QALY gained) was substantially higher than would normally be considered cost effective. The Committee was mindful of the limitations of the evidence base for vinflunine in the whole licensed population of patients who may receive treatment with vinflunine in UK clinical practice compared with best supportive care. However, the Committee was conscious of uncertainty in the overall survival results for vinflunine from the available evidence (see section 4.5), and the exceptionally high ICER which was based on this evidence. On balance, the Committee did not consider it plausible that additional evidence, even if available, would demonstrate the magnitude of survival gain which would be required to bring the cost effectiveness of vinflunine to a level considered an acceptable use of NHS resources. Therefore the Committee concluded that vinflunine could not be considered a cost-effective use of NHS resources for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy. # Summary of Appraisal Committee's key conclusions TA272 Appraisal title: Vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract Section Key conclusion Vinflunine is not recommended within its marketing authorisation for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy. The Committee considered that the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated. The Committee agreed that the most plausible ICER was above £120,000 per QALY gained and also noted the large incremental costs of £13,100 for 0.131 QALY gain. The Committee was not persuaded that an extension to life of at least 3 months had been proven, and therefore concluded that the end-of-life advice did not apply to this appraisal. The Committee concluded that vinflunine could not be considered a cost-effective use of NHS resources. Current practice Clinical need of patients, including the availability of alternative treatments The clinical specialists stated that there is currently no standard treatment for patients whose disease relapses after first-line chemotherapy and who are fit enough to receive further treatment, although a number of agents may be used. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The clinical specialists stated that there is currently no standard treatment for patients whose disease relapses after first-line chemotherapy and who are fit enough to receive further treatment, although a number of agents may be used. Vinflunine is the only treatment licensed for use for advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy. The Committee concluded that the extent of clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated because of the uncertainty of the overall survival results. What is the position of the treatment in the pathway of care for the condition? The Committee were aware that vinflunine is licensed as a second-line therapy following prior platinum-based chemotherapy. Adverse effects The Committee discussed the most common adverse events associated with vinflunine, namely constipation, anaemia, stomatitis and infusion-site reactions. It noted that grade 3 or 4 constipation occurred in 16% of patients receiving vinflunine. The Committee concluded that there were concerns about the tolerability of vinflunine. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee noted there was only 1 randomised clinical trial (study 302), and that this compared vinflunine with best supportive care alone. The Committee noted that no data were available for people in the whole licensed population for vinflunine with a better prognosis than the trial population. The Committee was mindful of the clinical specialists' comments regarding the differences in the characteristics and treatment pathway of patients in the trial compared with patients in UK clinical practice. The Committee was not persuaded that the evidence for the effectiveness of vinflunine would be generalisable to the whole population who might receive vinflunine in UK clinical practice compared with best supportive care. The Committee concluded that the nature and availability of the evidence would result in significant uncertainty regarding the effectiveness of vinflunine for the whole licensed population compared with best supportive care. The Committee noted that the difference in overall survival between the study arms was not statistically significant for the ITT population, but was significant for the eligible ITT population. It concluded that the extent of the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated. Relevance to general clinical practice in the NHS The Committee heard from the clinical specialists that the study population was younger, fitter and had better renal function than the general population of UK patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. The Committee heard from the clinical specialists that many patients in the UK who are eligible to receive second-line palliative chemotherapy will already have received 2 lines of treatment (that is, neoadjuvant chemotherapy, adjuvant chemotherapy or concurrent chemotherapy and radiotherapy, plus first-line palliative chemotherapy). Study 302 excluded patients who had had adjuvant or neoadjuvant chemotherapy. The Committee was not persuaded that the evidence for the effectiveness of vinflunine would be generalisable to the whole population who might receive vinflunine in UK clinical practice compared with best supportive care. Uncertainties generated by the evidence The Committee noted that the difference in overall survival between the study arms was not statistically significant for the ITT population, but was significant for the eligible ITT population. The Committee concluded that the extent of the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No relevant subgroups were identified in this appraisal. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that the extent of the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated. Evidence for cost effectiveness Availability and nature of evidence The Committee considered evidence on the cost effectiveness of vinflunine compared with best supportive care, including quality-of-life estimates, costs and ICERs presented by the manufacturer. to 4.11 Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee noted that the modelled hazard ratios of overall survival were based on the multivariate analysis of the results for the eligible ITT population and that these results were more favourable for vinflunine than those obtained from the ITT population. The Committee was aware that the costs for the intravenous administration of vinflunine included in the manufacturer's model were based on out-of-date NHS HRG figures which were lower than current estimates. The Committee considered the manufacturer's lack of inclusion of vial wastage in the model to be inappropriate because of the small number of patients who would be treated with vinflunine at any one centre and time. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee noted that the pre-progression utility was based on answers to 1 of the 30 questions in the EORTC questionnaire, which asked patients to rate their overall quality of life during the past week. The Committee considered that this question may have to be interpreted with caution because a patient's quality of life in the last week of a treatment cycle may not reflect their quality of life for the whole period before disease progression. It also noted that established algorithms for mapping EORTC responses to EQ-5D exist but were not used by the manufacturer. Are there specific groups of people for whom the technology is particularly cost effective? No subgroups were identified in this appraisal. What are the key drivers of cost effectiveness? The Committee noted the large incremental costs of £13,100 for 0.131 QALY gain. The Committee noted that in the manufacturer's sensitivity analyses the inclusion of vial wastage and the use of a lower pre-progression utility value increased the ICER significantly from the base case (to £121,100 and £133,100 per QALY gained respectively). It also noted that in the ERG's exploratory analysis, based on Kaplan–Meier estimates of survival from the ITT population rather than the eligible ITT population, the ICER was £126,400 per QALY gained. Most likely cost-effectiveness estimate (given as an ICER) The Committee agreed that the most plausible estimate of the ICER for vinflunine plus best supportive care compared with best supportive care alone was above £120,000 per QALY gained. Additional factors taken into account Patient access schemes (PPRS) Not applicable to this appraisal. End-of-life considerations The Committee considered that the life expectancy of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract whose disease has progressed after first-line chemotherapy is usually less than 6 months. It discussed the number of UK patients for whom vinflunine is licensed and concluded that this could be considered a small patient population. However, the Committee was not persuaded that an extension to life of at least 3 months had been proven, and therefore concluded that the end-of-life advice did not apply to this appraisal. Equalities considerations and social value judgements No equality issues were raised during the scoping exercise or through the course of this appraisal. –# Recommendations for further research The Committee noted the need for research on second-line treatments for transitional cell carcinoma of the urothelial tract. It noted that the vinflunine studies were the only studies in patients with transitional cell carcinoma of the urothelial tract whose disease had progressed after platinum-based chemotherapy. The Committee noted the lack of evidence for the relative effectiveness of treatment options at this stage in the pathway of care. It recommended that studies be undertaken to investigate the relative safety and efficacy of second-line treatments for transitional cell carcinoma of the urothelial tract, particularly randomised controlled trials.# Related NICE guidance Published Laparoscopic cystectomy. NICE interventional procedure guidance 287 (2009). Improving outcomes in urological cancers. NICE cancer service guidance (2002). In development Diagnosis and management of bladder cancer. NICE clinical guideline. Publication expected September 2014.# Review of guidance The guidance on this technology will be considered for review by the Guidance Executive in November 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveJanuary 2013# Changes after publication January 2014: minor maintenance.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Vinflunine is not recommended within its marketing authorisation for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy.\n\nPeople currently receiving vinflunine that is not recommended according to 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology ': "Vinflunine (Javlor, Pierre Fabre) is a chemotherapeutic agent belonging to the vinca-alkaloid class of drugs. Vinflunine has a marketing authorisation for use as 'monotherapy for the treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen'. The summary of product characteristics (SPC) notes that vinflunine has not been studied in patients with a performance status of 2 or more.\n\nAccording to the SPC, common undesirable effects associated with vinflunine include haematological disorders (neutropenia and anaemia), gastrointestinal disorders (constipation, nausea, stomatitis, vomiting, abdominal pain and diarrhoea), and general disorders (asthenia/fatigue). For full details of side effects and contraindications, see the SPC.\n\nThe SPC states that the recommended dosage of vinflunine is 320\xa0mg/m2 as a 20-minute intravenous infusion every 3\xa0weeks. The SPC also states that in patients with a World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 1 or of 0 who have had pelvic irradiation, treatment should be started at a dose of 280\xa0mg/m2; in the absence of any haematological toxicity during the first cycle causing treatment delay or dose reduction, the dosage can be increased to 320\xa0mg/m2 every 3\xa0weeks for the subsequent cycles. The SPC states that monitoring of complete blood counts should be conducted before each treatment cycle, and that oral hydration and laxatives should be given during each cycle. Vinflunine is available in 50\xa0mg and 250\xa0mg vials, costing £212.50 and £1062.50 respectively (excluding VAT; 'British National Formulary' edition\xa064). The acquisition cost of vinflunine for an entire course of treatment is £9817.50, assuming an average of 4.2\xa0cycles, a dose of 287\xa0mg/m2 and a body surface area of 1.85\xa0m2 (see section 3.10). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of vinflunine and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe main evidence for the clinical effectiveness of vinflunine was from 1\xa0open-label, phase III, randomised controlled trial (study\xa0302, the registration trial) that compared vinflunine plus best supportive care with best supportive care alone in patients with advanced or metastatic transitional cell carcinoma of the urothelial tract whose disease had progressed after platinum-based chemotherapy. Results from 2\xa0open-label, single-arm, phase II studies (study\xa0202 and CA001) were also provided. The manufacturer's submission highlighted issues around using best supportive care alone as the control arm in study\xa0302. In particular, patients had to be fit enough to receive chemotherapy but willing to accept randomisation to best supportive care. The manufacturer stated that patients in the trial had a poorer prognosis, as indicated by the high percentage (approximately 74%) of patients with visceral involvement in both groups in the trial. The manufacturer also highlighted that there is currently no standard chemotherapy regimen for patients with advanced transitional cell carcinoma of the urothelial tract whose disease has progressed after a prior platinum-containing chemotherapy, and there is a lack of trial evidence of survival advantage from chemotherapy in this clinical situation. Therefore no standard active treatments were available to use as a control, and best supportive care was considered the most appropriate comparator for vinflunine.\n\nPatients were included in study\xa0302 if they had progressive disease after at least 2\xa0cycles of platinum-based first-line chemotherapy (or after 1\xa0cycle if there was clear evidence of disease progression at this point), an ECOG performance status of 0 or 1, and an estimated life expectancy of at least 12\xa0weeks. Previous systemic chemotherapy must have been stopped at least 30\xa0days before randomisation. Patients were excluded if they had received more than 1\xa0previous systemic chemotherapy for advanced or metastatic disease, or if they had been treated with neoadjuvant or adjuvant chemotherapy. Patients were randomised on a 2:1 basis to vinflunine plus best supportive care (hereafter called the vinflunine arm) or best supportive care alone (hereafter called the best supportive care arm). Patients in the vinflunine arm initially received 320\xa0mg/m2 every 21\xa0days via infusion, but the protocol was subsequently amended to allow a lower starting dose (280\xa0mg/m2) in patients at greater risk of haematological toxicity. Best supportive care included palliative radiotherapy, antibiotics, analgesics, corticosteroids and blood transfusions.\n\nA total of 370\xa0patients were enrolled into the study (253 in the vinflunine arm and 117 in the best supportive care arm). The median age of study participants was 64\xa0years, and 79% were male. Most baseline characteristics were similar across the 2\xa0treatment arms. However, a greater proportion of patients in the vinflunine arm had an ECOG performance status of 1 compared with the best supportive care arm (72% and 62% respectively) although this difference was not statistically significant. Cisplatin was the most common first-line platinum treatment and had been received by more patients in the best supportive care arm than in the vinflunine arm (73% and 65% respectively), although this difference was not statistically significant. More patients in the vinflunine arm than in the best supportive care arm had received carboplatin as first-line platinum treatment (30% and 20% respectively; p=0.044).\n\nStudy results were provided for 4\xa0study populations, only 2 of which are presented here: the intention-to-treat (ITT) population, which included all randomised patients, and the 'eligible ITT population'. The latter excluded 13\xa0patients who were found, upon retrospective review of the patient inclusion criteria, not to have progressive disease at the time of entry into the study, and who therefore should not have been randomised (4\xa0patients in the vinflunine arm and 9 in the best supportive care arm; 3 of the 4 excluded patients in the vinflunine arm and 6 of the 9 excluded patients in the best supportive care arm were also ineligible because they had received neoadjuvant or adjuvant chemotherapy). The primary outcome of study\xa0302 was median overall survival. For the ITT population, this was 6.9 months in the vinflunine arm compared with 4.6\xa0months in the best supportive care arm (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.69 to 1.12, p=0.2868). A pre-planned multivariate analysis, adjusting for a number of prognostic factors (performance status, visceral invasion, alkaline phosphatase, haemoglobin and prior pelvic irradiation), showed a statistically significant overall survival benefit for vinflunine (HR\xa00.77, 95% CI 0.61 to 0.98, p=0.036). For the eligible ITT population, median overall survival was 6.9\xa0months in the vinflunine arm and 4.3\xa0months in the best supportive care arm (HR 0.78, 95% CI 0.61 to 0.99, p=0.0403). An extended multivariate analysis was also done, adjusting for the same prognostic factors outlined above plus additional baseline characteristics such as age, sex and disease stage at diagnosis. This analysis also showed a statistically significant overall survival benefit for vinflunine (HR 0.68, 95% CI 0.52 to 0.88, p=0.0035).\n\nProgression-free survival for the ITT population was 3.0\xa0months in the vinflunine arm compared with 1.5\xa0months in the best supportive care arm (HR 0.68, 95% CI 0.54 to 0.86, p=0.0012). In the vinflunine arm, 46.5% of patients had stable disease after second-line treatment, 44.9% had progressive disease, and 8.6% had a partial or complete response. In the best supportive care arm, 27% of patients had stable disease, 73% had progressive disease, and none had a partial or complete response. These outcomes were not reported for the eligible ITT population. After disease progression, 29% of patients in the vinflunine arm and 34% of patients in the best supportive care arm received palliative chemotherapy; 60% of these re-treated patients received multi-agent chemotherapy.\n\nQuality of life was assessed using the cancer-specific European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire. This was done at study entry and at the end of cycles 1, 2, 4 and 6 for both arms. There were no statistically significant differences in overall EORTC QLQ-C30 global health status score between the 2\xa0arms (p=0.658).\n\nIn the 2 phase II, single-arm trials (study 202 and CA001), vinflunine was given every 21\xa0days at a dose of 320 or 280\xa0mg/m2. In study\xa0202 (n=58), the overall response rate (partial or complete response) was 18%, median progression-free survival was 3\xa0months (95% CI 2.4 to 3.8 months) and median overall survival was 6.6\xa0months (95% CI 4.8 to 7.6 months). In CA001 (n=151), the overall response rate was 14.6% (95% CI 9.4% to 21.2%), median progression-free survival was 2.8\xa0months (95% CI 2.6 to 3.8\xa0months) and median overall survival was 7.9\xa0months (95% CI 6.7 to 9.7\xa0months).\n\nThe most common adverse events (any grade) associated with vinflunine across the 3 phase II and phase III studies (n=450) were constipation (55%), nausea (41%), infusion-site reactions (28%), stomatitis/mucositis (27%) and vomiting (27%). Overall, there were 6\xa0deaths related to treatment (1.3%), of which 4 were a result of myelotoxicity. Four treatment-related deaths occurred in the vinflunine arm of study\xa0302. Grade 3 or 4 toxicities relating to neutropenia, anaemia and constipation occurred in 50%, 19% and 16% respectively of patients in the vinflunine arm of study\xa0302, compared with 1%, 8% and 1% of patients respectively in the best supportive care arm. Febrile neutropenia occurred in 6% of patients receiving vinflunine (none in the best supportive care arm).\n\nThe manufacturer submitted an economic analysis comparing vinflunine plus best supportive care with best supportive care alone. The manufacturer's model was similar to a Markov cohort model in that it included 3 health states: pre-progression, post-progression and dead. The model calculated the proportion of patients expected to be in each health state, based on the estimated survival curves for the eligible ITT population from study\xa0302. The model assumed that treatment is administered in cycles of 21\xa0days until disease progression, major toxicity or other reason for treatment discontinuation, or death (if occurring before progression). All patients are assumed to be in a pre-progression health state at model entry (baseline). Patients who experience disease progression are assumed to stop treatment with vinflunine and remain in the post-progression state until death. The cycle length of the model was 1\xa0day and the time horizon was 5\xa0years.\n\nCosts of vinflunine were based on the mean dose (287\xa0mg/m2), the mean body surface area (1.85\xa0m2) and the mean number of treatment cycles (4.2) in study\xa0302. Other treatment costs included administration for intravenous infusion every 21\xa0days in an outpatient setting, complete blood count before drug administration and constipation prophylaxis. Drug wastage was assumed to be zero in the base-case analysis. The total per-patient cost of treatment with vinflunine included in the model was £10,207. Costs for 3\xa0common adverse events were included in the model: constipation (£39; based on 1 GP consultation and 1\xa0pack of laxatives), febrile neutropenia resulting in hospitalisation (£3538; NHS HRG [healthcare resource group] costs) and abdominal pain resulting in hospitalisation (£557; NHS HRG costs).\n\nCosts for best supportive care were calculated for the pre-progression and post-progression health states. For the pre-progression health state, best supportive care included: home visits by a GP, community nurse, health home visitor and dietician, an oncologist follow-up visit (assumed to be the same for each treatment group) and palliative radiation therapy (which differed by treatment group). For the post-progression health state, best supportive care included home visits by a GP, community nurse, health home visitor and dietician, a non-consultant oncologist follow-up visit, hospice care, pain medication (assumed to be the same for each treatment group), and palliative radiation therapy and palliative chemotherapy (which differed by treatment group).\n\nThe pre-progression utility values used in the manufacturer's submission were based on responses to 1\xa0item from the EORTC QLQ-C30 questionnaire used in study\xa0302, which asked patients to rate their overall quality of life in the previous week. Responses were transformed to health-state utilities using a published regression model relating this measure to utility values from a time-trade-off analysis in a sample of US cancer patients and their relatives. Post-progression utility values were taken from a study reporting EQ-5D values in 1270\xa0terminally ill cancer patients with painful bone metastases or poor-prognosis non-small-cell lung cancer. Disutility values associated with treatment-related adverse events were not included in the model.\n\nIn the manufacturer's base case, the incremental cost-effectiveness ratio (ICER) for vinflunine plus best supportive care compared with best supportive care alone was £100,144 per quality-adjusted life year (QALY) gained (incremental cost of £13,071 and incremental benefit of 0.131 QALYs). The manufacturer's deterministic sensitivity analyses showed that vial price and pre-progression utility values had the greatest impact on the base-case ICER. When a vial price of £0 was used, the ICER was £27,478 per QALY gained. When a pre-progression utility of 0.4 was used (instead of 0.65), the ICER was £133,094 per QALY gained. The ICER was also sensitive to assumptions about the number of vinflunine treatment cycles (£70,233 per QALY gained when 3\xa0cycles were costed) and vial wastage (£121,095 per QALY gained when wastage was accounted for). The manufacturer's probabilistic sensitivity analysis suggested that vinflunine had a 6% probability of being cost effective at a threshold of £30,000 per QALY gained when compared with best supportive care alone.\n\nThe ERG considered the modelling approach and model structure used by the manufacturer to be appropriate and reasonable; however, it commented on a number of areas of uncertainty. The ERG stated that the modelled population reflected that of the pivotal trial (study\xa0302) but may not be representative of the majority of patients whose disease progresses after first-line therapy. This was because patients who had received prior neoadjuvant or adjuvant platinum-based chemotherapy had been excluded from the trial. The ERG commented that best supportive care may not be the most appropriate comparator because alternative second-line treatments are available in UK clinical practice. However, the ERG noted that best supportive care was the comparator specified in the scope for the appraisal, and that there are no randomised controlled trials of relevant comparators for the population of interest. The ERG stated that data from the ITT population of study\xa0302 may have been a more appropriate basis for the economic model than the data from the eligible ITT population that were used by the manufacturer. It also stated that the utility values used did not fit with the preferred NICE reference case, and that there is considerable uncertainty around these estimates because standard methods were not used. The ERG also compared the overall survival curve for vinflunine used in the manufacturer's economic model with that obtained using Kaplan–Meier estimates. It concluded that the most realistic results were those obtained using the Kaplan–Meier estimates, although it noted that the choice of survival curve did not have a significant impact on the cost effectiveness of vinflunine in the manufacturer's sensitivity analysis.\n\nThe ERG conducted an exploratory analysis using the confidence intervals around the modelled estimates of overall survival and progression-free survival. This resulted in ICERs ranging from £87,871 to £117,938 per QALY gained. In a separate exploratory analysis the ERG used estimates of progression-free survival and overall survival from the ITT population of study\xa0302 (rather than the eligible ITT population) and corrected an error in the manufacturer's model in which the vinflunine vial cost was entered incorrectly. The resulting ICER was £99,792 per QALY gained when the manufacturer's method of estimating survival was used, and £126,422 per QALY gained when Kaplan–Meier estimates based on trial data for the ITT population were used.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of vinflunine, having considered evidence on the nature of transitional cell carcinoma of the urothelial tract and the value placed on the benefits of vinflunine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered current UK practice for the treatment of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. It heard from clinical specialists that patients with localised muscle-invasive disease who are fit enough usually undergo either radical surgery (frequently preceded by neoadjuvant chemotherapy) or radical radiotherapy with concurrent chemotherapy. For patients whose disease progresses after radical treatment, platinum-based chemotherapy may be given to improve survival and quality of life. The clinical specialists stated that there is currently no standard treatment for patients whose disease relapses after first-line chemotherapy for advanced disease and who are fit enough to receive further treatment, although a number of agents may be used. They commented that there is general agreement that this patient group can benefit from second-line treatment, particularly if their disease has shown a good response to previous chemotherapy, and therefore would not usually receive palliative care alone. The clinical specialists stated that there was no comparative evidence on the use of any agents for the second-line chemotherapy of advanced or metastatic transitional cell carcinoma of the urothelial tract and that studies in this setting would be welcomed. The Committee was aware that the lack of research on second-line treatments for advanced or metastatic transitional cell carcinoma of the urothelial tract meant there was a significant unmet need for evidence on the treatment of patients whose disease has progressed after platinum-based chemotherapy. It welcomed study\xa0302 as the first randomised controlled trial of a second-line treatment for advanced or metastatic transitional cell carcinoma of the urothelial tract.\n\n# Clinical effectiveness\n\nThe Committee considered the clinical evidence on the use of vinflunine for the second-line chemotherapy of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. It noted there was only 1\xa0randomised clinical trial (study\xa0302), and that this compared vinflunine with best supportive care alone. The Committee was aware that best supportive care was the only comparator listed in the scope for the appraisal. It was also aware that there are no proven standard agents for second-line chemotherapy (see section 4.2). For these reasons, the Committee concluded that best supportive care was the appropriate comparator for vinflunine.\n\nThe Committee discussed whether the population in study\xa0302 was representative of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract who would receive vinflunine in UK clinical practice. It heard from the clinical specialists that the study population was younger, fitter and had better renal function than the general population of UK patients with advanced or metastatic transitional cell carcinoma of the urothelial tract. The Committee was also aware that neoadjuvant chemotherapy, adjuvant chemotherapy and concurrent chemotherapy and radiotherapy are all used as part of radical treatment for localised muscle-invasive transitional cell carcinoma of the urothelial tract. The Committee noted that patients treated in this way had been excluded from study\xa0302. The Committee heard from the clinical specialists that many patients in the UK who are eligible to receive second-line palliative chemotherapy will already have received 2\xa0lines of treatment (that is, neoadjuvant chemotherapy, adjuvant chemotherapy or concurrent chemotherapy and radiotherapy, plus first-line palliative chemotherapy). Finally, the Committee noted that the manufacturer considered the trial population to be only people with a poor prognosis. The Committee understood that this was because 74% of people in the trial had visceral involvement, and because it was unlikely that people with a better prognosis would be willing to be randomised to a trial in which one of the treatment options was best supportive care. The Committee noted that the marketing authorisation for vinflunine is for all patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen. The manufacturer was invited to submit further evidence for vinflunine in the whole licensed patient population compared with best supportive care, but no data were submitted for the Committee to consider. The Committee considered whether the evidence from study\xa0302 might be generalisable to the full licensed population. It was mindful of clinical specialists' comments regarding the differences in the characteristics and treatment pathway of patients in the trial compared with patients in UK clinical practice. The Committee was not persuaded that the evidence for the effectiveness of vinflunine would be generalisable to the whole population who might receive vinflunine in UK clinical practice, compared with best supportive care. However the Committee was aware that study\xa0302 was the only available evidence on which a decision could be based. The Committee concluded that the nature and availability of the evidence base would result in significant uncertainty regarding the effectiveness of vinflunine for the whole licensed population compared with best supportive care.\n\nThe Committee discussed the results of study\xa0302. It noted that vinflunine was associated with improved progression-free survival and a higher disease control rate (defined as the percentage of patients with a complete response, a partial response or stable disease) compared with best supportive care alone. The Committee also noted that the difference in overall survival between the study arms was not statistically significant for the ITT population, but was significant for the eligible ITT population. The Committee was aware that the difference between the 2\xa0analyses resulted from the exclusion of 13\xa0patients from the ITT analysis because they had not been shown to have progressive disease after prior therapy. A greater proportion of ineligible patients came from the best supportive care arm than from the vinflunine arm (8% versus 2%) and this lowered the overall survival in the best supportive care arm in the eligible ITT analysis. The Committee considered that the results from the ITT population were the most appropriate basis for its deliberations because randomisation had not been broken. It also noted that there were no significant differences in health-related quality of life between patients receiving vinflunine and those receiving best supportive care alone. The Committee concluded that the extent of the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated because of the uncertainty in the overall survival results.\n\nThe Committee discussed the most common adverse events associated with vinflunine, namely constipation, anaemia, stomatitis and infusion-site reactions. It noted that grade 3 or 4 constipation occurred in 16% of patients receiving vinflunine. It was aware that grade 4 constipation can lead to intestinal obstruction or acute abdominal distension requiring hospitalisation. The Committee also noted the 6% incidence of febrile neutropenia in the vinflunine arm of the study. The clinical specialists stated that the safety profile of second-line chemotherapy in this setting needed to be predictable, acceptable to patients and manageable, and that they had concerns about vinflunine in this regard. The Committee concluded that there were concerns about the tolerability of vinflunine.\n\n# Cost effectiveness\n\nThe Committee reviewed the economic model submitted by the manufacturer and the ERG's critique of the model. The Committee was aware that the costs for the intravenous administration of vinflunine included in the manufacturer's model were based on out-of-date NHS HRG figures which were lower than current estimates. The Committee considered the manufacturer's lack of inclusion of vial wastage in the model to be inappropriate because of the small number of patients who would be treated with vinflunine at any one centre and time. The Committee concluded that the costs of treatment with vinflunine had been underestimated in the manufacturer's model.\n\nThe Committee discussed the utility values used in the manufacturer's model. It noted that different methods of estimating utilities were used for the post-progression and pre-progression health states. It noted that the utility for the post-progression health state was taken from a study of patients with lung cancer. The pre-progression utility was based on answers to 1 of the 30\xa0questions in the EORTC questionnaire, which asked patients to rate their overall quality of life during the past week. The questionnaire was administered at the end of each treatment cycle. The Committee noted clinical specialist opinion that quality of life varies considerably between 2 consecutive clinic visits. It therefore considered that this question may have to be interpreted with caution because a patient's quality of life in the last week of a treatment cycle may not reflect their quality of life for the whole period before disease progression. It also noted that established algorithms for mapping EORTC responses to EQ-5D exist but were not used by the manufacturer. The Committee noted that neither utility used in the economic model conformed to the preferred NICE reference case and concluded that the lack of appropriate utility data contributed to uncertainty in the model.\n\nThe Committee discussed the data on clinical effectiveness used in the model. It was aware that various hazard ratios of overall survival had been reported depending on the population analysed and the type of analysis used (multivariate analysis or extended multivariate analysis). The Committee noted that the modelled hazard ratios were based on the multivariate analysis of the results for the eligible ITT population and that these results were more favourable for vinflunine than those obtained from the ITT population. The Committee had previously concluded (see section\xa04.5) that the results from the ITT population were the most appropriate for this appraisal. It therefore concluded that the survival benefit of vinflunine compared with best supportive care alone was likely to be overestimated in the manufacturer's model.\n\nThe Committee discussed the inclusion of adverse events in the model and noted that although the costs of adverse events were included, the disutility associated with them was not. It discussed the costs for grade 3 and 4 constipation, and considered that these were likely to be significantly higher than the cost for constipation used in the model (£39).\n\nThe Committee discussed the manufacturer's base-case ICER of £100,100 per QALY gained (incremental cost of £13,100 and incremental QALYs of 0.131). It noted that in the manufacturer's sensitivity analyses the inclusion of vial wastage and the use of a lower pre-progression utility value increased the ICER significantly from the base case (to £121,100 and £133,100 per QALY gained respectively). It also noted that in the ERG's exploratory analysis, based on Kaplan–Meier estimates of survival from the ITT population rather than the eligible ITT population, the ICER was £126,400 per QALY gained. The Committee considered the most plausible ICER to be above £120,000 per QALY gained. It further considered that additional uncertainties around the costs of adverse events and the modelling of survival data would increase the ICER.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee considered that the life expectancy of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract whose disease has progressed after first-line chemotherapy is usually less than 6\xa0months. It discussed the number of UK patients for whom vinflunine is licensed, estimated by the manufacturer to be about 800–1500, and concluded that this could be considered a small patient population. The Committee discussed the extension to life offered by vinflunine in the study populations. In the manufacturer's model, the overall survival benefit of vinflunine was 3.2\xa0months. However, the overall survival benefit based on the trial results was 2.3\xa0months in the ITT population (not statistically significant) and 2.6\xa0months in the eligible ITT population. The Committee was not persuaded that an extension to life of at least 3\xa0months had been proven, and therefore concluded that the end-of-life advice did not apply to this appraisal. The Committee further noted that even if the end-of-life considerations were taken into account, the most plausible ICER for vinflunine compared with best supportive care (above £120,000 per QALY gained) was substantially higher than would normally be considered cost effective. The Committee was mindful of the limitations of the evidence base for vinflunine in the whole licensed population of patients who may receive treatment with vinflunine in UK clinical practice compared with best supportive care. However, the Committee was conscious of uncertainty in the overall survival results for vinflunine from the available evidence (see section 4.5), and the exceptionally high ICER which was based on this evidence. On balance, the Committee did not consider it plausible that additional evidence, even if available, would demonstrate the magnitude of survival gain which would be required to bring the cost effectiveness of vinflunine to a level considered an acceptable use of NHS resources. Therefore the Committee concluded that vinflunine could not be considered a cost-effective use of NHS resources for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA272\n\n\n\nAppraisal title: Vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract\n\nSection\n\nKey conclusion\n\nVinflunine is not recommended within its marketing authorisation for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy.\n\nThe Committee considered that the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated.\n\nThe Committee agreed that the most plausible ICER was above £120,000 per QALY gained and also noted the large incremental costs of £13,100 for 0.131 QALY gain. The Committee was not persuaded that an extension to life of at least 3 months had been proven, and therefore concluded that the end-of-life advice did not apply to this appraisal. The Committee concluded that vinflunine could not be considered a cost-effective use of NHS resources.\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe clinical specialists stated that there is currently no standard treatment for patients whose disease relapses after first-line chemotherapy and who are fit enough to receive further treatment, although a number of agents may be used.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\n\n\n\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe clinical specialists stated that there is currently no standard treatment for patients whose disease relapses after first-line chemotherapy and who are fit enough to receive further treatment, although a number of agents may be used.\n\n\n\nVinflunine is the only treatment licensed for use for advanced or metastatic transitional cell carcinoma of the urothelial tract that has progressed after treatment with platinum-based chemotherapy.\n\n\n\nThe Committee concluded that the extent of clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated because of the uncertainty of the overall survival results.\n\n, 4.5\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee were aware that vinflunine is licensed as a second-line therapy following prior platinum-based chemotherapy.\n\n\n\nAdverse effects\n\nThe Committee discussed the most common adverse events associated with vinflunine, namely constipation, anaemia, stomatitis and infusion-site reactions. It noted that grade 3 or 4 constipation occurred in 16% of patients receiving vinflunine. The Committee concluded that there were concerns about the tolerability of vinflunine.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted there was only 1 randomised clinical trial (study 302), and that this compared vinflunine with best supportive care alone.\n\n\n\nThe Committee noted that no data were available for people in the whole licensed population for vinflunine with a better prognosis than the trial population. The Committee was mindful of the clinical specialists' comments regarding the differences in the characteristics and treatment pathway of patients in the trial compared with patients in UK clinical practice. The Committee was not persuaded that the evidence for the effectiveness of vinflunine would be generalisable to the whole population who might receive vinflunine in UK clinical practice compared with best supportive care. The Committee concluded that the nature and availability of the evidence would result in significant uncertainty regarding the effectiveness of vinflunine for the whole licensed population compared with best supportive care.\n\n\n\nThe Committee noted that the difference in overall survival between the study arms was not statistically significant for the ITT population, but was significant for the eligible ITT population. It concluded that the extent of the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated.\n\n, 4.4, 4.5\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard from the clinical specialists that the study population was younger, fitter and had better renal function than the general population of UK patients with advanced or metastatic transitional cell carcinoma of the urothelial tract.\n\n\n\nThe Committee heard from the clinical specialists that many patients in the UK who are eligible to receive second-line palliative chemotherapy will already have received 2\xa0lines of treatment (that is, neoadjuvant chemotherapy, adjuvant chemotherapy or concurrent chemotherapy and radiotherapy, plus first-line palliative chemotherapy). Study 302 excluded patients who had had adjuvant or neoadjuvant chemotherapy.\n\n\n\nThe Committee was not persuaded that the evidence for the effectiveness of vinflunine would be generalisable to the whole population who might receive vinflunine in UK clinical practice compared with best supportive care.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted that the difference in overall survival between the study arms was not statistically significant for the ITT population, but was significant for the eligible ITT population.\n\n\n\nThe Committee concluded that the extent of the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo relevant subgroups were identified in this appraisal.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that the extent of the clinical effectiveness of vinflunine compared with best supportive care had not been conclusively demonstrated.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered evidence on the cost effectiveness of vinflunine compared with best supportive care, including quality-of-life estimates, costs and ICERs presented by the manufacturer.\n\nto 4.11\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the modelled hazard ratios of overall survival were based on the multivariate analysis of the results for the eligible ITT population and that these results were more favourable for vinflunine than those obtained from the ITT population.\n\n\n\nThe Committee was aware that the costs for the intravenous administration of vinflunine included in the manufacturer's model were based on out-of-date NHS HRG figures which were lower than current estimates.\n\n\n\nThe Committee considered the manufacturer's lack of inclusion of vial wastage in the model to be inappropriate because of the small number of patients who would be treated with vinflunine at any one centre and time.\n\n, 4.9\n\nIncorporation of health-related quality-of-life benefits and utility values\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that the pre-progression utility was based on answers to 1 of the 30\xa0questions in the EORTC questionnaire, which asked patients to rate their overall quality of life during the past week.\n\n\n\nThe Committee considered that this question may have to be interpreted with caution because a patient's quality of life in the last week of a treatment cycle may not reflect their quality of life for the whole period before disease progression.\n\n\n\nIt also noted that established algorithms for mapping EORTC responses to EQ-5D exist but were not used by the manufacturer.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo subgroups were identified in this appraisal.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted the large incremental costs of £13,100 for 0.131 QALY gain.\n\n\n\nThe Committee noted that in the manufacturer's sensitivity analyses the inclusion of vial wastage and the use of a lower pre-progression utility value increased the ICER significantly from the base case (to £121,100 and £133,100 per QALY gained respectively). It also noted that in the ERG's exploratory analysis, based on Kaplan–Meier estimates of survival from the ITT population rather than the eligible ITT population, the ICER was £126,400 per QALY gained.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee agreed that the most plausible estimate of the ICER for vinflunine plus best supportive care compared with best supportive care alone was above £120,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable to this appraisal.\n\n–\n\nEnd-of-life considerations\n\nThe Committee considered that the life expectancy of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract whose disease has progressed after first-line chemotherapy is usually less than 6 months.\n\nIt discussed the number of UK patients for whom vinflunine is licensed and concluded that this could be considered a small patient population.\n\nHowever, the Committee was not persuaded that an extension to life of at least 3 months had been proven, and therefore concluded that the end-of-life advice did not apply to this appraisal.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were raised during the scoping exercise or through the course of this appraisal.\n\n–", 'Recommendations for further research': 'The Committee noted the need for research on second-line treatments for transitional cell carcinoma of the urothelial tract. It noted that the vinflunine studies were the only studies in patients with transitional cell carcinoma of the urothelial tract whose disease had progressed after platinum-based chemotherapy. The Committee noted the lack of evidence for the relative effectiveness of treatment options at this stage in the pathway of care. It recommended that studies be undertaken to investigate the relative safety and efficacy of second-line treatments for transitional cell carcinoma of the urothelial tract, particularly randomised controlled trials.', 'Related NICE guidance': 'Published\n\nLaparoscopic cystectomy. NICE interventional procedure guidance 287 (2009).\n\nImproving outcomes in urological cancers. NICE cancer service guidance (2002).\n\nIn development\n\nDiagnosis and management of bladder cancer. NICE clinical guideline. Publication expected September 2014.', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in November 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJanuary 2013', 'Changes after publication': 'January 2014:\n minor maintenance.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta272	Evidence-based recommendations on vinflunine (Javlor) for treating advanced transitional cell carcinoma of the urothelial tract in adults.
a80a50fd14262ea4c9e8dde45d66037fec1904bd	nice	Tadalafil for the treatment of symptoms associated with benign prostatic hyperplasia (terminated appraisal)	Tadalafil for the treatment of symptoms associated with benign prostatic hyperplasia (terminated appraisal) # Background The manufacturer of tadalafil (Lilly) was invited to submit evidence for this single technology appraisal in August 2012. In September 2012, the manufacturer informed NICE that it would not be making an evidence submission for the appraisal of tadalafil for the treatment of benign prostatic hyperplasia. The manufacturer stated that there is insufficient evidence available to be able to undertake the appropriate analysis required to estimate the cost effectiveness of tadalafil within the defined treatment pathway outlined in Lower urinary tract symptoms: the management of lower urinary tract symptoms in men (NICE clinical guideline 97). NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of tadalafil for the treatment of symptoms associated with benign prostatic hyperplasia. If, after doing this, organisations still wish to consider tadalafil for the treatment of symptoms associated with benign prostatic hyperplasia, they should follow the advice set out in Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable. NICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission. # Related NICE guidance For information about NICE guidance that has been issued or is in development, see the NICE website. Lower urinary tract symptoms: the management of lower urinary tract symptoms in men. NICE clinical guideline 97 (2010). Referral guidelines for suspected cancer in adults and children. NICE clinical guideline 27 (2005). Laparoscopic prostatectomy for benign prostatic obstruction. NICE interventional procedure guidance 275 (2008).	{'Background': 'The manufacturer of tadalafil (Lilly) was invited to submit evidence for this single technology appraisal in August 2012.\n\nIn September 2012, the manufacturer informed NICE that it would not be making an evidence submission for the appraisal of tadalafil for the treatment of benign prostatic hyperplasia. The manufacturer stated that there is insufficient evidence available to be able to undertake the appropriate analysis required to estimate the cost effectiveness of tadalafil within the defined treatment pathway outlined in Lower urinary tract symptoms: the management of lower urinary tract symptoms in men (NICE clinical guideline 97).\n\nNICE has therefore terminated this single technology appraisal.', 'Information': 'NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of tadalafil for the treatment of symptoms associated with benign prostatic hyperplasia. If, after doing this, organisations still wish to consider tadalafil for the treatment of symptoms associated with benign prostatic hyperplasia, they should follow the advice set out in Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable.\n\nNICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission.\n\n# Related NICE guidance\n\nFor information about NICE guidance that has been issued or is in development, see the NICE website.\n\nLower urinary tract symptoms: the management of lower urinary tract symptoms in men. NICE clinical guideline 97 (2010).\n\nReferral guidelines for suspected cancer in adults and children. NICE clinical guideline 27 (2005).\n\nLaparoscopic prostatectomy for benign prostatic obstruction. NICE interventional procedure guidance 275 (2008).'}	https://www.nice.org.uk/guidance/ta273
8370806ac3cec8fed4c0c5e4ecbea82f21f325c1	nice	Percutaneous pulmonary valve implantation for right ventricular outflow tract dysfunction	Percutaneous pulmonary valve implantation for right ventricular outflow tract dysfunction # Guidance This document replaces previous guidance on percutaneous pulmonary valve implantation for right ventricular outflow tract dysfunction (interventional procedure guidance 237). The evidence on percutaneous pulmonary valve implantation (PPVI) for right ventricular outflow tract (RVOT) dysfunction shows good short-term efficacy. There is little evidence on long-term efficacy but it is well documented that these valves may need to be replaced in the longer term. With regard to safety there are well-recognised complications, particularly stent fractures in the longer term, which may or may not have clinical effects. Patients having this procedure are often very unwell and might otherwise need open heart surgery (typically reoperative) with its associated risks. Therefore, this procedure may be used with normal arrangements for clinical governance, consent and audit. The procedure should be performed only in specialist units and with arrangements in place for cardiac surgical support in the event of complications. Patient selection should be carried out by a multidisciplinary team including a cardiologist with a special interest in congenital heart disease, an interventional cardiologist and a cardiothoracic surgeon with a special interest in congenital heart disease. This is a technically challenging procedure that should be performed only by clinicians with training and experience in interventional cardiology and congenital heart disease. Clinicians should enter details about all patients undergoing PPVI for RVOT dysfunction onto the UK Central Cardiac Audit Database (UK CCAD). They should audit and review clinical outcomes locally, and in particular collect information on long-term outcomes.# The procedure # Indications and current treatments RVOT dysfunction often occurs as part of complex congenital heart conditions, such as tetralogy of Fallot. It may take the form of pulmonary valve stenosis, pulmonary valve incompetence (regurgitation) or both. Depending on the severity of the condition and associated structural abnormalities of the heart, RVOT dysfunction causes varying degrees of right ventricular hypertrophy and right heart failure. If left untreated, it can be a life-limiting condition. Reconstruction of the RVOT, done as part of surgery for congenital heart disease, is likely to need revision in the long term as a result of growth of the child and/or degeneration of any replacement valve. Normally, revision involves repeat surgery with replacement of the RVOT and/or any previously placed conduit. PPVI is an interim alternative to surgery for some patients. This approach is usually used for patients who have had a previous RVOT conduit or valve replacement. Many of the patients with this condition are adolescents or young adults, who may need multiple valve replacement procedures during their lifetime. # Outline of the procedure The aim of PPVI is to provide a less invasive intervention than open heart surgery to improve pulmonary valve function and circulation to the lungs while reducing pressure in the right ventricle. The treatment strategy may be to delay the need for further surgical revision. The procedure is done with the patient under general anaesthesia. PPVI is done by inserting a catheter system through a large vein (typically the femoral vein). Angiography is used to identify the anatomy of the RVOT and its relation to coronary arteries. A stent-mounted valve is introduced over a guidewire and is positioned in the RVOT, under fluoroscopic guidance. A balloon is then inflated to deploy the valve. Sometimes a plain stent is inserted first to dilate the RVOT and provide a regular surface onto which the stent-mounted valve can be fixed. This may decrease the risk of stent fracture, and thereby increase the longevity of the valve. The procedure can be repeated if necessary. Most valves used in this procedure are derived from animal sources. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised comparative study of 108 patients, 54 treated by PPVI alone and 54 treated by pre-stenting followed by PPVI, reported a significant decrease in mean right ventricular systolic pressure from 57 to 42 mmHg for patients treated by PPVI only (n=52) (p<0.0001) and from 65 to 41 mmHg for pre-stenting followed by PPVI (n=54) (p<0.0001) at 1-year follow-up (p=0.02 between groups). In a case series of 155 patients, there was a significant reduction in mean right ventricular systolic pressure from 63 to 45 mmHg (p<0.001) and RVOT gradient from 37 to 17 mmHg 'after the procedure' (no further details) (p<0.001). In a case series of 102 patients, pulmonary regurgitation (assessed by magnetic resonance imaging) significantly decreased from a median of 16% to 1% 'after the procedure' (p<0.001). In a case series of 36 patients, the percentage of patients with a New York Heart Association (NYHA) functional status of I (no limitation of physical activity) increased from 15% (5/33) at baseline to 82% (27/33) at 6-month follow-up and patients with NYHA functional status IV (inability to carry out any physical activity without physical discomfort) decreased from 6% at baseline to 0% at 6-month follow-up (absolute figures not reported). In a case series of 28 patients, cardiopulmonary exercise testing showed that the oxygen uptake (peak VO2) improved from 24 ml/kg/minute before treatment with PPVI (n=24) to 28 ml/kg/minute at median 6-month follow-up (n=19, p<0.0001). In the case series of 155 patients, 93%, 86%, 84% and 70% of patients did not need to have further surgery and 95%, 87%, 73% and 73% did not need any further transcatheter reintervention at 10, 30, 50 and 70 months respectively (absolute figures not reported). The Specialist Advisers listed the following additional efficacy outcomes: reduced pulmonary incompetence, avoiding a sternotomy incision and cardiopulmonary bypass, and shorter recovery time with less risk of postoperative infection and bleeding. # Safety Death was reported in 4% (2/54) of patients treated by PPVI alone and in 4% (2/54) of patients treated by pre-stenting followed by PPVI in the non-randomised comparative study of 108 patients (1 death was within 30 days because of pulmonary oedema). In patients treated by PPVI alone, 1 patient died after a chest infection 2 months after the procedure and 1 patient with pulmonary hypertension died after 'presumed' arrhythmia 24 months after the procedure. In patients treated by pre-stenting followed by PPVI, 1 patient died because of pulmonary oedema 1 day after the procedure (as noted above) and 1 patient died because of 'presumed' arrhythmia 8 months after the procedure. Death within 30 days was reported in less than 1% of patients (1/136) in a case series of 136 patients. The patient had coronary artery dissection and intracranial haemorrhage. Bacterial endocarditis was reported in 1 patient in the case series of 102 patients. The valve was surgically removed and replaced by a homograft valve 6 months after the procedure. One patient developed endocarditis in a case series of 20 patients and the valve was explanted at 6 months. Stent fractures were reported in 29% (15/52) of patients treated by PPVI alone and in 17% (9/52) of patients treated by pre-stenting followed by PPVI at 1-year follow-up in the non-randomised comparative study of 108 patients. Stent fractures occurred in 21% (absolute figures not reported) of patients in the case series of 155 patients. Nine patients had required reintervention (further details not reported) by median 28-month follow-up. Valve migration was reported in 9% (3/34) of patients in the case series of 36 patients. Two patients were treated by surgical pulmonary valve replacement. Valve migration during the procedure was reported in 1 patient who was treated by a further implantation during the same procedure (no further details reported). Conduit rupture/tear (no further details) was reported in 2 patients in the case series of 136 patients at 6-month follow-up. One patient was treated by replacement conduit and the other by covered stent placement. The valve had to be removed in 4% (2/54) of patients treated by PPVI alone in the non-randomised comparative study of 108 patients. This was because of RVOT pseudoaneurysm in 1 patient (at 16 months) and endocarditis in 1 patient (at 19 months). Complete atrioventricular block occurred in 1 patient during the procedure in the case series of 102 patients; the patient's heart rate reverted to sinus rhythm after 21 days. The Specialist Advisers listed the following theoretical adverse events: pulmonary artery dissection and rupture, perforation of the heart, embolisation of the device, bleeding from the cannulation site, and vascular perforation. # Other comments The Committee noted that the ages of the patients in the published studies varied. The number of previous procedures patients had undergone was often unclear: this may have influenced the outcomes of PPVI. The Committee noted apparent duplication of patients in published studies. The Committee recognised that stent fracture is a risk in the longer term and this underpinned the recommendation for continued data collection about long-term outcomes. It noted that devices continue to evolve and that developments in their design may have influenced long-term performance.# Further information This guidance is a review of 'Percutaneous pulmonary valve implantation for right ventricular outflow tract dysfunction' (NICE interventional procedure guidance 237). For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. It updates and replaces NICE interventional procedure guidance 237. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on percutaneous pulmonary valve implantation for right ventricular outflow tract dysfunction (interventional procedure guidance 237).\n\nThe evidence on percutaneous pulmonary valve implantation (PPVI) for right ventricular outflow tract (RVOT) dysfunction shows good short-term efficacy. There is little evidence on long-term efficacy but it is well documented that these valves may need to be replaced in the longer term. With regard to safety there are well-recognised complications, particularly stent fractures in the longer term, which may or may not have clinical effects. Patients having this procedure are often very unwell and might otherwise need open heart surgery (typically reoperative) with its associated risks. Therefore, this procedure may be used with normal arrangements for clinical governance, consent and audit.\n\nThe procedure should be performed only in specialist units and with arrangements in place for cardiac surgical support in the event of complications.\n\nPatient selection should be carried out by a multidisciplinary team including a cardiologist with a special interest in congenital heart disease, an interventional cardiologist and a cardiothoracic surgeon with a special interest in congenital heart disease.\n\nThis is a technically challenging procedure that should be performed only by clinicians with training and experience in interventional cardiology and congenital heart disease.\n\nClinicians should enter details about all patients undergoing PPVI for RVOT dysfunction onto the UK Central Cardiac Audit Database (UK CCAD). They should audit and review clinical outcomes locally, and in particular collect information on long-term outcomes.', 'The procedure': "# Indications and current treatments\n\nRVOT dysfunction often occurs as part of complex congenital heart conditions, such as tetralogy of Fallot. It may take the form of pulmonary valve stenosis, pulmonary valve incompetence (regurgitation) or both. Depending on the severity of the condition and associated structural abnormalities of the heart, RVOT dysfunction causes varying degrees of right ventricular hypertrophy and right heart failure. If left untreated, it can be a life-limiting condition.\n\nReconstruction of the RVOT, done as part of surgery for congenital heart disease, is likely to need revision in the long term as a result of growth of the child and/or degeneration of any replacement valve. Normally, revision involves repeat surgery with replacement of the RVOT and/or any previously placed conduit.\n\nPPVI is an interim alternative to surgery for some patients. This approach is usually used for patients who have had a previous RVOT conduit or valve replacement. Many of the patients with this condition are adolescents or young adults, who may need multiple valve replacement procedures during their lifetime.\n\n# Outline of the procedure\n\nThe aim of PPVI is to provide a less invasive intervention than open heart surgery to improve pulmonary valve function and circulation to the lungs while reducing pressure in the right ventricle. The treatment strategy may be to delay the need for further surgical revision.\n\nThe procedure is done with the patient under general anaesthesia. PPVI is done by inserting a catheter system through a large vein (typically the femoral vein). Angiography is used to identify the anatomy of the RVOT and its relation to coronary arteries. A stent-mounted valve is introduced over a guidewire and is positioned in the RVOT, under fluoroscopic guidance. A balloon is then inflated to deploy the valve. Sometimes a plain stent is inserted first to dilate the RVOT and provide a regular surface onto which the stent-mounted valve can be fixed. This may decrease the risk of stent fracture, and thereby increase the longevity of the valve. The procedure can be repeated if necessary.\n\nMost valves used in this procedure are derived from animal sources.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 108\xa0patients, 54\xa0treated by PPVI alone and 54\xa0treated by pre-stenting followed by PPVI, reported a significant decrease in mean right ventricular systolic pressure from 57 to 42\xa0mmHg for patients treated by PPVI only (n=52) (p<0.0001) and from 65 to 41\xa0mmHg for pre-stenting followed by PPVI (n=54) (p<0.0001) at 1-year follow-up (p=0.02 between groups).\n\nIn a case series of 155\xa0patients, there was a significant reduction in mean right ventricular systolic pressure from 63 to 45\xa0mmHg (p<0.001) and RVOT gradient from 37 to 17\xa0mmHg 'after the procedure' (no further details) (p<0.001).\n\nIn a case series of 102\xa0patients, pulmonary regurgitation (assessed by magnetic resonance imaging) significantly decreased from a median of 16% to 1% 'after the procedure' (p<0.001).\n\nIn a case series of 36\xa0patients, the percentage of patients with a New York Heart Association (NYHA) functional status of I (no limitation of physical activity) increased from 15% (5/33) at baseline to 82% (27/33) at 6-month follow-up and patients with NYHA functional status IV (inability to carry out any physical activity without physical discomfort) decreased from 6% at baseline to 0% at 6-month follow-up (absolute figures not reported).\n\nIn a case series of 28\xa0patients, cardiopulmonary exercise testing showed that the oxygen uptake (peak VO2) improved from 24\xa0ml/kg/minute before treatment with PPVI (n=24) to 28\xa0ml/kg/minute at median 6-month follow-up (n=19, p<0.0001).\n\nIn the case series of 155\xa0patients, 93%, 86%, 84% and 70% of patients did not need to have further surgery and 95%, 87%, 73% and 73% did not need any further transcatheter reintervention at 10, 30, 50 and 70\xa0months respectively (absolute figures not reported).\n\nThe Specialist Advisers listed the following additional efficacy outcomes: reduced pulmonary incompetence, avoiding a sternotomy incision and cardiopulmonary bypass, and shorter recovery time with less risk of postoperative infection and bleeding.\n\n# Safety\n\nDeath was reported in 4% (2/54) of patients treated by PPVI alone and in 4% (2/54) of patients treated by pre-stenting followed by PPVI in the non-randomised comparative study of 108\xa0patients (1\xa0death was within 30\xa0days because of pulmonary oedema). In patients treated by PPVI alone, 1\xa0patient died after a chest infection 2\xa0months after the procedure and 1\xa0patient with pulmonary hypertension died after 'presumed' arrhythmia 24\xa0months after the procedure. In patients treated by pre-stenting followed by PPVI, 1\xa0patient died because of pulmonary oedema 1\xa0day after the procedure (as noted above) and 1\xa0patient died because of 'presumed' arrhythmia 8\xa0months after the procedure. Death within 30\xa0days was reported in less than 1% of patients (1/136) in a case series of 136\xa0patients. The patient had coronary artery dissection and intracranial haemorrhage.\n\nBacterial endocarditis was reported in 1\xa0patient in the case series of 102\xa0patients. The valve was surgically removed and replaced by a homograft valve 6\xa0months after the procedure. One patient developed endocarditis in a case series of 20\xa0patients and the valve was explanted at 6\xa0months.\n\nStent fractures were reported in 29% (15/52) of patients treated by PPVI alone and in 17% (9/52) of patients treated by pre-stenting followed by PPVI at 1-year follow-up in the non-randomised comparative study of 108\xa0patients. Stent fractures occurred in 21% (absolute figures not reported) of patients in the case series of 155\xa0patients. Nine patients had required reintervention (further details not reported) by median 28-month follow-up.\n\nValve migration was reported in 9% (3/34) of patients in the case series of 36\xa0patients. Two patients were treated by surgical pulmonary valve replacement. Valve migration during the procedure was reported in 1\xa0patient who was treated by a further implantation during the same procedure (no further details reported).\n\nConduit rupture/tear (no further details) was reported in 2\xa0patients in the case series of 136\xa0patients at 6-month follow-up. One patient was treated by replacement conduit and the other by covered stent placement.\n\nThe valve had to be removed in 4% (2/54) of patients treated by PPVI alone in the non-randomised comparative study of 108\xa0patients. This was because of RVOT pseudoaneurysm in 1\xa0patient (at 16\xa0months) and endocarditis in 1\xa0patient (at 19\xa0months).\n\nComplete atrioventricular block occurred in 1\xa0patient during the procedure in the case series of 102\xa0patients; the patient's heart rate reverted to sinus rhythm after 21\xa0days.\n\nThe Specialist Advisers listed the following theoretical adverse events: pulmonary artery dissection and rupture, perforation of the heart, embolisation of the device, bleeding from the cannulation site, and vascular perforation.\n\n# Other comments\n\nThe Committee noted that the ages of the patients in the published studies varied. The number of previous procedures patients had undergone was often unclear: this may have influenced the outcomes of PPVI.\n\nThe Committee noted apparent duplication of patients in published studies.\n\nThe Committee recognised that stent fracture is a risk in the longer term and this underpinned the recommendation for continued data collection about long-term outcomes. It noted that devices continue to evolve and that developments in their design may have influenced long-term performance.", 'Further information': "This guidance is a review of 'Percutaneous pulmonary valve implantation for right ventricular outflow tract dysfunction' (NICE interventional procedure guidance 237).\n\nFor related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 237.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg436
dbd4ffea9cab32cf3b615cb252e19de56cf207b5	nice	Autologous blood injection for plantar fasciitis	Autologous blood injection for plantar fasciitis # Guidance The evidence on autologous blood injection for plantar fasciitis raises no major safety concerns. The evidence on efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake autologous blood injection for plantar fasciitis should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's efficacy, make them aware of alternative treatments and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having autologous blood injection for plantar fasciitis (see section 3.1). NICE encourages further research comparing autologous blood injection (with or without techniques to produce platelet-rich plasma) against established treatments for managing plantar fasciitis. Trials should clearly describe patient selection, including duration of symptoms and any prior treatments. Outcomes should include specific measures of pain and function.# The procedure # Indications and current treatments Plantar fasciitis is characterised by a painful inflammatory process involving the plantar fascia, causing pain on the underside of the heel. It is usually caused by overuse, injury or biomechanical abnormalities and may be associated with microtears, or fibrosis. It is usually a self-limiting condition. Conservative treatments include rest, analgesics, anti-inflammatory medication, use of orthotic devices, eccentric exercise, stretching and physiotherapy. Local injection of steroids, extracorporeal shockwave therapy and surgery to release the plantar fascia from the bone or to relieve muscular tightness are sometimes used for patients with refractory symptoms. # Outline of the procedure Autologous blood injection for plantar fasciitis is claimed to promote healing through the action of growth factors. It can be performed using either autologous whole blood or platelet-rich plasma. The latter aims to deliver a greater concentration of growth factors. A variable amount of blood is withdrawn from the patient by standard venesection. Sometimes the blood is centrifuged to produce a platelet-rich sample. About 2–3 ml of whole blood or platelet-rich plasma is injected into the plantar fascia, sometimes with ultrasound guidance. Local anaesthetic is usually used. 'Dry needling' (repeatedly passing a needle through the tissue to disrupt the fibres and induce bleeding) may be performed before injection of the blood. A 'peppering' technique is sometimes used to inject the autologous blood; this involves inserting the needle into the fascia, injecting some of the blood, withdrawing without emerging from the skin, slightly redirecting and reinserting. After the procedure, patients are usually advised to avoid high-impact activities for a few weeks, and to follow a programme of stretching exercises. The procedure may be repeated if needed. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial of 64 patients treated by autologous blood injection or corticosteroid injection reported that mean pain scores decreased from 7.3 and 6.9 at baseline to 3.6 and 2.4 respectively at 6 month follow-up (p<0.0001 for both groups; measured on a visual analogue scale from 0–10, with 0 indicating no pain and 10 the worst imaginable pain). The proportion of patients with no change in score was 10% in both groups (3/30 and 3/31 respectively). The mean tenderness threshold improved from 3.1 kg/cm2 at baseline to 6.5 kg/cm2 in the autologous blood injection group and from 3.7 kg/cm2 to 8.6 kg/cm2 in the corticosteroid group at 6 month follow-up (p<0.0001 for both groups). A randomised controlled trial of 45 patients treated by autologous blood injection, corticosteroid injection or peppering alone reported that mean pain scores reduced from 7.6, 7.3 and 6.4 at baseline to 2.4, 2.6 and 2.0 respectively at 6 month follow-up (p<0.001 for all groups; measured on a visual analogue scale from 0–10). The Rearfoot scores (scale 0–100 with higher scores indicating less pain and better function) improved from 72, 66 and 64 at baseline to 81, 80 and 78 respectively at 6 month follow-up (p=0.025, 0.030 and 0.018 respectively). There were no statistically significant differences between the groups. A non-randomised comparative trial of 100 patients treated by autologous blood injection, local anaesthetic with peppering, corticosteroid injection or corticosteroid injection with peppering reported an 'excellent' or 'good' outcome in 60% (15/25), 52% (13/25), 80% (20/25) and 88% (22/25) of patients respectively at 6 month follow-up (measured using a modified Roles and Maudsley scale, which measures pain and limitation of activity). There was a statistically significant difference between corticosteroid injection and autologous blood injection and local anaesthetic with peppering, with more successful outcomes in the corticosteroid groups (p<0.05). The randomised controlled trial of 45 patients treated by autologous blood injection, corticosteroid injection or peppering alone reported that 67% (10/15), 0% (0/14) and 47% (7/15) of patients respectively needed a third injection. The Specialist Advisers listed key efficacy outcomes as reduction in heel pain and improved function. # Safety The randomised controlled trial of 64 patients treated by autologous blood injection or corticosteroid injection reported that all patients found the procedure to be painful. After the procedure, pain needing analgesia, ice application or both was reported in 53% (16/30) and 13% (4/31) of patients respectively (p value not reported). The mean duration of symptoms was 7 days in the autologous blood injection group and 5 days in the corticosteroid injection group. A non-randomised comparative study of 60 patients treated by autologous blood injection or corticosteroid injection and a case series of 25 patients reported that there were no adverse events. The Specialist Advisers listed theoretical adverse events as rupture of the plantar fascia, local neurovascular damage, infection, and bruising. # Other comments The Committee noted that plantar fasciitis is normally a self-limiting condition, which introduces some uncertainty about the relative effect of interventions in the published studies. The comparators used in most of the studies were not useful in determining whether autologous blood injection for plantar fasciitis is efficacious. In addition, the procedure was often used in combination with other therapies. The Committee was advised that this procedure should only be considered for patients with refractory symptoms.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "The evidence on autologous blood injection for plantar fasciitis raises no major safety concerns. The evidence on efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake autologous blood injection for plantar fasciitis should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy, make them aware of alternative treatments and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having autologous blood injection for plantar fasciitis (see section 3.1).\n\nNICE encourages further research comparing autologous blood injection (with or without techniques to produce platelet-rich plasma) against established treatments for managing plantar fasciitis. Trials should clearly describe patient selection, including duration of symptoms and any prior treatments. Outcomes should include specific measures of pain and function.", 'The procedure': "# Indications and current treatments\n\nPlantar fasciitis is characterised by a painful inflammatory process involving the plantar fascia, causing pain on the underside of the heel. It is usually caused by overuse, injury or biomechanical abnormalities and may be associated with microtears, or fibrosis. It is usually a self-limiting condition.\n\nConservative treatments include rest, analgesics, anti-inflammatory medication, use of orthotic devices, eccentric exercise, stretching and physiotherapy. Local injection of steroids, extracorporeal shockwave therapy and surgery to release the plantar fascia from the bone or to relieve muscular tightness are sometimes used for patients with refractory symptoms.\n\n# Outline of the procedure\n\nAutologous blood injection for plantar fasciitis is claimed to promote healing through the action of growth factors. It can be performed using either autologous whole blood or platelet-rich plasma. The latter aims to deliver a greater concentration of growth factors.\n\nA variable amount of blood is withdrawn from the patient by standard venesection. Sometimes the blood is centrifuged to produce a platelet-rich sample. About 2–3\xa0ml of whole blood or platelet-rich plasma is injected into the plantar fascia, sometimes with ultrasound guidance. Local anaesthetic is usually used. 'Dry needling' (repeatedly passing a needle through the tissue to disrupt the fibres and induce bleeding) may be performed before injection of the blood. A 'peppering' technique is sometimes used to inject the autologous blood; this involves inserting the needle into the fascia, injecting some of the blood, withdrawing without emerging from the skin, slightly redirecting and reinserting. After the procedure, patients are usually advised to avoid high-impact activities for a few weeks, and to follow a programme of stretching exercises. The procedure may be repeated if needed.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial of 64\xa0patients treated by autologous blood injection or corticosteroid injection reported that mean pain scores decreased from 7.3 and 6.9 at baseline to 3.6 and 2.4 respectively at 6\xa0month follow-up (p<0.0001 for both groups; measured on a visual analogue scale from 0–10, with 0 indicating no pain and 10 the worst imaginable pain). The proportion of patients with no change in score was 10% in both groups (3/30 and 3/31 respectively). The mean tenderness threshold improved from 3.1\xa0kg/cm2 at baseline to 6.5\xa0kg/cm2 in the autologous blood injection group and from 3.7\xa0kg/cm2 to 8.6\xa0kg/cm2 in the corticosteroid group at 6\xa0month follow-up (p<0.0001 for both groups).\n\nA randomised controlled trial of 45\xa0patients treated by autologous blood injection, corticosteroid injection or peppering alone reported that mean pain scores reduced from 7.6, 7.3 and 6.4 at baseline to 2.4, 2.6 and 2.0 respectively at 6\xa0month follow-up (p<0.001 for all groups; measured on a visual analogue scale from 0–10). The Rearfoot scores (scale 0–100 with higher scores indicating less pain and better function) improved from 72, 66 and 64 at baseline to 81, 80 and 78 respectively at 6\xa0month follow-up (p=0.025, 0.030 and 0.018 respectively). There were no statistically significant differences between the groups.\n\nA non-randomised comparative trial of 100\xa0patients treated by autologous blood injection, local anaesthetic with peppering, corticosteroid injection or corticosteroid injection with peppering reported an 'excellent' or 'good' outcome in 60% (15/25), 52% (13/25), 80% (20/25) and 88% (22/25) of patients respectively at 6\xa0month follow-up (measured using a modified Roles and Maudsley scale, which measures pain and limitation of activity). There was a statistically significant difference between corticosteroid injection and autologous blood injection and local anaesthetic with peppering, with more successful outcomes in the corticosteroid groups (p<0.05).\n\nThe randomised controlled trial of 45\xa0patients treated by autologous blood injection, corticosteroid injection or peppering alone reported that 67% (10/15), 0% (0/14) and 47% (7/15) of patients respectively needed a third injection.\n\nThe Specialist Advisers listed key efficacy outcomes as reduction in heel pain and improved function.\n\n# Safety\n\nThe randomised controlled trial of 64\xa0patients treated by autologous blood injection or corticosteroid injection reported that all patients found the procedure to be painful. After the procedure, pain needing analgesia, ice application or both was reported in 53% (16/30) and 13% (4/31) of patients respectively (p value not reported). The mean duration of symptoms was 7\xa0days in the autologous blood injection group and 5\xa0days in the corticosteroid injection group.\n\nA non-randomised comparative study of 60\xa0patients treated by autologous blood injection or corticosteroid injection and a case series of 25\xa0patients reported that there were no adverse events.\n\nThe Specialist Advisers listed theoretical adverse events as rupture of the plantar fascia, local neurovascular damage, infection, and bruising.\n\n# Other comments\n\nThe Committee noted that plantar fasciitis is normally a self-limiting condition, which introduces some uncertainty about the relative effect of interventions in the published studies. The comparators used in most of the studies were not useful in determining whether autologous blood injection for plantar fasciitis is efficacious. In addition, the procedure was often used in combination with other therapies.\n\nThe Committee was advised that this procedure should only be considered for patients with refractory symptoms.", 'Further information': 'This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg437
fc10c1b31fb307a201c8359b1fee3612a75a0fc0	nice	Autologous blood injection for tendinopathy	Autologous blood injection for tendinopathy # Guidance This document replaces previous guidance on autologous blood injection for tendinopathy (interventional procedure guidance 279). The evidence on autologous blood injection for tendinopathy raises no major safety concerns. The evidence on efficacy remains inadequate, with few studies available that use appropriate comparators. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake autologous blood injection for tendinopathy should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's efficacy (especially in the long term), make them aware of alternative treatments and provide them with clear written information. In addition, use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having autologous blood injection for tendinopathy (see section 3.1). NICE encourages further research comparing autologous blood injections (with or without techniques to produce platelet-rich plasma) against established non-surgical methods for managing tendinopathy. Trials should clearly describe patient selection (including the site of tendinopathy, duration of symptoms and any prior treatments) and document whether a 'dry needling' technique is used. Outcomes should include specific measures of pain, quality of life and function, and whether subsequent surgical intervention is needed.# The procedure # Indications and current treatments 'Tendinopathy' describes a range of conditions that affect tendons, causing pain, weakness and stiffness. The symptoms are usually associated with overuse. Sites commonly involved are the extensor (elbow), Achilles (heel) and patellar (knee) tendons. Tendinopathy also has other names – for example, tendonosis and tendonitis – and it encapsulates a range of pathologies, including inflammatory, non-inflammatory and degenerative changes. Tendinopathy usually resolves over a period of several months. Conservative treatments include rest, analgesics, anti-inflammatory medication, use of orthotic devices, eccentric exercise and physiotherapy. Local injection of steroids, extracorporeal shockwave therapy, or sometimes surgery to release the tendon from the underlying bone or constricting surrounding tissues, can also be used. A period of rehabilitation is usually needed after any surgical intervention. # Outline of the procedure Autologous blood injection (using whole blood or platelet-rich plasma) is claimed to promote healing through the action of growth factors on the affected tendon. A variable amount of blood is withdrawn from the patient by standard venesection. Sometimes the blood is centrifuged to produce a platelet-rich sample. About 2–3 ml of whole blood or platelet-rich plasma is injected into and around the damaged tendon, sometimes with ultrasound guidance. Local anaesthetic is usually used. 'Dry needling' (repeatedly passing a needle through the tendon to disrupt the fibres and induce bleeding) may be performed before injection of the blood. A 'peppering' technique is sometimes used to inject the autologous blood; this involves inserting the needle into the tendon, injecting some of the blood, withdrawing without emerging from the skin, slightly redirecting and reinserting. After the procedure, patients are usually advised to avoid strenuous or excessive use of the tendon for a few weeks, after which physiotherapy is started. The procedure may be repeated if needed. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a randomised controlled trial (RCT) of 150 patients with tennis elbow, 70 were treated by autologous blood injection and 80 were treated by platelet-rich plasma injection. Technical success was defined as an improvement in patient-rated tennis elbow evaluation score of 25 points at final analysis; measured on a scale of 0–100, with a higher score indicating more pain and functional disability. Of those patients followed up at 6 months, technical success was reported in 72% (43/60) of patients treated by autologous blood injection and 66% (46/70) treated by platelet-rich plasma injection (p=0.59). In an RCT of 100 patients with tennis elbow, 51 were treated by platelet-rich plasma injection and 49 were treated by corticosteroid injection. Successful treatment was defined as a reduction of 25% on the visual analogue scale pain score (measured on a scale of 0–100, with a higher score indicating more pain) and no reintervention after 2 years. At 2-year follow-up, successful treatment was achieved in 76% (39/51) of patients treated by platelet-rich plasma injection and 43% (21/49) treated by corticosteroid injection (p<0.0001). In an RCT of 54 patients with Achilles tendinopathy, 27 were treated by platelet-rich plasma injection and 27 were treated by placebo injection. The mean difference on the Victorian Institute of Sports assessment – Achilles (VISA-A) scale (assessing the severity of Achilles tendinopathy on a scale of 0–100, with a lower score indicating higher severity) was not significant (6 points ) at 1-year follow-up (p value not reported). In the RCT of 100 patients with tennis elbow, 12% (6/51) of patients treated by platelet-rich plasma injection and 29% (14/49) of patients treated by corticosteroid injection needed further intervention within 2–14 months. Of those treated by platelet-rich plasma injection, 6% (3/51) had subsequent corticosteroid injections. Of those treated by corticosteroid injection, 16% (8/49) had subsequent corticosteroid or platelet-rich plasma injections. In the RCT of 54 patients with Achilles tendinopathy, 57% of the platelet-rich plasma group and 42% of the placebo group returned to their previous level of sporting activity (absolute figures not reported). The adjusted between-group difference for return to sports was 2% (95% CI −25 to 28) at 1-year follow-up. This difference was not significant (p=0.89). The Specialist Advisers listed key efficacy outcomes as pain relief and improved function. # Safety In a case series of 28 patients with tennis elbow, 7% (2/28) of patients needed narcotic analgesia because of pain after autologous blood injection. Most patients in this series reported that the pain was similar to the pain they had experienced after previous steroid injections into the tendon. Moderate pain and stiffness after the injections, which persisted for a few days, was reported in all patients in a case series of 20 patients with patellar tendinosis. One patient had more severe pain after the injection which took 3 weeks to resolve (no further information reported). The Specialist Advisers listed anecdotal adverse events to be increased pain, flare of pain, reduced functioning, and damage to surrounding tissues. Theoretical adverse events were considered to be tendon rupture, damage to the tendon and infection. # Other comments The Committee noted that autologous blood injection for tendinopathy can be performed using either autologous whole blood or platelet-rich plasma. The latter aims to deliver a greater concentration of growth factors. Studies comparing the use of whole blood and platelet-rich plasma did not demonstrate any substantial differences in efficacy. Therefore, the Committee considered it reasonable to evaluate the evidence on injection with either whole blood or platelet-rich plasma as equivalent treatments in this guidance. A number of RCTs have been published since this procedure was evaluated in 2009 (NICE interventional procedure guidance 279). However, the Committee considered that the comparators used in most of the studies were not useful in determining whether autologous blood injection for tendinopathy is efficacious. The Committee was advised that Achilles tendinopathy may respond differently to treatment compared with tendinopathy at other sites, so it may not be valid to extrapolate the findings of studies using this procedure to different sites. The Committee noted that some of the published studies involved the use of a 'dry needling' or 'peppering' technique before the injection of autologous blood, but it was not possible to differentiate between the effects of these variations to the procedure.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. It replaces NICE interventional procedure guidance 279. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "This document replaces previous guidance on autologous blood injection for tendinopathy (interventional procedure guidance 279).\n\nThe evidence on autologous blood injection for tendinopathy raises no major safety concerns. The evidence on efficacy remains inadequate, with few studies available that use appropriate comparators. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake autologous blood injection for tendinopathy should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy (especially in the long term), make them aware of alternative treatments and provide them with clear written information. In addition, use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having autologous blood injection for tendinopathy (see section 3.1).\n\nNICE encourages further research comparing autologous blood injections (with or without techniques to produce platelet-rich plasma) against established non-surgical methods for managing tendinopathy. Trials should clearly describe patient selection (including the site of tendinopathy, duration of symptoms and any prior treatments) and document whether a 'dry needling' technique is used. Outcomes should include specific measures of pain, quality of life and function, and whether subsequent surgical intervention is needed.", 'The procedure': "# Indications and current treatments\n\n'Tendinopathy' describes a range of conditions that affect tendons, causing pain, weakness and stiffness. The symptoms are usually associated with overuse. Sites commonly involved are the extensor (elbow), Achilles (heel) and patellar (knee) tendons. Tendinopathy also has other names – for example, tendonosis and tendonitis – and it encapsulates a range of pathologies, including inflammatory, non-inflammatory and degenerative changes.\n\nTendinopathy usually resolves over a period of several months. Conservative treatments include rest, analgesics, anti-inflammatory medication, use of orthotic devices, eccentric exercise and physiotherapy. Local injection of steroids, extracorporeal shockwave therapy, or sometimes surgery to release the tendon from the underlying bone or constricting surrounding tissues, can also be used. A period of rehabilitation is usually needed after any surgical intervention.\n\n# Outline of the procedure\n\nAutologous blood injection (using whole blood or platelet-rich plasma) is claimed to promote healing through the action of growth factors on the affected tendon.\n\nA variable amount of blood is withdrawn from the patient by standard venesection. Sometimes the blood is centrifuged to produce a platelet-rich sample. About 2–3\xa0ml of whole blood or platelet-rich plasma is injected into and around the damaged tendon, sometimes with ultrasound guidance. Local anaesthetic is usually used. 'Dry needling' (repeatedly passing a needle through the tendon to disrupt the fibres and induce bleeding) may be performed before injection of the blood. A 'peppering' technique is sometimes used to inject the autologous blood; this involves inserting the needle into the tendon, injecting some of the blood, withdrawing without emerging from the skin, slightly redirecting and reinserting. After the procedure, patients are usually advised to avoid strenuous or excessive use of the tendon for a few weeks, after which physiotherapy is started. The procedure may be repeated if needed.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a randomised controlled trial (RCT) of 150\xa0patients with tennis elbow, 70 were treated by autologous blood injection and 80 were treated by platelet-rich plasma injection. Technical success was defined as an improvement in patient-rated tennis elbow evaluation score of 25\xa0points at final analysis; measured on a scale of 0–100, with a higher score indicating more pain and functional disability. Of those patients followed up at 6\xa0months, technical success was reported in 72% (43/60) of patients treated by autologous blood injection and 66% (46/70) treated by platelet-rich plasma injection (p=0.59).\n\nIn an RCT of 100\xa0patients with tennis elbow, 51 were treated by platelet-rich plasma injection and 49 were treated by corticosteroid injection. Successful treatment was defined as a reduction of 25% on the visual analogue scale pain score (measured on a scale of 0–100, with a higher score indicating more pain) and no reintervention after 2\xa0years. At 2-year follow-up, successful treatment was achieved in 76% (39/51) of patients treated by platelet-rich plasma injection and 43% (21/49) treated by corticosteroid injection (p<0.0001).\n\nIn an RCT of 54\xa0patients with Achilles tendinopathy, 27 were treated by platelet-rich plasma injection and 27 were treated by placebo injection. The mean difference on the Victorian Institute of Sports assessment – Achilles (VISA-A) scale (assessing the severity of Achilles tendinopathy on a scale of 0–100, with a lower score indicating higher severity) was not significant (6\xa0points [95% confidence interval (CI) −5 to 16]) at 1-year follow-up (p value not reported).\n\nIn the RCT of 100\xa0patients with tennis elbow, 12% (6/51) of patients treated by platelet-rich plasma injection and 29% (14/49) of patients treated by corticosteroid injection needed further intervention within 2–14\xa0months. Of those treated by platelet-rich plasma injection, 6% (3/51) had subsequent corticosteroid injections. Of those treated by corticosteroid injection, 16% (8/49) had subsequent corticosteroid or platelet-rich plasma injections.\n\nIn the RCT of 54\xa0patients with Achilles tendinopathy, 57% of the platelet-rich plasma group and 42% of the placebo group returned to their previous level of sporting activity (absolute figures not reported). The adjusted between-group difference for return to sports was 2% (95% CI −25 to 28) at 1-year follow-up. This difference was not significant (p=0.89).\n\nThe Specialist Advisers listed key efficacy outcomes as pain relief and improved function.\n\n# Safety\n\nIn a case series of 28\xa0patients with tennis elbow, 7% (2/28) of patients needed narcotic analgesia because of pain after autologous blood injection. Most patients in this series reported that the pain was similar to the pain they had experienced after previous steroid injections into the tendon.\n\nModerate pain and stiffness after the injections, which persisted for a few days, was reported in all patients in a case series of 20\xa0patients with patellar tendinosis. One patient had more severe pain after the injection which took 3\xa0weeks to resolve (no further information reported).\n\nThe Specialist Advisers listed anecdotal adverse events to be increased pain, flare of pain, reduced functioning, and damage to surrounding tissues. Theoretical adverse events were considered to be tendon rupture, damage to the tendon and infection.\n\n# Other comments\n\nThe Committee noted that autologous blood injection for tendinopathy can be performed using either autologous whole blood or platelet-rich plasma. The latter aims to deliver a greater concentration of growth factors. Studies comparing the use of whole blood and platelet-rich plasma did not demonstrate any substantial differences in efficacy. Therefore, the Committee considered it reasonable to evaluate the evidence on injection with either whole blood or platelet-rich plasma as equivalent treatments in this guidance.\n\nA number of RCTs have been published since this procedure was evaluated in 2009 (NICE interventional procedure guidance 279). However, the Committee considered that the comparators used in most of the studies were not useful in determining whether autologous blood injection for tendinopathy is efficacious.\n\nThe Committee was advised that Achilles tendinopathy may respond differently to treatment compared with tendinopathy at other sites, so it may not be valid to extrapolate the findings of studies using this procedure to different sites.\n\nThe Committee noted that some of the published studies involved the use of a 'dry needling' or 'peppering' technique before the injection of autologous blood, but it was not possible to differentiate between the effects of these variations to the procedure.", 'Further information': 'This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt replaces NICE interventional procedure guidance 279.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg438
05c5c044ef8aa96102872f367791e7a9c0e6fab8	nice	Deep dermal injection of non-absorbable gel polymer for HIV-related lipoatrophy	Deep dermal injection of non-absorbable gel polymer for HIV-related lipoatrophy # Guidance This document replaces previous guidance on deep dermal injection of non-absorbable gel polymer for HIV-related lipoatrophy (interventional procedure guidance 291). Current evidence on the efficacy of deep dermal injection of non-absorbable gel polymer (NAGP) for HIV-related facial lipoatrophy is adequate. With regard to safety, infections that may need surgical removal of the implant are a risk in the longer term and other complications, including granuloma formation and migration, are common. Therefore, this procedure should be performed only with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake deep dermal injection of non-absorbable gel polymer for HIV-related facial lipoatrophy should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand that complications may occur in the short or long term – specifically infection, granuloma formation and migration – and that the implant may need to be removed. They should inform patients about the range of treatment options available. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having deep dermal injection of non-absorbable gel polymer for HIV-related facial lipoatrophy (see section 3.1). Clinicians using this procedure should be trained in the technique of injecting non-absorbable gel polymers. Injection should be carried out with strict aseptic technique in an appropriate environment. Further research and publication of observational data would be useful. Publications should describe details of patient selection, particularly in relation to previous treatments. They should also describe clinical outcomes (including all complications) and patient experience in the longer term. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Lipoatrophy is the localised loss of fat from within subcutaneous tissue. It can be a congenital condition or can be associated with subcutaneous injection sites. Facial lipoatrophy is commonly seen after HIV treatment, particularly with the older antiretroviral drugs. It involves wasting of the soft tissues of the cheeks, temples and around the eyes, producing changes in appearance that have severe psychological and social consequences for some patients. Current treatments for HIV-associated lipoatrophy include autologous fat transfer, dermal fat grafting, transfer of skin flaps and injection of temporary dermal fillers (such as collagen) or semi-permanent dermal fillers (such as polylactic acid). # Outline of the procedure Deep dermal injection of permanent or non-absorbable gel polymer aims to improve the appearance of HIV-associated lipoatrophy and its related psychological effects. It is intended to achieve a long-lasting result. The procedure is performed under general or local anaesthesia. Non-absorbable gel polymer is injected with a needle or cannula, deep into the subcutaneous tissue. Strict aseptic technique is used and prophylactic antibiotics are given. After injection the gel is massaged into position to produce a good aesthetic result. Once in place, the gel forms a thin external membrane or capsule that isolates it from the surrounding tissues and results in a liquid-filled endoprosthesis. The volume of gel injected depends on which part of the body is being treated and the degree of lipoatrophy; for facial treatment typically 1 ml is injected at each site at each treatment session. A course of injections over several weeks may be needed depending on the volume required. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised comparative study of 299 patients (130 treated by NAGP injection, 91 by polylactic acid injection, 54 by autologous fat transfer only and 24 by AFT plus PLA injection) reported significant improvements in facial aesthetic satisfaction (p<0.0001), body image satisfaction (p<0.0001) and depression score (p=0.014) at 48-week follow-up for the NAGP group. Patients were evaluated by visual analogue scale, the Assessment of Body Change and Distress questionnaire and the Beck Depression Inventory scale. A cohort study of 32 patients (5 from a pilot study and 27 from a randomised controlled trial comparing immediate against delayed dermal injection of NAGP) reported significant improvements in scores for anxiety (p<0.001) and depression (p<0.001) on the Hospital Anxiety Depression scale, the slightly modified Dermatology Quality of Life Survey (p<0.001), and the mental health domain (p=0.02) of the Medical Outcomes Study-HIV health survey at 4-year follow-up compared with baseline. The cohort study of 32 patients reported significant improvements in scores for median physician and patient-graded facial lipoatrophy severity (−2 and −1 ) at 4-year follow-up compared with baseline. A case series of 145 patients reported that 89% of patients were 'satisfied' or 'very satisfied' with the results 4 years after receiving NAGP injections (assessed using a 3-point scale ranging from not satisfied to very satisfied). The non-randomised comparative study of 299 patients reported a significant augmentation of cheek thickness (right cheek from 4.3±1.9 mm to 9.5 mm p<0.0001, left cheek from 4.4±2 mm to 9.6±3.1 mm, p<0.0001) from baseline to 48-week follow-up. The case series of 38 patients also reported a statistically highly significant improvement in cheek thickness (measured with ultrasound) from a pretreatment mean of 3.7 mm to 13.3 mm (p<0.0001) at a mean follow-up of 5 years. The Specialist Advisers listed key efficacy outcomes as restoration of appearance, volume augmentation and psychometric evaluation of satisfaction. # Safety Infection (confirmed by culture) was reported in 16% (5/32) of patients in the cohort study of 32 patients at 4-year follow-up; the median interval between NAGP injection and occurrence of infection was 2.8 years. An additional 9% (3/32) of patients had possible infection with a median time of occurrence of 3.7 years after treatment. All patients in this study with confirmed infections and 1 patient with possible infection had infections after dental treatment and were treated with antibiotics followed by surgical removal of the NAGP. The other 2 patients with possible infection were treated by antibiotic treatment alone. Infections occurred in 19% (56/267) of patients in a case series of 267 patients with a median follow-up of 30 months. The rate of primary infection was 0.07 per patient-year of follow-up, and the rate of definite infection was 0.02 per patient-year of follow-up. The median time from first treatment to infection was 32 months. Surgical management with antibiotics was needed for most patients. Prior facial manipulation for dental work or cosmetic surgery near the filler site in the month before infection was the most common factor associated with infection. Infections after revision procedures for correction of asymmetry were reported in 22% (4/18) of patients in a case series of 18 patients with follow-up of 2 months to 3 years. These occurred near the site of implant and were treated by antibiotics in 3 patients and by surgical removal of NAGP in 1 patient. Nodules were reported in 25% (8/32) of patients in the cohort study of 32 patients at 4 years. Non-visible nodules and indurations were found in 19% (28/145) and 6% (9/145) of patients respectively in the case series of 145 patients at a mean follow-up of 50 months after NAGP injection (no further details reported). Migration of the NAGP was reported in 25% (9/36) of patients at 7-year follow-up in a retrospective case series of 69 patients; mean time of onset was 12 months. This was treated by removal of the implant in 22% (8/36) of patients. Intra-oral extrusion of the NAGP through the buccal mucosa of the cheek was reported in 1 patient in the case series of 18 patients at 12-month follow-up. This was removed surgically by stab incisions and curettage. The Specialist Advisers listed theoretical adverse events as vascular occlusion, delayed granuloma formation, unsatisfactory cosmetic appearance and short duration of effect. # Other comments The Committee recognised that facial lipoatrophy can be a very distressing condition for patients with HIV, whose quality of life may be significantly improved by effective treatment. The balance of risks and benefits of deep dermal injection of NAGP in immunocompromised patients with HIV may differ from that in patients considering the procedure for other indications. The Committee noted that different types of gels used for this procedure may have different long-term effects. The Committee recognised that there have been concerns about complications in the longer term after deep dermal injection of NAGP. This underpinned the recommendation for continued data collection and research, in particular to address the balance of risks and benefits in patients with HIV-related facial lipoatrophy. The Committee noted reports of infection of implanted NAGP associated with subsequent dental procedures.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. It replaces NICE interventional procedure guidance 291. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "This document replaces previous guidance on deep dermal injection of non-absorbable gel polymer for HIV-related lipoatrophy (interventional procedure guidance 291).\n\nCurrent evidence on the efficacy of deep dermal injection of non-absorbable gel polymer (NAGP) for HIV-related facial lipoatrophy is adequate. With regard to safety, infections that may need surgical removal of the implant are a risk in the longer term and other complications, including granuloma formation and migration, are common. Therefore, this procedure should be performed only with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake deep dermal injection of non-absorbable gel polymer for HIV-related facial lipoatrophy should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand that complications may occur in the short or long term – specifically infection, granuloma formation and migration – and that the implant may need to be removed. They should inform patients about the range of treatment options available. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having deep dermal injection of non-absorbable gel polymer for HIV-related facial lipoatrophy (see section 3.1).\n\nClinicians using this procedure should be trained in the technique of injecting non-absorbable gel polymers. Injection should be carried out with strict aseptic technique in an appropriate environment.\n\nFurther research and publication of observational data would be useful. Publications should describe details of patient selection, particularly in relation to previous treatments. They should also describe clinical outcomes (including all complications) and patient experience in the longer term. NICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nLipoatrophy is the localised loss of fat from within subcutaneous tissue. It can be a congenital condition or can be associated with subcutaneous injection sites. Facial lipoatrophy is commonly seen after HIV treatment, particularly with the older antiretroviral drugs. It involves wasting of the soft tissues of the cheeks, temples and around the eyes, producing changes in appearance that have severe psychological and social consequences for some patients.\n\nCurrent treatments for HIV-associated lipoatrophy include autologous fat transfer, dermal fat grafting, transfer of skin flaps and injection of temporary dermal fillers (such as collagen) or semi-permanent dermal fillers (such as polylactic acid).\n\n# Outline of the procedure\n\nDeep dermal injection of permanent or non-absorbable gel polymer aims to improve the appearance of HIV-associated lipoatrophy and its related psychological effects. It is intended to achieve a long-lasting result.\n\nThe procedure is performed under general or local anaesthesia. Non-absorbable gel polymer is injected with a needle or cannula, deep into the subcutaneous tissue. Strict aseptic technique is used and prophylactic antibiotics are given. After injection the gel is massaged into position to produce a good aesthetic result. Once in place, the gel forms a thin external membrane or capsule that isolates it from the surrounding tissues and results in a liquid-filled endoprosthesis. The volume of gel injected depends on which part of the body is being treated and the degree of lipoatrophy; for facial treatment typically 1\xa0ml is injected at each site at each treatment session. A course of injections over several weeks may be needed depending on the volume required.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 299\xa0patients (130 treated by NAGP injection, 91 by polylactic acid [PLA] injection, 54 by autologous fat transfer only [AFT] and 24 by AFT plus PLA injection) reported significant improvements in facial aesthetic satisfaction (p<0.0001), body image satisfaction (p<0.0001) and depression score (p=0.014) at 48-week follow-up for the NAGP group. Patients were evaluated by visual analogue scale, the Assessment of Body Change and Distress questionnaire and the Beck Depression Inventory scale. A cohort study of 32\xa0patients (5 from a pilot study and 27 from a randomised controlled trial comparing immediate against delayed dermal injection of NAGP) reported significant improvements in scores for anxiety (p<0.001) and depression (p<0.001) on the Hospital Anxiety Depression scale, the slightly modified Dermatology Quality of Life Survey (p<0.001), and the mental health domain (p=0.02) of the Medical Outcomes Study-HIV health survey at 4-year follow-up compared with baseline.\n\nThe cohort study of 32\xa0patients reported significant improvements in scores for median physician and patient-graded facial lipoatrophy severity (−2 [interquartile range −2, −1; p<0.001] and −1 [interquartile range −3, −1; p<0.001]) at 4-year follow-up compared with baseline.\n\nA case series of 145\xa0patients reported that 89% of patients were 'satisfied' or 'very satisfied' with the results 4\xa0years after receiving NAGP injections (assessed using a 3-point scale ranging from not satisfied to very satisfied).\n\nThe non-randomised comparative study of 299\xa0patients reported a significant augmentation of cheek thickness (right cheek from 4.3±1.9\xa0mm to 9.5\xa0mm p<0.0001, left cheek from 4.4±2\xa0mm to 9.6±3.1\xa0mm, p<0.0001) from baseline to 48-week follow-up. The case series of 38\xa0patients also reported a statistically highly significant improvement in cheek thickness (measured with ultrasound) from a pretreatment mean of 3.7\xa0mm to 13.3\xa0mm (p<0.0001) at a mean follow-up of 5\xa0years.\n\nThe Specialist Advisers listed key efficacy outcomes as restoration of appearance, volume augmentation and psychometric evaluation of satisfaction.\n\n# Safety\n\nInfection (confirmed by culture) was reported in 16% (5/32) of patients in the cohort study of 32\xa0patients at 4-year follow-up; the median interval between NAGP injection and occurrence of infection was 2.8\xa0years. An additional 9% (3/32) of patients had possible infection with a median time of occurrence of 3.7\xa0years after treatment. All patients in this study with confirmed infections and 1\xa0patient with possible infection had infections after dental treatment and were treated with antibiotics followed by surgical removal of the NAGP. The other 2\xa0patients with possible infection were treated by antibiotic treatment alone.\n\nInfections occurred in 19% (56/267) of patients in a case series of 267\xa0patients with a median follow-up of 30\xa0months. The rate of primary infection was 0.07 per patient-year of follow-up, and the rate of definite infection was 0.02 per patient-year of follow-up. The median time from first treatment to infection was 32\xa0months. Surgical management with antibiotics was needed for most patients. Prior facial manipulation for dental work or cosmetic surgery near the filler site in the month before infection was the most common factor associated with infection.\n\nInfections after revision procedures for correction of asymmetry were reported in 22% (4/18) of patients in a case series of 18\xa0patients with follow-up of 2\xa0months to 3\xa0years. These occurred near the site of implant and were treated by antibiotics in 3\xa0patients and by surgical removal of NAGP in 1\xa0patient.\n\nNodules were reported in 25% (8/32) of patients in the cohort study of 32\xa0patients at 4\xa0years. Non-visible nodules and indurations were found in 19% (28/145) and 6% (9/145) of patients respectively in the case series of 145\xa0patients at a mean follow-up of 50\xa0months after NAGP injection (no further details reported).\n\nMigration of the NAGP was reported in 25% (9/36) of patients at 7-year follow-up in a retrospective case series of 69\xa0patients; mean time of onset was 12\xa0months. This was treated by removal of the implant in 22% (8/36) of patients. Intra-oral extrusion of the NAGP through the buccal mucosa of the cheek was reported in 1\xa0patient in the case series of 18\xa0patients at 12-month follow-up. This was removed surgically by stab incisions and curettage.\n\nThe Specialist Advisers listed theoretical adverse events as vascular occlusion, delayed granuloma formation, unsatisfactory cosmetic appearance and short duration of effect.\n\n# Other comments\n\nThe Committee recognised that facial lipoatrophy can be a very distressing condition for patients with HIV, whose quality of life may be significantly improved by effective treatment. The balance of risks and benefits of deep dermal injection of NAGP in immunocompromised patients with HIV may differ from that in patients considering the procedure for other indications.\n\nThe Committee noted that different types of gels used for this procedure may have different long-term effects.\n\nThe Committee recognised that there have been concerns about complications in the longer term after deep dermal injection of NAGP. This underpinned the recommendation for continued data collection and research, in particular to address the balance of risks and benefits in patients with HIV-related facial lipoatrophy.\n\nThe Committee noted reports of infection of implanted NAGP associated with subsequent dental procedures.", 'Further information': 'This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt replaces NICE interventional procedure guidance 291.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg439
a9619f6f4927b4e9f2396067a4d808409b7b2a0f	nice	Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma	Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma Evidence-based recommendations on ipilimumab (Yervoy) for previously treated advanced melanoma in adults. # Guidance Ipilimumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in people who have received prior therapy, only if the manufacturer provides ipilimumab with the discount agreed in the patient access scheme.# The technology Ipilimumab (Yervoy, Bristol-Myers Squibb Pharmaceuticals) is a fully human antibody that binds to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule expressed on T-cells that plays a critical role in regulating natural immune responses. Ipilimumab has a UK marketing authorisation for 'the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy'. For further information, see the summary of product characteristics. Ipilimumab is most commonly associated with adverse reactions resulting from increased or excessive immune activity including diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain. For full details of adverse reactions and contraindications, see the summary of product characteristics. The recommended dose of ipilimumab is 3 mg per kilogram of body weight (mg/kg) administered intravenously over a 90-minute period every 3 weeks, with a total of 4 doses for the full treatment course. The summary of product characteristics states that all 4 doses should be administered 'as tolerated, regardless of the appearance of new lesions or growth of existing lesions'. Ipilimumab costs £3750 for 50 mg and £15,000 for 200 mg (excluding VAT, British national formulary, September 2012). Assuming an average body weight of 70 kg, each dose of ipilimumab would need a 200 mg vial and a 50 mg vial costing £18,750. A 4-dose course would therefore cost £75,000, not including administration costs. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of ipilimumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of ipilimumab is offered. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ipilimumab and a review of this submission by the Evidence Review Group (ERG; appendix B). The key evidence for the clinical effectiveness of ipilimumab came from 1 trial (MDX010-20), which assessed the efficacy and safety of ipilimumab in adults with advanced, unresectable stage III or stage IV malignant melanoma who had been previously treated with interleukin-2, dacarbazine, temozolomide or other chemotherapies. This evidence was supported by results from a dose-ranging trial (CA 184-022), and a safety and tolerability trial (CA 184-007). The MDX010-20 trial was an international, multicentre, double-blind, 3-armed, randomised, controlled trial. A total of 676 adults with advanced malignant melanoma were randomised to receive ipilimumab 3 mg/kg in combination with an investigational gp100 peptide vaccine ('ipilimumab plus gp100'; n=403), ipilimumab 3 mg/kg in combination with placebo ('ipilimumab alone'; n=137), or gp100 in combination with placebo ('gp100 alone'; n=136) every 3 weeks for 4 cycles. Approximately 38% of patients in the trial were from Europe, with 8% from the UK. The patients were all HLA-A*0201 (human leukocyte antigen serotype group) positive and were generally well balanced for key baseline characteristics. At study entry, nearly all patients (98.2%) had stage IV disease. The primary outcome of the MDX010-20 trial was overall survival for people treated with ipilimumab plus gp100 compared with gp100 alone. Secondary outcomes in the trial included overall survival in people treated with ipilimumab plus gp100 compared with ipilimumab alone, best objective response rate, disease control rate, duration of response, progression-free survival, time to progression and health-related quality of life. Results from the MDX010-20 trial showed that ipilimumab plus gp100 led to a statistically significant increase in median overall survival by approximately 3.5 months compared with gp100 alone (hazard ratio 0.68; 95% confidence interval 0.55 to 0.85; p=0.0004). When ipilimumab alone was compared with gp100 alone, ipilimumab increased median overall survival by approximately 3.7 months (HR 0.66; 95% CI 0.51 to 0.87; p=0.0026). There was no statistically significant difference in median overall survival between people treated with ipilimumab plus gp100 and those treated with ipilimumab alone (HR 1.04; 95% CI 0.83 to 1.30; p=0.7575), which the manufacturer considered was evidence that gp100 did not influence the overall survival outcome when combined with ipilimumab treatment. Approximately 65% of people treated with an ipilimumab-containing regimen received all 4 doses of ipilimumab in line with the licensed regimen, and in this subgroup the median survival in both the gp100 and ipilimumab arms was greater than in those who received fewer than the full 4 doses. The differences in survival gain between the ipilimumab and gp100 arms were also more favourable in people treated with all 4 doses (results provided as academic in confidence). All response-related secondary outcomes (including best objective response rate and progression-free survival) showed positive results for people who received treatment with an ipilimumab-containing regimen compared with people who received gp100 alone. The CA 184-022 trial was a double-blind, multicentre, dose-ranging, randomised, controlled trial that included 217 patients with previously treated, treatment-refractory or treatment-intolerant unresectable stage III or stage IV melanoma. They were randomised to receive either ipilimumab 0.3 mg/kg, 3 mg/kg or 10 mg/kg every 3 weeks for 4 cycles followed by maintenance therapy every 3 months. The outcomes included estimated best objective response rate, progression-free survival at 24 weeks, median overall survival and duration of response. The CA 184-007 trial was a double-blind, multicentre, randomised, controlled trial. Patients (n=115) with unresectable stage III or stage IV melanoma who were treatment naive or who had been previously treated were randomised to receive open-label ipilimumab (10 mg/kg at weeks 1, 4, 7 and 10) with either concomitant oral budesonide or placebo. The outcomes included adverse reactions (specifically diarrhoea), best objective response rate, duration of response and overall survival. The most common adverse reactions associated with ipilimumab treatment reported in the 3 trials included in the manufacturer's submission resulted from increased or excessive immune activity. They included diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain. These adverse reactions were considered to be generally medically manageable and usually reversible with topical and/or systemic immunosuppressants. Progressive disease was the most frequent reason for death in the MDX010-20 and CA 184-022 studies. There were 14 (2.2%) adverse reactions with an outcome of death in the MDX010-20 trial that related to the study treatments; 8 deaths in the ipilimumab plus gp100 group, 4 in the ipilimumab alone group and 2 in the gp100 alone group. Of those deaths, 7 were associated with immune-related adverse reactions (including colitis, bowel perforation and organ failure): 5 in the ipilimumab plus gp100 group and 2 in the ipilimumab alone group. The manufacturer undertook a systematic search and identified 10 economic evaluations in pre-treated or advanced melanoma. None of the studies evaluated ipilimumab. The manufacturer therefore submitted a de novo economic evaluation in which people treated with ipilimumab were compared with those who received best supportive care. There were 4 mutually exclusive states included in the model: baseline disease, non-progressive disease, progressive disease and death. All people were assumed to start in the baseline disease state (after chemotherapy), then at the end of each cycle they could move to the non-progressed health state or to the progressed health state, or they could die. The model used daily cycles for the first 5 years during the trial period, and weekly cycles thereafter for a lifetime (30 year) horizon. The perspective adopted in the economic evaluation was that of the NHS and personal social services, and costs and benefits were discounted at 3.5% per year. The proportion of people in each health state was calculated using progression-free survival and overall survival data from the MDX010-20 trial. Data on progression-free survival and overall survival for people receiving best supportive care were not available directly from the trial. However, results from the trial showed that treatment with gp100 alone led to a median overall survival of 6.4 months, which was consistent with survival estimates achieved with best supportive care. Therefore, data from the gp100 arm of the trial were assumed by the manufacturer to be a proxy for the course of disease in people receiving best supportive care. Adverse-reaction rates for ipilimumab and best supportive care were estimated from the MDX010-20 trial. The resource costs included in the model were drug acquisition and administration costs, and the cost of the disease, which included costs related to each health state and of treating adverse reactions. In the manufacturer's original submission, 2 approaches to parametric curve fitting for the survival modelling were presented. The first strategy involved a single curve fit approach that showed that none of the curves fitted the Kaplan-Meier data from the MDX010-20 study. The second strategy involved using a 2-part curve fit in which the Kaplan-Meier estimates for overall survival and progression-free survival were used for the first 18 months and 'best-fit' parametric curves were used thereafter. The manufacturer concluded that the 'best-fit' curves were: exponential for progression-free survival in the ipilimumab arm, Gompertz for overall survival in the ipilimumab arm and exponential for overall survival in the best supportive care arm. Progression-free survival in the best supportive care arm was represented by the overall survival arm. Health-related quality of life was measured in the MDX010-20 trial, which used the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the short form 36 (SF-36) questionnaires. The questionnaires were predominantly completed by trial participants at baseline and week 12, with only 26 questionnaires completed after week 12. For the economic analysis, utilities were obtained from responses to the EORTC QLQ-C30 from 971 trial observations using a recently developed preference-based version of the instrument. The utility values assumed for the progression-free disease and progressive disease health states in the model were 0.80 (95% CI 0.53 to 0.97) and 0.76 (95% CI 0.46 to 0.97) respectively. The manufacturer also conducted a systematic review to identify studies that included health-related quality-of-life data for people with metastatic melanoma. One study was identified that included 63 patients from the UK and 77 patients from Australia who valued 'vignettes' or descriptions of advanced melanoma health states developed by the researchers. In the manufacturer's original base case, ipilimumab treatment led to an undiscounted incremental gain in overall survival of 33.8 months compared with best supportive care. The incremental cost-effectiveness ratio (ICER) for ipilimumab compared with best supportive care was £60,737 per quality-adjusted life year (QALY) gained (incremental cost of £83,351 and incremental benefit of 1.37 QALYs). This was based on the assumption that all patients received 3.3 doses of ipilimumab at 3 mg/kg body weight, corresponding with the average number of doses used in the clinical trial. Probabilistic sensitivity analysis reported a 14% chance of ipilimumab being cost effective compared with best supportive care at £50,000 per QALY gained. Deterministic sensitivity analyses showed that the ICER was sensitive to the utility values assumed for the progressive disease health state. An increase in this utility value reduced the ICER and conversely a reduction in utility increased the ICER. For example, using a lower utility (0.60) for progressive disease increased the base-case ICER to £73,854 per QALY gained. Structural sensitivity analysis also showed that decreasing the discount rate to 0% reduced the ICER from £60,737 to £42,871 per QALY gained because the long-term benefits of ipilimumab in the base case were discounted to a large degree, whereas costs of treatment were only incurred in the first year of the model, and therefore were unaffected by discounting. The manufacturer also conducted scenario analyses to explore the effect on the ICER of assumptions about the amount of each dose of ipilimumab needed per patient and the possibility of vial sharing. Results from these analyses showed that the dose of ipilimumab given per patient has a large impact on the manufacturer's ICER, with the minimum dose given in the trial and compassionate use programme (3×50 mg) resulting in an ICER of £38,387 per QALY gained and the maximum dose (2×200 mg) given resulting in an ICER of £88,788 per QALY gained. In addition, the results showed that vial sharing has the potential to reduce the manufacturer's original base-case ICER to £55,824 per QALY gained. The ERG reviewed the clinical-effectiveness evidence for ipilimumab and noted that none of the studies included in the manufacturer's submission compared ipilimumab with any of the comparators listed in the decision problem (best supportive care, carboplatin-based chemotherapy and dacarbazine). The ERG commented that the MDX010-20 study was well designed and that it was satisfied that the participants were representative of patients in UK clinical practice. The ERG expressed concern that the manufacturer considered gp100 clinically comparable to best supportive care because patient outcomes in the gp100 alone arm of the MDX010-20 study appeared less favourable than might be expected in untreated people. The ERG commented that the clinical data provided by the manufacturer suggested that treatment with ipilimumab was associated with a long-term overall survival benefit over gp100 for a small number of patients. However, it noted that to date no patient characteristics or biomarkers have been identified that can prospectively identify the people most likely to benefit from treatment with ipilimumab. The ERG noted that the European Medicines Agency considered a number of supplementary analyses carried out by the manufacturer in an attempt to identify possible subgroups of people who might (or might not) benefit from treatment with ipilimumab. However, the subgroups were small and the ERG determined that no conclusions could be drawn from this analysis. The ERG considered that the manufacturer's model was well constructed, but it proposed a number of minor corrections and modifications, which resulted in a reduction in the base-case ICER from £60,737 to £54,462 per QALY gained. However, the ERG noted that the main weakness of the manufacturer's original model was the estimate of mean overall survival. The ERG acknowledged that the natural history and prognosis for metastatic melanoma is not well understood and the manufacturer claimed a substantial improvement in mean survival on the basis of results from a single trial. The ERG cited a study published in 1999 involving a re-analysis of 8 trials of interleukin-2 for people with metastatic melanoma. Of the patients, 80% died within 2 years but most of those surviving the 2-year follow-up period survived for a further 9 years. The ERG noted that this response pattern was replicated in the MDX010-20 study and suggested that this was likely to be because survival rates for people with advanced metastatic melanoma vary substantially. In light of this, it is possible that the data available for analysis are weakest when improved survival is likely to generate the most added life years from the treatment. The ERG therefore noted that, although the MDX010-20 trial used by the manufacturer showed a survival advantage for ipilimumab, it was unable to reliably quantify the long-term survival benefit. The ERG had concerns about the manufacturer's interpretation of the MDX010-20 trial data. In particular, it noted that the fitted overall survival functions beyond 18-month follow-up generated mortality risks lower than those in the general (healthy) population at a comparable age and, as a consequence, the model predicted substantial numbers of people surviving to unreasonably advanced ages (beyond 100 years). To counter this anomaly, the manufacturer replaced the calculated model mortality risks with mortality risks experienced by the general population beyond 5-year follow-up. The ERG noted that this approach implied that anyone surviving beyond 5 years of second-line systemic treatment was effectively cured; however, no evidence was submitted by the manufacturer in the original submission to support this claim. In an exploratory analysis, based on the manufacturer's original submission, the ERG adopted a pragmatic approach to model overall survival by calculating the area under the Kaplan-Meier curve to a common late time point beyond which both the ipilimumab and best supportive care arms could be seen to be following long-term trend lines. It then projected further life expectancy based on calibrating a parametric function. The results from this method suggested mean undiscounted life years of 11.2 months for gp100 alone and 27.4 months for the combined ipilimumab arms from the MDX010-20 trial, which equated to a mean gain in overall survival of 16.2 months. These results were noted to be less than half the value calculated in the base case of the manufacturer's original model (that is, a mean gain in overall survival of 33.8 months). Using the revised projections, the ERG noted that the manufacturer's original base-case ICER increased to £96,717 per QALY gained. The ERG stated that its exploratory analysis on overall survival cannot be considered definitive because the volume and duration of patient data available from the MDX010-20 trial were inadequate to achieve survival projections that can be used as a basis for decision-making. However, the ERG considered that the manufacturer's original model is likely to have overestimated the extent of survival benefit associated with treatment with ipilimumab, which would have a considerable effect on the ICER. In response to consultation, the manufacturer offered an alternative approach to modelling long-term survival for people who are treated with ipilimumab. The manufacturer used a 3-part curve fit approach with Kaplan-Meier analysis results from MDX010-20 unmodified for the first 18 months, followed by a parametric model (Gompertz) fitted to the trial data from 18 months to 5 years and, thereafter, hazards derived from analysis of a malignant melanoma disease register modified by background mortality rates. The manufacturer used data from a published register of 1158 patients with stage IV melanoma in the USA. The manufacturer used the survival curve from this analysis as the basis for estimating the extended survival of patients (beyond 5 years) in the MDX010-20 trial. This was further modified to include age-related mortality because the register data included melanoma-related death only. In this revised model the survival estimates were further adjusted, using a Cox proportional hazards regression, to reflect the difference in overall survival for long-term survivors in the combined ipilimumab treatment groups (ipilimumab alone and ipilimumab plus gp100) and the gp100 alone group (HR 0.782). By including this revised approach in the model, the estimated survival gain for people treated with ipilimumab was 30.0 months (compared with their original estimate of 33.8 months). The Department of Health agreed a patient access scheme in which a simple discount is applied to the list price of ipilimumab. For the analyses including the scheme, the manufacturer presented additional survival data from 3 smaller trials (CA 184-007, CA 184-008 and CA 184-022: all individual parent studies included in CA 184-025) comprising patients who initially received 0.3 mg/kg, 3 mg/kg or 10 mg/kg dosages of ipilimumab. The manufacturer identified 72 patients from a dose-ranging study (CA 184-022), who had received previous treatment and then ipilimumab at the licensed dose of 3 mg/kg. These were considered to be comparable to the patients treated with ipilimumab in the MDX010-20 trial, and the manufacturer presented a pooled analysis of the MDX010-20 trial patients supplemented by these patients from the CA 184-022 trial. The manufacturer also proposed a broader pooling of all data from patients treated with ipilimumab, regardless of dosing level. The manufacturer stated that these additional data, which provided follow-up information on patients treated with ipilimumab for between 50 and 70 months, confirmed the long-term effect of ipilimumab at all dosages. The manufacturer's revised base-case analysis was calculated using the 3-part curve fit approach, the patient access scheme, and trial data for patients receiving the 3 mg/kg dose of ipilimumab in the MDX010-20 trial pooled with 72 patients from the CA 184-022 dose-ranging trial receiving the same dose. This resulted in a revised base-case deterministic ICER of £46,739 per QALY gained for ipilimumab compared with best supportive care. Using only the MDX010-20 trial data, the ICER was £42,211 per QALY gained. The manufacturer considered that the probabilistic sensitivity analyses showed a low level of parameter-related uncertainty around the baseline ICER and reported that there was an approximately 81% chance that the ICER for ipilimumab would be less than £50,000 per QALY gained when the patient access scheme was included. The manufacturer conducted structural sensitivity analyses and scenario analyses exploring the impact of alternate curve fits, varied cut-off points in the 3-part curve fit approach, alternative sources of observational data and the use of the ERG approach on the overall survival benefit of ipilimumab. The manufacturer stated that the only scenario in which the ICER rose above £50,000 per QALY gained was when the manufacturer adopted the ERG approach for survival estimation, which resulted in an ICER of £55,807 per QALY gained. Further scenario analyses involved excluding patients who crossed over between different doses of ipilimumab and resulted in a nominal reduction in the ICER to £44,426 per QALY gained. The manufacturer stated that the areas identified as potentially problematic by the ERG, such as cut-off points and sources of observational data, did not have a large impact on the ICER, and that the increased patient numbers and number of trials with similar results reduced the uncertainty associated with the estimation of longer-term survival. The manufacturer noted that, although the summary of product characteristics for ipilimumab does not recommend vial sharing, discussions with clinicians indicated that vial sharing may be possible in some clinical centres in the UK. The manufacturer provided scenario analyses to explore the impact of vial sharing and noted that, if 50% of ipilimumab wastage was avoided through vial sharing, then the revised base-case ICER would be reduced. The manufacturer also suggested that, if drug-specific utilities were used instead of pooled utilities (which were used in the original economic model), then the revised base-case ICER would decrease further. The manufacturer conducted sensitivity analyses using the discount rate of 1.5% for costs and benefits, and also a discount rate of 3.5% for costs and 1.5% for benefits. These resulted in ICERs of £39,714 and £38,323 respectively per QALY gained. The manufacturer's probabilistic sensitivity analysis indicated that, in these scenarios, the ICER for ipilimumab is 94% and 100% likely to be less than £50,000 per QALY gained respectively. The ERG considered the manufacturer's revised long-term survival projections submitted in response to consultation. It believed that the main weakness of the manufacturer's survival model was in not providing a rationale, other than replicating the observed data, to support the division of data into 3 time periods and the use of different methods in each period. Furthermore, there were substantial differences between the populations in the MDX010-20 trial and the disease register in terms of patients' initial diagnosis, treatment history and time from initial diagnosis. The ERG also considered that the manufacturer's approach to deriving the long-term hazard ratio was problematic because of the small number of people in the analysis for the gp100 group in the trial (n=19) and the fact that the long-term survival trends were established much earlier in the gp100 group (about 300 days) than in the combined ipilimumab treatment group (about 750 days), which could lead to bias in the hazard ratio. In light of these concerns, the ERG considered that the survival projections presented by the manufacturer in response to consultation were uncertain. The ERG reviewed the manufacturer's assumptions about vial sharing. It considered that although vial sharing is theoretically possible, in reality it would be difficult to implement because only 250–300 people nationally will need treatment each year, which only equates to 1–2 people in each centre each month. Therefore, the ERG was not convinced that any specialist centre could achieve regular savings in ipilimumab costs from organised vial sharing. ERG comments on manufacturer's additional analyses (including the patient access scheme) The ERG reviewed the manufacturer's alternative data sets based on the pooling of selected data from several smaller clinical studies with data from the main MDX010-20 trial. The ERG thought that the patient population was too dissimilar to the MDX010-20 trial to allow direct comparison, and that not all studies involved the dosing regimen of ipilimumab (3 mg/kg) for which marketing authorisation has been granted. Therefore, the ERG considered that the broader pooling of data from all patients who received ipilimumab, regardless of dosing regimen or patient baseline characteristics, would lead to uninterpretable results. Regarding the pooling of 3 mg/kg data from the MDX010-20 trial and the CA 184-022 study, the ERG thought that pooling isolated treatment arms across trials was inappropriate because it would break randomisation and therefore invalidate any comparison between the intervention treatment and the comparator. Furthermore, there were no equivalent comparator treatment arms available in the CA 184-022 study to balance the pooling of the ipilimumab trial arms. Finally, the ERG thought that the additional data from the CA 184-022 study did not extend the length of follow-up beyond that in the MDX010-20 trial, and therefore did not reduce the uncertainty surrounding long-term outcomes. Therefore, the ERG considered that it was only appropriate to include data from the MDX010-20 trial. Consequently, the ERG found that the patient access scheme would decrease the ICER for ipilimumab compared with best supportive care to £66,520 per QALY gained. However, the ERG carried out further analyses aimed at clarifying the possible mechanisms underlying the pattern of overall survival observed in the clinical trials and disease registers for patients with advanced malignant melanoma. The ERG proposed a hypothesis assuming that patients with advanced malignant melanoma are drawn from 2 distinct subgroups of unknown aetiology and that each subgroup is characterised by a separate hazard rate that does not vary over time. Based on this, a mixed exponential distribution for overall survival, which consisted of the proportion of the population comprising one of the subgroups and separate hazard rates for each of the subgroups, was considered appropriate. The ERG tested this approach by applying it to published results from 2 large patient registries, which resulted in strong correspondence to the observed data in both data sets and for each disease stage. The results of this method of projecting overall survival in the submitted model, using only the MDX010-20 trial data, resulted in a mean gain in overall survival of 20.9 months. Using this method, combined with the patient access scheme, resulted in an ICER of £58,590 per QALY gained. The ERG's revised approach implies that patients fall into 2 distinct groups in relation to mortality risk, but currently no direct evidence is available to explain how such a differentiation may occur. The ERG also noted that the melanoma databases used in testing the revised approach featured patients from the time of diagnosis, but their use in modelling (both by the manufacturer and by the ERG) began at the time of randomisation, at which point patients may have survived several years of treatment. As a result, direct use of database trends could be misleading. Full details of all the evidence are in the manufacturer's submission, the ERG report, the manufacturer's response to the appraisal consultation document, further evidence and analyses, and the ERG's critique of the manufacturer's responses, which are available from www.nice.org.uk/guidance/TA268.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ipilimumab, having considered evidence on the nature of advanced (unresectable or metastatic) melanoma and the value placed on the benefits of ipilimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee heard from the clinical specialists that they considered ipilimumab to represent a 'step-change' in the treatment of advanced melanoma and that it is the first new treatment available in 30 years that may offer clinical benefit and possible long-term survival gain for people with advanced, unresectable disease that has progressed after first-line therapy. Other drugs are also in development. The Committee heard that the optimal place for ipilimumab treatment in the clinical pathway for advanced (unresectable or metastatic) melanoma was still being debated in the clinical community. However, the Committee understood that most clinicians in the UK would use ipilimumab as a second-line treatment in line with its UK marketing authorisation. The Committee heard from a patient expert that unresectable melanoma substantially worsens quality of life and, without effective new therapies, the prognosis for advanced disease is very poor. The Committee concluded that there was a significant unmet need for effective therapies in this patient population. The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ipilimumab. It noted that the manufacturer derived efficacy data primarily from the MDX010-20 trial, which showed that treatment with ipilimumab led to a statistically significant median overall survival gain of approximately 3.7 months (HR 0.66; 95% CI 0.51 to 0.87; p=0.0026) compared with gp100 for people with progressive disease after first-line therapy. The Committee heard from the clinical specialists that people treated with ipilimumab will have some survival benefit, but only 10% of people may experience long-term benefits. The Committee was aware that the trial length was 56 months, and that survival benefit was demonstrated for the length of the trial, but that there was uncertainty about continuing benefit thereafter. The clinical specialists indicated that melanoma may have an unpredictable clinical course and that late recurrences are well recognised. The Committee noted that a curative treatment would be expected to result in the disappearance of all visible disease (complete response), but less than 1% of patients in the ipilimumab arms of the MDX010-20 trial showed a complete disease response. In addition, although there was trial evidence of some people whose disease remained stable after being treated with ipilimumab, it was not clear how prolonged that response might be. The clinical specialists agreed that it is too early to regard this as a curative treatment. The Committee further considered the additional data presented by the manufacturer. These data were presented to provide further evidence of the survival benefit of ipilimumab over a period of 50 to 70 months' follow-up, and to supplement the evidence from the MDX010-20 trial. The Committee agreed that these additional data supported the findings in the MDX010-20 trial, but agreed with the ERG that the pooling of these additional data with data from the MDX010-20 trial was inappropriate and should not be included in the economic modelling. The Committee concluded that the evidence on the clinical effectiveness of ipilimumab was robust for a period of at least 5 years, and that a small proportion of patients were likely to benefit from ipilimumab in the long term. The Committee considered the adverse reactions associated with treatment with ipilimumab. The Committee understood from the clinical specialists and patient experts that people being treated with ipilimumab can have immune-related adverse reactions, which have a substantial negative impact on their quality of life. The Committee noted that 12 deaths related to treatment with ipilimumab occurred in the MDX010-20 trial, but heard from the clinical specialists that subsequent trials of ipilimumab as first-line treatment have not reported any treatment-related deaths. The clinical specialists considered that this indicated that, as experience with ipilimumab grows, adverse reactions will be more quickly identified and treated. The Committee also heard from the patient experts that the possible survival benefits from adhering to treatment with ipilimumab outweigh the severe adverse reactions. The Committee concluded that although the adverse reactions and mortality associated with ipilimumab seen in the MDX010-20 trial were considerable, most adverse reactions, including those that led to hospital admission, were manageable and would be managed more effectively as clinicians become familiar with ipilimumab's toxicity profile. It also concluded that people may be willing to tolerate considerable toxicity if there are potential survival benefits. The Committee noted that the UK marketing authorisation for ipilimumab stipulates that people should receive all 4 doses of treatment, even if the disease appears to progress during treatment. The Committee heard from the clinical specialists that late responses to treatment have been reported. It heard that people should therefore continue to be treated unless their disease progresses to a degree that a response is very unlikely, or the side effects become intolerable. The Committee also understood from the clinical specialists that, although it is not possible to predict how a person's condition might respond to ipilimumab, people who experience a substantial decrease in performance status while receiving treatment are likely to have rapidly progressive disease and will not benefit from continued use of ipilimumab. The clinical specialists indicated that despite guidance on the use of all 4 doses, normal clinical evaluation and discussion with patients would be carried out to determine whether or not it was reasonable to continue with treatment. The Committee noted that approximately 65% of people treated with ipilimumab in the MDX010-20 trial received all 4 doses of treatment. They also heard from the clinical specialists that it is likely that more than 65% of people treated with ipilimumab in clinical practice would receive all 4 doses. The Committee concluded that it was reasonable to assume that not all patients would receive 4 doses of ipilimumab in clinical practice despite the administration advice in the UK marketing authorisation. The Committee discussed the cost-effectiveness estimates from the manufacturer's original and revised economic models, the assumptions on which these were based, and the ERG's critique and exploratory analyses. The Committee noted that the manufacturer assumed that the gp100 vaccine was clinically comparable to best supportive care and used the efficacy estimates from the gp100 arm in the MDX010-20 trial to inform model inputs. The Committee understood from the clinical specialists that, although studies of vaccines (other than gp100) in people with advanced and metastatic melanoma have shown a survival disadvantage, there is no evidence that this occurs for people treated with gp100. The Committee agreed with the clinical specialists that gp100 is likely to be an acceptable proxy for best supportive care in the model. The Committee heard from the manufacturer that EORTC-QLQ and SF-36 data were collected in the MDX010-20 trial. It noted the ERG's concerns that the number of respondents to the questionnaires dropped off considerably after week 12 in the MDX010-20 trial and that there was little difference between the utilities assigned to the progression-free and the progressive disease health states. The Committee noted that additional sensitivity analyses conducted by the manufacturer in response to the appraisal consultation document showed that the utility assumed for the progressive disease state was not a major driver of cost effectiveness. The Committee concluded that the utility estimates derived by the manufacturer were acceptable. The Committee noted that the length of follow-up in the MDX010-20 trial was too short to provide robust evidence of the overall survival gain beyond the length of the trial. The Committee expressed confidence in the data from the MDX010-20 trial, supported by data from 3 smaller trials, but noted that beyond this time period the calculation of overall survival gain was dependent on the modelling approach used for extrapolation. It was aware that the manufacturer and the ERG had each presented 2 different approaches. The manufacturer considered that the ERG's initial approach overestimated survival in the short term and underestimated it in the long term, such that the survival curve for the 3 mg/kg ipilimumab dose was below that seen in the observational data, which the Committee considered was implausible. The ERG considered that its updated approach using a mixed exponential approach better fitted the data than the manufacturer's model. The Committee accepted that the MDX010-20 trial showed that ipilimumab provides a 3.7 month median increase in overall survival when compared with best supportive care. However, when taking into account the small number of long-term survivors, there is a substantial degree of uncertainty about the modelling of long-term survival benefits. The Committee considered the revised base-case ICERs presented by the manufacturer, taking into account the patient access scheme. The Committee noted that the manufacturer's base-case ICER based on the pooled 3 mg data and its preferred modelling approach was £46,700 per QALY gained and that there was an 81% probability of ipilimumab being cost effective if the maximum acceptable ICER was £50,000 per QALY gained. The ICER showed relatively little change when re-evaluated using a single curve fit, or sensitivity analyses changing the cut-off points in the 3-part model. The ICER, however, rose to £55,800 per QALY gained when the manufacturer used the ERG's prior overall survival modelling approach. The Committee also noted that, when data from only the pivotal MDX010-20 trial were included, the manufacturer's ICER was £42,200 per QALY gained. The corresponding ICER calculated by the ERG using their preferred mixed exponential approach was £58,600 per QALY gained. The Committee previously considered (see section 4.4) that pooling of the 3 mg/kg data from the CA 184-022 trial with data from the MDX010-20 trial was inappropriate, and therefore only the ICERs calculated using the MDX010-20 data alone were appropriate for further consideration. It therefore gave further consideration to the manufacturer's ICER of £42,200 per QALY gained and the ERG's updated preferred estimate of £58,600 per QALY gained. The Committee appreciated that the correct modelling approach was uncertain, but found no evidence to indicate that the ERG's approach was based on more plausible assumptions than the manufacturer's approach. The Committee concluded that the manufacturer's ICER of £42,200 per QALY gained was a plausible estimate. The Committee considered the manufacturer's additional scenario analysis on vial sharing and noted that, if it was assumed that 50% of ipilimumab wastage could be avoided, the manufacturer's revised base-case deterministic ICER reduced by approximately £2000 per QALY gained (patient access scheme included). The Committee heard from the clinical specialists that it may be possible to avoid some wastage through vial sharing, particularly in the largest specialist centres, but that the manufacturer's estimate of 50% was overly optimistic. The Committee acknowledged that, although vial sharing may lead to cost savings in some specialist centres, this could be associated with additional administrative costs and logistic difficulties, and therefore it concluded that overall the impact of vial sharing on the cost effectiveness of ipilimumab was likely to be minimal. The Committee considered whether it would be appropriate to consider sensitivity analyses on the discount rates used in the model and their effects on the revised ICER. The Guide to the methods of technology appraisal clarification issued by the Board of NICE states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. Having referred to this clarification, the Committee considered that substantial restoration of health for a very long period equated to restoration of health to the extent that the person could be considered as having been effectively cured of their condition. It then considered whether ipilimumab is a treatment given with curative intent. It heard from the clinical specialists that unresectable malignant melanoma that has progressed on previous therapy is not considered to be curable. The Committee noted that a curative treatment would be expected to result in the disappearance of all visible disease (complete response), but that less than 1% of patients in the ipilimumab arms of the MDX010-20 trial showed a complete disease response. In addition, although there was trial evidence of some people whose disease remained stable after being treated with ipilimumab, it was not clear how prolonged that response might be. The clinical specialists agreed that it is too early to regard this as a curative treatment. The Committee concluded that evidence that ipilimumab was a curative treatment was lacking, and that it was unlikely to have substantial benefits for at least 30 years. The Committee therefore concluded that there was no case for differential discounting to be applied. The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust. The Committee discussed whether ipilimumab met the criteria set out for consideration as an end-of-life treatment. The Committee agreed that the life expectancy for people with advanced melanoma, particularly for those with distant metastases, as reflected in the trial population, was less than 24 months. The Committee also agreed that there was sufficient evidence to indicate that the treatment offers an extension to life of at least an additional 3 months, compared with current NHS treatment. The Committee heard from the clinical specialists that there are approximately 400–500 people with advanced melanoma that has progressed after chemotherapy each year in the UK, which represents a small patient population. Therefore the Committee was satisfied that ipilimumab met the criteria for being a life-extending end-of-life treatment and that the trial evidence presented for this was robust. The Committee was mindful that the NICE Guide to the methods of technology appraisal (2008) states that a strong case should be identified for accepting an ICER that is higher than £30,000 per QALY gained. The Committee noted that in these circumstances the NICE methods guide states that judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of: the degree of certainty around the ICER any strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured whether the innovative nature of the technology adds demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the QALY measure. Furthermore the Committee was aware of NICE's response to Sir Ian Kennedy's report Appraising the value of innovation and other benefits, which states that when considering a technology identified as having innovative characteristics, the Appraisal Committee should satisfy itself that: it can be regarded as a 'step-change' in the management of the condition, and either that the identified innovative characteristics have been taken into account in the QALY calculation (in other words, that their impact on health-related quality of life has been fully captured) or, if not, that they have been separately evaluated including their impact (if any) on the Committee's judgement of the most plausible ICER. Having accepted that the supplementary advice for appraising a life-extending end-of-life treatment applies, and that the manufacturer's ICER of £42,200 per QALY gained was plausible, but also recognising that it could be higher using other approaches to modelling overall survival, the Committee considered whether ipilimumab could be considered a cost-effective use of NHS resources. On balance, the Committee considered that, given the robust clinical data available for a period of 50 to 70 months, the likelihood of long-term effectiveness in a small proportion of patients and the innovative nature of ipilimumab, it could be concluded that ipilimumab is a cost-effective use of NHS resources. The Committee discussed whether the assessment of the change in health-related quality of life had been adequately captured in the economic analysis. It heard from a patient expert that people who are successfully treated, although in the minority, could lead an active and fulfilling life and were able to contribute to society. The Committee accepted that ipilimumab represents a valuable new therapy and that the mechanism of action is novel. It acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need. Nevertheless, the Committee considered that the clinical benefit of ipilimumab had been fully captured in the QALY calculation and concluded that, with the patient access scheme applied to the cost of ipilimumab, it had been demonstrated to be a cost-effective use of NHS resources for the treatment of advanced (unresectable or metastatic) malignant melanoma for people who have received prior therapy. # Summary of Appraisal Committee's key conclusions TA268 Appraisal title: Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma Section Key conclusions Ipilimumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in people who have received prior therapy, only if the manufacturer provides ipilimumab with the discount agreed in the patient access scheme. The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ipilimumab. It noted that the manufacturer derived efficacy data primarily from the MDX010-20 trial, which showed that treatment with ipilimumab led to a statistically significant median overall survival gain of approximately 3.7 months (HR 0.66; 95% CI 0.51 to 0.87; p=0.0026) compared with gp100 for people with progressive disease after first-line therapy. The Committee heard from the clinical specialists that people treated with ipilimumab will have some survival benefit, but only 10% of people may experience long-term benefits. The Committee was aware that the trial length was 56 months, and that survival benefit was demonstrated for the length of the trial, but that there was uncertainty about continuing benefit thereafter. Although the Committee did not agree that pooling of additional data was appropriate, it considered that additional survival evidence presented by the manufacturer supported the pivotal MDX010-20 trial results and increased confidence in the benefits of ipilimumab. The Committee was satisfied that ipilimumab met the criteria for being a life-extending end-of-life treatment, and that the trial evidence presented for this consideration was robust. The Committee acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need. The Committee considered that the manufacturer's ICER of £42,200 per QALY gained was a plausible estimate and within the range that may be considered a cost-effective use of NHS resources in the context of an end-of-life treatment, but recognised that the ICER could be higher using other approaches to overall survival modelling. Current practice Clinical need of patients, including the availability of alternative treatments Unresectable melanoma substantially worsens quality of life and, without effective new therapies, the prognosis for advanced disease is very poor. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee heard from the clinical specialists that they considered ipilimumab to represent a 'step-change' in the treatment of advanced melanoma and that it is the first new treatment available in 30 years that may offer clinical benefit and possible long-term survival gain for people with advanced, unresectable disease that has progressed after first-line therapy. What is the position of the treatment in the pathway of care for the condition? The optimal place for ipilimumab in the current clinical pathway for advanced (unresectable or metastatic) melanoma is still being debated in the clinical community. But the Committee understood that most clinicians in the UK would use ipilimumab as a second-line treatment in line with its UK marketing authorisation. Adverse reactions Although the adverse reactions and mortality associated with ipilimumab seen in the MDX010-20 trial were considerable, most adverse reactions, including those that led to hospital admission, are considered manageable and are likely to be managed more effectively as clinicians become familiar with ipilimumab's toxicity profile. The Committee concluded that people may be willing to tolerate considerable toxicity if there are potential survival benefits. Evidence for clinical effectiveness Availability, nature and quality of evidence The manufacturer derived efficacy data primarily from the MDX010-20 trial, which showed that treatment with ipilimumab led to a statistically significant median overall survival gain of approximately 3.7 months compared with gp100 for people with progressive disease after first-line therapy. The Committee was aware that the trial length was 56 months, and that survival benefit was demonstrated for the length of the trial, but that there was uncertainty about continuing benefit thereafter. The Committee considered that the additional data presented by the manufacturer provided support for the MDX010-20 trial results and increased confidence in the benefits of ipilimumab. The ERG commented that the MDX010-20 study was well designed. Relevance to general clinical practice in the NHS The Committee heard from the ERG that it was satisfied that the participants in the MDX010-20 study were representative of patients in UK clinical practice. The UK marketing authorisation for ipilimumab stipulates that people should receive all 4 doses of treatment, even if the disease appears to progress during treatment. The Committee heard from the clinical specialists that late responses to treatment have been reported. It heard that people should therefore continue to be treated, unless their disease progresses so far that a response is very unlikely, or the side effects become intolerable. Uncertainties generated by the evidence The Committee noted that a curative treatment would be expected to result in the disappearance of all visible disease (complete response), but less than 1% of patients in the ipilimumab arms of the MDX010-20 trial showed a complete disease response. In addition, although there was trial evidence of some people whose disease remained stable after being treated with ipilimumab, it was not clear how prolonged that response might be. The clinical specialists agreed that it is too early to regard this as a curative treatment. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? No clinically relevant subgroups were identified. No patient characteristics or biomarkers have been identified that can prospectively identify the minority of people most likely to benefit from receiving ipilimumab. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee heard from the clinical specialists that people treated with ipilimumab will have some survival benefit, but only 10% of people may experience long-term benefits. Evidence for cost effectiveness Availability and nature of evidence The manufacturer developed a model in which people treated with ipilimumab were compared with those who received best supportive care. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee noted that the manufacturer assumed that the gp100 vaccine was clinically comparable to best supportive care and used the efficacy estimates from the gp100 arm in the MDX010-20 trial to inform model inputs. The Committee agreed with the clinical specialists that gp100 was likely to be an acceptable proxy for best supportive care in the model. The length of follow-up in the MDX010-20 trial was too short to provide robust evidence of the overall survival gain beyond the length of the trial. The Committee expressed confidence in the data from the MDX010-20 trial, supported by data from 3 smaller trials, but noted that beyond this time period the calculation of overall survival gain was dependent on the modelling approach used for extrapolation. The Committee accepted that the supplementary advice for appraising a life-extending end-of-life treatment applies, and that the manufacturer's ICER of £42,200 per QALY gained was plausible, but recognised that it could be higher using other approaches to modelling overall survival. On balance, the Committee considered that, given the robust clinical data available for a period of 50 to 70 months, the likelihood of long-term effectiveness in a small proportion of patients and the innovative nature of ipilimumab, it could be concluded that ipilimumab is a cost-effective use of NHS resources. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? EORTC-QLQ and SF-36 data were collected in the MDX010-20 trial. The Committee noted the ERG's concerns that the number of respondents to the questionnaires dropped off considerably after week 12 in the MDX010-20 trial and that there was little difference between the utilities assigned to the progression-free and the progressive disease health states. The Committee noted that additional sensitivity analyses conducted by the manufacturer in response to the appraisal consultation document showed that the utility assumed for the progressive disease state was not a major driver of cost effectiveness. The Committee concluded that the utility estimates derived by the manufacturer were acceptable. The Committee considered that the clinical benefit of ipilimumab had been fully captured in the QALY calculation. Are there specific groups of people for whom the technology is particularly cost effective? No specific groups were identified for whom ipilimumab was particularly cost effective. What are the key drivers of cost effectiveness? The Committee noted that the approach to modelling overall survival was the key driver of cost effectiveness for ipilimumab. Most likely cost-effectiveness estimate (given as an ICER) The Committee concluded that the manufacturer's ICER of £42,200 per QALY gained was a plausible estimate, but recognised that the ICER could be higher using other approaches to overall survival modelling. Additional factors taken into account Patient access schemes (PPRS) The manufacturer of ipilimumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of ipilimumab is offered. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. End-of-life considerations The Committee agreed that the life expectancy for people with advanced melanoma, particularly for those with distant metastases, was less than 24 months. The Committee also agreed that there was sufficient evidence to indicate that the treatment offers an extension to life of at least an additional 3 months, compared with current NHS treatment. The Committee heard from the clinical specialists that there are approximately 400–500 people with advanced melanoma that has progressed after chemotherapy each year in the UK, which represents a small patient population. The Committee was satisfied that ipilimumab met the criteria for being a life-extending end-of-life treatment and that the trial evidence presented for this consideration was robust. Equalities considerations and social value judgements No equalities issues were identified during the scoping exercise or appraisal process. -# Recommendations for further research Currently, there is an ongoing trial investigating the immunogenicity and analysing biomarkers in people receiving neoadjuvant ipilimumab treatment for melanoma. There is also a trial analysing tissue and blood biomarkers from people with stage III or stage IV melanoma treated with ipilimumab with or without granulocyte-macrophage colony-stimulating factor. The Committee noted the fact that no biomarkers have yet been identified in people with melanoma in whom ipilimumab had a long-term benefit. The Committee considered that further research should be conducted to identify biomarkers or patient characteristics in people who receive long-term benefit from ipilimumab. These biomarkers or patient characteristics could lead to a better targeted treatment pathway that would improve outcomes for people with melanoma. Furthermore, the Committee considered that, with the subsequent advent of melanoma treatments for specific mutations, further research should be conducted to assess the impact of ipilimumab on subgroups based on mutation type.# Related NICE guidance Published Improving outcomes for people with skin tumours including melanoma. NICE cancer service guidance (2006) Referral guidelines for suspected cancer. NICE clinical guideline 27 (2005). Improving supportive and palliative care for adults with cancer. NICE cancer service guidance (2004). Under development NICE is developing the following guidance (details available from the NICE website): Ipilimumab in combination with dacarbazine for previously untreated unresectable stage III or IV malignant melanoma (publication date to be confirmed). Skin cancer: how the NHS and local authorities can help prevent skin cancer using public information, sun protection resources and by making changes to the environment (publication date to be confirmed).# Review of guidance The guidance on this technology will be considered for review in November 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveDecember 2012# Changes after publication January 2014: minor maintenance.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Ipilimumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in people who have received prior therapy, only if the manufacturer provides ipilimumab with the discount agreed in the patient access scheme.', 'The technology ': "Ipilimumab (Yervoy, Bristol-Myers Squibb Pharmaceuticals) is a fully human antibody that binds to cytotoxic T lymphocyte-associated antigen\xa04 (CTLA-4), a molecule expressed on T-cells that plays a critical role in regulating natural immune responses. Ipilimumab has a UK marketing authorisation for 'the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy'. For further information, see the summary of product characteristics.\n\nIpilimumab is most commonly associated with adverse reactions resulting from increased or excessive immune activity including diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe recommended dose of ipilimumab is 3\xa0mg per kilogram of body weight (mg/kg) administered intravenously over a 90-minute period every 3\xa0weeks, with a total of 4\xa0doses for the full treatment course. The summary of product characteristics states that all 4\xa0doses should be administered 'as tolerated, regardless of the appearance of new lesions or growth of existing lesions'. Ipilimumab costs £3750 for 50\xa0mg and £15,000 for 200\xa0mg (excluding VAT, British national formulary, September 2012). Assuming an average body weight of 70\xa0kg, each dose of ipilimumab would need a 200\xa0mg vial and a 50\xa0mg vial costing £18,750. A 4-dose course would therefore cost £75,000, not including administration costs. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of ipilimumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of ipilimumab is offered. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ipilimumab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe key evidence for the clinical effectiveness of ipilimumab came from 1\xa0trial (MDX010-20), which assessed the efficacy and safety of ipilimumab in adults with advanced, unresectable stage\xa0III or stage\xa0IV malignant melanoma who had been previously treated with interleukin-2, dacarbazine, temozolomide or other chemotherapies. This evidence was supported by results from a dose-ranging trial (CA\xa0184-022), and a safety and tolerability trial (CA\xa0184-007).\n\nThe MDX010-20 trial was an international, multicentre, double-blind, 3-armed, randomised, controlled trial. A total of 676\xa0adults with advanced malignant melanoma were randomised to receive ipilimumab 3\xa0mg/kg in combination with an investigational gp100 peptide vaccine ('ipilimumab plus gp100'; n=403), ipilimumab 3\xa0mg/kg in combination with placebo ('ipilimumab alone'; n=137), or gp100 in combination with placebo ('gp100 alone'; n=136) every 3\xa0weeks for 4\xa0cycles. Approximately 38% of patients in the trial were from Europe, with 8% from the UK. The patients were all HLA-A*0201 (human leukocyte antigen serotype group) positive and were generally well balanced for key baseline characteristics. At study entry, nearly all patients (98.2%) had stage\xa0IV disease.\n\nThe primary outcome of the MDX010-20 trial was overall survival for people treated with ipilimumab plus gp100 compared with gp100 alone. Secondary outcomes in the trial included overall survival in people treated with ipilimumab plus gp100 compared with ipilimumab alone, best objective response rate, disease control rate, duration of response, progression-free survival, time to progression and health-related quality of life.\n\nResults from the MDX010-20 trial showed that ipilimumab plus gp100 led to a statistically significant increase in median overall survival by approximately 3.5\xa0months compared with gp100 alone (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.55 to 0.85; p=0.0004). When ipilimumab alone was compared with gp100 alone, ipilimumab increased median overall survival by approximately 3.7\xa0months (HR\xa00.66; 95% CI 0.51 to 0.87; p=0.0026). There was no statistically significant difference in median overall survival between people treated with ipilimumab plus gp100 and those treated with ipilimumab alone (HR\xa01.04; 95% CI 0.83 to 1.30; p=0.7575), which the manufacturer considered was evidence that gp100 did not influence the overall survival outcome when combined with ipilimumab treatment. Approximately 65% of people treated with an ipilimumab-containing regimen received all 4\xa0doses of ipilimumab in line with the licensed regimen, and in this subgroup the median survival in both the gp100 and ipilimumab arms was greater than in those who received fewer than the full 4\xa0doses. The differences in survival gain between the ipilimumab and gp100 arms were also more favourable in people treated with all 4\xa0doses (results provided as academic in confidence). All response-related secondary outcomes (including best objective response rate and progression-free survival) showed positive results for people who received treatment with an ipilimumab-containing regimen compared with people who received gp100 alone.\n\nThe CA\xa0184-022 trial was a double-blind, multicentre, dose-ranging, randomised, controlled trial that included 217\xa0patients with previously treated, treatment-refractory or treatment-intolerant unresectable stage\xa0III or stage\xa0IV melanoma. They were randomised to receive either ipilimumab 0.3\xa0mg/kg, 3\xa0mg/kg or 10\xa0mg/kg every 3\xa0weeks for 4\xa0cycles followed by maintenance therapy every 3\xa0months. The outcomes included estimated best objective response rate, progression-free survival at 24\xa0weeks, median overall survival and duration of response. The CA\xa0184-007 trial was a double-blind, multicentre, randomised, controlled trial. Patients (n=115) with unresectable stage\xa0III or stage\xa0IV melanoma who were treatment naive or who had been previously treated were randomised to receive open-label ipilimumab (10\xa0mg/kg at weeks\xa01, 4, 7 and 10) with either concomitant oral budesonide or placebo. The outcomes included adverse reactions (specifically diarrhoea), best objective response rate, duration of response and overall survival.\n\nThe most common adverse reactions associated with ipilimumab treatment reported in the 3\xa0trials included in the manufacturer's submission resulted from increased or excessive immune activity. They included diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain. These adverse reactions were considered to be generally medically manageable and usually reversible with topical and/or systemic immunosuppressants. Progressive disease was the most frequent reason for death in the MDX010-20 and CA\xa0184-022 studies. There were 14 (2.2%) adverse reactions with an outcome of death in the MDX010-20 trial that related to the study treatments; 8\xa0deaths in the ipilimumab plus gp100 group, 4 in the ipilimumab alone group and 2 in the gp100 alone group. Of those deaths, 7 were associated with immune-related adverse reactions (including colitis, bowel perforation and organ failure): 5 in the ipilimumab plus gp100 group and 2 in the ipilimumab alone group.\n\nThe manufacturer undertook a systematic search and identified 10 economic evaluations in pre-treated or advanced melanoma. None of the studies evaluated ipilimumab. The manufacturer therefore submitted a de novo economic evaluation in which people treated with ipilimumab were compared with those who received best supportive care. There were 4\xa0mutually exclusive states included in the model: baseline disease, non-progressive disease, progressive disease and death. All people were assumed to start in the baseline disease state (after chemotherapy), then at the end of each cycle they could move to the non-progressed health state or to the progressed health state, or they could die. The model used daily cycles for the first 5\xa0years during the trial period, and weekly cycles thereafter for a lifetime (30\xa0year) horizon. The perspective adopted in the economic evaluation was that of the NHS and personal social services, and costs and benefits were discounted at 3.5% per year.\n\nThe proportion of people in each health state was calculated using progression-free survival and overall survival data from the MDX010-20 trial. Data on progression-free survival and overall survival for people receiving best supportive care were not available directly from the trial. However, results from the trial showed that treatment with gp100 alone led to a median overall survival of 6.4\xa0months, which was consistent with survival estimates achieved with best supportive care. Therefore, data from the gp100 arm of the trial were assumed by the manufacturer to be a proxy for the course of disease in people receiving best supportive care. Adverse-reaction rates for ipilimumab and best supportive care were estimated from the MDX010-20 trial. The resource costs included in the model were drug acquisition and administration costs, and the cost of the disease, which included costs related to each health state and of treating adverse reactions.\n\nIn the manufacturer's original submission, 2\xa0approaches to parametric curve fitting for the survival modelling were presented. The first strategy involved a single curve fit approach that showed that none of the curves fitted the Kaplan-Meier data from the MDX010-20 study. The second strategy involved using a 2-part curve fit in which the Kaplan-Meier estimates for overall survival and progression-free survival were used for the first 18\xa0months and 'best-fit' parametric curves were used thereafter. The manufacturer concluded that the 'best-fit' curves were: exponential for progression-free survival in the ipilimumab arm, Gompertz for overall survival in the ipilimumab arm and exponential for overall survival in the best supportive care arm. Progression-free survival in the best supportive care arm was represented by the overall survival arm.\n\nHealth-related quality of life was measured in the MDX010-20 trial, which used the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the short form 36 (SF-36) questionnaires. The questionnaires were predominantly completed by trial participants at baseline and week\xa012, with only 26\xa0questionnaires completed after week\xa012. For the economic analysis, utilities were obtained from responses to the EORTC QLQ-C30 from 971 trial observations using a recently developed preference-based version of the instrument. The utility values assumed for the progression-free disease and progressive disease health states in the model were 0.80 (95% CI 0.53 to 0.97) and 0.76 (95% CI 0.46 to 0.97) respectively. The manufacturer also conducted a systematic review to identify studies that included health-related quality-of-life data for people with metastatic melanoma. One study was identified that included 63\xa0patients from the UK and 77\xa0patients from Australia who valued 'vignettes' or descriptions of advanced melanoma health states developed by the researchers.\n\nIn the manufacturer's original base case, ipilimumab treatment led to an undiscounted incremental gain in overall survival of 33.8\xa0months compared with best supportive care. The incremental cost-effectiveness ratio (ICER) for ipilimumab compared with best supportive care was £60,737 per quality-adjusted life year (QALY) gained (incremental cost of £83,351 and incremental benefit of 1.37 QALYs). This was based on the assumption that all patients received 3.3\xa0doses of ipilimumab at 3\xa0mg/kg body weight, corresponding with the average number of doses used in the clinical trial.\n\nProbabilistic sensitivity analysis reported a 14% chance of ipilimumab being cost effective compared with best supportive care at £50,000 per QALY gained. Deterministic sensitivity analyses showed that the ICER was sensitive to the utility values assumed for the progressive disease health state. An increase in this utility value reduced the ICER and conversely a reduction in utility increased the ICER. For example, using a lower utility (0.60) for progressive disease increased the base-case ICER to £73,854 per QALY gained. Structural sensitivity analysis also showed that decreasing the discount rate to 0% reduced the ICER from £60,737 to £42,871 per QALY gained because the long-term benefits of ipilimumab in the base case were discounted to a large degree, whereas costs of treatment were only incurred in the first year of the model, and therefore were unaffected by discounting.\n\nThe manufacturer also conducted scenario analyses to explore the effect on the ICER of assumptions about the amount of each dose of ipilimumab needed per patient and the possibility of vial sharing. Results from these analyses showed that the dose of ipilimumab given per patient has a large impact on the manufacturer's ICER, with the minimum dose given in the trial and compassionate use programme (3×50\xa0mg) resulting in an ICER of £38,387 per QALY gained and the maximum dose (2×200\xa0mg) given resulting in an ICER of £88,788 per QALY gained. In addition, the results showed that vial sharing has the potential to reduce the manufacturer's original base-case ICER to £55,824 per QALY gained.\n\nThe ERG reviewed the clinical-effectiveness evidence for ipilimumab and noted that none of the studies included in the manufacturer's submission compared ipilimumab with any of the comparators listed in the decision problem (best supportive care, carboplatin-based chemotherapy and dacarbazine). The ERG commented that the MDX010-20 study was well designed and that it was satisfied that the participants were representative of patients in UK clinical practice. The ERG expressed concern that the manufacturer considered gp100 clinically comparable to best supportive care because patient outcomes in the gp100 alone arm of the MDX010-20 study appeared less favourable than might be expected in untreated people.\n\nThe ERG commented that the clinical data provided by the manufacturer suggested that treatment with ipilimumab was associated with a long-term overall survival benefit over gp100 for a small number of patients. However, it noted that to date no patient characteristics or biomarkers have been identified that can prospectively identify the people most likely to benefit from treatment with ipilimumab. The ERG noted that the European Medicines Agency considered a number of supplementary analyses carried out by the manufacturer in an attempt to identify possible subgroups of people who might (or might not) benefit from treatment with ipilimumab. However, the subgroups were small and the ERG determined that no conclusions could be drawn from this analysis.\n\nThe ERG considered that the manufacturer's model was well constructed, but it proposed a number of minor corrections and modifications, which resulted in a reduction in the base-case ICER from £60,737 to £54,462 per QALY gained. However, the ERG noted that the main weakness of the manufacturer's original model was the estimate of mean overall survival. The ERG acknowledged that the natural history and prognosis for metastatic melanoma is not well understood and the manufacturer claimed a substantial improvement in mean survival on the basis of results from a single trial. The ERG cited a study published in 1999 involving a re-analysis of 8\xa0trials of interleukin-2 for people with metastatic melanoma. Of the patients, 80% died within 2\xa0years but most of those surviving the 2-year follow-up period survived for a further 9\xa0years. The ERG noted that this response pattern was replicated in the MDX010-20 study and suggested that this was likely to be because survival rates for people with advanced metastatic melanoma vary substantially. In light of this, it is possible that the data available for analysis are weakest when improved survival is likely to generate the most added life years from the treatment. The ERG therefore noted that, although the MDX010-20 trial used by the manufacturer showed a survival advantage for ipilimumab, it was unable to reliably quantify the long-term survival benefit.\n\nThe ERG had concerns about the manufacturer's interpretation of the MDX010-20 trial data. In particular, it noted that the fitted overall survival functions beyond 18-month follow-up generated mortality risks lower than those in the general (healthy) population at a comparable age and, as a consequence, the model predicted substantial numbers of people surviving to unreasonably advanced ages (beyond 100\xa0years). To counter this anomaly, the manufacturer replaced the calculated model mortality risks with mortality risks experienced by the general population beyond 5-year follow-up. The ERG noted that this approach implied that anyone surviving beyond 5\xa0years of second-line systemic treatment was effectively cured; however, no evidence was submitted by the manufacturer in the original submission to support this claim.\n\nIn an exploratory analysis, based on the manufacturer's original submission, the ERG adopted a pragmatic approach to model overall survival by calculating the area under the Kaplan-Meier curve to a common late time point beyond which both the ipilimumab and best supportive care arms could be seen to be following long-term trend lines. It then projected further life expectancy based on calibrating a parametric function. The results from this method suggested mean undiscounted life years of 11.2\xa0months for gp100 alone and 27.4\xa0months for the combined ipilimumab arms from the MDX010-20 trial, which equated to a mean gain in overall survival of 16.2\xa0months. These results were noted to be less than half the value calculated in the base case of the manufacturer's original model (that is, a mean gain in overall survival of 33.8\xa0months). Using the revised projections, the ERG noted that the manufacturer's original base-case ICER increased to £96,717 per QALY gained. The ERG stated that its exploratory analysis on overall survival cannot be considered definitive because the volume and duration of patient data available from the MDX010-20 trial were inadequate to achieve survival projections that can be used as a basis for decision-making. However, the ERG considered that the manufacturer's original model is likely to have overestimated the extent of survival benefit associated with treatment with ipilimumab, which would have a considerable effect on the ICER.\n\nIn response to consultation, the manufacturer offered an alternative approach to modelling long-term survival for people who are treated with ipilimumab. The manufacturer used a 3-part curve fit approach with Kaplan-Meier analysis results from MDX010-20 unmodified for the first 18\xa0months, followed by a parametric model (Gompertz) fitted to the trial data from 18\xa0months to 5\xa0years and, thereafter, hazards derived from analysis of a malignant melanoma disease register modified by background mortality rates. The manufacturer used data from a published register of 1158\xa0patients with stage\xa0IV melanoma in the USA. The manufacturer used the survival curve from this analysis as the basis for estimating the extended survival of patients (beyond 5\xa0years) in the MDX010-20 trial. This was further modified to include age-related mortality because the register data included melanoma-related death only. In this revised model the survival estimates were further adjusted, using a Cox proportional hazards regression, to reflect the difference in overall survival for long-term survivors in the combined ipilimumab treatment groups (ipilimumab alone and ipilimumab plus gp100) and the gp100 alone group (HR\xa00.782). By including this revised approach in the model, the estimated survival gain for people treated with ipilimumab was 30.0\xa0months (compared with their original estimate of 33.8\xa0months).\n\nThe Department of Health agreed a patient access scheme in which a simple discount is applied to the list price of ipilimumab. For the analyses including the scheme, the manufacturer presented additional survival data from 3\xa0smaller trials (CA\xa0184-007, CA\xa0184-008 and CA\xa0184-022: all individual parent studies included in CA\xa0184-025) comprising patients who initially received 0.3\xa0mg/kg, 3\xa0mg/kg or 10\xa0mg/kg dosages of ipilimumab. The manufacturer identified 72\xa0patients from a dose-ranging study (CA\xa0184-022), who had received previous treatment and then ipilimumab at the licensed dose of 3\xa0mg/kg. These were considered to be comparable to the patients treated with ipilimumab in the MDX010-20 trial, and the manufacturer presented a pooled analysis of the MDX010-20 trial patients supplemented by these patients from the CA\xa0184-022 trial. The manufacturer also proposed a broader pooling of all data from patients treated with ipilimumab, regardless of dosing level. The manufacturer stated that these additional data, which provided follow-up information on patients treated with ipilimumab for between 50 and 70\xa0months, confirmed the long-term effect of ipilimumab at all dosages.\n\nThe manufacturer's revised base-case analysis was calculated using the 3-part curve fit approach, the patient access scheme, and trial data for patients receiving the 3\xa0mg/kg dose of ipilimumab in the MDX010-20 trial pooled with 72\xa0patients from the CA\xa0184-022 dose-ranging trial receiving the same dose. This resulted in a revised base-case deterministic ICER of £46,739 per QALY gained for ipilimumab compared with best supportive care. Using only the MDX010-20 trial data, the ICER was £42,211 per QALY gained. The manufacturer considered that the probabilistic sensitivity analyses showed a low level of parameter-related uncertainty around the baseline ICER and reported that there was an approximately 81% chance that the ICER for ipilimumab would be less than £50,000 per QALY gained when the patient access scheme was included.\n\nThe manufacturer conducted structural sensitivity analyses and scenario analyses exploring the impact of alternate curve fits, varied cut-off points in the 3-part curve fit approach, alternative sources of observational data and the use of the ERG approach on the overall survival benefit of ipilimumab. The manufacturer stated that the only scenario in which the ICER rose above £50,000 per QALY gained was when the manufacturer adopted the ERG approach for survival estimation, which resulted in an ICER of £55,807 per QALY gained. Further scenario analyses involved excluding patients who crossed over between different doses of ipilimumab and resulted in a nominal reduction in the ICER to £44,426 per QALY gained. The manufacturer stated that the areas identified as potentially problematic by the ERG, such as cut-off points and sources of observational data, did not have a large impact on the ICER, and that the increased patient numbers and number of trials with similar results reduced the uncertainty associated with the estimation of longer-term survival.\n\nThe manufacturer noted that, although the summary of product characteristics for ipilimumab does not recommend vial sharing, discussions with clinicians indicated that vial sharing may be possible in some clinical centres in the UK. The manufacturer provided scenario analyses to explore the impact of vial sharing and noted that, if 50% of ipilimumab wastage was avoided through vial sharing, then the revised base-case ICER would be reduced. The manufacturer also suggested that, if drug-specific utilities were used instead of pooled utilities (which were used in the original economic model), then the revised base-case ICER would decrease further.\n\nThe manufacturer conducted sensitivity analyses using the discount rate of 1.5% for costs and benefits, and also a discount rate of 3.5% for costs and 1.5% for benefits. These resulted in ICERs of £39,714 and £38,323 respectively per QALY gained. The manufacturer's probabilistic sensitivity analysis indicated that, in these scenarios, the ICER for ipilimumab is 94% and 100% likely to be less than £50,000 per QALY gained respectively.\n\nThe ERG considered the manufacturer's revised long-term survival projections submitted in response to consultation. It believed that the main weakness of the manufacturer's survival model was in not providing a rationale, other than replicating the observed data, to support the division of data into 3\xa0time periods and the use of different methods in each period. Furthermore, there were substantial differences between the populations in the MDX010-20 trial and the disease register in terms of patients' initial diagnosis, treatment history and time from initial diagnosis. The ERG also considered that the manufacturer's approach to deriving the long-term hazard ratio was problematic because of the small number of people in the analysis for the gp100 group in the trial (n=19) and the fact that the long-term survival trends were established much earlier in the gp100 group (about 300\xa0days) than in the combined ipilimumab treatment group (about 750\xa0days), which could lead to bias in the hazard ratio. In light of these concerns, the ERG considered that the survival projections presented by the manufacturer in response to consultation were uncertain.\n\nThe ERG reviewed the manufacturer's assumptions about vial sharing. It considered that although vial sharing is theoretically possible, in reality it would be difficult to implement because only 250–300\xa0people nationally will need treatment each year, which only equates to 1–2\xa0people in each centre each month. Therefore, the ERG was not convinced that any specialist centre could achieve regular savings in ipilimumab costs from organised vial sharing.\n\nERG comments on manufacturer's additional analyses (including the patient access scheme)\n\nThe ERG reviewed the manufacturer's alternative data sets based on the pooling of selected data from several smaller clinical studies with data from the main MDX010-20 trial. The ERG thought that the patient population was too dissimilar to the MDX010-20 trial to allow direct comparison, and that not all studies involved the dosing regimen of ipilimumab (3\xa0mg/kg) for which marketing authorisation has been granted. Therefore, the ERG considered that the broader pooling of data from all patients who received ipilimumab, regardless of dosing regimen or patient baseline characteristics, would lead to uninterpretable results.\n\nRegarding the pooling of 3\xa0mg/kg data from the MDX010-20 trial and the CA\xa0184-022 study, the ERG thought that pooling isolated treatment arms across trials was inappropriate because it would break randomisation and therefore invalidate any comparison between the intervention treatment and the comparator. Furthermore, there were no equivalent comparator treatment arms available in the CA\xa0184-022 study to balance the pooling of the ipilimumab trial arms. Finally, the ERG thought that the additional data from the CA\xa0184-022 study did not extend the length of follow-up beyond that in the MDX010-20 trial, and therefore did not reduce the uncertainty surrounding long-term outcomes. Therefore, the ERG considered that it was only appropriate to include data from the MDX010-20 trial. Consequently, the ERG found that the patient access scheme would decrease the ICER for ipilimumab compared with best supportive care to £66,520 per QALY gained.\n\nHowever, the ERG carried out further analyses aimed at clarifying the possible mechanisms underlying the pattern of overall survival observed in the clinical trials and disease registers for patients with advanced malignant melanoma. The ERG proposed a hypothesis assuming that patients with advanced malignant melanoma are drawn from 2\xa0distinct subgroups of unknown aetiology and that each subgroup is characterised by a separate hazard rate that does not vary over time. Based on this, a mixed exponential distribution for overall survival, which consisted of the proportion of the population comprising one of the subgroups and separate hazard rates for each of the subgroups, was considered appropriate. The ERG tested this approach by applying it to published results from 2\xa0large patient registries, which resulted in strong correspondence to the observed data in both data sets and for each disease stage. The results of this method of projecting overall survival in the submitted model, using only the MDX010-20 trial data, resulted in a mean gain in overall survival of 20.9\xa0months. Using this method, combined with the patient access scheme, resulted in an ICER of £58,590 per QALY gained. The ERG's revised approach implies that patients fall into 2\xa0distinct groups in relation to mortality risk, but currently no direct evidence is available to explain how such a differentiation may occur. The ERG also noted that the melanoma databases used in testing the revised approach featured patients from the time of diagnosis, but their use in modelling (both by the manufacturer and by the ERG) began at the time of randomisation, at which point patients may have survived several years of treatment. As a result, direct use of database trends could be misleading.\n\nFull details of all the evidence are in the manufacturer's submission, the ERG report, the manufacturer's response to the appraisal consultation document, further evidence and analyses, and the ERG's critique of the manufacturer's responses, which are available from www.nice.org.uk/guidance/TA268.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ipilimumab, having considered evidence on the nature of advanced (unresectable or metastatic) melanoma and the value placed on the benefits of ipilimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from the clinical specialists that they considered ipilimumab to represent a 'step-change' in the treatment of advanced melanoma and that it is the first new treatment available in 30\xa0years that may offer clinical benefit and possible long-term survival gain for people with advanced, unresectable disease that has progressed after first-line therapy. Other drugs are also in development. The Committee heard that the optimal place for ipilimumab treatment in the clinical pathway for advanced (unresectable or metastatic) melanoma was still being debated in the clinical community. However, the Committee understood that most clinicians in the UK would use ipilimumab as a second-line treatment in line with its UK marketing authorisation. The Committee heard from a patient expert that unresectable melanoma substantially worsens quality of life and, without effective new therapies, the prognosis for advanced disease is very poor. The Committee concluded that there was a significant unmet need for effective therapies in this patient population.\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ipilimumab. It noted that the manufacturer derived efficacy data primarily from the MDX010-20 trial, which showed that treatment with ipilimumab led to a statistically significant median overall survival gain of approximately 3.7\xa0months (HR\xa00.66; 95% CI 0.51 to 0.87; p=0.0026) compared with gp100 for people with progressive disease after first-line therapy. The Committee heard from the clinical specialists that people treated with ipilimumab will have some survival benefit, but only 10% of people may experience long-term benefits. The Committee was aware that the trial length was 56\xa0months, and that survival benefit was demonstrated for the length of the trial, but that there was uncertainty about continuing benefit thereafter. The clinical specialists indicated that melanoma may have an unpredictable clinical course and that late recurrences are well recognised. The Committee noted that a curative treatment would be expected to result in the disappearance of all visible disease (complete response), but less than 1% of patients in the ipilimumab arms of the MDX010-20 trial showed a complete disease response. In addition, although there was trial evidence of some people whose disease remained stable after being treated with ipilimumab, it was not clear how prolonged that response might be. The clinical specialists agreed that it is too early to regard this as a curative treatment.\n\nThe Committee further considered the additional data presented by the manufacturer. These data were presented to provide further evidence of the survival benefit of ipilimumab over a period of 50 to 70\xa0months' follow-up, and to supplement the evidence from the MDX010-20 trial. The Committee agreed that these additional data supported the findings in the MDX010-20 trial, but agreed with the ERG that the pooling of these additional data with data from the MDX010-20 trial was inappropriate and should not be included in the economic modelling. The Committee concluded that the evidence on the clinical effectiveness of ipilimumab was robust for a period of at least 5\xa0years, and that a small proportion of patients were likely to benefit from ipilimumab in the long term.\n\nThe Committee considered the adverse reactions associated with treatment with ipilimumab. The Committee understood from the clinical specialists and patient experts that people being treated with ipilimumab can have immune-related adverse reactions, which have a substantial negative impact on their quality of life. The Committee noted that 12\xa0deaths related to treatment with ipilimumab occurred in the MDX010-20 trial, but heard from the clinical specialists that subsequent trials of ipilimumab as first-line treatment have not reported any treatment-related deaths. The clinical specialists considered that this indicated that, as experience with ipilimumab grows, adverse reactions will be more quickly identified and treated. The Committee also heard from the patient experts that the possible survival benefits from adhering to treatment with ipilimumab outweigh the severe adverse reactions. The Committee concluded that although the adverse reactions and mortality associated with ipilimumab seen in the MDX010-20 trial were considerable, most adverse reactions, including those that led to hospital admission, were manageable and would be managed more effectively as clinicians become familiar with ipilimumab's toxicity profile. It also concluded that people may be willing to tolerate considerable toxicity if there are potential survival benefits.\n\nThe Committee noted that the UK marketing authorisation for ipilimumab stipulates that people should receive all 4\xa0doses of treatment, even if the disease appears to progress during treatment. The Committee heard from the clinical specialists that late responses to treatment have been reported. It heard that people should therefore continue to be treated unless their disease progresses to a degree that a response is very unlikely, or the side effects become intolerable. The Committee also understood from the clinical specialists that, although it is not possible to predict how a person's condition might respond to ipilimumab, people who experience a substantial decrease in performance status while receiving treatment are likely to have rapidly progressive disease and will not benefit from continued use of ipilimumab. The clinical specialists indicated that despite guidance on the use of all 4\xa0doses, normal clinical evaluation and discussion with patients would be carried out to determine whether or not it was reasonable to continue with treatment. The Committee noted that approximately 65% of people treated with ipilimumab in the MDX010-20 trial received all 4\xa0doses of treatment. They also heard from the clinical specialists that it is likely that more than 65% of people treated with ipilimumab in clinical practice would receive all 4\xa0doses. The Committee concluded that it was reasonable to assume that not all patients would receive 4\xa0doses of ipilimumab in clinical practice despite the administration advice in the UK marketing authorisation.\n\nThe Committee discussed the cost-effectiveness estimates from the manufacturer's original and revised economic models, the assumptions on which these were based, and the ERG's critique and exploratory analyses. The Committee noted that the manufacturer assumed that the gp100 vaccine was clinically comparable to best supportive care and used the efficacy estimates from the gp100 arm in the MDX010-20 trial to inform model inputs. The Committee understood from the clinical specialists that, although studies of vaccines (other than gp100) in people with advanced and metastatic melanoma have shown a survival disadvantage, there is no evidence that this occurs for people treated with gp100. The Committee agreed with the clinical specialists that gp100 is likely to be an acceptable proxy for best supportive care in the model.\n\nThe Committee heard from the manufacturer that EORTC-QLQ and SF-36 data were collected in the MDX010-20 trial. It noted the ERG's concerns that the number of respondents to the questionnaires dropped off considerably after week\xa012 in the MDX010-20 trial and that there was little difference between the utilities assigned to the progression-free and the progressive disease health states. The Committee noted that additional sensitivity analyses conducted by the manufacturer in response to the appraisal consultation document showed that the utility assumed for the progressive disease state was not a major driver of cost effectiveness. The Committee concluded that the utility estimates derived by the manufacturer were acceptable.\n\nThe Committee noted that the length of follow-up in the MDX010-20 trial was too short to provide robust evidence of the overall survival gain beyond the length of the trial. The Committee expressed confidence in the data from the MDX010-20 trial, supported by data from 3\xa0smaller trials, but noted that beyond this time period the calculation of overall survival gain was dependent on the modelling approach used for extrapolation. It was aware that the manufacturer and the ERG had each presented 2\xa0different approaches. The manufacturer considered that the ERG's initial approach overestimated survival in the short term and underestimated it in the long term, such that the survival curve for the 3\xa0mg/kg ipilimumab dose was below that seen in the observational data, which the Committee considered was implausible. The ERG considered that its updated approach using a mixed exponential approach better fitted the data than the manufacturer's model. The Committee accepted that the MDX010-20 trial showed that ipilimumab provides a 3.7\xa0month median increase in overall survival when compared with best supportive care. However, when taking into account the small number of long-term survivors, there is a substantial degree of uncertainty about the modelling of long-term survival benefits.\n\nThe Committee considered the revised base-case ICERs presented by the manufacturer, taking into account the patient access scheme. The Committee noted that the manufacturer's base-case ICER based on the pooled 3\xa0mg data and its preferred modelling approach was £46,700 per QALY gained and that there was an 81% probability of ipilimumab being cost effective if the maximum acceptable ICER was £50,000 per QALY gained. The ICER showed relatively little change when re-evaluated using a single curve fit, or sensitivity analyses changing the cut-off points in the 3-part model. The ICER, however, rose to £55,800 per QALY gained when the manufacturer used the ERG's prior overall survival modelling approach. The Committee also noted that, when data from only the pivotal MDX010-20 trial were included, the manufacturer's ICER was £42,200 per QALY gained. The corresponding ICER calculated by the ERG using their preferred mixed exponential approach was £58,600 per QALY gained. The Committee previously considered (see section 4.4) that pooling of the 3\xa0mg/kg data from the CA\xa0184-022 trial with data from the MDX010-20 trial was inappropriate, and therefore only the ICERs calculated using the MDX010-20 data alone were appropriate for further consideration. It therefore gave further consideration to the manufacturer's ICER of £42,200 per QALY gained and the ERG's updated preferred estimate of £58,600 per QALY gained. The Committee appreciated that the correct modelling approach was uncertain, but found no evidence to indicate that the ERG's approach was based on more plausible assumptions than the manufacturer's approach. The Committee concluded that the manufacturer's ICER of £42,200 per QALY gained was a plausible estimate.\n\nThe Committee considered the manufacturer's additional scenario analysis on vial sharing and noted that, if it was assumed that 50% of ipilimumab wastage could be avoided, the manufacturer's revised base-case deterministic ICER reduced by approximately £2000 per QALY gained (patient access scheme included). The Committee heard from the clinical specialists that it may be possible to avoid some wastage through vial sharing, particularly in the largest specialist centres, but that the manufacturer's estimate of 50% was overly optimistic. The Committee acknowledged that, although vial sharing may lead to cost savings in some specialist centres, this could be associated with additional administrative costs and logistic difficulties, and therefore it concluded that overall the impact of vial sharing on the cost effectiveness of ipilimumab was likely to be minimal.\n\nThe Committee considered whether it would be appropriate to consider sensitivity analyses on the discount rates used in the model and their effects on the revised ICER. The Guide to the methods of technology appraisal clarification issued by the Board of NICE states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30\xa0years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. Having referred to this clarification, the Committee considered that substantial restoration of health for a very long period equated to restoration of health to the extent that the person could be considered as having been effectively cured of their condition. It then considered whether ipilimumab is a treatment given with curative intent. It heard from the clinical specialists that unresectable malignant melanoma that has progressed on previous therapy is not considered to be curable. The Committee noted that a curative treatment would be expected to result in the disappearance of all visible disease (complete response), but that less than 1% of patients in the ipilimumab arms of the MDX010-20 trial showed a complete disease response. In addition, although there was trial evidence of some people whose disease remained stable after being treated with ipilimumab, it was not clear how prolonged that response might be. The clinical specialists agreed that it is too early to regard this as a curative treatment. The Committee concluded that evidence that ipilimumab was a curative treatment was lacking, and that it was unlikely to have substantial benefits for at least 30\xa0years. The Committee therefore concluded that there was no case for differential discounting to be applied.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether ipilimumab met the criteria set out for consideration as an end-of-life treatment. The Committee agreed that the life expectancy for people with advanced melanoma, particularly for those with distant metastases, as reflected in the trial population, was less than 24\xa0months. The Committee also agreed that there was sufficient evidence to indicate that the treatment offers an extension to life of at least an additional 3\xa0months, compared with current NHS treatment. The Committee heard from the clinical specialists that there are approximately 400–500\xa0people with advanced melanoma that has progressed after chemotherapy each year in the UK, which represents a small patient population. Therefore the Committee was satisfied that ipilimumab met the criteria for being a life-extending end-of-life treatment and that the trial evidence presented for this was robust.\n\nThe Committee was mindful that the NICE Guide to the methods of technology appraisal (2008) states that a strong case should be identified for accepting an ICER that is higher than £30,000 per QALY gained. The Committee noted that in these circumstances the NICE methods guide states that judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of:\n\nthe degree of certainty around the ICER\n\nany strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured\n\nwhether the innovative nature of the technology adds demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the QALY measure. Furthermore the Committee was aware of NICE's response to Sir Ian Kennedy's report Appraising the value of innovation and other benefits, which states that when considering a technology identified as having innovative characteristics, the Appraisal Committee should satisfy itself that:\n\nit can be regarded as a 'step-change' in the management of the condition, and\n\neither that the identified innovative characteristics have been taken into account in the QALY calculation (in other words, that their impact on health-related quality of life has been fully captured) or, if not, that they have been separately evaluated including their impact (if any) on the Committee's judgement of the most plausible ICER.\n\nHaving accepted that the supplementary advice for appraising a life-extending end-of-life treatment applies, and that the manufacturer's ICER of £42,200 per QALY gained was plausible, but also recognising that it could be higher using other approaches to modelling overall survival, the Committee considered whether ipilimumab could be considered a cost-effective use of NHS resources. On balance, the Committee considered that, given the robust clinical data available for a period of 50 to 70\xa0months, the likelihood of long-term effectiveness in a small proportion of patients and the innovative nature of ipilimumab, it could be concluded that ipilimumab is a cost-effective use of NHS resources.\n\nThe Committee discussed whether the assessment of the change in health-related quality of life had been adequately captured in the economic analysis. It heard from a patient expert that people who are successfully treated, although in the minority, could lead an active and fulfilling life and were able to contribute to society. The Committee accepted that ipilimumab represents a valuable new therapy and that the mechanism of action is novel. It acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need. Nevertheless, the Committee considered that the clinical benefit of ipilimumab had been fully captured in the QALY calculation and concluded that, with the patient access scheme applied to the cost of ipilimumab, it had been demonstrated to be a cost-effective use of NHS resources for the treatment of advanced (unresectable or metastatic) malignant melanoma for people who have received prior therapy.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA268\n\nAppraisal title: Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma\n\nSection\n\nKey conclusions\n\nIpilimumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in people who have received prior therapy, only if the manufacturer provides ipilimumab with the discount agreed in the patient access scheme.\n\n\n\n\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ipilimumab. It noted that the manufacturer derived efficacy data primarily from the MDX010-20 trial, which showed that treatment with ipilimumab led to a statistically significant median overall survival gain of approximately 3.7\xa0months (HR\xa00.66; 95% CI 0.51 to 0.87; p=0.0026) compared with gp100 for people with progressive disease after first-line therapy. The Committee heard from the clinical specialists that people treated with ipilimumab will have some survival benefit, but only 10% of people may experience long-term benefits. The Committee was aware that the trial length was 56\xa0months, and that survival benefit was demonstrated for the length of the trial, but that there was uncertainty about continuing benefit thereafter.\n\n\n\nAlthough the Committee did not agree that pooling of additional data was appropriate, it considered that additional survival evidence presented by the manufacturer supported the pivotal MDX010-20 trial results and increased confidence in the benefits of ipilimumab.\n\n\n\nThe Committee was satisfied that ipilimumab met the criteria for being a life-extending end-of-life treatment, and that the trial evidence presented for this consideration was robust.\n\n\n\nThe Committee acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need.\n\n\n\nThe Committee considered that the manufacturer's ICER of £42,200 per QALY gained was a plausible estimate and within the range that may be considered a cost-effective use of NHS resources in the context of an end-of-life treatment, but recognised that the ICER could be higher using other approaches to overall survival modelling.\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nUnresectable melanoma substantially worsens quality of life and, without effective new therapies, the prognosis for advanced disease is very poor.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee heard from the clinical specialists that they considered ipilimumab to represent a 'step-change' in the treatment of advanced melanoma and that it is the first new treatment available in 30\xa0years that may offer clinical benefit and possible long-term survival gain for people with advanced, unresectable disease that has progressed after first-line therapy.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe optimal place for ipilimumab in the current clinical pathway for advanced (unresectable or metastatic) melanoma is still being debated in the clinical community. But the Committee understood that most clinicians in the UK would use ipilimumab as a second-line treatment in line with its UK marketing authorisation.\n\n\n\nAdverse reactions\n\nAlthough the adverse reactions and mortality associated with ipilimumab seen in the MDX010-20 trial were considerable, most adverse reactions, including those that led to hospital admission, are considered manageable and are likely to be managed more effectively as clinicians become familiar with ipilimumab's toxicity profile.\n\nThe Committee concluded that people may be willing to tolerate considerable toxicity if there are potential survival benefits.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe manufacturer derived efficacy data primarily from the MDX010-20 trial, which showed that treatment with ipilimumab led to a statistically significant median overall survival gain of approximately 3.7\xa0months compared with gp100 for people with progressive disease after first-line therapy.\n\n\n\nThe Committee was aware that the trial length was 56\xa0months, and that survival benefit was demonstrated for the length of the trial, but that there was uncertainty about continuing benefit thereafter.\n\n\n\nThe Committee considered that the additional data presented by the manufacturer provided support for the MDX010-20 trial results and increased confidence in the benefits of ipilimumab.\n\n\n\nThe ERG commented that the MDX010-20 study was well designed.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard from the ERG that it was satisfied that the participants in the MDX010-20 study were representative of patients in UK clinical practice.\n\n\n\n\n\nThe UK marketing authorisation for ipilimumab stipulates that people should receive all 4\xa0doses of treatment, even if the disease appears to progress during treatment. The Committee heard from the clinical specialists that late responses to treatment have been reported. It heard that people should therefore continue to be treated, unless their disease progresses so far that a response is very unlikely, or the side effects become intolerable.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted that a curative treatment would be expected to result in the disappearance of all visible disease (complete response), but less than 1% of patients in the ipilimumab arms of the MDX010-20 trial showed a complete disease response. In addition, although there was trial evidence of some people whose disease remained stable after being treated with ipilimumab, it was not clear how prolonged that response might be. The clinical specialists agreed that it is too early to regard this as a curative treatment.\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo clinically relevant subgroups were identified.\n\n\n\n\n\n\n\nNo patient characteristics or biomarkers have been identified that can prospectively identify the minority of people most likely to benefit from receiving ipilimumab.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee heard from the clinical specialists that people treated with ipilimumab will have some survival benefit, but only 10% of people may experience long-term benefits.\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer developed a model in which people treated with ipilimumab were compared with those who received best supportive care.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the manufacturer assumed that the gp100 vaccine was clinically comparable to best supportive care and used the efficacy estimates from the gp100 arm in the MDX010-20 trial to inform model inputs. The Committee agreed with the clinical specialists that gp100 was likely to be an acceptable proxy for best supportive care in the model.\n\n\n\nThe length of follow-up in the MDX010-20 trial was too short to provide robust evidence of the overall survival gain beyond the length of the trial. The Committee expressed confidence in the data from the MDX010-20 trial, supported by data from 3 smaller trials, but noted that beyond this time period the calculation of overall survival gain was dependent on the modelling approach used for extrapolation.\n\n\n\nThe Committee accepted that the supplementary advice for appraising a life-extending end-of-life treatment applies, and that the manufacturer's ICER of £42,200 per QALY gained was plausible, but recognised that it could be higher using other approaches to modelling overall survival. On balance, the Committee considered that, given the robust clinical data available for a period of 50 to 70\xa0months, the likelihood of long-term effectiveness in a small proportion of patients and the innovative nature of ipilimumab, it could be concluded that ipilimumab is a cost-effective use of NHS resources.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nEORTC-QLQ and SF-36 data were collected in the MDX010-20 trial. The Committee noted the ERG's concerns that the number of respondents to the questionnaires dropped off considerably after week\xa012 in the MDX010-20 trial and that there was little difference between the utilities assigned to the progression-free and the progressive disease health states. The Committee noted that additional sensitivity analyses conducted by the manufacturer in response to the appraisal consultation document showed that the utility assumed for the progressive disease state was not a major driver of cost effectiveness. The Committee concluded that the utility estimates derived by the manufacturer were acceptable.\n\n\n\n\n\nThe Committee considered that the clinical benefit of ipilimumab had been fully captured in the QALY calculation.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo specific groups were identified for whom ipilimumab was particularly cost effective.\n\n–\n\n\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted that the approach to modelling overall survival was the key driver of cost effectiveness for ipilimumab.\n\n\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that the manufacturer's ICER of £42,200 per QALY gained was a plausible estimate, but recognised that the ICER could be higher using other approaches to overall survival modelling.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer of ipilimumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of ipilimumab is offered. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd-of-life considerations\n\nThe Committee agreed that the life expectancy for people with advanced melanoma, particularly for those with distant metastases, was less than 24\xa0months.\n\nThe Committee also agreed that there was sufficient evidence to indicate that the treatment offers an extension to life of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe Committee heard from the clinical specialists that there are approximately 400–500\xa0people with advanced melanoma that has progressed after chemotherapy each year in the UK, which represents a small patient population.\n\nThe Committee was satisfied that ipilimumab met the criteria for being a life-extending end-of-life treatment and that the trial evidence presented for this consideration was robust.\n\n\n\nEqualities considerations and social value judgements\n\nNo equalities issues were identified during the scoping exercise or appraisal process.\n\n-", 'Recommendations for further research ': 'Currently, there is an ongoing trial investigating the immunogenicity and analysing biomarkers in people receiving neoadjuvant ipilimumab treatment for melanoma. There is also a trial analysing tissue and blood biomarkers from people with stage\xa0III or stage\xa0IV melanoma treated with ipilimumab with or without granulocyte-macrophage colony-stimulating factor.\n\nThe Committee noted the fact that no biomarkers have yet been identified in people with melanoma in whom ipilimumab had a long-term benefit. The Committee considered that further research should be conducted to identify biomarkers or patient characteristics in people who receive long-term benefit from ipilimumab. These biomarkers or patient characteristics could lead to a better targeted treatment pathway that would improve outcomes for people with melanoma. Furthermore, the Committee considered that, with the subsequent advent of melanoma treatments for specific mutations, further research should be conducted to assess the impact of ipilimumab on subgroups based on mutation type.', 'Related NICE guidance': 'Published\n\nImproving outcomes for people with skin tumours including melanoma. NICE cancer service guidance (2006)\n\nReferral guidelines for suspected cancer. NICE clinical guideline 27 (2005).\n\nImproving supportive and palliative care for adults with cancer. NICE cancer service guidance (2004).\n\nUnder development\n\nNICE is developing the following guidance (details available from the NICE website):\n\nIpilimumab in combination with dacarbazine for previously untreated unresectable stage\xa0III or IV malignant melanoma (publication date to be confirmed).\n\nSkin cancer: how the NHS and local authorities can help prevent skin cancer using public information, sun protection resources and by making changes to the environment (publication date to be confirmed).', 'Review of guidance': 'The guidance on this technology will be considered for review in November 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveDecember 2012', 'Changes after publication': 'January 2014:\n minor maintenance.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta268	Evidence-based recommendations on ipilimumab (Yervoy) for previously treated advanced melanoma in adults.
02455f1483e648c094b4429c6a12c535a6f44ebe	nice	Decitabine for the treatment of acute myeloid leukaemia (terminated appraisal)	Decitabine for the treatment of acute myeloid leukaemia (terminated appraisal) # Background The manufacturer of decitabine (Janssen) was invited to submit evidence for this single technology appraisal in September 2012. The manufacturer informed NICE that it had decided not to provide an evidence submission because it could not provide adequate evidence to appraise the technology in accordance with the methods and reference case employed by NICE. The manufacturer stated that the single randomised controlled trial of decitabine in acute myeloid leukaemia did not provide enough data for certain outcomes (for example, low completion rates for patient-reported health outcomes) and that the trial's design (with a mixed treatment comparator) meant there were several potential subgroups with the potential for confounding. The manufacturer also said that it would be challenging to develop an economic model to meet the decision problem because the clinical outcomes would be complicated by subsequent rescue treatments. The manufacturer said that it would therefore not be able to address the clinical and cost effectiveness of decitabine in people with acute myeloid leukaemia. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of decitabine for the treatment of acute myeloid leukaemia. If, after doing this, organisations still wish to consider decitabine for the treatment of acute myeloid leukaemia, they should follow the advice set out in Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance, which outlines the approach that should be adopted in circumstances in which NICE guidance is unavailable. NICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission. Related NICE guidance For information about NICE guidance that has been issued or is in development, see the NICE website. Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia. NICE technology appraisal guidance 218 (2011). Improving outcomes in haematological cancers. NICE cancer service guidance (2003).	{'Background': "The manufacturer of decitabine (Janssen) was invited to submit evidence for this single technology appraisal in September 2012.\n\nThe manufacturer informed NICE that it had decided not to provide an evidence submission because it could not provide adequate evidence to appraise the technology in accordance with the methods and reference case employed by NICE. The manufacturer stated that the single randomised controlled trial of decitabine in acute myeloid leukaemia did not provide enough data for certain outcomes (for example, low completion rates for patient-reported health outcomes) and that the trial's design (with a mixed treatment comparator) meant there were several potential subgroups with the potential for confounding. The manufacturer also said that it would be challenging to develop an economic model to meet the decision problem because the clinical outcomes would be complicated by subsequent rescue treatments. The manufacturer said that it would therefore not be able to address the clinical and cost effectiveness of decitabine in people with acute myeloid leukaemia.\n\nNICE has therefore terminated this single technology appraisal.", 'Information': 'NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of decitabine for the treatment of acute myeloid leukaemia. If, after doing this, organisations still wish to consider decitabine for the treatment of acute myeloid leukaemia, they should follow the advice set out in Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance, which outlines the approach that should be adopted in circumstances in which NICE guidance is unavailable.\n\nNICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission.\n\nRelated NICE guidance\n\nFor information about NICE guidance that has been issued or is in development, see the NICE website.\n\nAzacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia. NICE technology appraisal guidance 218 (2011).\n\nImproving outcomes in haematological cancers. NICE cancer service guidance (2003).'}	https://www.nice.org.uk/guidance/ta270
2d5c06e4e269776a29a7d4cda0108c80b168dfbf	nice	Dronedarone for the treatment of non-permanent atrial fibrillation	Dronedarone for the treatment of non-permanent atrial fibrillation Evidence-based recommendations on dronedarone (Multaq) for treating non-permanent atrial fibrillation in adults. # Guidance This guidance has been amended and re-issued in December 2012 to reflect changes to dronedarone's UK marketing authorisation. Please see the European Medicines Agency (EMA) website for details of the decision and the revised marketing authorisation. The therapeutic indication for dronedarone is now more restricted than that originally appraised in NICE technology appraisal guidance 197. For more information, see the summary of product characteristics for dronedarone. Dronedarone is recommended as an option for the maintenance of sinus rhythm after successful cardioversion in people with paroxysmal or persistent atrial fibrillation: whose atrial fibrillation is not controlled by first-line therapy (usually including beta-blockers), that is, as a second-line treatment option and after alternative options have been considered and who have at least 1 of the following cardiovascular risk factors: hypertension requiring drugs of at least 2 different classes diabetes mellitus previous transient ischaemic attack, stroke or systemic embolism left atrial diameter of 50 mm or greater or age 70 years or older and who do not have left ventricular systolic dysfunction and who do not have a history of, or current, heart failure. People who do not meet the criteria in section 1.1 who are currently receiving dronedarone should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# The technology Please note that the recommendations in section 1 for dronedarone have been amended to reflect changes made to the UK marketing authorisation. The information in this section is based on dronedarone's marketing authorisation at the time the appraisal was initially considered in 2010. Please refer to the revised summary of product characteristics for dronedarone for further information. Dronedarone (Multaq, Sanofi-Aventis) is an antiarrhythmic drug belonging to the benzofuran class of antiarrhythmic compounds. Dronedarone has a marketing authorisation for the treatment of adult clinically stable patients with a history of, or current, non-permanent atrial fibrillation to prevent recurrence of atrial fibrillation or to lower ventricular rate. The SPC states that because of the unexplained results of the ANDROMEDA study, the use of dronedarone in unstable patients with NYHA class III and IV heart failure is contraindicated. There is also a recommendation in the SPC (under 'special warnings and precautions for use') which states that because of limited experience in stable patients with recent (1 to 3 months) NYHA class III heart failure or with left ventricular ejection fraction less than 35%, the use of dronedarone is not recommended in these patients. According to the SPC, the most frequently observed adverse events in people receiving dronedarone are elevated blood creatinine levels and prolongation of the QT interval. Other common adverse events include bradycardia, gastrointestinal events such as diarrhoea and vomiting, rashes, pruritus, fatigue and asthenia. For full details of side effects and contraindications, see the SPC. The recommended dosage of dronedarone is 400 mg twice daily. Dronedarone is available in 400 mg tablets and comes in packs of 20 tablets or 60 tablets. The cost of a pack of 20 tablets is £22.50 and the cost of a pack of 60 tablets is £67.50 (excluding VAT; 'Monthly index of medical specialities' ). The cost per patient per day based on the recommended dosage is £2.25 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of dronedarone and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer's submission presented the use of dronedarone in two positions in the rhythm control treatment pathway for paroxysmal and persistent atrial fibrillation. According to 'The management of atrial fibrillation' (NICE clinical guideline 36), beta-blockers (in addition to anticoagulation) should be the initial treatment option for people with symptomatic paroxysmal atrial fibrillation and people with persistent atrial fibrillation in whom an antiarrhythmic drug is needed to maintain sinus rhythm after cardioversion. For those in whom standard beta-blockers are contraindicated, not tolerated or fail to suppress symptoms, the guideline states that amiodarone, sotalol or a class 1c drug should be used (that is, as a second-line treatment). The choice of amiodarone, sotalol or a class 1c drug depends on the type of atrial fibrillation (persistent or paroxysmal) and the presence or absence of structural heart disease, left ventricular dysfunction or coronary heart disease. The manufacturer's submission considered the use of dronedarone as an alternative to amiodarone, sotalol and class 1c drugs for people in whom one of these antiarrhythmic drugs is indicated. The submission also considered the use of dronedarone as part of first-line treatment in addition to standard baseline therapy (usually including beta-blockers and anticoagulation), but only for people with a CHADS2 score of 4 or more. The CHADS2 score is used to estimate the risk of stroke in people with atrial fibrillation to determine whether they need treatment with anticoagulation therapy. The score is calculated by giving one point each for the presence of congestive heart failure, hypertension or diabetes mellitus, and being aged 75 years or older. Two points are given if people have already had an ischaemic stroke or transient ischaemic attack. The main clinical evidence on dronedarone in the manufacturer's submission was based on four randomised controlled trials comparing dronedarone with placebo and one comparing it with amiodarone: EURIDIS and ADONIS (n = 1237, 12-month follow-up), phase III multicentre, parallel, randomised, double-blind, placebo-controlled trials. EURIDIS and ADONIS were European and non-European trials of the same design and the results were combined and reported together. Both dronedarone and placebo were given in addition to standard first-line therapy, which included beta-blockers (in about 60% of participants) and anticoagulation (in about 70% of participants). ATHENA (n = 4628, mean follow-up: 21 months), a phase III multicentre, parallel, randomised, double-blind, placebo-controlled trial. Both dronedarone and placebo were given in addition to standard first-line therapy, which included beta-blockers (in 71% of participants) and anticoagulation (in 60% of participants). DIONYSOS (n = 504, 6-month follow-up), a phase III multicentre, parallel, randomised, double-blind trial comparing dronedarone with amiodarone. The EURIDIS and ADONIS trials included people with paroxysmal or persistent atrial fibrillation or atrial flutter, who had an episode of atrial fibrillation in the 3 months before study entry but were in sinus rhythm on entry into the study. Both trials excluded people with NYHA class III and IV heart failure. The trial population across the two trials had a mean age of 63 years, and 69% were male. Eleven per cent of people had atrial flutter, 41% had structural heart disease and 17% of people had congestive heart failure. The results showed that fewer people in the dronedarone arm had atrial fibrillation recurrence at 12 months than in the placebo group (64% and 75% respectively, hazard ratio 0.75, 95% confidence interval 0.65 to 0.87, p < 0.001). The median time to atrial fibrillation recurrence was 116 days in the dronedarone group and 53 days in the placebo group. In the dronedarone group, the mean ventricular rate during the first adjudicated atrial fibrillation recurrence was 103 beats per minute compared with 117 beats per minute in the placebo group (p < 0.001). Most adverse events were similar between the study groups (numbers not reported), although there was a lower incidence of hyperthyroidism in the dronedarone group (8.4% and 14.1% respectively, p = 0.002) and a higher incidence of serum creatinine elevation (2.4% and 0.2% respectively, p = 0.004). A post-hoc analysis showed that 23% of people in the dronedarone groups had been admitted to hospital or had died at 12 months versus 31% in the placebo groups (hazard ratio 0.73, 95% CI 0.57 to 0.93, p = 0.01). The ATHENA trial included people with paroxysmal or persistent atrial fibrillation or atrial flutter with at least one of the following additional risk factors for a major cardiovascular event: aged 70 years or older; hypertension needing treatment with at least two antihypertensive drugs of different classes; diabetes; previous stroke, transient ischaemic attack or systemic embolism; left atrial diameter of greater than or equal to 50 mm; left ventricular ejection fraction of less than 40%. During the course of the trial, overall mortality figures were lower than expected. As a consequence the inclusion criteria were changed so that people were required to be aged 75 years or older to be eligible, or aged 70–75 years with at least one of the previously specified risk factors, and people younger than 70 years of age were no longer eligible. People were excluded from the ATHENA trial if they had permanent atrial fibrillation, an unstable haemodynamic condition, NYHA class IV congestive heart failure or an acute myocardial infarction. The ATHENA trial population had a mean age of 72 years, and 53% were male. The primary outcome was a composite of first unplanned hospitalisation because of a cardiovascular event and death before hospitalisation. This outcome occurred in 31.9% of the dronedarone group, of whom 29.3% had a first unplanned hospitalisation because of a cardiovascular event and 2.6% died before hospitalisation. The primary outcome occurred in 39.4% of the placebo group, of whom 36.9% had a first unplanned hospitalisation because of a cardiovascular event and 2.5% died before hospitalisation. The hazard ratio for the primary composite outcome in the dronedarone group was 0.76 (95% CI 0.69 to 0.84, p < 0.001). There was no statistically significant difference in all-cause mortality between the dronedarone and placebo groups (5% and 6% respectively, hazard ratio 0.84, 95% CI 0.66 to 1.08, p = 0.18); however there were significantly fewer deaths from cardiovascular causes in the dronedarone group than the placebo group (2.7% and 3.9% respectively, hazard ratio 0.71, 95% CI 0.51 to 0.98, p = 0.03). A post-hoc analysis of the ATHENA trial found that dronedarone was associated with a statistically significant reduction in the risk of stroke compared with placebo (hazard ratio 0.66, 95% CI 0.46 to 0.96, p = 0.027). Another post-hoc analysis reported that dronedarone was associated with a statistically significant reduction in all-cause mortality compared with placebo in people with a CHADS2 score of 4 or more (hazard ratio 0.53, 95% CI 0.31 to 0.91, p = 0.022). In the ATHENA trial, treatment was stopped early in 30.2% of the dronedarone group compared with 30.8% of the placebo group (statistical significance not reported). The main reasons for discontinuation were: adverse events (12.7% in the dronedarone group and 8.1% in the placebo group, p < 0.001), participant's request (7.5% in each group), and other reasons (9.4% in the dronedarone group and 14.4% in the placebo group). Gastrointestinal events (including diarrhoea and nausea) were the most common adverse events in both groups, but were more frequent in the dronedarone than the placebo group (26.2% and 22.0% respectively, p < 0.001). The dronedarone group also had higher incidences of bradycardia (p < 0.001), QT-interval prolongation (p < 0.001), rash (p = 0.006) and serum creatinine elevation (p < 0.001) than the placebo group. There was no statistically significant difference between the dronedarone and placebo groups in the number of serious treatment-emergent adverse events (456 and 489 in each group respectively). The DIONYSOS trial included people with paroxysmal or persistent atrial fibrillation or atrial flutter in whom cardioversion and antiarrhythmic treatment were indicated and who were also receiving anticoagulation. The trial population had a mean age of 64 years, and two-thirds were male. The primary composite outcome of first incidence of either recurrence of atrial fibrillation or premature study discontinuation because of intolerance or lack of efficacy occurred in 75.5% of the dronedarone group and 58.8% of the amiodarone group (hazard ratio 1.59, p < 0.0001). This difference was mainly because of the higher incidence of recurrence of atrial fibrillation in the dronedarone group than in the amiodarone group (63.5% and 42.0% respectively). The main safety endpoint was defined as the incidence of thyroid-, hepatic-, pulmonary-, neurological-, skin-, eye- or gastrointestinal-specific events, or early study drug discontinuation after any adverse event. This endpoint occurred in 39.3% of the dronedarone group after 12 months of treatment compared with 44.5% in the amiodarone group (hazard ratio 0.80, 95% CI 0.60 to 1.07, p = 0.13). Dronedarone was associated with lower incidences of adverse drug reactions including thyroid dysfunction, significant bradycardia and effects on the central nervous system. There were two (0.8%) deaths in the on-treatment period in the dronedarone group compared with five (2.0%) in the amiodarone group (the causes of the deaths were provided but marked academic in confidence). The manufacturer carried out direct and indirect analyses and a mixed treatment comparison of dronedarone compared with amiodarone, sotalol and class 1c drugs (flecainide and propafenone combined) and of each antiarrhythmic drug compared with placebo. The analyses were conducted for five outcomes: atrial fibrillation recurrence, all-cause mortality, treatment discontinuation, treatment discontinuation because of adverse events and stroke. The meta-analysis demonstrated that atrial fibrillation recurrence was significantly lower with all antiarrhythmic drugs compared with placebo and that dronedarone was the least effective of all antiarrhythmic drugs (odds ratios were marked academic in confidence). The mixed treatment comparison indicated that dronedarone was associated with a lower risk of all-cause mortality than amiodarone (odds ratio 3.19, 95% CI 1.16 to 8.76, p = 0.032) and sotalol (odds ratio 5.05, 95% CI 1.84 to 13.87, p = 0.009). There was no statistically significant difference in all-cause mortality between dronedarone and placebo and not enough evidence to compare dronedarone with class 1c drugs. The mixed treatment comparison showed that dronedarone was associated with a lower risk of stroke than placebo (odds ratio 1.44, 95% CI 1.19 to 1.76, p = 0.015), but there was no difference between dronedarone and sotalol or amiodarone. However, this analysis was based on limited data. The manufacturer provided information on two trials of dronedarone that were outside its licensed indication and that therefore did not form the main evidence base for the submission. These were the ERATO trial, in people with permanent atrial fibrillation, and the ANDROMEDA trial, in people with severe heart failure. In addition, the manufacturer submitted results of an analysis of safety using pooled data from five placebo-controlled dronedarone trials (ATHENA, EURIDIS and ADONIS plus two additional trials that did not meet inclusion criteria for the main clinical-effectiveness review: ERATO and DAFNE). The analysis included a total of 6285 people and the average duration of dronedarone exposure was 12 months. The main adverse events associated with dronedarone were diarrhoea, nausea or vomiting, serum creatinine elevation, rash, and cardiac events (bradycardia and QT prolongation). The incidence of serious adverse events was similar in the dronedarone and placebo groups (18.0% and 19.7% respectively) and these were mainly related to infections and infestations, gastrointestinal disorders, and cardiac disorders. There were more early discontinuations in the dronedarone group than the placebo group (11.8% and 7.7% respectively) and the most common reason for stopping dronedarone was diarrhoea (statistical significance not reported). The model used in the manufacturer's cost-effectiveness analysis was a discrete event simulation that predicts a person's course if they are treated with dronedarone compared with the predicted course with alternative treatment pathways. The manufacturer stratified people depending on their type of atrial fibrillation and baseline risk factors into five groups in accordance with the NICE guidance on atrial fibrillation (NICE clinical guideline 36): paroxysmal atrial fibrillation without structural heart disease, paroxysmal atrial fibrillation with coronary heart disease, paroxysmal atrial fibrillation with left ventricular dysfunction, persistent atrial fibrillation without structural heart disease, and persistent atrial fibrillation with structural heart disease. For each of these subgroups, the manufacturer evaluated the cost effectiveness of dronedarone at two positions in the care pathway for atrial fibrillation (see section 3.1). When dronedarone was evaluated as part of a first-line treatment for people with a CHADS2 score of 4 or more (in addition to standard baseline therapy), the comparator was standard baseline therapy alone (including beta-blockers and anticoagulation). When dronedarone was evaluated as a second-line treatment option, the comparators were the antiarrhythmic drugs amiodarone, sotalol and class 1c drugs, depending on the type of atrial fibrillation and baseline risk factors described above. The manufacturer's model used a lifetime time horizon and included four health states: normal sinus rhythm, permanent atrial fibrillation with uncontrolled symptoms, permanent atrial fibrillation with controlled symptoms and death. From the normal sinus rhythm state, people could move to any of the other states. From the two permanent atrial fibrillation health states, people could move between these states or to death. Transition between health states was determined by the following events: atrial fibrillation recurrence, acute coronary syndrome, stroke, congestive heart failure, treatment discontinuation, change in symptoms (for the permanent atrial fibrillation states) or death. The baseline risk of these events was taken from the ATHENA trial, extrapolated to a lifetime time horizon and adjusted for each treatment arm using odds ratios from the mixed treatment comparison. All-cause mortality was estimated using age-specific UK life tables (from the Government Actuary's Department) and adjusted for CHADS2 score. The risk of death after stroke and congestive heart failure events was estimated using published sources. The model included adverse events associated with each treatment. Adverse event rates for dronedarone were taken from a pooled analysis of the six dronedarone trials (DAFNE, ADONIS, ERATO, EURIDIS, ATHENA and DIONYSOS), for amiodarone they were taken from the DIONYSOS trial, and for sotalol and class 1c drugs they came from the SPCs. Utilities for the health states were taken from the AFTER cohort of the European Heart Survey on atrial fibrillation. The disutilities associated with adverse events were taken from a study undertaken by the manufacturer (n = 127) using a time trade-off approach. In the model, drug costs for comparators were taken from the 'British national formulary' (edition 57). Doses were based on the recommended dosage stated in the SPCs. Drug administration costs were sourced from NHS Reference Costs 2007–08. For dronedarone these consisted of a specialist outpatient visit for treatment initiation and a GP visit for a day-7 creatinine test (£213). For comparators, it was assumed that hospitalisation was required for treatment initiation (£249) and 6-monthly GP visits and tests were required for monitoring (£58–76 depending on the treatment). Costs for the majority of health events occurring in the model were taken from published literature. Most events were assumed to incur a one-off cost; but for stroke and congestive heart failure, ongoing daily costs were assumed. Costs for adverse events came from NHS Reference Costs 2007–08. A proportion of adverse events were assumed to require hospitalisation (based on expert clinical opinion) and the rest were assumed to require an outpatient consultant visit. For short-term adverse events, a one-off cost at treatment initiation was incurred and for adverse events with lifetime effects, a 6-monthly GP visit was assumed to be required. Data on resource use were sourced from clinical opinion and published literature. In the manufacturer's base-case analysis, the incremental cost-effectiveness ratios (ICERs) for the analysis of dronedarone if given in addition to standard baseline therapy (for people with a CHADS2 score of 4 or more) compared with standard baseline therapy alone ranged from £6757 to £7890 per quality-adjusted life year (QALY) gained (incremental costs £3053 and £3307 and incremental benefits 0.45 and 0.42 QALYs for these two ICERs respectively). The ICERs varied depending on the type of atrial fibrillation and the presence of structural heart disease, coronary heart disease or left ventricular dysfunction. For the analysis of dronedarone as an alternative antiarrhythmic drug to amiodarone, the ICERs were £2645 per QALY gained (incremental cost £3528 and incremental benefit 1.33 QALYs) for paroxysmal atrial fibrillation with left ventricular dysfunction and £3113 per QALY gained (incremental cost £3986 and incremental benefit 1.28 QALYs) for persistent atrial fibrillation with structural heart disease. For the comparison of dronedarone with class 1c drugs, the ICERs were £20,003 per QALY gained (incremental cost £1980 and incremental benefit 0.10 QALYs) for paroxysmal atrial fibrillation with no structural heart disease and £20,761 per QALY gained (incremental cost £2069 and incremental benefit 0.10 QALYs) for persistent atrial fibrillation with no structural heart disease. For the comparison of dronedarone with sotalol, the ICERs ranged from £1929 to £2197 per QALY gained (incremental costs £3986 and £4384 and incremental benefits 2.07 and 2.00 QALYs for these two ICERs respectively) (depending on the type of atrial fibrillation and the presence or absence of underlying heart disease). The manufacturer conducted a number of sensitivity analyses including: subgroup analyses based on CHADS2 scores and gender using alternative sources for the baseline distribution of CHADS2 score varying the model time horizon assuming a minimum mortality benefit from dronedarone relative to its comparators by using the lower end of the 95% CI of the mortality estimate for comparators and the upper end of the 95% CI for dronedarone (rather than the point estimates), and vice versa (that is, assuming a maximum relative mortality benefit from dronedarone) using different curve fits for the modelled clinical events such as stroke and treatment discontinuations using different estimates for various parameters including mortality treatment effect, stroke treatment effect, treatment discontinuation, adverse event rate, costs of dronedarone and utilities. The analyses that had the greatest effect on the ICERs were using a 1-year time horizon (rather than a lifetime time horizon) and assuming a minimum mortality benefit from dronedarone relative to its comparators. The ERG considered that all relevant trials of dronedarone had been included in the manufacturer's submission. It noted that the ATHENA trial included people who were older and had a higher risk of a major cardiovascular event than people in the other trials and that the application of this evidence to a lower-risk and younger population was uncertain. The ERG commented that the DIONYSOS trial was the only head-to-head trial of dronedarone versus an antiarrhythmic drug and therefore the relative efficacy of dronedarone compared with antiarrhythmic drugs other than amiodarone was unknown. It also noted that the DIONYSOS trial was short-term (minimum follow-up: 6 months). The ERG commented on a number of limitations of the meta-analyses and mixed treatment comparison in the manufacturer's submission. These included: a lack of consideration of clinical and statistical heterogeneity of the studies included in the analyses uncertainty about the validity of pooling the individual studies in the different analyses few events in the studies the use of outcomes that were neither pre-specified endpoints nor centrally adjudicated inconsistencies in the selection of studies across the different analyses the restriction of randomised controlled trials in the mixed treatment comparison. The ERG considered that the assumption that class 1c drugs have a similar effect on all-cause mortality to dronedarone and no effect on the risk of stroke (made because of a lack of evidence) might not be valid. It noted an inconsistency in the direction of effect between results of the direct and indirect analyses and the mixed treatment comparison for the outcome of treatment discontinuations because of any cause. The ERG considered that the existing clinical evidence across the antiarrhythmic drugs appeared most robust for the outcome of atrial fibrillation recurrence, but considerably more uncertain for the other major clinical endpoints such as stroke and all-cause mortality. The ERG also noted that although the marketing authorisation for dronedarone states that it should be used to lower ventricular rate, there was little evidence presented on this outcome. The ERG considered that in general, the manufacturer's approach to the economic evaluation met the requirements of the NICE reference case, had an appropriate structure for the decision problem, and was of high quality, overall. However, the ERG noted a number of issues with the cost-effectiveness analysis, including concern over the pivotal assumption of mortality benefit: The treatment pathways evaluated by the manufacturer might not represent the full range of treatment strategies or sequences for dronedarone. The baseline data from the ATHENA trial, used in the model, might not be generalisable to people with atrial fibrillation in the NHS because they came from an older and higher-risk population. The results of the meta-analyses and mixed treatment comparisons, used in the model, might not be appropriate because of concerns about the methodology of these analyses. The lack of health-related quality-of-life data from any of the dronedarone studies. The assumption of lower initiation and monitoring costs for dronedarone compared with other antiarrhythmic drugs might not be appropriate. The uncertainty associated with modelling the benefits of dronedarone over the longer term because of the short duration of the trials. The ERG made revisions to the manufacturer's model to correct coding errors (relating to adverse events costs and the length of time that mortality treatment benefits were applied). The revisions resulted in considerably lower ICERs than those reported in the manufacturer's base case for the comparisons of dronedarone with sotalol and amiodarone (ICERs ranged from £1895 to £4014 per QALY gained in the ERG's analysis applying a lifetime mortality benefit compared with £1980 to £8142 per QALY gained in the base case). The results for dronedarone compared with class 1c drugs were unaffected because both drugs were assumed to have the same mortality benefit. The ERG stated that the manufacturer's base-case ICERs were based on the estimates of relative effectiveness of dronedarone compared with other antiarrhythmic drugs derived from the manufacturer's mixed treatment comparison. It had previously noted concerns about this mixed treatment comparison (section 3.16). The ERG therefore performed a number of analyses exploring the impact of assumptions about treatment effects on the ICERs. These included: assuming that dronedarone has the same effect on mortality across all CHADS2 subgroups (for the comparison of dronedarone with standard baseline therapy) assuming that sotalol and amiodarone have no effect on mortality, but keeping the assumed mortality benefit of dronedarone assuming that class 1c drugs, sotalol and amiodarone have the same effect on mortality as dronedarone assuming that class 1c drugs have a more beneficial effect on mortality than dronedarone assuming that class 1c drugs have the same effect on stroke as dronedarone using effect estimates from a reanalysis of the mixed treatment comparison of all-cause mortality using a wider range of studies than that used in the manufacturer's analysis. For most analyses, the ICERs increased but remained below £20,000 per QALY gained. However, when sotalol and amiodarone were assumed to have the same effect on mortality as dronedarone, the ICERs increased to between £55,063 and £119,704 per QALY gained. When class 1c drugs were assumed to have the same effect on the risk of stroke as dronedarone, the ICERs approximately doubled (to about £38,000 per QALY gained) and when class 1c drugs were assumed to have greater mortality benefits than dronedarone, class 1c drugs had both higher effectiveness and lower costs than dronedarone. The ERG also explored the uncertainty around treatment initiation, monitoring costs and utility weights used in the model. The impact on the ICERs for all analyses and comparisons was marginal. The ERG conducted exploratory analyses to identify the main drivers of the cost-effectiveness results. The first was to explore the effect on the ICERs when all treatment effects are excluded from the economic analysis except atrial fibrillation recurrence. The ICERs either increased to between £1,355,984 and £70,323,846 per QALY gained or dronedarone was shown to have both higher costs and lower effectiveness than the comparators. The ERG then explored the effect on the ICERs when the treatment effects on all-cause mortality were included in the analysis in addition to atrial fibrillation recurrence. The ICERs decreased to between £1815 and £4566 per QALY gained for the comparisons of dronedarone with standard baseline therapy, sotalol and amiodarone. For the comparison of dronedarone with class 1c drugs, the ICERs were either £370,690 or dronedarone was shown to have both higher costs and lower effectiveness than the comparators (because both drugs were assumed to have the same effect on mortality). Based on these analyses, the ERG concluded that the main driver of the cost effectiveness of dronedarone compared with standard baseline therapy, sotalol or amiodarone is the reduction in all-cause mortality associated with dronedarone. To explore the main driver of the cost effectiveness of dronedarone compared with class 1c drugs, the ERG conducted a further analysis including the treatment effects on stroke in addition to atrial fibrillation recurrence and mortality. This resulted in ICERs of £43,543 and £46,500 per QALY gained. The ERG noted that when treatment effects on adverse events were included in the analysis (as in the manufacturer's base-case analysis), the ICERs were around £18,000 per QALY gained. It therefore advised that the combined effect of reduced risk of stroke and fewer adverse events was the main driver of cost effectiveness for dronedarone compared with class 1c drugs. After consultation on the first appraisal consultation document (ACD), the ERG conducted two further scenario analyses in which the treatment effects on all-cause mortality were varied. In the first analysis, dronedarone was assumed to have no effect on all-cause mortality compared with placebo, whereas amiodarone, sotalol and class 1c drugs were assumed to increase the risk of all-cause mortality (using effect estimates from the ERG's mixed treatment comparison). For the comparison of dronedarone with standard baseline therapy (in people with a CHADS2 score of 4 or more), the ICERs increased from the ERG's revised base case (between £3358 and £4014 per QALY gained) to between £56,798 and £69,575 per QALY gained. For the comparisons with amiodarone and sotalol, the ICERs increased from between £1692 and £2349 to between £2588 and £5853 per QALY gained and for the comparison with class 1c drugs, the ICERs were lower (£11,648 and £12,760 per QALY gained) than in the ERG's revised base case (£18,206 and £18,955 per QALY gained). In the second analysis, amiodarone, sotalol and class 1c drugs were assumed to have no effect on all-cause mortality compared with placebo, and the effect of dronedarone compared with placebo was varied from an odds ratio of 0.84 (that is, a beneficial effect as in the manufacturer's model) to 1.0 (that is, no effect on all-cause mortality). This threshold analysis showed that when the odds ratio was 0.95 or lower (that is, when dronedarone was assumed to reduce all-cause mortality by at least 5%), the ICERs for all comparisons were between £9323 and £20,689 per QALY gained. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence Please note that the recommendations in section 1 for dronedarone have been amended to reflect changes made to the UK marketing authorisation. The information in this section is based on dronedarone's marketing authorisation at the time the appraisal was initially considered in 2010. Please refer to the revised summary of product characteristics for dronedarone for further information. The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dronedarone, having considered evidence on the nature of atrial fibrillation and the value placed on the benefits of dronedarone by people with the condition, those who represent them, and clinical specialists. It considered comments received at consultation on the ACDs. It also took into account the effective use of NHS resources. The Committee discussed the positions for dronedarone in the treatment pathway for atrial fibrillation proposed by the manufacturer. It noted that the NICE guidance on atrial fibrillation (NICE clinical guideline 36) states that a standard beta-blocker should be the initial treatment for people with symptomatic atrial fibrillation (in addition to anticoagulation) and that an antiarrhythmic drug should be used when beta-blockers fail to control symptoms or are contraindicated (that is, as a second-line treatment). The Committee initially discussed using dronedarone in addition to standard baseline therapy of beta-blockers and anticoagulation (that is, as a first-line treatment). It noted that the manufacturer had only presented cost-effectiveness evidence at this position in the care pathway for the subgroup of people with a CHADS2 score of 4 or more (that is, people with a high risk of stroke). The Committee also noted that the licensed indication for dronedarone was to prevent recurrence of atrial fibrillation or to lower ventricular rate, but that the only outcome that was presented in this subgroup was all-cause mortality. The Committee then discussed the use of dronedarone as an alternative antiarrhythmic drug for second-line treatment of atrial fibrillation and considered that the comparators assessed in the manufacturer's submission (sotalol, class 1c drugs and amiodarone) were appropriate. The Committee considered that not all possible uses of dronedarone had been evaluated in the manufacturer's submission. It heard from clinical specialists and patient experts that a potential use of dronedarone would be in people who are unable to tolerate other antiarrhythmic drugs, in particular amiodarone. However, no evidence was provided relating to the clinical effectiveness and adverse effects of dronedarone in this group of people. The Committee understood from clinical specialists and patient experts that they considered amiodarone to be an effective antiarrhythmic drug for controlling atrial fibrillation symptoms, but that it had a high level of toxicity and many people were not able to tolerate it. The clinical specialists and patient experts commented that antiarrhythmic treatment options for people with atrial fibrillation are limited and they would welcome an antiarrhythmic drug that was effective at controlling atrial fibrillation symptoms and that was more tolerable than amiodarone. The Committee also heard from patient experts that younger people, who cannot take class 1c drugs or sotalol, might benefit from an antiarrhythmic drug that is more tolerable than amiodarone because of the longer length of time that they are likely to need treatment. It discussed comments received at consultation stating that younger people with atrial fibrillation who also had congenital heart problems would value dronedarone as a treatment option. However, the Committee concluded that because no evidence was presented for people with congenital heart disease, it could not make any recommendations specifically in this group. The Committee considered it appropriate that dronedarone is initiated by a specialist in a secondary care setting, which clinical specialists commented is usual practice for second-line treatment with antiarrhythmic drugs. The Committee noted that the cost-effectiveness model submitted by the manufacturer assumed that treatment with dronedarone was initiated by a specialist during an outpatient visit. # Clinical effectiveness The Committee discussed the evidence on the effect of dronedarone on atrial fibrillation recurrence. It considered that the randomised controlled trials (ATHENA, EURIDIS, ADONIS and DIONYSOS) demonstrated that dronedarone was more effective than placebo at reducing atrial fibrillation recurrence, but less effective than amiodarone. It discussed the results of the meta-analyses and mixed treatment comparison conducted by the manufacturer that indicated that all antiarrhythmic drugs, including dronedarone, were effective at reducing atrial fibrillation recurrence, but that dronedarone was the least effective. The Committee concluded that dronedarone reduced atrial fibrillation recurrence compared with placebo, but that it appeared to be less effective for atrial fibrillation recurrence than other antiarrhythmic drugs. The Committee discussed the evidence on the effect of dronedarone on ventricular rate. It noted that the licensed indication for dronedarone was to prevent recurrence of atrial fibrillation or to lower ventricular rate, but that the only studies that assessed ventricular rate in people with non-permanent atrial fibrillation were the EURIDIS and ADONIS trials. It noted that these trials reported a lower ventricular rate in the dronedarone group than the placebo group. The Committee was also aware that ventricular rate was not included in the manufacturer's economic model. It heard from clinical specialists that the ERATO trial had shown that dronedarone reduces ventricular rate compared with placebo. However, the Committee noted that this study was in people with permanent atrial fibrillation, which is not a licensed indication for dronedarone. The Committee considered that there was insufficient evidence to reach a definitive conclusion about the benefits of dronedarone for reducing ventricular rate in people with non-permanent atrial fibrillation. The Committee discussed the trial evidence on the effect of dronedarone on mortality. It considered the results of the ATHENA trial, which reported lower cardiovascular mortality in the dronedarone group compared with the placebo group but no statistically significant difference in all-cause mortality (for the whole trial population). The Committee concluded that a reduction in all-cause mortality with dronedarone compared with placebo had not been demonstrated by the ATHENA trial for the whole trial population. The Committee discussed the post-hoc subgroup analysis of the ATHENA trial that reported a lower risk of all-cause mortality in the dronedarone group compared with the placebo group for people with a CHADS2 score of 4 or more. It discussed the use of the CHADS2 score to predict mortality. It heard from clinical specialists that the CHADS2 score was a useful method of assessing stroke risk in people with atrial fibrillation to determine the need for anticoagulation treatment, but that it was not used to predict mortality. It noted published evidence that reported an association between CHADS2 score and risk of all-cause mortality for people who have had a stroke. However, the Committee considered that no evidence had been presented to validate the use of CHADS2 score for more generally predicting all-cause mortality in people with atrial fibrillation. The Committee discussed the issue of all-cause mortality in relation to the DIONYSOS trial, which provided the only direct head-to-head comparison of dronedarone with another antiarrhythmic drug, and reported fewer deaths in the dronedarone group than in the amiodarone group. However, the Committee noted the short follow-up of the trial and the small number of deaths in the study, and it considered whether all the deaths in the amiodarone group were because of cardiovascular causes (noting that the causes of death were marked commercial in confidence). Therefore the Committee considered that no conclusion about the relative effect of dronedarone and amiodarone on mortality could be made on the basis of this trial. The Committee discussed the results of the manufacturer's mixed treatment comparison, which reported a lower risk of all-cause mortality for dronedarone compared with placebo. It noted the ERG's criticism about the methodology used for the mixed treatment comparison. It also noted that the CIs for this analysis crossed the null effect value, indicating that the difference was not statistically significant. The Committee considered that the mixed treatment comparison was largely based on the difference in all-cause mortality between the treatment arms in the ATHENA trial, which itself was not statistically significant. The Committee concluded that there was considerable uncertainty about the effect of dronedarone on all-cause mortality. It was not persuaded that a reduction in the risk of all-cause mortality for dronedarone compared with placebo had been demonstrated by the mixed treatment comparison. The Committee then discussed the evidence on the risk of all-cause mortality for the other antiarrhythmic drugs. It noted results from the mixed treatment comparison showing that sotalol and amiodarone were associated with a higher risk of mortality than placebo. It discussed the results of the ERG's reanalysis of the mixed treatment comparison and also considered evidence from two published meta-analyses of antiarrhythmic drugs. The Committee noted that all of these analyses reported a trend towards increased all-cause mortality with sotalol and amiodarone compared with placebo, albeit less than that reported in the manufacturer's mixed treatment comparison. It also noted that only the hazard ratio for the comparison of sotalol with placebo for all-cause mortality had a CI that did not cross 1.0, indicating a statistically significant difference between these drugs. The Committee was aware that there were limited data on class 1c drugs. It considered comments received at consultation and from the clinical specialists that amiodarone, sotalol and class 1c drugs were associated with an increased risk of mortality. Overall, the Committee accepted that the risk of mortality with the other antiarrhythmic drugs was likely to be higher than with dronedarone. The Committee considered the evidence on the effect of dronedarone on the risk of stroke. It heard from clinical specialists that stroke was a known complication of arrhythmias such as atrial fibrillation. Therefore, drugs that are more effective in reducing atrial fibrillation might be expected to have a greater long-term benefit in relation to stroke prevention. The Committee discussed the post-hoc analysis of the ATHENA trial and noted that the ATHENA investigators concluded that 'the observation of a reduced rate of stroke in patients receiving dronedarone cannot be considered a definitive conclusion'. It discussed the mixed treatment comparison that resulted in reduced risk of stroke with dronedarone compared with placebo. It noted that this analysis was based on a small number of studies with very few events and no studies had any prospective collection of data on stroke incidence. The Committee concluded there was considerable uncertainty about the effect of dronedarone on the risk of stroke. It was not persuaded that a reduction in the risk of stroke with dronedarone compared with other antiarrhythmic drugs had been demonstrated. The Committee discussed the adverse events associated with dronedarone. It was aware of the ANDROMEDA trial in which dronedarone was associated with an increased risk of mortality in people with severe congestive heart failure and noted that having atrial fibrillation was not an inclusion criterion for this trial. It was also aware that the SPC states that dronedarone is contraindicated in people with unstable NYHA class III and IV heart failure, and that it is not recommended in people with stable, recent NYHA class III heart failure and people with left ventricular ejection fraction less than 35%. The Committee noted that the most common adverse events reported across the trials of dronedarone were gastrointestinal. It discussed the possibility of serious adverse events such as pulmonary fibrosis, thyroid disease and torsades de pointes (an arrhythmia). It noted that there were very few cases reported in the randomised controlled trials, but that these trials were all relatively short term. The Committee considered evidence from the DIONYSOS trial that showed that people in the dronedarone group had fewer adverse events than those in the amiodarone group. However, it noted that these results were also based on short-term data. It noted there was no direct evidence comparing the adverse effects of dronedarone with sotalol or class 1c drugs. The Committee heard from patient experts that they did not consider that the adverse events associated with dronedarone would impact significantly on quality of life for people with atrial fibrillation. It noted comments from patients and clinical specialists received during consultation on the first ACD that all current antiarrhythmic drugs had side effects that had a significant impact on quality of life, but particularly amiodarone, with long-term use. Overall, the Committee concluded that the adverse effect profile of dronedarone was likely to be more favourable than amiodarone. The Committee specifically considered the balance between the better short-term side-effect profile and the lower effectiveness of dronedarone compared with amiodarone. It heard from patient experts that some people with atrial fibrillation might prefer to take an antiarrhythmic drug that has better tolerability, despite it having less effect on atrial fibrillation recurrence. It also heard that effectiveness of an antiarrhythmic drug for reducing atrial fibrillation recurrence and its tolerability could be more important to some people with atrial fibrillation than longer-term benefits such as a reduction in the risk of stroke or death. The Committee was aware of the potential value placed on dronedarone by patients when it examined the cost-effectiveness analyses. # Cost effectiveness The Committee discussed the economic analysis provided by the manufacturer. It noted the ERG's conclusion that the approach used was, in general, appropriate and in accordance with the NICE reference case. However, the Committee was concerned about some of the key assumptions in the model, in particular that there was a beneficial effect of dronedarone on mortality and that the ATHENA trial was an appropriate source of data for the baseline risk of events. It also had concerns about the modelled costs of dronedarone and other antiarrhythmic drugs and the utilities used in the model. In addition, the Committee noted that the economic analysis was based on pair-wise comparisons of two treatments and did not use incremental analyses to compare all treatments simultaneously. It also noted that the economic analysis did not evaluate all possible uses of dronedarone. The Committee discussed the use of the placebo arm of the ATHENA trial to inform the baseline event rates in the model. It considered that this was based on an assumption that the ATHENA population was representative of people with atrial fibrillation in the UK. The Committee noted that the ATHENA trial included people who were older and had higher cardiovascular risk than people in the other dronedarone trials. It considered that the ATHENA population represented a higher-risk group than the more general population of people with atrial fibrillation in the UK in whom dronedarone would be used. Therefore, the Committee concluded that the cost-effectiveness estimates it had been presented with were only relevant to the population represented by the ATHENA trial (that is, people with additional cardiovascular risk). The Committee noted that in the manufacturer's base-case analysis, the ICERs ranged from £1900 to £20,800 per QALY gained depending on the type of atrial fibrillation, the presence of structural heart disease, left ventricular dysfunction and coronary heart disease, and the comparator. It considered the ERG's revisions to the model to be appropriate, involving correction of coding errors and use of a lifetime time horizon for mortality benefits, which resulted in decreased ICERs ranging from £1700 to £19,000 per QALY gained. However, it noted that these figures did not incorporate changes in other key assumptions such as the mortality benefit associated with dronedarone. The Committee discussed the ERG's analyses exploring the main factors that influenced the cost effectiveness of dronedarone. It considered that the relative effect of dronedarone and antiarrhythmic drugs on mortality was a key factor in the economic analysis. It again considered comments received during consultation on the first ACD and from the clinical specialists about the likely excess mortality associated with other antiarrhythmic drugs. In light of the uncertainty about the effect of dronedarone on mortality, the Committee discussed several exploratory scenario analyses conducted by the ERG in which the relative all-cause mortality effects of each antiarrhythmic drug were varied. It considered the scenario in which dronedarone had no effect on mortality compared with placebo, and other antiarrhythmic drugs were associated with some increase in mortality (as calculated in the ERG's meta-analysis), to be the most appropriate, given the uncertainty about the mortality effect of dronedarone. It noted the ICERs from this analysis were below £15,000 per QALY gained for the use of dronedarone as a second-line treatment alternative to sotalol, class 1c drugs and amiodarone. It also noted the ICERs from this analysis were above £50,000 per QALY gained for the use of dronedarone as part of first-line treatment in addition to standard baseline therapy (in people with a CHADS2 score of 4 or more). The Committee concluded that these cost-effectiveness estimates were the most plausible of all those presented. The Committee discussed the costs and utilities included in the economic analysis. It noted that lower initiation and monitoring costs were attributed to dronedarone than other antiarrhythmic drugs. The Committee also noted the ERG's criticism that the utilities used in the model appeared to exceed general population values for healthy states. It considered the ERG's analyses that used revised drug administration costs and utilities, and concluded that these changes had a marginal impact on the cost-effectiveness estimates of dronedarone. The Committee noted comments received at consultation on the first ACD that the economic analysis had not taken into account the potential cost savings of the reduced cardiovascular hospitalisations associated with dronedarone (shown in the ATHENA trial). It considered that the costs and effects of hospitalisation were included in the analysis through the modelling of events such as atrial fibrillation recurrence and stroke for which hospitalisation costs may be incurred. The Committee also considered comments received at consultation on the first ACD that treatment with dronedarone would be stopped if it was not effective and this was not considered in the economic evaluation. It noted that the submission provided by the manufacturer did not specifically evaluate treatment stopping rules and also did not consider the full range of potential treatment sequences for dronedarone. However, the Committee considered that some element of treatment discontinuation had been accounted for in the modelling of withdrawal because of adverse events or lack of efficacy. In light of the above considerations, the Committee discussed the cost effectiveness of dronedarone as a first-line treatment for atrial fibrillation (in addition to standard baseline therapy usually including beta-blockers). It noted that cost-effectiveness evidence for dronedarone as a first-line therapy had only been provided for the subgroup of people with a CHADS2 score of 4 or more. In addition to concerns about the validity of the CHADS2 score in this context, the Committee considered that the beneficial effect of dronedarone on all-cause mortality assumed in the manufacturer's submission was not proven. It noted that when this effect was removed from the economic analysis the cost per QALY gained was above £50,000. The Committee concluded that the use of dronedarone in people with a CHADS2 score of 4 or more (in addition to standard baseline therapy) for the first-line treatment of atrial fibrillation could not be considered a cost-effective use of NHS resources. The Committee also noted that no evidence had been provided for first-line treatment with dronedarone other than in people with a CHADS2 score of 4 or more. Therefore it could not make any conclusions about the first-line use of dronedarone in other people with non-permanent atrial fibrillation. The Committee concluded that dronedarone could not be recommended as a first-line treatment for atrial fibrillation (in addition to standard baseline therapy usually including beta-blockers). The Committee discussed the cost effectiveness of dronedarone as a second-line treatment for people whose atrial fibrillation is not controlled by standard baseline therapy (that is, as an alternative to the antiarrhythmic drugs: amiodarone, sotalol and class 1c agents). It considered that a beneficial effect of dronedarone on all-cause mortality was not proven; however, it accepted that the risk of mortality with the other antiarrhythmic drugs was likely to be higher than with dronedarone. It considered that when this scenario was modelled, the costs per QALY gained were within an acceptable range. The Committee noted that these cost-effectiveness estimates were largely based on data from the ATHENA trial, which included people who had a higher risk of a major cardiovascular event, and it was uncertain whether these data were applicable to people in England and Wales who would receive second-line treatment for atrial fibrillation. Therefore the Committee concluded that using dronedarone as a second-line alternative to amiodarone, class 1c drugs, or sotalol for the treatment of non-permanent atrial fibrillation could be considered a cost-effective use of NHS resources in people who have the same characteristics as the population in the ATHENA trial, that is, they have at least one of the following additional cardiovascular risk factors: hypertension requiring drugs of at least two different classes, diabetes, previous transient ischaemic attack, stroke or systemic embolism, left atrial diameter at least 50 mm, left ventricular ejection fraction less than 40% or age 70 years or older. The Committee was mindful that there might be some overlap between people with cardiovascular risk factors and those in whom dronedarone is contraindicated (with unstable NYHA class III or IV heart failure) or not recommended (with left ventricular ejection fraction less than 35%). Therefore the Committee considered it important to emphasise in its recommendations that dronedarone should not be used in people with unstable NYHA class III or IV heart failure and to refer to the recommendation in the SPC about the use of dronedarone in people with left ventricular ejection fraction less than 35%. This refers to the licensed indication at the time of the appraisal and not the indication amended in 2011. This refers to the licensed indication at the time of the appraisal and not the indication amended in 2011. This refers to the licensed indication at the time of the appraisal and not the indication amended in 2011.# Recommendations for further research The Committee considered that research directly comparing antiarrhythmic drugs would be valuable, in particular assessing the relative effect of the different antiarrhythmic drugs on clinical outcomes and mortality.# Related NICE guidance Atrial fibrillation: the management of atrial fibrillation. NICE clinical guideline 36 (2006). Percutaneous radiofrequency ablation for atrial fibrillation. NICE interventional procedure guidance 168 (2006).# Review of guidance The guidance on this technology will be considered for review in March 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveIssued: August 2010 Re-issued: December 2012# Changes after publication May 2014: minor maintenance February 2014: implementation section updated to clarify that dronedarone is recommended as an option for treating non-permanent atrial fibrillation. Additional minor maintenance update also carried out. December 2012: recommendation 1.1 amended to reflect the change in the dronedarone marketing authorisation. October 2012: a note has been added explaining the review decision for this guidance and the change in the dronedarone marketing authorisation. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance has been amended and re-issued in December 2012 to reflect changes to dronedarone's UK marketing authorisation. Please see the European Medicines Agency (EMA) website for details of the decision and the revised marketing authorisation. The therapeutic indication for dronedarone is now more restricted than that originally appraised in NICE technology appraisal guidance 197. For more information, see the summary of product characteristics for dronedarone.\n\nDronedarone is recommended as an option for the maintenance of sinus rhythm after successful cardioversion in people with paroxysmal or persistent atrial fibrillation:\n\nwhose atrial fibrillation is not controlled by first-line therapy (usually including beta-blockers), that is, as a second-line treatment option and after alternative options have been considered and\n\nwho have at least 1 of the following cardiovascular risk factors:\n\n\n\nhypertension requiring drugs of at least 2 different classes\n\ndiabetes mellitus\n\nprevious transient ischaemic attack, stroke or systemic embolism\n\nleft atrial diameter of 50\xa0mm or greater or\n\nage 70 years or older and\n\n\n\nwho do not have left ventricular systolic dysfunction and\n\nwho do not have a history of, or current, heart failure.\n\nPeople who do not meet the criteria in section\xa01.1 who are currently receiving dronedarone should have the option to continue treatment until they and their clinicians consider it appropriate to stop.", 'The technology ': "Please note that the recommendations in section 1 for dronedarone have been amended to reflect changes made to the UK marketing authorisation. The information in this section is based on dronedarone's marketing authorisation at the time the appraisal was initially considered in 2010. Please refer to the revised summary of product characteristics for dronedarone for further information.\n\nDronedarone (Multaq, Sanofi-Aventis) is an antiarrhythmic drug belonging to the benzofuran class of antiarrhythmic compounds. Dronedarone has a marketing authorisation for the treatment of adult clinically stable patients with a history of, or current, non-permanent atrial fibrillation to prevent recurrence of atrial fibrillation or to lower ventricular rate.\n\nThe SPC states that because of the unexplained results of the ANDROMEDA study, the use of dronedarone in unstable patients with NYHA class\xa0III and IV heart failure is contraindicated. There is also a recommendation in the SPC (under 'special warnings and precautions for use') which states that because of limited experience in stable patients with recent (1\xa0to 3\xa0months) NYHA class\xa0III heart failure or with left ventricular ejection fraction less than 35%, the use of dronedarone is not recommended in these patients.\n\nAccording to the SPC, the most frequently observed adverse events in people receiving dronedarone are elevated blood creatinine levels and prolongation of the QT interval. Other common adverse events include bradycardia, gastrointestinal events such as diarrhoea and vomiting, rashes, pruritus, fatigue and asthenia. For full details of side effects and contraindications, see the SPC.\n\nThe recommended dosage of dronedarone is 400\xa0mg twice daily. Dronedarone is available in 400\xa0mg tablets and comes in packs of 20\xa0tablets or 60\xa0tablets. The cost of a pack of 20\xa0tablets is £22.50 and the cost of a pack of 60\xa0tablets is £67.50 (excluding VAT; 'Monthly index of medical specialities' [MIMS]). The cost per patient per day based on the recommended dosage is £2.25 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of dronedarone and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission presented the use of dronedarone in two positions in the rhythm control treatment pathway for paroxysmal and persistent atrial fibrillation. According to 'The management of atrial fibrillation' (NICE clinical guideline\xa036), beta-blockers (in addition to anticoagulation) should be the initial treatment option for people with symptomatic paroxysmal atrial fibrillation and people with persistent atrial fibrillation in whom an antiarrhythmic drug is needed to maintain sinus rhythm after cardioversion. For those in whom standard beta-blockers are contraindicated, not tolerated or fail to suppress symptoms, the guideline states that amiodarone, sotalol or a class\xa01c drug should be used (that is, as a second-line treatment). The choice of amiodarone, sotalol or a class\xa01c drug depends on the type of atrial fibrillation (persistent or paroxysmal) and the presence or absence of structural heart disease, left ventricular dysfunction or coronary heart disease. The manufacturer's submission considered the use of dronedarone as an alternative to amiodarone, sotalol and class\xa01c drugs for people in whom one of these antiarrhythmic drugs is indicated. The submission also considered the use of dronedarone as part of first-line treatment in addition to standard baseline therapy (usually including beta-blockers and anticoagulation), but only for people with a CHADS2 score of 4 or more. The CHADS2 score is used to estimate the risk of stroke in people with atrial fibrillation to determine whether they need treatment with anticoagulation therapy. The score is calculated by giving one point each for the presence of congestive heart failure, hypertension or diabetes mellitus, and being aged 75\xa0years or older. Two points are given if people have already had an ischaemic stroke or transient ischaemic attack.\n\nThe main clinical evidence on dronedarone in the manufacturer's submission was based on four randomised controlled trials comparing dronedarone with placebo and one comparing it with amiodarone:\n\nEURIDIS and ADONIS (n\xa0=\xa01237, 12-month follow-up), phase\xa0III multicentre, parallel, randomised, double-blind, placebo-controlled trials. EURIDIS and ADONIS were European and non-European trials of the same design and the results were combined and reported together. Both dronedarone and placebo were given in addition to standard first-line therapy, which included beta-blockers (in about 60% of participants) and anticoagulation (in about 70% of participants).\n\nATHENA (n\xa0=\xa04628, mean follow-up: 21\xa0months), a phase\xa0III multicentre, parallel, randomised, double-blind, placebo-controlled trial. Both dronedarone and placebo were given in addition to standard first-line therapy, which included beta-blockers (in 71% of participants) and anticoagulation (in 60% of participants).\n\nDIONYSOS (n\xa0=\xa0504, 6-month follow-up), a phase\xa0III multicentre, parallel, randomised, double-blind trial comparing dronedarone with amiodarone.\n\nThe EURIDIS and ADONIS trials included people with paroxysmal or persistent atrial fibrillation or atrial flutter, who had an episode of atrial fibrillation in the 3\xa0months before study entry but were in sinus rhythm on entry into the study. Both trials excluded people with NYHA class\xa0III and IV heart failure. The trial population across the two trials had a mean age of 63\xa0years, and 69% were male. Eleven per cent of people had atrial flutter, 41% had structural heart disease and 17% of people had congestive heart failure. The results showed that fewer people in the dronedarone arm had atrial fibrillation recurrence at 12\xa0months than in the placebo group (64% and 75% respectively, hazard ratio 0.75, 95% confidence interval [CI] 0.65 to 0.87, p\xa0<\xa00.001). The median time to atrial fibrillation recurrence was 116\xa0days in the dronedarone group and 53\xa0days in the placebo group. In the dronedarone group, the mean ventricular rate during the first adjudicated atrial fibrillation recurrence was 103\xa0beats per minute compared with 117\xa0beats per minute in the placebo group (p\xa0<\xa00.001). Most adverse events were similar between the study groups (numbers not reported), although there was a lower incidence of hyperthyroidism in the dronedarone group (8.4% and 14.1% respectively, p\xa0=\xa00.002) and a higher incidence of serum creatinine elevation (2.4% and 0.2% respectively, p\xa0=\xa00.004). A post-hoc analysis showed that 23% of people in the dronedarone groups had been admitted to hospital or had died at 12\xa0months versus 31% in the placebo groups (hazard ratio 0.73, 95% CI 0.57 to 0.93, p\xa0=\xa00.01).\n\nThe ATHENA trial included people with paroxysmal or persistent atrial fibrillation or atrial flutter with at least one of the following additional risk factors for a major cardiovascular event: aged 70\xa0years or older; hypertension needing treatment with at least two antihypertensive drugs of different classes; diabetes; previous stroke, transient ischaemic attack or systemic embolism; left atrial diameter of greater than or equal to 50\xa0mm; left ventricular ejection fraction of less than 40%. During the course of the trial, overall mortality figures were lower than expected. As a consequence the inclusion criteria were changed so that people were required to be aged 75\xa0years or older to be eligible, or aged 70–75\xa0years with at least one of the previously specified risk factors, and people younger than 70\xa0years of age were no longer eligible. People were excluded from the ATHENA trial if they had permanent atrial fibrillation, an unstable haemodynamic condition, NYHA class\xa0IV congestive heart failure or an acute myocardial infarction.\n\nThe ATHENA trial population had a mean age of 72\xa0years, and 53% were male. The primary outcome was a composite of first unplanned hospitalisation because of a cardiovascular event and death before hospitalisation. This outcome occurred in 31.9% of the dronedarone group, of whom 29.3% had a first unplanned hospitalisation because of a cardiovascular event and 2.6% died before hospitalisation. The primary outcome occurred in 39.4% of the placebo group, of whom 36.9% had a first unplanned hospitalisation because of a cardiovascular event and 2.5% died before hospitalisation. The hazard ratio for the primary composite outcome in the dronedarone group was 0.76 (95% CI 0.69 to 0.84, p\xa0<\xa00.001). There was no statistically significant difference in all-cause mortality between the dronedarone and placebo groups (5% and 6% respectively, hazard ratio 0.84, 95% CI 0.66 to 1.08, p\xa0=\xa00.18); however there were significantly fewer deaths from cardiovascular causes in the dronedarone group than the placebo group (2.7% and 3.9% respectively, hazard ratio 0.71, 95% CI 0.51 to 0.98, p\xa0=\xa00.03). A post-hoc analysis of the ATHENA trial found that dronedarone was associated with a statistically significant reduction in the risk of stroke compared with placebo (hazard ratio 0.66, 95% CI 0.46 to 0.96, p\xa0=\xa00.027). Another post-hoc analysis reported that dronedarone was associated with a statistically significant reduction in all-cause mortality compared with placebo in people with a CHADS2 score of 4 or more (hazard ratio 0.53, 95% CI 0.31 to 0.91, p\xa0=\xa00.022).\n\nIn the ATHENA trial, treatment was stopped early in 30.2% of the dronedarone group compared with 30.8% of the placebo group (statistical significance not reported). The main reasons for discontinuation were: adverse events (12.7% in the dronedarone group and 8.1% in the placebo group, p\xa0<\xa00.001), participant's request (7.5% in each group), and other reasons (9.4% in the dronedarone group and 14.4% in the placebo group). Gastrointestinal events (including diarrhoea and nausea) were the most common adverse events in both groups, but were more frequent in the dronedarone than the placebo group (26.2% and 22.0% respectively, p\xa0<\xa00.001). The dronedarone group also had higher incidences of bradycardia (p\xa0<\xa00.001), QT-interval prolongation (p\xa0<\xa00.001), rash (p\xa0=\xa00.006) and serum creatinine elevation (p\xa0<\xa00.001) than the placebo group. There was no statistically significant difference between the dronedarone and placebo groups in the number of serious treatment-emergent adverse events (456 and 489 in each group respectively).\n\nThe DIONYSOS trial included people with paroxysmal or persistent atrial fibrillation or atrial flutter in whom cardioversion and antiarrhythmic treatment were indicated and who were also receiving anticoagulation. The trial population had a mean age of 64\xa0years, and two-thirds were male. The primary composite outcome of first incidence of either recurrence of atrial fibrillation or premature study discontinuation because of intolerance or lack of efficacy occurred in 75.5% of the dronedarone group and 58.8% of the amiodarone group (hazard ratio 1.59, p\xa0<\xa00.0001). This difference was mainly because of the higher incidence of recurrence of atrial fibrillation in the dronedarone group than in the amiodarone group (63.5% and 42.0% respectively). The main safety endpoint was defined as the incidence of thyroid-, hepatic-, pulmonary-, neurological-, skin-, eye- or gastrointestinal-specific events, or early study drug discontinuation after any adverse event. This endpoint occurred in 39.3% of the dronedarone group after 12\xa0months of treatment compared with 44.5% in the amiodarone group (hazard ratio 0.80, 95% CI 0.60 to 1.07, p\xa0=\xa00.13). Dronedarone was associated with lower incidences of adverse drug reactions including thyroid dysfunction, significant bradycardia and effects on the central nervous system. There were two (0.8%) deaths in the on-treatment period in the dronedarone group compared with five (2.0%) in the amiodarone group (the causes of the deaths were provided but marked academic in confidence).\n\nThe manufacturer carried out direct and indirect analyses and a mixed treatment comparison of dronedarone compared with amiodarone, sotalol and class\xa01c drugs (flecainide and propafenone combined) and of each antiarrhythmic drug compared with placebo. The analyses were conducted for five outcomes: atrial fibrillation recurrence, all-cause mortality, treatment discontinuation, treatment discontinuation because of adverse events and stroke. The meta-analysis demonstrated that atrial fibrillation recurrence was significantly lower with all antiarrhythmic drugs compared with placebo and that dronedarone was the least effective of all antiarrhythmic drugs (odds ratios were marked academic in confidence). The mixed treatment comparison indicated that dronedarone was associated with a lower risk of all-cause mortality than amiodarone (odds ratio 3.19, 95% CI 1.16 to 8.76, p\xa0=\xa00.032) and sotalol (odds ratio 5.05, 95% CI 1.84 to 13.87, p\xa0=\xa00.009). There was no statistically significant difference in all-cause mortality between dronedarone and placebo and not enough evidence to compare dronedarone with class\xa01c drugs. The mixed treatment comparison showed that dronedarone was associated with a lower risk of stroke than placebo (odds ratio 1.44, 95% CI 1.19 to 1.76, p\xa0=\xa00.015), but there was no difference between dronedarone and sotalol or amiodarone. However, this analysis was based on limited data.\n\nThe manufacturer provided information on two trials of dronedarone that were outside its licensed indication and that therefore did not form the main evidence base for the submission. These were the ERATO trial, in people with permanent atrial fibrillation, and the ANDROMEDA trial, in people with severe heart failure. In addition, the manufacturer submitted results of an analysis of safety using pooled data from five placebo-controlled dronedarone trials (ATHENA, EURIDIS and ADONIS plus two additional trials that did not meet inclusion criteria for the main clinical-effectiveness review: ERATO and DAFNE). The analysis included a total of 6285\xa0people and the average duration of dronedarone exposure was 12\xa0months. The main adverse events associated with dronedarone were diarrhoea, nausea or vomiting, serum creatinine elevation, rash, and cardiac events (bradycardia and QT prolongation). The incidence of serious adverse events was similar in the dronedarone and placebo groups (18.0% and 19.7% respectively) and these were mainly related to infections and infestations, gastrointestinal disorders, and cardiac disorders. There were more early discontinuations in the dronedarone group than the placebo group (11.8% and 7.7% respectively) and the most common reason for stopping dronedarone was diarrhoea (statistical significance not reported).\n\nThe model used in the manufacturer's cost-effectiveness analysis was a discrete event simulation that predicts a person's course if they are treated with dronedarone compared with the predicted course with alternative treatment pathways. The manufacturer stratified people depending on their type of atrial fibrillation and baseline risk factors into five groups in accordance with the NICE guidance on atrial fibrillation (NICE clinical guideline\xa036): paroxysmal atrial fibrillation without structural heart disease, paroxysmal atrial fibrillation with coronary heart disease, paroxysmal atrial fibrillation with left ventricular dysfunction, persistent atrial fibrillation without structural heart disease, and persistent atrial fibrillation with structural heart disease. For each of these subgroups, the manufacturer evaluated the cost effectiveness of dronedarone at two positions in the care pathway for atrial fibrillation (see section\xa03.1). When dronedarone was evaluated as part of a first-line treatment for people with a CHADS2 score of 4 or more (in addition to standard baseline therapy), the comparator was standard baseline therapy alone (including beta-blockers [excluding sotalol] and anticoagulation). When dronedarone was evaluated as a second-line treatment option, the comparators were the antiarrhythmic drugs amiodarone, sotalol and class\xa01c drugs, depending on the type of atrial fibrillation and baseline risk factors described above.\n\nThe manufacturer's model used a lifetime time horizon and included four health states: normal sinus rhythm, permanent atrial fibrillation with uncontrolled symptoms, permanent atrial fibrillation with controlled symptoms and death. From the normal sinus rhythm state, people could move to any of the other states. From the two permanent atrial fibrillation health states, people could move between these states or to death. Transition between health states was determined by the following events: atrial fibrillation recurrence, acute coronary syndrome, stroke, congestive heart failure, treatment discontinuation, change in symptoms (for the permanent atrial fibrillation states) or death. The baseline risk of these events was taken from the ATHENA trial, extrapolated to a lifetime time horizon and adjusted for each treatment arm using odds ratios from the mixed treatment comparison. All-cause mortality was estimated using age-specific UK life tables (from the Government Actuary's Department) and adjusted for CHADS2 score. The risk of death after stroke and congestive heart failure events was estimated using published sources.\n\nThe model included adverse events associated with each treatment. Adverse event rates for dronedarone were taken from a pooled analysis of the six dronedarone trials (DAFNE, ADONIS, ERATO, EURIDIS, ATHENA and DIONYSOS), for amiodarone they were taken from the DIONYSOS trial, and for sotalol and class\xa01c drugs they came from the SPCs. Utilities for the health states were taken from the AFTER cohort of the European Heart Survey on atrial fibrillation. The disutilities associated with adverse events were taken from a study undertaken by the manufacturer (n\xa0=\xa0127) using a time trade-off approach.\n\nIn the model, drug costs for comparators were taken from the 'British national formulary' (edition 57). Doses were based on the recommended dosage stated in the SPCs. Drug administration costs were sourced from NHS Reference Costs 2007–08. For dronedarone these consisted of a specialist outpatient visit for treatment initiation and a GP visit for a day-7 creatinine test (£213). For comparators, it was assumed that hospitalisation was required for treatment initiation (£249) and 6-monthly GP visits and tests were required for monitoring (£58–76 depending on the treatment). Costs for the majority of health events occurring in the model were taken from published literature. Most events were assumed to incur a one-off cost; but for stroke and congestive heart failure, ongoing daily costs were assumed. Costs for adverse events came from NHS Reference Costs 2007–08. A proportion of adverse events were assumed to require hospitalisation (based on expert clinical opinion) and the rest were assumed to require an outpatient consultant visit. For short-term adverse events, a one-off cost at treatment initiation was incurred and for adverse events with lifetime effects, a 6-monthly GP visit was assumed to be required. Data on resource use were sourced from clinical opinion and published literature.\n\nIn the manufacturer's base-case analysis, the incremental cost-effectiveness ratios (ICERs) for the analysis of dronedarone if given in addition to standard baseline therapy (for people with a CHADS2 score of 4 or more) compared with standard baseline therapy alone ranged from £6757 to £7890 per quality-adjusted life year (QALY) gained (incremental costs £3053 and £3307 and incremental benefits 0.45 and 0.42 QALYs for these two ICERs respectively). The ICERs varied depending on the type of atrial fibrillation and the presence of structural heart disease, coronary heart disease or left ventricular dysfunction. For the analysis of dronedarone as an alternative antiarrhythmic drug to amiodarone, the ICERs were £2645 per QALY gained (incremental cost £3528 and incremental benefit 1.33 QALYs) for paroxysmal atrial fibrillation with left ventricular dysfunction and £3113 per QALY gained (incremental cost £3986 and incremental benefit 1.28 QALYs) for persistent atrial fibrillation with structural heart disease. For the comparison of dronedarone with class\xa01c drugs, the ICERs were £20,003 per QALY gained (incremental cost £1980 and incremental benefit 0.10\xa0QALYs) for paroxysmal atrial fibrillation with no structural heart disease and £20,761 per QALY gained (incremental cost £2069 and incremental benefit 0.10 QALYs) for persistent atrial fibrillation with no structural heart disease. For the comparison of dronedarone with sotalol, the ICERs ranged from £1929 to £2197 per QALY gained (incremental costs £3986 and £4384 and incremental benefits 2.07 and 2.00 QALYs for these two ICERs respectively) (depending on the type of atrial fibrillation and the presence or absence of underlying heart disease).\n\nThe manufacturer conducted a number of sensitivity analyses including:\n\nsubgroup analyses based on CHADS2 scores and gender\n\nusing alternative sources for the baseline distribution of CHADS2 score\n\nvarying the model time horizon\n\nassuming a minimum mortality benefit from dronedarone relative to its comparators by using the lower end of the 95% CI of the mortality estimate for comparators and the upper end of the 95% CI for dronedarone (rather than the point estimates), and vice versa (that is, assuming a maximum relative mortality benefit from dronedarone)\n\nusing different curve fits for the modelled clinical events such as stroke and treatment discontinuations\n\nusing different estimates for various parameters including mortality treatment effect, stroke treatment effect, treatment discontinuation, adverse event rate, costs of dronedarone and utilities. The analyses that had the greatest effect on the ICERs were using a 1-year time horizon (rather than a lifetime time horizon) and assuming a minimum mortality benefit from dronedarone relative to its comparators.\n\nThe ERG considered that all relevant trials of dronedarone had been included in the manufacturer's submission. It noted that the ATHENA trial included people who were older and had a higher risk of a major cardiovascular event than people in the other trials and that the application of this evidence to a lower-risk and younger population was uncertain. The ERG commented that the DIONYSOS trial was the only head-to-head trial of dronedarone versus an antiarrhythmic drug and therefore the relative efficacy of dronedarone compared with antiarrhythmic drugs other than amiodarone was unknown. It also noted that the DIONYSOS trial was short-term (minimum follow-up: 6\xa0months). The ERG commented on a number of limitations of the meta-analyses and mixed treatment comparison in the manufacturer's submission. These included:\n\na lack of consideration of clinical and statistical heterogeneity of the studies included in the analyses\n\nuncertainty about the validity of pooling the individual studies in the different analyses\n\nfew events in the studies\n\nthe use of outcomes that were neither pre-specified endpoints nor centrally adjudicated\n\ninconsistencies in the selection of studies across the different analyses\n\nthe restriction of randomised controlled trials in the mixed treatment comparison. The ERG considered that the assumption that class\xa01c drugs have a similar effect on all-cause mortality to dronedarone and no effect on the risk of stroke (made because of a lack of evidence) might not be valid. It noted an inconsistency in the direction of effect between results of the direct and indirect analyses and the mixed treatment comparison for the outcome of treatment discontinuations because of any cause. The ERG considered that the existing clinical evidence across the antiarrhythmic drugs appeared most robust for the outcome of atrial fibrillation recurrence, but considerably more uncertain for the other major clinical endpoints such as stroke and all-cause mortality. The ERG also noted that although the marketing authorisation for dronedarone states that it should be used to lower ventricular rate, there was little evidence presented on this outcome.\n\nThe ERG considered that in general, the manufacturer's approach to the economic evaluation met the requirements of the NICE reference case, had an appropriate structure for the decision problem, and was of high quality, overall. However, the ERG noted a number of issues with the cost-effectiveness analysis, including concern over the pivotal assumption of mortality benefit:\n\nThe treatment pathways evaluated by the manufacturer might not represent the full range of treatment strategies or sequences for dronedarone.\n\nThe baseline data from the ATHENA trial, used in the model, might not be generalisable to people with atrial fibrillation in the NHS because they came from an older and higher-risk population.\n\nThe results of the meta-analyses and mixed treatment comparisons, used in the model, might not be appropriate because of concerns about the methodology of these analyses.\n\nThe lack of health-related quality-of-life data from any of the dronedarone studies.\n\nThe assumption of lower initiation and monitoring costs for dronedarone compared with other antiarrhythmic drugs might not be appropriate.\n\nThe uncertainty associated with modelling the benefits of dronedarone over the longer term because of the short duration of the trials.\n\nThe ERG made revisions to the manufacturer's model to correct coding errors (relating to adverse events costs and the length of time that mortality treatment benefits were applied). The revisions resulted in considerably lower ICERs than those reported in the manufacturer's base case for the comparisons of dronedarone with sotalol and amiodarone (ICERs ranged from £1895 to £4014 per QALY gained in the ERG's analysis applying a lifetime mortality benefit compared with £1980 to £8142 per QALY gained in the base case). The results for dronedarone compared with class\xa01c drugs were unaffected because both drugs were assumed to have the same mortality benefit.\n\nThe ERG stated that the manufacturer's base-case ICERs were based on the estimates of relative effectiveness of dronedarone compared with other antiarrhythmic drugs derived from the manufacturer's mixed treatment comparison. It had previously noted concerns about this mixed treatment comparison (section\xa03.16). The ERG therefore performed a number of analyses exploring the impact of assumptions about treatment effects on the ICERs. These included:\n\nassuming that dronedarone has the same effect on mortality across all CHADS2 subgroups (for the comparison of dronedarone with standard baseline therapy)\n\nassuming that sotalol and amiodarone have no effect on mortality, but keeping the assumed mortality benefit of dronedarone\n\nassuming that class\xa01c drugs, sotalol and amiodarone have the same effect on mortality as dronedarone\n\nassuming that class\xa01c drugs have a more beneficial effect on mortality than dronedarone\n\nassuming that class\xa01c drugs have the same effect on stroke as dronedarone\n\nusing effect estimates from a reanalysis of the mixed treatment comparison of all-cause mortality using a wider range of studies than that used in the manufacturer's analysis.\n\nFor most analyses, the ICERs increased but remained below £20,000 per QALY gained. However, when sotalol and amiodarone were assumed to have the same effect on mortality as dronedarone, the ICERs increased to between £55,063 and £119,704 per QALY gained. When class\xa01c drugs were assumed to have the same effect on the risk of stroke as dronedarone, the ICERs approximately doubled (to about £38,000 per QALY gained) and when class\xa01c drugs were assumed to have greater mortality benefits than dronedarone, class\xa01c drugs had both higher effectiveness and lower costs than dronedarone. The ERG also explored the uncertainty around treatment initiation, monitoring costs and utility weights used in the model. The impact on the ICERs for all analyses and comparisons was marginal.\n\nThe ERG conducted exploratory analyses to identify the main drivers of the cost-effectiveness results. The first was to explore the effect on the ICERs when all treatment effects are excluded from the economic analysis except atrial fibrillation recurrence. The ICERs either increased to between £1,355,984 and £70,323,846 per QALY gained or dronedarone was shown to have both higher costs and lower effectiveness than the comparators. The ERG then explored the effect on the ICERs when the treatment effects on all-cause mortality were included in the analysis in addition to atrial fibrillation recurrence. The ICERs decreased to between £1815 and £4566 per QALY gained for the comparisons of dronedarone with standard baseline therapy, sotalol and amiodarone. For the comparison of dronedarone with class\xa01c drugs, the ICERs were either £370,690 or dronedarone was shown to have both higher costs and lower effectiveness than the comparators (because both drugs were assumed to have the same effect on mortality). Based on these analyses, the ERG concluded that the main driver of the cost effectiveness of dronedarone compared with standard baseline therapy, sotalol or amiodarone is the reduction in all-cause mortality associated with dronedarone. To explore the main driver of the cost effectiveness of dronedarone compared with class\xa01c drugs, the ERG conducted a further analysis including the treatment effects on stroke in addition to atrial fibrillation recurrence and mortality. This resulted in ICERs of £43,543 and £46,500 per QALY gained. The ERG noted that when treatment effects on adverse events were included in the analysis (as in the manufacturer's base-case analysis), the ICERs were around £18,000 per QALY gained. It therefore advised that the combined effect of reduced risk of stroke and fewer adverse events was the main driver of cost effectiveness for dronedarone compared with class\xa01c drugs.\n\nAfter consultation on the first appraisal consultation document (ACD), the ERG conducted two further scenario analyses in which the treatment effects on all-cause mortality were varied. In the first analysis, dronedarone was assumed to have no effect on all-cause mortality compared with placebo, whereas amiodarone, sotalol and class\xa01c drugs were assumed to increase the risk of all-cause mortality (using effect estimates from the ERG's mixed treatment comparison). For the comparison of dronedarone with standard baseline therapy (in people with a CHADS2 score of 4 or more), the ICERs increased from the ERG's revised base case (between £3358 and £4014 per QALY gained) to between £56,798 and £69,575 per QALY gained. For the comparisons with amiodarone and sotalol, the ICERs increased from between £1692 and £2349 to between £2588 and £5853 per QALY gained and for the comparison with class\xa01c drugs, the ICERs were lower (£11,648 and £12,760 per QALY gained) than in the ERG's revised base case (£18,206 and £18,955 per QALY gained). In the second analysis, amiodarone, sotalol and class\xa01c drugs were assumed to have no effect on all-cause mortality compared with placebo, and the effect of dronedarone compared with placebo was varied from an odds ratio of 0.84 (that is, a beneficial effect as in the manufacturer's model) to 1.0 (that is, no effect on all-cause mortality). This threshold analysis showed that when the odds ratio was 0.95 or lower (that is, when dronedarone was assumed to reduce all-cause mortality by at least 5%), the ICERs for all comparisons were between £9323 and £20,689 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "Please note that the recommendations in section 1 for dronedarone have been amended to reflect changes made to the UK marketing authorisation. The information in this section is based on dronedarone's marketing authorisation at the time the appraisal was initially considered in 2010. Please refer to the revised summary of product characteristics for dronedarone for further information.\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dronedarone, having considered evidence on the nature of atrial fibrillation and the value placed on the benefits of dronedarone by people with the condition, those who represent them, and clinical specialists. It considered comments received at consultation on the ACDs. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the positions for dronedarone in the treatment pathway for atrial fibrillation proposed by the manufacturer. It noted that the NICE guidance on atrial fibrillation (NICE clinical guideline\xa036) states that a standard beta-blocker should be the initial treatment for people with symptomatic atrial fibrillation (in addition to anticoagulation) and that an antiarrhythmic drug should be used when beta-blockers fail to control symptoms or are contraindicated (that is, as a second-line treatment). The Committee initially discussed using dronedarone in addition to standard baseline therapy of beta-blockers and anticoagulation (that is, as a first-line treatment). It noted that the manufacturer had only presented cost-effectiveness evidence at this position in the care pathway for the subgroup of people with a CHADS2 score of 4 or more (that is, people with a high risk of stroke). The Committee also noted that the licensed indication for dronedarone was to prevent recurrence of atrial fibrillation or to lower ventricular rate, but that the only outcome that was presented in this subgroup was all-cause mortality. The Committee then discussed the use of dronedarone as an alternative antiarrhythmic drug for second-line treatment of atrial fibrillation and considered that the comparators assessed in the manufacturer's submission (sotalol, class\xa01c drugs and amiodarone) were appropriate.\n\nThe Committee considered that not all possible uses of dronedarone had been evaluated in the manufacturer's submission. It heard from clinical specialists and patient experts that a potential use of dronedarone would be in people who are unable to tolerate other antiarrhythmic drugs, in particular amiodarone. However, no evidence was provided relating to the clinical effectiveness and adverse effects of dronedarone in this group of people.\n\nThe Committee understood from clinical specialists and patient experts that they considered amiodarone to be an effective antiarrhythmic drug for controlling atrial fibrillation symptoms, but that it had a high level of toxicity and many people were not able to tolerate it. The clinical specialists and patient experts commented that antiarrhythmic treatment options for people with atrial fibrillation are limited and they would welcome an antiarrhythmic drug that was effective at controlling atrial fibrillation symptoms and that was more tolerable than amiodarone. The Committee also heard from patient experts that younger people, who cannot take class\xa01c drugs or sotalol, might benefit from an antiarrhythmic drug that is more tolerable than amiodarone because of the longer length of time that they are likely to need treatment. It discussed comments received at consultation stating that younger people with atrial fibrillation who also had congenital heart problems would value dronedarone as a treatment option. However, the Committee concluded that because no evidence was presented for people with congenital heart disease, it could not make any recommendations specifically in this group.\n\nThe Committee considered it appropriate that dronedarone is initiated by a specialist in a secondary care setting, which clinical specialists commented is usual practice for second-line treatment with antiarrhythmic drugs. The Committee noted that the cost-effectiveness model submitted by the manufacturer assumed that treatment with dronedarone was initiated by a specialist during an outpatient visit.\n\n# Clinical effectiveness\n\nThe Committee discussed the evidence on the effect of dronedarone on atrial fibrillation recurrence. It considered that the randomised controlled trials (ATHENA, EURIDIS, ADONIS and DIONYSOS) demonstrated that dronedarone was more effective than placebo at reducing atrial fibrillation recurrence, but less effective than amiodarone. It discussed the results of the meta-analyses and mixed treatment comparison conducted by the manufacturer that indicated that all antiarrhythmic drugs, including dronedarone, were effective at reducing atrial fibrillation recurrence, but that dronedarone was the least effective. The Committee concluded that dronedarone reduced atrial fibrillation recurrence compared with placebo, but that it appeared to be less effective for atrial fibrillation recurrence than other antiarrhythmic drugs.\n\nThe Committee discussed the evidence on the effect of dronedarone on ventricular rate. It noted that the licensed indication for dronedarone was to prevent recurrence of atrial fibrillation or to lower ventricular rate, but that the only studies that assessed ventricular rate in people with non-permanent atrial fibrillation were the EURIDIS and ADONIS trials. It noted that these trials reported a lower ventricular rate in the dronedarone group than the placebo group. The Committee was also aware that ventricular rate was not included in the manufacturer's economic model. It heard from clinical specialists that the ERATO trial had shown that dronedarone reduces ventricular rate compared with placebo. However, the Committee noted that this study was in people with permanent atrial fibrillation, which is not a licensed indication for dronedarone. The Committee considered that there was insufficient evidence to reach a definitive conclusion about the benefits of dronedarone for reducing ventricular rate in people with non-permanent atrial fibrillation.\n\nThe Committee discussed the trial evidence on the effect of dronedarone on mortality. It considered the results of the ATHENA trial, which reported lower cardiovascular mortality in the dronedarone group compared with the placebo group but no statistically significant difference in all-cause mortality (for the whole trial population). The Committee concluded that a reduction in all-cause mortality with dronedarone compared with placebo had not been demonstrated by the ATHENA trial for the whole trial population. The Committee discussed the post-hoc subgroup analysis of the ATHENA trial that reported a lower risk of all-cause mortality in the dronedarone group compared with the placebo group for people with a CHADS2 score of 4 or more. It discussed the use of the CHADS2 score to predict mortality. It heard from clinical specialists that the CHADS2 score was a useful method of assessing stroke risk in people with atrial fibrillation to determine the need for anticoagulation treatment, but that it was not used to predict mortality. It noted published evidence that reported an association between CHADS2 score and risk of all-cause mortality for people who have had a stroke. However, the Committee considered that no evidence had been presented to validate the use of CHADS2 score for more generally predicting all-cause mortality in people with atrial fibrillation.\n\nThe Committee discussed the issue of all-cause mortality in relation to the DIONYSOS trial, which provided the only direct head-to-head comparison of dronedarone with another antiarrhythmic drug, and reported fewer deaths in the dronedarone group than in the amiodarone group. However, the Committee noted the short follow-up of the trial and the small number of deaths in the study, and it considered whether all the deaths in the amiodarone group were because of cardiovascular causes (noting that the causes of death were marked commercial in confidence). Therefore the Committee considered that no conclusion about the relative effect of dronedarone and amiodarone on mortality could be made on the basis of this trial.\n\nThe Committee discussed the results of the manufacturer's mixed treatment comparison, which reported a lower risk of all-cause mortality for dronedarone compared with placebo. It noted the ERG's criticism about the methodology used for the mixed treatment comparison. It also noted that the CIs for this analysis crossed the null effect value, indicating that the difference was not statistically significant. The Committee considered that the mixed treatment comparison was largely based on the difference in all-cause mortality between the treatment arms in the ATHENA trial, which itself was not statistically significant. The Committee concluded that there was considerable uncertainty about the effect of dronedarone on all-cause mortality. It was not persuaded that a reduction in the risk of all-cause mortality for dronedarone compared with placebo had been demonstrated by the mixed treatment comparison.\n\nThe Committee then discussed the evidence on the risk of all-cause mortality for the other antiarrhythmic drugs. It noted results from the mixed treatment comparison showing that sotalol and amiodarone were associated with a higher risk of mortality than placebo. It discussed the results of the ERG's reanalysis of the mixed treatment comparison and also considered evidence from two published meta-analyses of antiarrhythmic drugs. The Committee noted that all of these analyses reported a trend towards increased all-cause mortality with sotalol and amiodarone compared with placebo, albeit less than that reported in the manufacturer's mixed treatment comparison. It also noted that only the hazard ratio for the comparison of sotalol with placebo for all-cause mortality had a CI that did not cross 1.0, indicating a statistically significant difference between these drugs. The Committee was aware that there were limited data on class\xa01c drugs. It considered comments received at consultation and from the clinical specialists that amiodarone, sotalol and class\xa01c drugs were associated with an increased risk of mortality. Overall, the Committee accepted that the risk of mortality with the other antiarrhythmic drugs was likely to be higher than with dronedarone.\n\nThe Committee considered the evidence on the effect of dronedarone on the risk of stroke. It heard from clinical specialists that stroke was a known complication of arrhythmias such as atrial fibrillation. Therefore, drugs that are more effective in reducing atrial fibrillation might be expected to have a greater long-term benefit in relation to stroke prevention. The Committee discussed the post-hoc analysis of the ATHENA trial and noted that the ATHENA investigators concluded that 'the observation of a reduced rate of stroke in patients receiving dronedarone cannot be considered a definitive conclusion'. It discussed the mixed treatment comparison that resulted in reduced risk of stroke with dronedarone compared with placebo. It noted that this analysis was based on a small number of studies with very few events and no studies had any prospective collection of data on stroke incidence. The Committee concluded there was considerable uncertainty about the effect of dronedarone on the risk of stroke. It was not persuaded that a reduction in the risk of stroke with dronedarone compared with other antiarrhythmic drugs had been demonstrated.\n\nThe Committee discussed the adverse events associated with dronedarone. It was aware of the ANDROMEDA trial in which dronedarone was associated with an increased risk of mortality in people with severe congestive heart failure and noted that having atrial fibrillation was not an inclusion criterion for this trial. It was also aware that the SPC states that dronedarone is contraindicated in people with unstable NYHA class\xa0III and IV heart failure, and that it is not recommended in people with stable, recent NYHA class\xa0III heart failure and people with left ventricular ejection fraction less than 35%. The Committee noted that the most common adverse events reported across the trials of dronedarone were gastrointestinal. It discussed the possibility of serious adverse events such as pulmonary fibrosis, thyroid disease and torsades de pointes (an arrhythmia). It noted that there were very few cases reported in the randomised controlled trials, but that these trials were all relatively short term. The Committee considered evidence from the DIONYSOS trial that showed that people in the dronedarone group had fewer adverse events than those in the amiodarone group. However, it noted that these results were also based on short-term data. It noted there was no direct evidence comparing the adverse effects of dronedarone with sotalol or class\xa01c drugs. The Committee heard from patient experts that they did not consider that the adverse events associated with dronedarone would impact significantly on quality of life for people with atrial fibrillation. It noted comments from patients and clinical specialists received during consultation on the first ACD that all current antiarrhythmic drugs had side effects that had a significant impact on quality of life, but particularly amiodarone, with long-term use. Overall, the Committee concluded that the adverse effect profile of dronedarone was likely to be more favourable than amiodarone.\n\nThe Committee specifically considered the balance between the better short-term side-effect profile and the lower effectiveness of dronedarone compared with amiodarone. It heard from patient experts that some people with atrial fibrillation might prefer to take an antiarrhythmic drug that has better tolerability, despite it having less effect on atrial fibrillation recurrence. It also heard that effectiveness of an antiarrhythmic drug for reducing atrial fibrillation recurrence and its tolerability could be more important to some people with atrial fibrillation than longer-term benefits such as a reduction in the risk of stroke or death. The Committee was aware of the potential value placed on dronedarone by patients when it examined the cost-effectiveness analyses.\n\n# Cost effectiveness\n\nThe Committee discussed the economic analysis provided by the manufacturer. It noted the ERG's conclusion that the approach used was, in general, appropriate and in accordance with the NICE reference case. However, the Committee was concerned about some of the key assumptions in the model, in particular that there was a beneficial effect of dronedarone on mortality and that the ATHENA trial was an appropriate source of data for the baseline risk of events. It also had concerns about the modelled costs of dronedarone and other antiarrhythmic drugs and the utilities used in the model. In addition, the Committee noted that the economic analysis was based on pair-wise comparisons of two treatments and did not use incremental analyses to compare all treatments simultaneously. It also noted that the economic analysis did not evaluate all possible uses of dronedarone.\n\nThe Committee discussed the use of the placebo arm of the ATHENA trial to inform the baseline event rates in the model. It considered that this was based on an assumption that the ATHENA population was representative of people with atrial fibrillation in the UK. The Committee noted that the ATHENA trial included people who were older and had higher cardiovascular risk than people in the other dronedarone trials. It considered that the ATHENA population represented a higher-risk group than the more general population of people with atrial fibrillation in the UK in whom dronedarone would be used. Therefore, the Committee concluded that the cost-effectiveness estimates it had been presented with were only relevant to the population represented by the ATHENA trial (that is, people with additional cardiovascular risk).\n\nThe Committee noted that in the manufacturer's base-case analysis, the ICERs ranged from £1900 to £20,800 per QALY gained depending on the type of atrial fibrillation, the presence of structural heart disease, left ventricular dysfunction and coronary heart disease, and the comparator. It considered the ERG's revisions to the model to be appropriate, involving correction of coding errors and use of a lifetime time horizon for mortality benefits, which resulted in decreased ICERs ranging from £1700 to £19,000 per QALY gained. However, it noted that these figures did not incorporate changes in other key assumptions such as the mortality benefit associated with dronedarone.\n\nThe Committee discussed the ERG's analyses exploring the main factors that influenced the cost effectiveness of dronedarone. It considered that the relative effect of dronedarone and antiarrhythmic drugs on mortality was a key factor in the economic analysis. It again considered comments received during consultation on the first ACD and from the clinical specialists about the likely excess mortality associated with other antiarrhythmic drugs. In light of the uncertainty about the effect of dronedarone on mortality, the Committee discussed several exploratory scenario analyses conducted by the ERG in which the relative all-cause mortality effects of each antiarrhythmic drug were varied. It considered the scenario in which dronedarone had no effect on mortality compared with placebo, and other antiarrhythmic drugs were associated with some increase in mortality (as calculated in the ERG's meta-analysis), to be the most appropriate, given the uncertainty about the mortality effect of dronedarone. It noted the ICERs from this analysis were below £15,000 per QALY gained for the use of dronedarone as a second-line treatment alternative to sotalol, class\xa01c drugs and amiodarone. It also noted the ICERs from this analysis were above £50,000 per QALY gained for the use of dronedarone as part of first-line treatment in addition to standard baseline therapy (in people with a CHADS2 score of 4 or more). The Committee concluded that these cost-effectiveness estimates were the most plausible of all those presented.\n\nThe Committee discussed the costs and utilities included in the economic analysis. It noted that lower initiation and monitoring costs were attributed to dronedarone than other antiarrhythmic drugs. The Committee also noted the ERG's criticism that the utilities used in the model appeared to exceed general population values for healthy states. It considered the ERG's analyses that used revised drug administration costs and utilities, and concluded that these changes had a marginal impact on the cost-effectiveness estimates of dronedarone.\n\nThe Committee noted comments received at consultation on the first ACD that the economic analysis had not taken into account the potential cost savings of the reduced cardiovascular hospitalisations associated with dronedarone (shown in the ATHENA trial). It considered that the costs and effects of hospitalisation were included in the analysis through the modelling of events such as atrial fibrillation recurrence and stroke for which hospitalisation costs may be incurred. The Committee also considered comments received at consultation on the first ACD that treatment with dronedarone would be stopped if it was not effective and this was not considered in the economic evaluation. It noted that the submission provided by the manufacturer did not specifically evaluate treatment stopping rules and also did not consider the full range of potential treatment sequences for dronedarone. However, the Committee considered that some element of treatment discontinuation had been accounted for in the modelling of withdrawal because of adverse events or lack of efficacy.\n\nIn light of the above considerations, the Committee discussed the cost effectiveness of dronedarone as a first-line treatment for atrial fibrillation (in addition to standard baseline therapy usually including beta-blockers). It noted that cost-effectiveness evidence for dronedarone as a first-line therapy had only been provided for the subgroup of people with a CHADS2 score of 4 or more. In addition to concerns about the validity of the CHADS2 score in this context, the Committee considered that the beneficial effect of dronedarone on all-cause mortality assumed in the manufacturer's submission was not proven. It noted that when this effect was removed from the economic analysis the cost per QALY gained was above £50,000. The Committee concluded that the use of dronedarone in people with a CHADS2 score of 4 or more (in addition to standard baseline therapy) for the first-line treatment of atrial fibrillation could not be considered a cost-effective use of NHS resources. The Committee also noted that no evidence had been provided for first-line treatment with dronedarone other than in people with a CHADS2 score of 4 or more. Therefore it could not make any conclusions about the first-line use of dronedarone in other people with non-permanent atrial fibrillation. The Committee concluded that dronedarone could not be recommended as a first-line treatment for atrial fibrillation (in addition to standard baseline therapy usually including beta-blockers).\n\nThe Committee discussed the cost effectiveness of dronedarone as a second-line treatment for people whose atrial fibrillation is not controlled by standard baseline therapy (that is, as an alternative to the antiarrhythmic drugs: amiodarone, sotalol and class\xa01c agents). It considered that a beneficial effect of dronedarone on all-cause mortality was not proven; however, it accepted that the risk of mortality with the other antiarrhythmic drugs was likely to be higher than with dronedarone. It considered that when this scenario was modelled, the costs per QALY gained were within an acceptable range. The Committee noted that these cost-effectiveness estimates were largely based on data from the ATHENA trial, which included people who had a higher risk of a major cardiovascular event, and it was uncertain whether these data were applicable to people in England and Wales who would receive second-line treatment for atrial fibrillation. Therefore the Committee concluded that using dronedarone as a second-line alternative to amiodarone, class\xa01c drugs, or sotalol for the treatment of non-permanent atrial fibrillation could be considered a cost-effective use of NHS resources in people who have the same characteristics as the population in the ATHENA trial, that is, they have at least one of the following additional cardiovascular risk factors: hypertension requiring drugs of at least two different classes, diabetes, previous transient ischaemic attack, stroke or systemic embolism, left atrial diameter at least 50\xa0mm, left ventricular ejection fraction less than 40% or age 70\xa0years or older. The Committee was mindful that there might be some overlap between people with cardiovascular risk factors and those in whom dronedarone is contraindicated (with unstable NYHA class\xa0III or IV heart failure) or not recommended (with left ventricular ejection fraction less than 35%). Therefore the Committee considered it important to emphasise in its recommendations that dronedarone should not be used in people with unstable NYHA class\xa0III or IV heart failure and to refer to the recommendation in the SPC about the use of dronedarone in people with left ventricular ejection fraction less than 35%.\n\n This refers to the licensed indication at the time of the appraisal and not the indication amended in 2011.\n\n This refers to the licensed indication at the time of the appraisal and not the indication amended in 2011.\n\n This refers to the licensed indication at the time of the appraisal and not the indication amended in 2011.", 'Recommendations for further research ': 'The Committee considered that research directly comparing antiarrhythmic drugs would be valuable, in particular assessing the relative effect of the different antiarrhythmic drugs on clinical outcomes and mortality.', 'Related NICE guidance': 'Atrial fibrillation: the management of atrial fibrillation. NICE clinical guideline\xa036 (2006).\n\nPercutaneous radiofrequency ablation for atrial fibrillation. NICE interventional procedure guidance 168 (2006).', 'Review of guidance': 'The guidance on this technology will be considered for review in March 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveIssued: August 2010\n\nRe-issued: December 2012', 'Changes after publication': 'May 2014: minor maintenance\n\nFebruary 2014: implementation section updated to clarify that dronedarone is recommended as an option for treating non-permanent atrial fibrillation. Additional minor maintenance update also carried out.\n\nDecember 2012: recommendation 1.1 amended to reflect the change in the dronedarone marketing authorisation.\n\nOctober 2012: a note has been added explaining the review decision for this guidance and the change in the dronedarone marketing authorisation.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta197	Evidence-based recommendations on dronedarone (Multaq) for treating non-permanent atrial fibrillation in adults.
ac465c8454d457f8dd8ca38e2fe172d64ba29494	nice	Physical activity: walking and cycling	Physical activity: walking and cycling This guideline covers encouraging people to increase the amount they walk or cycle for travel or recreation purposes. # What is this guidance about? This guidance aims to set out how people can be encouraged to increase the amount they walk or cycle for travel or recreation purposes. This will help meet public health and other goals (for instance, to reduce traffic congestion, air pollution and greenhouse gas emissions). The recommendations cover: policy and planning local programmes schools, workplaces and the NHS. This guidance does not cover: Environmental changes to encourage walking or cycling. (see the NICE guideline on physical activity and the environment covers the physical infrastructure and planning needed to make non-motorised transport an easier option.) National actions to support walking and cycling, such as fiscal measures and other policy interventions to alter the balance between active and motorised travel in terms of cost and convenience. Measures to reduce the risk of unintentional injuries from walking and cycling. (See the NICE guideline on strategies to prevent unintentional injuries among under-15s.) # Who is this guidance for? The guidance is for commissioners, managers and practitioners involved in physical activity promotion or who work in the environment, parks and leisure or transport planning sectors. They could be working in local authorities, the NHS and other organisations in the public, private, voluntary and community sectors. It is also aimed at: employers estate managers highways authorities those involved in land use planning and development control private developers public transport operators those involved in carbon reduction or sustainability planning -thers responsible for workplace travel, carbon reduction or sustainability plans. In addition, it will be of interest to people who promote walking and cycling in an unpaid capacity, those who want to walk or cycle and other members of the public.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The guidance complements NICE guidance on physical activity and the environment. The evidence statements underpinning the recommendations are listed in appendix C. The Programme Development Group (PDG) considers that the recommended approaches are highly cost effective. See also the recommendations for research, gaps in the evidence and the evidence reviews, supporting evidence statements and economic modelling report. # Background This guidance considers walking and cycling as forms of transport, for example, to get to work, school or the shops. It also considers them as recreational activities, for example, as a means of exploring parks or the countryside. Walking and cycling are distinct activities which are likely to appeal to different segments of the population. A range of factors may be important in helping or restricting people from taking part. These will vary according to whether someone is walking or cycling for transport purposes, for recreation or to improve their health. Wherever the term 'walking and cycling' is used in this guidance, these variations should be kept in mind. In the context of this guidance, walking and cycling includes the use of adapted cycles (such as trikes, tandems and handcycles), wheelchairs and similar mobility aids. The action needed to increase levels of walking and cycling will vary according to people's local and personal circumstances. For instance, it will differ according to whether someone lives or works in an urban or rural area, the local traffic conditions and their perceptions of safety. 'Local' may refer to an area defined by geography or for administrative purposes. It may comprise an area larger than that covered by a single local authority such as Greater London, Manchester or Merseyside. It may also refer to a housing estate, a small town or a village. # Benefits of walking and cycling Increasing how much someone walks or cycles may increase their overall level of physical activity, leading to associated health benefits. These include: Reducing the risk of coronary heart disease, stroke, cancer, obesity and type 2 diabetes. Keeping the musculoskeletal system healthy. Promoting mental wellbeing. An increase in walking or cycling can also help: Reduce car travel, leading to reductions in air pollution, carbon dioxide emissions and congestion. Reduce road danger and noise. Increase the number of people of all ages who are out on the streets, making public spaces seem more welcoming and providing opportunities for social interaction. Provide an opportunity for everyone, including people with an impairment, to participate in and enjoy the outdoor environment. # Encouraging people to walk and cycle Encouraging and enabling people to walk or cycle requires action on many fronts – and by many different sectors. A range of issues have to be addressed, including environmental, social, financial and personal factors. In addition to the recommendations made in this (and related) NICE guidance, other measures are needed to tackle the wider influences on walking or cycling. This includes measures to reduce road dangers and to reallocate road space to create a more supportive environment (see the scope for further detail). Action in these areas is particularly important in tackling inequalities in health, including with regard to people with impairments. # Whose health will benefit? Unless otherwise stated, the recommendations will benefit everyone. # Policy and planning ## Recommendation 1 High-level support from the health sector Directors of public health. Public health portfolio holders in local authorities. Clinical commissioning groups. Ensure a senior member of the public health team is responsible for promoting walking and cycling. They should support coordinated, cross-sector working, for example, by ensuring programmes offered by different sectors complement rather than duplicate each other (see recommendation 2). The senior member should also ensure the recommendations in NICE's guideline on physical activity and the environment are implemented. Ensure the joint strategic needs assessment, the joint health and wellbeing strategy and other local needs assessments and strategies take into account opportunities to increase walking and cycling. They should also consider how impediments to walking and cycling can be addressed. Ensure walking and cycling are considered, alongside other interventions, when working to achieve specific health outcomes in relation to the local population (such as a reduction in the risk of cardiovascular disease, cancer, obesity and diabetes, or the promotion of mental wellbeing). These include outcomes identified through the joint strategic needs assessment process. Descriptions of the links between physical activity and health outcomes can be found in the Department of Health's start active, stay active. Ensure walking and cycling are included in chronic disease pathways. Ensure all relevant sectors contribute resources and funding to encourage and support people to walk and cycle. Where appropriate, ensure walking and cycling are treated as separate activities which may require different approaches. Ensure walking and cycling projects are rigorously evaluated. This includes evaluating their impact on health inequalities. For more on the role of the NHS in promoting walking and cycling, see recommendations 9 and 10. ## Recommendation 2 Ensuring all relevant policies and plans consider walking and cycling Local authorities, in particular, portfolio holders, lead members and directors responsible for: adult and older people's services children and young people's services community safety countryside management disability education environment health and wellbeing (including mental health) land use, planning and development control parks and leisure planning (including district planning) regeneration and economic development social services transport. National parks authorities. Integrated transport authorities. Local enterprise partnerships. Chief constables, police authorities and elected police commissioners. Agencies with an interest in walking and cycling. Agencies with an interest in health and wellbeing or that work with population groups such as older people or people with disabilities. Ensure local, high-level strategic policies and plans support and encourage both walking and cycling. This includes a commitment to invest sufficient resources to ensure more walking and cycling – and a recognition that this will benefit individuals and the wider community. Relevant policies and plans include those on: air quality community safety disability education environment (including sustainability and carbon reduction) health and wellbeing housing land use, planning and development control physical activity regeneration and economic development transport. Ensure the walking and cycling aspects of these plans are developed in conjunction with relevant voluntary and community organisations. Ensure strategies to promote walking and cycling address factors which influence activity at various levels – from policy down to the individual. This includes ensuring the recommendations in NICE's guideline on physical activity and the environment are implemented. Assess the impact of relevant policies and decisions on people's ability to walk and cycle. Where necessary, amend them to ensure support for walking and cycling. Ensure plans relevant to walking and cycling are implemented and evaluated. Further advice on evaluation can be found in the National Obesity Observatory guide to evaluation. # Local action ## Recommendation 3 Developing programmes Local authority directors and portfolio holders for: countryside management environment (including sustainability) leisure services parks public health regeneration and economic development transport. Police traffic officers and neighbourhood policing teams. Develop coordinated, cross-sector programmes to promote walking and cycling for recreation as well as for transport purposes, based on a long-term vision of what is achievable and current best practice. Ensure the needs of all sections of the population are addressed. Incorporate public health goals to increase the prevalence of people cycling and walking, as well as the distance covered by those who already walk and cycle regularly. Aim to shift attention away from focusing on individual risk factors and isolated, small-scale interventions and ensure programmes comprise an integrated package of measures, implemented by all relevant sectors and stakeholders. Where appropriate, they should link to existing national and local walking and cycling initiatives, and incorporate actions in specific settings, such as workplace or schools (see recommendations 8 and 9). Ensure walking and cycling programmes form a core part of local transport investment planning, on a continuing basis. In line with the Department for Transport's manual for streets and the Chartered Institution of Highways and Transportation's manual for streets 2 – wider application of the principles, pedestrians and cyclists should be considered before other user groups in the design process – this helps ensure that they are not provided for as an afterthought. Draw on data, including the transport and physical activity elements of the joint strategic needs assessment, to ensure programmes are based on an understanding of: the local population and the journeys people take using all modes of transport (the aim is to assess the potential for a 'modal change' towards walking and cycling) the opportunities available to increase people's level of walking and cycling, given the right circumstances the behaviour and preferences of existing walkers and cyclists the needs of people with impairments general factors influencing people's behaviour such as their attitudes, existing habits, what motivates them and their barriers to change, taking into account the recommendations in NICE's guideline on behaviour change: general approaches. Ensure programmes address the behavioural and environmental factors that encourage or discourage people from walking and cycling. These include measures to reduce road danger or the perception of danger. (Environmental factors can be tackled by implementing NICE's guideline on physical activity and the environment.) Ensure local expertise is available so that programmes are based on a realistic understanding of the scale of changes needed to encourage the population to change its behaviour. Ensure programmes take account of recommendations on developing local and regional programmes (recommendations 13–18) in NICE's guideline on preventing cardiovascular disease, in particular those relating to the need for long-term action. Ensure programmes take account of the geography of the surrounding area (for instance, connections with neighbouring local authority areas), as well as local factors such as major road and rail routes, rivers and hills. Ensure programmes include communications strategies to publicise the available facilities (such as walking or cycle routes) and to motivate people to use them. Include information that people with impairments will require, such as where dropped kerbs are located, the location and design of barriers at access points to cycle paths, and where public transport links and disabled toilets can be found. Ensure programmes, including specific elements within them, are evaluated. Assess how much walking and cycling people are doing. Also assess the number of trips undertaken, using different modes of transport, by different groups within the local population. Where appropriate, control groups should be used. (See, for example, the National Obesity Observatory's evaluation tool.) Use an appropriate tool to establish the cost effectiveness of initiatives. For instance, use the World Health Organization's health economic assessment tool (HEAT) for cycling and walking. Consider providing specific support for people at a 'transition point' in their lives, for instance, when they are changing job, house or school. At these times people may be open to trying a new mode of transport or new types of recreation. Note: some people may be considering motorised transport, instead of walking or cycling – and support may be needed to help them maintain their active travel habits. ## Recommendation 4 Personalised travel planning Transport planners. Directors of public health. Help those interested in changing their travel behaviour to make small, daily changes by commissioning personalised travel planning programmes. These should be based on current best practice (see the Department for Transport's making personal travel planning work: practitioners' guide). Staff running these programmes should: Identify those willing to make changes, for example, people at transitional points in their life (such as when moving house, job or school). Provide people with information and help, such as tickets, maps, timetables and, if required, more support to make different travel choices. This includes people with impairments who may rely on wheelchairs or adapted cycles. Consider implementing NICE's guideline on physical activity and the environment to create a supportive environment to encourage and sustain walking or cycling. ## Recommendation 5 Cycling programmes Adult and child disability services. Clinical commissioning groups. Local authority transport leads, transport planners and other transport department staff. Local education services. Organisations with an interest in cycling. Public health practitioners. Public transport operators. Address infrastructure and planning issues that may discourage people from wanting to cycle. Take into account NICE's guidelines on physical activity and the environment and unintentional injuries on the road. For example, ensure local facilities and services are easily accessible by bicycle and make changes to existing roads, where necessary, to reduce traffic speeds. Implement town-wide programmes to promote cycling for both transport and recreational purposes. These should be linked to existing national and local initiatives. (Note: 'town-wide' in this case could include cities or suburban areas.) Programmes could include: provision of information, including maps and route signing fun rides, recreational and sponsored group rides and school sports promotions use of leisure routes on and off roads use of off-road mountain bikes, BMX courses, circuits and parks car-free events or days, virtual cycle races and links with cycle sports events cycle hire schemes intensive sessions in particular settings or aimed at particular groups, such as: 'Bike to work' weeks and workplace challenges; activities aimed at children and families (such as 'Bike it', 'Bike club' and other school programmes); and activities for people with impairments who may use specially adapted cycles activities and campaigns to emphasise the benefits of cycling (including the health benefits, the reliability and ease of access to local facilities and services). Ensure programmes are based on an accepted theoretical framework for behaviour change and take into account NICE's guideline on behaviour change: general approaches. They should also be based on an understanding of the needs of existing and potential cyclists, including those with impairments (see recommendation 3). Ensure cycle parking and residential storage issues are addressed. Ensure travel by cycle and public transport is integrated to support longer journeys. This includes providing secure cycle parking at public transport sites as well as support to transport adapted cycles and tandems for people with disabilities. Ensure training is available for those who are interested in cycling, either as a form of transport or as a recreational activity. An example of a cycle training programme is the Department for Transport's bikeability. Ensure all training is sensitive to cultural issues, for instance, by providing women-only groups with female trainers, where appropriate. Also ensure it includes an understanding of the needs of people with impairments Consider providing free cycle safety checks (such as Dr Bike sessions) and cycle maintenance training. Use local media to publicise activities and to clarify the links between different elements of the programme (for instance, the programme may include the provision of maps, local cycling classes and local challenges and events). In addition, use local media to raise awareness of any new or improved infrastructure. Also provide success stories from different elements of the programme to create momentum. ## Recommendation 6 Walking: community-wide programmes Adult and child disability services. Clinical commissioning groups. Local transport leads, transport planners and other transport department staff. Local authority leisure services. Organisations with an interest in walking. Public health practitioners. Address infrastructure issues that may discourage people from walking, for example, motor traffic volume and speed, lack of convenient road crossings, poorly maintained footways or lack of dropped kerbs, where needed. Take into account NICE's guidelines on physical activity and the environment and unintentional injuries on the road. Develop walking programmes for adults who are not active enough, based on an accepted theoretical framework for behaviour change and taking into account NICE's guideline on behaviour change: general approaches. Ensure groups that are likely to be the least active are encouraged to participate, by addressing issues that may act as a barrier. Ensure walking programmes for all adults link to existing national and local walking initiatives. Ensure all programmes address safety, cultural and disability issues. Ensure all programmes offer a variety of routes, paces and distances at different times of the day (including evenings and on different days of the week or at the weekend). Local people with different preferences, time constraints and physical abilities should all be able to participate. Programmes could include: community-wide events, such as mass participation walking groups, community challenges and 'walkathons' walks led by suitably trained walk leaders (paid or voluntary) and aimed at people who are currently inactive. Ensure walking routes are integrated with accessible public transport links to support longer journeys. Signage should give details of the distance and/or walking time, in both directions, between public transport facilities and key destinations. Provide information tailored for individuals who want to go walking without joining a group or club. Offer continued support in line with recommendation 7. Develop and implement a publicity strategy to let the local community know about the walking routes and events and how accessible they are. Provide support to help people who have started walking as a leisure activity to also consider walking as a means of transport. ## Recommendation 7 Walking: individual support, including the use of pedometers Adult and child disability services. Clinical commissioning groups. Directors of public health and public health specialists with responsibility for physical activity. Local authority leisure services. Organisations with an interest in walking. Ensure individual support is available for anyone who is walking on their own, walking informally with others in a group, or participating in local walking programmes. This includes helping to assess their activity levels and to set goals which build on this. The aim should be to increase the distance walked gradually, rather than providing them with a set target to aim for. Ensure additional, one-to-one support is offered at regular intervals to help people develop a long-term walking habit. This could be provided face-to-face, via the telephone or by using print-based materials, email, the Internet or text messaging. The support could include: individual, targeted information goal-setting (which may or may not include the use of pedometers), monitoring and feedback. Provide general information including: maps, signs and other details about walking routes how to visit places of interest on foot (such as shops, educational or recreational facilities) details on surface quality and accessibility. Only use pedometers as part of a package which includes support to set realistic goals (whereby the number of steps taken is gradually increased), monitoring and feedback. # Schools, workplaces and the NHS ## Recommendation 8 Schools Pupils, siblings, their parents and carers. School staff. Visitors to schools. Head teachers and school governors. Local authority PHSE coordinators, school travel advisers and transport planners. Police traffic officers and neighbourhood policing teams. Road danger reduction and/or road safety officers. Foster a culture that supports physically active travel for journeys to school (for all staff, parents and students) and during the school day. For example, promote the health benefits of cycling and walking and provide sufficient, secure cycle parking. Also ensure it is easy to get into the school grounds by foot or by bike. In addition, schools should provide suitable cycle and road safety training for all pupils. Develop and implement school travel plans that encourage children to walk or cycle all or part of the way to school, including children with limited mobility. Integrate these plans with those produced by other local schools and other travel plans available for the local community. Involve pupils in the development and implementation of plans. Map safe routes to school and to local play and leisure facilities, taking into account the views of pupils, parents and carers. Also consult with the local community, including people with expertise in accessibility issues (such as those with mobility difficulties or community groups that work with them). Develop programmes to ensure the local environment around schools and the nearby catchment area provide opportunities for all children to cycle or walk. This should include addressing motor vehicle speed, parking and dangerous driving practices. Introduce regular 'walking buses' and other activities, such as 'Walk once a week' projects, which support and encourage walking and cycling to school. Set performance targets for school travel plans which are audited annually and which form part of delivery plans. Remedial action should be taken when agreed targets are not reached. Ensure all children can take part in Department for Transport's bikeability training. Ensure cycle training is age-appropriate and timed to allow cycling to school to become a habit. In addition, ensure it is appropriate for those with limited mobility who may need additional support. Schools should develop parents' and carers' awareness of the wider benefits of walking and cycling and other physically active modes of travel. For example, they should explain how it can improve children and young people's movement skills, social wellbeing, self-confidence and independence. They should also explain how it can help children to explore and become more familiar (and at ease) with their local environment while, at the same time, being physically active. Head teachers should identify a walking or cycling champion (or champions) with sufficient senior support to coordinate activities. The champion/s should liaise with the local authority and other potential partners to address any environmental or organisational barriers to walking and cycling to school. ## Recommendation 9 Workplaces Staff and others who use workplaces. Employers, including the NHS and local authorities. Directors and senior staff including managers, health and safety staff, estates managers and human resources professionals. Active travel champions. Develop strategies in consultation with staff (and other relevant stakeholders, for example, students in universities and colleges) to promote walking and cycling in and around the workplace. Ensure activities are developed in line with wider local activities (see recommendations 2, 3 and 4) and are linked to existing national and local initiatives. Liaise with local authority transport departments, neighbouring businesses and other partners to improve walking and cycling access to workplace sites. (Also see NICE's guidelines on physical activity and the environment and physical activity in the workplace.) Identify an 'active travel champion' (or champions) within the workplace, at a sufficiently senior level. They should coordinate activities such as led and informal walking groups, workplace 'challenges' and promotional competitions (for example, using pedometers), bicycle user groups and walking interest groups. The active travel champion/s should also develop (or promote) schemes that give staff access to a pool of bicycles for short-distance business travel, or access to discounted cycle purchases (such as cycle to work schemes). Ensure workplace walking and cycling programmes are developed using an evidence-based theoretical model of behaviour change (see NICE's guideline on behaviour change: general approaches). Provide information tailored for the specific workplace on walking and cycling routes and circuits. This should include details on the distances involved, maps, routes and safety information. See the NICE guideline on physical activity in the workplace for further recommendations. ## Recommendation 10 NHS Clinical commissioning groups. National commissioning board. Primary and secondary healthcare professionals. Incorporate information on walking and cycling into all physical activity advice given by health professionals. (See also NICE's guidelines on physical activity: brief advice for adults in primary care and exercise referral schemes to promote physical activity.) Ensure walking and cycling are among the options provided by the Let's get moving physical activity care pathway. Ensure people who express an interest in walking or cycling as a way of being more physically active are given information about appropriate national and local initiatives. Also provide individual support and follow-up (see recommendation 7). Direct people with limited mobility to specialist centres where adapted equipment, assessment and training are available for walking and cycling. Ensure walking and cycling programmes link to existing national and local initiatives. For more on the role of the NHS in promoting walking and cycling, see also recommendations 1 and 9.# Public health need and practice # Introduction Physical activity is essential for good health. It can help reduce the risk of coronary heart disease, stroke, cancer, obesity and type 2 diabetes (Chief Medical Officers of England, Scotland, Wales and Northern Ireland 2011). It also helps keep the musculoskeletal system healthy and promotes mental wellbeing. As well as a direct benefit from physical activity, walking and cycling offer pleasure, independence and exposure to outdoor environments. These benefits may be particularly significant for people with disabilities whose participation in other activities may be more restricted. New national physical activity guidelines were issued in 2011 (Chief Medical Officers of England, Scotland, Wales and Northern Ireland 2011) for: the under-5s, those aged 5–18, adults aged from 19–64 and for those aged 65 plus. Key points include the need to: be physically active at all ages be flexible (combining moderate and vigorous-intensity activity can be effective) participate in daily activity minimise sedentary behaviour consider strength and balance activities for adults and older adults. Depending on factors such as speed and the terrain, walking and cycling can both be moderate or vigorous activities. Moderate intensity activities will make the participant breathe faster, experience an increase in heart rate and feel warmer. They may sweat on hot or humid days. The amount of activity needed to reach this varies from one person to another. # Physical activity levels in England Based on self-reporting, 61% of men (71% of women) in England aged 16 and over did not meet the national recommended physical activity levels (Craig et al. 2009). (These figures refer to the pre-2011 guidelines for physical activity; that is: adults should be active for at least 30 minutes at least five times a week at moderate intensity or greater.) The proportion of men who are physically active enough decreases markedly as they get older (from 53% at age 16–24 to 16% at 65-plus). The level of activity among women was considerably lower once they reach 65-plus, from a lower base. (Around 12% of women over 65 met the recommended levels compared to 28–36% of younger women.) (Craig et al. 2009). Black African and Asian adults and black Caribbean women were less likely to achieve the recommendations than the general population (Sproston and Mindell 2006). Sixty three per cent of girls (72% of boys) aged between 2 and 15 report being physically active for 60 minutes or more on 7 days a week (girls' activity declines after the age of 10) (Craig and Shelton 2008). However, objective data suggest the above self-reporting data is an overestimate. Based on accelerometry, only 6% of men and 4% of women achieved at least 30 minutes of moderate or vigorous activity on at least 5 days (Craig et al. 2009). Only 2.5% (5.1% of boys and 0.4% of girls) actually did more than 60 minutes of moderate-to-vigorous physical activity daily (Riddoch et al. 2007). There is a lack of information on the levels of physical activity among people with disabilities, although they are likely to be low for those with limited mobility. The Chief Medical Officers' 2011 report notes: 'there is a clear causal relationship between the amount of physical activity people do and all-cause mortality. While increasing the activity levels of all adults who are not meeting the recommendations is important, targeting those adults who are significantly inactive (that is, engaging in less than 30 minutes of activity per week) will produce the greatest reduction in chronic disease' (Chief Medical Officers of England, Scotland, Wales, and Northern Ireland 2011). # Walking and cycling Walking is reported to be the most common – and cycling the fourth most common – recreational and sporting activity undertaken by adults in Britain (Fox and Rickards 2004). Walking (for any purpose) accounted for between 37% and 45% of the time that women of all ages spent doing moderate or vigorous-intensity physical activity. It also accounted for between 26% and 42% of the time devoted to such activities by men of all ages (Belanger et al. 2011). As a result, it is the most likely way all adults can achieve the recommended levels of physical activity. Bicycles are used for around 2% of journeys in Britain – compared to about 26% in the Netherlands, 19% in Denmark and 5% in France (Ministry of Transport, Public Works and Water Management 2009). Yet of all trips made in Great Britain in 2009, 20% covered less than 1 mile and more than half (56%) of car journeys covered less than 5 miles (Department for Transport 2010a). In England on average, 10% of adults cycle at least once a week (this figure varies from over 50% to less than 5% according to the area) (Department for Transport and Sport England 2012). On average, 11% of adults cycle for at least half an hour, at least once a month (again, this figure varies from 4% to 35% according to the area (Department for Transport and Sport England 2012). Today, on an average day in London, it is estimated that around 4.3 million trips are 'potentially cyclable' (Transport for London 2010). The majority (85.8%) of adults claim they can ride a bicycle (around 92.9% of men and 79% of women) (Department for Culture Media and Sport 2011). However, the average time spent travelling on foot or by bicycle in Britain has decreased from 12.9 minutes per day in 1995/97 to 11 minutes per day in 2007 (Department for Transport 2010a). More starkly, the average distance walked, per person per year, has fallen from 255 miles in 1975/76 to 201 miles in 2006. Bicycle mileage for the same years fell from 51 to 39 miles per person per year (Department for Transport 2007). # Air pollution and climate change Motorised transport in urban areas of England is associated with poor air quality, congestion, collisions and physical inactivity – each costing society around £10 billion a year (Department for Transport 2009a). The cost of greenhouse gas emissions and the annoyance associated with noise are smaller, but still significant. In the case of greenhouse gases, costs are expected to rise sharply in future years (Department for Transport 2009a). Exposure to air pollution is a significant cause of mortality in England. The House of Commons environmental audit report on air quality noted that: 'poor air quality reduces the life-expectancy of everyone in the UK by an average of 7 to 8 months and up to 50,000 people a year may die prematurely because of it' (House of Commons Environmental Audit Committee 2010). Air pollution is caused by a range of factors and people's exposure depends on the level of emissions, dispersion and other factors. Particulate matter, especially small particles less than 10 or 2.5 microns (PM10 or PM2.5) in diameter, has a significant impact on health. Other significant pollutants include nitrogen oxides (NOx) and ozone. Industrial sources produce a larger percentage of PM10 and NOx than road transport (46% and 30% respectively for NOx and 36% and 18% for PM10). However, road transport is responsible for up to 70% of air pollution in urban areas where most human exposure to air pollution occurs (House of Commons Environmental Audit Committee 2010). Greenhouse gas emissions from domestic transport in Great Britain stayed at the same level between 1990 and 2009 (around 120 million tonnes of carbon dioxide equivalent ; different gases have a different impact on the warming of the atmosphere so converting to MtCO2e enables a direct comparison of the impact of different gases or mixtures on the atmosphere). Over this period, an improvement in the fuel economy of new cars was offset by increases in mileage. At the same time, the overall emission of greenhouse gases from all sources in this country has decreased. As a result, as a percentage, the proportion from transport has increased from 16% to 22%. Ninety per cent of these emissions are from road transport (58% from cars and around 30% from heavy goods vehicles and light vans) (Department for Transport 2010a). The transportation of goods and general travel in urban areas accounts for around 20% of the distance travelled by motor vehicle, but the contribution to air pollution and climate change is greater, because of driving conditions and frequent cold starts (Favez et al. 2009). Climate change, driven by human emissions of gases such as carbon dioxide, will lead to higher temperatures, more frequent extreme weather events, changes in rainfall and weather patterns, food and waterborne diseases and changes in distribution of vector-borne diseases. This will all have a significant impact on health in England (and globally). Changes associated with migration, following events such as flood or famine and higher levels of stress from extreme events are also likely to have a negative effect (World Health Organization 2009). Reducing transport-related carbon emissions, by supporting a shift to walking and cycling, will help to address these adverse effects. It will also help ensure people are more physically active, so improving their health (Vardoulakis and Heaviside 2012). # Wider economic impacts The wider economic impact of supporting walking and cycling are difficult to identify with certainty. Excess delays from traffic congestion in English urban areas are estimated to cost the economy around £10.9 billion a year (based on 2009 prices and values) (Department for Transport 2009a). A Living Streets report highlights that improvements to the walking environment can increase the economic value of, and economic activity within, an area. This can be reflected by the sale price of residential properties and the rental price of retail premises (Sinnett et al. 2011). The report points out that local retailers may overestimate the proportion of shoppers arriving by car (41% compared with the actual proportion of 22%, in a study in Bristol). Transport for London's 'Town centre study' (Transport for London 2011) found that people walking to a town centre spent an average of £93 per week there, compared with £56 for car drivers or passengers. Bus users spent £70 per week.# Considerations The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations. # General The PDG noted that encouraging people to walk or cycle for recreation purposes is different from encouraging them to walk or cycle as a mode of transport. The PDG considered walking and cycling as two separate activities. Most people should be able to fit these activities into their daily lives and both are relatively cheap or may save money. The PDG is aware of the volume of work and guidance available that is relevant to walking and cycling. It is also aware of the range of examples of good practice, both in this country and abroad. This guidance is intended to support, rather than replace that information. People with disabilities are less likely to be physically active and more likely to face barriers to being active than those without impairments. Many of this group can walk or cycle. However, they may require additional support, for example, involving specially adapted equipment or changes to the physical environment. The PDG noted that local authority structures and roles vary across the country and that this will affect who has responsibility for specific actions. As a result, the recommendations tend to refer to general areas of responsibility, rather than to specific job titles. Similarly, as different administrative areas may produce plans on similar issues under a different title, the recommendations refer to generic plans. Achieving change is likely to be a long-term task and will involve participation by many professionals. This includes those working in local authorities and the NHS, as well as those working in communities (such as voluntary and faith sector organisations). The actions needed include those recommended in this and related NICE guidance. The PDG noted that in the 'Cycle cities and towns' where cycling and walking had increased, the level of spending to encourage walking and cycling for transport purposes had been in the region of £5–10 per head per year. This had been maintained for a prolonged period. The PDG noted that this level of funding could be achieved by changing investment priorities within existing budgets rather than requiring additional funds. # Evidence Evidence related to walking and cycling comes from a number of different professional sectors, in particular, transport and health. Each sector has its own approach to research and evaluation which can lead to difficulties in identifying and interpreting the evidence. Health sector evidence tends to involve controlling for as many factors as possible to help identify and explain any causal links between a given activity and health. While this provides greater certainty about cause and effect, it has tended to limit investigation to topics which lend themselves to this strict approach. Examples include promotional work with individuals to encourage them to walk or cycle, or within a limited setting, such as a school. Transport and other professional sectors are more likely to address population-level factors – and are more likely to have a range of outcomes or intentions in mind. For instance, both public health and transport professionals might have an interest in the benefits of cycling. However, the former might want to know how it impacts on levels of physical activity (and hence health), particularly among those who were previously inactive. Transport professionals, meanwhile, might want to know which particular journey would be cycled (and hence, the impact on motor traffic and congestion levels). They would tend to have less interest in who has changed their mode of transport. As a result, while both groups might have a legitimate interest in activities to increase cycling levels, the outcomes of evaluations might be different. The PDG noted that different professionals have different reasons for wanting to encourage people to walk and cycle. For instance, transport professionals may aim to reduce the volume of motorised traffic (by identifying and influencing people who are most likely to move from motorised transport to cycling). From a public health point of view, the goal might be to encourage people who are currently inactive to take up walking or cycling in order to increase the amount of physical activity they do. While the 2 goals are very closely related (and can be complementary) they may focus on different groups and involve different approaches and outcomes. The evidence identified was predominantly from an urban perspective, so rural issues are under-represented in the recommendations. It is difficult to apply the findings of non-UK cycling studies to England because of the cultural and legal differences – and the fact that levels of cycling are considerably higher in many other countries. Equally, the value of findings from older literature may be of limited relevance because of the social and environmental changes that have since taken place. There is evidence that interventions tailored to people's needs and aimed at either the most sedentary groups – or at those who are most motivated to change – can encourage people to walk more. Evidence showed that interventions could work if aimed at individuals, households or groups. Evidence showed that community-wide promotional activities, combined with an improved infrastructure, had the potential to increase cycling rates by modest amounts. Studies of marketing activities aimed at individuals reported a consistent, positive effect on cycling behaviour. However, the PDG noted that more robust study designs were needed to generate more detailed evidence of the best way to achieve this improvement. (For instance, detail is needed on whether the increases are sustained over time or are limited to certain subgroups such as young men.) Practical experience indicates that two particular factors play a key role in increasing walking and cycling rates: having a 'champion' who is committed to promoting walking or cycling, and effective local authority support. Four interventions, including two multi-component interventions (Cycling Demonstration Towns and Sustainable Travel Towns) were included in the economic modelling. Using cost per quality-adjusted life year (QALY) gained, the interventions were highly cost effective, even when the effect disappeared after year 1. The PDG noted that the key factors influencing the outcome of the economic model were: threshold cost, level of effects, decay in effects and costs related to initial effects. Members also noted the importance of offering the most appropriate interventions for different local settings and needs. Data from a UK randomised control trial (RCT) were used to model the cost-effectiveness of led walks. The PDG raised concerns because the RCT showed no difference in effect between led walks and the provision of advice only. The results were not used for the recommendations. Using evidence from an evaluation of 'Get walking, keep walking', a large UK study, produced a cost per QALY of around £2700. In addition to a cost–utility analysis, cost–benefit ratios were also calculated for environmental and traffic outcomes. These considered a range of benefits associated with increased walking or cycling and a consequent change in motor vehicle miles driven. The methodology was based on that used by the Department for Transport. However, health benefits (which account for most of the benefits calculated using the Department for Transport methodology) were not included, as these had been calculated in the cost–utility analysis. The PDG recognised the importance of considering children. However the modelling did not consider under-18s due to a lack of direct evidence on children's behaviour in many of the studies. # Pedometers Pedometers are cheap, effective and 'user-friendly'. The PDG noted that they may play an important role in helping people to walk more, provided they are used within a programme involving monitoring, support and goal setting. However, the PDG also noted that the use of set targets (such as 10,000 steps a day) was unlikely to be helpful if it did not take into account someone's current level of activity. In addition, some people may be put off if pedometers are used as part of a competition. The PDG discussed the role of other technologies that might replicate pedometers, including mobile phone apps. While these may have a role to play in getting people to walk more, there is a lack of robust evidence to indicate whether or not they are effective. # Wider influences A wide range of factors influence whether or not people walk or cycle. Many were outside the scope of this guidance. In particular, the PDG noted that environmental factors such as the quality, accessibility and availability of walking and cycling networks are likely to be important. Other issues, such as the relative costs and convenience, are also likely to be significant. As a result, it recommended that this guidance should be implemented in conjunction with other related NICE recommendations, in particular NICE's guideline on physical activity and the environment. The scope for this guidance included an adapted logic model (Sallis et al. 2006) which sets out local factors and interventions which can impact on walking and cycling rates. It demonstrates the conceptual link between local interventions targeting the physical or social environment (or individuals) and intermediate outcomes in relation to walking and cycling. These outcomes, in turn, link to impacts on health, the environment and other areas (such as the economy). The model also highlights how local policy, resources and other factors influence the effectiveness of local interventions to improve rates if walking and cycling. For example, a decision to use cycling as a form of transport can be influenced by the level and speed of motor traffic, attitudes to safety, the ability to plan and execute a route, and the ability to carry baggage. (Please note: although national factors such as legislation and fuel duty also have an important impact, these are not included here as they fall outside the scope of the guidance.) A number of legal issues differentiate England from parts of continental Europe, where levels of cycling are significantly higher. In parts of continental Europe, 'strict liability' means that pedestrians or cyclists injured in a collision involving a motor vehicle do not have to prove fault in seeking compensation. In addition, drivers have a civil responsibility to have insurance that will pay vulnerable victims independently of fault, while not changing criminal responsibility (see 'Expert paper 2'). Such legal requirements may act as an incentive for drivers to behave in a way that protects the most vulnerable road users. The PDG noted that relatively few people in England cycle on a regular basis for transport purposes. This is not the case in other parts of Europe. For example, in Denmark and the Netherlands, it is considered the norm to use a bicycle for many journeys. Age is not necessarily a barrier. In the Netherlands, 26% of all journeys –and 19% of all the journeys made by people over 75 – are by bike (Ministry of Transport, Public Works and Water Management 2009). The PDG considered these examples as possible aspirational goals for England. The PDG noted that moving towards the higher levels of cycle use seen in some Northern European countries is a process that will involve change over a prolonged period. It also noted that some of these changes are beyond the scope of this guidance. However, it felt that substantial public health benefits (such as increased levels of physical activity and reduced emissions of air pollutants) could be achieved as a result of such a process. The PDG noted a range of issues which, if tackled in isolation, are unlikely to lead to a significant increase in walking or cycling. It also noted that tackling such issues could, nevertheless, provide a necessary foundation for interventions which will have a significant impact. For example, a key factor preventing people from walking and cycling is the danger as well as the perceived danger (including personal security fears) facing them on or near roads, paths or trails. The PDG discussed a range of measures that may help overcome this problem. These included: Awareness-raising of the comparatively low risks posed on the roads and contextualising these in terms of other risks (such as the potential risks caused by having a sedentary lifestyle). Awareness-raising among motorists and cyclists of the needs of pedestrians (for instance, the need to avoid causing a hazard by pavement parking). Awareness-raising among motorists of the needs of cyclists (for instance, by making motorists aware that they should give way, where appropriate, and should give cyclists a wide berth when overtaking them). Appropriate enforcement of road traffic law. The potential role of engineering measures such as chicanes or raised junctions and 20 mph limits in helping to restrict motor traffic speed. The needs of children and older people (see NICE guidelines on strategies to prevent unintentional injuries among under-15s and unintentional injuries on the road) The needs of people with mobility difficulties or other impairments which may increase their vulnerability on the road. Action to increase walking and cycling rates may reduce motor traffic volume and the PDG was concerned that the resulting benefits (of reduced congestion and reduced air pollution) should not be lost. For example, less traffic could lead to increases in vehicle speed, or may encourage some people to drive for journeys previously undertaken using other modes of transport. Members noted that action to ensure this does not happen could include a reallocation of road space or a reallocation of time at junctions to favour walkers or cyclists, or restricted motor vehicle access. Local roads may act as a barrier to walking and cycling for children. Although it is not a panacea (addressing road conditions is vital), achieving 'Bikeability' level 3 would mean they could deal with all types of road conditions and more challenging traffic situations. This may be important, at least, for older children. The PDG noted that cycling off-road, where there is no exposure to motor vehicles may be appropriate for those who find road cycling too challenging. # Physical activity Most people can walk, including groups such as older people and those with some functional difficulties. While the majority of adults (85.8%) in the UK say they can ride a bicycle (Department of Culture, Media and Sport 2011), cycling as a means of transport is a minority activity. It accounts for a small percentage of all journeys – and for a small part of overall physical activity in this country. Nevertheless, 43% of adults own a bicycle and 14% use it at least monthly (Department for Transport 2009b). Cycling remains popular among children and young people, with 41% of those aged 5–16 years cycling at least weekly (Department for Transport: unpublished data 2012). In London, an estimated 4.3 million trips a day (around two thirds taken by car, the remainder mainly by bus) could be cycled. For this survey, trips were assessed according to a set of criteria designed to reflect trips currently made by bicycle (Transport for London, 2010). # Inequalities Overall physical activity levels vary across the population (see section 2). This is also the case with specific activities, particularly cycling. Most adult cyclists in most areas of England are male. The highest number of cyclists are among people who are middle-aged. Black and minority ethnic groups cycle the least. Cycling participation is roughly equal across income quintiles but the biggest growth has come among the more wealthy. The variation in levels of walking among groups in terms of gender, race or socioeconomic status is probably the smallest for any type of physical activity. People in households without a car walk, on average, 284 miles per year, compared to 176 miles per year walked by people in households with a car (Department for Transport 2010b). People who are most physically active do not necessarily walk or use a bicycle as a mode of transport. For some, the fact they have access to a car may have a positive influence on their physical activity levels. The distance walked in Great Britain varies per person per year. In the quintile with the lowest household income, the distance walked is 223 miles, then it is 202, 182 and 177 miles respectively for people in the next 3 quintiles. In the quintile with the highest household income, people walk an average 201 miles per year. For cycling, the distance increases across the spectrum. Miles cycled per person per year is 32 in the lowest 2 quintiles, then 39, 49 and 77 miles respectively (Department for Transport 2010b). One way of encouraging people to walk or cycle, as a form of transport, might be to apply greater levels of restraint on car usage in urban areas. This could be achieved, for instance, by introducing restricted parking and higher parking charges. However, there is a need to consider how this would impact on car owners living in areas where the environment is not conducive to walking or cycling, or where there is little real alternative to driving. The guidance recommends an integrated package of measures which address a range of barriers to walking and cycling. It should be noted that reducing car use may have a beneficial influence on the environment by reducing traffic volume and air pollution and this may have a positive impact on the health of the whole population. The PDG discussed the impacts that the recommendations may have on health inequalities. It acknowledged that those who are better off may have more opportunity to respond to the choices on offer. It also acknowledged that some transport interventions may deliberately target those most likely to change their mode of transport, rather than those who are least active. In addition, it noted that people with disabilities have specific needs. Taking these issues into account, the PDG emphasised that the recommendations should be accompanied by action to address factors such as a hostile and degraded environment, restricted access points, poor surfaces and the availability of disabled toilets. The Group also noted that some people with, for example, sensory or cognitive impairments, may need specially adapted equipment or information. Interventions which reduce motor traffic will reduce air pollution and road danger (assuming the benefits of a reduction in motorised traffic are 'locked in' and not accompanied by, for instance, an increase in traffic speeds). Planners may be reluctant to apply traffic reduction measures in one locality for fear of 'gridlock' on other, neighbouring roads. However, in most cases, the overall level of motorised traffic will be reduced. This is likely to have a positive impact on health inequalities because people from deprived groups, who are exposed to the greatest risks from air pollution and traffic injuries, are most likely to benefit. The very old and the very young, as well as those with pre-existing respiratory or circulatory problems, will also benefit from a reduction in overall exposure to air pollutants. # Barriers and facilitators When making transport choices, habit is important for most people, most of the time. Choosing to use a different mode of transport from usual is also likely to require more planning and thought. For instance, making a decision to start cycling might mean obtaining appropriate clothing, preparing the bike, route planning and allowing time for a trip of an unknown duration. The PDG noted that these factors are unlikely to remain as significant barriers once walking or cycling becomes the norm. For instance, both will usually involve reliable and more predictable journey times. Many journeys may be quicker, as well as being more healthy. There are also wider community benefits from reduced congestion and pollution. The PDG noted that changing travel mode might require stopping old habits, such as using the car for short trips. Or it might involve an even more fundamental lifestyle choice, such as deciding to give up having a car altogether. The PDG felt it was important that, where possible, health professionals (and others) set a positive example through their own behaviour in relation to walking and cycling. The PDG noted that the times when someone has to reconsider their transport choices (such as when changing job or school, retiring or moving house) may offer important opportunities to influence their behaviour. Despite walking and cycling being different activities, sometimes they are grouped together. The PDG felt this was often unhelpful, as barriers and facilitators to walking and cycling vary – and, in turn, they differ according to whether the activity is chosen for transport or recreational purposes. They can also be specific to the purpose and location of the trip – and to the person undertaking it. Successful interventions to increase cycling and walking need to take into account this wide range of factors. Walking and cycling, like any form of transport, involve exposure to a certain level of risk. This includes the risk of injury from falls or from collisions and exposure to air pollution. These risks are not unique to transport involving physical activity. However, evidence shows that the health benefits of being more physically active outweigh these disbenefits. The whole population benefits from less exposure to polluted air and congested streets when there is a general shift away from motorised vehicles. Risk of injury or collision is a key consideration when walking and cycling in places where there are other people. As well as the actual level of risk, perception of risk is important. The PDG noted that cyclists and pedestrians are more vulnerable in the event of a collision than those in a motor vehicle. At the same time, they are much less likely to cause injury in the event of a collision, due to their lower mass and lower speed of travel. There is evidence to support the hypothesis (usually called 'safety in numbers') that areas where there are higher numbers of cyclists have better safety records than others. One of the reasons for this may be increased driver awareness of the likelihood of encountering a cyclist – and the fact that they modify their driving as a result. The PDG concurred that transport planning could be a way to reduce road dangers for all users. These dangers relate to motorised traffic volumes and speeds. They are also caused by a lack of driver awareness of the risks of poor driving and the need to fully consider pedestrians and cyclists, including those with restricted mobility. Attitudes to walking and cycling are generally positive or neutral, with walking generally regarded more favourably. However, a combination of factors discourages people from taking up either if it is a question of choice, rather than necessity. These include: Concerns about the physical environment, in particular, with regard to perceptions of and actual safety. Motor traffic is a major deterrent for many cyclists (potential and current) and pedestrians in rural areas – and for children in all areas. Fear of violence or robbery is another deterrent. Many potential walkers restrict their journeys on foot because of their perception that empty streets, particularly at night, are dangerous. Complex household routines (especially for those with young children). For many people it is a combination of circumstances that prevent them from walking or cycling for everyday travel. These include: the logistics of organising and travelling with children, pressures of time and other commitments, and parental concerns about safety. The perception that walking and cycling are not things to do as a matter of routine. # Wider impacts Traffic volume and speed act as barriers to walking and cycling (for recreation, as well as for transport purposes). The PDG noted that the level of motor traffic creates congestion which, in turn, imposes costs on the economy, through loss of productive time. Motor vehicles are also major contributors to air and noise pollution, as well as to carbon dioxide emissions. Increasing the amount people walk or cycle, particularly in urban areas, results in a change in exposure to air pollution. Moving journeys from motorised transport to walking or cycling may alter individual exposure to air pollution, while reducing the total emissions of pollutants. Modelling by De Hartog et al. (2010) suggests that an individual's risk from increased exposure to air pollutants is modest in comparison with the benefits of them being more physically active. In addition, the overall decrease in air pollutant emissions benefits the health of the whole population. The PDG noted that a range of other potential benefits might accrue from a shift to physically active travel. These include reductions in road danger, noise, congestion and emissions of carbon dioxide. Walking and cycling can also benefit local communities by encouraging more people of all ages to be out on the streets, so making streets appear less threatening. Personal exposure to air pollution is influenced by route choice. Routes which avoid busy roads may have much lower levels of air pollutants. This can be a much more significant influence on personal exposure than the mode of transport used. Cost–utility calculations were based on the increased longevity associated with walking and cycling. They incorporate the effects of deaths from collisions. In addition, the economic modelling included an assessment of the cost–benefit ratios associated with environmental pollution and congestion. In most cases, interventions to promote walking and cycling led to greater benefits than costs, when considering their impact on congestion, infrastructure, collisions, local air quality, noise, greenhouse gases and indirect taxation. Costs associated with collisions were included, based on the expected reduction in car kilometres. Changes in levels of injury, based on changes in walking and cycling behaviour, are difficult to predict, partly because the relationship is not linear (see 3.50). Large increases in cycling and walking, especially if accompanied by interventions to increase safety, could reduce the absolute number of related accidents. As a result, the model did not include an additional modelled effect on injuries. Only for Cycling Demonstration Town interventions were the costs greater than the benefits. However, the modelling did not include the substantial benefits (likely to be in excess of 80% of the total) to be gained from reducing the range of health conditions associated with not being physically active enough. (These were calculated separately.) The PDG agreed that both walking and cycling provide a wide range of health, social, environmental and economic benefits. Members also agreed that there is significant scope to increase the levels of walking and cycling in England – and that this would result in gains across society.# Recommendations for research The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects. All the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity. . How could existing guidance on evaluating complex, population-wide interventions be most usefully adapted and applied to approaches that aim to increase rates of walking and cycling? Issues to consider include: population-level health outcomes such as pollution emissions and exposure, the impact of an intervention on risk and danger and other, wider outcomes of interest such as the impact on the local economy. Approaches should be developed to take account of the backgrounds and needs of the different professional groups involved in helping to influence walking and cycling for transport or recreation. This includes professionals working in public health, transport, environment, economic development and regeneration. . What key factors influence the effectiveness of population-level or whole-area approaches to encouraging walking or cycling? How do these factors interact? (Specifically, how do infrastructure changes, promotion of these changes, promotion of walking and cycling generally, the provision of individual support and approaches in specific settings interact?) How does effectiveness vary between different geographical areas? . How do individual and local factors influence the effectiveness of specific approaches to encouraging walking or cycling? (This includes people's level and perception of risk, the degree of connectivity for cycling trips, and the local 'visibility' of cycling or walking as a mode of transport.) How do these factors interact with personal factors (such as willingness to try walking or cycling) and how do these personal factors influence effectiveness? In particular, do local factors influence the effectiveness of cycle training and personalised travel planning? . What key factors ensure people continue to walk or cycle in the long term (over a year)? How do individual interventions (such as follow-up or goal-setting) interact with environmental factors (such as distance, perception of danger or provision of facilities) in encouraging people to continue to walk or cycle? . What key factors influence differences in walking and cycling behaviour among different groups – and what are the implications for interventions aiming to achieve population-level change and reduce inequalities? This should take into account transport-related variables such as level of car ownership. See also the detail on the gaps in the evidence identified during development of this guidance.# Glossary # Dr Bike Generally, Dr Bike sessions are basic safety and maintenance checks provided free to the cyclist. They cover topics such as brakes, steering, mechanical integrity and the overall condition of the bicycle. Minor adjustments are carried out free of charge. Sessions may also include security marking, visibility and cycling tips. They may be provided by local authorities, cycling groups or employers. # Handcycles Handcycles are two or three-wheeled bikes powered by the arms rather than the legs. They come in a variety of styles which make them suitable for many people with disabilities. # Local enterprise partnerships Local enterprise partnerships are led by local authorities and businesses. They provide the vision, knowledge and strategic leadership needed to drive sustainable private sector growth and job creation in their area. # Mode Transport mode refers to the form of transport used (such as by car, lorry, bicycle, public transport or on foot). # Moderate-intensity physical activity Moderate-intensity physical activity requires a degree of effort and noticeably increases the heart rate. Examples include brisk walking, cycling and gardening. # Moderate-to-vigorous physical activity Moderate-to-vigorous physical activity requires a large amount of effort, causes rapid breathing and a substantial increase in heart rate. Examples include running and climbing briskly up a hill. # Personalised travel planning Personalised travel planning aims to encourage people to change their travel habits by providing them with detailed information on possible alternatives. People running these schemes provide individuals (usually across a specified geographical area) with information on, and encouragement to use, alternatives to a car for the trips they make. # Portfolio holder A portfolio holder is a local authority member with a specific responsibility delegated by the leader of the local authority. # Quality-adjusted life year (QALY) A quality-adjusted life year (QALY) is a measure used in health economics to assess the cost effectiveness of an intervention. It is defined as a measure of the state of health of a person or group in which the benefits, in terms of length of life, are adjusted to reflect the quality of life. One QALY is equal to 1 year of life in perfect health. # Recommended level of physical activity The Chief Medical Officers for England, Wales, Scotland and Northern Ireland Start active, stay active report sets out target levels of physical activity for different groups. For adults, the recommendation is that 'over a week, activity should add up to at least 150 minutes (2½ hours) of moderate-intensity activity, in bouts of 10 minutes or more (one way to approach this is to do 30 minutes on at least 5 days a week)'. For children, the recommendation is that 'all children and young people should engage in moderate- to vigorous-intensity physical activity for at least 60 minutes and up to several hours every day'. # Virtual cycle races These are competitions where participants log the number of miles they have cycled on their own or as part of a team. The aim is to cycle a predetermined number of miles over a certain time. A target could be, for example, to cycle the number of miles it would take to travel from Lands End to John O'Groats.# References Belanger M, Townsend N, Foster C (2011) Age-related differences in physical activity profiles of English adults. Preventive Medicine 52: 247–9 Chief Medical Officers of England, Scotland, Wales and Northern Ireland (2011) Start active, stay active: a report on physical activity from the four home countries' Chief Medical Officers Craig R, Shelton N (2008) Health survey for England 2007. Healthy lifestyles: knowledge, attitudes and behaviour. Leeds: The Information Centre for Health and Social Care Craig R, Mindell J, Hirani V (2009) Health survey for England 2008. London: The Information Centre for Health and Social Care Department for Culture, Media and Sport (2011) Taking part 2011/12 quarter 2. London: Department for Culture, Media and Sport Department for Transport (2007) National travel survey 2006. London: Department for Transport Department for Transport (2009a) The wider costs of transport in English urban areas in 2009. London: Department for Transport Department for Transport (2009b) National travel survey 2008. London: Department for Transport Department for Transport (2010a) Transport trends 2009. London: Department for Transport Department for Transport (2010b) National travel survey 2009. London: Department for Transport Department for Transport, Sport England (2012) Local area walking and cycling statistics: England 2010/11. London: Department for Transport Department of Health (2004) At least five a week. London: Department of Health Favez J, Weilenmann M, Stilli J (2009) Cold start extra emissions as a function of engine stop time: evolution over the last 10 years. Atmospheric Environment 43: 996–1007 Fox K, Rickards L (2004) Sport and leisure: results from the sport and leisure module of the 2002 general household survey. London: The Stationery Office House of Commons Environmental Audit Committee (2010) Air quality: fifth report of session 2009–10. London: The Stationery Office Ministry of Transport, Public Works and Water Management (2009) Cycling in the Netherlands. The Netherlands: Ministry of Transport, Public Works and Water Management Riddoch CJ, Mattocks C, Deere K et al. (2007) Objective measurement of levels and patterns of physical activity. Archives of Disease in Childhood 92: 963–9 Sinnett D, Williams K, Chatterjee K et al. (2011) Making the case for investment in the walking environment: a review of the evidence. London: Living Streets Sproston K, Mindell J (Editors) (2006) Health survey for England 2004. The health of ethnic minorities. London: The Information Centre for Health and Social Care'. Transport for London (2010) Analysis of cycling potential. London: Transport for London Transport for London (2011) Town centre study 2011. London: Transport for London Vardoulakis S, Heaviside C (Editors) (2012) Health effects of climate change in the UK 2012. Current evidence, recommendations and research gaps. Chilton: Health Protection Agency World Health Organization (2009) Climate change is affecting our health: Something should be done now. Geneva: World Health Organization# Appendix B Summary of the methods used to develop this guidance # Introduction The reviews, primary research, expert testimony and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations. All supporting documents are listed in appendix E. # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were: Which local interventions are effective and cost effective at promoting and increasing cycling and walking for recreational and travel purposes? Which local interventions are effective and cost effective at changing population-level norms and behaviour in relation to cycling and walking for recreational and travel purposes? What factors help or hinder the planning and delivery of walking and cycling-related interventions for recreation or travel purposes? What factors help or prevent people from walking and cycling for recreation or travel? What health and other outcomes may be achieved by increasing cycling and walking for travel and recreation? These questions were made more specific for each review (see reviews for further details). # Reviewing the evidence ## Effectiveness reviews One review of effectiveness was conducted (review 1). A number of databases were searched in August 2011 for papers relating to walking and cycling published since 1990. See the review for details of the databases searched. In addition, specific websites were examined and papers from stakeholders and members of the PDG were considered. Studies were included in the effectiveness review if they considered the impact of local interventions to raise awareness of, encourage or increase uptake of, walking and cycling for recreational and travel purposes. Studies were excluded if they covered: national policy, fiscal or legislative changes local interventions which solely aimed to change the physical environment. ## Other reviews A review of barriers and facilitators (review 2) was conducted. A number of databases were searched in August 2011 for papers relating to walking and cycling published since 1990. See the review for details of the databases searched. In addition, specific websites were examined and papers from stakeholders and members of the PDG were considered. ## Selection criteria Studies were included if they focused on interventions identified in the scope and addressed barriers and facilitators to walking and cycling. Studies were excluded if they focused on: National policy, fiscal and legislative changes. Local interventions which solely aimed to change the physical environment (such as traffic-calming measures, provision of cycle parking facilities or construction of cycle routes). ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. – Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. The evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable). ## Summarising the evidence and making evidence statements The review data was summarised in evidence tables (see full reviews). The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors/public health collaborating centres (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope. # Cost effectiveness There was a review of economic evaluations and an economic modelling exercise. ## Review of economic evaluations Studies were identified by searching the NHS Economic Evaluation Database (NHSEED). An additional search was undertaken using an economics study filter. The search focused on health economic studies that dealt with: interventions to increase walking and/or cycling and reported relevant health-related outcomes cost–benefit analysis results studies which considered wider outcomes, including travel, congestion and pollution. Simplified search strategies were also used to search another economic specific database EconLit. ## Economic modelling An economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in: 'Walking and cycling: local measures to promote walking and cycling as forms of travel or recreation: health economic and modelling report'. # How the PDG formulated the recommendations At its meetings in November 2011 and January, February and March 2012, the Programme Development Group (PDG) considered the evidence, expert reports and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guidance. The PDG developed draft recommendations through informal consensus, based on the following criteria: Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. The PDG noted that effectiveness can vary according to the context. For instance, geographical factors such as population density in rural or urban areas influence the likelihood of walking or cycling being a viable option for utility travel. Where evidence was lacking, the PDG also considered whether a recommendation should only be implemented as part of a research programme. Where possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).# Appendix C The evidence # Introduction This appendix lists the evidence statements and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) Note: the evidence statements in review 1 (see appendix A for details of the evidence reviews) were amended by NICE and endorsed by the Programme Development Group (PDG). This appendix includes the amended evidence statements from review 1. Appendix C also lists six expert reports and their links to the recommendations and sets out a brief summary of findings from the economic analysis. The evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document. Evidence statement number R1.ES1 indicates that the linked statement is numbered 1 in the document 'Evidence statements on the effectiveness of local interventions to promote cycling and walking for recreational and travel purposes'. Evidence statement numbered R2.ES1 indicates that the linked statement is numbered 1 in the document 'Synthesis of evidence relating to barriers and facilitators to implementing interventions that promote cycling and walking, and to carrying out cycling and walking for recreational and travel purposes'. Evidence statement EM.ES1 indicates that the linked statement is numbered 1 in 'Interventions to promote cycling and walking for recreational and travel purposes: Health economic and modelling report' The reviews, expert reports and economic analysis are available online. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Where the PDG has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix. Recommendation 1: IDE; Additional evidence expert papers 2, 4, 6 Recommendation 2: IDE; Additional evidence expert papers 2, 4, 6 Recommendation 3: Evidence statements R1.ES5, R1.ES6, R1.ES7; Additional evidence expert papers 2, 4, 6 Recommendation 4: Evidence statements R1.ES4, EM.ES4 Recommendation 5: Evidence statements R1.ES3, R1.ES5, R1.ES6, R1.ES7, R1.ES9, R1.ES12, R1.ES19, R2.ES9, R2.ES15, R2.ES18, EM.ES3, EM.ES5; Additional evidence expert papers 2, 3, 4, 5, 6 Recommendation 6: Evidence statements R1.ES1, R1.ES2, R1.ES7, R1.ES13, R1.ES18, R1.ES21, R1.ES22, R2.ES1, R2.ES2, R2.ES3, R2.ES5, R2.ES6, R2.ES10, R2.ES12, R2.ES13, EM.ES1, EM.ES3; Additional evidence expert papers 1, 5 Recommendation 7: Evidence statements R1.ES13, R1.ES14, R1.ES18, R1.ES21, R1.ES22, R2.ES3, R2.ES13, EM.ES2; Additional evidence expert paper 5 Recommendation 8: Evidence statements R1.ES8, R1.ES9, R1.ES10a, R1.ES10b, R1.ES10c, R2.ES15, R2.ES16, EM.ES1; Additional evidence expert paper 1 Recommendation 9: Evidence statements R1.ES11, R1.ES15, R1.ES16, R1.ES17, R1.ES23, R2.ES2, R2.ES4, R2.ES7, R2.ES9, R2.ES18; Additional evidence expert papers 1, 3 Recommendation 10: Evidence statements R1.ES20, R2.ES2, R2.ES4 # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the evidence review(s) to make them more consistent with each other and NICE's standard house style. ## Evidence statement R1.ES1: Population-level change in mass-media interventions to increase walking There was inconsistent evidence from two studies (both ) on the effectiveness of mass-media interventions (which included paid advertisements , billboards/posters, public relations, educational activities and community participation), delivered in the community in increasing population levels of walking for leisure or travel in adults up to 1 year post intervention. One before-and-after (BA) study showed no effect on walking (the reporting of data in this study was poor) and one cross-sectional (CS) study showed a small, but positive effect on walking. One (+) BA study (UK n=3476, 12 months) – 40-second TV advert supported by a telephone helpline – showed no change in the number of days spent walking for at least 30 minutes: mean of 4.26 days in 1995 and 4.13 days in 1996, no significance statistics given. One (+) CS study (USA n=297, 5 months) – billboard, newspaper, radio, and poster advertisements – showed that those exposed to the campaign were more likely to walk for at least 10 minutes on more days of the week than the control group (5.2 days versus 4.52 days t=2.34, p=0.02). Population-level evidence on mass-media interventions to increase walking is partially applicable to the UK as one study was conducted in the UK. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES2: Multi-component community-based interventions to promote walking There was inconsistent evidence from six studies concerning the effectiveness of multi-component interventions on increasing population levels of walking for leisure or travel in the long term. Four non-randomised control studies (nRCT) papers (three and one ) showed positive effects on walking and two nRCT papers (one and one ) indicated that the interventions were not effective in increasing walking. One (+) nRCT (Australia n=two wards, 2 years) – park modifications, media campaign, walking maps – showed that those in the intervention ward were more likely than those in the control ward to have walked in the 2 weeks prior to follow up (89.3% versus 81.0% respectively; X2=11.51, p=0.001), and within-ward analysis indicated that walking increased from baseline in the intervention ward (X2=5.85, p=0.016), but not in the control ward (X2=0.07, p=0.794). There was no difference in the number reaching adequate levels of physical activity (health department recommendations). One (++) nRCT (USA n=1233, 12 months) – individually tailored newsletters, interpersonal activities that stressed social support, community-wide events such as walk-a-thons – showed that rates of 7-day walking for any purpose or for exercise declined slightly in the intervention communities compared with the comparison sites (-1.4 min, p=0.91; and -5.6, p=0.37 respectively). One (+) nRCT (USA n=1531, 12 months) as above found that the change in walking was higher in intervention (11.7 minutes) than comparison (6.5 minutes), although not statistically significant. Percentage of respondents who met the recommendation for walking was the same across the intervention and comparison areas: 22.2% and 21.6%, p=0.811. One (+) nRCT (USA n=1472, 8 weeks) – paid advertising, public relations events to generate media coverage, public health educational activities at work sites, churches and local organisations – found a 23% increase in walking observations in the intervention community versus a 6% decrease in the comparison community (OR 1.31, 95% CI 1.14–1.50; p<0.0001). One (++) nRCT (USA n=1472, 12 months) – paid advertisements (TV, radio, cable, newspapers), public relations and community participation – found that the least active group in the intervention population were more likely than control population to have increased daily walking (OR=1.72, 95%CI 1.01–2.95). One (+) nRCT (USA n=4 communities, 8 weeks) – four interventions: Welch Walks (WW): paid media, media relations, community activities; Broome County (BC) walks (BC): WW components + website; Wheeling walks and West Virginia (WV) walks: BC components +12-week participatory planning, policy and environmental changes – found that 32% of insufficiently active persons in Wheeling Walks reported meeting the criteria for regular walking immediately post campaign compared to an 18% increase in the comparator community (OR=2.12, 95%CI 1.41–2.24). An increase in reaching regular walking was observed for the most sedentary group in WV walks (p<0.05). The intervention community in Welch walks demonstrated a twofold (OR=2.0 95%CI 1.01–3.97) gain in weekly walking by at least 30 minutes versus the comparison community. Forty one per cent of the BC walks intervention community increased walking by 30 minutes per week compared to 30% in the control (OR=1.56 95%CI 1.07–2.28). The population-level evidence on multi-component interventions to increase walking is only partially applicable to the UK as studies were conducted in the US and Australia. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES3: Population-level change in mass-media interventions to increase walking and cycling – Australia 'Walk to work day' Moderate evidence from one BA study reported in two papers (both ) suggests that the mass-media campaign 'Australia walk to work day' (a collaborative annual event in which members of the public are encouraged to walk to work) may be effective in increasing population levels of walking and cycling for travel in adults up to 1 year post intervention. This intervention resulted in positive effects on both walking and cycling. One (+) study (n=1100, at least 1 year) found that overall, total weekly minutes of moderate physical activity increased by 20 minutes per week (t=4.76, p<0.005 with, an decrease in the proportion who were inactive -4.0% p<0.005). Significant population increase in total walk time (+16minutes per week t=2.04, p<0.05) in participants who were employed, and in minutes spent walking increased by 21 minutes per week in 'passive commuters' (t = 2.42, p< 0.05). One (+) study (n=1100, 2 months) found a significant population-level increase in health enhancing active commuting (3.9%, p=0.01). The evidence on mass-media interventions to increase walking and cycling is only partially applicable to the UK as studies were conducted in Australia. The differing environment in Australia must be considered in reference to these studies. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES4: Population-level change in TravelSmart as an intervention to increase walking and cycling Weak evidence from a series of evaluation reports (ER) (both ) suggests that TravelSmart is effective in increasing population levels of walking and cycling for travel in adults (who volunteered to participate) at least over 1 year. TravelSmart uses 'Individualised travel marketing' (ITM) which aims to highlight travel choices 'people may not know they have' by providing locally relevant information and support to households. The evidence is moderate as the reports only present percentage change data and limited methodologies. The intervention targets individuals, but data is reported at population level. One (+) evaluation report (Australia n=5 regions, various) found household projects routinely showed decreases in car use of 4–15% and rise in use of walking, cycling and public transport. One (+) evaluation report (UK n=19 regions, various) found cycling for travel increased by between 14% and 69%, travel by walking increased between 9% and 29%, travel by car decreased at each site by between 10 and 14%, overall sustainable travel trips increased at each site (between 9% and 29%). The evidence on this intervention to increase walking and cycling is fully applicable to the UK as most of the data reported is from UK sites. However, the differing environment in Australia must be considered in reference to the data collected there. Individual local contexts as well as the setting will also impact on the applicability of data from individual sites. ## Evidence statement R1.ES5: Population-level change in cycle demonstration towns as interventions to increase cycling There is moderate evidence indicating that cycling demonstration towns (CDT) (multi-component interventions to increase cycling in six towns) are effective in increasing population levels of cycling for active travel in the general population up to 10 years post intervention. One (-) ER, one (+) BA and one (+) interrupted time series (ITS) study showed positive effects on cycling in cycle demonstration towns, although the significance of the effects is not reported. See also R1.ES7 and R1.ES6. One (+) ITS (UK n= six towns, 4 years) found automatic counter data indicated an average increase in cycles counted of 27%. Proportion of pupils cycling to school at least once a week increased from 12% pre-survey to 26% post-survey. One (-) ER (UK n=6 towns, 10 years) found data from automatic cycle counts indicated a 12% increase overall in usage of cycle routes and up to 60% at specific sites (this report also uses data from other interventions). One (+) BA (UK n=1500, 4 years) found the proportion of adult cycling for at least 30 minutes once or more per month increased from 11.8% in 2006 to 15.1% in 2008, an increase of 3.3%-points or 28%. The evidence on cycle demonstration town is directly applicable as it was conducted in the UK. ## Evidence statement R1.ES6: Population-level change in multi-component interventions to increase cycling Weak evidence from one (+) nRCT study suggests that multi-component interventions are not effective in increasing population levels of cycling in the general population up to 2 years post intervention, but may result in increased use of bicycle paths and increase in cycling among new/beginner cyclists. See also R1.ES5. One (+) nRCT (n=909, 2 years) – multi-component community-based intervention including: organised bike rides and events, cycling skills courses, distribution of cycling maps of the area, local press coverage – found significantly greater use of the bicycle paths in the intervention area (28.3%) at follow-up compared with the comparison area (16.2%) p<0.001. No self-reported increase in residents who said they cycled in the last year, however, significantly more 'novice'/beginner riders had cycled in the last year in the intervention area (11.5% versus1.4% in the comparison area; p=0.013). The population-level evidence on multi-component interventions to increase cycling is only partially applicable to the UK as the study was conducted in Australia. The differing environment in Australia must be considered in all studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES7: Population-level change in multi-component interventions to increase walking and cycling in adults Weak evidence from four (two , two ) of five studies indicates that multi-component interventions delivered in the community are effective in increasing population levels of walking and cycling for travel and/or leisure up to 9 years post-intervention. Evidence from the three BA, and one ITS, showed mostly positive effects of community interventions to encourage cycling and walking for travel and/or leisure. One (+) nRCT indicated that multi-component interventions may reduce a natural decline in walking in women and that among those with a low educational level, cycling may show a small increase. See also R1.ES5 and R1.ES6. One (+) BA (Belgium n=438, 1 year) – physical activity promoted in the entire city of Ghent. Central theme of '10,000 steps/day', with secondary taglines of 'every step counts') and 'every revolution (of bicycle pedals) counts', pedometers given – found that 47.5% increased average step counts by 896 steps/day or more at 1-year follow-up (no statistical analysis; cycling was 'converted' to step counts). One (-) BA (USA n=not reported, 12 months) – multi-component intervention to increase safe physical activity opportunities and encourage walking and biking for short trips – found the number of people seen using active transportation increased from 1028 in 2005 to 1853 in 2006 (63% increase). Walking to school more than doubled at three of four schools engaged for at least 2 years (no other analysis). One (+) BA (UK n=at least 12,000, 4 years) – three 'Sustainable travel towns' which implemented intensive town-wide Smarter Choice Programmes to encourage use of non-car options; bus use, cycling and walking, and less single occupancy cars – found that cycle trips per head grew substantially in all three towns by 26–30%. Comparison towns cycle trips decreased. Walking trips per head grew substantially by 10–13% compared to a national decline in similar towns. One (-) ITS (USA n=not reported, 1 year) – Project U-Turn, active transportation (biking, walking, and transit use) through an integrated approach to active living, ran for 5 years, targeting 36,000. City-wide count of people using active transport, showed an increase of 63% over 1 year, limited study details provided. Also had a major schools component and reported an increase in walking over time, no statistics given. One (+) nRCT (Netherlands n=3114, 5 years) – community-based project with 790 lifestyle interventions, 361 were physical activity focused, example: printed guides of walking and cycling routes – found that there was a smaller decline in walking in women in the intervention compared to control region (-0.3 hours/week versus -2.3 hours/week; p≤0.05); and among those with a low education level there was a significant difference in change in cycling and walking in the intervention versus control region (0.2 hours/week versus -0.3 hours week respectively for cycling and 0.0 hours/week versus -2.2 hours week for walking; both p≤0.05). The population-level evidence on multi-component interventions to increase walking and cycling in adults is only partially applicable to the UK as one studies was conducted in the UK. The differing environment in the USA and Europe must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES8: Population-level change in multi-component interventions to increase walking and cycling in children Inconsistent evidence from three studies on the effectiveness of school-based multi-component interventions to increase levels of walking and cycling for children. Evidence from two (+) BA studies showed positive effects on school population-level walking in children however evidence from one (++) cluster randomised control study (RCT) showed no effect on cycling and walking for school travel. One (+) BA (UK n=179, 41 months) – school travel plan group developed a walking bus scheme, incentive scheme 'going for gold' included children cycling or scooting to school, also cycle training, pedestrian training, park and walk scheme, curriculum work, school assemblies and newsletters – found walking to school increased from 30% to 58.8%, cycling to school increased from 0– 4%. One (++) cluster RCT (UK n=21 schools, 12 months) – multi-component school travel plans were developed by a school travel coordinator – found the proportion of children walking or cycling to school was not affected by the intervention. One (+) BA (UK n=11 schools, up to approximately 18 months) – 'Safe routes to school'– identified and created safe routes to school, invites community-wide involvement, full-time educator employed to develop curriculum and volunteer team leader in each school – found an increase in number of school trips made by walking (64%) and biking (114%). The population-level evidence on multi-component interventions to increase walking and cycling in children is applicable to the UK as all studies were conducted in the UK. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES9: School-based change in interventions to increase cycling in children Weak evidence from one (+) BA study suggests that school-based multi-component interventions may be effective in increasing school population levels of cycling in children. Evidence showed positive effects on walking at the school population level. The study (UK n=52 schools, 1 year) – 'Bike it': school travel plans, cycling champions in schools to demonstrate to parents and pupils that cycling is a popular choice. Percentage of school pupils cycling to school every day increased from 3% to 10%. Number of pupils cycling at least once a week increased from 10% to 27%. Number of pupils who never cycled decreased from 80% to 55%. The evidence on multi-component interventions to increase cycling in children is applicable in the UK as the study was carried out in the UK. ## Evidence statement R1.ES10a: Walking school bus interventions to increase walking Moderate evidence from three (+) BA studies and one (+) nRCT suggests that walking school bus interventions may be effective in increasing levels of walking at the school population level for children up to 30 months post-intervention. One (+) BA (UK n=309, 14 months) – walking school buses supported by environmental interventions such as street lighting on walking routes – found that participants walking increased from 60% to 68.3%, 25% of that was due to walking buses. One (+) nRCT (USA n=3 primary schools, follow up 6 months after baseline) – Walking School Bus (WSB). The school implemented three routes staffed by parent volunteers, and were compared to two nearby schools without a WSB – found that the number of children who walked to school increased from baseline to follow up by 25% (from 19–26%). Comparison schools showed a decrease in the proportion of children walking to school over the same period (no data given). One (+) BA (UK n=64, 18–30 months) – walking buses at five schools. Information sent home to parents to encourage participation – found that there was an overall average increase of 513 metres walked per day. For children that had previously walked to school the WSB resulted in an average increase of only 19 metres/day, for those that previously travelled to school by a mixture of car and walking: average increase of 309 metres/day and for those that previously regularly travelled by car to get to school: average increase of 1549 metres/day (no statistical analyses reported). Participation in the walking buses declined over time. One (+) nRCT (USA n=643, 12 months) – WSB run by a part-time coordinator and parent volunteers. The intervention included three routes which ranged from 0.3 to 1.5 miles and took 15–40 minutes. The WSB operated once or twice a week – found that higher proportions of students walked to the intervention (25% +/- 2%) versus the control schools (7% +/-1%: p<0.001). Significant increase in walking to school in intervention school from 20% (+/-2%) at baseline. The evidence on school-based walking sessions to increase walking is partially applicable to the UK as two studies were conducted in the UK. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES10b: School-based interventions using pedometers to increase walking Moderate evidence from one (+) cluster RCT and one (+) ITS suggests that school-based walking interventions which incorporate pedometers may be effective in increasing levels of walking at the school population level for children up to 12 weeks post intervention. One (+) ITS (USA n=169, 6 weeks) – pedometers and a 'Fit bits' programme to implement physical activity breaks in the classroom – mean steps increased from 19,149 (95%CI 18,224–20,073) week 1 to 21,248 (95%CI 19,730-22,765) week 6 (p<0.001) found that overall, walking peaked at week 3; and younger students had a stronger response to the intervention. One (+) cluster RCT (New Zealand n=85, 12 weeks) – physical activity self-monitoring and educative programme – the pedometer (PED) group set daily step targets, and the minutes (MIN) group set daily time based activity goals – found that both intervention groups had significant increase in steps between baseline and week 12 (p<0.001), no significant differences between time points for the control group (p=0.23). The evidence on school-based walking sessions to increase walking is only partially applicable to the UK as studies were undertaken in the USA and New Zealand. The differing environments in these countries must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES10c: School-based walking session interventions to increase walking Inconsistent evidence from five studies (reported in six papers) on the effectiveness of school-based walking session interventions in increasing levels of walking at the school population level for children up to 48 months post intervention. Evidence from one (+) nRCT and two (+) BA studies (reported in three papers) showed positive effects on school population walking. However one (+) nRCT showed no effect on walking and one (+) cluster RCT had conflicting evidence concerning the intervention effect on walking for school travel. One (+) BA (UK n=585, 48 months) – 'Walk on Tuesday and Thursday' (WOTT) encouraged walking to school, included incentives – found that walking to school increased from 53.3% to 58.7% (percentages only reported). Also reported in a second (+) BA. One (+) nRCT (UK n=60, 10 weeks) – school-based active travel project. Active travel was integrated into the curriculum, and participants used interactive travel planning resources at home – found that mean distance travelled to school by walking increased significantly more in the intervention (389%) than the control (17%: t=-4.679, p<0.001, 95% CI -315 to -795 m). One (+) nRCT (UK n=13 schools, 4 weeks) – interventions linked to national walk to school week – found no difference between intervention and control schools in walking before or after the intervention. One (+) cluster RCT (Australia n=24 schools, 2 months) – health promoting schools policy: classroom activities, pedometer-based walking activities (some schools) development of school travel access guides, parent newsletters, and improving environments with local councils – found that, based on student survey data while both intervention and control groups increased walking by about 4% from baseline, there was no statistically significant difference in mean percentages of change in mode of transport to or from school from baseline to follow-up between the intervention and control groups (no data given).But parent survey data (n=807) indicated a significant increase in walking trips by students in the intervention compared to control schools (28.8% versus 19%, p=0.05). One (+) BA (Australia n=234, 4 weeks) – classroom activities supported by a weekly newsletter to encourage walking to school – found the percentage of walking trips increased by 3.4% and car trips decreased by 3.4%. The evidence on school-based walking sessions to increase walking is partially applicable to the UK as three studies were conducted in the UK. The differing environments in Australia must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES11: Population-level change in workplace-based interventions to increase independent walking and cycling Weak evidence from one (+) BA study and one (+) ITS indicates that multi-component interventions delivered in the workplace are effective in increasing population levels of walking and cycling One (+) ITS (UK n=1850 to 2829 in each of four staff surveys, 9 years) – university transport plan: limiting the number of available parking spaces and permits, improving, installing secure cycle storage, subsidised cycle purchase scheme, car share scheme, free bus travel, and discounted season tickets – found that respondents who usually walked to work increased from 19 to 30% (Z=4.24, p<0.001) and regular cyclists increased from 7.0% to 11.8% (not significant). One (+) BA (UK n=2240, 3 years) – Well@Work programmes which consisted of a diverse set of initiatives and actions aimed at promoting and supporting healthy lifestyles – found an increase of 9% in the proportion of employees participating in active travel (walking or cycling), significant increase in employees cycling (4%) or walking (8%) to work. The population-level evidence on multi-component interventions to increase walking and cycling in adults is applicable to the UK as both studies were conducted in the UK. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES12: Individual-level change from participation event to increase cycling Weak evidence from one study suggests that a mass participation intervention may be effective in increasing individual-level cycling for leisure in adults. Evidence from one (+) BA study showed a positive effect on cycling 1 month after the intervention. One (+) BA (Australia n=918, 2 months) – mass cycling event – found that participants with low pre-event self-reported cycling ability reported an average of four sessions of cycling in the month before the event and an average of 6.8 sessions in the month after the event (t=5.25, p<0.001). The evidence on mass participation event intervention to increase cycling is only partially applicable to the UK as the study was conducted in Australia. The differing environment in Australia must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES13: Individual-level change in community delivered targeted health information interventions to increase walking Moderate evidence from six studies suggests that individual, targeted provision of health information (including printed media, telephone support and text messages) delivered in the community are effective in increasing individual levels of walking for leisure or travel in adults up to 1 year post intervention. Five (++) RCTs showed positive effects on walking. One further (++) RCT also showed positive effects on walking, but was designed to test intervention fidelity. One (++) RCT (USA n=117, 3 months) – ten weekly emails containing links to a webpage with an interactive information tailoring tool to promote physical activity – found that walking increased at a faster rate in the intervention group than the control group (β=15.04 , p=.035 ). Intervention group increased walking by 69 minutes/week versus 32 minutes/week in control. One (++) RCT (Australia n=399, 10 weeks) – print only (participants were mailed self-help brochures weekly for 3 weeks) or print plus telephone (participants received the same print programme plus three weekly telephone support calls – found that both intervention groups significantly increased time reported walking for exercise per week (from 130 to 147 minutes: t =-3.50, p<0.001; and from 132 to 150 minutes, t= -2.44, p=0.016). One (++) RCT (USA n=197, 6 months) – counselling weekly telephone calls to assess physical activity levels and problem solve how to fit adequate walking activity into their week – found that women in the intervention group reported more time walked each day than the control women (F =4.10, p<0.05). One (++) RCT (USA n=253, 12 months) – telephone calls with or without counselling, or a control video – found that women in the intervention group showed a linear increase in walking from baseline to 6 months (latent growth analysis to assess the relationship between time and intervention group membership). One (++) RCT (UK n=149, 4 weeks) – two theory-based interventions consisting of forming 'implementation intentions' along with text message reminders to achieve walking-related plans or goals – found a differential change across groups in brisk walking or fast walking (F = 3.12, p=0.048). Two intervention groups which differed in having a plan reminder or goal reminder had a 45% and 42% increase of at least 2 days a week meeting physical activity daily guidelines respectively, with a 22% increase in the control group. One (++) RCT (USA n=50, 12 months) – two interventions consisting of forming 'implementation intentions' along with text message reminders to achieve walking-related plans or goals using social cognitive theory (SCT) – found the greatest increase in walking in interventions that adhered more closely to SCT. High fidelity intervention increased walking by 34.23 minutes a week (+/-81.91) compared to a low fidelity increase of 7.91 minutes a week (+/-47.93, F=3.207 p=0.08). The evidence on community delivered health information interventions is only partially applicable to the UK as most studies were conducted in Australia or the USA with only one UK study included. The differing environment in Australia and the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. Note: pedometers are a technology which offers an opportunity to present individualised information about walking and so are closely linked to the studies above. Use of pedometers is related to goal setting and monitoring rather than to delivery of information about health benefits or methods to overcome barriers. Studies may use pedometers as one of a number of factors to support increases in walking, in common with other approaches, or may use pedometers solely as a means of measuring change. Pedometer studies are considered below. ## Evidence statement R1.ES14: Individual-level change in community-based pedometer interventions to increase walking Moderate evidence from 12 studies suggests that pedometer-based interventions delivered in the community are effective in adults (or women only) to increase individual levels of walking for leisure or travel, up to 6 months post intervention. Evidence from five (++) RCTs and 2 BA studies (one and one) showed positive effects on walking for leisure and/or travel in adults. This is supported by data from a (-) CS study. However, one (++) RCT found that short-term improvements in walking 4 weeks post intervention had decreased by 12 months follow-up. Evidence from one (++) RCT and one (+) BA study showed substantial positive effects on walking for leisure and/or travel in women. An additional (++) RCT found that a pedometer-based intervention increased walking in environments with low aesthetics, but not in those with aesthetically pleasing environments. One (++) RCT (UK n=61, 52 weeks) – walking programme with goals set in minutes, or steps or using a pedometer – found that the pedometer group increased walking at 4 weeks (p<0.001), but decreased between 4 weeks and 12 months. No change in minutes or control groups. One (++) RCT (UK n=130, 4 weeks) – motivational component had three stages: participants were shown 10 statements about what would make it easier for them to walk more, asked to complete a scale to show how confident they would be about walking in each situation, and discussed with facilitator and walking plan developed; pedometers were worn – found a significant difference in number of minutes spent walking to week 2 between the control group (M=138.7, SD=93.3) and the intervention group (M=22.5 SD=100.3), from a mean of 19.8 minutes to 32.2 minutes per day (increase of over 60%). Also a significant increase in the number of minutes spent walking per week for intervention group from week 1 to week 4 (mean 287.3, SD=129.4 t=8.12, p<0.001). One (+) BA (USA n=36, 6 weeks) – women who were designated as insufficiently active were given brochures and pedometers and were sent emails. Participants received a pedometer, 6 weeks of step log sheets, self-addressed envelopes, and three commercial brochures describing strategies based on transtheoretical model (TTM) for increasing physical activity and the risks and benefits of physical activity – found that participants significantly increased their total walking minutes from baseline (median 55) to post intervention (median 245: Z=4.03, p=0.001) including walking while at work (Z=2.79, p=0.005, d=0.63), for transport (Z=2.86, p=0.004, d=0.60) and during leisure time (Z=3.54, p=0.001, d=0.81). One (++) RCT (Japan n=68,12 weeks) – feedback based on accelerometer daily physical activity, number of daily steps and time spent performing daily moderate physical activity (MPA) which was provided to each participant every 2 weeks. Participants were recommended to accumulate 9000 steps and 30 minutes of MPA per day – found a significant group interaction for steps (f=10.53, p<0.01). The intervention group increased their steps by 16% (7811 +/-3268 to 9046 +/-2620 steps). There was no significant change in the control group. One (++) RCT (Australia n=314, 3 months) – self-help booklet based on social cognitive theory constructs, plus six weekly diaries printed on reply-paid postcards (WP group), plus a pedometer (WPP group). Three incremental stages, starting with short walks (<15 minutes) 3 days a week, typically by incidental walking, gradually increasing the duration of walks to 3 to 4 days, then (continuously) walking briskly for 30 minutes – found that the mean change in total sessions of all-purpose walking/week increased within all groups from baseline, but increased the most within WPP. The control group had a mean increase of 1.2 sessions/week (95% CI: 0.6-1.8, t=3.97, p<0.001); WP: 1.3 sessions/week (0.5–2.0, t=3.32, p<0.001); WPP: 2.3 sessions/week (1.6–3.1, t=6.30, p<0.001). Leisure time walking sessions/week for the previous 3 months also increased within all groups, with both WP (2.0 sessions/week 1.6–2.4, t=9.49, p<0.001) and WPP (2.1 sessions/week 1.7–2.6, t=9.63, p<0.001) showing a significantly larger increase than the control group (0.9 sessions/week 0.6–1.2, t=5.82, p<0.001). There was a similar pattern for leisure time walking minutes/week for the previous 3 months, but only the WPP group (66 minutes/week 50–82, t=8.05, p<0.001) showed a significant increase compared to the control group (34 minutes/week 21–48, t=5.03, p<0.001). The WPP group was also more likely than controls to meet physical activity recommendations. Unclear if the provision of pedometers provides benefit over and above standardised structure walking programme. One (++) RCT (Australia n=369, 3 months) – participants received a single mail-out of a self-help walking programme (WP) or the same programme plus a pedometer (WPP) – found that only the WPP group were significantly more likely than controls to increase total walking time (Exp = 2.53, p<0.01) and to undertake regular walking (OR=5.85, 95% CI 2.60–12.2) where environment aesthetics (level of greenery and interesting scenery) were perceived to be low; while in aesthetically pleasing environments, the differences in walking measures between intervention and control groups were non-significant. One (+) BA (Japan n=56, 4 months) – subjects were given a pedometer and instructed to walk at least 7,500 steps each day. They were also given additional monthly advice on healthy diet and lifestyle provided in a newsletter – found the mean steps per day increased significantly from 9389 to 11846 (p<0.01). One (++) RCT (USA n=24, 24 weeks) – given pedometer and initially, all (post-menopausal) women were prescribed a distance of 1.4 km/day above their baseline. Distance was then increased by 0.5 km/day until the desired walking distance was met – found that the intervention group increased their daily walking by 4300 steps (2.9 ± 0.2 km/day); significantly different from baseline and from the control group (both p<0.05). One (++) RCT (Australia n=26, 12 weeks) – participants (overweight middle-aged women) in the pedometer group were told to record their pedometer steps on a daily basis for 12 weeks; those in the control group were asked to wear a sealed pedometer for 12 weeks with weekly recording. The pedometer group was also encouraged to reach a daily step goal of 10,000 steps/day – found that the pedometer group daily average number of steps at weeks 6 (8321 ± 884 steps/day) and 12 (9703 ± 921 steps/day) were significantly higher than the baseline daily average (of 6242 ± 541 steps/day: p=0.046 and p=0.035) respectively. One (-) BA (USA n=12, 2 weeks) – participants over 65 years of age; site-specific walking route maps, health counselling session with individualised goal-setting and pedometers – average daily pedometer steps increased between baseline (M=3020, SD=1858) and week 1 (M=4314, SD=2627; t= -2.99, p=0.012) and week 2 (M=4246, SD=2331; t=3.42, p=0.006) found that all participants met their daily step goals in week 1 while 50% met their step goals in week 2. One (-) CS (Canada n=41, 6 months) – lending pedometers to patrons of five public libraries. The pedometers were loaned for maximum of 9 weeks. Education packages were handed out with the pedometer including: information on pedometer use, physical activity/walking recommendations, maps of local trails, and a walking challenge questionnaire – found that 39.5% indicated they walked more since borrowing the pedometer and 60.5% reported walking about the same. One (++) RCT (n=79 12 weeks) – the sessions were based on the Transtheoretical Model of exercise behaviour change. Strategies used included enhancing motivation, overcoming barriers and developing appropriate walking plans. Followed a 12-week pedometer-based walking program – found a significant increase in steps/day for the intervention group between baseline (M=6802, SD=3212) and week 12 (M=9977, SD=4669, t(38)=-6.06, p<0.001, d=0.79, CI 2,115–4236). No significant difference was observed in the control group (t(39)= -0.50, p=0.618, CI -463–770). The evidence on community pedometer interventions to increase walking is only partially applicable to the UK. Three studies were conducted in the UK, with the majority in the USA, Australian, Canada, and Japan. The differing environments must be considered in reference to the studies, particularly for those conducted in Japan. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES15: Individual-level change in workplace pedometer interventions to increase walking Moderate evidence from 11 studies suggests that pedometer-based interventions delivered in the workplace may be effective in increasing individual levels of walking for leisure or travel, up to 12 months post intervention. Evidence from three (++) RCTs, one (+) nRCT, two (+) BA and two (+) ITS studies showed positive effects on walking for leisure and/or travel in the short term (up to 12 weeks). However, one (+) ITS study which used a competition format, saw the initial increase in walking decline over 12 weeks. One (+) nRCT found significant increases in walking 12 months after the intervention, while another (++) RCT found that initial increase in walking declined by 52 weeks follow-up. A (++) RCT (UK n=50, 52 weeks) – walking programme with goals set in steps using an open pedometer for feedback – found that both groups significantly increased step counts from baseline to week 4. Significantly greater number of participants in the intervention (77%) compared with the control (54%) achieved their week 4 goals (X2= 4.752, p=0.03). There was no significant change in step counts from week 4–16 and a significant decrease from week 16–52. A (+) ITS (USA n=640 (in 64 teams of 10), 12 weeks) – competition-based employer sponsored physical activity programme using pedometers. Employees formed groups of 10 to undertake the challenge of attaining 10,000 steps per participant per day – found that total weekly steps for all teams combined increased between weeks 1 and 8 (p<0.0001), but declined from weeks 9–12. Increase in total weekly step count between week 1 and 12 not significant. Significant difference in team steps, with post-hoc comparisons indicating significant differences from baseline step counts during weeks 6–8 (F=71.15, p<0.001) but not at the end of the programme. A (+) nRCT (Australia n=205, 12 months) – staff defined as inactive received a 3-month self-help walking programme and pedometer plus four maintenance newsletters over 9 months to assist them to maintain their new activity levels. Control received pedometer and programme but no maintenance – found that both intervention groups significantly increased minutes walking (p=0.01). Change in moderate or vigorous physical activity (MVPA) minutes was significantly higher in the standard plus maintenance group compared with the standard group (118 minutes versus 69 minutes, P=0.029). No significant differences between groups were observed for total physical activity (161 minutes versus 117 minutes, P=0.187). A (+) ITS (Canada n=106, 12 weeks) – adoption phase: participants met in workplace-based groups with a facilitator for 30–60 minutes each week during a lunch break. Set individual steps per day goals and self-monitored their progress using a pedometer to record daily accumulated steps taken. Then adherence measured for 8 weeks – found that steps per day increased (from 7,029 +/- 3,100 at baseline to a plateau of 10,480 +/- 3,224 steps/day by 3.96 +/- 3.28 weeks of the intervention). Some decreases in activity relative to baseline steps per day, (ranging from -2.4% to -20.6% ). A (+) nRCT (Australia n=56, 6 weeks) – the intervention group received a pedometer and step logs. Set a daily step goal based on the previous week's step counts. They received weekly email reminders to wear the pedometer and return that week's log. They also received three commercial brochures. The control group received the intervention but without commercial brochures, intervention emails contained transtheoretical model (TTM)-based strategies – found that daily steps increased significantly (from 6419 ± 2386 during week 1 to 7984 ± 2742 during week 6: p<0.001) for both groups combined. Increases did not differ between groups. A (+) ITS (USA n=206, 10 weeks) – each day participants put on pedometers upon arriving at work, prior to getting out of their cars. To increase motivation, participants were encouraged to develop teams, and each team chose a team leader. Weekly motivational emails were sent to participants – found a significant increase in the number of steps per week for weeks 2, 3, 4, 6 and 8 compared to baseline (p=0.001). A (++) RCT (UK n=64, 10 weeks) – walking routes which employed prescribed walks around campus with participants asked to complete at least 15 minutes continuous brisk walking every day and 'Walking in task' which encouraged the accumulation of step counts through the working day – found a decrease in steps for the control group (-767 steps/day) and increases in intervention groups for walking routes (+926 steps/day) and walking in tasks (+997 steps/day). (Control versus walking routes p<0.008, control versus walking in tasks p<0.005). A (++) RCT (UK, Australia and Spain n=64, 70 and 80 respectively, 10 weeks) – participants in the first intervention group were directed to increase their step count through brisk, sustained, route-based walking during work breaks. The second intervention group was asked to engage in incidental walking and accumulate step counts during working tasks, both groups were instructed to use pedometers to motivate and regulate walking – found that average step count data decreased in the control group (-391 steps/day t=1.76; p <0.08) and significant increases in both the routes (968 steps/day; t=3.9; p<0.001) and the incidental group (699 steps/day; t=2.5; p<0.014). A (+) BA (USA n=290, 12 weeks) – participants wore a pedometer at least 5 days per week for 12 weeks and completed questionnaires assessing demographic information. After baseline (week 1) they were given suggested number of steps to meet recommendations, instructions for goal-setting and other behaviour-change strategies to gradually increase number of daily steps – found that the average number of steps increased from week 1 to week 6 (p<0.001) and week 12 (p=0.002). A (++) RCT (Canada n=63, 1 week) – intervention group pedometer was worn for 1 week for all waking hours to encourage walking. Control (non-pedometer) participants were informed they could wear a pedometer the following week – found that, compared to the no pedometer group, the pedometer group reported more walking (F=5.22, p=0.03). A (+) BA (USA n=188, 10 weeks) – participants were provided with pedometers and given personalised daily and weekly step goals over the 10 week intervention. Local strategies available to the participants included walking groups, marked walking circuits and posted walking maps – found a mean increase of 1503 steps (38% increase over baseline). Mean weekly step counts values for all intervention weeks were significantly higher than baseline (p<0.01). The evidence on workplace pedometer interventions to increase walking is partially applicable to the UK. Three studies were conducted in the UK but most studies were conducted abroad: in USA, Australia, Canada or Spain which may limit the applicability in some cases. The differing environments must be considered in reference to the studies. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES16: Individual-level change in workplace delivered targeted health information interventions to increase walking Weak evidence from two studies suggests that individual, targeted provision of health information delivered in the workplace (including flyers, email, telephone calls, website postings, and information booths) may be effective in increasing individual levels of walking for leisure or travel in adults up to 24 weeks post intervention. One (+) RCT study showed a positive effect on walking and one (+) BA study showed a small (borderline significance) positive effect on walking. A (+) RCT (USA n=135, 24 weeks) – phone calls once a week versus every 3 weeks, and structured versus non-structured feedback – survival curves indicated that there was a significant effect on walking for treated (the combined four treatment conditions) versus the control condition (LD=17.661 p<0.001) and for frequency of prompting (those prompted once a week against every 3 weeks) (LD=17.719, p<0.0001). A (+) BA (USA, n=not reported, 2 weeks) – promotional material distributed via flyers, email, website postings, and at bi-weekly information booths – borderline statistically significant increases in walking counts on a route ('Path to health') from baseline midway through the campaign (p=0.069) and following the campaign: (p=0.075 – p values only reported). The evidence on workplace health information interventions is only partially applicable to the UK as the studies were conducted in the USA. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES17: Individual-level change in workplace delivered targeted health information interventions to increase walking and cycling Moderate evidence from one (++) RCT study suggests that individual, targeted provision of health information (including a booklet of interactive materials, social marketing and individualised marketing strategies) in the workplace may be effective in increasing individual levels of walking, but not cycling, for travel in adults for up to 6 months post intervention. See also R1.ES4. A (++) RCT (UK n=295, 6 months) – interactive materials based on the transtheoretical model of behaviour change: choosing routes, maintaining personal safety, shower and safe cycle storage information, and useful contacts – found a significant increase in time per week spent walking to work (mean 125 minutes/week intervention versus 61 minutes/week control), but no difference in average weekly minutes of cycling between cyclists in the intervention group (n=9) and control group (n=9). The evidence on health information intervention to increase walking and cycling is applicable to the UK as the study was conducted in the UK. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES18: Individual-level change in multi-component interventions to increase walking Weak evidence from two (++) BA studies suggests that multi-component interventions have a positive effective on increasing individual levels of walking for leisure or travel up to three months post intervention. A (+) BA (USA n=124, 8 weeks) – multi physical activity and dietary program, pedometers – found post intervention that 46.2% (n=43) met the 10,000 steps/day criteria for high activity (no further statistics). This increased from 11.8% at baseline. Average steps increased from 5,969 steps/day to 9,757 steps/day A (+) BA (USA n=53, 3 months) – sponsored walking groups, improving walking routes, providing information about walking options, and advocating for pedestrian safety – found self reported walking activity increased from 65 to 109 minutes per day: 44.1% increase (95%CI= 28.0-60.2, p=0.001). The proportion that reported being at least moderately active for at least 150 minutes per week increased from 62% to 81% (19.2 % increase 95% CI= 2.2, 36.3 P=018). The individual level evidence on multi-component interventions to increase walking is only partially applicable to the UK as studies were conducted in the USA. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES19: Individual-level change from cycle training interventions to increase cycling Weak evidence from one BA (+) study suggests that cycle training interventions may be effective in increasing individual levels of cycling for active travel amongst those not cycling at baseline, up to 2 months post intervention. A (+) BA (Aus n=81, 2 months) – practical skills development and supervised on road or cycle path training. Free courses for beginner and intermediate level cyclists were conducted. Promoted through flyers, posters, media releases, articles and TV and newspaper adverts – found non cyclists at baseline reported significant increase (p<0.001) in minutes cycling. The individual level evidence on multi-component interventions to increase cycling is only partially applicable to the UK as the study was conducted in Australia. The differing environment in Australia must be considered in all studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES20: Individual-level change in healthcare delivered multi-component interventions to increase both walking and cycling in adults Moderate evidence from 1 (++) RCT study concerning the effect of multi-component interventions on increasing individual levels of both walking and cycling for travel and/or leisure up to 18 months post intervention indicated a positive effect on cycling but no effect on walking. A (++) RCT (Sweden n=120, 18 months) – physician meetings, physical activity prescriptions, group counselling, and bicycle provision; control and intervention groups received pedometers – found the intervention group was more likely to achieve recommended level of cycling than controls (38.7% versus. 8.9%, OR=7.8, 95%CI 4.0-15.0, p<0.001) but there was no difference in compliance with the walking recommendation (45.7 versus. 39.3%, OR 1.2, 95%CI 0.7-2.0, p=0.5). Commuting by car and public transport were reduced by 34% (P<0.01) and 37% (P<0.001), respectively in the whole sample, with no differences between groups. The individual level evidence on multi-component interventions to increase walking and cycling in adults is only partially applicable to the UK as the study was conducted in Sweden. The differing environment in Sweden must be considered in reference to this study. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1ES21: Individual-level change in community-based led walking group interventions to increase walking Inconsistent evidence from 5 studies on the effects of a community-based led walking group interventions on walking. 1 (++) RCT, 1 (++) clustered RCT, 1 (++) nRCT and 1 BA (+) study showed positive effects on walking from community-based walking group interventions; but evidence from a further (++) RCT showed no difference between groups at 12 months. A (++) nRCT (UK n=7883, 12 weeks) – 'Get walking, keep walking': Bespoke, led walks and sessions and walking packs aimed at encouraging (predominantly) inactive people, those from deprived communities, black and minority backgrounds, women and younger adults to walk – found 67% of participants increased the amount of exercise they did each week. Walking from 'place to place' increased by 1.1 day/week and walking for leisure by 1 day/week. A (++) cluster RCT (USA n=501, 6 months) – leader-led walking group activity or an information-only control group – found significant increase observed in walking activity: p <0.05. A (+) BA (Australia n=169, 6 months) – walk leaders received a prescriptive progressive weekly exercise program guided by social cognitive theory, that contained written information on the appropriate length for the walking program; stretching exercises; and ball skills, such as side twist leader ball, participants aged 65-74 – found baseline mean walking time for recreation was one hour (SD =1.65), increasing to 2.69 hours (SD =2.02) per week by the end of the program. A (++) RCT (UK n=260, 12 months) – accompanied walks were provided at several different times in the day and evening, during the week and at weekends, and were led by lay volunteers – found at 12 months, although both walking and control groups increased activity (by 35.7% and 22.6% respectively; 95% CI 0.003% to 25.9%) p=0.05), there was no significant difference between them. A (++) RCT (USA n=114, 20 weeks) – efficacy based Exercise classes were conducted by trained exercise specialists and employed brisk walking as the aerobic component – found at the end of the 20 week program, subjects in the intervention group walked more miles per week than the control group: p<0.05.Intervention group subjects also walked more often (p<0.01) and accumulated more minutes (p<0.01) than control The evidence on community based walking group sessions to increase walking is only partially applicable to the UK as only two studies were conducted in the UK. The differing environment in the USA and Australia must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES22: Individual-level change in interventions to increase independent community-based walking Weak evidence from 2 (+) BA studies and 1 (++) RCT suggests that interventions to increase independent community based walking may be effective in increasing individual walking for leisure, exercise or travel up to 13 weeks post intervention in adults or the whole community. A (+) BA (Canada n=39, 8 weeks) – 'mall walking programme', participants provided with pedometers. Participants self-selected the pace, time, and frequency of walking. Encouraged to attend as often as possible between 8am and 10am Monday to Friday – found average daily mall walk steps increased from 5055 (SD 1374) to 5969 (SD 1543): p=0.002, and average daily mall walk time increased from 42.9 (SD 10.6) min to 50.4 (SD 13.5) min: p=0.002. A (+) RCT (Aus n=88, 13 weeks) – participants: postnatal women; information, goal setting consultations, activity and self-monitoring daily planner, tailored SMS, nominated social support person – found frequency of walking for exercise (days/week) increased over time in the intervention compared to control group (time×group interaction effect F(2,85)=5.38, p=0.023, medium effect size partial η2=0.06); while change in duration of walking did not show a significant time×group interaction effect (p=0.081; effect size partial η2=0.05), there was a significant group effect with increases in walking duration in the intervention compared to control (p=0.005; medium to large effect size partial η2=0.09). A (+) BA (USA n=16, 12 weeks) – walking intervention facilitated by community health workers. Weekly sessions encouraged participants to accumulate at least 30 min of moderate intensity walking on most/all days of the week – found that exposure to the programme resulted in significant increase in walking: 915.8 metabolic equivalent min/week, p=0.002. The evidence on interventions to increase independent community based walking may not be applicable to the UK as studies were conducted in the USA and Canada. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R1.ES23: Individual-level change in workplace-based interventions to increase independent walking Inconsistent evidence from 2 (++) RCT studies concerning workplace walking session interventions (conducted in universities) effectiveness in increasing individual levels of walking for staff and/or student participants up to 12 months post intervention. Evidence from 1 RCT showed positive effects on walking while one RCT showed no effect on walking. A (++) RCT (USA n=32, 32 weeks) – sedentary adults; walking prescription: 3 brisk walking conditions: 30 continuous minutes, 3 10-minute bouts, or 30 minutes made up of any combination of bouts each at least 5 minutes long; 1 hour information and modelling session followed by weekly meetings with an activity counsellor for 15 weeks. Behavioural methods used to promote adherence: goal setting and mastery, self-management techniques, weekly personal feedback, problem solving, behavioural contracting participants paid $50, refunded on successful completion – found self-reported walking for all intervention groups significantly increased throughout the program: F(6, 186)= 26.16; p<0.001. A (++) RCT (USA n=26, 6 weeks) – two 8-week walking for fitness classes – found that neither group increased walking time or number of steps significantly over time. The evidence on workplace (university) based walking sessions to increase walking is only partially applicable to the UK as the studies were conducted in the USA. The differing environments must be considered in reference to the studies conducted in the US. Individual local contexts as well as the setting will also impact on the applicability of individual studies. ## Evidence statement R2.ES1: Providers' and researchers' views of barriers and facilitators to planning and delivering interventions to increase walking Moderate evidence from four studies suggests that facilitators to planning and delivering interventions included organisational support and sufficient planning time. It may be beneficial to include volunteer leaders at the planning stage. Having previous experience in marketing and a conceptual framework facilitated recruitment efforts. Personal satisfaction, social interaction and a positive rapport with group members were motivational effects of leading walking groups. Barriers to planning and delivery included lack of inter-organisational collaboration. This was facilitated by introducing staff in different organisations to each other and being clear about shared goals. Employing an individual to co-ordinate between organisations was a facilitator to implementation. De-motivators to being involved in organising and monitoring groups included researchers' perceived workload, efforts required for effective recruitment, lack of support from and feelings of responsibility for group members. A (+) UK evaluation suggested that sufficient planning time is required for successful implementation of a family-based intervention. Involvement of proposed walking leads at the planning stage was suggested as a way of increasing their engagement with the programme. A US (+) pilot evaluation reported that walking group policy makers supported the walking group by promoting the intervention and assisting with recruitment. Administrative support was also supplied, and events were organised. A (+) study that included interviews from the UK reported that the process of recruiting members to a walking group was draining on time and resources for the organisers, and some volunteers lacked skills in recruitment. Having experience in marketing and a conceptual framework around recruitment was a facilitator to recruiting new members. However, word of mouth was regarded as the most effective recruitment strategy. A pilot evaluation reported that running the walking group provided a sense of personal satisfaction for organisers as well as an opportunity for personal development and health promotion. Interaction with club members was a motivator for organisers. Collaboration with other organisations was an issue in two studies, due to a focus on their own organisation and lack of communication. In one study this meant that walking routes were not shared and events were less well attended. Club directors could also feel isolated. In the other study, collaboration between a walking association and a family support group was improved through members getting to know each other and being clear that goals were to be shared, and that interventions would run alongside each other rather than new initiatives replacing existing ones. Coordination by one designated officer also facilitated implementation. One study reported that group organisers expressed views about their burden of responsibility for the wellbeing and safety of members, especially if leadership was not shared. Recruitment and maintenance of membership numbers were regarded as a burden, and strategies were developed by the club to limit drop-out. Having to walk at a slow pace with other members was a de-motivator. One UK (+) interview study found that carrying out routine physiological measurements in a pedometer study was regarded as a burden for researchers. Findings from these studies have partial applicability to other walking groups. The organisation of walking interventions will differ across countries, regions and groups. Groups may have different goals, and recruit specific populations. There is no reason to believe that the barriers and facilitators described are not applicable to other similar interventions. ## Evidence statement R2.ES2 Participants' views about motivators and barriers to participating in interventions to increase walking Moderate evidence from five studies suggests that participating in a walking intervention motivated people to walk through the presence of role models, organised routes, and the support of being part of a group. Families were motivated by the opportunity for children to participate in an activity that was free of charge. For others, the opportunity to improve health and enjoy fresh air and nature were motivational. Barriers to motivation include conflicts between walking activities and work / school schedules, and cultural lack of acceptance in regard to work-based activity. One US (+) pilot evaluation reported that having access to a role model and to organised walk routes were motivators to attendance. For women, having the support and security of a group was a motivator (one focus groups, US). For families, the opportunity for children to participate in activities with the family, free of charge, and outside of nursery hours were incentives (one evaluation, UK). For adults, a sense of routine and structure was valued for those who were not in employment (one focus groups, UK). Participants in one (+) UK focus groups study were motivated by the opportunity to improve their health and be out in the fresh air and natural environment. However, barriers to participation included conflicting schedules with school attendance or workplace responsibilities (one interviews, UK). In a workplace setting, they also reported that increasing walking time required acceptance from colleagues, and this varied depending on the status of the employee within the organisation. Applicability: The findings from these studies are applicable to other walking groups. The acceptability of walking interventions will depend upon specific walking group characteristics, settings and aims. There is no reason to believe that the barriers and facilitators reported are not applicable to interventions implemented in the UK. ## Evidence statement R2.ES3 Participants' views about maintaining participation in interventions to increase walking Moderate evidence from ten studies provided evidence regarding factors associated with maintenance of participation. Social interaction and social support were major factors in maintaining participation. Maintenance was also related to the extent to which activities could be integrated into daily life. Monitoring activity, providing people remembered to self-monitor, could increase motivation, though it could also introduce unwanted competition between members. Other motivators included variation in walking routes, and incentives such as gifts. Barriers to maintenance included the difficulty of integrating walking and attendance at clubs into daily routines. Boredom, dissatisfaction with elements of the club, and incongruent aims were reported factors associated with discontinued membership. The social factor associated with walking in groups was supported by six studies. The social factor was particularly strong for women and older adults. One (+) UK focus group study reported a strong bond and sense of loyalty to the group that facilitated attendance. For men, the social factor was not so important with males tending to prefer walking alone (one focus groups, US). Support was also important; in one intervention, feedback from providers was welcome, though e-mail was the preferred mode. A US (+) RCT highlighted the importance of family and friends in supporting the maintenance of walking behaviours. Walking also had a positive effect on interactions with family members. A UK (+) interview study reported that walking to deliver messages at work instead of e-mailing created a greater sense of community. An important aspect of walking was the ability to integrate interventions into daily life. The ability to turn up without booking was a positive factor for some, and a sense of routine and structure was valued for those who were not in employment (one focus groups, UK). However, one study reported that women in particular found difficulty integrating extra walking into daily routines. Life changes, coinciding schedules and other commitments were also a barrier. Wearing female-oriented clothing such as high heels was a barrier to walking while at work. For African–American women, it was difficult to focus on self-based activities. Monitoring activities was reported as a motivator. Two studies reported that pedometer use and the process of self-monitoring increased walking behaviours. One reported that step counting gave a sense of achievement. However, a US observation and interviews (+) study found that in older adults (mainly female), pedometer use and fitness objectives conflicted with the moral economy (shared values regarding social interaction) of the walking group, which was based on sociability rather than competition. In addition, people often forget to complete logs, or to use their pedometer. Other incentives included rewards and gifts. One study reported that the atmosphere of the club, mismatch between aims of the club and aims of the participant, as well as the pace required to walk could be barriers to participation in walking interventions. Another also added that boredom could dissuade attendance, and for African–American women, one study reported lack of objectives as potential barriers. Applicability: The findings from these studies are applicable to other walking groups. The motivation to maintain walking behaviour within an intervention will depend upon individual circumstances and requirements as well as the characteristics and aims of the club. There is no reason to believe that the barriers and facilitators reported are not applicable in the UK. ## Evidence statement R2.ES4: Participants' views of the benefits of participating in a walking intervention Moderate evidence from eight studies highlighted the reported benefits of walking as part of a walking intervention. Perceived benefits to walking were reported to facilitate motivation and hence walking behaviour (one focus groups, US). Such benefits could be emphasised when encouraging participation in interventions. Reported benefits included physical and psychological benefits, adding variety to the day and getting out of the house or office. Walking could provide a sense of peace and solitude, and was also fun, providing an opportunity to be out in fresh air and see the sights. Reported physical benefits were feeling healthy, (one focus groups, US), and fit (one pilot evaluation, US), (one RCT, US), increased energy, (one interview studies, UK), lower blood pressure, weight loss and improved body shape. Psychological benefits included enhanced mood, stress reduction, mental and emotional satisfaction, feeling rejuvenated, and having meditative or spiritual feelings. Feeling tired at the end of a walk was associated with a sense of achievement (one focus groups, UK). In a workplace intervention, walking was reported to add variety to the day and improved output at work. For a group of previously sedentary adults, walking became fun, and was a chance to get out of the house. Walking for one group of mid-age women allowed them time to think, time out of the office, time with the family and fresh air. Benefits reported from two (+) pedometer-based interventions included seeing the sights (interviews, UK), and socialising with members of the group (observation and interviews, US). Applicability: The findings from these studies are applicable to other walking groups. Benefits of walking may differ by setting, though there is no reason to believe that the benefits reported are not applicable in those settings within the UK. ## Evidence statement R2.ES5: Walking intervention participant's views of perceived barriers to walking Moderate evidence from seven studies highlighted perceived barriers to walking for participants of walking interventions. These included physical and psychological limitations, environmental barriers, and poor weather conditions. Physical barriers to continuing with the walking programme included health problems such as arthritis (one focus groups, US), and physical limitations such as illness and injuries (one RCT,US). Tiredness and depression also prevented some women from continuing attendance. Poor weather conditions or hot weather were reported disincentives to walking (one interviews,UK; one pilot evaluation, US;one focus groups, US;one focus groups, UK). One study reported costs of participation as a barrier. Lack of access to the walking route, and obstacles such as poorly maintained stiles along the walking route were also reported barriers. Applicability: The findings from these studies are applicable to other walking groups. The barriers to participation in walking interventions might depend upon individual circumstances, such as age and physical fitness as well as seasonal weather conditions. Weather conditions may be better, or more extreme, in the US, Canada and Australia than in the UK, though there is no reason to believe that the barriers reported are not applicable in the UK. ## Evidence statement R2.ES6: Suggested strategies to overcoming barriers to maintaining walking in a walking intervention Moderate evidence from two studies highlighted reported strategies to overcome perceived barriers to participating in walking interventions. These included making time, and integrating walking into daily life as well as thinking positively. A (+) US RCT reported strategies including scheduling time to walk, problem-solving and using motivators such as positive thinking and focusing on the long-term benefits. Goals were more achievable if walking was made a priority and was fitted into daily life as much as possible. Similarly, a (+) US study (focus groups) reported that for African–American women, weaving walking into family life was a strategy that allowed themselves and the family to participate. Applicability: The findings from these studies are applicable to other walking groups. The ability to implement strategies to overcome barriers to participation in walking interventions will depend upon individual circumstances. ## Evidence statement R2. ES7: Providers' views about effective intervention components that motivate walking and cycling Moderate evidence from one study suggests that workplace efforts to encourage walking and cycling are most successful where they attend to cultural attitude, access, security and available facilities. Incentives and provision of equipment are also motivating. The (+) study (survey and interviews, UK) provides evidence that, across 20 workplace initiatives, walking and cycling are increased where good onsite and offsite access is available, along with provision of showers, drying and changing facilities. Organised walks at lunchtime and cycling groups were an incentive. Organisational attitude was important, with some workplaces marketing the benefits of walking to staff. Motivators such as complementary products or financial incentives were used. For cycling, the ability to borrow equipment or receive discounts on cycling equipment was important, as was having secure parking for cycles. Applicability: Findings from this study were taken from a range of workplace initiatives within the UK and so are applicable in UK workplace settings. ## Evidence statement R2.ES9: Participants' views about taking part in interventions to increase cycling Moderate evidence from one exploratory study and one evaluation showed that facilitators to a led cycling intervention were a feeling of safety and acceptance that was obtained from cycling in a group. Provision of acceptable equipment and the need not to wear a helmet was a facilitator for boys. In a workplace-based cycling intervention, facilitators included the provision of storage and changing facilities and raised awareness about benefits. The (++) exploratory study (focus groups, UK) elicited community members' views about use of a cycle trail and a proposed intervention that included led cycling groups. The main facilitator to using the trail for led cycle groups was the protection of riding together in a group. For young women, the image of cycling as 'uncool' was an issue, but this barrier would be lessened if they were cycling with friends. Image was also an issue for boys, whose participation would be facilitated by the provision of the 'right' bike, and not having to wear a cycling helmet. The (+) UK evaluation study (found that the main influences on increase in cycling following an intervention were the provision of workplace cycling facilities, a house or job move that made cycling more attractive, and heightened awareness of the importance of physical activity for health. Welcomed and best used measures were secure cycle parking, showering and changing facilities, and cycle purchase loans. Applicability: The findings from these UK-based studies are applicable to other potential cycling interventions. The motivation to participate in cycling interventions might depend upon individual circumstances, as well as local geography and usage of the proposed site. Some areas of the UK may be more or less attractive as cycling venues than the one described here. Workplaces will also differ in provision of facilities, and interventions may be affected by factors outside the control of organisers, such as weather conditions. ## Evidence statement R2.ES10: Young people's views about walking for travel or leisure (not related to an intervention) Moderate evidence from one interview study and one survey study suggests that walking for leisure was facilitated by walking as a social event or as part of a challenge. Barriers to walking for travel or leisure for young people are mainly related to lack of time. In addition, having a lot to carry and wearing shoes that were not comfortable were disincentives. Young people report busy lives as a barrier to walking for transport. For men, walking was not sufficiently vigorous to be considered 'exercise'. The (++) UK interview study reported that young people, and especially young men, did not regard walking as vigorous enough to provide exercise. Walking for transport required too much time out of a busy day. Walking for leisure was only acceptable if it included some form of teamwork or challenge. For those that did walk for transport, listening to music was a facilitator as it drowned out noise from traffic and construction sites. The (+) US survey study reported that undergraduates found that lack of time, having a lot to carry, and wearing shoes that were uncomfortable were the most highly rated barriers. Applicability: The findings from these studies are applicable to young people in the UK and US. Evidence reflects aspects of daily life that alter with changes through the life course. Participants in this study are constricted by timescales associated with the working day that might not apply to some other populations. There are also specific gender differences in perceptions of walking for fitness. ## Evidence statement R2.ES12: Older people's views about walking for travel or leisure (not related to an intervention) Moderate evidence from six studies suggests that the main facilitator to walking for travel or leisure in older adults was social interaction. Barriers to walking for travel or leisure for older adults are related to limited mobility and fears for safety. These factors were mediated by the external environment, with fears of falling or of swift traffic being commonly voiced. Walking indoors was a relatively safe and comfortable alternative if designed appropriately. Walking indoors also incorporated a social aspect to walking. Older adults reported factors that impacted on safety as the main barriers. When walking outside, narrow pavements and obstacles such as parked cars on pavements, and construction sites were barriers to access (one interviews, UK). Traffic was also an issue, with cycle tracks and bus lanes creating hazards. Suggested improvements were wider pavements and better provision for cyclists. In addition, two focus group studies from Canada (one and one ) reported that fear of falling was a barrier to older adults, particularly in icy weather. Uneven pavements and car parks that are not designed for pedestrians were hazards. Older adults often require more time to cross roads, and it was reported that fast roads and poor visibility at crossroads were barriers to outdoor walking. Suggestions for improving the walking experience for this group were access to toilets and seating, as well as adequate access to local amenities and pedestrianised shopping areas. Making sure that pavements were smooth and clear of snow and ice was also a factor. A (+) UK survey reported that obstructions to mobility included crossings without dropped kerbs, narrow footpaths, and a dropped curb with a steep angle. The authors report that 19% of people aged >80 years could not reach key places if they need to pass through a gap of 1000 mm. Two studies assessed indoor walking for older adults. A (++) observations and interviews study from the UK reported on mall walking that not only contributed to improved physical activity, but also provided a social network and a meaningful work replacement following retirement. Routines were adapted and events were organised in a relatively safe environment compared to outdoors. For older adults in assisted living facilities, a (++) focus group study from the US reported similar facilitators in corridor walking, such as relative safety of being indoors, and the social incentive of meeting people in the corridors. Handrails were valued, as well as appropriate flooring, seating in corridors and adequate toilet arrangements. Public rooms needed to be thoughtfully placed to allow residents optimum access. Reported barriers to this activity were the lack of varied things to see compared with outside. Facilities with outdoor walking areas provided an opportunity to overcome this barrier providing the walking surfaces were adequate. Applicability: The findings from these studies are applicable to older adults in the UK and North America. The evidence reflected safety concerns that alter with changes through the life course such as ageing. Participants in this study were constricted by limited mobility that might not apply to some other populations. Social interaction is important for this population to prevent social exclusion. ## Evidence statement R2.ES13: Views of people from deprived areas about walking for travel or leisure (not related to an intervention) Moderate evidence from two studies suggests that the main barriers to walking for travel or leisure in people from deprived areas were safety, lack of time and lack of motivation. Women were constricted by perceived dangers from the external environment, family commitments, lack of motivation and lack of walking companions. There was evidence that participants were either out of the habit of walking, or that walking was enforced due to a lack of options. For men, walking was not sufficiently vigorous to be considered 'exercise'. Two studies assessed the views of populations from deprived groups. One (+) UK interview study reported that males did not associate walking with exercise as it is not strenuous enough. Women more often preferred to walk with someone else rather than alone, so walking with a friend, or children was an incentive. Walking with a dog was a motivator for men or women. Though health benefits such as weight management and reducing aggression or boredom were recognised by those that did maintain walking activities, there was a habit of not walking that needed to be broken. Lack of motivation, other commitments, lack of time and bad weather were all barriers to continuing walking. A (+) UK interview study examined the experiences of women without access to a car and reported feelings of social exclusion due to having to walk in neglected areas and often with very young children, who were tired. Women often had to walk long distances to shops, and feared for their children's safety at busy roads. Applicability: The findings from these studies are applicable to people living in deprived areas in the UK. The evidence reflected safety concerns associated with perceived environmental dangers. Participants in this study were constricted by reduced options that might not apply to some other populations. Social interaction is important for this population to increase the feeling of safety, particularly for women. There were also specific gender differences in perceptions of walking for fitness. ## Evidence statement R2.ES15: Views about barriers and facilitators to active travel to school (walking and/or cycling for transport) Moderate evidence from nine studies suggested that the main facilitators to active travel included the social aspect of walking and spending time with friends, or having quality time with parents. Barriers for schoolchildren contemplating active travel to and from school were parental and children's lack of time and dangers from traffic and from intimidation or attack by other people. The missed opportunity by schools to develop children's existing awareness, and displaying conflicting messages was also a barrier. Peer pressure was an important factor for this age group in terms of choices. Other reported barriers included distance, carrying heavy bags, and poor weather conditions. Parental habits and commitments as well as fears for their children's safety were also influential on decisions about walking. Barriers to cycling for children included a lack of cycle lanes and a lack of facilities to store bicycles. The perceived image of cycling, and a dislike of wearing cycling helmets was also reported to be a barrier. Three studies (one focus groups, UK; one focus groups, US; and one survey and interviews, UK) identified recognition in parents and children that walking or cycling would be beneficial to health and could increase a child's confidence and sense of independence around roads. In addition, two studies, (one focus groups, UK) reported that walking with a parent provided valuable time together. Spending time with friends was an important social aspect for older children. However, barriers to walking or cycling included lack of time; parents often needed to accompany children to different schools and arrive at their place of work in time. Children and parents would need to get out of bed much earlier in the morning in order to fit in walking. Laziness was reported as a reason for not using active travel. Peer pressure and the trend toward car ownership was a factor, particularly for cycling, which for some groups was socially unacceptable. Schools may also miss opportunities to develop children's knowledge about sustainable transport choices. A US (+) survey and an Australian (+) survey found that among children that did not walk to school, distance was the most commonly reported barrier, followed by traffic danger. Parents restricted their children to playing close to home on their bicycles (one focus groups, UK). Children having to carry heavy bags of books and equipment was a barrier to both walking and cycling, as were bad weather, dark mornings and hilly terrain. For older children who travel without an adult, there were fears for personal safety, of accidents and abductions, of strangers and bullies and of busy traffic. Environmental factors such as poor lighting, secluded areas or woodland on the journey exacerbated these fears. A (+) survey from Australia showed that parental perceptions were a factor in decisions to walk. These included parents own physical activity habits, parental working schedules, and parental concerns about safety. Having to attend out-of-school activities was also a factor. Cycling was associated with particular barriers, such as lack of cycle lanes, and general support for cycling at school such as provision to store bicycles and helmets. Fear of having a bicycle stolen was a disincentive. The image that cycling conveyed was an issue for some. For teenage girls, cycling was perceived as childish. For children that did cycle, the 'coolest' bike was required, and cycling helmets were regarded as 'uncool' (one action research, Australia), lacking in style and fit, with consequences such as negative comments from others. In addition, cycling impacted on personal appearance; for example, cycling helmets dishevelled one's hair. Applicability: The findings from these studies are partially applicable as the findings are specific to schoolchildren. While some barriers and facilitators to active travel are applicable to any population, schoolchildren and their parents face particular issues pertaining to safety and practicalities for children. Some barriers differ by age group and gender. ## Evidence statement R2.ES16: Suggestions for strategies to encourage active travel to school (walking and/or cycling for transport) Moderate evidence from five studies provided suggestions for strategies that might encourage safe active travel in schoolchildren. Suggested strategies included environmental improvements to increase safety, changing attitudes to car use, school-based campaigns to assist in cycling skills and awareness, and personal-level encouragement by provision of storage facilities and better design of cycling helmets. Suggested strategies that may overcome some of the reported barriers included employing crossing patrols near to schools (one focus groups, US), escort schemes, traffic calming schemes, and pedestrian training (one focus groups, UK). A (+) survey from the UK reported that modifying attitudes to car-centredness would be a useful policy; more so than promoting general environmental awareness. To reduce cycling accidents, improved cycle paths and compulsory helmet wearing was suggested in one (+) study (action research, Australia). Other suggestions included schools organising walking and cycling groups, providing training in cycling proficiency, and support such as storage for wet clothes and bicycles (one focus groups, UK). Improved design of cycling helmets might impact on their use and on cycling behaviour by children. Applicability: The findings from these studies are partially applicable as the findings are specific to schoolchildren. While some suggestions to encourage active travel are applicable to any population, schoolchildren and their parents face particular issues pertaining to safety and practicalities for this age group. ## Evidence statement R2.ES18: Adult views about cycling for transport Moderate evidence from five studies was available regarding barriers and facilitators to adult cycling for transport. Benefits of cycling for transport were reported motivators, such as the ability to travel relatively quickly through traffic, the feeling of autonomy and freedom, and benefits for health and the environment. Cycling rather than driving could be encouraged by workplace initiatives. Barriers to cycling were reported such as obstacles in the road, pollution and poor weather. Carrying bags and changes of clothing required after getting wet were also reported disincentives. Cycling for transport requires negotiating space on the road; major barriers were traffic volume, inconsiderate driving and lack of adequate cycling tracks. Some cycling behaviours were perceived as inappropriate by some other road users, giving cyclists a poor image and limited relationship with drivers. Cycling was perceived as male, white and middle class. There was evidence that resistance to this image from female cyclists includes adopting and disseminating ideas for a feminine cycling image. Reported benefits from commuting by bicycle included swiftness of travel through busy traffic, not having to rely on public transport, and improved fitness (for men) or body shape (for women). An additional factor was reassurance that the environment is being protected (one interviews, UK). Parents were reported to drive less to work when cycling was encouraged by their workplace (one survey, Australia). However, cyclists in the city report a number of obstacles that can interrupt the journey, such as poor road surfaces, manhole covers, glass, rough gutters, hilly terrain, parked cars and buses. In addition, pollution and bad weather can be a disincentive (one interviews, UK; one survey and interviews, UK). A (+) survey from Australia reported that women cyclists preferred off-road paths compared to roads with no facilities, and off-road paths compared to on-road lanes. Commuting by cycle often involved carrying extra clothes to work and extra time at work to get changed from cycling outfits to work attire, including re-styling hair after wearing a helmet. Lack of available facilities was a barrier to cycling, as were saddle-soreness and tiredness. Cycling on the road also requires negotiation with other road users. Cyclists reported fears of traffic and of accidents which meant having to be constantly alert for other traffic in order not to collide, and feeling vulnerable when crossing traffic to turn right. Cyclists reported feeling segregated and invisible on the road. In areas where cycling is traditionally less prominent, there was a 'strangeness' about cycling, which was internalised by cyclists. There was also a perception that cycling is a male (predominantly white) activity, and some women felt the need to construct their own cycling identity, which could mean resisting the 'blokey' image and embracing femininity (for example, wearing heels while cycling; using blogs to reinforce identity). Applicability: The findings from these studies are applicable to cyclists who commute in the UK and Australia. Differences in experiences between cycling populations (gender, ethnicity etc.) and between settings in their promotion and support of cycling need to be taken into account. ## Evidence statement R2.ES19: Views about cycling identities Moderate evidence from one (+) UK focus groups and interviews study that obtained car driver views of adult cycling identities. Cycling for transport requires negotiating space on the road. Some cycling behaviours were perceived as inappropriate by some other road users, giving cyclists a poor image and limited relationship with drivers. Car drivers reported being fearful of collisions, since cars and cycles travel at different speeds, and gave cyclists a wide berth. Some cyclists were reported as behaving poorly on the roads, for example passing through red lights, and this contributed for some, to cyclists having a negative image. Drivers that cycled were more likely to have empathy with cyclists on the road. Cycling proficiency testing, road taxes and compulsory helmet wearing were suggestions for improving the status of cyclists on the road. Applicability: Findings from this study are applicable to car drivers in the UK. How cyclists are perceived by other road users and the impact that this may have for cyclists needs to be taken into account. ## Evidence statement EM.ES1: Led walking including 'walking school bus' Moderate evidence from four studies suggests that led walking interventions (seven different interventions analysed in four studies) could be cost effective. A Spanish study: 6-month programme to promote walking-based exercise via a supervised exercise programme with three 50-minute sessions per week. Incremental cost per QALY range of €94– 871 per QALY. A US study: community-based social support strategies, including organised walking groups, home visits and phone calls, and newsletters, maps and handouts. Incremental cost per QALY of $27,373 and $39,690 for the two different led walking interventions versus do nothing. A UK study: organised community walking groups. The two organised walking group interventions showed a cost per QALY of £301 and £475. Another UK study:walking bus intervention designed to encourage schoolchildren to walk to school. Incremental cost per QALY estimated to be approx. £4007 per QALY gained. The evidence is partially applicable to the UK, with two of the studies UK-based, and the other international studies concerning interventions that could be of UK relevance. ## Evidence statement EM.ES2: Pedometers Moderate evidence from one Australian study suggests pedometer interventions could be cost effective: pedometer interventions, which used a meta-analysis of eight randomised control trials. Pedometer interventions maintained a net saving even when the intervention effect was modelled to decay completely by the end of the first year. That is, the modelled lifetime cost savings to the health service outweighed the pedometer costs as well as providing health benefits. The evidence is partially applicable to the UK as similar pedometer interventions are of relevance. ## Evidence statement EM.ES3: Media campaigns Moderate evidence from one UK study suggests media campaigns could be cost-effective: media campaigns circulating maps of walking and cycling routes. The cost-per-QALY of £86 for provision of a healthy living map with walking and cycling routes, and £288 for the promotion of walking and cycling through printed media. The evidence is applicable to the UK. ## Evidence statement EM.ES4: Community health information (TravelSmart) Moderate evidence from one Australian study suggests TravelSmart interventions could be cost-effective: TravelSmart intervention with individualised information to households on travel choices measuring change in the number of walking and cycling trips made per week. The TravelSmart programme resulted in a cost of $18,000 per disability-adjusted life year (DALY) assuming 50% decay per annum. The TravelSmart programme had net savings with annual decay rates of 0% and 25%, but costs rose to $41,000 per DALY at 75%, and $63,000 per DALY at 100% decay. The evidence is partially applicable to the UK as the TravelSmart style intervention is relevant in the UK. ## Evidence statement EM.ES5: Multi-component (Cycling Demonstration Towns) Moderate evidence from one UK study suggests that the Cycling Demonstration Towns projects have a good benefit/cost rate. The study: infrastructure measures such as the building of cycle paths, combined with a programme of education and marketing aimed at the general population. Benefits converted to monetary values and compared with the initial investment and running costs to produce a benefit–cost ratio. A range of 2.6–3.5 was given, reflecting the different approaches available for estimating accident and absenteeism benefits. Under all but the most pessimistic of scenarios considered, the benefit–cost ratio remained above one. The evidence on cycle demonstration town is directly applicable as it was conducted in the UK. # Additional evidence Expert paper 1 'Paving the way for everyday walking: 'Living Streets' interventions and public health' Expert paper 2 'Making walking and cycling normal: key findings from the understanding walking and cycling research project': Expert paper 3 'Programmes to promote cycling – evidence for NICE from CTC': Expert paper 4 'Evidence to NICE PDG walking and cycling: experience from Bristol City Council and cycling city (2008–2011)': Ed Plowden, Bristol City Council Expert paper 5 'Submission to the NICE programme development group on walking and cycling' Expert paper 6 'Effectiveness of interventions to increase cycling'. # Economic modelling Overall, all the interventions modelled were found to be highly cost effective, with each estimated to cost below £10,000 per quality-adjusted life years (QALYs) gained. The economic model was constructed to incorporate, where possible, data from the reviews of effectiveness and cost effectiveness. In addition, it built on the relationship between: physical activity and relative risk of mortality levels of walking and cycling and overall physical activity levels of walking and cycling and motorised travel (especially driving distance, but also driving time and number of trips). Four interventions were modelled: Two multi-component interventions (Cycling Demonstration Towns and SustainableTravel Towns). Personalised travel advice (TravelSmart). Use of pedometers. Community-based led walks. Health outcomes were expressed using QALYs gained and incremental net benefit (INB). Wider impacts (environmental and traffic-related outcomes) were based on a limited selection of environmental outcomes and the value of a statistical life, expressed in terms of environmental benefit-cost ratios. The ratios were calculated based on the framework used by the Department for Transport. It should be noted, that in the Department for Transport framework, most of the calculated benefits derived from health outcomes related to increased physical activity (up to 83%). However, health outcomes were excluded when calculating the environmental benefit-cost ratio, as they had been considered separately in a cost–utility analysis. Thus the results should be interpreted with caution. A series of 'what if' analyses was undertaken to determine if the level of cost is justified for interventions producing a particular level of effect. In addition, the trade-off between narrow interventions with large effects per person were compared with wider interventions leading to smaller effects per person. A number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions. The results of the modeling were non-linear. The key factors influencing outcome were: threshold cost, level of effects, decay in effects and costs related to initial effects. The specific scenarios considered and the full results can be found in 'Interventions to promote cycling and walking for recreational and travel purposes: Health economic and modelling report'.# Appendix D Gaps in the evidence The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below. . There is a lack of UK evidence on whether or not interventions to increase walking or cycling for transport or leisure result in a decrease or increase in participation in other types of physical activity. Evidence is needed for a range of groups within different community settings. . There is a lack of evidence on whether people who cycle or walk for recreational purposes, eventually adopt it as a form of transport. . There is a lack of evidence on the long-term health, social and environmental impact of short-term interventions to increase walking or cycling. Specifically, there is a lack of evidence on the impact of interventions to encourage walking, cycling or both, for a range of groups within different community settings. . There is a lack of evidence on whether it is effective and cost effective to support physically active travel as a segment of a longer journey. Specifically, it is not clear whether such support increases walking or cycling levels and, if it does, how this impacts on the environment. . There is a lack of UK evidence on whether differences in urban and rural settings and environments impact on the implementation and effectiveness of interventions to increase walking or cycling. Evidence is needed for a range of groups within different community settings. . There is a lack of evidence on the barriers to, and facilitators for, inter-sector and inter-agency collaboration to promote walking and cycling. Evidence is also needed on the interventions that could overcome any identified barriers. Barriers may include the working cultures of different professionals. . There is a lack of UK evidence on how effective and cost effective it is to address walking and cycling together or separately. Specifically, there is a lack of evidence on how combining interventions impacts on their effectiveness – and whether multiple interventions have a positive, synergistic effect. Evidence is needed for a range of groups within different community settings. . There is a lack of evidence on how people can be helped to make walking or cycling an habitual activity. Evidence is needed for a range of groups within different community settings. . There is a lack of UK evidence on the extent to which the provision of a free bus service impacts on walking levels. Evidence is needed for a range of groups within different community settings. . There is a lack of UK evidence on the impact that an individual's perception of distance has on their view of how viable cycling or walking is as a mode of transport. There is also a lack of evidence on what interventions can effectively change someone's perception of distance as a barrier to walking and cycling. Evidence is needed for a range of groups within different community settings. . There is a lack of UK evidence on the social constructs which act as barriers to, and facilitators for, the uptake of walking or cycling as a mode of transport. Evidence is needed for a range of groups within different communities. The Group made 5 recommendations for research into areas that it believes will be a priority for developing future guidance.# Appendix E Supporting documents Supporting documents include the following. Evidence reviews: Review 1: 'Systematic review and narrative synthesis of the effectiveness of local interventions to promote cycling and walking for recreational and travel purposes', and 'Evidence statements on the effectiveness of local interventions to promote cycling and walking for recreational and travel purposes' Review 2: 'Synthesis of evidence relating to barriers and facilitators to implementing interventions that promote cycling and walking, and to carrying out cycling and walking for recreational and travel purposes'. Economic modeling: 'Interventions to promote cycling and walking for recreational and travel purposes: Health economic and modelling report'. Expert papers: Expert paper 1 'Paving the way for everyday walking: Living Streets interventions and public health' Expert paper 2 'Making walking and cycling normal: key findings from the understanding walking and cycling research project' Expert paper 3 'Programmes to promote cycling – evidence for NICE from CTC' Expert paper 4 'Evidence to NICE PDG walking and cycling: experience from Bristol City Council and cycling city (2008–2011)' Expert paper 5 'Submission to the NICE programme development group on walking and cycling' Expert paper 6 'Effectiveness of interventions to increase cycling'.	{'What is this guidance about?': 'This guidance aims to set out how people can be encouraged to increase the amount they walk or cycle for travel or recreation purposes. This will help meet public health and other goals (for instance, to reduce traffic congestion, air pollution and greenhouse gas emissions). The recommendations cover:\n\npolicy and planning\n\nlocal programmes\n\nschools, workplaces and the NHS.\n\nThis guidance does not cover:\n\nEnvironmental changes to encourage walking or cycling. (see the NICE guideline on physical activity and the environment covers the physical infrastructure and planning needed to make non-motorised transport an easier option.)\n\nNational actions to support walking and cycling, such as fiscal measures and other policy interventions to alter the balance between active and motorised travel in terms of cost and convenience.\n\nMeasures to reduce the risk of unintentional injuries from walking and cycling. (See the NICE guideline on strategies to prevent unintentional injuries among under-15s.)\n\n# Who is this guidance for?\n\nThe guidance is for commissioners, managers and practitioners involved in physical activity promotion or who work in the environment, parks and leisure or transport planning sectors. They could be working in local authorities, the NHS and other organisations in the public, private, voluntary and community sectors. It is also aimed at:\n\nemployers\n\nestate managers\n\nhighways authorities\n\nthose involved in land use planning and development control\n\nprivate developers\n\npublic transport operators\n\nthose involved in carbon reduction or sustainability planning\n\nothers responsible for workplace travel, carbon reduction or sustainability plans.\n\nIn addition, it will be of interest to people who promote walking and cycling in an unpaid capacity, those who want to walk or cycle and other members of the public.', 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe guidance complements NICE guidance on physical activity and the environment.\n\nThe evidence statements underpinning the recommendations are listed in appendix C.\n\nThe Programme Development Group (PDG) considers that the recommended approaches are highly cost effective.\n\nSee also the recommendations for research, gaps in the evidence and the evidence reviews, supporting evidence statements and economic modelling report.\n\n# Background\n\nThis guidance considers walking and cycling as forms of transport, for example, to get to work, school or the shops. It also considers them as recreational activities, for example, as a means of exploring parks or the countryside.\n\nWalking and cycling are distinct activities which are likely to appeal to different segments of the population. A range of factors may be important in helping or restricting people from taking part. These will vary according to whether someone is walking or cycling for transport purposes, for recreation or to improve their health. Wherever the term 'walking and cycling' is used in this guidance, these variations should be kept in mind.\n\nIn the context of this guidance, walking and cycling includes the use of adapted cycles (such as trikes, tandems and handcycles), wheelchairs and similar mobility aids.\n\nThe action needed to increase levels of walking and cycling will vary according to people's local and personal circumstances. For instance, it will differ according to whether someone lives or works in an urban or rural area, the local traffic conditions and their perceptions of safety.\n\n'Local' may refer to an area defined by geography or for administrative purposes. It may comprise an area larger than that covered by a single local authority such as Greater London, Manchester or Merseyside. It may also refer to a housing estate, a small town or a village.\n\n# Benefits of walking and cycling\n\nIncreasing how much someone walks or cycles may increase their overall level of physical activity, leading to associated health benefits. These include:\n\nReducing the risk of coronary heart disease, stroke, cancer, obesity and type 2 diabetes.\n\nKeeping the musculoskeletal system healthy.\n\nPromoting mental wellbeing.\n\nAn increase in walking or cycling can also help:\n\nReduce car travel, leading to reductions in air pollution, carbon dioxide emissions and congestion.\n\nReduce road danger and noise.\n\nIncrease the number of people of all ages who are out on the streets, making public spaces seem more welcoming and providing opportunities for social interaction.\n\nProvide an opportunity for everyone, including people with an impairment, to participate in and enjoy the outdoor environment.\n\n# Encouraging people to walk and cycle\n\nEncouraging and enabling people to walk or cycle requires action on many fronts – and by many different sectors. A range of issues have to be addressed, including environmental, social, financial and personal factors.\n\nIn addition to the recommendations made in this (and related) NICE guidance, other measures are needed to tackle the wider influences on walking or cycling. This includes measures to reduce road dangers and to reallocate road space to create a more supportive environment (see the scope for further detail). Action in these areas is particularly important in tackling inequalities in health, including with regard to people with impairments.\n\n# Whose health will benefit?\n\nUnless otherwise stated, the recommendations will benefit everyone.\n\n# Policy and planning\n\n## Recommendation 1 High-level support from the health sector\n\nDirectors of public health.\n\nPublic health portfolio holders in local authorities.\n\nClinical commissioning groups.\n\nEnsure a senior member of the public health team is responsible for promoting walking and cycling. They should support coordinated, cross-sector working, for example, by ensuring programmes offered by different sectors complement rather than duplicate each other (see recommendation 2). The senior member should also ensure the recommendations in NICE's guideline on physical activity and the environment are implemented.\n\nEnsure the joint strategic needs assessment, the joint health and wellbeing strategy and other local needs assessments and strategies take into account opportunities to increase walking and cycling. They should also consider how impediments to walking and cycling can be addressed.\n\nEnsure walking and cycling are considered, alongside other interventions, when working to achieve specific health outcomes in relation to the local population (such as a reduction in the risk of cardiovascular disease, cancer, obesity and diabetes, or the promotion of mental wellbeing). These include outcomes identified through the joint strategic needs assessment process. Descriptions of the links between physical activity and health outcomes can be found in the Department of Health's start active, stay active.\n\nEnsure walking and cycling are included in chronic disease pathways.\n\nEnsure all relevant sectors contribute resources and funding to encourage and support people to walk and cycle.\n\nWhere appropriate, ensure walking and cycling are treated as separate activities which may require different approaches.\n\nEnsure walking and cycling projects are rigorously evaluated. This includes evaluating their impact on health inequalities.\n\nFor more on the role of the NHS in promoting walking and cycling, see recommendations 9 and 10.\n\n## Recommendation 2 Ensuring all relevant policies and plans consider walking and cycling\n\nLocal authorities, in particular, portfolio holders, lead members and directors responsible for:\n\n\n\nadult and older people's services\n\nchildren and young people's services\n\ncommunity safety\n\ncountryside management\n\ndisability\n\neducation\n\nenvironment\n\nhealth and wellbeing (including mental health)\n\nland use, planning and development control\n\nparks and leisure\n\nplanning (including district planning)\n\nregeneration and economic development\n\nsocial services\n\ntransport.\n\n\n\nNational parks authorities.\n\nIntegrated transport authorities.\n\nLocal enterprise partnerships.\n\nChief constables, police authorities and elected police commissioners.\n\nAgencies with an interest in walking and cycling.\n\nAgencies with an interest in health and wellbeing or that work with population groups such as older people or people with disabilities.\n\nEnsure local, high-level strategic policies and plans support and encourage both walking and cycling. This includes a commitment to invest sufficient resources to ensure more walking and cycling – and a recognition that this will benefit individuals and the wider community. Relevant policies and plans include those on:\n\n\n\nair quality\n\ncommunity safety\n\ndisability\n\neducation\n\nenvironment (including sustainability and carbon reduction)\n\nhealth and wellbeing\n\nhousing\n\nland use, planning and development control\n\nphysical activity\n\nregeneration and economic development\n\ntransport.\n\n\n\nEnsure the walking and cycling aspects of these plans are developed in conjunction with relevant voluntary and community organisations.\n\nEnsure strategies to promote walking and cycling address factors which influence activity at various levels – from policy down to the individual. This includes ensuring the recommendations in NICE's guideline on physical activity and the environment are implemented.\n\nAssess the impact of relevant policies and decisions on people's ability to walk and cycle. Where necessary, amend them to ensure support for walking and cycling.\n\nEnsure plans relevant to walking and cycling are implemented and evaluated. Further advice on evaluation can be found in the National Obesity Observatory guide to evaluation.\n\n# Local action\n\n## Recommendation 3 Developing programmes\n\nLocal authority directors and portfolio holders for:\n\n\n\ncountryside management\n\nenvironment (including sustainability)\n\nleisure services\n\nparks\n\npublic health\n\nregeneration and economic development\n\ntransport.\n\n\n\nPolice traffic officers and neighbourhood policing teams.\n\nDevelop coordinated, cross-sector programmes to promote walking and cycling for recreation as well as for transport purposes, based on a long-term vision of what is achievable and current best practice. Ensure the needs of all sections of the population are addressed. Incorporate public health goals to increase the prevalence of people cycling and walking, as well as the distance covered by those who already walk and cycle regularly.\n\nAim to shift attention away from focusing on individual risk factors and isolated, small-scale interventions and ensure programmes comprise an integrated package of measures, implemented by all relevant sectors and stakeholders. Where appropriate, they should link to existing national and local walking and cycling initiatives, and incorporate actions in specific settings, such as workplace or schools (see recommendations 8 and 9).\n\nEnsure walking and cycling programmes form a core part of local transport investment planning, on a continuing basis. In line with the Department for Transport's manual for streets and the Chartered Institution of Highways and Transportation's manual for streets 2 – wider application of the principles, pedestrians and cyclists should be considered before other user groups in the design process – this helps ensure that they are not provided for as an afterthought.\n\nDraw on data, including the transport and physical activity elements of the joint strategic needs assessment, to ensure programmes are based on an understanding of:\n\n\n\nthe local population and the journeys people take using all modes of transport (the aim is to assess the potential for a 'modal change' towards walking and cycling)\n\nthe opportunities available to increase people's level of walking and cycling, given the right circumstances\n\nthe behaviour and preferences of existing walkers and cyclists\n\nthe needs of people with impairments\n\ngeneral factors influencing people's behaviour such as their attitudes, existing habits, what motivates them and their barriers to change, taking into account the recommendations in NICE's guideline on behaviour change: general approaches.\n\n\n\nEnsure programmes address the behavioural and environmental factors that encourage or discourage people from walking and cycling. These include measures to reduce road danger or the perception of danger. (Environmental factors can be tackled by implementing NICE's guideline on physical activity and the environment.)\n\nEnsure local expertise is available so that programmes are based on a realistic understanding of the scale of changes needed to encourage the population to change its behaviour.\n\nEnsure programmes take account of recommendations on developing local and regional programmes (recommendations 13–18) in NICE's guideline on preventing cardiovascular disease, in particular those relating to the need for long-term action.\n\nEnsure programmes take account of the geography of the surrounding area (for instance, connections with neighbouring local authority areas), as well as local factors such as major road and rail routes, rivers and hills.\n\nEnsure programmes include communications strategies to publicise the available facilities (such as walking or cycle routes) and to motivate people to use them. Include information that people with impairments will require, such as where dropped kerbs are located, the location and design of barriers at access points to cycle paths, and where public transport links and disabled toilets can be found.\n\nEnsure programmes, including specific elements within them, are evaluated. Assess how much walking and cycling people are doing. Also assess the number of trips undertaken, using different modes of transport, by different groups within the local population. Where appropriate, control groups should be used. (See, for example, the National Obesity Observatory's evaluation tool.)\n\nUse an appropriate tool to establish the cost effectiveness of initiatives. For instance, use the World Health Organization's health economic assessment tool (HEAT) for cycling and walking.\n\nConsider providing specific support for people at a 'transition point' in their lives, for instance, when they are changing job, house or school. At these times people may be open to trying a new mode of transport or new types of recreation. Note: some people may be considering motorised transport, instead of walking or cycling – and support may be needed to help them maintain their active travel habits.\n\n## Recommendation 4 Personalised travel planning\n\nTransport planners.\n\nDirectors of public health.\n\nHelp those interested in changing their travel behaviour to make small, daily changes by commissioning personalised travel planning programmes. These should be based on current best practice (see the Department for Transport's making personal travel planning work: practitioners' guide). Staff running these programmes should:\n\nIdentify those willing to make changes, for example, people at transitional points in their life (such as when moving house, job or school).\n\nProvide people with information and help, such as tickets, maps, timetables and, if required, more support to make different travel choices. This includes people with impairments who may rely on wheelchairs or adapted cycles.\n\nConsider implementing NICE's guideline on physical activity and the environment to create a supportive environment to encourage and sustain walking or cycling.\n\n## Recommendation 5 Cycling programmes\n\nAdult and child disability services.\n\nClinical commissioning groups.\n\nLocal authority transport leads, transport planners and other transport department staff.\n\nLocal education services.\n\nOrganisations with an interest in cycling.\n\nPublic health practitioners.\n\nPublic transport operators.\n\nAddress infrastructure and planning issues that may discourage people from wanting to cycle. Take into account NICE's guidelines on physical activity and the environment and unintentional injuries on the road. For example, ensure local facilities and services are easily accessible by bicycle and make changes to existing roads, where necessary, to reduce traffic speeds.\n\nImplement town-wide programmes to promote cycling for both transport and recreational purposes. These should be linked to existing national and local initiatives. (Note: 'town-wide' in this case could include cities or suburban areas.) Programmes could include:\n\n\n\nprovision of information, including maps and route signing\n\nfun rides, recreational and sponsored group rides and school sports promotions\n\nuse of leisure routes on and off roads\n\nuse of off-road mountain bikes, BMX courses, circuits and parks\n\ncar-free events or days, virtual cycle races and links with cycle sports events\n\ncycle hire schemes\n\nintensive sessions in particular settings or aimed at particular groups, such as: 'Bike to work' weeks and workplace challenges; activities aimed at children and families (such as 'Bike it', 'Bike club' and other school programmes); and activities for people with impairments who may use specially adapted cycles\n\nactivities and campaigns to emphasise the benefits of cycling (including the health benefits, the reliability and ease of access to local facilities and services).\n\n\n\nEnsure programmes are based on an accepted theoretical framework for behaviour change and take into account NICE's guideline on behaviour change: general approaches. They should also be based on an understanding of the needs of existing and potential cyclists, including those with impairments (see recommendation 3).\n\nEnsure cycle parking and residential storage issues are addressed.\n\nEnsure travel by cycle and public transport is integrated to support longer journeys. This includes providing secure cycle parking at public transport sites as well as support to transport adapted cycles and tandems for people with disabilities.\n\nEnsure training is available for those who are interested in cycling, either as a form of transport or as a recreational activity. An example of a cycle training programme is the Department for Transport's bikeability.\n\nEnsure all training is sensitive to cultural issues, for instance, by providing women-only groups with female trainers, where appropriate. Also ensure it includes an understanding of the needs of people with impairments\n\nConsider providing free cycle safety checks (such as Dr Bike sessions) and cycle maintenance training.\n\nUse local media to publicise activities and to clarify the links between different elements of the programme (for instance, the programme may include the provision of maps, local cycling classes and local challenges and events). In addition, use local media to raise awareness of any new or improved infrastructure. Also provide success stories from different elements of the programme to create momentum.\n\n## Recommendation 6 Walking: community-wide programmes\n\nAdult and child disability services.\n\nClinical commissioning groups.\n\nLocal transport leads, transport planners and other transport department staff.\n\nLocal authority leisure services.\n\nOrganisations with an interest in walking.\n\nPublic health practitioners.\n\nAddress infrastructure issues that may discourage people from walking, for example, motor traffic volume and speed, lack of convenient road crossings, poorly maintained footways or lack of dropped kerbs, where needed. Take into account NICE's guidelines on physical activity and the environment and unintentional injuries on the road.\n\nDevelop walking programmes for adults who are not active enough, based on an accepted theoretical framework for behaviour change and taking into account NICE's guideline on behaviour change: general approaches. Ensure groups that are likely to be the least active are encouraged to participate, by addressing issues that may act as a barrier.\n\nEnsure walking programmes for all adults link to existing national and local walking initiatives.\n\nEnsure all programmes address safety, cultural and disability issues.\n\nEnsure all programmes offer a variety of routes, paces and distances at different times of the day (including evenings and on different days of the week or at the weekend). Local people with different preferences, time constraints and physical abilities should all be able to participate. Programmes could include:\n\n\n\ncommunity-wide events, such as mass participation walking groups, community challenges and 'walkathons'\n\nwalks led by suitably trained walk leaders (paid or voluntary) and aimed at people who are currently inactive.\n\n\n\nEnsure walking routes are integrated with accessible public transport links to support longer journeys. Signage should give details of the distance and/or walking time, in both directions, between public transport facilities and key destinations.\n\nProvide information tailored for individuals who want to go walking without joining a group or club. Offer continued support in line with recommendation 7.\n\nDevelop and implement a publicity strategy to let the local community know about the walking routes and events and how accessible they are.\n\nProvide support to help people who have started walking as a leisure activity to also consider walking as a means of transport.\n\n## Recommendation 7 Walking: individual support, including the use of pedometers\n\nAdult and child disability services.\n\nClinical commissioning groups.\n\nDirectors of public health and public health specialists with responsibility for physical activity.\n\nLocal authority leisure services.\n\nOrganisations with an interest in walking.\n\nEnsure individual support is available for anyone who is walking on their own, walking informally with others in a group, or participating in local walking programmes. This includes helping to assess their activity levels and to set goals which build on this. The aim should be to increase the distance walked gradually, rather than providing them with a set target to aim for.\n\nEnsure additional, one-to-one support is offered at regular intervals to help people develop a long-term walking habit. This could be provided face-to-face, via the telephone or by using print-based materials, email, the Internet or text messaging. The support could include:\n\n\n\nindividual, targeted information\n\ngoal-setting (which may or may not include the use of pedometers), monitoring and feedback.\n\n\n\nProvide general information including:\n\n\n\nmaps, signs and other details about walking routes\n\nhow to visit places of interest on foot (such as shops, educational or recreational facilities)\n\ndetails on surface quality and accessibility.\n\n\n\nOnly use pedometers as part of a package which includes support to set realistic goals (whereby the number of steps taken is gradually increased), monitoring and feedback.\n\n# Schools, workplaces and the NHS\n\n## Recommendation 8 Schools\n\nPupils, siblings, their parents and carers.\n\nSchool staff.\n\nVisitors to schools.\n\nHead teachers and school governors.\n\nLocal authority PHSE coordinators, school travel advisers and transport planners.\n\nPolice traffic officers and neighbourhood policing teams.\n\nRoad danger reduction and/or road safety officers.\n\nFoster a culture that supports physically active travel for journeys to school (for all staff, parents and students) and during the school day. For example, promote the health benefits of cycling and walking and provide sufficient, secure cycle parking. Also ensure it is easy to get into the school grounds by foot or by bike. In addition, schools should provide suitable cycle and road safety training for all pupils.\n\nDevelop and implement school travel plans that encourage children to walk or cycle all or part of the way to school, including children with limited mobility. Integrate these plans with those produced by other local schools and other travel plans available for the local community. Involve pupils in the development and implementation of plans.\n\nMap safe routes to school and to local play and leisure facilities, taking into account the views of pupils, parents and carers. Also consult with the local community, including people with expertise in accessibility issues (such as those with mobility difficulties or community groups that work with them).\n\nDevelop programmes to ensure the local environment around schools and the nearby catchment area provide opportunities for all children to cycle or walk. This should include addressing motor vehicle speed, parking and dangerous driving practices.\n\nIntroduce regular 'walking buses' and other activities, such as 'Walk once a week' projects, which support and encourage walking and cycling to school.\n\nSet performance targets for school travel plans which are audited annually and which form part of delivery plans. Remedial action should be taken when agreed targets are not reached.\n\nEnsure all children can take part in Department for Transport's bikeability training. Ensure cycle training is age-appropriate and timed to allow cycling to school to become a habit. In addition, ensure it is appropriate for those with limited mobility who may need additional support.\n\nSchools should develop parents' and carers' awareness of the wider benefits of walking and cycling and other physically active modes of travel. For example, they should explain how it can improve children and young people's movement skills, social wellbeing, self-confidence and independence. They should also explain how it can help children to explore and become more familiar (and at ease) with their local environment while, at the same time, being physically active.\n\nHead teachers should identify a walking or cycling champion (or champions) with sufficient senior support to coordinate activities. The champion/s should liaise with the local authority and other potential partners to address any environmental or organisational barriers to walking and cycling to school.\n\n## Recommendation 9 Workplaces\n\nStaff and others who use workplaces.\n\nEmployers, including the NHS and local authorities.\n\nDirectors and senior staff including managers, health and safety staff, estates managers and human resources professionals.\n\nActive travel champions.\n\nDevelop strategies in consultation with staff (and other relevant stakeholders, for example, students in universities and colleges) to promote walking and cycling in and around the workplace. Ensure activities are developed in line with wider local activities (see recommendations 2, 3 and 4) and are linked to existing national and local initiatives.\n\nLiaise with local authority transport departments, neighbouring businesses and other partners to improve walking and cycling access to workplace sites. (Also see NICE's guidelines on physical activity and the environment and physical activity in the workplace.)\n\nIdentify an 'active travel champion' (or champions) within the workplace, at a sufficiently senior level. They should coordinate activities such as led and informal walking groups, workplace 'challenges' and promotional competitions (for example, using pedometers), bicycle user groups and walking interest groups. The active travel champion/s should also develop (or promote) schemes that give staff access to a pool of bicycles for short-distance business travel, or access to discounted cycle purchases (such as cycle to work schemes).\n\nEnsure workplace walking and cycling programmes are developed using an evidence-based theoretical model of behaviour change (see NICE's guideline on behaviour change: general approaches).\n\nProvide information tailored for the specific workplace on walking and cycling routes and circuits. This should include details on the distances involved, maps, routes and safety information.\n\nSee the NICE guideline on physical activity in the workplace for further recommendations.\n\n## Recommendation 10 NHS\n\nClinical commissioning groups.\n\nNational commissioning board.\n\nPrimary and secondary healthcare professionals.\n\nIncorporate information on walking and cycling into all physical activity advice given by health professionals. (See also NICE's guidelines on physical activity: brief advice for adults in primary care\xa0and exercise referral schemes to promote physical activity.)\n\nEnsure walking and cycling are among the options provided by the Let's get moving physical activity care pathway.\n\nEnsure people who express an interest in walking or cycling as a way of being more physically active are given information about appropriate national and local initiatives. Also provide individual support and follow-up (see recommendation 7).\n\nDirect people with limited mobility to specialist centres where adapted equipment, assessment and training are available for walking and cycling.\n\nEnsure walking and cycling programmes link to existing national and local initiatives.\n\nFor more on the role of the NHS in promoting walking and cycling, see also recommendations 1 and 9.", 'Public health need and practice': "# Introduction\n\nPhysical activity is essential for good health. It can help reduce the risk of coronary heart disease, stroke, cancer, obesity and type 2 diabetes (Chief Medical Officers of England, Scotland, Wales and Northern Ireland 2011). It also helps keep the musculoskeletal system healthy and promotes mental wellbeing.\n\nAs well as a direct benefit from physical activity, walking and cycling offer pleasure, independence and exposure to outdoor environments. These benefits may be particularly significant for people with disabilities whose participation in other activities may be more restricted.\n\nNew national physical activity guidelines were issued in 2011 (Chief Medical Officers of England, Scotland, Wales and Northern Ireland 2011) for: the under-5s, those aged 5–18, adults aged from 19–64 and for those aged 65 plus. Key points include the need to:\n\nbe physically active at all ages\n\nbe flexible (combining moderate and vigorous-intensity activity can be effective)\n\nparticipate in daily activity\n\nminimise sedentary behaviour\n\nconsider strength and balance activities for adults and older adults.\n\nDepending on factors such as speed and the terrain, walking and cycling can both be moderate or vigorous activities. Moderate intensity activities will make the participant breathe faster, experience an increase in heart rate and feel warmer. They may sweat on hot or humid days. The amount of activity needed to reach this varies from one person to another.\n\n# Physical activity levels in England\n\nBased on self-reporting, 61% of men (71% of women) in England aged 16 and over did not meet the national recommended physical activity levels (Craig et al. 2009). (These figures refer to the pre-2011 guidelines for physical activity; that is: adults should be active for at least 30 minutes at least five times a week at moderate intensity or greater.)\n\nThe proportion of men who are physically active enough decreases markedly as they get older (from 53% at age 16–24 to 16% at 65-plus). The level of activity among women was considerably lower once they reach 65-plus, from a lower base. (Around 12% of women over 65 met the recommended levels compared to 28–36% of younger women.) (Craig et al. 2009).\n\nBlack African and Asian adults and black Caribbean women were less likely to achieve the recommendations than the general population (Sproston and Mindell 2006).\n\nSixty three per cent of girls (72% of boys) aged between 2 and 15 report being physically active for 60 minutes or more on 7 days a week (girls' activity declines after the age of 10) (Craig and Shelton 2008).\n\nHowever, objective data suggest the above self-reporting data is an overestimate. Based on accelerometry, only 6% of men and 4% of women achieved at least 30 minutes of moderate or vigorous activity on at least 5 days (Craig et al. 2009). Only 2.5% (5.1% of boys and 0.4% of girls) actually did more than 60 minutes of moderate-to-vigorous physical activity daily (Riddoch et al. 2007).\n\nThere is a lack of information on the levels of physical activity among people with disabilities, although they are likely to be low for those with limited mobility.\n\nThe Chief Medical Officers' 2011 report notes: 'there is a clear causal relationship between the amount of physical activity people do and all-cause mortality. While increasing the activity levels of all adults who are not meeting the recommendations is important, targeting those adults who are significantly inactive (that is, engaging in less than 30 minutes of activity per week) will produce the greatest reduction in chronic disease' (Chief Medical Officers of England, Scotland, Wales, and Northern Ireland 2011).\n\n# Walking and cycling\n\nWalking is reported to be the most common – and cycling the fourth most common – recreational and sporting activity undertaken by adults in Britain (Fox and Rickards 2004). Walking (for any purpose) accounted for between 37% and 45% of the time that women of all ages spent doing moderate or vigorous-intensity physical activity. It also accounted for between 26% and 42% of the time devoted to such activities by men of all ages (Belanger et al. 2011). As a result, it is the most likely way all adults can achieve the recommended levels of physical activity.\n\nBicycles are used for around 2% of journeys in Britain – compared to about 26% in the Netherlands, 19% in Denmark and 5% in France (Ministry of Transport, Public Works and Water Management 2009). Yet of all trips made in Great Britain in 2009, 20% covered less than 1 mile and more than half (56%) of car journeys covered less than 5 miles (Department for Transport 2010a).\n\nIn England on average, 10% of adults cycle at least once a week (this figure varies from over 50% to less than 5% according to the area) (Department for Transport and Sport England 2012). On average, 11% of adults cycle for at least half an hour, at least once a month (again, this figure varies from 4% to 35% according to the area (Department for Transport and Sport England 2012). Today, on an average day in London, it is estimated that around 4.3 million trips are 'potentially cyclable' (Transport for London 2010).\n\nThe majority (85.8%) of adults claim they can ride a bicycle (around 92.9% of men and 79% of women) (Department for Culture Media and Sport 2011). However, the average time spent travelling on foot or by bicycle in Britain has decreased from 12.9 minutes per day in 1995/97 to 11 minutes per day in 2007 (Department for Transport 2010a). More starkly, the average distance walked, per person per year, has fallen from 255 miles in 1975/76 to 201 miles in 2006. Bicycle mileage for the same years fell from 51 to 39 miles per person per year (Department for Transport 2007).\n\n# Air pollution and climate change\n\nMotorised transport in urban areas of England is associated with poor air quality, congestion, collisions and physical inactivity – each costing society around £10 billion a year (Department for Transport 2009a). The cost of greenhouse gas emissions and the annoyance associated with noise are smaller, but still significant. In the case of greenhouse gases, costs are expected to rise sharply in future years (Department for Transport 2009a).\n\nExposure to air pollution is a significant cause of mortality in England. The House of Commons environmental audit report on air quality noted that: 'poor air quality reduces the life-expectancy of everyone in the UK by an average of 7 to 8 months and up to 50,000 people a year may die prematurely because of it' (House of Commons Environmental Audit Committee 2010).\n\nAir pollution is caused by a range of factors and people's exposure depends on the level of emissions, dispersion and other factors. Particulate matter, especially small particles less than 10 or 2.5\xa0microns (PM10 or PM2.5) in diameter, has a significant impact on health. Other significant pollutants include nitrogen oxides (NOx) and ozone.\n\nIndustrial sources produce a larger percentage of PM10 and NOx than road transport (46% and 30% respectively for NOx and 36% and 18% for PM10). However, road transport is responsible for up to 70% of air pollution in urban areas where most human exposure to air pollution occurs (House of Commons Environmental Audit Committee 2010).\n\nGreenhouse gas emissions from domestic transport in Great Britain stayed at the same level between 1990 and 2009 (around 120\xa0million tonnes of carbon dioxide equivalent [MtCO2e]; different gases have a different impact on the warming of the atmosphere so converting to MtCO2e enables a direct comparison of the impact of different gases or mixtures on the atmosphere). Over this period, an improvement in the fuel economy of new cars was offset by increases in mileage. At the same time, the overall emission of greenhouse gases from all sources in this country has decreased. As a result, as a percentage, the proportion from transport has increased from 16% to 22%. Ninety per cent of these emissions are from road transport (58% from cars and around 30% from heavy goods vehicles and light vans) (Department for Transport 2010a).\n\nThe transportation of goods and general travel in urban areas accounts for around 20% of the distance travelled by motor vehicle, but the contribution to air pollution and climate change is greater, because of driving conditions and frequent cold starts (Favez et al. 2009).\n\nClimate change, driven by human emissions of gases such as carbon dioxide, will lead to higher temperatures, more frequent extreme weather events, changes in rainfall and weather patterns, food and waterborne diseases and changes in distribution of vector-borne diseases. This will all have a significant impact on health in England (and globally). Changes associated with migration, following events such as flood or famine and higher levels of stress from extreme events are also likely to have a negative effect (World Health Organization 2009).\n\nReducing transport-related carbon emissions, by supporting a shift to walking and cycling, will help to address these adverse effects. It will also help ensure people are more physically active, so improving their health (Vardoulakis and Heaviside 2012).\n\n# Wider economic impacts\n\nThe wider economic impact of supporting walking and cycling are difficult to identify with certainty.\n\nExcess delays from traffic congestion in English urban areas are estimated to cost the economy around £10.9 billion a year (based on 2009 prices and values) (Department for Transport 2009a).\n\nA Living Streets report highlights that improvements to the walking environment can increase the economic value of, and economic activity within, an area. This can be reflected by the sale price of residential properties and the rental price of retail premises (Sinnett et al. 2011). The report points out that local retailers may overestimate the proportion of shoppers arriving by car (41% compared with the actual proportion of 22%, in a study in Bristol).\n\nTransport for London's 'Town centre study' (Transport for London 2011) found that people walking to a town centre spent an average of £93 per week there, compared with £56 for car drivers or passengers. Bus users spent £70 per week.", 'Considerations': "The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.\n\n# General\n\nThe PDG noted that encouraging people to walk or cycle for recreation purposes is different from encouraging them to walk or cycle as a mode of transport.\n\nThe PDG considered walking and cycling as two separate activities.\n\nMost people should be able to fit these activities into their daily lives and both are relatively cheap or may save money.\n\nThe PDG is aware of the volume of work and guidance available that is relevant to walking and cycling. It is also aware of the range of examples of good practice, both in this country and abroad. This guidance is intended to support, rather than replace that information.\n\nPeople with disabilities are less likely to be physically active and more likely to face barriers to being active than those without impairments. Many of this group can walk or cycle. However, they may require additional support, for example, involving specially adapted equipment or changes to the physical environment.\n\nThe PDG noted that local authority structures and roles vary across the country and that this will affect who has responsibility for specific actions. As a result, the recommendations tend to refer to general areas of responsibility, rather than to specific job titles. Similarly, as different administrative areas may produce plans on similar issues under a different title, the recommendations refer to generic plans.\n\nAchieving change is likely to be a long-term task and will involve participation by many professionals. This includes those working in local authorities and the NHS, as well as those working in communities (such as voluntary and faith sector organisations). The actions needed include those recommended in this and related NICE guidance.\n\nThe PDG noted that in the 'Cycle cities and towns' where cycling and walking had increased, the level of spending to encourage walking and cycling for transport purposes had been in the region of £5–10 per head per year. This had been maintained for a prolonged period. The PDG noted that this level of funding could be achieved by changing investment priorities within existing budgets rather than requiring additional funds.\n\n# Evidence\n\nEvidence related to walking and cycling comes from a number of different professional sectors, in particular, transport and health. Each sector has its own approach to research and evaluation which can lead to difficulties in identifying and interpreting the evidence.\n\nHealth sector evidence tends to involve controlling for as many factors as possible to help identify and explain any causal links between a given activity and health. While this provides greater certainty about cause and effect, it has tended to limit investigation to topics which lend themselves to this strict approach. Examples include promotional work with individuals to encourage them to walk or cycle, or within a limited setting, such as a school. Transport and other professional sectors are more likely to address population-level factors – and are more likely to have a range of outcomes or intentions in mind. For instance, both public health and transport professionals might have an interest in the benefits of cycling. However, the former might want to know how it impacts on levels of physical activity (and hence health), particularly among those who were previously inactive. Transport professionals, meanwhile, might want to know which particular journey would be cycled (and hence, the impact on motor traffic and congestion levels). They would tend to have less interest in who has changed their mode of transport. As a result, while both groups might have a legitimate interest in activities to increase cycling levels, the outcomes of evaluations might be different.\n\nThe PDG noted that different professionals have different reasons for wanting to encourage people to walk and cycle. For instance, transport professionals may aim to reduce the volume of motorised traffic (by identifying and influencing people who are most likely to move from motorised transport to cycling). From a public health point of view, the goal might be to encourage people who are currently inactive to take up walking or cycling in order to increase the amount of physical activity they do. While the 2 goals are very closely related (and can be complementary) they may focus on different groups and involve different approaches and outcomes.\n\nThe evidence identified was predominantly from an urban perspective, so rural issues are under-represented in the recommendations.\n\nIt is difficult to apply the findings of non-UK cycling studies to England because of the cultural and legal differences – and the fact that levels of cycling are considerably higher in many other countries. Equally, the value of findings from older literature may be of limited relevance because of the social and environmental changes that have since taken place.\n\nThere is evidence that interventions tailored to people's needs and aimed at either the most sedentary groups – or at those who are most motivated to change – can encourage people to walk more. Evidence showed that interventions could work if aimed at individuals, households or groups.\n\nEvidence showed that community-wide promotional activities, combined with an improved infrastructure, had the potential to increase cycling rates by modest amounts. Studies of marketing activities aimed at individuals reported a consistent, positive effect on cycling behaviour. However, the PDG noted that more robust study designs were needed to generate more detailed evidence of the best way to achieve this improvement. (For instance, detail is needed on whether the increases are sustained over time or are limited to certain subgroups such as young men.)\n\nPractical experience indicates that two particular factors play a key role in increasing walking and cycling rates: having a 'champion' who is committed to promoting walking or cycling, and effective local authority support.\n\nFour interventions, including two multi-component interventions (Cycling Demonstration Towns and Sustainable Travel Towns) were included in the economic modelling. Using cost per quality-adjusted life year (QALY) gained, the interventions were highly cost effective, even when the effect disappeared after year 1. The PDG noted that the key factors influencing the outcome of the economic model were: threshold cost, level of effects, decay in effects and costs related to initial effects. Members also noted the importance of offering the most appropriate interventions for different local settings and needs.\n\nData from a UK randomised control trial (RCT) were used to model the cost-effectiveness of led walks. The PDG raised concerns because the RCT showed no difference in effect between led walks and the provision of advice only. The results were not used for the recommendations. Using evidence from an evaluation of 'Get walking, keep walking', a large UK study, produced a cost per QALY of around £2700.\n\nIn addition to a cost–utility analysis, cost–benefit ratios were also calculated for environmental and traffic outcomes. These considered a range of benefits associated with increased walking or cycling and a consequent change in motor vehicle miles driven. The methodology was based on that used by the Department for Transport. However, health benefits (which account for most of the benefits calculated using the Department for Transport methodology) were not included, as these had been calculated in the cost–utility analysis.\n\nThe PDG recognised the importance of considering children. However the modelling did not consider under-18s due to a lack of direct evidence on children's behaviour in many of the studies.\n\n# Pedometers\n\nPedometers are cheap, effective and 'user-friendly'. The PDG noted that they may play an important role in helping people to walk more, provided they are used within a programme involving monitoring, support and goal setting. However, the PDG also noted that the use of set targets (such as 10,000 steps a day) was unlikely to be helpful if it did not take into account someone's current level of activity. In addition, some people may be put off if pedometers are used as part of a competition.\n\nThe PDG discussed the role of other technologies that might replicate pedometers, including mobile phone apps. While these may have a role to play in getting people to walk more, there is a lack of robust evidence to indicate whether or not they are effective.\n\n# Wider influences\n\nA wide range of factors influence whether or not people walk or cycle. Many were outside the scope of this guidance. In particular, the PDG noted that environmental factors such as the quality, accessibility and availability of walking and cycling networks are likely to be important. Other issues, such as the relative costs and convenience, are also likely to be significant. As a result, it recommended that this guidance should be implemented in conjunction with other related NICE recommendations, in particular NICE's guideline on physical activity and the environment.\n\nThe scope for this guidance included an adapted logic model (Sallis et al. 2006) which sets out local factors and interventions which can impact on walking and cycling rates. It demonstrates the conceptual link between local interventions targeting the physical or social environment (or individuals) and intermediate outcomes in relation to walking and cycling. These outcomes, in turn, link to impacts on health, the environment and other areas (such as the economy). The model also highlights how local policy, resources and other factors influence the effectiveness of local interventions to improve rates if walking and cycling. For example, a decision to use cycling as a form of transport can be influenced by the level and speed of motor traffic, attitudes to safety, the ability to plan and execute a route, and the ability to carry baggage. (Please note: although national factors such as legislation and fuel duty also have an important impact, these are not included here as they fall outside the scope of the guidance.)\n\nA number of legal issues differentiate England from parts of continental Europe, where levels of cycling are significantly higher. In parts of continental Europe, 'strict liability' means that pedestrians or cyclists injured in a collision involving a motor vehicle do not have to prove fault in seeking compensation. In addition, drivers have a civil responsibility to have insurance that will pay vulnerable victims independently of fault, while not changing criminal responsibility (see 'Expert paper 2'). Such legal requirements may act as an incentive for drivers to behave in a way that protects the most vulnerable road users.\n\nThe PDG noted that relatively few people in England cycle on a regular basis for transport purposes. This is not the case in other parts of Europe. For example, in Denmark and the Netherlands, it is considered the norm to use a bicycle for many journeys. Age is not necessarily a barrier. In the Netherlands, 26% of all journeys –and 19% of all the journeys made by people over 75 – are by bike (Ministry of Transport, Public Works and Water Management 2009). The PDG considered these examples as possible aspirational goals for England.\n\nThe PDG noted that moving towards the higher levels of cycle use seen in some Northern European countries is a process that will involve change over a prolonged period. It also noted that some of these changes are beyond the scope of this guidance. However, it felt that substantial public health benefits (such as increased levels of physical activity and reduced emissions of air pollutants) could be achieved as a result of such a process.\n\nThe PDG noted a range of issues which, if tackled in isolation, are unlikely to lead to a significant increase in walking or cycling. It also noted that tackling such issues could, nevertheless, provide a necessary foundation for interventions which will have a significant impact. For example, a key factor preventing people from walking and cycling is the danger as well as the perceived danger (including personal security fears) facing them on or near roads, paths or trails. The PDG discussed a range of measures that may help overcome this problem. These included:\n\nAwareness-raising of the comparatively low risks posed on the roads and contextualising these in terms of other risks (such as the potential risks caused by having a sedentary lifestyle).\n\nAwareness-raising among motorists and cyclists of the needs of pedestrians (for instance, the need to avoid causing a hazard by pavement parking).\n\nAwareness-raising among motorists of the needs of cyclists (for instance, by making motorists aware that they should give way, where appropriate, and should give cyclists a wide berth when overtaking them).\n\nAppropriate enforcement of road traffic law.\n\nThe potential role of engineering measures such as chicanes or raised junctions and 20\xa0mph limits in helping to restrict motor traffic speed.\n\nThe needs of children and older people (see NICE guidelines on strategies to prevent unintentional injuries among under-15s and unintentional injuries on the road)\n\nThe needs of people with mobility difficulties or other impairments which may increase their vulnerability on the road.\n\nAction to increase walking and cycling rates may reduce motor traffic volume and the PDG was concerned that the resulting benefits (of reduced congestion and reduced air pollution) should not be lost. For example, less traffic could lead to increases in vehicle speed, or may encourage some people to drive for journeys previously undertaken using other modes of transport. Members noted that action to ensure this does not happen could include a reallocation of road space or a reallocation of time at junctions to favour walkers or cyclists, or restricted motor vehicle access.\n\nLocal roads may act as a barrier to walking and cycling for children. Although it is not a panacea (addressing road conditions is vital), achieving 'Bikeability' level 3 would mean they could deal with all types of road conditions and more challenging traffic situations. This may be important, at least, for older children. The PDG noted that cycling off-road, where there is no exposure to motor vehicles may be appropriate for those who find road cycling too challenging.\n\n# Physical activity\n\nMost people can walk, including groups such as older people and those with some functional difficulties. While the majority of adults (85.8%) in the UK say they can ride a bicycle (Department of Culture, Media and Sport 2011), cycling as a means of transport is a minority activity. It accounts for a small percentage of all journeys – and for a small part of overall physical activity in this country. Nevertheless, 43% of adults own a bicycle and 14% use it at least monthly (Department for Transport 2009b). Cycling remains popular among children and young people, with 41% of those aged 5–16 years cycling at least weekly (Department for Transport: unpublished data 2012).\n\nIn London, an estimated 4.3 million trips a day (around two thirds taken by car, the remainder mainly by bus) could be cycled. For this survey, trips were assessed according to a set of criteria designed to reflect trips currently made by bicycle (Transport for London, 2010).\n\n# Inequalities\n\nOverall physical activity levels vary across the population (see section 2). This is also the case with specific activities, particularly cycling.\n\nMost adult cyclists in most areas of England are male. The highest number of cyclists are among people who are middle-aged. Black and minority ethnic groups cycle the least. Cycling participation is roughly equal across income quintiles but the biggest growth has come among the more wealthy.\n\nThe variation in levels of walking among groups in terms of gender, race or socioeconomic status is probably the smallest for any type of physical activity.\n\nPeople in households without a car walk, on average, 284 miles per year, compared to 176 miles per year walked by people in households with a car (Department for Transport 2010b). People who are most physically active do not necessarily walk or use a bicycle as a mode of transport. For some, the fact they have access to a car may have a positive influence on their physical activity levels.\n\nThe distance walked in Great Britain varies per person per year. In the quintile with the lowest household income, the distance walked is 223 miles, then it is 202, 182 and 177 miles respectively for people in the next 3 quintiles. In the quintile with the highest household income, people walk an average 201 miles per year. For cycling, the distance increases across the spectrum. Miles cycled per person per year is 32 in the lowest 2 quintiles, then 39, 49 and 77 miles respectively (Department for Transport 2010b).\n\nOne way of encouraging people to walk or cycle, as a form of transport, might be to apply greater levels of restraint on car usage in urban areas. This could be achieved, for instance, by introducing restricted parking and higher parking charges. However, there is a need to consider how this would impact on car owners living in areas where the environment is not conducive to walking or cycling, or where there is little real alternative to driving.\n\nThe guidance recommends an integrated package of measures which address a range of barriers to walking and cycling. It should be noted that reducing car use may have a beneficial influence on the environment by reducing traffic volume and air pollution and this may have a positive impact on the health of the whole population.\n\nThe PDG discussed the impacts that the recommendations may have on health inequalities. It acknowledged that those who are better off may have more opportunity to respond to the choices on offer. It also acknowledged that some transport interventions may deliberately target those most likely to change their mode of transport, rather than those who are least active. In addition, it noted that people with disabilities have specific needs. Taking these issues into account, the PDG emphasised that the recommendations should be accompanied by action to address factors such as a hostile and degraded environment, restricted access points, poor surfaces and the availability of disabled toilets. The Group also noted that some people with, for example, sensory or cognitive impairments, may need specially adapted equipment or information.\n\nInterventions which reduce motor traffic will reduce air pollution and road danger (assuming the benefits of a reduction in motorised traffic are 'locked in' and not accompanied by, for instance, an increase in traffic speeds). Planners may be reluctant to apply traffic reduction measures in one locality for fear of 'gridlock' on other, neighbouring roads. However, in most cases, the overall level of motorised traffic will be reduced. This is likely to have a positive impact on health inequalities because people from deprived groups, who are exposed to the greatest risks from air pollution and traffic injuries, are most likely to benefit. The very old and the very young, as well as those with pre-existing respiratory or circulatory problems, will also benefit from a reduction in overall exposure to air pollutants.\n\n# Barriers and facilitators\n\nWhen making transport choices, habit is important for most people, most of the time. Choosing to use a different mode of transport from usual is also likely to require more planning and thought. For instance, making a decision to start cycling might mean obtaining appropriate clothing, preparing the bike, route planning and allowing time for a trip of an unknown duration. The PDG noted that these factors are unlikely to remain as significant barriers once walking or cycling becomes the norm. For instance, both will usually involve reliable and more predictable journey times. Many journeys may be quicker, as well as being more healthy. There are also wider community benefits from reduced congestion and pollution.\n\nThe PDG noted that changing travel mode might require stopping old habits, such as using the car for short trips. Or it might involve an even more fundamental lifestyle choice, such as deciding to give up having a car altogether.\n\nThe PDG felt it was important that, where possible, health professionals (and others) set a positive example through their own behaviour in relation to walking and cycling.\n\nThe PDG noted that the times when someone has to reconsider their transport choices (such as when changing job or school, retiring or moving house) may offer important opportunities to influence their behaviour.\n\nDespite walking and cycling being different activities, sometimes they are grouped together. The PDG felt this was often unhelpful, as barriers and facilitators to walking and cycling vary – and, in turn, they differ according to whether the activity is chosen for transport or recreational purposes. They can also be specific to the purpose and location of the trip – and to the person undertaking it. Successful interventions to increase cycling and walking need to take into account this wide range of factors.\n\nWalking and cycling, like any form of transport, involve exposure to a certain level of risk. This includes the risk of injury from falls or from collisions and exposure to air pollution. These risks are not unique to transport involving physical activity. However, evidence shows that the health benefits of being more physically active outweigh these disbenefits.\n\nThe whole population benefits from less exposure to polluted air and congested streets when there is a general shift away from motorised vehicles.\n\nRisk of injury or collision is a key consideration when walking and cycling in places where there are other people. As well as the actual level of risk, perception of risk is important. The PDG noted that cyclists and pedestrians are more vulnerable in the event of a collision than those in a motor vehicle. At the same time, they are much less likely to cause injury in the event of a collision, due to their lower mass and lower speed of travel.\n\nThere is evidence to support the hypothesis (usually called 'safety in numbers') that areas where there are higher numbers of cyclists have better safety records than others. One of the reasons for this may be increased driver awareness of the likelihood of encountering a cyclist – and the fact that they modify their driving as a result.\n\nThe PDG concurred that transport planning could be a way to reduce road dangers for all users. These dangers relate to motorised traffic volumes and speeds. They are also caused by a lack of driver awareness of the risks of poor driving and the need to fully consider pedestrians and cyclists, including those with restricted mobility.\n\nAttitudes to walking and cycling are generally positive or neutral, with walking generally regarded more favourably. However, a combination of factors discourages people from taking up either if it is a question of choice, rather than necessity. These include:\n\nConcerns about the physical environment, in particular, with regard to perceptions of and actual safety. Motor traffic is a major deterrent for many cyclists (potential and current) and pedestrians in rural areas – and for children in all areas. Fear of violence or robbery is another deterrent. Many potential walkers restrict their journeys on foot because of their perception that empty streets, particularly at night, are dangerous.\n\nComplex household routines (especially for those with young children). For many people it is a combination of circumstances that prevent them from walking or cycling for everyday travel. These include: the logistics of organising and travelling with children, pressures of time and other commitments, and parental concerns about safety.\n\nThe perception that walking and cycling are not things to do as a matter of routine.\n\n# Wider impacts\n\nTraffic volume and speed act as barriers to walking and cycling (for recreation, as well as for transport purposes). The PDG noted that the level of motor traffic creates congestion which, in turn, imposes costs on the economy, through loss of productive time. Motor vehicles are also major contributors to air and noise pollution, as well as to carbon dioxide emissions.\n\nIncreasing the amount people walk or cycle, particularly in urban areas, results in a change in exposure to air pollution. Moving journeys from motorised transport to walking or cycling may alter individual exposure to air pollution, while reducing the total emissions of pollutants. Modelling by De Hartog et al. (2010) suggests that an individual's risk from increased exposure to air pollutants is modest in comparison with the benefits of them being more physically active. In addition, the overall decrease in air pollutant emissions benefits the health of the whole population. The PDG noted that a range of other potential benefits might accrue from a shift to physically active travel. These include reductions in road danger, noise, congestion and emissions of carbon dioxide. Walking and cycling can also benefit local communities by encouraging more people of all ages to be out on the streets, so making streets appear less threatening.\n\nPersonal exposure to air pollution is influenced by route choice. Routes which avoid busy roads may have much lower levels of air pollutants. This can be a much more significant influence on personal exposure than the mode of transport used.\n\nCost–utility calculations were based on the increased longevity associated with walking and cycling. They incorporate the effects of deaths from collisions. In addition, the economic modelling included an assessment of the cost–benefit ratios associated with environmental pollution and congestion. In most cases, interventions to promote walking and cycling led to greater benefits than costs, when considering their impact on congestion, infrastructure, collisions, local air quality, noise, greenhouse gases and indirect taxation. Costs associated with collisions were included, based on the expected reduction in car kilometres. Changes in levels of injury, based on changes in walking and cycling behaviour, are difficult to predict, partly because the relationship is not linear (see 3.50). Large increases in cycling and walking, especially if accompanied by interventions to increase safety, could reduce the absolute number of related accidents. As a result, the model did not include an additional modelled effect on injuries. Only for Cycling Demonstration Town interventions were the costs greater than the benefits. However, the modelling did not include the substantial benefits (likely to be in excess of 80% of the total) to be gained from reducing the range of health conditions associated with not being physically active enough. (These were calculated separately.)\n\nThe PDG agreed that both walking and cycling provide a wide range of health, social, environmental and economic benefits. Members also agreed that there is significant scope to increase the levels of walking and cycling in England – and that this would result in gains across society.", 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects.\n\nAll the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity.\n\n. How could existing guidance on evaluating complex, population-wide interventions be most usefully adapted and applied to approaches that aim to increase rates of walking and cycling? Issues to consider include: population-level health outcomes such as pollution emissions and exposure, the impact of an intervention on risk and danger and other, wider outcomes of interest such as the impact on the local economy. Approaches should be developed to take account of the backgrounds and needs of the different professional groups involved in helping to influence walking and cycling for transport or recreation. This includes professionals working in public health, transport, environment, economic development and regeneration.\n\n. What key factors influence the effectiveness of population-level or whole-area approaches to encouraging walking or cycling? How do these factors interact? (Specifically, how do infrastructure changes, promotion of these changes, promotion of walking and cycling generally, the provision of individual support and approaches in specific settings interact?) How does effectiveness vary between different geographical areas?\n\n. How do individual and local factors influence the effectiveness of specific approaches to encouraging walking or cycling? (This includes people's level and perception of risk, the degree of connectivity for cycling trips, and the local 'visibility' of cycling or walking as a mode of transport.) How do these factors interact with personal factors (such as willingness to try walking or cycling) and how do these personal factors influence effectiveness? In particular, do local factors influence the effectiveness of cycle training and personalised travel planning?\n\n. What key factors ensure people continue to walk or cycle in the long term (over a year)? How do individual interventions (such as follow-up or goal-setting) interact with environmental factors (such as distance, perception of danger or provision of facilities) in encouraging people to continue to walk or cycle?\n\n. What key factors influence differences in walking and cycling behaviour among different groups – and what are the implications for interventions aiming to achieve population-level change and reduce inequalities? This should take into account transport-related variables such as level of car ownership.\n\nSee also the detail on the gaps in the evidence identified during development of this guidance.", 'Glossary': "# Dr Bike\n\nGenerally, Dr Bike sessions are basic safety and maintenance checks provided free to the cyclist. They cover topics such as brakes, steering, mechanical integrity and the overall condition of the bicycle. Minor adjustments are carried out free of charge. Sessions may also include security marking, visibility and cycling tips. They may be provided by local authorities, cycling groups or employers.\n\n# Handcycles\n\nHandcycles are two or three-wheeled bikes powered by the arms rather than the legs. They come in a variety of styles which make them suitable for many people with disabilities.\n\n# Local enterprise partnerships\n\nLocal enterprise partnerships are led by local authorities and businesses. They provide the vision, knowledge and strategic leadership needed to drive sustainable private sector growth and job creation in their area.\n\n# Mode\n\nTransport mode refers to the form of transport used (such as by car, lorry, bicycle, public transport or on foot).\n\n# Moderate-intensity physical activity\n\nModerate-intensity physical activity requires a degree of effort and noticeably increases the heart rate. Examples include brisk walking, cycling and gardening.\n\n# Moderate-to-vigorous physical activity\n\nModerate-to-vigorous physical activity requires a large amount of effort, causes rapid breathing and a substantial increase in heart rate. Examples include running and climbing briskly up a hill.\n\n# Personalised travel planning\n\nPersonalised travel planning aims to encourage people to change their travel habits by providing them with detailed information on possible alternatives. People running these schemes provide individuals (usually across a specified geographical area) with information on, and encouragement to use, alternatives to a car for the trips they make.\n\n# Portfolio holder\n\nA portfolio holder is a local authority member with a specific responsibility delegated by the leader of the local authority.\n\n# Quality-adjusted life year (QALY)\n\nA quality-adjusted life year (QALY) is a measure used in health economics to assess the cost effectiveness of an intervention. It is defined as a measure of the state of health of a person or group in which the benefits, in terms of length of life, are adjusted to reflect the quality of life. One QALY is equal to 1\xa0year of life in perfect health.\n\n# Recommended level of physical activity\n\nThe Chief Medical Officers for England, Wales, Scotland and Northern Ireland Start active, stay active report sets out target levels of physical activity for different groups. For adults, the recommendation is that 'over a week, activity should add up to at least 150\xa0minutes (2½ hours) of moderate-intensity activity, in bouts of 10\xa0minutes or more (one way to approach this is to do 30\xa0minutes on at least 5\xa0days a week)'.\n\nFor children, the recommendation is that 'all children and young people should engage in moderate- to vigorous-intensity physical activity for at least 60\xa0minutes and up to several hours every day'.\n\n# Virtual cycle races\n\nThese are competitions where participants log the number of miles they have cycled on their own or as part of a team. The aim is to cycle a predetermined number of miles over a certain time. A target could be, for example, to cycle the number of miles it would take to travel from Lands End to John O'Groats.", 'References': "Belanger M, Townsend N, Foster C (2011) Age-related differences in physical activity profiles of English adults. Preventive Medicine 52: 247–9\n\nChief Medical Officers of England, Scotland, Wales and Northern Ireland (2011) Start active, stay active: a report on physical activity from the four home countries' Chief Medical Officers [online]\n\nCraig R, Shelton N (2008) Health survey for England 2007. Healthy lifestyles: knowledge, attitudes and behaviour. Leeds: The Information Centre for Health and Social Care\n\nCraig R, Mindell J, Hirani V (2009) Health survey for England 2008. London: The Information Centre for Health and Social Care\n\nDepartment for Culture, Media and Sport (2011) Taking part 2011/12 quarter 2. London: Department for Culture, Media and Sport\n\nDepartment for Transport (2007) National travel survey 2006. London: Department for Transport\n\nDepartment for Transport (2009a) The wider costs of transport in English urban areas in 2009. London: Department for Transport\n\nDepartment for Transport (2009b) National travel survey 2008. London: Department for Transport\n\nDepartment for Transport (2010a) Transport trends 2009. London: Department for Transport\n\nDepartment for Transport (2010b) National travel survey 2009. London: Department for Transport\n\nDepartment for Transport, Sport England (2012) Local area walking and cycling statistics: England 2010/11. London: Department for Transport\n\nDepartment of Health (2004) At least five a week. London: Department of Health\n\nFavez J, Weilenmann M, Stilli J (2009) Cold start extra emissions as a function of engine stop time: evolution over the last 10 years. Atmospheric Environment 43: 996–1007\n\nFox K, Rickards L (2004) Sport and leisure: results from the sport and leisure module of the 2002 general household survey. London: The Stationery Office\n\nHouse of Commons Environmental Audit Committee (2010) Air quality: fifth report of session 2009–10. London: The Stationery Office\n\nMinistry of Transport, Public Works and Water Management (2009) Cycling in the Netherlands. The Netherlands: Ministry of Transport, Public Works and Water Management\n\nRiddoch CJ, Mattocks C, Deere K et al. (2007) Objective measurement of levels and patterns of physical activity. Archives of Disease in Childhood 92: 963–9\n\nSinnett D, Williams K, Chatterjee K et al. (2011) Making the case for investment in the walking environment: a review of the evidence. London: Living Streets\n\nSproston K, Mindell J (Editors) (2006) Health survey for England 2004. The health of ethnic minorities. London: The Information Centre for Health and Social Care'.\n\nTransport for London (2010) Analysis of cycling potential. London: Transport for London\n\nTransport for London (2011) Town centre study 2011. London: Transport for London\n\nVardoulakis S, Heaviside C (Editors) (2012) Health effects of climate change in the UK 2012. Current evidence, recommendations and research gaps. Chilton: Health Protection Agency\n\nWorld Health Organization (2009) Climate change is affecting our health: Something should be done now. Geneva: World Health Organization", 'Appendix B Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews, primary research, expert testimony and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were:\n\nWhich local interventions are effective and cost effective at promoting and increasing cycling and walking for recreational and travel purposes?\n\nWhich local interventions are effective and cost effective at changing population-level norms and behaviour in relation to cycling and walking for recreational and travel purposes?\n\nWhat factors help or hinder the planning and delivery of walking and cycling-related interventions for recreation or travel purposes?\n\nWhat factors help or prevent people from walking and cycling for recreation or travel?\n\nWhat health and other outcomes may be achieved by increasing cycling and walking for travel and recreation?\n\nThese questions were made more specific for each review (see reviews for further details).\n\n# Reviewing the evidence\n\n## Effectiveness reviews\n\nOne review of effectiveness was conducted (review 1).\n\nA number of databases were searched in August 2011 for papers relating to walking and cycling published since 1990. See the review for details of the databases searched.\n\nIn addition, specific websites were examined and papers from stakeholders and members of the PDG were considered.\n\nStudies were included in the effectiveness review if they considered the impact of local interventions to raise awareness of, encourage or increase uptake of, walking and cycling for recreational and travel purposes.\n\nStudies were excluded if they covered:\n\nnational policy, fiscal or legislative changes\n\nlocal interventions which solely aimed to change the physical environment.\n\n## Other reviews\n\nA review of barriers and facilitators (review 2) was conducted.\n\nA number of databases were searched in August 2011 for papers relating to walking and cycling published since 1990. See the review for details of the databases searched.\n\nIn addition, specific websites were examined and papers from stakeholders and members of the PDG were considered.\n\n## Selection criteria\n\nStudies were included if they focused on interventions identified in the scope and addressed barriers and facilitators to walking and cycling.\n\nStudies were excluded if they focused on:\n\nNational policy, fiscal and legislative changes.\n\nLocal interventions which solely aimed to change the physical environment (such as traffic-calming measures, provision of cycle parking facilities or construction of cycle routes).\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nThe evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable).\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors/public health collaborating centres (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and an economic modelling exercise.\n\n## Review of economic evaluations\n\nStudies were identified by searching the NHS Economic Evaluation Database (NHSEED). An additional search was undertaken using an economics study filter.\n\nThe search focused on health economic studies that dealt with:\n\ninterventions to increase walking and/or cycling and reported relevant health-related outcomes\n\ncost–benefit analysis results studies which considered wider outcomes, including travel, congestion and pollution.\n\nSimplified search strategies were also used to search another economic specific database EconLit.\n\n## Economic modelling\n\nAn economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in: 'Walking and cycling: local measures to promote walking and cycling as forms of travel or recreation: health economic and modelling report'.\n\n# How the PDG formulated the recommendations\n\nAt its meetings in November 2011 and January, February and March 2012, the Programme Development Group (PDG) considered the evidence, expert reports and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nThe PDG noted that effectiveness can vary according to the context. For instance, geographical factors such as population density in rural or urban areas influence the likelihood of walking or cycling being a viable option for utility travel.\n\nWhere evidence was lacking, the PDG also considered whether a recommendation should only be implemented as part of a research programme.\n\nWhere possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).", 'Appendix C The evidence': "# Introduction\n\nThis appendix lists the evidence statements and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) Note: the evidence statements in review 1 (see appendix A for details of the evidence reviews) were amended by NICE and endorsed by the Programme Development Group (PDG). This appendix includes the amended evidence statements from review 1.\n\nAppendix C also lists six expert reports and their links to the recommendations and sets out a brief summary of findings from the economic analysis.\n\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document.\n\nEvidence statement number R1.ES1 indicates that the linked statement is numbered 1 in the document 'Evidence statements on the effectiveness of local interventions to promote cycling and walking for recreational and travel purposes'. Evidence statement numbered R2.ES1 indicates that the linked statement is numbered 1 in the document 'Synthesis of evidence relating to barriers and facilitators to implementing interventions that promote cycling and walking, and to carrying out cycling and walking for recreational and travel purposes'. Evidence statement EM.ES1 indicates that the linked statement is numbered 1 in 'Interventions to promote cycling and walking for recreational and travel purposes: Health economic and modelling report'\n\nThe reviews, expert reports and economic analysis are available online. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nWhere the PDG has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix.\n\nRecommendation 1: IDE; Additional evidence expert papers 2, 4, 6\n\nRecommendation 2: IDE; Additional evidence expert papers 2, 4, 6\n\nRecommendation 3: Evidence statements R1.ES5, R1.ES6, R1.ES7; Additional evidence expert papers 2, 4, 6\n\nRecommendation 4: Evidence statements R1.ES4, EM.ES4\n\nRecommendation 5: Evidence statements R1.ES3, R1.ES5, R1.ES6, R1.ES7, R1.ES9, R1.ES12, R1.ES19, R2.ES9, R2.ES15, R2.ES18, EM.ES3, EM.ES5; Additional evidence expert papers 2, 3, 4, 5, 6\n\nRecommendation 6: Evidence statements R1.ES1, R1.ES2, R1.ES7, R1.ES13, R1.ES18, R1.ES21, R1.ES22, R2.ES1, R2.ES2, R2.ES3, R2.ES5, R2.ES6, R2.ES10, R2.ES12, R2.ES13, EM.ES1, EM.ES3; Additional evidence expert papers 1, 5\n\nRecommendation 7: Evidence statements R1.ES13, R1.ES14, R1.ES18, R1.ES21, R1.ES22, R2.ES3, R2.ES13, EM.ES2; Additional evidence expert paper 5\n\nRecommendation 8: Evidence statements R1.ES8, R1.ES9, R1.ES10a, R1.ES10b, R1.ES10c, R2.ES15, R2.ES16, EM.ES1; Additional evidence expert paper 1\n\nRecommendation 9: Evidence statements R1.ES11, R1.ES15, R1.ES16, R1.ES17, R1.ES23, R2.ES2, R2.ES4, R2.ES7, R2.ES9, R2.ES18; Additional evidence expert papers 1, 3\n\nRecommendation 10: Evidence statements R1.ES20, R2.ES2, R2.ES4\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence review(s) to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement R1.ES1: Population-level change in mass-media interventions to increase walking\n\nThere was inconsistent evidence from two studies (both [+]) on the effectiveness of mass-media interventions (which included paid advertisements [TV, radio, cable, newspapers], billboards/posters, public relations, educational activities and community participation), delivered in the community in increasing population levels of walking for leisure or travel in adults up to 1 year post intervention. One before-and-after (BA) study showed no effect on walking (the reporting of data in this study was poor) and one cross-sectional (CS) study showed a small, but positive effect on walking.\n\nOne (+) BA study (UK n=3476, 12 months) – 40-second TV advert supported by a telephone helpline – showed no change in the number of days spent walking for at least 30 minutes: mean of 4.26 days in 1995 and 4.13 days in 1996, no significance statistics given.\n\nOne (+) CS study (USA n=297, 5 months) – billboard, newspaper, radio, and poster advertisements – showed that those exposed to the campaign were more likely to walk for at least 10 minutes on more days of the week than the control group (5.2 days versus 4.52 days t=2.34, p=0.02).\n\nPopulation-level evidence on mass-media interventions to increase walking is partially applicable to the UK as one study was conducted in the UK. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES2: Multi-component community-based interventions to promote walking\n\nThere was inconsistent evidence from six studies concerning the effectiveness of multi-component interventions on increasing population levels of walking for leisure or travel in the long term. Four non-randomised control studies (nRCT) papers (three [+] and one [++]) showed positive effects on walking and two nRCT papers (one [++] and one [+]) indicated that the interventions were not effective in increasing walking.\n\nOne (+) nRCT (Australia n=two wards, 2 years) – park modifications, media campaign, walking maps – showed that those in the intervention ward were more likely than those in the control ward to have walked in the 2 weeks prior to follow up (89.3% versus 81.0% respectively; X2=11.51, p=0.001), and within-ward analysis indicated that walking increased from baseline in the intervention ward (X2=5.85, p=0.016), but not in the control ward (X2=0.07, p=0.794). There was no difference in the number reaching adequate levels of physical activity (health department recommendations).\n\nOne (++) nRCT (USA n=1233, 12 months) – individually tailored newsletters, interpersonal activities that stressed social support, community-wide events such as walk-a-thons – showed that rates of 7-day walking for any purpose or for exercise declined slightly in the intervention communities compared with the comparison sites (-1.4\xa0min, p=0.91; and -5.6, p=0.37 respectively).\n\nOne (+) nRCT (USA n=1531, 12 months) as above found that the change in walking was higher in intervention (11.7\xa0minutes) than comparison (6.5\xa0minutes), although not statistically significant. Percentage of respondents who met the recommendation for walking was the same across the intervention and comparison areas: 22.2% and 21.6%, p=0.811.\n\nOne (+) nRCT (USA n=1472, 8 weeks) – paid advertising, public relations events to generate media coverage, public health educational activities at work sites, churches and local organisations – found a 23% increase in walking observations in the intervention community versus a 6% decrease in the comparison community (OR 1.31, 95% CI 1.14–1.50; p<0.0001).\n\nOne (++) nRCT (USA n=1472, 12 months) – paid advertisements (TV, radio, cable, newspapers), public relations and community participation – found that the least active group in the intervention population were more likely than control population to have increased daily walking (OR=1.72, 95%CI 1.01–2.95).\n\nOne (+) nRCT (USA n=4 communities, 8 weeks) – four interventions: Welch Walks (WW): paid media, media relations, community activities; Broome County (BC) walks (BC): WW components + website; Wheeling walks and West Virginia (WV) walks: BC components +12-week participatory planning, policy and environmental changes – found that 32% of insufficiently active persons in Wheeling Walks reported meeting the criteria for regular walking immediately post campaign compared to an 18% increase in the comparator community (OR=2.12, 95%CI 1.41–2.24). An increase in reaching regular walking was observed for the most sedentary group in WV walks (p<0.05). The intervention community in Welch walks demonstrated a twofold (OR=2.0 95%CI 1.01–3.97) gain in weekly walking by at least 30 minutes versus the comparison community. Forty one per cent of the BC walks intervention community increased walking by 30\xa0minutes per week compared to 30% in the control (OR=1.56 95%CI 1.07–2.28).\n\nThe population-level evidence on multi-component interventions to increase walking is only partially applicable to the UK as studies were conducted in the US and Australia. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES3: Population-level change in mass-media interventions to increase walking and cycling – Australia 'Walk to work day'\n\nModerate evidence from one BA study reported in two papers (both [+]) suggests that the mass-media campaign 'Australia walk to work day' (a collaborative annual event in which members of the public are encouraged to walk [or cycle] to work) may be effective in increasing population levels of walking and cycling for travel in adults up to 1 year post intervention. This intervention resulted in positive effects on both walking and cycling.\n\nOne (+) study (n=1100, at least 1 year) found that overall, total weekly minutes of moderate physical activity increased by 20\xa0minutes per week (t=4.76, p<0.005 with, an decrease in the proportion who were inactive -4.0% p<0.005). Significant population increase in total walk time (+16minutes per week t=2.04, p<0.05) in participants who were employed, and in minutes spent walking increased by 21\xa0minutes per week in 'passive commuters' (t = 2.42, p< 0.05).\n\nOne (+) study (n=1100, 2 months) found a significant population-level increase in health enhancing active commuting (3.9%, p=0.01).\n\nThe evidence on mass-media interventions to increase walking and cycling is only partially applicable to the UK as studies were conducted in Australia. The differing environment in Australia must be considered in reference to these studies. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES4: Population-level change in TravelSmart as an intervention to increase walking and cycling\n\nWeak evidence from a series of evaluation reports (ER) (both [+]) suggests that TravelSmart is effective in increasing population levels of walking and cycling for travel in adults (who volunteered to participate) at least over 1 year. TravelSmart uses 'Individualised travel marketing' (ITM) which aims to highlight travel choices 'people may not know they have' by providing locally relevant information and support to households. The evidence is moderate as the reports only present percentage change data and limited methodologies. The intervention targets individuals, but data is reported at population level.\n\nOne (+) evaluation report (Australia n=5 regions, various) found household projects routinely showed decreases in car use of 4–15% and rise in use of walking, cycling and public transport.\n\nOne (+) evaluation report (UK n=19 regions, various) found cycling for travel increased by between 14% and 69%, travel by walking increased between 9% and 29%, travel by car decreased at each site by between 10 and 14%, overall sustainable travel trips increased at each site (between 9% and 29%).\n\nThe evidence on this intervention to increase walking and cycling is fully applicable to the UK as most of the data reported is from UK sites. However, the differing environment in Australia must be considered in reference to the data collected there. Individual local contexts as well as the setting will also impact on the applicability of data from individual sites.\n\n## Evidence statement R1.ES5: Population-level change in cycle demonstration towns as interventions to increase cycling\n\nThere is moderate evidence indicating that cycling demonstration towns (CDT) (multi-component interventions to increase cycling in six towns) are effective in increasing population levels of cycling for active travel in the general population up to 10 years post intervention. One (-) ER, one (+) BA and one (+) interrupted time series (ITS) study showed positive effects on cycling in cycle demonstration towns, although the significance of the effects is not reported. See also R1.ES7 and R1.ES6.\n\nOne (+) ITS (UK n= six towns, 4 years) found automatic counter data indicated an average increase in cycles counted of 27%. Proportion of pupils cycling to school at least once a week increased from 12% pre-survey to 26% post-survey.\n\nOne (-) ER (UK n=6 towns, 10 years) found data from automatic cycle counts indicated a 12% increase overall in usage of cycle routes and up to 60% at specific sites (this report also uses data from other interventions).\n\nOne (+) BA (UK n=1500, 4 years) found the proportion of adult cycling for at least 30 minutes once or more per month increased from 11.8% in 2006 to 15.1% in 2008, an increase of 3.3%-points or 28%.\n\nThe evidence on cycle demonstration town is directly applicable as it was conducted in the UK.\n\n## Evidence statement R1.ES6: Population-level change in multi-component interventions to increase cycling\n\nWeak evidence from one (+) nRCT study suggests that multi-component interventions are not effective in increasing population levels of cycling in the general population up to 2 years post intervention, but may result in increased use of bicycle paths and increase in cycling among new/beginner cyclists. See also R1.ES5.\n\nOne (+) nRCT (n=909, 2 years) – multi-component community-based intervention including: organised bike rides and events, cycling skills courses, distribution of cycling maps of the area, local press coverage – found significantly greater use of the bicycle paths in the intervention area (28.3%) at follow-up compared with the comparison area (16.2%) p<0.001. No self-reported increase in residents who said they cycled in the last year, however, significantly more 'novice'/beginner riders had cycled in the last year in the intervention area (11.5% versus1.4% in the comparison area; p=0.013).\n\nThe population-level evidence on multi-component interventions to increase cycling is only partially applicable to the UK as the study was conducted in Australia. The differing environment in Australia must be considered in all studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES7: Population-level change in multi-component interventions to increase walking and cycling in adults\n\nWeak evidence from four (two [+], two [-]) of five studies indicates that multi-component interventions delivered in the community are effective in increasing population levels of walking and cycling for travel and/or leisure up to 9 years post-intervention. Evidence from the three BA, and one ITS, showed mostly positive effects of community interventions to encourage cycling and walking for travel and/or leisure. One (+) nRCT indicated that multi-component interventions may reduce a natural decline in walking in women and that among those with a low educational level, cycling may show a small increase. See also R1.ES5 and R1.ES6.\n\nOne (+) BA (Belgium n=438, 1 year) – physical activity promoted in the entire city of Ghent. Central theme of '10,000 steps/day', with secondary taglines of 'every step counts') and 'every revolution (of bicycle pedals) counts', pedometers given – found that 47.5% increased average step counts by 896 steps/day or more at 1-year follow-up (no statistical analysis; cycling was 'converted' to step counts).\n\nOne (-) BA (USA n=not reported, 12 months) – multi-component intervention to increase safe physical activity opportunities and encourage walking and biking for short trips – found the number of people seen using active transportation increased from 1028 in 2005 to 1853 in 2006 (63% increase). Walking to school more than doubled at three of four schools engaged for at least 2 years (no other analysis).\n\nOne (+) BA (UK n=at least 12,000, 4 years) – three 'Sustainable travel towns' which implemented intensive town-wide Smarter Choice Programmes to encourage use of non-car options; bus use, cycling and walking, and less single occupancy cars – found that cycle trips per head grew substantially in all three towns by 26–30%. Comparison towns cycle trips decreased. Walking trips per head grew substantially by 10–13% compared to a national decline in similar towns.\n\nOne (-) ITS (USA n=not reported, 1 year) – Project U-Turn, active transportation (biking, walking, and transit use) through an integrated approach to active living, ran for 5 years, targeting 36,000. City-wide count of people using active transport, showed an increase of 63% over 1 year, limited study details provided. Also had a major schools component and reported an increase in walking over time, no statistics given.\n\nOne (+) nRCT (Netherlands n=3114, 5 years) – community-based project with 790 lifestyle interventions, 361 were physical activity focused, example: printed guides of walking and cycling routes – found that there was a smaller decline in walking in women in the intervention compared to control region (-0.3\xa0hours/week versus -2.3\xa0hours/week; p≤0.05); and among those with a low education level there was a significant difference in change in cycling and walking in the intervention versus control region (0.2\xa0hours/week versus -0.3\xa0hours week respectively for cycling and 0.0\xa0hours/week versus -2.2 hours week for walking; both p≤0.05).\n\nThe population-level evidence on multi-component interventions to increase walking and cycling in adults is only partially applicable to the UK as one studies was conducted in the UK. The differing environment in the USA and Europe must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES8: Population-level change in multi-component interventions to increase walking and cycling in children\n\nInconsistent evidence from three studies on the effectiveness of school-based multi-component interventions to increase levels of walking and cycling for children. Evidence from two (+) BA studies showed positive effects on school population-level walking in children however evidence from one (++) cluster randomised control study (RCT) showed no effect on cycling and walking for school travel.\n\nOne (+) BA (UK n=179, 41 months) – school travel plan group developed a walking bus scheme, incentive scheme 'going for gold' included children cycling or scooting to school, also cycle training, pedestrian training, park and walk scheme, curriculum work, school assemblies and newsletters – found walking to school increased from 30% to 58.8%, cycling to school increased from 0– 4%.\n\nOne (++) cluster RCT (UK n=21 schools, 12 months) – multi-component school travel plans were developed by a school travel coordinator – found the proportion of children walking or cycling to school was not affected by the intervention.\n\nOne (+) BA (UK n=11 schools, up to approximately 18 months) – 'Safe routes to school'– identified and created safe routes to school, invites community-wide involvement, full-time educator employed to develop curriculum and volunteer team leader in each school – found an increase in number of school trips made by walking (64%) and biking (114%).\n\nThe population-level evidence on multi-component interventions to increase walking and cycling in children is applicable to the UK as all studies were conducted in the UK. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES9: School-based change in interventions to increase cycling in children\n\nWeak evidence from one (+) BA study suggests that school-based multi-component interventions may be effective in increasing school population levels of cycling in children. Evidence showed positive effects on walking at the school population level.\n\nThe study (UK n=52 schools, 1 year) – 'Bike it': school travel plans, cycling champions in schools to demonstrate to parents and pupils that cycling is a popular choice. Percentage of school pupils cycling to school every day increased from 3% to 10%. Number of pupils cycling at least once a week increased from 10% to 27%. Number of pupils who never cycled decreased from 80% to 55%.\n\nThe evidence on multi-component interventions to increase cycling in children is applicable in the UK as the study was carried out in the UK.\n\n## Evidence statement R1.ES10a: Walking school bus interventions to increase walking\n\nModerate evidence from three (+) BA studies and one (+) nRCT suggests that walking school bus interventions may be effective in increasing levels of walking at the school population level for children up to 30 months post-intervention.\n\nOne (+) BA (UK n=309, 14 months) – walking school buses supported by environmental interventions such as street lighting on walking routes – found that participants walking increased from 60% to 68.3%, 25% of that was due to walking buses.\n\nOne (+) nRCT (USA n=3 primary schools, follow up 6 months after baseline) – Walking School Bus (WSB). The school implemented three routes staffed by parent volunteers, and were compared to two nearby schools without a WSB – found that the number of children who walked to school increased from baseline to follow up by 25% (from 19–26%). Comparison schools showed a decrease in the proportion of children walking to school over the same period (no data given).\n\nOne (+) BA (UK n=64, 18–30 months) – walking buses at five schools. Information sent home to parents to encourage participation – found that there was an overall average increase of 513\xa0metres walked per day. For children that had previously walked to school the WSB resulted in an average increase of only 19\xa0metres/day, for those that previously travelled to school by a mixture of car and walking: average increase of 309\xa0metres/day and for those that previously regularly travelled by car to get to school: average increase of 1549\xa0metres/day (no statistical analyses reported). Participation in the walking buses declined over time.\n\nOne (+) nRCT (USA n=643, 12 months) – WSB run by a part-time coordinator and parent volunteers. The intervention included three routes which ranged from 0.3 to 1.5 miles and took 15–40 minutes. The WSB operated once or twice a week – found that higher proportions of students walked to the intervention (25% +/- 2%) versus the control schools (7% +/-1%: p<0.001). Significant increase in walking to school in intervention school from 20% (+/-2%) at baseline.\n\nThe evidence on school-based walking sessions to increase walking is partially applicable to the UK as two studies were conducted in the UK. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES10b: School-based interventions using pedometers to increase walking\n\nModerate evidence from one (+) cluster RCT and one (+) ITS suggests that school-based walking interventions which incorporate pedometers may be effective in increasing levels of walking at the school population level for children up to 12 weeks post intervention.\n\nOne (+) ITS (USA n=169, 6 weeks) – pedometers and a 'Fit bits' programme to implement physical activity breaks in the classroom – mean steps increased from 19,149 (95%CI 18,224–20,073) week 1 to 21,248 (95%CI 19,730-22,765) week 6 (p<0.001) found that overall, walking peaked at week 3; and younger students had a stronger response to the intervention.\n\nOne (+) cluster RCT (New Zealand n=85, 12 weeks) – physical activity self-monitoring and educative programme – the pedometer (PED) group set daily step targets, and the minutes (MIN) group set daily time based activity goals – found that both intervention groups had significant increase in steps between baseline and week 12 (p<0.001), no significant differences between time points for the control group (p=0.23).\n\nThe evidence on school-based walking sessions to increase walking is only partially applicable to the UK as studies were undertaken in the USA and New Zealand. The differing environments in these countries must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES10c: School-based walking session interventions to increase walking\n\nInconsistent evidence from five studies (reported in six papers) on the effectiveness of school-based walking session interventions in increasing levels of walking at the school population level for children up to 48 months post intervention. Evidence from one (+) nRCT and two (+) BA studies (reported in three papers) showed positive effects on school population walking. However one (+) nRCT showed no effect on walking and one (+) cluster RCT had conflicting evidence concerning the intervention effect on walking for school travel.\n\nOne (+) BA (UK n=585, 48 months) – 'Walk on Tuesday and Thursday' (WOTT) encouraged walking to school, included incentives – found that walking to school increased from 53.3% to 58.7% (percentages only reported). Also reported in a second (+) BA.\n\nOne (+) nRCT (UK n=60, 10 weeks) – school-based active travel project. Active travel was integrated into the curriculum, and participants used interactive travel planning resources at home – found that mean distance travelled to school by walking increased significantly more in the intervention (389%) than the control (17%: t=-4.679, p<0.001, 95% CI -315 to -795\xa0m).\n\nOne (+) nRCT (UK n=13 schools, 4 weeks) – interventions linked to national walk to school week – found no difference between intervention and control schools in walking before or after the intervention.\n\nOne (+) cluster RCT (Australia n=24 schools, 2 months) – health promoting schools policy: classroom activities, pedometer-based walking activities (some schools) development of school travel access guides, parent newsletters, and improving environments with local councils – found that, based on student survey data while both intervention and control groups increased walking by about 4% from baseline, there was no statistically significant difference in mean percentages of change in mode of transport to or from school from baseline to follow-up between the intervention and control groups (no data given).But parent survey data (n=807) indicated a significant increase in walking trips by students in the intervention compared to control schools (28.8% versus 19%, p=0.05).\n\nOne (+) BA (Australia n=234, 4 weeks) – classroom activities supported by a weekly newsletter to encourage walking to school – found the percentage of walking trips increased by 3.4% and car trips decreased by 3.4%.\n\nThe evidence on school-based walking sessions to increase walking is partially applicable to the UK as three studies were conducted in the UK. The differing environments in Australia must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES11: Population-level change in workplace-based interventions to increase independent walking and cycling\n\nWeak evidence from one (+) BA study and one (+) ITS indicates that multi-component interventions delivered in the workplace are effective in increasing population levels of walking and cycling\n\nOne (+) ITS (UK n=1850 to 2829 in each of four staff surveys, 9 years) – university transport plan: limiting the number of available parking spaces and permits, improving, installing secure cycle storage, subsidised cycle purchase scheme, car share scheme, free bus travel, and discounted season tickets – found that respondents who usually walked to work increased from 19 to 30% (Z=4.24, p<0.001) and regular cyclists increased from 7.0% to 11.8% (not significant).\n\nOne (+) BA (UK n=2240, 3 years) – Well@Work programmes which consisted of a diverse set of initiatives and actions aimed at promoting and supporting healthy lifestyles – found an increase of 9% in the proportion of employees participating in active travel (walking or cycling), significant increase in employees cycling (4%) or walking (8%) to work.\n\nThe population-level evidence on multi-component interventions to increase walking and cycling in adults is applicable to the UK as both studies were conducted in the UK. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES12: Individual-level change from participation event to increase cycling\n\nWeak evidence from one study suggests that a mass participation intervention may be effective in increasing individual-level cycling for leisure in adults. Evidence from one (+) BA study showed a positive effect on cycling 1 month after the intervention.\n\nOne (+) BA (Australia n=918, 2 months) – mass cycling event – found that participants with low pre-event self-reported cycling ability reported an average of four sessions of cycling in the month before the event and an average of 6.8 sessions in the month after the event (t=5.25, p<0.001).\n\nThe evidence on mass participation event intervention to increase cycling is only partially applicable to the UK as the study was conducted in Australia. The differing environment in Australia must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES13: Individual-level change in community delivered targeted health information interventions to increase walking\n\nModerate evidence from six studies suggests that individual, targeted provision of health information (including printed media, telephone support and text messages) delivered in the community are effective in increasing individual levels of walking for leisure or travel in adults up to 1 year post intervention. Five (++) RCTs showed positive effects on walking. One further (++) RCT also showed positive effects on walking, but was designed to test intervention fidelity.\n\nOne (++) RCT (USA n=117, 3 months) – ten weekly emails containing links to a webpage with an interactive information tailoring tool to promote physical activity – found that walking increased at a faster rate in the intervention group than the control group (β=15.04 [SE=8.38], p=.035 [one-tailed]). Intervention group increased walking by 69\xa0minutes/week versus 32\xa0minutes/week in control.\n\nOne (++) RCT (Australia n=399, 10 weeks) – print only (participants were mailed self-help brochures weekly for 3 weeks) or print plus telephone (participants received the same print programme plus three weekly telephone support calls – found that both intervention groups significantly increased time reported walking for exercise per week (from 130 to 147 minutes: t[1,277] =-3.50, p<0.001; and from 132 to 150 minutes, t[1,106]= -2.44, p=0.016).\n\nOne (++) RCT (USA n=197, 6 months) – counselling weekly telephone calls to assess physical activity levels and problem solve how to fit adequate walking activity into their week – found that women in the intervention group reported more time walked each day than the control women (F [1,191]=4.10, p<0.05).\n\nOne (++) RCT (USA n=253, 12 months) – telephone calls with or without counselling, or a control video – found that women in the intervention group showed a linear increase in walking from baseline to 6 months (latent growth analysis to assess the relationship between time and intervention group membership).\n\nOne (++) RCT (UK n=149, 4 weeks) – two theory-based interventions consisting of forming 'implementation intentions' along with text message reminders to achieve walking-related plans or goals – found a differential change across groups in brisk walking or fast walking (F [2,130]= 3.12, p=0.048). Two intervention groups which differed in having a plan reminder or goal reminder had a 45% and 42% increase of at least 2 days a week meeting physical activity daily guidelines respectively, with a 22% increase in the control group.\n\nOne (++) RCT (USA n=50, 12 months) – two interventions consisting of forming 'implementation intentions' along with text message reminders to achieve walking-related plans or goals using social cognitive theory (SCT) – found the greatest increase in walking in interventions that adhered more closely to SCT. High fidelity intervention increased walking by 34.23\xa0minutes a week (+/-81.91) compared to a low fidelity increase of 7.91\xa0minutes a week (+/-47.93, F=3.207 p=0.08).\n\nThe evidence on community delivered health information interventions is only partially applicable to the UK as most studies were conducted in Australia or the USA with only one UK study included. The differing environment in Australia and the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\nNote: pedometers are a technology which offers an opportunity to present individualised information about walking and so are closely linked to the studies above. Use of pedometers is related to goal setting and monitoring rather than to delivery of information about health benefits or methods to overcome barriers. Studies may use pedometers as one of a number of factors to support increases in walking, in common with other approaches, or may use pedometers solely as a means of measuring change. Pedometer studies are considered below.\n\n## Evidence statement R1.ES14: Individual-level change in community-based pedometer interventions to increase walking\n\nModerate evidence from 12 studies suggests that pedometer-based interventions delivered in the community are effective in adults (or women only) to increase individual levels of walking for leisure or travel, up to 6 months post intervention. Evidence from five (++) RCTs and 2 BA studies (one [+] and one[-]) showed positive effects on walking for leisure and/or travel in adults. This is supported by data from a (-) CS study. However, one (++) RCT found that short-term improvements in walking 4 weeks post intervention had decreased by 12 months follow-up. Evidence from one (++) RCT and one (+) BA study showed substantial positive effects on walking for leisure and/or travel in women. An additional (++) RCT found that a pedometer-based intervention increased walking in environments with low aesthetics, but not in those with aesthetically pleasing environments.\n\nOne (++) RCT (UK n=61, 52 weeks) – walking programme with goals set in minutes, or steps or using a pedometer – found that the pedometer group increased walking at 4 weeks (p<0.001), but decreased between 4 weeks and 12 months. No change in minutes or control groups.\n\nOne (++) RCT (UK n=130, 4 weeks) – motivational component had three stages: participants were shown 10 statements about what would make it easier for them to walk more, asked to complete a scale to show how confident they would be about walking in each situation, and discussed with facilitator and walking plan developed; pedometers were worn – found a significant difference in number of minutes spent walking to week 2 between the control group (M=138.7, SD=93.3) and the intervention group (M=22.5 SD=100.3), from a mean of 19.8\xa0minutes to 32.2\xa0minutes per day (increase of over 60%). Also a significant increase in the number of minutes spent walking per week for intervention group from week 1 to week 4 (mean 287.3, SD=129.4 t=8.12, p<0.001).\n\nOne (+) BA (USA n=36, 6 weeks) – women who were designated as insufficiently active were given brochures and pedometers and were sent emails. Participants received a pedometer, 6 weeks of step log sheets, self-addressed envelopes, and three commercial brochures describing strategies based on transtheoretical model (TTM) for increasing physical activity and the risks and benefits of physical activity – found that participants significantly increased their total walking minutes from baseline (median 55) to post intervention (median 245: Z=4.03, p=0.001) including walking while at work (Z=2.79, p=0.005, d=0.63), for transport (Z=2.86, p=0.004, d=0.60) and during leisure time (Z=3.54, p=0.001, d=0.81).\n\nOne (++) RCT (Japan n=68,12 weeks) – feedback based on accelerometer daily physical activity, number of daily steps and time spent performing daily moderate physical activity (MPA) which was provided to each participant every 2 weeks. Participants were recommended to accumulate 9000 steps and 30 minutes of MPA per day – found a significant group interaction for steps (f=10.53, p<0.01). The intervention group increased their steps by 16% (7811 +/-3268 to 9046 +/-2620 steps). There was no significant change in the control group.\n\nOne (++) RCT (Australia n=314, 3 months) – self-help booklet based on social cognitive theory constructs, plus six weekly diaries printed on reply-paid postcards (WP group), plus a pedometer (WPP group). Three incremental stages, starting with short walks (<15 minutes) 3 days a week, typically by incidental walking, gradually increasing the duration of walks to 3 to 4 days, then (continuously) walking briskly for 30 minutes – found that the mean change in total sessions of all-purpose walking/week increased within all groups from baseline, but increased the most within WPP. The control group had a mean increase of 1.2 sessions/week (95% CI: 0.6-1.8, t=3.97, p<0.001); WP: 1.3 sessions/week (0.5–2.0, t=3.32, p<0.001); WPP: 2.3 sessions/week (1.6–3.1, t=6.30, p<0.001). Leisure time walking sessions/week for the previous 3 months also increased within all groups, with both WP (2.0 sessions/week 1.6–2.4, t=9.49, p<0.001) and WPP (2.1 sessions/week 1.7–2.6, t=9.63, p<0.001) showing a significantly larger increase than the control group (0.9 sessions/week 0.6–1.2, t=5.82, p<0.001). There was a similar pattern for leisure time walking minutes/week for the previous 3 months, but only the WPP group (66 minutes/week 50–82, t=8.05, p<0.001) showed a significant increase compared to the control group (34 minutes/week 21–48, t=5.03, p<0.001). The WPP group was also more likely than controls to meet physical activity recommendations. Unclear if the provision of pedometers provides benefit over and above standardised structure walking programme.\n\nOne (++) RCT (Australia n=369, 3 months) – participants received a single mail-out of a self-help walking programme (WP) or the same programme plus a pedometer (WPP) – found that only the WPP group were significantly more likely than controls to increase total walking time (Exp [b] = 2.53, p<0.01) and to undertake regular walking (OR=5.85, 95% CI 2.60–12.2) where environment aesthetics (level of greenery and interesting scenery) were perceived to be low; while in aesthetically pleasing environments, the differences in walking measures between intervention and control groups were non-significant.\n\nOne (+) BA (Japan n=56, 4 months) – subjects were given a pedometer and instructed to walk at least 7,500 steps each day. They were also given additional monthly advice on healthy diet and lifestyle provided in a newsletter – found the mean steps per day increased significantly from 9389 to 11846 (p<0.01).\n\nOne (++) RCT (USA n=24, 24 weeks) – given pedometer and initially, all (post-menopausal) women were prescribed a distance of 1.4\xa0km/day above their baseline. Distance was then increased by 0.5\xa0km/day until the desired walking distance was met – found that the intervention group increased their daily walking by 4300 steps (2.9 ± 0.2\xa0km/day); significantly different from baseline and from the control group (both p<0.05).\n\nOne (++) RCT (Australia n=26, 12 weeks) – participants (overweight middle-aged women) in the pedometer group were told to record their pedometer steps on a daily basis for 12 weeks; those in the control group were asked to wear a sealed pedometer for 12 weeks with weekly recording. The pedometer group was also encouraged to reach a daily step goal of 10,000 steps/day – found that the pedometer group daily average number of steps at weeks 6 (8321 ± 884 steps/day) and 12 (9703 ± 921 steps/day) were significantly higher than the baseline daily average (of 6242 ± 541 steps/day: p=0.046 and p=0.035) respectively.\n\nOne (-) BA (USA n=12, 2 weeks) – participants over 65 years of age; site-specific walking route maps, health counselling session with individualised goal-setting and pedometers – average daily pedometer steps increased between baseline (M=3020, SD=1858) and week 1 (M=4314, SD=2627; t= -2.99, p=0.012) and week 2 (M=4246, SD=2331; t=3.42, p=0.006) found that all participants met their daily step goals in week 1 while 50% met their step goals in week 2.\n\nOne (-) CS (Canada n=41, 6 months) – lending pedometers to patrons of five public libraries. The pedometers were loaned for maximum of 9 weeks. Education packages were handed out with the pedometer including: information on pedometer use, physical activity/walking recommendations, maps of local trails, and a walking challenge questionnaire – found that 39.5% indicated they walked more since borrowing the pedometer and 60.5% reported walking about the same.\n\nOne (++) RCT (n=79 12 weeks) – the sessions were based on the Transtheoretical Model of exercise behaviour change. Strategies used included enhancing motivation, overcoming barriers and developing appropriate walking plans. Followed a 12-week pedometer-based walking program – found a significant increase in steps/day for the intervention group between baseline (M=6802, SD=3212) and week 12 (M=9977, SD=4669, t(38)=-6.06, p<0.001, d=0.79, CI 2,115–4236). No significant difference was observed in the control group (t(39)= -0.50, p=0.618, CI -463–770).\n\nThe evidence on community pedometer interventions to increase walking is only partially applicable to the UK. Three studies were conducted in the UK, with the majority in the USA, Australian, Canada, and Japan. The differing environments must be considered in reference to the studies, particularly for those conducted in Japan. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES15: Individual-level change in workplace pedometer interventions to increase walking\n\nModerate evidence from 11 studies suggests that pedometer-based interventions delivered in the workplace may be effective in increasing individual levels of walking for leisure or travel, up to 12 months post intervention. Evidence from three (++) RCTs, one (+) nRCT, two (+) BA and two (+) ITS studies showed positive effects on walking for leisure and/or travel in the short term (up to 12 weeks). However, one (+) ITS study which used a competition format, saw the initial increase in walking decline over 12 weeks. One (+) nRCT found significant increases in walking 12 months after the intervention, while another (++) RCT found that initial increase in walking declined by 52 weeks follow-up.\n\nA (++) RCT (UK n=50, 52 weeks) – walking programme with goals set in steps using an open pedometer for feedback – found that both groups significantly increased step counts from baseline to week 4. Significantly greater number of participants in the intervention (77%) compared with the control (54%) achieved their week 4 goals (X2= 4.752, p=0.03). There was no significant change in step counts from week 4–16 and a significant decrease from week 16–52.\n\nA (+) ITS (USA n=640 (in 64 teams of 10), 12 weeks) – competition-based employer sponsored physical activity programme using pedometers. Employees formed groups of 10 to undertake the challenge of attaining 10,000 steps per participant per day – found that total weekly steps for all teams combined increased between weeks 1 and 8 (p<0.0001), but declined from weeks 9–12. Increase in total weekly step count between week 1 and 12 not significant. Significant difference in team steps, with post-hoc comparisons indicating significant differences from baseline step counts during weeks 6–8 (F=71.15, p<0.001) but not at the end of the programme.\n\nA (+) nRCT (Australia n=205, 12 months) – staff defined as inactive received a 3-month self-help walking programme and pedometer plus four maintenance newsletters over 9 months to assist them to maintain their new activity levels. Control received pedometer and programme but no maintenance – found that both intervention groups significantly increased minutes walking (p=0.01). Change in moderate or vigorous physical activity (MVPA) minutes was significantly higher in the standard plus maintenance group compared with the standard group (118\xa0minutes versus 69\xa0minutes, P=0.029). No significant differences between groups were observed for total physical activity (161\xa0minutes versus 117\xa0minutes, P=0.187).\n\nA (+) ITS (Canada n=106, 12 weeks) – adoption phase: participants met in workplace-based groups with a facilitator for 30–60 minutes each week during a lunch break. Set individual steps per day goals and self-monitored their progress using a pedometer to record daily accumulated steps taken. Then adherence measured for 8 weeks – found that steps per day increased (from 7,029 +/- 3,100 [SD] at baseline to a plateau of 10,480 +/- 3,224 steps/day by 3.96 +/- 3.28 weeks of the intervention). Some decreases in activity relative to baseline steps per day, (ranging from -2.4% to -20.6% [12.0% ± 7.6%]).\n\nA (+) nRCT (Australia n=56, 6 weeks) – the intervention group received a pedometer and step logs. Set a daily step goal based on the previous week's step counts. They received weekly email reminders to wear the pedometer and return that week's log. They also received three commercial brochures. The control group received the intervention but without commercial brochures, intervention emails contained transtheoretical model (TTM)-based strategies – found that daily steps increased significantly (from 6419 ± 2386 during week 1 to 7984 ± 2742 during week 6: p<0.001) for both groups combined. Increases did not differ between groups.\n\nA (+) ITS (USA n=206, 10 weeks) – each day participants put on pedometers upon arriving at work, prior to getting out of their cars. To increase motivation, participants were encouraged to develop teams, and each team chose a team leader. Weekly motivational emails were sent to participants – found a significant increase in the number of steps per week for weeks 2, 3, 4, 6 and 8 compared to baseline (p=0.001).\n\nA (++) RCT (UK n=64, 10 weeks) – walking routes which employed prescribed walks around campus with participants asked to complete at least 15\xa0minutes continuous brisk walking every day and 'Walking in task' which encouraged the accumulation of step counts through the working day – found a decrease in steps for the control group (-767 steps/day) and increases in intervention groups for walking routes (+926 steps/day) and walking in tasks (+997 steps/day). (Control versus walking routes p<0.008, control versus walking in tasks p<0.005).\n\nA (++) RCT (UK, Australia and Spain n=64, 70 and 80 respectively, 10 weeks) – participants in the first intervention group were directed to increase their step count through brisk, sustained, route-based walking during work breaks. The second intervention group was asked to engage in incidental walking and accumulate step counts during working tasks, both groups were instructed to use pedometers to motivate and regulate walking – found that average step count data decreased in the control group (-391 steps/day t=1.76; p <0.08) and significant increases in both the routes (968 steps/day; t=3.9; p<0.001) and the incidental group (699 steps/day; t=2.5; p<0.014).\n\nA (+) BA (USA n=290, 12 weeks) – participants wore a pedometer at least 5 days per week for 12 weeks and completed questionnaires assessing demographic information. After baseline (week 1) they were given suggested number of steps to meet recommendations, instructions for goal-setting and other behaviour-change strategies to gradually increase number of daily steps – found that the average number of steps increased from week 1 to week 6 (p<0.001) and week 12 (p=0.002).\n\nA (++) RCT (Canada n=63, 1 week) – intervention group pedometer was worn for 1 week for all waking hours to encourage walking. Control (non-pedometer) participants were informed they could wear a pedometer the following week – found that, compared to the no pedometer group, the pedometer group reported more walking (F=5.22, p=0.03).\n\nA (+) BA (USA n=188, 10 weeks) – participants were provided with pedometers and given personalised daily and weekly step goals over the 10 week intervention. Local strategies available to the participants included walking groups, marked walking circuits and posted walking maps – found a mean increase of 1503 steps (38% increase over baseline). Mean weekly step counts values for all intervention weeks were significantly higher than baseline (p<0.01).\n\nThe evidence on workplace pedometer interventions to increase walking is partially applicable to the UK. Three studies were conducted in the UK but most studies were conducted abroad: in USA, Australia, Canada or Spain which may limit the applicability in some cases. The differing environments must be considered in reference to the studies. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES16: Individual-level change in workplace delivered targeted health information interventions to increase walking\n\nWeak evidence from two studies suggests that individual, targeted provision of health information delivered in the workplace (including flyers, email, telephone calls, website postings, and information booths) may be effective in increasing individual levels of walking for leisure or travel in adults up to 24 weeks post intervention. One (+) RCT study showed a positive effect on walking and one (+) BA study showed a small (borderline significance) positive effect on walking.\n\nA (+) RCT (USA n=135, 24 weeks) – phone calls once a week versus every 3 weeks, and structured versus non-structured feedback – survival curves indicated that there was a significant effect on walking for treated (the combined four treatment conditions) versus the control condition (LD=17.661 p<0.001) and for frequency of prompting (those prompted once a week against every 3 weeks) (LD=17.719, p<0.0001).\n\nA (+) BA (USA, n=not reported, 2 weeks) – promotional material distributed via flyers, email, website postings, and at bi-weekly information booths – borderline statistically significant increases in walking counts on a route ('Path to health') from baseline midway through the campaign (p=0.069) and following the campaign: (p=0.075 – p values only reported).\n\nThe evidence on workplace health information interventions is only partially applicable to the UK as the studies were conducted in the USA. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES17: Individual-level change in workplace delivered targeted health information interventions to increase walking and cycling\n\nModerate evidence from one (++) RCT study suggests that individual, targeted provision of health information (including a booklet of interactive materials, social marketing and individualised marketing strategies) in the workplace may be effective in increasing individual levels of walking, but not cycling, for travel in adults for up to 6 months post intervention. See also R1.ES4.\n\nA (++) RCT (UK n=295, 6 months) – interactive materials based on the transtheoretical model of behaviour change: choosing routes, maintaining personal safety, shower and safe cycle storage information, and useful contacts – found a significant increase in time per week spent walking to work (mean 125\xa0minutes/week intervention versus 61\xa0minutes/week control), but no difference in average weekly minutes of cycling between cyclists in the intervention group (n=9) and control group (n=9).\n\nThe evidence on health information intervention to increase walking and cycling is applicable to the UK as the study was conducted in the UK. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES18: Individual-level change in multi-component interventions to increase walking\n\nWeak evidence from two (++) BA studies suggests that multi-component interventions have a positive effective on increasing individual levels of walking for leisure or travel up to three months post intervention.\n\nA (+) BA (USA n=124, 8 weeks) – multi physical activity and dietary program, pedometers – found post intervention that 46.2% (n=43) met the 10,000 steps/day criteria for high activity (no further statistics). This increased from 11.8% at baseline. Average steps increased from 5,969 steps/day to 9,757 steps/day\n\nA (+) BA (USA n=53, 3 months) – sponsored walking groups, improving walking routes, providing information about walking options, and advocating for pedestrian safety – found self reported walking activity increased from 65 to 109 minutes per day: 44.1% increase (95%CI= 28.0-60.2, p=0.001). The proportion that reported being at least moderately active for at least 150 minutes per week increased from 62% to 81% (19.2 % increase 95% CI= 2.2, 36.3 P=018).\n\nThe individual level evidence on multi-component interventions to increase walking is only partially applicable to the UK as studies were conducted in the USA. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES19: Individual-level change from cycle training interventions to increase cycling\n\nWeak evidence from one BA (+) study suggests that cycle training interventions may be effective in increasing individual levels of cycling for active travel amongst those not cycling at baseline, up to 2 months post intervention.\n\nA (+) BA (Aus n=81, 2 months) – practical skills development and supervised on road or cycle path training. Free courses for beginner and intermediate level cyclists were conducted. Promoted through flyers, posters, media releases, articles and TV and newspaper adverts – found non cyclists at baseline reported significant increase (p<0.001) in minutes cycling.\n\nThe individual level evidence on multi-component interventions to increase cycling is only partially applicable to the UK as the study was conducted in Australia. The differing environment in Australia must be considered in all studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES20: Individual-level change in healthcare delivered multi-component interventions to increase both walking and cycling in adults\n\nModerate evidence from 1 (++) RCT study concerning the effect of multi-component interventions on increasing individual levels of both walking and cycling for travel and/or leisure up to 18 months post intervention indicated a positive effect on cycling but no effect on walking.\n\nA (++) RCT (Sweden n=120, 18 months) – physician meetings, physical activity prescriptions, group counselling, and bicycle provision; control and intervention groups received pedometers – found the intervention group was more likely to achieve recommended level of cycling than controls (38.7% versus. 8.9%, OR=7.8, 95%CI 4.0-15.0, p<0.001) but there was no difference in compliance with the walking recommendation (45.7 versus. 39.3%, OR 1.2, 95%CI 0.7-2.0, p=0.5). Commuting by car and public transport were reduced by 34% (P<0.01) and 37% (P<0.001), respectively in the whole sample, with no differences between groups.\n\nThe individual level evidence on multi-component interventions to increase walking and cycling in adults is only partially applicable to the UK as the study was conducted in Sweden. The differing environment in Sweden must be considered in reference to this study. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1ES21: Individual-level change in community-based led walking group interventions to increase walking\n\nInconsistent evidence from 5 studies on the effects of a community-based led walking group interventions on walking. 1 (++) RCT, 1 (++) clustered RCT, 1 (++) nRCT and 1 BA (+) study showed positive effects on walking from community-based walking group interventions; but evidence from a further (++) RCT showed no difference between groups at 12 months.\n\nA (++) nRCT (UK n=7883, 12 weeks) – 'Get walking, keep walking': Bespoke, led walks and sessions and walking packs aimed at encouraging (predominantly) inactive people, those from deprived communities, black and minority backgrounds, women and younger adults to walk – found 67% of participants increased the amount of exercise they did each week. Walking from 'place to place' increased by 1.1 day/week and walking for leisure by 1 day/week.\n\nA (++) cluster RCT (USA n=501, 6 months) – leader-led walking group activity or an information-only control group – found significant increase observed in walking activity: p <0.05.\n\nA (+) BA (Australia n=169, 6 months) – walk leaders received a prescriptive progressive weekly exercise program guided by social cognitive theory, that contained written information on the appropriate length for the walking program; stretching exercises; and ball skills, such as side twist leader ball, participants aged 65-74 – found baseline mean walking time for recreation was one hour (SD =1.65), increasing to 2.69 hours (SD =2.02) per week by the end of the program.\n\nA (++) RCT (UK n=260, 12 months) – accompanied walks were provided at several different times in the day and evening, during the week and at weekends, and were led by lay volunteers – found at 12 months, although both walking and control groups increased activity (by 35.7% and 22.6% respectively; 95% CI 0.003% to 25.9%) p=0.05), there was no significant difference between them.\n\nA (++) RCT (USA n=114, 20 weeks) – efficacy based Exercise classes were conducted by trained exercise specialists and employed brisk walking as the aerobic component – found at the end of the 20 week program, subjects in the intervention group walked more miles per week than the control group: p<0.05.Intervention group subjects also walked more often (p<0.01) and accumulated more minutes (p<0.01) than control\n\nThe evidence on community based walking group sessions to increase walking is only partially applicable to the UK as only two studies were conducted in the UK. The differing environment in the USA and Australia must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES22: Individual-level change in interventions to increase independent community-based walking\n\nWeak evidence from 2 (+) BA studies and 1 (++) RCT suggests that interventions to increase independent community based walking may be effective in increasing individual walking for leisure, exercise or travel up to 13 weeks post intervention in adults or the whole community.\n\nA (+) BA (Canada n=39, 8 weeks) – 'mall walking programme', participants provided with pedometers. Participants self-selected the pace, time, and frequency of walking. Encouraged to attend as often as possible between 8am and 10am Monday to Friday – found average daily mall walk steps increased from 5055 (SD 1374) to 5969 (SD 1543): p=0.002, and average daily mall walk time increased from 42.9 (SD 10.6) min to 50.4 (SD 13.5) min: p=0.002.\n\nA (+) RCT (Aus n=88, 13 weeks) – participants: postnatal women; information, goal setting consultations, activity and self-monitoring daily planner, tailored SMS, nominated social support person – found frequency of walking for exercise (days/week) increased over time in the intervention compared to control group (time×group interaction effect F(2,85)=5.38, p=0.023, medium effect size partial η2=0.06); while change in duration of walking did not show a significant time×group interaction effect (p=0.081; effect size partial η2=0.05), there was a significant group effect with increases in walking duration in the intervention compared to control (p=0.005; medium to large effect size partial η2=0.09).\n\nA (+) BA (USA n=16, 12 weeks) – walking intervention facilitated by community health workers. Weekly sessions encouraged participants to accumulate at least 30 min of moderate intensity walking on most/all days of the week – found that exposure to the programme resulted in significant increase in walking: 915.8 metabolic equivalent min/week, p=0.002.\n\nThe evidence on interventions to increase independent community based walking may not be applicable to the UK as studies were conducted in the USA and Canada. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES23: Individual-level change in workplace-based interventions to increase independent walking\n\nInconsistent evidence from 2 (++) RCT studies concerning workplace walking session interventions (conducted in universities) effectiveness in increasing individual levels of walking for staff and/or student participants up to 12 months post intervention. Evidence from 1 RCT showed positive effects on walking while one RCT showed no effect on walking.\n\nA (++) RCT (USA n=32, 32 weeks) – sedentary adults; walking prescription: 3 brisk walking conditions: 30 continuous minutes, 3 10-minute bouts, or 30 minutes made up of any combination of bouts each at least 5 minutes long; 1 hour information and modelling session followed by weekly meetings with an activity counsellor for 15 weeks. Behavioural methods used to promote adherence: goal setting and mastery, self-management techniques, weekly personal feedback, problem solving, behavioural contracting participants paid $50, refunded on successful completion – found self-reported walking for all intervention groups significantly increased throughout the program: F(6, 186)= 26.16; p<0.001.\n\nA (++) RCT (USA n=26, 6 weeks) – two 8-week walking for fitness classes – found that neither group increased walking time or number of steps significantly over time.\n\nThe evidence on workplace (university) based walking sessions to increase walking is only partially applicable to the UK as the studies were conducted in the USA. The differing environments must be considered in reference to the studies conducted in the US. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R2.ES1: Providers' and researchers' views of barriers and facilitators to planning and delivering interventions to increase walking\n\nModerate evidence from four studies suggests that facilitators to planning and delivering interventions included organisational support and sufficient planning time. It may be beneficial to include volunteer leaders at the planning stage.\n\nHaving previous experience in marketing and a conceptual framework facilitated recruitment efforts. Personal satisfaction, social interaction and a positive rapport with group members were motivational effects of leading walking groups.\n\nBarriers to planning and delivery included lack of inter-organisational collaboration. This was facilitated by introducing staff in different organisations to each other and being clear about shared goals. Employing an individual to co-ordinate between organisations was a facilitator to implementation.\n\nDe-motivators to being involved in organising and monitoring groups included researchers' perceived workload, efforts required for effective recruitment, lack of support from and feelings of responsibility for group members.\n\nA (+) UK evaluation suggested that sufficient planning time is required for successful implementation of a family-based intervention. Involvement of proposed walking leads at the planning stage was suggested as a way of increasing their engagement with the programme.\n\nA US (+) pilot evaluation reported that walking group policy makers supported the walking group by promoting the intervention and assisting with recruitment. Administrative support was also supplied, and events were organised.\n\nA (+) study that included interviews from the UK reported that the process of recruiting members to a walking group was draining on time and resources for the organisers, and some volunteers lacked skills in recruitment. Having experience in marketing and a conceptual framework around recruitment was a facilitator to recruiting new members. However, word of mouth was regarded as the most effective recruitment strategy.\n\nA pilot evaluation reported that running the walking group provided a sense of personal satisfaction for organisers as well as an opportunity for personal development and health promotion. Interaction with club members was a motivator for organisers.\n\nCollaboration with other organisations was an issue in two studies, due to a focus on their own organisation and lack of communication. In one study this meant that walking routes were not shared and events were less well attended. Club directors could also feel isolated. In the other study, collaboration between a walking association and a family support group was improved through members getting to know each other and being clear that goals were to be shared, and that interventions would run alongside each other rather than new initiatives replacing existing ones. Coordination by one designated officer also facilitated implementation.\n\nOne study reported that group organisers expressed views about their burden of responsibility for the wellbeing and safety of members, especially if leadership was not shared. Recruitment and maintenance of membership numbers were regarded as a burden, and strategies were developed by the club to limit drop-out. Having to walk at a slow pace with other members was a de-motivator.\n\nOne UK (+) interview study found that carrying out routine physiological measurements in a pedometer study was regarded as a burden for researchers.\n\nFindings from these studies have partial applicability to other walking groups. The organisation of walking interventions will differ across countries, regions and groups. Groups may have different goals, and recruit specific populations. There is no reason to believe that the barriers and facilitators described are not applicable to other similar interventions.\n\n## Evidence statement R2.ES2 Participants' views about motivators and barriers to participating in interventions to increase walking\n\nModerate evidence from five studies suggests that participating in a walking intervention motivated people to walk through the presence of role models, organised routes, and the support of being part of a group.\n\nFamilies were motivated by the opportunity for children to participate in an activity that was free of charge. For others, the opportunity to improve health and enjoy fresh air and nature were motivational.\n\nBarriers to motivation include conflicts between walking activities and work / school schedules, and cultural lack of acceptance in regard to work-based activity.\n\nOne US (+) pilot evaluation reported that having access to a role model and to organised walk routes were motivators to attendance. For women, having the support and security of a group was a motivator (one [++] focus groups, US). For families, the opportunity for children to participate in activities with the family, free of charge, and outside of nursery hours were incentives (one [+] evaluation, UK). For adults, a sense of routine and structure was valued for those who were not in employment (one [+] focus groups, UK).\n\nParticipants in one (+) UK focus groups study were motivated by the opportunity to improve their health and be out in the fresh air and natural environment.\n\nHowever, barriers to participation included conflicting schedules with school attendance or workplace responsibilities (one [+] interviews, UK). In a workplace setting, they also reported that increasing walking time required acceptance from colleagues, and this varied depending on the status of the employee within the organisation.\n\nApplicability: The findings from these studies are applicable to other walking groups. The acceptability of walking interventions will depend upon specific walking group characteristics, settings and aims. There is no reason to believe that the barriers and facilitators reported are not applicable to interventions implemented in the UK.\n\n## Evidence statement R2.ES3 Participants' views about maintaining participation in interventions to increase walking\n\nModerate evidence from ten studies provided evidence regarding factors associated with maintenance of participation.\n\nSocial interaction and social support were major factors in maintaining participation. Maintenance was also related to the extent to which activities could be integrated into daily life.\n\nMonitoring activity, providing people remembered to self-monitor, could increase motivation, though it could also introduce unwanted competition between members.\n\nOther motivators included variation in walking routes, and incentives such as gifts.\n\nBarriers to maintenance included the difficulty of integrating walking and attendance at clubs into daily routines. Boredom, dissatisfaction with elements of the club, and incongruent aims were reported factors associated with discontinued membership.\n\nThe social factor associated with walking in groups was supported by six studies. The social factor was particularly strong for women and older adults. One (+) UK focus group study reported a strong bond and sense of loyalty to the group that facilitated attendance. For men, the social factor was not so important with males tending to prefer walking alone (one [++] focus groups, US).\n\nSupport was also important; in one intervention, feedback from providers was welcome, though e-mail was the preferred mode.\n\nA US (+) RCT highlighted the importance of family and friends in supporting the maintenance of walking behaviours. Walking also had a positive effect on interactions with family members.\n\nA UK (+) interview study reported that walking to deliver messages at work instead of e-mailing created a greater sense of community.\n\nAn important aspect of walking was the ability to integrate interventions into daily life. The ability to turn up without booking was a positive factor for some, and a sense of routine and structure was valued for those who were not in employment (one [+] focus groups, UK).\n\nHowever, one study reported that women in particular found difficulty integrating extra walking into daily routines. Life changes, coinciding schedules and other commitments were also a barrier. Wearing female-oriented clothing such as high heels was a barrier to walking while at work. For African–American women, it was difficult to focus on self-based activities.\n\nMonitoring activities was reported as a motivator. Two studies reported that pedometer use and the process of self-monitoring increased walking behaviours. One reported that step counting gave a sense of achievement.\n\nHowever, a US observation and interviews (+) study found that in older adults (mainly female), pedometer use and fitness objectives conflicted with the moral economy (shared values regarding social interaction) of the walking group, which was based on sociability rather than competition. In addition, people often forget to complete logs, or to use their pedometer.\n\nOther incentives included rewards and gifts.\n\nOne study reported that the atmosphere of the club, mismatch between aims of the club and aims of the participant, as well as the pace required to walk could be barriers to participation in walking interventions. Another also added that boredom could dissuade attendance, and for African–American women, one study reported lack of objectives as potential barriers.\n\nApplicability: The findings from these studies are applicable to other walking groups. The motivation to maintain walking behaviour within an intervention will depend upon individual circumstances and requirements as well as the characteristics and aims of the club. There is no reason to believe that the barriers and facilitators reported are not applicable in the UK.\n\n## Evidence statement R2.ES4: Participants' views of the benefits of participating in a walking intervention\n\nModerate evidence from eight studies highlighted the reported benefits of walking as part of a walking intervention.\n\nPerceived benefits to walking were reported to facilitate motivation and hence walking behaviour (one [+] focus groups, US). Such benefits could be emphasised when encouraging participation in interventions.\n\nReported benefits included physical and psychological benefits, adding variety to the day and getting out of the house or office. Walking could provide a sense of peace and solitude, and was also fun, providing an opportunity to be out in fresh air and see the sights.\n\nReported physical benefits were feeling healthy, (one [++] focus groups, US), and fit (one [+] pilot evaluation, US), (one [+] RCT, US), increased energy, (one [+] interview studies, UK), lower blood pressure, weight loss and improved body shape.\n\nPsychological benefits included enhanced mood, stress reduction, mental and emotional satisfaction, feeling rejuvenated, and having meditative or spiritual feelings. Feeling tired at the end of a walk was associated with a sense of achievement (one [+] focus groups, UK).\n\nIn a workplace intervention, walking was reported to add variety to the day and improved output at work. For a group of previously sedentary adults, walking became fun, and was a chance to get out of the house. Walking for one group of mid-age women allowed them time to think, time out of the office, time with the family and fresh air.\n\nBenefits reported from two (+) pedometer-based interventions included seeing the sights (interviews, UK), and socialising with members of the group (observation and interviews, US).\n\nApplicability: The findings from these studies are applicable to other walking groups. Benefits of walking may differ by setting, though there is no reason to believe that the benefits reported are not applicable in those settings within the UK.\n\n## Evidence statement R2.ES5: Walking intervention participant's views of perceived barriers to walking\n\nModerate evidence from seven studies highlighted perceived barriers to walking for participants of walking interventions. These included physical and psychological limitations, environmental barriers, and poor weather conditions.\n\nPhysical barriers to continuing with the walking programme included health problems such as arthritis (one [+] focus groups, US), and physical limitations such as illness and injuries (one [+] RCT,US). Tiredness and depression also prevented some women from continuing attendance.\n\nPoor weather conditions or hot weather were reported disincentives to walking (one [+] interviews,UK; one [+] pilot evaluation, US;one [++] focus groups, US;one [+] focus groups, UK). One study reported costs of participation as a barrier.\n\nLack of access to the walking route, and obstacles such as poorly maintained stiles along the walking route were also reported barriers.\n\nApplicability: The findings from these studies are applicable to other walking groups. The barriers to participation in walking interventions might depend upon individual circumstances, such as age and physical fitness as well as seasonal weather conditions. Weather conditions may be better, or more extreme, in the US, Canada and Australia than in the UK, though there is no reason to believe that the barriers reported are not applicable in the UK.\n\n## Evidence statement R2.ES6: Suggested strategies to overcoming barriers to maintaining walking in a walking intervention\n\nModerate evidence from two studies highlighted reported strategies to overcome perceived barriers to participating in walking interventions. These included making time, and integrating walking into daily life as well as thinking positively.\n\nA (+) US RCT reported strategies including scheduling time to walk, problem-solving and using motivators such as positive thinking and focusing on the long-term benefits. Goals were more achievable if walking was made a priority and was fitted into daily life as much as possible. Similarly, a (+) US study (focus groups) reported that for African–American women, weaving walking into family life was a strategy that allowed themselves and the family to participate.\n\nApplicability: The findings from these studies are applicable to other walking groups. The ability to implement strategies to overcome barriers to participation in walking interventions will depend upon individual circumstances.\n\n## Evidence statement R2. ES7: Providers' views about effective intervention components that motivate walking and cycling\n\nModerate evidence from one study suggests that workplace efforts to encourage walking and cycling are most successful where they attend to cultural attitude, access, security and available facilities. Incentives and provision of equipment are also motivating.\n\nThe (+) study (survey and interviews, UK) provides evidence that, across 20 workplace initiatives, walking and cycling are increased where good onsite and offsite access is available, along with provision of showers, drying and changing facilities. Organised walks at lunchtime and cycling groups were an incentive.\n\nOrganisational attitude was important, with some workplaces marketing the benefits of walking to staff. Motivators such as complementary products or financial incentives were used.\n\nFor cycling, the ability to borrow equipment or receive discounts on cycling equipment was important, as was having secure parking for cycles.\n\nApplicability: Findings from this study were taken from a range of workplace initiatives within the UK and so are applicable in UK workplace settings.\n\n## Evidence statement R2.ES9: Participants' views about taking part in interventions to increase cycling\n\nModerate evidence from one exploratory study and one evaluation showed that facilitators to a led cycling intervention were a feeling of safety and acceptance that was obtained from cycling in a group.\n\nProvision of acceptable equipment and the need not to wear a helmet was a facilitator for boys.\n\nIn a workplace-based cycling intervention, facilitators included the provision of storage and changing facilities and raised awareness about benefits.\n\nThe (++) exploratory study (focus groups, UK) elicited community members' views about use of a cycle trail and a proposed intervention that included led cycling groups.\n\nThe main facilitator to using the trail for led cycle groups was the protection of riding together in a group. For young women, the image of cycling as 'uncool' was an issue, but this barrier would be lessened if they were cycling with friends.\n\nImage was also an issue for boys, whose participation would be facilitated by the provision of the 'right' bike, and not having to wear a cycling helmet.\n\nThe (+) UK evaluation study (found that the main influences on increase in cycling following an intervention were the provision of workplace cycling facilities, a house or job move that made cycling more attractive, and heightened awareness of the importance of physical activity for health. Welcomed and best used measures were secure cycle parking, showering and changing facilities, and cycle purchase loans.\n\nApplicability: The findings from these UK-based studies are applicable to other potential cycling interventions. The motivation to participate in cycling interventions might depend upon individual circumstances, as well as local geography and usage of the proposed site. Some areas of the UK may be more or less attractive as cycling venues than the one described here. Workplaces will also differ in provision of facilities, and interventions may be affected by factors outside the control of organisers, such as weather conditions.\n\n## Evidence statement R2.ES10: Young people's views about walking for travel or leisure (not related to an intervention)\n\nModerate evidence from one interview study and one survey study suggests that walking for leisure was facilitated by walking as a social event or as part of a challenge.\n\nBarriers to walking for travel or leisure for young people are mainly related to lack of time. In addition, having a lot to carry and wearing shoes that were not comfortable were disincentives. Young people report busy lives as a barrier to walking for transport. For men, walking was not sufficiently vigorous to be considered 'exercise'.\n\nThe (++) UK interview study reported that young people, and especially young men, did not regard walking as vigorous enough to provide exercise. Walking for transport required too much time out of a busy day. Walking for leisure was only acceptable if it included some form of teamwork or challenge. For those that did walk for transport, listening to music was a facilitator as it drowned out noise from traffic and construction sites.\n\nThe (+) US survey study reported that undergraduates found that lack of time, having a lot to carry, and wearing shoes that were uncomfortable were the most highly rated barriers.\n\nApplicability: The findings from these studies are applicable to young people in the UK and US. Evidence reflects aspects of daily life that alter with changes through the life course. Participants in this study are constricted by timescales associated with the working day that might not apply to some other populations. There are also specific gender differences in perceptions of walking for fitness.\n\n## Evidence statement R2.ES12: Older people's views about walking for travel or leisure (not related to an intervention)\n\nModerate evidence from six studies suggests that the main facilitator to walking for travel or leisure in older adults was social interaction.\n\nBarriers to walking for travel or leisure for older adults are related to limited mobility and fears for safety. These factors were mediated by the external environment, with fears of falling or of swift traffic being commonly voiced.\n\nWalking indoors was a relatively safe and comfortable alternative if designed appropriately. Walking indoors also incorporated a social aspect to walking.\n\nOlder adults reported factors that impacted on safety as the main barriers. When walking outside, narrow pavements and obstacles such as parked cars on pavements, and construction sites were barriers to access (one [-] interviews, UK). Traffic was also an issue, with cycle tracks and bus lanes creating hazards. Suggested improvements were wider pavements and better provision for cyclists.\n\nIn addition, two focus group studies from Canada (one [++] and one [+]) reported that fear of falling was a barrier to older adults, particularly in icy weather. Uneven pavements and car parks that are not designed for pedestrians were hazards. Older adults often require more time to cross roads, and it was reported that fast roads and poor visibility at crossroads were barriers to outdoor walking.\n\nSuggestions for improving the walking experience for this group were access to toilets and seating, as well as adequate access to local amenities and pedestrianised shopping areas. Making sure that pavements were smooth and clear of snow and ice was also a factor.\n\nA (+) UK survey reported that obstructions to mobility included crossings without dropped kerbs, narrow footpaths, and a dropped curb with a steep angle. The authors report that 19% of people aged >80 years could not reach key places if they need to pass through a gap of 1000\xa0mm.\n\nTwo studies assessed indoor walking for older adults. A (++) observations and interviews study from the UK reported on mall walking that not only contributed to improved physical activity, but also provided a social network and a meaningful work replacement following retirement. Routines were adapted and events were organised in a relatively safe environment compared to outdoors.\n\nFor older adults in assisted living facilities, a (++) focus group study from the US reported similar facilitators in corridor walking, such as relative safety of being indoors, and the social incentive of meeting people in the corridors. Handrails were valued, as well as appropriate flooring, seating in corridors and adequate toilet arrangements. Public rooms needed to be thoughtfully placed to allow residents optimum access.\n\nReported barriers to this activity were the lack of varied things to see compared with outside. Facilities with outdoor walking areas provided an opportunity to overcome this barrier providing the walking surfaces were adequate.\n\nApplicability: The findings from these studies are applicable to older adults in the UK and North America. The evidence reflected safety concerns that alter with changes through the life course such as ageing. Participants in this study were constricted by limited mobility that might not apply to some other populations. Social interaction is important for this population to prevent social exclusion.\n\n## Evidence statement R2.ES13: Views of people from deprived areas about walking for travel or leisure (not related to an intervention)\n\nModerate evidence from two studies suggests that the main barriers to walking for travel or leisure in people from deprived areas were safety, lack of time and lack of motivation.\n\nWomen were constricted by perceived dangers from the external environment, family commitments, lack of motivation and lack of walking companions.\n\nThere was evidence that participants were either out of the habit of walking, or that walking was enforced due to a lack of options.\n\nFor men, walking was not sufficiently vigorous to be considered 'exercise'.\n\nTwo studies assessed the views of populations from deprived groups. One (+) UK interview study reported that males did not associate walking with exercise as it is not strenuous enough. Women more often preferred to walk with someone else rather than alone, so walking with a friend, or children was an incentive. Walking with a dog was a motivator for men or women.\n\nThough health benefits such as weight management and reducing aggression or boredom were recognised by those that did maintain walking activities, there was a habit of not walking that needed to be broken. Lack of motivation, other commitments, lack of time and bad weather were all barriers to continuing walking.\n\nA (+) UK interview study examined the experiences of women without access to a car and reported feelings of social exclusion due to having to walk in neglected areas and often with very young children, who were tired. Women often had to walk long distances to shops, and feared for their children's safety at busy roads.\n\nApplicability: The findings from these studies are applicable to people living in deprived areas in the UK. The evidence reflected safety concerns associated with perceived environmental dangers. Participants in this study were constricted by reduced options that might not apply to some other populations. Social interaction is important for this population to increase the feeling of safety, particularly for women. There were also specific gender differences in perceptions of walking for fitness.\n\n## Evidence statement R2.ES15: Views about barriers and facilitators to active travel to school (walking and/or cycling for transport)\n\nModerate evidence from nine studies suggested that the main facilitators to active travel included the social aspect of walking and spending time with friends, or having quality time with parents.\n\nBarriers for schoolchildren contemplating active travel to and from school were parental and children's lack of time and dangers from traffic and from intimidation or attack by other people. The missed opportunity by schools to develop children's existing awareness, and displaying conflicting messages was also a barrier. Peer pressure was an important factor for this age group in terms of choices.\n\nOther reported barriers included distance, carrying heavy bags, and poor weather conditions. Parental habits and commitments as well as fears for their children's safety were also influential on decisions about walking.\n\nBarriers to cycling for children included a lack of cycle lanes and a lack of facilities to store bicycles.\n\nThe perceived image of cycling, and a dislike of wearing cycling helmets was also reported to be a barrier.\n\nThree studies (one [++] focus groups, UK; one [++] focus groups, US; and one [+] survey and interviews, UK) identified recognition in parents and children that walking or cycling would be beneficial to health and could increase a child's confidence and sense of independence around roads. In addition, two studies, (one [+] focus groups, UK) reported that walking with a parent provided valuable time together. Spending time with friends was an important social aspect for older children.\n\nHowever, barriers to walking or cycling included lack of time; parents often needed to accompany children to different schools and arrive at their place of work in time. Children and parents would need to get out of bed much earlier in the morning in order to fit in walking. Laziness was reported as a reason for not using active travel.\n\nPeer pressure and the trend toward car ownership was a factor, particularly for cycling, which for some groups was socially unacceptable. Schools may also miss opportunities to develop children's knowledge about sustainable transport choices.\n\nA US (+) survey and an Australian (+) survey found that among children that did not walk to school, distance was the most commonly reported barrier, followed by traffic danger. Parents restricted their children to playing close to home on their bicycles (one [+] focus groups, UK).\n\nChildren having to carry heavy bags of books and equipment was a barrier to both walking and cycling, as were bad weather, dark mornings and hilly terrain.\n\nFor older children who travel without an adult, there were fears for personal safety, of accidents and abductions, of strangers and bullies and of busy traffic. Environmental factors such as poor lighting, secluded areas or woodland on the journey exacerbated these fears.\n\nA (+) survey from Australia showed that parental perceptions were a factor in decisions to walk. These included parents own physical activity habits, parental working schedules, and parental concerns about safety. Having to attend out-of-school activities was also a factor.\n\nCycling was associated with particular barriers, such as lack of cycle lanes, and general support for cycling at school such as provision to store bicycles and helmets. Fear of having a bicycle stolen was a disincentive.\n\nThe image that cycling conveyed was an issue for some. For teenage girls, cycling was perceived as childish. For children that did cycle, the 'coolest' bike was required, and cycling helmets were regarded as 'uncool' (one [+] action research, Australia), lacking in style and fit, with consequences such as negative comments from others. In addition, cycling impacted on personal appearance; for example, cycling helmets dishevelled one's hair.\n\nApplicability: The findings from these studies are partially applicable as the findings are specific to schoolchildren. While some barriers and facilitators to active travel are applicable to any population, schoolchildren and their parents face particular issues pertaining to safety and practicalities for children. Some barriers differ by age group and gender.\n\n## Evidence statement R2.ES16: Suggestions for strategies to encourage active travel to school (walking and/or cycling for transport)\n\nModerate evidence from five studies provided suggestions for strategies that might encourage safe active travel in schoolchildren.\n\nSuggested strategies included environmental improvements to increase safety, changing attitudes to car use, school-based campaigns to assist in cycling skills and awareness, and personal-level encouragement by provision of storage facilities and better design of cycling helmets.\n\nSuggested strategies that may overcome some of the reported barriers included employing crossing patrols near to schools (one [++] focus groups, US), escort schemes, traffic calming schemes, and pedestrian training (one [+] focus groups, UK).\n\nA (+) survey from the UK reported that modifying attitudes to car-centredness would be a useful policy; more so than promoting general environmental awareness.\n\nTo reduce cycling accidents, improved cycle paths and compulsory helmet wearing was suggested in one (+) study (action research, Australia).\n\nOther suggestions included schools organising walking and cycling groups, providing training in cycling proficiency, and support such as storage for wet clothes and bicycles (one [++] focus groups, UK).\n\nImproved design of cycling helmets might impact on their use and on cycling behaviour by children.\n\nApplicability: The findings from these studies are partially applicable as the findings are specific to schoolchildren. While some suggestions to encourage active travel are applicable to any population, schoolchildren and their parents face particular issues pertaining to safety and practicalities for this age group.\n\n## Evidence statement R2.ES18: Adult views about cycling for transport\n\nModerate evidence from five studies was available regarding barriers and facilitators to adult cycling for transport.\n\nBenefits of cycling for transport were reported motivators, such as the ability to travel relatively quickly through traffic, the feeling of autonomy and freedom, and benefits for health and the environment. Cycling rather than driving could be encouraged by workplace initiatives.\n\nBarriers to cycling were reported such as obstacles in the road, pollution and poor weather. Carrying bags and changes of clothing required after getting wet were also reported disincentives.\n\nCycling for transport requires negotiating space on the road; major barriers were traffic volume, inconsiderate driving and lack of adequate cycling tracks.\n\nSome cycling behaviours were perceived as inappropriate by some other road users, giving cyclists a poor image and limited relationship with drivers.\n\nCycling was perceived as male, white and middle class. There was evidence that resistance to this image from female cyclists includes adopting and disseminating ideas for a feminine cycling image.\n\nReported benefits from commuting by bicycle included swiftness of travel through busy traffic, not having to rely on public transport, and improved fitness (for men) or body shape (for women). An additional factor was reassurance that the environment is being protected (one [+] interviews, UK).\n\nParents were reported to drive less to work when cycling was encouraged by their workplace (one [+] survey, Australia).\n\nHowever, cyclists in the city report a number of obstacles that can interrupt the journey, such as poor road surfaces, manhole covers, glass, rough gutters, hilly terrain, parked cars and buses. In addition, pollution and bad weather can be a disincentive (one [++] interviews, UK; one [+] survey and interviews, UK). A (+) survey from Australia reported that women cyclists preferred off-road paths compared to roads with no facilities, and off-road paths compared to on-road lanes.\n\nCommuting by cycle often involved carrying extra clothes to work and extra time at work to get changed from cycling outfits to work attire, including re-styling hair after wearing a helmet. Lack of available facilities was a barrier to cycling, as were saddle-soreness and tiredness.\n\nCycling on the road also requires negotiation with other road users. Cyclists reported fears of traffic and of accidents which meant having to be constantly alert for other traffic in order not to collide, and feeling vulnerable when crossing traffic to turn right.\n\nCyclists reported feeling segregated and invisible on the road. In areas where cycling is traditionally less prominent, there was a 'strangeness' about cycling, which was internalised by cyclists. There was also a perception that cycling is a male (predominantly white) activity, and some women felt the need to construct their own cycling identity, which could mean resisting the 'blokey' image and embracing femininity (for example, wearing heels while cycling; using blogs to reinforce identity).\n\nApplicability: The findings from these studies are applicable to cyclists who commute in the UK and Australia. Differences in experiences between cycling populations (gender, ethnicity etc.) and between settings in their promotion and support of cycling need to be taken into account.\n\n## Evidence statement R2.ES19: Views about cycling identities\n\nModerate evidence from one (+) UK focus groups and interviews study that obtained car driver views of adult cycling identities.\n\nCycling for transport requires negotiating space on the road. Some cycling behaviours were perceived as inappropriate by some other road users, giving cyclists a poor image and limited relationship with drivers.\n\nCar drivers reported being fearful of collisions, since cars and cycles travel at different speeds, and gave cyclists a wide berth. Some cyclists were reported as behaving poorly on the roads, for example passing through red lights, and this contributed for some, to cyclists having a negative image. Drivers that cycled were more likely to have empathy with cyclists on the road. Cycling proficiency testing, road taxes and compulsory helmet wearing were suggestions for improving the status of cyclists on the road.\n\nApplicability: Findings from this study are applicable to car drivers in the UK. How cyclists are perceived by other road users and the impact that this may have for cyclists needs to be taken into account.\n\n## Evidence statement EM.ES1: Led walking including 'walking school bus'\n\nModerate evidence from four studies suggests that led walking interventions (seven different interventions analysed in four studies) could be cost effective.\n\nA Spanish study: 6-month programme to promote walking-based exercise via a supervised exercise programme with three 50-minute sessions per week. Incremental cost per QALY range of €94– 871 per QALY.\n\nA US study: community-based social support strategies, including organised walking groups, home visits and phone calls, and newsletters, maps and handouts. Incremental cost per QALY of $27,373 and $39,690 for the two different led walking interventions versus do nothing.\n\nA UK study: organised community walking groups. The two organised walking group interventions showed a cost per QALY of £301 and £475.\n\nAnother UK study:walking bus intervention designed to encourage schoolchildren to walk to school. Incremental cost per QALY estimated to be approx. £4007 per QALY gained.\n\nThe evidence is partially applicable to the UK, with two of the studies UK-based, and the other international studies concerning interventions that could be of UK relevance.\n\n## Evidence statement EM.ES2: Pedometers\n\nModerate evidence from one Australian study suggests pedometer interventions could be cost effective: pedometer interventions, which used a meta-analysis of eight randomised control trials. Pedometer interventions maintained a net saving even when the intervention effect was modelled to decay completely by the end of the first year. That is, the modelled lifetime cost savings to the health service outweighed the pedometer costs as well as providing health benefits.\n\nThe evidence is partially applicable to the UK as similar pedometer interventions are of relevance.\n\n## Evidence statement EM.ES3: Media campaigns\n\nModerate evidence from one UK study suggests media campaigns could be cost-effective: media campaigns circulating maps of walking and cycling routes. The cost-per-QALY of £86 for provision of a healthy living map with walking and cycling routes, and £288 for the promotion of walking and cycling through printed media.\n\nThe evidence is applicable to the UK.\n\n## Evidence statement EM.ES4: Community health information (TravelSmart)\n\nModerate evidence from one Australian study suggests TravelSmart interventions could be cost-effective: TravelSmart intervention with individualised information to households on travel choices measuring change in the number of walking and cycling trips made per week. The TravelSmart programme resulted in a cost of $18,000 per disability-adjusted life year (DALY) assuming 50% decay per annum. The TravelSmart programme had net savings with annual decay rates of 0% and 25%, but costs rose to $41,000 per DALY at 75%, and $63,000 per DALY at 100% decay.\n\nThe evidence is partially applicable to the UK as the TravelSmart style intervention is relevant in the UK.\n\n## Evidence statement EM.ES5: Multi-component (Cycling Demonstration Towns)\n\nModerate evidence from one UK study suggests that the Cycling Demonstration Towns projects have a good benefit/cost rate.\n\nThe study: infrastructure measures such as the building of cycle paths, combined with a programme of education and marketing aimed at the general population. Benefits converted to monetary values and compared with the initial investment and running costs to produce a benefit–cost ratio. A range of 2.6–3.5 was given, reflecting the different approaches available for estimating accident and absenteeism benefits. Under all but the most pessimistic of scenarios considered, the benefit–cost ratio remained above one.\n\nThe evidence on cycle demonstration town is directly applicable as it was conducted in the UK.\n\n# Additional evidence\n\nExpert paper 1 'Paving the way for everyday walking: 'Living Streets' interventions and public health'\n\nExpert paper 2 'Making walking and cycling normal: key findings from the understanding walking and cycling research project':\n\nExpert paper 3 'Programmes to promote cycling – evidence for NICE from CTC':\n\nExpert paper 4 'Evidence to NICE PDG walking and cycling: experience from Bristol City Council and cycling city (2008–2011)': Ed Plowden, Bristol City Council\n\nExpert paper 5 'Submission to the NICE programme development group on walking and cycling'\n\nExpert paper 6 'Effectiveness of interventions to increase cycling'.\n\n# Economic modelling\n\nOverall, all the interventions modelled were found to be highly cost effective, with each estimated to cost below £10,000 per quality-adjusted life years (QALYs) gained.\n\nThe economic model was constructed to incorporate, where possible, data from the reviews of effectiveness and cost effectiveness. In addition, it built on the relationship between:\n\nphysical activity and relative risk of mortality\n\nlevels of walking and cycling and overall physical activity\n\nlevels of walking and cycling and motorised travel (especially driving distance, but also driving time and number of trips).\n\nFour interventions were modelled:\n\nTwo multi-component interventions (Cycling Demonstration Towns and SustainableTravel Towns).\n\nPersonalised travel advice (TravelSmart).\n\nUse of pedometers.\n\nCommunity-based led walks.\n\nHealth outcomes were expressed using QALYs gained and incremental net benefit (INB).\n\nWider impacts (environmental and traffic-related outcomes) were based on a limited selection of environmental outcomes and the value of a statistical life, expressed in terms of environmental benefit-cost ratios. The ratios were calculated based on the framework used by the Department for Transport.\n\nIt should be noted, that in the Department for Transport framework, most of the calculated benefits derived from health outcomes related to increased physical activity (up to 83%). However, health outcomes were excluded when calculating the environmental benefit-cost ratio, as they had been considered separately in a cost–utility analysis. Thus the results should be interpreted with caution.\n\nA series of 'what if' analyses was undertaken to determine if the level of cost is justified for interventions producing a particular level of effect. In addition, the trade-off between narrow interventions with large effects per person were compared with wider interventions leading to smaller effects per person.\n\nA number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions. The results of the modeling were non-linear. The key factors influencing outcome were: threshold cost, level of effects, decay in effects and costs related to initial effects.\n\nThe specific scenarios considered and the full results can be found in 'Interventions to promote cycling and walking for recreational and travel purposes: Health economic and modelling report'.", 'Appendix D Gaps in the evidence': "The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below.\n\n. There is a lack of UK evidence on whether or not interventions to increase walking or cycling for transport or leisure result in a decrease or increase in participation in other types of physical activity. Evidence is needed for a range of groups within different community settings.\n\n. There is a lack of evidence on whether people who cycle or walk for recreational purposes, eventually adopt it as a form of transport.\n\n. There is a lack of evidence on the long-term health, social and environmental impact of short-term interventions to increase walking or cycling. Specifically, there is a lack of evidence on the impact of interventions to encourage walking, cycling or both, for a range of groups within different community settings.\n\n. There is a lack of evidence on whether it is effective and cost effective to support physically active travel as a segment of a longer journey. Specifically, it is not clear whether such support increases walking or cycling levels and, if it does, how this impacts on the environment.\n\n. There is a lack of UK evidence on whether differences in urban and rural settings and environments impact on the implementation and effectiveness of interventions to increase walking or cycling. Evidence is needed for a range of groups within different community settings.\n\n. There is a lack of evidence on the barriers to, and facilitators for, inter-sector and inter-agency collaboration to promote walking and cycling. Evidence is also needed on the interventions that could overcome any identified barriers. Barriers may include the working cultures of different professionals.\n\n. There is a lack of UK evidence on how effective and cost effective it is to address walking and cycling together or separately. Specifically, there is a lack of evidence on how combining interventions impacts on their effectiveness – and whether multiple interventions have a positive, synergistic effect. Evidence is needed for a range of groups within different community settings.\n\n. There is a lack of evidence on how people can be helped to make walking or cycling an habitual activity. Evidence is needed for a range of groups within different community settings.\n\n. There is a lack of UK evidence on the extent to which the provision of a free bus service impacts on walking levels. Evidence is needed for a range of groups within different community settings.\n\n. There is a lack of UK evidence on the impact that an individual's perception of distance has on their view of how viable cycling or walking is as a mode of transport. There is also a lack of evidence on what interventions can effectively change someone's perception of distance as a barrier to walking and cycling. Evidence is needed for a range of groups within different community settings.\n\n. There is a lack of UK evidence on the social constructs which act as barriers to, and facilitators for, the uptake of walking or cycling as a mode of transport. Evidence is needed for a range of groups within different communities.\n\nThe Group made 5 recommendations for research into areas that it believes will be a priority for developing future guidance.", 'Appendix E Supporting documents': "Supporting documents include the following.\n\nEvidence reviews:\n\n\n\nReview 1: 'Systematic review and narrative synthesis of the effectiveness of local interventions to promote cycling and walking for recreational and travel purposes', and 'Evidence statements on the effectiveness of local interventions to promote cycling and walking for recreational and travel purposes'\n\nReview 2: 'Synthesis of evidence relating to barriers and facilitators to implementing interventions that promote cycling and walking, and to carrying out cycling and walking for recreational and travel purposes'.\n\n\n\nEconomic modeling: 'Interventions to promote cycling and walking for recreational and travel purposes: Health economic and modelling report'.\n\nExpert papers:\n\n\n\nExpert paper 1 'Paving the way for everyday walking: Living Streets interventions and public health'\n\nExpert paper 2 'Making walking and cycling normal: key findings from the understanding walking and cycling research project'\n\nExpert paper 3 'Programmes to promote cycling – evidence for NICE from CTC'\n\nExpert paper 4 'Evidence to NICE PDG walking and cycling: experience from Bristol City Council and cycling city (2008–2011)'\n\nExpert paper 5 'Submission to the NICE programme development group on walking and cycling'\n\nExpert paper 6 'Effectiveness of interventions to increase cycling'.\n\n"}	https://www.nice.org.uk/guidance/ph41	This guideline covers encouraging people to increase the amount they walk or cycle for travel or recreation purposes.
2a8ce388e7d1c0bf619852c859fd1f7a3d18bce2	nice	Mannitol dry powder for inhalation for treating cystic fibrosis	Mannitol dry powder for inhalation for treating cystic fibrosis # Guidance Mannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults: who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and whose lung function is rapidly declining (forced expiratory volume in 1 second decline greater than 2% annually) and for whom other osmotic agents are not considered appropriate. People currently receiving mannitol whose cystic fibrosis does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology Mannitol (Bronchitol, Pharmaxis) is a mucoactive agent that causes water to enter the airway lumen and hydrate airway secretions. This reduces the viscosity of secretions and stimulates cough, thereby increasing the clearance of secretions and pathogenic bacteria. Mannitol dry powder is inhaled from a hand-held, breath-activated device. Mannitol has a marketing authorisation as an add-on therapy to best standard of care in adults with cystic fibrosis. The summary of product characteristics states that the recommended dose is 400 mg twice a day. The most common and important adverse reactions associated with mannitol as stated in the summary of product characteristics are hyperresponsiveness to mannitol, cough, bronchospasm, exacerbation of cystic fibrosis, chest discomfort, wheezing, throat irritation, vomiting, headache and pharyngolaryngeal pain. The most clinically significant adverse reaction associated with mannitol use is haemoptysis (coughing up of blood). Mannitol is available as a 40 mg powder capsule for inhalation. The list price for a 14-day pack of 280 capsules and 2 inhalers is £231.66 (excluding VAT; 'Monthly Index of Medical Specialities' September 2012). This equates to £0.83 per 40 mg capsule, or an average cost of £16.55 per day, including the cost of the inhaler. These prices do not include VAT. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of mannitol and a review of this submission by the Evidence Review Group (ERG; appendix B). # Clinical effectiveness The manufacturer presented clinical-effectiveness data from 2 randomised multinational double-blind controlled trials (DPM-CF-301 and DPM-CF-302). The trials were designed to assess the effectiveness of twice-daily mannitol at a dose of 400 mg compared with a 50 mg dose of mannitol twice daily, assumed to be sub-therapeutic. Patients in both arms also received best supportive care with or without rhDNase. Best supportive care included, but was not limited to, inhaled antibiotics, anti-inflammatory agents, bronchodilators, vitamin supplements, pancreatic enzymes, and antidiabetic agents for people with diabetes. The trials had 26-week double-blind phases, followed by further unblinded phases of 26–52 weeks. The inclusion and exclusion criteria for the 2 trials were similar but differed in the lower cut-off for 'FEV1% predicted' (FEV1% of the patient adjusted for the average FEV1% in the population for any person without cystic fibrosis of similar age, sex and body composition); this was 30% in DPM-CF-301 and 40% in DPM-CF-302. DPM-CF-301 included 295 patients (190 adults) and took place at 40 centres in Australia, New Zealand, the UK and Ireland. The manufacturer presented results for adults only, in line with the marketing authorisation. There were 114 adults in the mannitol arm, of whom 58 used rhDNase and 56 did not use rhDNase, and 76 adults in the control arm, of whom 44 used rhDNase and 32 did not use rhDNase. There were 30 adults in the mannitol arm and 13 in the control arm (43 in total) who could not take rhDNase because of ineligibility, intolerance, or inadequate response to rhDNase. The remaining 45 patients did not use rhDNase for other reasons that were not recorded. DPM-CF-302 included 305 patients (151 adults) and took place at 53 centres in the USA, Canada, Argentina, Germany, Belgium, France and the Netherlands. The manufacturer presented results for adults only. There were 93 adults in the mannitol arm, of whom 64 used rhDNase and 29 did not use rhDNase, and 58 adults in the control arm, of whom 41 used rhDNase and 17 did not use rhDNase. There were 15 adults in the mannitol arm and 7 in the control arm (22 in total) who could not take rhDNase because of ineligibility, intolerance, or inadequate response to rhDNase. The remaining 24 patients did not use rhDNase for other reasons that were not recorded. After a request by the ERG for clarification, the manufacturer submitted information on 2 groups defined by their use of rhDNase: (1) people using rhDNase and (2) people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The trial protocols for DPM-CF-301 and DPM-CF-302 were similar. Because mannitol and hypertonic saline have similar modes of actions, patients taking nebulised hypertonic saline were excluded from DPM-CF-301 and, in DPM-CF-302, patients could use nebulised hypertonic saline at initial assessment but had to stop 4 weeks before the baseline assessment. Potential participants were screened for bronchial hyperresponsiveness to mannitol, and those with hyperresponsiveness were excluded before randomisation. Randomisation was stratified by region and rhDNase use. The studies were powered to show an improvement in FEV1 in both patients who took rhDNase and also the total trial population. There were 4 follow-up visits after the screening visit, at week 0 (start of treatment with mannitol or control) and at weeks 6, 14, and 26. In both trials, patients were offered the opportunity to continue or start mannitol treatment in an open-label phase for a further 26 weeks to gain more information on adverse reactions; in DPM-CF-301, there was an additional open-label extension phase of 26 weeks, giving a total of 78 weeks. The primary outcome in both trials was the absolute FEV1 as measured in millilitres over 26 weeks. Both trials reported changes in FEV1 from baseline in the mannitol group compared with the control group. Secondary outcomes included the proportion of patients who responded by FEV1 criteria defined as achieving an increase from baseline of at least 100 ml in FEV1, or at least a 5% increase in absolute FEV1 in millilitres, or at least a 5 percentage point increase in FEV1% predicted. Protocol-defined pulmonary exacerbations (PDPE) were defined as pulmonary events with 4 or more pre-defined symptoms or signs needing intravenous antibiotics. Reductions in the frequency of both PDPE and hospital care were measured in both trials. Both trials measured quality of life using the Cystic Fibrosis Questionnaire – Revised (CFQ-R); DPM-CF-302 also used the Health Utility Index 2 (HUI2). The CFQ-R was administered to patients at week 0 and then at weeks 14 and 26. Antibiotic use and adverse events were also measured in both trials. In the manufacturer's original submission, lung function was reported only for the subgroup of adults using rhDNase, in line with the fact that only 1 subgroup was pre-specified in the statistical plan of the study protocol. After a request by the ERG for clarification, the manufacturer submitted data on change in FEV1 and exacerbations for adults using rhDNase and also for adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. In the DPM-CF-301 trial, mannitol statistically significantly improved lung function over 26 weeks compared with the control, as measured by a change in FEV1 from baseline of 109.3 ml (95% confidence interval 52.8 to 165.8; p<0.001) in adults using rhDNase. This difference was evident at 6 weeks of treatment and was maintained over the 26-week double-blind phase. For the other measures of lung function, the mean difference from baseline between adults randomised to receive mannitol plus rhDNase compared with the control group were: mean percentage change in FEV1 from baseline of 4.2% (95% CI 0.3 to 8.1); change in FEV1% predicted of 2.7% (95% CI 0.6 to 4.7) and change in forced vital capacity (FVC) of 117.4 ml (95% CI 1.0 to 233.9). After a request for clarification, the manufacturer provided the change in FEV1 over 26 weeks for the 43 adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase; this was 147.0 ml, a difference that was statistically significant between the mannitol and control group (95% CI 23.2 to 270.7, p=0.02). In the DPM-CF-301 trial, for people using rhDNase, the incidence of PDPE (over the 26-week time horizon of the trial) was 27.6% for adults randomised to mannitol compared with 36.4% in the control group. For adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the incidence of PDPE was 16.7% in the mannitol group compared with 30.8% in the control group. The rate of PDPE per year was 1.41 for adults receiving mannitol plus rhDNase compared with 1.58 in the control group. The estimated PDPE rate per year was 0.41 for adults randomised to receive mannitol who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase compared with an estimated 0.64 in the control group. There was a 36.5% reduction in the rate of exacerbations in the mannitol group compared with the control group for patients who could not use rhDNase, but this was not statistically significant. The trials were not powered to demonstrate statistically significant differences for PDPE outcomes in these subgroups. In the DPM-CF-302 trial, the mean change in FEV1 over 26 weeks for adults using rhDNase and randomised to receive mannitol was not statistically significantly different from the control group (88.5 ml, 95% CI −8.5 to 185.4). For the other measures of lung function in adults using rhDNase randomised to receive mannitol compared with the control group, the mean difference in the changes from baseline were 5.4% (95% CI −0.4 to 11.3) for FEV1, 3.0% (95% CI −0.6 to 6.5) for change in FEV1% predicted and 96.9 ml (95% CI −7.7 to 201.6) for changes in FVC. After clarification, the manufacturer provided the difference in the change in FEV1 over 26 weeks for mannitol in 22 adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase compared with the control group; this was 208.6 ml (95% CI −9.3 to 426.5, p=0.061). In the DPM-CF-302 trial, the incidence of PDPE (over the 26 weeks of the trial) was 18.8% in adults using rhDNase alone compared with 9.8% for adults receiving mannitol plus rhDNase. For adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the PDPE incidence was 13.3% for adults randomised to mannitol compared with 42.9% in the control group. The estimated PDPE rate per year was 0.83 for adults randomised to mannitol plus rhDNase compared with 0.19 in the control group. The estimated PDPE rate per year was 0.26 for adults randomised to receive mannitol who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase compared with an estimated 0.86 in the control group. However, the trials were not powered to demonstrate statistically significant differences for these outcomes in patients not receiving rhDNase or patients who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. In response to the appraisal consultation document (ACD), the manufacturer presented analyses pooling the results of the DPM-CF-301 and DPM-CF-302 trials. The outcomes in the pooled analyses did not include the primary outcome, absolute FEV1, but instead were FEV1% predicted, the proportion responding according to FEV1 criteria, and the estimated rate of PDPE per patient per year. For the pooled adult population of people using rhDNase, the mean change in FEV1 over 26 weeks for patients receiving mannitol plus rhDNase was 94.1 ml (95% CI 29.7 to 158.42). For people who received mannitol but did not take rhDNase (irrespective of the reason), the change was 110.3 ml (95% CI not given, p<0.005). The change was 166.7 ml (95% CI 52.0 to 280.6) for the subgroup of adults receiving mannitol who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The pooled results for both trials for adults who could not use rhDNase were 0.27 PDPE per year in the mannitol group compared with 0.96 PDPE per year in the control group (not statistically significant). The manufacturer reported on adverse events for the whole adult population, but not for the rhDNase subgroups based on rhDNase use. Overall, 87% of all adults experienced at least 1 adverse event, the most common adverse event being cough (the only adverse event that occurred in more than 10% of adults). However, the manufacturer considered productive cough a desired effect of treatment with mannitol. Other adverse events with an incidence of between 1% and 10% over 26 weeks were decreased appetite, headache, haemoptysis, bronchospasm, wheezing, asthma, condition aggravated, pharyngolaryngeal pain, and chest discomfort. Haemoptysis was the most clinically significant adverse event in both studies and was observed in 11.9% of adults on treatment with mannitol and 8.5% in the control group in the DPM-CF-301 trial, and in 7.1% in the mannitol group and 2.5% in the control group in the DPM-CF-302 trial. In response to the ACD, the manufacturer submitted pooled analyses on haemoptysis events based on the protocol-defined criteria for PDPE. For all adults using rhDNase, 16.4% experienced haemoptysis in the mannitol group and 20.0% in the control group. For adults not using rhDNase, these figures were 14.1% in the mannitol group and 14.3% in the control group. Health-related quality of life was only presented for the whole adult population in the original manufacturer's submission. There were no statistically significant changes in the CFQ-R domains in either trial for adults randomised to receive mannitol relative to the control group. The results suggested some improvement in the respiratory, physical and vitality domains of CFQ-R, but these did not achieve statistical significance. In DPM-CF-302, there was no statistically significant difference in HUI2 measurements between adults randomised to receive mannitol and the control group. In response to the ACD, the manufacturer submitted the proportion of adults whose condition was considered to respond to treatment based on FEV1 criteria for both trials. In the DPM-CF-301 trial, for adults using rhDNase, the condition responded in 41.4% in the mannitol group and 27.3% in the control group; for adults not using rhDNase, these figures were 60.7% in the mannitol group and 40.6% in the control group. In the DPM-CF-302 trial, for adults using rhDNase, the condition responded in 45.3% in the mannitol group and 39.0% in the control group; for adults not using rhDNase, these figures were 44.8% in the mannitol group and 44.8% in the control group. # Cost effectiveness The manufacturer developed a Markov health-state transition model, implemented as a patient-level simulation model evolving over the lifetime of the patient, and modelling 2 treatment options: treatment with inhaled mannitol and treatment without inhaled mannitol. The manufacturer did not model inhaled hypertonic saline as a treatment that a patient may use with, or instead of, mannitol. The model assumed treatment with mannitol for lifetime or until drop-out (according to the rate modelled on the trials). The analysis had a time horizon of 100 years, at which point all patients would have died. The cycle lengths were taken from the time between visits in the 2 trials, and were 6 weeks for the first cycle, 8 weeks for the second cycle and 12 weeks for each subsequent cycle. The transition parameters between the health states depended on characteristics derived from the clinical trial such as age, history of pulmonary exacerbations and use of mannitol. The health states in the model include cystic fibrosis, cystic fibrosis with improved respiratory symptoms, lung transplantation, death from cystic fibrosis, and death from an unrelated cause. At baseline, all patients enter the cystic fibrosis health state. As patients progress, if their FEV1% predicted falls below 30%, they enter the lung transplantation state in which they have a probability of receiving a transplant in subsequent cycles. The model includes a discontinuation rule under which patients whose condition does not respond to mannitol treatment within 6 weeks stop mannitol and switch to best standard of care. Modelled to mirror the clinical trial, the definition of a response is either a relative increase of 5% or more in absolute FEV1 or an absolute increase of 100 ml or more in FEV1 at week 6 from baseline. In subsequent cycles, a patient may switch between the health states of cystic fibrosis and cystic fibrosis with improved respiratory symptoms and back again, and patients in either state may experience a pulmonary exacerbation. Patient characteristics such as body mass index (BMI), age and FEV1% predicted are updated. The manufacturer used clinical-effectiveness data from the DPM-CF-301 and DPM-CF-302 trials to obtain baseline values and some, but not all, transition parameters used in the model, such as FEV1% predicted at week 26, the probability of being a 'responder' at 26 weeks and the relative risk of pulmonary exacerbations for 'responders' to treatment. Other transition parameters were derived from the literature and from the commissioned BioGrid study using regression analysis, such as FEV1% predicted over time, the rate of exacerbations and mortality after lung transplant. The baseline characteristics (age, sex, BMI and FEV1% predicted) were taken from the pooled adult population from the DPM-CF-301 and DPM-CF-302 trials. The manufacturer also used data from the trials to estimate the probability of response to mannitol, FEV1% predicted after 26 weeks of treatment, the effect of treatment on pulmonary exacerbations, and the probability of improvement in respiratory symptoms. The manufacturer estimated changes in FEV1% predicted and the risk of an exacerbation after baseline from the BioGrid retrospective observational study of disease progression in cystic fibrosis, which used data from Australia (the BioGrid data) and was commissioned by the manufacturer. The decline over time in FEV1% predicted was modelled dependent on age, age above 30 years, and pulmonary exacerbations (using hospital admissions as a proxy). The manufacturer estimated the relationship between FEV1% predicted and mortality rate from the BioGrid data using survival analyses. In the model, mortality depended on FEV1, exacerbations, age, sex, concurrent infection with Burkholderia cepacia and lung transplantation. After a request for clarification from the ERG, data on these variables were provided to update the model for patients who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. Utility values were drawn largely from HUI2 data collected during the DPM-CF-302 trial; the manufacturer also included values from the literature for lung transplantation and pulmonary exacerbations. The baseline utility was taken as the mean overall HUI2 global utility score at baseline (0.899). The manufacturer calculated the change in utility between baseline and visit 3 or in week 14, or between baseline and the last visit in the case of early withdrawal. The manufacturer calculated the HUI2 global utility scores for each health state by adding the average change to the baseline utility. The increase in utility value for patients with improved symptoms was 0.009 in the control group and 0.019 in the mannitol group. The decrease in utility for patients without improved symptoms was 0.046 for patients in the control group and 0.022 in the mannitol group. Utility values were not linked directly to lung function. The HUI2 questionnaire was administered in the trial at weeks 0, 12 and 26, but had a recall period of 1 week, and so did not necessarily capture the effect of PDPEs on health-related quality of life at the time they occurred. Therefore, the manufacturer took utility data for PDPEs and post-lung transplantation from the literature. Adverse events had a negative impact on CFQ-R data in both trials. The manufacturer calculated the costs of treatment with or without mannitol accumulated up to 26 weeks, but made no distinction between patients whose lung function improved and those whose did not. The model included costs related to pulmonary exacerbation and for the time periods before and after lung transplantation. Costs were taken from national reference costs. The manufacturer included costs for concomitant medications (mostly antibiotics) for both groups, and used a mean cost of £3253 in the mannitol group and £2972 in the control group (with a cost of £0 for the subclinical trial dose). In the trials, most patients were admitted to hospital at least once, and approximately 40% had a community visit during the 26-week randomised phase of the trial. Costs of pulmonary exacerbation were taken from the trial data. For patients receiving mannitol, the mean total cost of medications, community visits and hospitalisations without a PDPE in the 26-week trial period was £4391, and taking into account PDPE the cost was £12,852. From the trial, for patients in the control group, the mean total costs without PDPE were £4664 and with at least 1 PDPE were £10,354. The manufacturer used peri-transplant costs from the UK literature and resource use from the trial and patient records. The manufacturer applied a discount rate of 3.5% to both costs and benefits. The manufacturer's base-case results indicated an incremental cost-effectiveness ratio (ICER) for mannitol compared with treatment without mannitol (best supportive care) of £47,095 per quality-adjusted life year (QALY) gained in adults using rhDNase and £41,074 per QALY gained in adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The manufacturer undertook extensive scenario analyses and deterministic sensitivity analyses for the treatment of adults using rhDNase and for adults not using rhDNase (irrespective of the reason for non-use). The parameters that changed the ICER by more than 10% were: FEV1% predicted at baseline the regression parameter estimate for mannitol treatment used to predict the FEV1% predicted after 26 weeks of treatment (that is, the effect of treatment) the relative risk of an exacerbation with mannitol relative to not using mannitol for people whose condition was considered to respond to treatment the relative risk of a subsequent exacerbation if there had been an exacerbation in the previous year hazard rate of death for the FEV1% predicted the utility decrement associated with an exacerbation the utility associated with no improvement in respiratory symptoms among patients using or not using mannitol the cost of an exacerbation. The manufacturer also performed sensitivity analyses showing the effect of several parameters, including treatment failure after 1, 5, 10 and 20 years. The base-case model assumed that patients using mannitol maintained the difference in lung function over their lifetime. Not maintaining the improvements in FEV1% predicted over the long term had a large effect on the ICER. If the improvements in FEV1% predicted were maintained for only 1 year the ICER was £149,587 per QALY gained; if improvements were maintained for 5, 10 and 20 years, the ICERs were £86,981, £63,539 and £49,907 per QALY gained respectively. Other factors that had an impact on the ICER were the rate ratio of pulmonary exacerbations between people receiving and those not receiving mannitol, whether the discontinuation rule was applied, the relative risk of a PDPE if the patient experienced an exacerbation in the previous year, costs and utilities. The manufacturer concluded that the main factors affecting the ICER were: the cost of mannitol the relative risk of pulmonary exacerbations in the mannitol group the impact of pulmonary exacerbations on quality of life the FEV1% predicted when starting mannitol the improvement in FEV1% predicted on mannitol treatment the hazard rate of death for FEV1% predicted utility for patients whose symptoms do not improve. After a request from the ERG, the manufacturer provided scenario analyses taking into account reduced adherence to treatments, which reduced the costs in the mannitol group. Using a lower mean adherence gave an ICER of £37,387 per QALY gained for mannitol compared with the control in adults using rhDNase, and £33,934 per QALY gained for mannitol compared with the control in adults not using rhDNase. There was uncertainty around the relative risk of PDPE, and the model was sensitive to fluctuation in this parameter. Using the relative risk of exacerbation of 0.7 associated with treatment with mannitol for the total adult population (provided by the manufacturer in response to a request for clarification from the ERG), the ICER for mannitol compared with not using mannitol was £54,329 per QALY gained in adults using rhDNase and £27,673 per QALY gained in adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. Using a relative risk of exacerbations based on adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the ICER per QALY gained was £19,828. In the manufacturer's probabilistic sensitivity analyses, as an add-on therapy to best standard of care, mannitol had a 16.4% probability of being cost effective at an ICER of £30,000 per QALY gained and a 7.4% probability at an ICER of £20,000 per QALY gained. For non-users of rhDNase, mannitol had a 25.8% probability of being cost effective at an ICER of £30,000 per QALY gained and a 10.9% probability at an ICER of £20,000 per QALY gained. In response to a request from the ERG to estimate the cost effectiveness separately for adults using rhDNase and adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the manufacturer re-ran the probabilistic sensitivity analysis. This resulted in mean ICERs of £53,796 per QALY gained for adults using rhDNase and £30,080 per QALY gained for adults ineligible for rhDNase. The manufacturer conducted 2 further subgroup analyses, one by baseline FEV1% predicted and the other among patients whose condition responded to treatment with mannitol by 6 weeks. The analyses showed that, as baseline FEV1% predicted declines, the ICER decreases. For FEV1% predicted 80% or more, the ICERs were £56,228 per QALY gained for adults using rhDNase and £50,688 per QALY gained for adults not using rhDNase. For FEV1% predicted less than 40%, the corresponding ICERs were £30,746 per QALY gained for adults using rhDNase and £23,704 per QALY gained for adults not using rhDNase. In response to the ACD, the manufacturer submitted a revised model for people with cystic fibrosis not using rhDNase, including people whose reason for not using rhDNase was not reported in the trials and is not known. In addition, the manufacturer changed several key parameters in the model. The health states in the model more closely model health states rather than treatment states. The costs and utility values in the revised model no longer depend on treatment, but rather on whether the simulated patient has improved respiratory symptoms or not. The utility values are no longer directly tied to lung function. The manufacturer also included a new stopping rule, centred on the Committee's concerns that a stopping rule based on an FEV1 improvement as defined would be unlikely to be implemented in practice. In the new stopping rule, people are permitted to continue using mannitol if their FEV1 improves by more than 0%, that is, if their FEV1 improves at all. The manufacturer continued to base its model on the BioGrid data, but submitted evidence in an effort to show that the BioGrid population was similar to the UK population with cystic fibrosis. For people not using rhDNase, the manufacturer used a revised utility value of 0.896. In the original model, the change in utility value was 0.015 for people using mannitol who had improved respiratory symptoms, and 0.031 for people using mannitol who did not have improved respiratory symptoms. In the revised model, the change in utility value for people not using rhDNase and who took mannitol and had improved respiratory symptoms increased to 0.025 and for people who did not use rhDNase who took mannitol and had no improvement it decreased to 0.001. In the ERG's analyses, treatment for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase had costs of £3885 if they improved and £4385 if they did not improve, a difference of £500. In the model developed in response to the ACD, treatment for people who did not use rhDNase had costs of £2307 if they improved and £3255 if they did not improve, a difference of £948. The manufacturer chose a baseline PDPE rate of 1.01, based on the ERG's critique of the original model. The manufacturer did not provide revised estimates of cost effectiveness for the whole population. The revised ICER for mannitol compared with best supportive care was £19,993 per QALY gained in people not using rhDNase, and had an 82.2% probability of being cost effective at an ICER of £30,000 per QALY gained and a 46.5% probability at an ICER of £20,000 per QALY gained. Furthermore, the manufacturer provided a new analysis based on adherence rates of 30% and 70%. Keeping the QALYs constant, the ICER per QALY gained was £6327 at a compliance of 30% and £14,137 at a compliance of 70%. The manufacturer submitted additional clinical evidence indicating that the relative benefit with respect to FEV1 associated with taking mannitol was maintained over 78 weeks. This evidence derived from an extension of the 2 trials. The manufacturer also provided scenario analyses showing the ICERs for shortening the model's time horizon from lifetime (100 years) to 5, 10 and 50 years to be £45,329, £25,151 and £20,018 per QALY gained respectively. In response to the ACD, the manufacturer also conducted a survey defining the treatment pathway for managing sputum in cystic fibrosis. The manufacturer noted that this survey showed 82% of people with cystic fibrosis have trialled hypertonic saline before age 18 years. The manufacturer stated that clinicians would be reluctant to change treatments for people with well-controlled cystic fibrosis. They also noted that approximately a third of people currently using hypertonic saline did not have well-controlled cystic fibrosis and may be able to benefit from mannitol. # Evidence Review Group comments The ERG regarded DPM-CF-301 and DPM-CF-302 as well designed, high-quality trials, with a large combined study population. The ERG noted the change in therapeutic indication of mannitol limiting it to adults, which reduced the combined study population to 341 and consequently reduced the statistical power of all the analyses. The ERG conducted pooled analyses on the results of the DPM-CF-301 and DPM-CF-302 trials. These showed statistically significant differences between mannitol and the control with all outcomes related to lung function. Among adults using rhDNase, the differences between mannitol and control over 26 weeks were as follows: 91.8 ml (95% CI 30.9 to 152.7) for change in FEV1, 4.6 (95% CI 1.3 to 7.8) for percentage change in FEV1, 2.7 (95% CI 0.9 to 4.5) for FEV1% predicted and 106.1 ml (95% CI 28.3 to 183.9) for FVC. The ERG analysed data from adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, rather than from the broader group of adults not using rhDNase because that reflected the anticipated marketing authorisation at that time, but the marketing authorisation was eventually not restricted to this group. For adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the change in FEV1 from baseline was 162.3 ml (95% CI 51.8 to 272.9). The ERG's pooled analyses showed that, for the adults using rhDNase, there were no statistically significant differences between the mannitol and control arm in incident PDPE over the 26 week trial period (relative risk 1.00, 95% CI 0.61 to 1.66), and no statistically significant difference in the estimated rate of PDPE per year (RR 1.14, 95% CI 0.75 to 1.73). In the group of people who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, there were also no statistically significant differences between mannitol and the control in the incidence of PDPE (RR 0.44, 95% CI 0.18 to 1.10) over the course of the trial. The ERG stated that restriction of the therapeutic indication to adults meant that the analysis was under-powered, a problem compounded by the post-hoc subgroup analyses of the pooled trial data, and contributed to the uncertainty around the results. The ERG conducted an indirect comparison of mannitol with hypertonic saline, in line with the scope. The 2 measures common to the identified study of hypertonic saline (0.9% saline) (Elkins et al. 2006) and the DPM-CF-301 and DPM-CF-302 trials were measurements of FEV1 and pulmonary exacerbations. The ERG found that mannitol improved FEV1 compared with hypertonic saline, although this was statistically significant only for the subgroup that could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. FEV1 was 94.3 ml (95% CI 29.0 to 159.6) higher with mannitol than with hypertonic saline, regardless of rhDNase use, and for adults using rhDNase FEV1 was 23.8 ml (95% CI −65.0 to 112.5) higher with mannitol than with hypertonic saline. In the ERG's view, the basic structure of the manufacturer's Markov model was appropriate for the research question, sufficiently inclusive and diverse to model the complexities of cystic fibrosis, but the ERG expressed concerns about the cost-effectiveness model. The ERG questioned the assumption by the manufacturer in the model that mannitol use was completely independent of rhDNase use (that is, that any benefit of mannitol did not depend on whether a patient used, or did not use, rhDNase). This led the ERG to re-analyse the data according to rhDNase use and to divide the group not using rhDNase into those who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and those who could use rhDNase but did not do so for unknown reasons. The ERG indicated that there was statistically significant heterogeneity in the overall group of people not using rhDNase. Patients who were able to take rhDNase but did not do so had different characteristics than those who were unable to take rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The ERG noted that mannitol is more likely to provide effective treatment to people who cannot rather than do not take rhDNase and who do not take hypertonic saline. The ERG noted that the manufacturer had not used the results of the trials in the model, but instead had developed regression equations to estimate lung function. The ERG felt that the use of regression was appropriate for this Markov patient-level model, and noted that the manufacturer had consulted with experts on cystic fibrosis and modelling. The manufacturer also ran a microsimulation (100,000 trials) to compare the model output with the pooled results of the DPM-CF-301 and DPM-CF-302 trials. The ERG found small mistakes in the manufacturer's model, but noted that the validation checks matched the results of the clinical studies at a time point of 26 weeks. The ERG noted that one of the most important assumptions made by the manufacturer was that any absolute improvement in FEV1% predicted relative to patients not using mannitol would be maintained throughout the lifetime of the patient, and would directly translate into lower rates of morbidity and mortality. That is, a patient on mannitol would experience a decline in lung function over time consistent with the natural history of disease but, on cessation of mannitol treatment, would start the decline at a higher level of FEV1% predicted than a patient not taking mannitol. The ERG was concerned that there were no long-term data to support this assumption. The ERG questioned the manufacturer's use of Australian BioGrid data for transition parameters, which may not be generalisable to the UK. The ERG was concerned about several assumptions made by the manufacturer in the original model about pulmonary exacerbations, namely the narrow confidence intervals around the baseline rate based on the BioGrid data used in the deterministic sensitivity analysis, and questioned whether it applied to a UK population. The ERG was concerned about assumptions made by the manufacturer in the original model that HUI2 utility and cost parameters depended on treatment, but not on health state. The ERG questioned that there was no direct link between lung function and utility and suggested that a model linking lung function to utility could have altered the cost effectiveness and could have decreased the ICER. The ERG conducted exploratory analyses to examine the effect on the ICER of varying the model assumptions and the input parameters, including the difference in costs and utilities associated with respiratory symptoms and exacerbations, and the mortality rate of cystic fibrosis by varying the FEV1% predicted. However, because of a lack of data, the ERG could not investigate the manufacturer's assumption that the probability of moving between health states remained the same over the lifetime of the patient. The ERG amended the model to include treatment-independent and improvement-specific values for costs and utilities; using rhDNase subgroup-specific relative risks associating treatment with exacerbations, changing the cost of rhDNase from £16.88 to the most recent price of £16.55 (British national formulary 61); and adjusting model parameters, probabilities and distributions. The ERG's exploratory cost-effectiveness analysis included the treatment options of best standard of care, rhDNase and mannitol, but not hypertonic saline. The ERG compared best standard of care with mannitol plus best standard of care. In people using rhDNase, best standard of care included rhDNase, and in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, best standard of care did not include rhDNase. These amendments resulted in the ERG's ICER for mannitol plus best supportive care compared with best supportive care of £80,098 per QALY gained in adults using rhDNase and £29,883 per QALY gained in adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The main reasons for the changes to the ICERs were the use of health-state specific costs and utilities used by the ERG rather than treatment specific costs and utilities used by the manufacturer, and the population specific relative risks for exacerbations. The ERG investigated the relationship between improvements in FEV1% predicted and survival, and found evidence to support the assumption that a 1 percentage point improvement in FEV1% predicted was related to an approximate 5% reduction in mortality. The ERG examined the assumption that the improvement in FEV1% predicted caused by mannitol would be maintained over the lifetime of the patient by reducing the time horizon of the model as a proxy for a shorter duration of effectiveness. This was similar to a scenario analysis conducted by the manufacturer. The ERG's analyses in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase resulted in ICERs for a time horizon of 5 years of £90,126 per QALY gained. For a time horizon of 10 years, the ICER was £49,854 per QALY gained for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The ERG pointed out that the manufacturer had generated cost data based on whether a patient received mannitol or not, rather than whether the patient was in a given health state. The manufacturer divided costs according to respiratory symptoms or according to rhDNase use, but did not estimate costs by both factors simultaneously. However, the ERG acknowledged that, in its revised model in response to the ACD, the manufacturer derived costs using patient-level data. The ERG used the information available to calculate the ratio of the improvement-specific costs to the overall mean costs as an estimate of the difference in costs by health state. The ERG calculated that patients with improved respiratory symptoms have 93% of the overall costs, whereas patients without improved symptoms have 105% of the overall costs. The ERG assumed these percentages also applied to mean costs with rhDNase. The ERG estimated 6-month treatment costs for improved and not improved respiratory symptoms in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The ERG decided that health-state specific costs should be used rather than treatment specific costs. The ERG confirmed that the manufacturer used treatment specific values in its revised analysis of people not using rhDNase. The ERG re-ran the probabilistic sensitivity analyses with assumptions based on its exploratory analyses, varying the exacerbation rate in the control group, making the costs and utilities improvement specific rather than treatment specific, and using shorter time horizons. The ERG calculated that there was a zero probability that the ICER for mannitol would lie below £30,000 per QALY gained for people using rhDNase. For those who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the probability that the ICER would be below £20,000 per QALY gained was 5%, and the probability it would be below £30,000 per QALY gained was 50%. The ERG considered the health-related quality-of-life data provided by the manufacturer in the form of HUI2 data collected in the DPM-CF-302 trial, and questioned the use of treatment-dependent values for utility. For its own sensitivity analyses, the ERG used values for utilities received from the manufacturer in response to a request for clarification and assumed that these values were independent of treatment. The ERG did not identify any other substantial health-related benefits not included in the QALY. The factors identified by the ERG as causing substantial differences in the ICERs generated by the ERG and the manufacturer included whether or not someone took rhDNase alongside mannitol, the assumption that any improvement in FEV1% predicted caused by mannitol would be sustained over the patient's lifetime, the assumption that patients whose condition did not respond to mannitol would discontinue therapy, and the effect of pulmonary exacerbations on utility. The manufacturer addressed these in their response to the ACD and in the second Committee meeting by changing these assumptions to be in line with those used by the ERG. In their response to the ACD, the manufacturer provided evidence to suggest that the BioGrid data were similar to the UK population with cystic fibrosis. The ERG explained to the Committee that there was a clinically meaningful difference in the FEV1% predicted values for the BioGrid data and the UK data (of 60.2% for the BioGrid data and 66.3% for the UK data) because every percentage point decrease in predicted FEV1% predicted has an impact on mortality. The ERG highlighted the additional analyses in the manufacturer's response to the ACD, which supported its assumption that improvements in FEV1% predicted would be maintained throughout the lifetime of the patient. In the second Committee meeting, the ERG stated that there was uncertainty about whether the benefit of mannitol would persist over time, decrease at the same rate as that of the control group, or decrease at a slower rate. The ERG commented that a time horizon of 50 years was likely to accurately represent the lifetime horizon of the adult UK population with cystic fibrosis. In examining the manufacturer's revised analysis in people who do not use rhDNase, the ERG identified 3 drivers that decreased the ICER from that in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase (as originally modelled): including the exacerbation rate chosen for the model; acknowledging that some people treated with mannitol stop taking it ('drop-outs'); and the change in the estimated price for best supportive care, with the difference between best supportive care and mannitol being smaller in the original model (£500) than in the revised model (£948). Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of mannitol, having considered evidence on the nature of cystic fibrosis and the value placed on the benefits of mannitol by people with cystic fibrosis, the people who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical practice The Committee discussed the clinical needs of people with cystic fibrosis. It heard from clinical specialists that cystic fibrosis leads to considerable morbidity and early mortality, and that there is no single standard care pathway in the UK. Clinicians and patients working with cystic fibrosis centres decide on treatment according to each patient's needs. The clinical specialists added that the aim of treatment in adults is to maintain lung function (as measured primarily by the absolute volume of FEV1 in millilitres), particularly after the age of 30 years. In response to the consultation, the clinical specialists added that it is particularly important to manage cystic fibrosis to prevent a further decline in lung function in patients with rapidly declining lung function (that is, more than 2% per year decline in FEV1% predicted). Clinicians and patients manage lung function primarily through efforts to reduce airway infections, increase airway clearance, aid sputum clearance and maintain body weight through good nutrition. The Committee heard from the clinical specialists that approximately 98% of people with cystic fibrosis are registered with cystic fibrosis centres, and that clinicians use the Cystic Fibrosis Trust guidelines as the basis for best standard of care. The Committee heard from the clinical specialists that, as with hypertonic saline, rhDNase is inhaled as a nebulised solution and is an adjunct to physiotherapy, along with inhaled, oral or intravenous antibiotics for Pseudomonas aeruginosa, and that use of rhDNase varies widely across the UK. The Committee concluded that best standard of care for cystic fibrosis was complex and tailored to patient needs, and that rhDNase treatment was considered a component of best standard of care. The Committee considered the place of mannitol within the cystic fibrosis treatment pathway, particularly in relation to the use of hypertonic saline. It noted the therapeutic indication of mannitol as an add-on therapy to best standard of care. The Committee heard from the clinical specialists that, after treatment with rhDNase, a patient would be offered either mannitol or hypertonic saline. The clinical specialists stated that approximately 40% of patients in the UK are treated with hypertonic saline. However, the patient expert highlighted that the unpleasant taste and experience of hypertonic saline can lead to poor adherence and this was confirmed by the clinical specialists. The Committee considered whether mannitol could replace nebulised hypertonic saline, but noted that the decision problem and the marketing authorisation clearly defined mannitol as an add-on therapy, and it would not be expected to replace any component of current treatment. The Committee was aware that both of the trials presented by the manufacturer excluded patients taking hypertonic saline, and therefore that the manufacturer had not provided the Committee with any evidence of effectiveness of mannitol added on to hypertonic saline. At the second meeting, the manufacturer noted that, because mannitol and hypertonic saline have a similar mechanism of action (both are osmotic agents), the manufacturer did not expect that mannitol would be added on to a treatment regime containing hypertonic saline. Also, taking into consideration the treatment pathway survey provided by the manufacturer in response to the ACD, the Committee acknowledged that mannitol was unlikely to be used in most patients, and that mannitol would be used as an add-on therapy to best standard of care, but not as a replacement for hypertonic saline use in people with stable cystic fibrosis. The Committee also noted that the manufacturer in its response to the ACD proposed that mannitol should only be considered in people with cystic fibrosis for whom hypertonic saline is not appropriate. The Committee considered a patient's experience of cystic fibrosis, which involves several treatments, and how patients would use mannitol. The patient expert explained the difficulties in adhering to treatments, and stated that using mannitol with an inhaler would be much easier than using hypertonic saline with a nebuliser and would likely encourage adherence. Again, the Committee was aware that the marketing authorisation for mannitol stipulates that it would add on to, rather than replace, existing therapies. The Committee heard from the patient expert and clinical specialists that the treatment time for mannitol could be cut to 2–3 minutes twice a day with training and practice, whereas nebulised treatments take much longer. The patient expert also described the issues faced by carers, with increased burdens from both assisting with treatment and helping patients to maintain normal lives. The patient expert and clinical specialists stated that current therapies (particularly therapies delivered by nebulisers) are complex to set up and to deliver, and equipment needs careful cleaning, which adds to the treatment burden, as do the difficulties in travelling with nebuliser equipment. The patient expert also highlighted the cost to patients of treatments, which are not fully funded by the NHS. The Committee agreed that there were potential advantages to patients of having a wider choice of treatment options. The Committee concluded that cystic fibrosis and its management had a major impact on the quality of life of patients and their carers, and that mannitol could ease some of this burden because it is a dry powder for inhalation, is associated with fewer unpleasant effects, needs less costly equipment and needs less time to administer than nebulised treatments. # Clinical effectiveness The Committee noted that the manufacturer's original submission was in line with the anticipated marketing authorisation (treatment of cystic fibrosis in adults aged 18 years and over as an add-on therapy to rhDNase, and in patients ineligible for, intolerant of, or whose condition inadequately responded to, rhDNase), and did not reflect the current approved marketing authorisation (treatment of cystic fibrosis in adults as an add-on therapy to best standard of care). The Committee also noted that the population specified in the scope included children, and included rhDNase and hypertonic saline as comparators. The Committee noted that the group of all people not using rhDNase was a clinically heterogeneous group, and included patients who cannot use rhDNase, and patients who can but do not use rhDNase for reasons not recorded. The Committee heard from the clinical specialists that the use of rhDNase varies geographically within the NHS. The Committee concluded that the analyses carried out for the populations described as people using rhDNase and all people not using rhDNase would reflect the population in the final marketing authorisation. The Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of mannitol. The Committee was concerned that the statistical power of the presented analyses was reduced by having to limit the population to adults, which reduced the population to almost half of the original trial population, as well as by differentiating according to rhDNase use, and then further according to the reasons for not using rhDNase. The Committee was also concerned that a considerable number of initial study participants did not proceed to randomisation. The Committee further noted that the analysis of the subgroups using and not using rhDNase was part of the trial protocol, but that the trials were powered for statistical significance only for the group using rhDNase, and not for the group not using rhDNase. The Committee concluded there were some concerns about the design of the trials and the resulting analyses, particularly with the post-hoc analyses and low statistical power, and that these factors increased the uncertainty in the results, including the possibility that real differences existed that the study did not demonstrate statistically. The Committee heard from the manufacturer that 50 mg mannitol twice daily was used as the placebo in the trials after a request from regulatory authorities. The Committee heard from the manufacturer that it chose this dose from a dose-ranging study. Both the manufacturer and clinical specialists acknowledged that there was likely to be a small therapeutic effect at this dose, as also suggested by the FEV1 increasing from baseline by 52.4 ml in the DPM-CF-302 trial in the control group. The Committee concluded that mannitol would be more effective than reported in the trials, if the placebo had had a clinical effect. The Committee considered the outcomes used in the trials, and how these differed from the outcomes used in clinical practice in adults with cystic fibrosis. The Committee discussed the manufacturer's selection of absolute change in FEV1 in millilitres in the trial and FEV1% predicted in the economic model, and the manufacturer's definition of 'responders' as people whose absolute FEV1 improved by 100 ml or 5% or more, or whose FEV1% predicted improved by 5% points. The Committee heard from clinical specialists that both absolute FEV1 and FEV1% predicted measurements are used in clinical practice, that a change in absolute FEV1 between 75 and 100 ml is clinically meaningful, and that FEV1% predicted is used for children and to compare across different adult patient populations. The clinical specialists explained that the manufacturer's definition of a response did not accurately reflect clinical practice in the UK. If a patient felt better, but did not reach the threshold defining response (for example, their absolute FEV1 increased by only 80 ml), the clinician would be unlikely to recommend stopping treatment. The patient expert concurred, stating that lung function can vary from day to day, and that small changes could make a difference to daily life and activity. The Committee concluded that the FEV1 response outcomes were clinically relevant, but that the definition of 'responders' in the original manufacturer's submission differed from UK practice. The Committee considered whether the 2 trials presented were equivalent, as the eligibility criteria at the lower end of FEV1% differed between the 2 studies. The clinical specialists explained this was because DPM-CF-301 was conducted largely in the UK, and DPM-CF-302 largely in the US, where prophylactic antibiotics and rhDNase are used more frequently than in the UK, and because there are differences in the regulations of the Food and Drug Administration and European Medicines Agency pertaining to the lower limit of FEV1% predicted for inhaled substances. The Committee was concerned about the way in which the 2 trials were blinded, and whether functional unblinding existed. It was also concerned that mannitol may cause rebound bronchoconstriction, but acknowledged that patients had undergone a mannitol tolerance test before entering the trials, and also heard from the clinical specialists that rebound bronchoconstriction did not occur in the trials. Overall, the Committee concluded that the 2 trials presented were equivalent and that it was reasonable to pool the results, but that there were methodological concerns about the analysis of clinical outcomes in the studies, and that there may have been functional unblinding, which would increase uncertainty about the clinical effectiveness of mannitol. The Committee discussed the issue that hypertonic saline was not included as a comparator in the manufacturer's submission, although it was included in the scope and the ERG's indirect comparison (see section 3.37). Being aware that the use of nebulised hypertonic saline was an exclusion criterion in both the DPM-CF-301 and DPM-CF-302 trials, the Committee noted that there was no clinical-effectiveness data for mannitol in people who used hypertonic saline. The Committee heard from the manufacturer and the ERG that there were difficulties in comparing the 2 osmotic agents, in particular because of the heterogeneity in the outcome measures in the clinical trials of the 2 osmotic agents and the lack of definition of the concentration of hypertonic saline solution used in clinical practice in the UK. The Committee noted the Cochrane review of hypertonic saline for cystic fibrosis, and the apparent improvement in pulmonary exacerbations and quality of life compared with isotonic saline, and heard that the clinical specialists considered the review to have been well-performed and valid. The Committee noted that, despite the final marketing authorisation permitting the addition of mannitol to best standard of care, mannitol would be unlikely to be used as an add-on to hypertonic saline because mannitol and hypertonic saline have similar mechanisms of action (see section 4.3). However, because the lack of clinical evidence precluded the use of hypertonic saline as a comparator in the analysis, and because the Committee was not presented with any evidence demonstrating the effectiveness of mannitol in people using hypertonic saline, the Committee concluded that the only possible recommendation is for people for whom other osmotic agents are not considered appropriate. The Committee concluded that adults with cystic fibrosis who cannot take hypertonic saline, for example for reasons of intolerability, represent a population with unmet need who would be able to benefit from the use of mannitol. The Committee further concluded that a clinical trial would be needed to establish the relative effectiveness of mannitol compared with hypertonic saline. The Committee considered the incidence of adverse reactions during the trials, and their effects on people with cystic fibrosis. The Committee heard from the clinical specialists that productive cough is seen as a positive effect whereas irritating cough is seen as negative, but noted that learning to control cough is an important part of managing cystic fibrosis. The patient expert discussed the experience of using current therapies, and how the negative effects (such as unpleasant taste and sensations) affect a person's daily life and increase the burden of treatment. The Committee considered the manufacturer's response to the ACD and noted that mannitol was not more likely to cause haemoptysis than best supportive care. In the Committee's view, adverse reactions were not sufficiently captured by effects on quality of life through the HUI2 measurement in DPM-CF-302, given that a week could elapse between the adverse reaction and reporting, and the bias towards a higher chance of filling in the questionnaire when feeling well, rather than feeling ill. The Committee concluded that the treatment of cystic fibrosis can cause several moderate and severe adverse reactions, and that it can be difficult to establish the effect of adverse reactions on health-related quality of life in a disease as complex as cystic fibrosis. The Committee noted that each trial collected quality-of-life data but that the manufacturer had not submitted EQ-5D data as preferred by NICE. The Committee heard from the clinical specialists and the patient expert that assessing quality of life in people with cystic fibrosis is very difficult because they often describe their quality of life as being equivalent to people without cystic fibrosis or without other chronic conditions. The patient expert explained that she perceived her life as 'normal', and had never known any other health state. The Committee recognised the difficulty in valuing health states in chronic conditions, but that the standard method of using the general population's valuation of descriptions of health-related quality of life to generate utility values was appropriate. The Committee concluded that current measures of quality of life may not accurately capture the consequences of having cystic fibrosis and of its treatments. The Committee considered the relationship between absolute change in FEV1 and pulmonary exacerbations. The Committee heard from the clinical specialists that FEV1 and pulmonary exacerbations have not previously been shown to be directly related. The Committee noted that the average rate of pulmonary exacerbations was lower in people considered 'responders' than in 'non-responders' in DPM-CF-301. The Committee questioned that incidence of pulmonary exacerbations in people not using rhDNase was lower than in people using rhDNase in DPM-CF-301, but it was the other way around in DPM-CF-302, and the manufacturer could not explain this difference. The Committee was aware that the 36.5% relative risk reduction in the rate of exacerbations with mannitol compared with control in people not using rhDNase was not statistically significant, but acknowledged that this could be a result of the post-hoc subgrouping (see section 3.10). On balance, however, the Committee acknowledged that it was plausible that absolute change in FEV1 and pulmonary exacerbations could be related. The Committee concluded that mannitol is clinically effective in improving both lung function (FEV1) and pulmonary exacerbations in people with cystic fibrosis. The Committee further concluded that there are subgroups of people who may experience greater benefit from mannitol, such as people who cannot use rhDNase, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness. # Cost effectiveness The Committee considered the manufacturer's cost-effectiveness analysis, and the ERG's critique and exploratory analyses. It noted that the manufacturer originally used a patient-level simulation model to evaluate the cost-effectiveness of mannitol compared with best standard of care in people using rhDNase and people ineligible for or intolerant of, or whose condition inadequately responded to, rhDNase. The Committee also noted that clinical-effectiveness data presented in the submission were not used directly in the model, instead the manufacturer derived transition parameters from the 2 mannitol trials and from the literature, and incorporated them into the model through regression analysis. In a response to the ACD, the manufacturer provided a revised cost-effectiveness model, addressing some of the Committee's concerns. The Committee noted that the structure of the original model was not a health-state model, but rather was a model of the cystic fibrosis treatment pathway. The Committee was aware of the ERG's concerns about the manufacturer's original assumptions that any improvement in FEV1% predicted would be maintained throughout the lifetime of the patient, and that it would be directly translated into lowered morbidity and mortality rates. The Committee considered that not all relevant UK data were identified by the manufacturer's search strategy in the original submission, and that the manufacturer's response to the ACD addressed these concerns in part. The Committee acknowledged the changes to the model made by the manufacturer in their response to the ACD, but that substantial uncertainty remained about the long-term benefits of using mannitol. The Committee noted that the ICER would increase if the effects of mannitol were only maintained in the short term. The Committee concluded that the cost-effectiveness model was complex and may not adequately reflect the clinical trial data. The Committee considered the way in which the manufacturer had incorporated the clinical-effectiveness data in the model, and was concerned by the limited number of variables incorporated from the trials. It noted that the modelling of treatment effect used FEV1% predicted, and not the trials' primary outcomes of absolute FEV1. The Committee considered the assumptions and variables incorporated into the manufacturer's model, one of which being that mortality depended only on FEV1% predicted, the presence or absence of Burkholderia cepacia infection, age and sex. The Committee was aware that other studies, including one using UK data, demonstrated a wider range of variables associated with mortality in cystic fibrosis than the variables in the BioGrid data used by the manufacturer. The Committee particularly noted that BMI was not included in the manufacturer's mortality calculations, whereas it was a parameter for other variables in the model, and had been identified in registry studies as an independent risk factor for death in cystic fibrosis. In addition, the Committee noted that the hazard ratio associated with Burkholderia cepacia infection was greater in the manufacturer's analysis than in multivariate survival analyses of UK and US registry data. The Committee noted that the manufacturer stated that mannitol did not affect the risk of infection with Burkholderia cepacia complex in the model. The Committee acknowledged that there was little evidence that mannitol would alter other factors associated with mortality, but concluded that the mortality rate in the manufacturer's model may not accurately reflect mortality in cystic fibrosis. The Committee considered that other validated models of cystic fibrosis mortality exist, and that the manufacturer's model was unlikely to accurately represent the cystic fibrosis population in the UK. The Committee concluded that the model underestimated the mortality rate, and that a higher mortality rate would increase the ICER. The Committee expressed concerns about the assumption used in the model related to how change in FEV1% predicted is modelled over time derived from the BioGrid study, but was satisfied with the manufacturer's clarification at the second meeting that FEV1% predicted declined over time in the model, as expected in a cohort of patients with cystic fibrosis. Given that there is a rise in the rate of pulmonary exacerbations with age, the Committee considered it was difficult to interpret with any certainty the evidence provided by the regression model. The Committee was also concerned that the manufacturer did not consider the effect of treatment with mannitol on BMI, even though BMI was a parameter in the model used to estimate FEV1% predicted. The Committee concluded that there was substantial uncertainty in the assumptions surrounding the changes in FEV1% predicted with age and that this led to uncertainty about the applicability of the model to the UK population with cystic fibrosis. The Committee considered the assumption that the difference in FEV1% predicted from treatment with mannitol observed at week 26 would be maintained over the patient's lifetime, and whether this was likely to be seen in clinical practice. The Committee noted that this delay in FEV1 decline would prolong the time before, but possibly not prevent, future lung transplants. The Committee noted that the assumption of a maintained long-term benefit of mannitol would affect the ICER favourably, but that there was substantial uncertainty around this assumption. The Committee noted the sensitivity analyses carried out by the manufacturer and the ERG in which the time horizon was shortened to 5 and 10 years, which could be used as a proxy for a shorter duration of benefit, and that the ICERs were considerably increased with these shorter time horizons. However, it noted the ERG's opinion that a longer time horizon of 50 years may reflect the expected benefit of patients who entered the clinical studies with a mean age around 30 years. The Committee concluded that although there was evidence on the short-term effectiveness of mannitol on FEV1, the long-term effect of mannitol on FEV1 was unknown and that this increased the uncertainty in the ICER. The Committee considered the effect of varying adherence to treatment and of stopping rules on the ICERs, and discussed the ERG's sensitivity analysis and the manufacturer's revised analysis of reduced adherence. The Committee noted that, in the trial, the adherence was 87% based on the date of the last treatment, but the manufacturer had assumed costs reflecting 100% adherence in the model. The Committee therefore concluded that the costs of mannitol were overestimated in the original submission. However, the Committee noted that the sensitivity analyses reported in the manufacturer's response to the ACD lacked face validity because the analyses included reduced costs for mannitol, but no changes to the benefits. The Committee concluded that there is uncertainty around the validity of the assumptions around adherence and whether stopping rules reflect clinical practice, but that an adherence rate as seen in the trial might reduce the base-case ICER. The Committee noted from the manufacturer's comments that the original definition of PDPE, as used in the trials, was different from the definition used in clinical practice, and therefore more clinical exacerbations would be seen in clinical practice. The Committee considered that this could imply that mannitol may be more effective in preventing exacerbations and hospital admissions than assumed in the cost-effectiveness model, which used the trial definition of PDPE. The Committee concluded that, in clinical practice, mannitol could prevent more exacerbations than those within the PDPE definition, which would decrease the ICER. The Committee considered that adverse reactions were not incorporated into the manufacturer's model. The Committee heard from the patient expert and clinical specialists that quality-of-life measurements did not accurately capture the effect of adverse reactions on the quality of life of people with cystic fibrosis. The Committee noted that treatments for cystic fibrosis can increase the incidence of haemoptysis, but that haemoptysis was also associated with exacerbations, which occurred less frequently in people taking mannitol compared with people not taking mannitol. The Committee concluded that the economic model had not incorporated the specific impact of adverse reactions on the health-related quality of life in people with cystic fibrosis and that there was uncertainty about how this would affect the ICER. The Committee considered the generalisability and internal validity of the model. The Committee considered that the relationship between FEV1% predicted and lung transplantation in the model could not be fully explained by the manufacturer or the ERG. The Committee heard from the ERG that the proportion of people with cystic fibrosis alive at 55 years predicted by the model (15%) was greater than that found in the UK cystic fibrosis population. The Committee heard from the ERG that approximately 2% of people with cystic fibrosis are still alive at 50 years, but the clinical specialists questioned the validity of this number from the cystic fibrosis registry data. The Committee noted the comparison of the Australian data with UK registry data provided by the manufacturer in response to the ACD, and the manufacturer's interpretation that this indicated a similar trend in mortality. The Committee noted that there was a difference between the mean FEV1% predicted values in the BioGrid and UK population datasets (see section 3.54). The Committee considered the clinical specialists' and ERG's comments that any improvement in FEV1% predicted would reduce the mortality rate. Based on this, the Committee was not persuaded by the manufacturer's interpretation, and remained concerned that mortality was not modelled in a way that accurately reflected the mortality rate in people with cystic fibrosis in the UK. The Committee noted that, when the relative risk of death for the individual subgroups was used in the model, more QALYs were gained with mannitol in people not using rhDNase than in people using rhDNase. The Committee heard from the manufacturer that this was possibly a chance finding because of the small sample size in the subgroup of people who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The Committee concluded that there were substantial issues with generalisability and internal validity of the model, and that this would increase the uncertainty around the ICERs. The Committee considered the quality-of-life measurements collected in the 2 trials and those used in the model. The Committee noted that the manufacturer had used the HUI2 utility measure, rather than the EQ-5D measure preferred by NICE. The Committee noted that the multiple comorbidities associated with cystic fibrosis and their large impact on daily life suggested that the baseline utility value of 0.899 was high, and that the revised figure of 0.896 for people not using rhDNase was not substantially different. The Committee was also aware that the model was sensitive to the baseline utility with the ICER increasing as the baseline utility decreased. In the original model, the utility increase in patients with improved respiratory symptoms was greater in the mannitol group than in the control group, whereas the utility decrease in patients without improved symptoms was greater in the control group than in the mannitol group. In response to the ACD, the manufacturer submitted a model where the utility values for the health states were the same, irrespective of treatment. However, the Committee concluded that it was not convinced that the health-related quality of life of the health states in the model had been valued with any certainty, and that this led to increased uncertainty around the calculated ICERs for mannitol compared with best standard of care. The Committee considered the relationship between the outcomes, mortality, and quality of life within the model. The Committee noted the uncertainty around the effect of mannitol on life expectancy given the assumption of lifetime efficacy in the model. The Committee noted that virtually all of the benefit of mannitol was from its modelled extension of life-years gained, with very little benefit resulting from improved health-related quality of life, and that the ERG suggested that a more direct link between lung function and quality-of-life utilities could have produced lower ICERs. The Committee considered whether this was likely to be an accurate reflection of real life, and heard from the patient expert that there were substantial quality-of-life improvements in taking an inhaled treatment such as mannitol. The Committee concluded that there was uncertainty about the accuracy of the quality-of-life data and the projected benefits of mannitol on life expectancy, and as a consequence there was further uncertainty as to the robustness of the modelled ICERs. The Committee noted that the costs presented initially by the manufacturer were treatment specific rather than health-state specific. The Committee agreed that the use of health-state specific costs was more appropriate and acknowledged that the manufacturer had incorporated health-state specific costs in the model provided as part of the manufacturer's response to the ACD. The Committee concluded that the modelling incorporating health-state specific costs was more appropriate than that based on treatment specific costs, but that a model based on lung-function specific costs and utilities would be even more appropriate. The Committee considered the ICERs produced by the manufacturer and the ERG. The Committee noted that the manufacturer's original base-case ICERs were above £40,000 per QALY gained in both people using and people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. Furthermore, the Committee noted that the ERG's base-case ICERs were £82,500 per QALY gained in people using rhDNase and £29,900 per QALY gained in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, when subgroup specific model inputs were used. The Committee noted that, in response to a request for clarification, the manufacturer's probabilistic ICERs were £27,700 per QALY gained for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and £54,300 per QALY gained in people using rhDNase, and the respective ERG's estimates were £30,100 per QALY gained for those who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and £53,800 per QALY gained for the rhDNase group. The Committee had not been provided with an ICER for the whole population for which mannitol is licensed, but could conclude from the subgroup data by rhDNase use that mannitol would not represent a cost-effective treatment for the whole population for which it is licensed. Noting that the ICERs for the subgroup of people using rhDNase were between £50,000 and £80,000 per QALY gained, the Committee concluded that mannitol was not cost effective for people using rhDNase, and could not be recommended for this subgroup. The Committee concluded that the ICERs for mannitol in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase were underestimates because mortality in the model was underestimated, and also associated with several uncertainties because of the lack of validity in the model (for example, the duration of the effect long term). Therefore, the Committee concluded that the ICERs for mannitol were likely to be above £30,000 per QALY gained in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and that mannitol could not be recommended for this subgroup. The Committee was aware of the ICERs provided in the manufacturer's response to the ACD in the subgroup of people not using rhDNase (irrespective of the reason for not using rhDNase). The Committee understood from the ERG's critique that this new ICER in people not using rhDNase was lower than the ICER in the original subgroup of people who cannot use rhDNase. According to the ERG there were several factors that could have led to the lower new ICER for adults not using rhDNase, including the manufacturer having used a bigger difference in cost between mannitol and control, having used exacerbation rates suggested by the ERG, and having included drop-out rates derived from the trials, rather than having assumed that all people whose condition responded to mannitol remained on treatment for their lifetime. However the Committee was also aware that mannitol improved lung function less in the people not using rhDNase than in people who cannot use rhDNase, and therefore found the new ICERs counterintuitive. Importantly, the Committee noted that the subgroup of people not using rhDNase (for unspecified reasons) is clinically not clearly identifiable, and therefore it could not make recommendations for this subgroup. The Committee further explored whether there was a group of adults with cystic fibrosis in whom treatment with mannitol would provide a cost-effective use of NHS resources, taking into consideration the responses received on the ACD. The Committee was aware that the manufacturer had, in its response to the ACD, made a proposition for increased cost effectiveness for mannitol treatment in patients with rapidly declining lung function irrespective of rhDNase use. Furthermore, the Committee noted a statement from the clinical specialists in response to ACD consultation, which identified patients with rapidly declining lung function, despite best standard of care, because those patients would particularly benefit from mannitol, a suggestion that the Committee considered was biologically plausible. The Committee noted that any increase in lung function would be proportionally greater for patients with rapidly declining lung function because they would have more to gain than patients with more stable lung function. The Committee was therefore aware that a group with rapidly declining lung function has higher capacity to benefit from mannitol treatment. The Committee further noted that mannitol appeared to be more clinically effective in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase (see section 4.13). The Committee concluded that there is an unmet clinical need in patients with rapidly declining lung function, particularly if there are no other therapies appropriate to offer the patient. The Committee discussed the cost effectiveness of mannitol in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function declines rapidly (yearly FEV1% predicted decline of more than 2%). The Committee used, as a starting point for these discussions, the manufacturer's original probabilistic ICER of £27,700 per QALY gained in people who cannot use rhDNase and the ERG's ICER of £30,100 per QALY gained. There were factors that the Committee agreed would increase uncertainty around the ICERs; those that may increase the ICERs include assumptions about mortality and the long-term effect of mannitol on lung function. Factors that may decrease the ICERs include the possibility of higher rates of pulmonary exacerbations in clinical practice, a rate of adherence reflecting clinical practice, establishing if there is a link between lung function and quality-of-life utilities, and estimating more realistic utility values associated with mannitol use. The Committee agreed that, if mannitol treatment was offered only to patients with a rapid decline in lung function, the ICER would most likely be lower because of this group's lower quality-of-life and lung function, and a greater potential to improve. The Committee concluded that the ICER for mannitol in patients for whom hypertonic saline is not considered appropriate (see section 4.10), who cannot use rhDNase, and whose lung function is rapidly declining would be under £30,000 per QALY gained. It also took into account the severity of the disease and the importance of treatment options for people with cystic fibrosis who have few alternative options. The Committee concluded that mannitol should be recommended as an acceptable use of NHS resources as a treatment option for people with cystic fibrosis who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, whose lung function is rapidly declining, and for whom other osmotic agents are considered inappropriate. The Committee discussed whether mannitol should be considered an innovative technology, or if there were any significant and substantial health benefits that were not included in the economic model. It heard from the clinical specialists and the patient expert that the treatment burden is substantially less for an inhaler than for a nebuliser and that mannitol, being a dry powder, represents a step-change in the way cystic fibrosis is managed in the UK. When questioned, the manufacturer stated that the model accurately reflected the utility gain to patients. The Committee concluded that treatment with an inhaler provided practical advantages over treatment with nebulisers, but mannitol as an add-on therapy would not replace the use of nebulisers, and so could not be considered a step-change in treatment. The Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The only potential equality issue identified was whether the inhaler used for mannitol inhalation would present a disproportionate burden on patients with physical disabilities. However, the Committee noted the clinical specialists' and patient expert's view that all available treatments are difficult to administer, and that the use mannitol as an add-on therapy to best standard of care would not increase the treatment burden. # Summary of Appraisal Committee's key conclusions TA266 Appraisal title: Mannitol dry powder for inhalation for treating cystic fibrosis Section Key conclusion Mannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults: who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and whose lung function is rapidly declining (forced expiratory volume in 1 second decline greater than 2% annually) and for whom other osmotic agents are not considered appropriate. The Committee had not been provided with an ICER for the whole population for which mannitol is licensed. The manufacturer made cases for other subgroups, some based on the anticipated, but later amended wording of the marketing authorisation, for example people using rhDNase or people who cannot use rhDNase. However, the Committee concluded that the ICERs for these subgroups were too high for mannitol to be an appropriate use of NHS resources. The Committee agreed that people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function declined rapidly (yearly FEV1% predicted decline of more than 2%) have an unmet clinical need, particularly as there are no other therapies available, and an increased capacity to benefit from treatment with mannitol. Although no ICER was specifically presented for this subgroup, the Committee was able to infer from the other evidence that the ICER for mannitol in this subgroup would be under £30,000 per QALY gained. Current practice Clinical need of patients, including the availability of alternative treatments The Committee heard from the patient expert and clinical specialists that current treatments are difficult to use and do not encourage adherence. The Committee concluded that cystic fibrosis and its management had a major impact on the quality of life of patients and their carers. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The patient expert explained the difficulties in adhering to current treatments, and felt that using mannitol with an inhaler would be easier than using hypertonic saline with a nebuliser and would be likely to encourage adherence. However, the Committee concluded that mannitol could not be considered an innovative step-change because it would not replace the use of nebulisers in cystic fibrosis treatments. What is the position of the treatment in the pathway of care for the condition? Clinical specialists explained that after treatment with rhDNase, a patient would be offered either mannitol or hypertonic saline. A treatment pathway survey provided in response to the ACD found that mannitol was unlikely to be used in most patients, and that it would be unlikely to replace hypertonic saline in people with stable cystic fibrosis. Adverse reactions Treatments for cystic fibrosis can increase the incidence of haemoptysis, but haemoptysis is also associated with exacerbations, which occurred less frequently in people taking mannitol compared with people not taking mannitol. The Committee concluded that the treatment of cystic fibrosis can cause a number of moderate and severe adverse reactions, and that it can be difficult to establish the effect of adverse reactions on health-related quality of life. Evidence for clinical effectiveness Availability, nature and quality of evidence The evidence of clinical effectiveness was derived from 2 randomised multinational double-blind controlled trials (DPM-CF-301 and DPM-CF-302). The trials were designed to assess the effectiveness of twice-daily mannitol at a dose of 400 mg compared with mannitol at a sub-therapeutic dose of 50 mg in addition to best supportive care with or without rhDNase. The trials had 26-week double-blind phases, followed by an unblinded phase of 26–52 weeks. The inclusion and exclusion criteria for the 2 trials were similar. Dividing the adult-only intention-to-treat population of 341 into users and non-users of rhDNase, and then into different populations of non-users of rhDNase further reduced the statistical power of the analyses. Relevance to general clinical practice in the NHS The Committee heard from the clinical specialists that best standard of care for cystic fibrosis has a complex treatment pathway, that approximately 98% of patients with cystic fibrosis are registered with cystic fibrosis centres, and that clinicians use the Cystic Fibrosis Trust guidelines as the basis for best standard of care on an individual basis. Uncertainties generated by the evidence The Committee noted that there were significant concerns about the post-hoc stratification into subgroups by rhDNase use and lung function. It noted that the analysis was underpowered and the small numbers in these analyses increased uncertainty and reduced the statistical power of the trial results. The Committee noted that hypertonic saline was not presented as a comparator, and that mannitol would be unlikely to replace hypertonic saline in people with stable cystic fibrosis. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The manufacturer provided data for people using rhDNase, and people who cannot use rhDNAse because of ineligibility, intolerance or inadequate response to rhDNase. The Committee concluded that people who cannot use rhDNase may experience greater benefit from mannitol, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness. Furthermore, data for people not using rhDNAse (irrespective of the reason) were also provided as part of the manufacturer's response to the ACD. The Committee noted that the subgroup of people not using rhDNase (for unspecified reasons) is clinically not clearly identifiable, and therefore it could not make recommendations for this subgroup. The Committee also considered a subgroup of people with rapidly declining lung function (of greater than 2% per year). The Committee was aware that a group with rapidly declining lung function has higher capacity to benefit from mannitol treatment. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that mannitol is clinically effective in improving both lung function (FEV1) and pulmonary exacerbations in people with cystic fibrosis. The Committee further concluded that there are subgroups of people who may experience greater benefit from mannitol, such as people who cannot use rhDNase, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness. Evidence for cost effectiveness Availability and nature of evidence The manufacturer developed a Markov health-state transition model, taking into account individual patient pathways over a lifetime horizon, and modelling 2 treatment options: treatment with inhaled mannitol and treatment without inhaled mannitol. The manufacturer did include hypertonic saline as a comparator. The manufacturer did not use clinical-effectiveness data from the trials presented in the submission other than to obtain baseline values and some transition parameters; instead, the manufacturer derived transition parameters from the literature and from its own commissioned studies, incorporating them into the model using regression analysis. The Committee noted that the structure of the original model was not a health-state model, but rather was a model of the cystic fibrosis treatment pathway. The Committee acknowledged the changes to the model made by the manufacturer in their response to the ACD, in light of the ERG's concerns. The Committee concluded that the cost-effectiveness model was complex and may not adequately reflect the clinical trial data. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee was concerned about the manufacturer's assumptions that any improvement in FEV1 would be maintained throughout the lifetime of the patient, and that it would be directly translated into lower morbidity and mortality rates. It was concerned about the limited number of variables incorporated into the model, and that there were other models of cystic fibrosis that had incorporated a greater variety of variables. The Committee concluded that there was substantial uncertainty surrounding the assumption that FEV1% predicted changed with age and that the use of UK data would have been more appropriate, and that this led to uncertainty about the applicability of the model to the UK population with cystic fibrosis. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee was also aware that the model was sensitive to the baseline utility, with the ICER increasing as the baseline utility decreased. The Committee noted that adverse events and their effect on quality of life were not incorporated into the model. The Committee was concerned by the use of HUI2 data rather than the EQ-5D. The Committee concluded that it was not convinced that the health-related quality-of-life of patients with cystic fibrosis had been valued with any certainty. The Committee noted that virtually all of the benefit of mannitol was from its modelled extension of life years gained, with very little benefit resulting from improved health-related quality of life. The Committee agreed with the manufacturer's statement at the meeting that the model included all potential benefits associated with mannitol treatment, and that no additional health-related benefits had been identified that had not been adequately captured by the economic model. Are there specific groups of people for whom the technology is particularly cost effective? The Committee considered the subgroup defined by rapidly declining lung function (greater than 2% per annum) whose condition was unsuitable for treatment with rhDNase. The Committee noted that any increase in lung function would be proportionally greater, and that mannitol was likely to be more clinically effective in this subgroup, which would consequently decrease the ICER. What are the key drivers of cost effectiveness? Factors that would increase the ICERs include alternative assumptions about mortality and the long-term effect of mannitol on lung function. Factors that could decrease the ICERs included the possibility of higher rates of pulmonary exacerbations seen in clinical practice, a rate of compliance reflecting the trials, establishing if there is a link between lung function and quality-of-life utilities, and estimating more realistic utilities associated with mannitol use. Most likely cost-effectiveness estimate (given as an ICER) The Committee noted that if mannitol treatment was offered only to patients with a rapid decline in lung function, the ICER would most likely be lower than in the whole population because of this group's lower quality of life and lung function, and a greater potential to improve. The Committee concluded that the ICER for mannitol in patients for whom hypertonic saline is not considered appropriate, who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function is rapidly declining would be under £30,000 per QALY gained. It also took into account the severity of the disease and the importance of treatment options for people with cystic fibrosis who have few alternative options. The Committee concluded that mannitol should be recommended as an acceptable use of NHS resources as a treatment option in this group. Additional factors taken into account Patient access schemes (PPRS) Not applicable End-of-life considerations Not applicable Equalities considerations and social value judgements The only potential equality issue identified was whether the inhaler used for mannitol inhalation would present a disproportionate burden on patients with physical disabilities. However, the Committee noted the clinical specialists' and patient expert's view that all available treatments are difficult to administer, and that the use mannitol as an add-on therapy to best standard of care would not increase the treatment burden. # Recommendations for further research The Committee concluded that a clinical trial is needed to establish the relative effectiveness of mannitol compared with hypertonic saline.# Related NICE guidance There is no related guidance for this technology.# Review of guidance The guidance on this technology will be considered for review in October 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveNovember 2012# Changes after publication February 2014: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Mannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults:\n\nwho cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and\n\nwhose lung function is rapidly declining (forced expiratory volume in 1 second [FEV1] decline greater than 2% annually) and\n\nfor whom other osmotic agents are not considered appropriate.\n\nPeople currently receiving mannitol whose cystic fibrosis does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology': "Mannitol (Bronchitol, Pharmaxis) is a mucoactive agent that causes water to enter the airway lumen and hydrate airway secretions. This reduces the viscosity of secretions and stimulates cough, thereby increasing the clearance of secretions and pathogenic bacteria. Mannitol dry powder is inhaled from a hand-held, breath-activated device. Mannitol has a marketing authorisation as an add-on therapy to best standard of care in adults with cystic fibrosis. The summary of product characteristics states that the recommended dose is 400 mg twice a day.\n\nThe most common and important adverse reactions associated with mannitol as stated in the summary of product characteristics are hyperresponsiveness to mannitol, cough, bronchospasm, exacerbation of cystic fibrosis, chest discomfort, wheezing, throat irritation, vomiting, headache and pharyngolaryngeal pain. The most clinically significant adverse reaction associated with mannitol use is haemoptysis (coughing up of blood).\n\nMannitol is available as a 40 mg powder capsule for inhalation. The list price for a 14-day pack of 280 capsules and 2 inhalers is £231.66 (excluding VAT; 'Monthly Index of Medical Specialities' [MIMS] September 2012). This equates to £0.83 per 40 mg capsule, or an average cost of £16.55 per day, including the cost of the inhaler. These prices do not include VAT. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of mannitol and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\n# Clinical effectiveness\n\nThe manufacturer presented clinical-effectiveness data from 2 randomised multinational double-blind controlled trials (DPM-CF-301 and DPM-CF-302). The trials were designed to assess the effectiveness of twice-daily mannitol at a dose of 400 mg compared with a 50 mg dose of mannitol twice daily, assumed to be sub-therapeutic. Patients in both arms also received best supportive care with or without rhDNase. Best supportive care included, but was not limited to, inhaled antibiotics, anti-inflammatory agents, bronchodilators, vitamin supplements, pancreatic enzymes, and antidiabetic agents for people with diabetes. The trials had 26-week double-blind phases, followed by further unblinded phases of 26–52\xa0weeks. The inclusion and exclusion criteria for the 2 trials were similar but differed in the lower cut-off for 'FEV1% predicted' (FEV1% of the patient adjusted for the average FEV1% in the population for any person without cystic fibrosis of similar age, sex and body composition); this was 30% in DPM-CF-301 and 40% in DPM-CF-302.\n\nDPM-CF-301 included 295 patients (190 adults) and took place at 40 centres in Australia, New Zealand, the UK and Ireland. The manufacturer presented results for adults only, in line with the marketing authorisation. There were 114 adults in the mannitol arm, of whom 58 used rhDNase and 56 did not use rhDNase, and 76 adults in the control arm, of whom 44 used rhDNase and 32 did not use rhDNase. There were 30 adults in the mannitol arm and 13 in the control arm (43 in total) who could not take rhDNase because of ineligibility, intolerance, or inadequate response to rhDNase. The remaining 45 patients did not use rhDNase for other reasons that were not recorded.\n\nDPM-CF-302 included 305 patients (151 adults) and took place at 53 centres in the USA, Canada, Argentina, Germany, Belgium, France and the Netherlands. The manufacturer presented results for adults only. There were 93 adults in the mannitol arm, of whom 64 used rhDNase and 29 did not use rhDNase, and 58 adults in the control arm, of whom 41 used rhDNase and 17 did not use rhDNase. There were 15 adults in the mannitol arm and 7 in the control arm (22 in total) who could not take rhDNase because of ineligibility, intolerance, or inadequate response to rhDNase. The remaining 24 patients did not use rhDNase for other reasons that were not recorded. After a request by the ERG for clarification, the manufacturer submitted information on 2 groups defined by their use of rhDNase: (1) people using rhDNase and (2) people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\n\nThe trial protocols for DPM-CF-301 and DPM-CF-302 were similar. Because mannitol and hypertonic saline have similar modes of actions, patients taking nebulised hypertonic saline were excluded from DPM-CF-301 and, in DPM-CF-302, patients could use nebulised hypertonic saline at initial assessment but had to stop 4\xa0weeks before the baseline assessment. Potential participants were screened for bronchial hyperresponsiveness to mannitol, and those with hyperresponsiveness were excluded before randomisation. Randomisation was stratified by region and rhDNase use. The studies were powered to show an improvement in FEV1 in both patients who took rhDNase and also the total trial population. There were 4 follow-up visits after the screening visit, at\xa0week 0 (start of treatment with mannitol or control) and at\xa0weeks 6, 14, and 26. In both trials, patients were offered the opportunity to continue or start mannitol treatment in an open-label phase for a further 26\xa0weeks to gain more information on adverse reactions; in DPM-CF-301, there was an additional open-label extension phase of 26\xa0weeks, giving a total of 78\xa0weeks.\n\nThe primary outcome in both trials was the absolute FEV1 as measured in millilitres over 26\xa0weeks. Both trials reported changes in FEV1 from baseline in the mannitol group compared with the control group.\n\nSecondary outcomes included the proportion of patients who responded by FEV1 criteria defined as achieving an increase from baseline of at least 100\xa0ml in FEV1, or at least a 5% increase in absolute FEV1 in millilitres, or at least a 5 percentage point increase in FEV1% predicted. Protocol-defined pulmonary exacerbations (PDPE) were defined as pulmonary events with 4 or more pre-defined symptoms or signs needing intravenous antibiotics. Reductions in the frequency of both PDPE and hospital care were measured in both trials.\n\nBoth trials measured quality of life using the Cystic Fibrosis Questionnaire – Revised (CFQ-R); DPM-CF-302 also used the Health Utility Index 2 (HUI2). The CFQ-R was administered to patients at week\xa00 and then at weeks\xa014 and 26. Antibiotic use and adverse events were also measured in both trials.\n\nIn the manufacturer's original submission, lung function was reported only for the subgroup of adults using rhDNase, in line with the fact that only 1 subgroup was pre-specified in the statistical plan of the study protocol. After a request by the ERG for clarification, the manufacturer submitted data on change in FEV1 and exacerbations for adults using rhDNase and also for adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\n\nIn the DPM-CF-301 trial, mannitol statistically significantly improved lung function over 26\xa0weeks compared with the control, as measured by a change in FEV1 from baseline of 109.3\xa0ml (95% confidence interval [CI] 52.8 to 165.8; p<0.001) in adults using rhDNase. This difference was evident at 6\xa0weeks of treatment and was maintained over the 26-week double-blind phase. For the other measures of lung function, the mean difference from baseline between adults randomised to receive mannitol plus rhDNase compared with the control group were: mean percentage change in FEV1 from baseline of 4.2% (95%\xa0CI\xa00.3 to 8.1); change in FEV1% predicted of 2.7% (95%\xa0CI\xa00.6 to 4.7) and change in forced vital capacity (FVC) of 117.4\xa0ml (95%\xa0CI\xa01.0 to 233.9). After a request for clarification, the manufacturer provided the change in FEV1 over 26\xa0weeks for the 43 adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase; this was 147.0\xa0ml, a difference that was statistically significant between the mannitol and control group (95%\xa0CI\xa023.2 to 270.7, p=0.02).\n\nIn the DPM-CF-301 trial, for people using rhDNase, the incidence of PDPE (over the 26-week time horizon of the trial) was 27.6% for adults randomised to mannitol compared with 36.4% in the control group. For adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the incidence of PDPE was 16.7% in the mannitol group compared with 30.8% in the control group. The rate of PDPE per year was 1.41 for adults receiving mannitol plus rhDNase compared with 1.58 in the control group. The estimated PDPE rate per year was 0.41 for adults randomised to receive mannitol who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase compared with an estimated 0.64 in the control group. There was a 36.5% reduction in the rate of exacerbations in the mannitol group compared with the control group for patients who could not use rhDNase, but this was not statistically significant. The trials were not powered to demonstrate statistically significant differences for PDPE outcomes in these subgroups.\n\nIn the DPM-CF-302 trial, the mean change in FEV1 over 26\xa0weeks for adults using rhDNase and randomised to receive mannitol was not statistically significantly different from the control group (88.5\xa0ml, 95%\xa0CI\xa0−8.5 to 185.4). For the other measures of lung function in adults using rhDNase randomised to receive mannitol compared with the control group, the mean difference in the changes from baseline were 5.4% (95%\xa0CI\xa0−0.4 to 11.3) for FEV1, 3.0% (95%\xa0CI\xa0−0.6 to 6.5) for change in FEV1% predicted and 96.9\xa0ml (95%\xa0CI\xa0−7.7 to 201.6) for changes in FVC. After clarification, the manufacturer provided the difference in the change in FEV1 over 26\xa0weeks for mannitol in 22 adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase compared with the control group; this was 208.6\xa0ml (95%\xa0CI\xa0−9.3 to 426.5, p=0.061).\n\nIn the DPM-CF-302 trial, the incidence of PDPE (over the 26\xa0weeks of the trial) was 18.8% in adults using rhDNase alone compared with 9.8% for adults receiving mannitol plus rhDNase. For adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the PDPE incidence was 13.3% for adults randomised to mannitol compared with 42.9% in the control group. The estimated PDPE rate per year was 0.83 for adults randomised to mannitol plus rhDNase compared with 0.19 in the control group. The estimated PDPE rate per year was 0.26 for adults randomised to receive mannitol who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase compared with an estimated 0.86 in the control group. However, the trials were not powered to demonstrate statistically significant differences for these outcomes in patients not receiving rhDNase or patients who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\n\nIn response to the appraisal consultation document (ACD), the manufacturer presented analyses pooling the results of the DPM-CF-301 and DPM-CF-302 trials. The outcomes in the pooled analyses did not include the primary outcome, absolute FEV1, but instead were FEV1% predicted, the proportion responding according to FEV1 criteria, and the estimated rate of PDPE per patient per year. For the pooled adult population of people using rhDNase, the mean change in FEV1 over 26\xa0weeks for patients receiving mannitol plus rhDNase was 94.1\xa0ml (95%\xa0CI\xa029.7 to 158.42). For people who received mannitol but did not take rhDNase (irrespective of the reason), the change was 110.3\xa0ml (95%\xa0CI\xa0not given, p<0.005). The change was 166.7\xa0ml (95%\xa0CI\xa052.0 to 280.6) for the subgroup of adults receiving mannitol who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The pooled results for both trials for adults who could not use rhDNase were 0.27 PDPE per year in the mannitol group compared with 0.96 PDPE per year in the control group (not statistically significant).\n\nThe manufacturer reported on adverse events for the whole adult population, but not for the rhDNase subgroups based on rhDNase use. Overall, 87% of all adults experienced at least 1 adverse event, the most common adverse event being cough (the only adverse event that occurred in more than 10% of adults). However, the manufacturer considered productive cough a desired effect of treatment with mannitol. Other adverse events with an incidence of between 1% and 10% over 26\xa0weeks were decreased appetite, headache, haemoptysis, bronchospasm, wheezing, asthma, condition aggravated, pharyngolaryngeal pain, and chest discomfort.\n\nHaemoptysis was the most clinically significant adverse event in both studies and was observed in 11.9% of adults on treatment with mannitol and 8.5% in the control group in the DPM-CF-301 trial, and in 7.1% in the mannitol group and 2.5% in the control group in the DPM-CF-302 trial. In response to the ACD, the manufacturer submitted pooled analyses on haemoptysis events based on the protocol-defined criteria for PDPE. For all adults using rhDNase, 16.4% experienced haemoptysis in the mannitol group and 20.0% in the control group. For adults not using rhDNase, these figures were 14.1% in the mannitol group and 14.3% in the control group.\n\nHealth-related quality of life was only presented for the whole adult population in the original manufacturer's submission. There were no statistically significant changes in the CFQ-R domains in either trial for adults randomised to receive mannitol relative to the control group. The results suggested some improvement in the respiratory, physical and vitality domains of CFQ-R, but these did not achieve statistical significance. In DPM-CF-302, there was no statistically significant difference in HUI2 measurements between adults randomised to receive mannitol and the control group.\n\nIn response to the ACD, the manufacturer submitted the proportion of adults whose condition was considered to respond to treatment based on FEV1 criteria for both trials. In the DPM-CF-301 trial, for adults using rhDNase, the condition responded in 41.4% in the mannitol group and 27.3% in the control group; for adults not using rhDNase, these figures were 60.7% in the mannitol group and 40.6% in the control group. In the DPM-CF-302 trial, for adults using rhDNase, the condition responded in 45.3% in the mannitol group and 39.0% in the control group; for adults not using rhDNase, these figures were 44.8% in the mannitol group and 44.8% in the control group.\n\n# Cost effectiveness\n\nThe manufacturer developed a Markov health-state transition model, implemented as a patient-level simulation model evolving over the lifetime of the patient, and modelling 2 treatment options: treatment with inhaled mannitol and treatment without inhaled mannitol. The manufacturer did not model inhaled hypertonic saline as a treatment that a patient may use with, or instead of, mannitol. The model assumed treatment with mannitol for lifetime or until drop-out (according to the rate modelled on the trials). The analysis had a time horizon of 100 years, at which point all patients would have died. The cycle lengths were taken from the time between visits in the 2 trials, and were 6\xa0weeks for the first cycle, 8\xa0weeks for the second cycle and 12\xa0weeks for each subsequent cycle. The transition parameters between the health states depended on characteristics derived from the clinical trial such as age, history of pulmonary exacerbations and use of mannitol.\n\nThe health states in the model include cystic fibrosis, cystic fibrosis with improved respiratory symptoms, lung transplantation, death from cystic fibrosis, and death from an unrelated cause. At baseline, all patients enter the cystic fibrosis health state. As patients progress, if their FEV1% predicted falls below 30%, they enter the lung transplantation state in which they have a probability of receiving a transplant in subsequent cycles. The model includes a discontinuation rule under which patients whose condition does not respond to mannitol treatment within 6\xa0weeks stop mannitol and switch to best standard of care. Modelled to mirror the clinical trial, the definition of a response is either a relative increase of 5% or more in absolute FEV1 or an absolute increase of 100\xa0ml or more in FEV1 at week\xa06 from baseline. In subsequent cycles, a patient may switch between the health states of cystic fibrosis and cystic fibrosis with improved respiratory symptoms and back again, and patients in either state may experience a pulmonary exacerbation. Patient characteristics such as body mass index (BMI), age and FEV1% predicted are updated.\n\nThe manufacturer used clinical-effectiveness data from the DPM-CF-301 and DPM-CF-302 trials to obtain baseline values and some, but not all, transition parameters used in the model, such as FEV1% predicted at week\xa026, the probability of being a 'responder' at 26\xa0weeks and the relative risk of pulmonary exacerbations for 'responders' to treatment. Other transition parameters were derived from the literature and from the commissioned BioGrid study using regression analysis, such as FEV1% predicted over time, the rate of exacerbations and mortality after lung transplant. The baseline characteristics (age, sex, BMI and FEV1% predicted) were taken from the pooled adult population from the DPM-CF-301 and DPM-CF-302 trials. The manufacturer also used data from the trials to estimate the probability of response to mannitol, FEV1% predicted after 26\xa0weeks of treatment, the effect of treatment on pulmonary exacerbations, and the probability of improvement in respiratory symptoms. The manufacturer estimated changes in FEV1% predicted and the risk of an exacerbation after baseline from the BioGrid retrospective observational study of disease progression in cystic fibrosis, which used data from Australia (the BioGrid data) and was commissioned by the manufacturer. The decline over time in FEV1% predicted was modelled dependent on age, age above 30 years, and pulmonary exacerbations (using hospital admissions as a proxy). The manufacturer estimated the relationship between FEV1% predicted and mortality rate from the BioGrid data using survival analyses. In the model, mortality depended on FEV1, exacerbations, age, sex, concurrent infection with Burkholderia cepacia and lung transplantation. After a request for clarification from the ERG, data on these variables were provided to update the model for patients who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\n\nUtility values were drawn largely from HUI2 data collected during the DPM-CF-302 trial; the manufacturer also included values from the literature for lung transplantation and pulmonary exacerbations. The baseline utility was taken as the mean overall HUI2 global utility score at baseline (0.899). The manufacturer calculated the change in utility between baseline and visit\xa03 or in week\xa014, or between baseline and the last visit in the case of early withdrawal. The manufacturer calculated the HUI2 global utility scores for each health state by adding the average change to the baseline utility. The increase in utility value for patients with improved symptoms was 0.009 in the control group and 0.019 in the mannitol group. The decrease in utility for patients without improved symptoms was 0.046 for patients in the control group and 0.022 in the mannitol group. Utility values were not linked directly to lung function. The HUI2 questionnaire was administered in the trial at weeks\xa00, 12 and 26, but had a recall period of 1\xa0week, and so did not necessarily capture the effect of PDPEs on health-related quality of life at the time they occurred. Therefore, the manufacturer took utility data for PDPEs and post-lung transplantation from the literature. Adverse events had a negative impact on CFQ-R data in both trials.\n\nThe manufacturer calculated the costs of treatment with or without mannitol accumulated up to 26\xa0weeks, but made no distinction between patients whose lung function improved and those whose did not. The model included costs related to pulmonary exacerbation and for the time periods before and after lung transplantation. Costs were taken from national reference costs. The manufacturer included costs for concomitant medications (mostly antibiotics) for both groups, and used a mean cost of £3253 in the mannitol group and £2972 in the control group (with a cost of £0 for the subclinical trial dose). In the trials, most patients were admitted to hospital at least once, and approximately 40% had a community visit during the 26-week randomised phase of the trial. Costs of pulmonary exacerbation were taken from the trial data. For patients receiving mannitol, the mean total cost of medications, community visits and hospitalisations without a PDPE in the 26-week trial period was £4391, and taking into account PDPE the cost was £12,852. From the trial, for patients in the control group, the mean total costs without PDPE were £4664 and with at least 1 PDPE were £10,354. The manufacturer used peri-transplant costs from the UK literature and resource use from the trial and patient records. The manufacturer applied a discount rate of 3.5% to both costs and benefits.\n\nThe manufacturer's base-case results indicated an incremental cost-effectiveness ratio (ICER) for mannitol compared with treatment without mannitol (best supportive care) of £47,095 per quality-adjusted life year (QALY) gained in adults using rhDNase and £41,074 per QALY gained in adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\n\nThe manufacturer undertook extensive scenario analyses and deterministic sensitivity analyses for the treatment of adults using rhDNase and for adults not using rhDNase (irrespective of the reason for non-use). The parameters that changed the ICER by more than 10% were:\n\nFEV1% predicted at baseline\n\nthe regression parameter estimate for mannitol treatment used to predict the FEV1% predicted after 26\xa0weeks of treatment (that is, the effect of treatment)\n\nthe relative risk of an exacerbation with mannitol relative to not using mannitol for people whose condition was considered to respond to treatment\n\nthe relative risk of a subsequent exacerbation if there had been an exacerbation in the previous year\n\nhazard rate of death for the FEV1% predicted\n\nthe utility decrement associated with an exacerbation\n\nthe utility associated with no improvement in respiratory symptoms among patients using or not using mannitol\n\nthe cost of an exacerbation.\n\nThe manufacturer also performed sensitivity analyses showing the effect of several parameters, including treatment failure after 1, 5, 10 and 20 years. The base-case model assumed that patients using mannitol maintained the difference in lung function over their lifetime. Not maintaining the improvements in FEV1% predicted over the long term had a large effect on the ICER. If the improvements in FEV1% predicted were maintained for only 1 year the ICER was £149,587 per QALY gained; if improvements were maintained for 5, 10 and 20 years, the ICERs were £86,981, £63,539 and £49,907 per QALY gained respectively. Other factors that had an impact on the ICER were the rate ratio of pulmonary exacerbations between people receiving and those not receiving mannitol, whether the discontinuation rule was applied, the relative risk of a PDPE if the patient experienced an exacerbation in the previous year, costs and utilities. The manufacturer concluded that the main factors affecting the ICER were:\n\nthe cost of mannitol\n\nthe relative risk of pulmonary exacerbations in the mannitol group\n\nthe impact of pulmonary exacerbations on quality of life\n\nthe FEV1% predicted when starting mannitol\n\nthe improvement in FEV1% predicted on mannitol treatment\n\nthe hazard rate of death for FEV1% predicted\n\nutility for patients whose symptoms do not improve.\n\nAfter a request from the ERG, the manufacturer provided scenario analyses taking into account reduced adherence to treatments, which reduced the costs in the mannitol group. Using a lower mean adherence gave an ICER of £37,387 per QALY gained for mannitol compared with the control in adults using rhDNase, and £33,934 per QALY gained for mannitol compared with the control in adults not using rhDNase.\n\nThere was uncertainty around the relative risk of PDPE, and the model was sensitive to fluctuation in this parameter. Using the relative risk of exacerbation of 0.7 associated with treatment with mannitol for the total adult population (provided by the manufacturer in response to a request for clarification from the ERG), the ICER for mannitol compared with not using mannitol was £54,329 per QALY gained in adults using rhDNase and £27,673 per QALY gained in adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. Using a relative risk of exacerbations based on adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the ICER per QALY gained was £19,828.\n\nIn the manufacturer's probabilistic sensitivity analyses, as an add-on therapy to best standard of care, mannitol had a 16.4% probability of being cost effective at an ICER of £30,000 per QALY gained and a 7.4% probability at an ICER of £20,000 per QALY gained. For non-users of rhDNase, mannitol had a 25.8% probability of being cost effective at an ICER of £30,000 per QALY gained and a 10.9% probability at an ICER of £20,000 per QALY gained. In response to a request from the ERG to estimate the cost effectiveness separately for adults using rhDNase and adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the manufacturer re-ran the probabilistic sensitivity analysis. This resulted in mean ICERs of £53,796 per QALY gained for adults using rhDNase and £30,080 per QALY gained for adults ineligible for rhDNase.\n\nThe manufacturer conducted 2 further subgroup analyses, one by baseline FEV1% predicted and the other among patients whose condition responded to treatment with mannitol by 6\xa0weeks. The analyses showed that, as baseline FEV1% predicted declines, the ICER decreases. For FEV1% predicted 80% or more, the ICERs were £56,228 per QALY gained for adults using rhDNase and £50,688 per QALY gained for adults not using rhDNase. For FEV1% predicted less than 40%, the corresponding ICERs were £30,746 per QALY gained for adults using rhDNase and £23,704 per QALY gained for adults not using rhDNase.\n\nIn response to the ACD, the manufacturer submitted a revised model for people with cystic fibrosis not using rhDNase, including people whose reason for not using rhDNase was not reported in the trials and is not known. In addition, the manufacturer changed several key parameters in the model. The health states in the model more closely model health states rather than treatment states. The costs and utility values in the revised model no longer depend on treatment, but rather on whether the simulated patient has improved respiratory symptoms or not. The utility values are no longer directly tied to lung function. The manufacturer also included a new stopping rule, centred on the Committee's concerns that a stopping rule based on an FEV1 improvement as defined would be unlikely to be implemented in practice. In the new stopping rule, people are permitted to continue using mannitol if their FEV1 improves by more than 0%, that is, if their FEV1 improves at all. The manufacturer continued to base its model on the BioGrid data, but submitted evidence in an effort to show that the BioGrid population was similar to the UK population with cystic fibrosis. For people not using rhDNase, the manufacturer used a revised utility value of 0.896. In the original model, the change in utility value was 0.015 for people using mannitol who had improved respiratory symptoms, and 0.031 for people using mannitol who did not have improved respiratory symptoms. In the revised model, the change in utility value for people not using rhDNase and who took mannitol and had improved respiratory symptoms increased to 0.025 and for people who did not use rhDNase who took mannitol and had no improvement it decreased to 0.001. In the ERG's analyses, treatment for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase had costs of £3885 if they improved and £4385 if they did not improve, a difference of £500. In the model developed in response to the ACD, treatment for people who did not use rhDNase had costs of £2307 if they improved and £3255 if they did not improve, a difference of £948. The manufacturer chose a baseline PDPE rate of 1.01, based on the ERG's critique of the original model.\n\nThe manufacturer did not provide revised estimates of cost effectiveness for the whole population. The revised ICER for mannitol compared with best supportive care was £19,993 per QALY gained in people not using rhDNase, and had an 82.2% probability of being cost effective at an ICER of £30,000 per QALY gained and a 46.5% probability at an ICER of £20,000 per QALY gained. Furthermore, the manufacturer provided a new analysis based on adherence rates of 30% and 70%. Keeping the QALYs constant, the ICER per QALY gained was £6327 at a compliance of 30% and £14,137 at a compliance of 70%.\n\nThe manufacturer submitted additional clinical evidence indicating that the relative benefit with respect to FEV1 associated with taking mannitol was maintained over 78\xa0weeks. This evidence derived from an extension of the 2 trials. The manufacturer also provided scenario analyses showing the ICERs for shortening the model's time horizon from lifetime (100 years) to 5, 10 and 50 years to be £45,329, £25,151 and £20,018 per QALY gained respectively.\n\nIn response to the ACD, the manufacturer also conducted a survey defining the treatment pathway for managing sputum in cystic fibrosis. The manufacturer noted that this survey showed 82% of people with cystic fibrosis have trialled hypertonic saline before age 18 years. The manufacturer stated that clinicians would be reluctant to change treatments for people with well-controlled cystic fibrosis. They also noted that approximately a third of people currently using hypertonic saline did not have well-controlled cystic fibrosis and may be able to benefit from mannitol.\n\n# Evidence Review Group comments\n\nThe ERG regarded DPM-CF-301 and DPM-CF-302 as well designed, high-quality trials, with a large combined study population. The ERG noted the change in therapeutic indication of mannitol limiting it to adults, which reduced the combined study population to 341 and consequently reduced the statistical power of all the analyses.\n\nThe ERG conducted pooled analyses on the results of the DPM-CF-301 and DPM-CF-302 trials. These showed statistically significant differences between mannitol and the control with all outcomes related to lung function. Among adults using rhDNase, the differences between mannitol and control over 26\xa0weeks were as follows: 91.8\xa0ml (95%\xa0CI\xa030.9 to 152.7) for change in FEV1, 4.6 (95%\xa0CI\xa01.3 to 7.8) for percentage change in FEV1, 2.7 (95%\xa0CI\xa00.9 to 4.5) for FEV1% predicted and 106.1\xa0ml (95%\xa0CI\xa028.3 to 183.9) for FVC. The ERG analysed data from adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, rather than from the broader group of adults not using rhDNase because that reflected the anticipated marketing authorisation at that time, but the marketing authorisation was eventually not restricted to this group. For adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the change in FEV1 from baseline was 162.3\xa0ml (95%\xa0CI\xa051.8 to 272.9).\n\nThe ERG's pooled analyses showed that, for the adults using rhDNase, there were no statistically significant differences between the mannitol and control arm in incident PDPE over the 26\xa0week trial period (relative risk [RR] 1.00, 95%\xa0CI\xa00.61 to 1.66), and no statistically significant difference in the estimated rate of PDPE per year (RR\xa01.14, 95%\xa0CI\xa00.75 to 1.73). In the group of people who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, there were also no statistically significant differences between mannitol and the control in the incidence of PDPE (RR\xa00.44, 95%\xa0CI\xa00.18 to 1.10) over the course of the trial. The ERG stated that restriction of the therapeutic indication to adults meant that the analysis was under-powered, a problem compounded by the post-hoc subgroup analyses of the pooled trial data, and contributed to the uncertainty around the results.\n\nThe ERG conducted an indirect comparison of mannitol with hypertonic saline, in line with the scope. The 2 measures common to the identified study of hypertonic saline (0.9% saline) (Elkins et al. 2006) and the DPM-CF-301 and DPM-CF-302 trials were measurements of FEV1 and pulmonary exacerbations. The ERG found that mannitol improved FEV1 compared with hypertonic saline, although this was statistically significant only for the subgroup that could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. FEV1 was 94.3\xa0ml (95%\xa0CI\xa029.0 to 159.6) higher with mannitol than with hypertonic saline, regardless of rhDNase use, and for adults using rhDNase FEV1 was 23.8\xa0ml (95%\xa0CI\xa0−65.0 to 112.5) higher with mannitol than with hypertonic saline.\n\nIn the ERG's view, the basic structure of the manufacturer's Markov model was appropriate for the research question, sufficiently inclusive and diverse to model the complexities of cystic fibrosis, but the ERG expressed concerns about the cost-effectiveness model.\n\nThe ERG questioned the assumption by the manufacturer in the model that mannitol use was completely independent of rhDNase use (that is, that any benefit of mannitol did not depend on whether a patient used, or did not use, rhDNase). This led the ERG to re-analyse the data according to rhDNase use and to divide the group not using rhDNase into those who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and those who could use rhDNase but did not do so for unknown reasons.\n\nThe ERG indicated that there was statistically significant heterogeneity in the overall group of people not using rhDNase. Patients who were able to take rhDNase but did not do so had different characteristics than those who were unable to take rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The ERG noted that mannitol is more likely to provide effective treatment to people who cannot rather than do not take rhDNase and who do not take hypertonic saline.\n\nThe ERG noted that the manufacturer had not used the results of the trials in the model, but instead had developed regression equations to estimate lung function. The ERG felt that the use of regression was appropriate for this Markov patient-level model, and noted that the manufacturer had consulted with experts on cystic fibrosis and modelling. The manufacturer also ran a microsimulation (100,000 trials) to compare the model output with the pooled results of the DPM-CF-301 and DPM-CF-302 trials. The ERG found small mistakes in the manufacturer's model, but noted that the validation checks matched the results of the clinical studies at a time point of 26\xa0weeks.\n\nThe ERG noted that one of the most important assumptions made by the manufacturer was that any absolute improvement in FEV1% predicted relative to patients not using mannitol would be maintained throughout the lifetime of the patient, and would directly translate into lower rates of morbidity and mortality. That is, a patient on mannitol would experience a decline in lung function over time consistent with the natural history of disease but, on cessation of mannitol treatment, would start the decline at a higher level of FEV1% predicted than a patient not taking mannitol. The ERG was concerned that there were no long-term data to support this assumption. The ERG questioned the manufacturer's use of Australian BioGrid data for transition parameters, which may not be generalisable to the UK.\n\nThe ERG was concerned about several assumptions made by the manufacturer in the original model about pulmonary exacerbations, namely the narrow confidence intervals around the baseline rate based on the BioGrid data used in the deterministic sensitivity analysis, and questioned whether it applied to a UK population.\n\nThe ERG was concerned about assumptions made by the manufacturer in the original model that HUI2 utility and cost parameters depended on treatment, but not on health state. The ERG questioned that there was no direct link between lung function and utility and suggested that a model linking lung function to utility could have altered the cost effectiveness and could have decreased the ICER.\n\nThe ERG conducted exploratory analyses to examine the effect on the ICER of varying the model assumptions and the input parameters, including the difference in costs and utilities associated with respiratory symptoms and exacerbations, and the mortality rate of cystic fibrosis by varying the FEV1% predicted. However, because of a lack of data, the ERG could not investigate the manufacturer's assumption that the probability of moving between health states remained the same over the lifetime of the patient.\n\nThe ERG amended the model to include treatment-independent and improvement-specific values for costs and utilities; using rhDNase subgroup-specific relative risks associating treatment with exacerbations, changing the cost of rhDNase from £16.88 to the most recent price of £16.55 (British national formulary 61); and adjusting model parameters, probabilities and distributions.\n\nThe ERG's exploratory cost-effectiveness analysis included the treatment options of best standard of care, rhDNase and mannitol, but not hypertonic saline. The ERG compared best standard of care with mannitol plus best standard of care. In people using rhDNase, best standard of care included rhDNase, and in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, best standard of care did not include rhDNase. These amendments resulted in the ERG's ICER for mannitol plus best supportive care compared with best supportive care of £80,098 per QALY gained in adults using rhDNase and £29,883 per QALY gained in adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The main reasons for the changes to the ICERs were the use of health-state specific costs and utilities used by the ERG rather than treatment specific costs and utilities used by the manufacturer, and the population specific relative risks for exacerbations.\n\nThe ERG investigated the relationship between improvements in FEV1% predicted and survival, and found evidence to support the assumption that a 1 percentage point improvement in FEV1% predicted was related to an approximate 5% reduction in mortality.\n\nThe ERG examined the assumption that the improvement in FEV1% predicted caused by mannitol would be maintained over the lifetime of the patient by reducing the time horizon of the model as a proxy for a shorter duration of effectiveness. This was similar to a scenario analysis conducted by the manufacturer. The ERG's analyses in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase resulted in ICERs for a time horizon of 5 years of £90,126 per QALY gained. For a time horizon of 10 years, the ICER was £49,854 per QALY gained for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\n\nThe ERG pointed out that the manufacturer had generated cost data based on whether a patient received mannitol or not, rather than whether the patient was in a given health state. The manufacturer divided costs according to respiratory symptoms or according to rhDNase use, but did not estimate costs by both factors simultaneously. However, the ERG acknowledged that, in its revised model in response to the ACD, the manufacturer derived costs using patient-level data. The ERG used the information available to calculate the ratio of the improvement-specific costs to the overall mean costs as an estimate of the difference in costs by health state. The ERG calculated that patients with improved respiratory symptoms have 93% of the overall costs, whereas patients without improved symptoms have 105% of the overall costs. The ERG assumed these percentages also applied to mean costs with rhDNase. The ERG estimated 6-month treatment costs for improved and not improved respiratory symptoms in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The ERG decided that health-state specific costs should be used rather than treatment specific costs. The ERG confirmed that the manufacturer used treatment specific values in its revised analysis of people not using rhDNase.\n\nThe ERG re-ran the probabilistic sensitivity analyses with assumptions based on its exploratory analyses, varying the exacerbation rate in the control group, making the costs and utilities improvement specific rather than treatment specific, and using shorter time horizons. The ERG calculated that there was a zero probability that the ICER for mannitol would lie below £30,000 per QALY gained for people using rhDNase. For those who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the probability that the ICER would be below £20,000 per QALY gained was 5%, and the probability it would be below £30,000 per QALY gained was 50%.\n\nThe ERG considered the health-related quality-of-life data provided by the manufacturer in the form of HUI2 data collected in the DPM-CF-302 trial, and questioned the use of treatment-dependent values for utility. For its own sensitivity analyses, the ERG used values for utilities received from the manufacturer in response to a request for clarification and assumed that these values were independent of treatment. The ERG did not identify any other substantial health-related benefits not included in the QALY.\n\nThe factors identified by the ERG as causing substantial differences in the ICERs generated by the ERG and the manufacturer included whether or not someone took rhDNase alongside mannitol, the assumption that any improvement in FEV1% predicted caused by mannitol would be sustained over the patient's lifetime, the assumption that patients whose condition did not respond to mannitol would discontinue therapy, and the effect of pulmonary exacerbations on utility. The manufacturer addressed these in their response to the ACD and in the second Committee meeting by changing these assumptions to be in line with those used by the ERG.\n\nIn their response to the ACD, the manufacturer provided evidence to suggest that the BioGrid data were similar to the UK population with cystic fibrosis. The ERG explained to the Committee that there was a clinically meaningful difference in the FEV1% predicted values for the BioGrid data and the UK data (of 60.2% for the BioGrid data and 66.3% for the UK data) because every percentage point decrease in predicted FEV1% predicted has an impact on mortality.\n\nThe ERG highlighted the additional analyses in the manufacturer's response to the ACD, which supported its assumption that improvements in FEV1% predicted would be maintained throughout the lifetime of the patient. In the second Committee meeting, the ERG stated that there was uncertainty about whether the benefit of mannitol would persist over time, decrease at the same rate as that of the control group, or decrease at a slower rate. The ERG commented that a time horizon of 50 years was likely to accurately represent the lifetime horizon of the adult UK population with cystic fibrosis.\n\nIn examining the manufacturer's revised analysis in people who do not use rhDNase, the ERG identified 3 drivers that decreased the ICER from that in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase (as originally modelled): including the exacerbation rate chosen for the model; acknowledging that some people treated with mannitol stop taking it ('drop-outs'); and the change in the estimated price for best supportive care, with the difference between best supportive care and mannitol being smaller in the original model (£500) than in the revised model (£948).\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of mannitol, having considered evidence on the nature of cystic fibrosis and the value placed on the benefits of mannitol by people with cystic fibrosis, the people who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical practice\n\nThe Committee discussed the clinical needs of people with cystic fibrosis. It heard from clinical specialists that cystic fibrosis leads to considerable morbidity and early mortality, and that there is no single standard care pathway in the UK. Clinicians and patients working with cystic fibrosis centres decide on treatment according to each patient's needs. The clinical specialists added that the aim of treatment in adults is to maintain lung function (as measured primarily by the absolute volume of FEV1 in millilitres), particularly after the age of 30 years. In response to the consultation, the clinical specialists added that it is particularly important to manage cystic fibrosis to prevent a further decline in lung function in patients with rapidly declining lung function (that is, more than 2% per year decline in FEV1% predicted). Clinicians and patients manage lung function primarily through efforts to reduce airway infections, increase airway clearance, aid sputum clearance and maintain body weight through good nutrition. The Committee heard from the clinical specialists that approximately 98% of people with cystic fibrosis are registered with cystic fibrosis centres, and that clinicians use the Cystic Fibrosis Trust guidelines as the basis for best standard of care. The Committee heard from the clinical specialists that, as with hypertonic saline, rhDNase is inhaled as a nebulised solution and is an adjunct to physiotherapy, along with inhaled, oral or intravenous antibiotics for Pseudomonas aeruginosa, and that use of rhDNase varies widely across the UK. The Committee concluded that best standard of care for cystic fibrosis was complex and tailored to patient needs, and that rhDNase treatment was considered a component of best standard of care.\n\nThe Committee considered the place of mannitol within the cystic fibrosis treatment pathway, particularly in relation to the use of hypertonic saline. It noted the therapeutic indication of mannitol as an add-on therapy to best standard of care. The Committee heard from the clinical specialists that, after treatment with rhDNase, a patient would be offered either mannitol or hypertonic saline. The clinical specialists stated that approximately 40% of patients in the UK are treated with hypertonic saline. However, the patient expert highlighted that the unpleasant taste and experience of hypertonic saline can lead to poor adherence and this was confirmed by the clinical specialists. The Committee considered whether mannitol could replace nebulised hypertonic saline, but noted that the decision problem and the marketing authorisation clearly defined mannitol as an add-on therapy, and it would not be expected to replace any component of current treatment. The Committee was aware that both of the trials presented by the manufacturer excluded patients taking hypertonic saline, and therefore that the manufacturer had not provided the Committee with any evidence of effectiveness of mannitol added on to hypertonic saline. At the second meeting, the manufacturer noted that, because mannitol and hypertonic saline have a similar mechanism of action (both are osmotic agents), the manufacturer did not expect that mannitol would be added on to a treatment regime containing hypertonic saline. Also, taking into consideration the treatment pathway survey provided by the manufacturer in response to the ACD, the Committee acknowledged that mannitol was unlikely to be used in most patients, and that mannitol would be used as an add-on therapy to best standard of care, but not as a replacement for hypertonic saline use in people with stable cystic fibrosis. The Committee also noted that the manufacturer in its response to the ACD proposed that mannitol should only be considered in people with cystic fibrosis for whom hypertonic saline is not appropriate.\n\nThe Committee considered a patient's experience of cystic fibrosis, which involves several treatments, and how patients would use mannitol. The patient expert explained the difficulties in adhering to treatments, and stated that using mannitol with an inhaler would be much easier than using hypertonic saline with a nebuliser and would likely encourage adherence. Again, the Committee was aware that the marketing authorisation for mannitol stipulates that it would add on to, rather than replace, existing therapies. The Committee heard from the patient expert and clinical specialists that the treatment time for mannitol could be cut to 2–3 minutes twice a day with training and practice, whereas nebulised treatments take much longer. The patient expert also described the issues faced by carers, with increased burdens from both assisting with treatment and helping patients to maintain normal lives. The patient expert and clinical specialists stated that current therapies (particularly therapies delivered by nebulisers) are complex to set up and to deliver, and equipment needs careful cleaning, which adds to the treatment burden, as do the difficulties in travelling with nebuliser equipment. The patient expert also highlighted the cost to patients of treatments, which are not fully funded by the NHS. The Committee agreed that there were potential advantages to patients of having a wider choice of treatment options. The Committee concluded that cystic fibrosis and its management had a major impact on the quality of life of patients and their carers, and that mannitol could ease some of this burden because it is a dry powder for inhalation, is associated with fewer unpleasant effects, needs less costly equipment and needs less time to administer than nebulised treatments.\n\n# Clinical effectiveness\n\nThe Committee noted that the manufacturer's original submission was in line with the anticipated marketing authorisation (treatment of cystic fibrosis in adults aged 18 years and over as an add-on therapy to rhDNase, and in patients ineligible for, intolerant of, or whose condition inadequately responded to, rhDNase), and did not reflect the current approved marketing authorisation (treatment of cystic fibrosis in adults as an add-on therapy to best standard of care). The Committee also noted that the population specified in the scope included children, and included rhDNase and hypertonic saline as comparators. The Committee noted that the group of all people not using rhDNase was a clinically heterogeneous group, and included patients who cannot use rhDNase, and patients who can but do not use rhDNase for reasons not recorded. The Committee heard from the clinical specialists that the use of rhDNase varies geographically within the NHS. The Committee concluded that the analyses carried out for the populations described as people using rhDNase and all people not using rhDNase would reflect the population in the final marketing authorisation.\n\nThe Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of mannitol. The Committee was concerned that the statistical power of the presented analyses was reduced by having to limit the population to adults, which reduced the population to almost half of the original trial population, as well as by differentiating according to rhDNase use, and then further according to the reasons for not using rhDNase. The Committee was also concerned that a considerable number of initial study participants did not proceed to randomisation. The Committee further noted that the analysis of the subgroups using and not using rhDNase was part of the trial protocol, but that the trials were powered for statistical significance only for the group using rhDNase, and not for the group not using rhDNase. The Committee concluded there were some concerns about the design of the trials and the resulting analyses, particularly with the post-hoc analyses and low statistical power, and that these factors increased the uncertainty in the results, including the possibility that real differences existed that the study did not demonstrate statistically.\n\nThe Committee heard from the manufacturer that 50 mg mannitol twice daily was used as the placebo in the trials after a request from regulatory authorities. The Committee heard from the manufacturer that it chose this dose from a dose-ranging study. Both the manufacturer and clinical specialists acknowledged that there was likely to be a small therapeutic effect at this dose, as also suggested by the FEV1 increasing from baseline by 52.4\xa0ml in the DPM-CF-302 trial in the control group. The Committee concluded that mannitol would be more effective than reported in the trials, if the placebo had had a clinical effect.\n\nThe Committee considered the outcomes used in the trials, and how these differed from the outcomes used in clinical practice in adults with cystic fibrosis. The Committee discussed the manufacturer's selection of absolute change in FEV1 in millilitres in the trial and FEV1% predicted in the economic model, and the manufacturer's definition of 'responders' as people whose absolute FEV1 improved by 100\xa0ml or 5% or more, or whose FEV1% predicted improved by 5% points. The Committee heard from clinical specialists that both absolute FEV1 and FEV1% predicted measurements are used in clinical practice, that a change in absolute FEV1 between 75 and 100\xa0ml is clinically meaningful, and that FEV1% predicted is used for children and to compare across different adult patient populations. The clinical specialists explained that the manufacturer's definition of a response did not accurately reflect clinical practice in the UK. If a patient felt better, but did not reach the threshold defining response (for example, their absolute FEV1 increased by only 80\xa0ml), the clinician would be unlikely to recommend stopping treatment. The patient expert concurred, stating that lung function can vary from day to day, and that small changes could make a difference to daily life and activity. The Committee concluded that the FEV1 response outcomes were clinically relevant, but that the definition of 'responders' in the original manufacturer's submission differed from UK practice.\n\nThe Committee considered whether the 2 trials presented were equivalent, as the eligibility criteria at the lower end of FEV1% differed between the 2 studies. The clinical specialists explained this was because DPM-CF-301 was conducted largely in the UK, and DPM-CF-302 largely in the US, where prophylactic antibiotics and rhDNase are used more frequently than in the UK, and because there are differences in the regulations of the Food and Drug Administration and European Medicines Agency pertaining to the lower limit of FEV1% predicted for inhaled substances. The Committee was concerned about the way in which the 2 trials were blinded, and whether functional unblinding existed. It was also concerned that mannitol may cause rebound bronchoconstriction, but acknowledged that patients had undergone a mannitol tolerance test before entering the trials, and also heard from the clinical specialists that rebound bronchoconstriction did not occur in the trials. Overall, the Committee concluded that the 2 trials presented were equivalent and that it was reasonable to pool the results, but that there were methodological concerns about the analysis of clinical outcomes in the studies, and that there may have been functional unblinding, which would increase uncertainty about the clinical effectiveness of mannitol.\n\nThe Committee discussed the issue that hypertonic saline was not included as a comparator in the manufacturer's submission, although it was included in the scope and the ERG's indirect comparison (see section 3.37). Being aware that the use of nebulised hypertonic saline was an exclusion criterion in both the DPM-CF-301 and DPM-CF-302 trials, the Committee noted that there was no clinical-effectiveness data for mannitol in people who used hypertonic saline. The Committee heard from the manufacturer and the ERG that there were difficulties in comparing the 2 osmotic agents, in particular because of the heterogeneity in the outcome measures in the clinical trials of the 2 osmotic agents and the lack of definition of the concentration of hypertonic saline solution used in clinical practice in the UK. The Committee noted the Cochrane review of hypertonic saline for cystic fibrosis, and the apparent improvement in pulmonary exacerbations and quality of life compared with isotonic saline, and heard that the clinical specialists considered the review to have been well-performed and valid. The Committee noted that, despite the final marketing authorisation permitting the addition of mannitol to best standard of care, mannitol would be unlikely to be used as an add-on to hypertonic saline because mannitol and hypertonic saline have similar mechanisms of action (see section 4.3). However, because the lack of clinical evidence precluded the use of hypertonic saline as a comparator in the analysis, and because the Committee was not presented with any evidence demonstrating the effectiveness of mannitol in people using hypertonic saline, the Committee concluded that the only possible recommendation is for people for whom other osmotic agents are not considered appropriate. The Committee concluded that adults with cystic fibrosis who cannot take hypertonic saline, for example for reasons of intolerability, represent a population with unmet need who would be able to benefit from the use of mannitol. The Committee further concluded that a clinical trial would be needed to establish the relative effectiveness of mannitol compared with hypertonic saline.\n\nThe Committee considered the incidence of adverse reactions during the trials, and their effects on people with cystic fibrosis. The Committee heard from the clinical specialists that productive cough is seen as a positive effect whereas irritating cough is seen as negative, but noted that learning to control cough is an important part of managing cystic fibrosis. The patient expert discussed the experience of using current therapies, and how the negative effects (such as unpleasant taste and sensations) affect a person's daily life and increase the burden of treatment. The Committee considered the manufacturer's response to the ACD and noted that mannitol was not more likely to cause haemoptysis than best supportive care. In the Committee's view, adverse reactions were not sufficiently captured by effects on quality of life through the HUI2 measurement in DPM-CF-302, given that a\xa0week could elapse between the adverse reaction and reporting, and the bias towards a higher chance of filling in the questionnaire when feeling well, rather than feeling ill. The Committee concluded that the treatment of cystic fibrosis can cause several moderate and severe adverse reactions, and that it can be difficult to establish the effect of adverse reactions on health-related quality of life in a disease as complex as cystic fibrosis.\n\nThe Committee noted that each trial collected quality-of-life data but that the manufacturer had not submitted EQ-5D data as preferred by NICE. The Committee heard from the clinical specialists and the patient expert that assessing quality of life in people with cystic fibrosis is very difficult because they often describe their quality of life as being equivalent to people without cystic fibrosis or without other chronic conditions. The patient expert explained that she perceived her life as 'normal', and had never known any other health state. The Committee recognised the difficulty in valuing health states in chronic conditions, but that the standard method of using the general population's valuation of descriptions of health-related quality of life to generate utility values was appropriate. The Committee concluded that current measures of quality of life may not accurately capture the consequences of having cystic fibrosis and of its treatments.\n\nThe Committee considered the relationship between absolute change in FEV1 and pulmonary exacerbations. The Committee heard from the clinical specialists that FEV1 and pulmonary exacerbations have not previously been shown to be directly related. The Committee noted that the average rate of pulmonary exacerbations was lower in people considered 'responders' than in 'non-responders' in DPM-CF-301. The Committee questioned that incidence of pulmonary exacerbations in people not using rhDNase was lower than in people using rhDNase in DPM-CF-301, but it was the other way around in DPM-CF-302, and the manufacturer could not explain this difference. The Committee was aware that the 36.5% relative risk reduction in the rate of exacerbations with mannitol compared with control in people not using rhDNase was not statistically significant, but acknowledged that this could be a result of the post-hoc subgrouping (see section 3.10). On balance, however, the Committee acknowledged that it was plausible that absolute change in FEV1 and pulmonary exacerbations could be related. The Committee concluded that mannitol is clinically effective in improving both lung function (FEV1) and pulmonary exacerbations in people with cystic fibrosis. The Committee further concluded that there are subgroups of people who may experience greater benefit from mannitol, such as people who cannot use rhDNase, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's cost-effectiveness analysis, and the ERG's critique and exploratory analyses. It noted that the manufacturer originally used a patient-level simulation model to evaluate the cost-effectiveness of mannitol compared with best standard of care in people using rhDNase and people ineligible for or intolerant of, or whose condition inadequately responded to, rhDNase. The Committee also noted that clinical-effectiveness data presented in the submission were not used directly in the model, instead the manufacturer derived transition parameters from the 2 mannitol trials and from the literature, and incorporated them into the model through regression analysis. In a response to the ACD, the manufacturer provided a revised cost-effectiveness model, addressing some of the Committee's concerns. The Committee noted that the structure of the original model was not a health-state model, but rather was a model of the cystic fibrosis treatment pathway. The Committee was aware of the ERG's concerns about the manufacturer's original assumptions that any improvement in FEV1% predicted would be maintained throughout the lifetime of the patient, and that it would be directly translated into lowered morbidity and mortality rates. The Committee considered that not all relevant UK data were identified by the manufacturer's search strategy in the original submission, and that the manufacturer's response to the ACD addressed these concerns in part. The Committee acknowledged the changes to the model made by the manufacturer in their response to the ACD, but that substantial uncertainty remained about the long-term benefits of using mannitol. The Committee noted that the ICER would increase if the effects of mannitol were only maintained in the short term. The Committee concluded that the cost-effectiveness model was complex and may not adequately reflect the clinical trial data.\n\nThe Committee considered the way in which the manufacturer had incorporated the clinical-effectiveness data in the model, and was concerned by the limited number of variables incorporated from the trials. It noted that the modelling of treatment effect used FEV1% predicted, and not the trials' primary outcomes of absolute FEV1. The Committee considered the assumptions and variables incorporated into the manufacturer's model, one of which being that mortality depended only on FEV1% predicted, the presence or absence of Burkholderia cepacia infection, age and sex. The Committee was aware that other studies, including one using UK data, demonstrated a wider range of variables associated with mortality in cystic fibrosis than the variables in the BioGrid data used by the manufacturer. The Committee particularly noted that BMI was not included in the manufacturer's mortality calculations, whereas it was a parameter for other variables in the model, and had been identified in registry studies as an independent risk factor for death in cystic fibrosis. In addition, the Committee noted that the hazard ratio associated with Burkholderia cepacia infection was greater in the manufacturer's analysis than in multivariate survival analyses of UK and US registry data. The Committee noted that the manufacturer stated that mannitol did not affect the risk of infection with Burkholderia cepacia complex in the model. The Committee acknowledged that there was little evidence that mannitol would alter other factors associated with mortality, but concluded that the mortality rate in the manufacturer's model may not accurately reflect mortality in cystic fibrosis. The Committee considered that other validated models of cystic fibrosis mortality exist, and that the manufacturer's model was unlikely to accurately represent the cystic fibrosis population in the UK. The Committee concluded that the model underestimated the mortality rate, and that a higher mortality rate would increase the ICER.\n\nThe Committee expressed concerns about the assumption used in the model related to how change in FEV1% predicted is modelled over time derived from the BioGrid study, but was satisfied with the manufacturer's clarification at the second meeting that FEV1% predicted declined over time in the model, as expected in a cohort of patients with cystic fibrosis. Given that there is a rise in the rate of pulmonary exacerbations with age, the Committee considered it was difficult to interpret with any certainty the evidence provided by the regression model. The Committee was also concerned that the manufacturer did not consider the effect of treatment with mannitol on BMI, even though BMI was a parameter in the model used to estimate FEV1% predicted. The Committee concluded that there was substantial uncertainty in the assumptions surrounding the changes in FEV1% predicted with age and that this led to uncertainty about the applicability of the model to the UK population with cystic fibrosis.\n\nThe Committee considered the assumption that the difference in FEV1% predicted from treatment with mannitol observed at\xa0week 26 would be maintained over the patient's lifetime, and whether this was likely to be seen in clinical practice. The Committee noted that this delay in FEV1 decline would prolong the time before, but possibly not prevent, future lung transplants. The Committee noted that the assumption of a maintained long-term benefit of mannitol would affect the ICER favourably, but that there was substantial uncertainty around this assumption. The Committee noted the sensitivity analyses carried out by the manufacturer and the ERG in which the time horizon was shortened to 5 and 10 years, which could be used as a proxy for a shorter duration of benefit, and that the ICERs were considerably increased with these shorter time horizons. However, it noted the ERG's opinion that a longer time horizon of 50 years may reflect the expected benefit of patients who entered the clinical studies with a mean age around 30 years. The Committee concluded that although there was evidence on the short-term effectiveness of mannitol on FEV1, the long-term effect of mannitol on FEV1 was unknown and that this increased the uncertainty in the ICER.\n\nThe Committee considered the effect of varying adherence to treatment and of stopping rules on the ICERs, and discussed the ERG's sensitivity analysis and the manufacturer's revised analysis of reduced adherence. The Committee noted that, in the trial, the adherence was 87% based on the date of the last treatment, but the manufacturer had assumed costs reflecting 100% adherence in the model. The Committee therefore concluded that the costs of mannitol were overestimated in the original submission. However, the Committee noted that the sensitivity analyses reported in the manufacturer's response to the ACD lacked face validity because the analyses included reduced costs for mannitol, but no changes to the benefits. The Committee concluded that there is uncertainty around the validity of the assumptions around adherence and whether stopping rules reflect clinical practice, but that an adherence rate as seen in the trial might reduce the base-case ICER.\n\nThe Committee noted from the manufacturer's comments that the original definition of PDPE, as used in the trials, was different from the definition used in clinical practice, and therefore more clinical exacerbations would be seen in clinical practice. The Committee considered that this could imply that mannitol may be more effective in preventing exacerbations and hospital admissions than assumed in the cost-effectiveness model, which used the trial definition of PDPE. The Committee concluded that, in clinical practice, mannitol could prevent more exacerbations than those within the PDPE definition, which would decrease the ICER.\n\nThe Committee considered that adverse reactions were not incorporated into the manufacturer's model. The Committee heard from the patient expert and clinical specialists that quality-of-life measurements did not accurately capture the effect of adverse reactions on the quality of life of people with cystic fibrosis. The Committee noted that treatments for cystic fibrosis can increase the incidence of haemoptysis, but that haemoptysis was also associated with exacerbations, which occurred less frequently in people taking mannitol compared with people not taking mannitol. The Committee concluded that the economic model had not incorporated the specific impact of adverse reactions on the health-related quality of life in people with cystic fibrosis and that there was uncertainty about how this would affect the ICER.\n\nThe Committee considered the generalisability and internal validity of the model. The Committee considered that the relationship between FEV1% predicted and lung transplantation in the model could not be fully explained by the manufacturer or the ERG. The Committee heard from the ERG that the proportion of people with cystic fibrosis alive at 55 years predicted by the model (15%) was greater than that found in the UK cystic fibrosis population. The Committee heard from the ERG that approximately 2% of people with cystic fibrosis are still alive at 50 years, but the clinical specialists questioned the validity of this number from the cystic fibrosis registry data. The Committee noted the comparison of the Australian data with UK registry data provided by the manufacturer in response to the ACD, and the manufacturer's interpretation that this indicated a similar trend in mortality. The Committee noted that there was a difference between the mean FEV1% predicted values in the BioGrid and UK population datasets (see section 3.54). The Committee considered the clinical specialists' and ERG's comments that any improvement in FEV1% predicted would reduce the mortality rate. Based on this, the Committee was not persuaded by the manufacturer's interpretation, and remained concerned that mortality was not modelled in a way that accurately reflected the mortality rate in people with cystic fibrosis in the UK. The Committee noted that, when the relative risk of death for the individual subgroups was used in the model, more QALYs were gained with mannitol in people not using rhDNase than in people using rhDNase. The Committee heard from the manufacturer that this was possibly a chance finding because of the small sample size in the subgroup of people who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The Committee concluded that there were substantial issues with generalisability and internal validity of the model, and that this would increase the uncertainty around the ICERs.\n\nThe Committee considered the quality-of-life measurements collected in the 2 trials and those used in the model. The Committee noted that the manufacturer had used the HUI2 utility measure, rather than the EQ-5D measure preferred by NICE. The Committee noted that the multiple comorbidities associated with cystic fibrosis and their large impact on daily life suggested that the baseline utility value of 0.899 was high, and that the revised figure of 0.896 for people not using rhDNase was not substantially different. The Committee was also aware that the model was sensitive to the baseline utility with the ICER increasing as the baseline utility decreased. In the original model, the utility increase in patients with improved respiratory symptoms was greater in the mannitol group than in the control group, whereas the utility decrease in patients without improved symptoms was greater in the control group than in the mannitol group. In response to the ACD, the manufacturer submitted a model where the utility values for the health states were the same, irrespective of treatment. However, the Committee concluded that it was not convinced that the health-related quality of life of the health states in the model had been valued with any certainty, and that this led to increased uncertainty around the calculated ICERs for mannitol compared with best standard of care.\n\nThe Committee considered the relationship between the outcomes, mortality, and quality of life within the model. The Committee noted the uncertainty around the effect of mannitol on life expectancy given the assumption of lifetime efficacy in the model. The Committee noted that virtually all of the benefit of mannitol was from its modelled extension of life-years gained, with very little benefit resulting from improved health-related quality of life, and that the ERG suggested that a more direct link between lung function and quality-of-life utilities could have produced lower ICERs. The Committee considered whether this was likely to be an accurate reflection of real life, and heard from the patient expert that there were substantial quality-of-life improvements in taking an inhaled treatment such as mannitol. The Committee concluded that there was uncertainty about the accuracy of the quality-of-life data and the projected benefits of mannitol on life expectancy, and as a consequence there was further uncertainty as to the robustness of the modelled ICERs.\n\nThe Committee noted that the costs presented initially by the manufacturer were treatment specific rather than health-state specific. The Committee agreed that the use of health-state specific costs was more appropriate and acknowledged that the manufacturer had incorporated health-state specific costs in the model provided as part of the manufacturer's response to the ACD. The Committee concluded that the modelling incorporating health-state specific costs was more appropriate than that based on treatment specific costs, but that a model based on lung-function specific costs and utilities would be even more appropriate.\n\nThe Committee considered the ICERs produced by the manufacturer and the ERG. The Committee noted that the manufacturer's original base-case ICERs were above £40,000 per QALY gained in both people using and people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. Furthermore, the Committee noted that the ERG's base-case ICERs were £82,500 per QALY gained in people using rhDNase and £29,900 per QALY gained in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, when subgroup specific model inputs were used. The Committee noted that, in response to a request for clarification, the manufacturer's probabilistic ICERs were £27,700 per QALY gained for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and £54,300 per QALY gained in people using rhDNase, and the respective ERG's estimates were £30,100 per QALY gained for those who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and £53,800 per QALY gained for the rhDNase group. The Committee had not been provided with an ICER for the whole population for which mannitol is licensed, but could conclude from the subgroup data by rhDNase use that mannitol would not represent a cost-effective treatment for the whole population for which it is licensed. Noting that the ICERs for the subgroup of people using rhDNase were between £50,000 and £80,000 per QALY gained, the Committee concluded that mannitol was not cost effective for people using rhDNase, and could not be recommended for this subgroup. The Committee concluded that the ICERs for mannitol in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase were underestimates because mortality in the model was underestimated, and also associated with several uncertainties because of the lack of validity in the model (for example, the duration of the effect long term). Therefore, the Committee concluded that the ICERs for mannitol were likely to be above £30,000 per QALY gained in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and that mannitol could not be recommended for this subgroup.\n\nThe Committee was aware of the ICERs provided in the manufacturer's response to the ACD in the subgroup of people not using rhDNase (irrespective of the reason for not using rhDNase). The Committee understood from the ERG's critique that this new ICER in people not using rhDNase was lower than the ICER in the original subgroup of people who cannot use rhDNase. According to the ERG there were several factors that could have led to the lower new ICER for adults not using rhDNase, including the manufacturer having used a bigger difference in cost between mannitol and control, having used exacerbation rates suggested by the ERG, and having included drop-out rates derived from the trials, rather than having assumed that all people whose condition responded to mannitol remained on treatment for their lifetime. However the Committee was also aware that mannitol improved lung function less in the people not using rhDNase than in people who cannot use rhDNase, and therefore found the new ICERs counterintuitive. Importantly, the Committee noted that the subgroup of people not using rhDNase (for unspecified reasons) is clinically not clearly identifiable, and therefore it could not make recommendations for this subgroup.\n\nThe Committee further explored whether there was a group of adults with cystic fibrosis in whom treatment with mannitol would provide a cost-effective use of NHS resources, taking into consideration the responses received on the ACD. The Committee was aware that the manufacturer had, in its response to the ACD, made a proposition for increased cost effectiveness for mannitol treatment in patients with rapidly declining lung function irrespective of rhDNase use. Furthermore, the Committee noted a statement from the clinical specialists in response to ACD consultation, which identified patients with rapidly declining lung function, despite best standard of care, because those patients would particularly benefit from mannitol, a suggestion that the Committee considered was biologically plausible. The Committee noted that any increase in lung function would be proportionally greater for patients with rapidly declining lung function because they would have more to gain than patients with more stable lung function. The Committee was therefore aware that a group with rapidly declining lung function has higher capacity to benefit from mannitol treatment. The Committee further noted that mannitol appeared to be more clinically effective in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase (see section 4.13). The Committee concluded that there is an unmet clinical need in patients with rapidly declining lung function, particularly if there are no other therapies appropriate to offer the patient.\n\nThe Committee discussed the cost effectiveness of mannitol in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function declines rapidly (yearly FEV1% predicted decline of more than 2%). The Committee used, as a starting point for these discussions, the manufacturer's original probabilistic ICER of £27,700 per QALY gained in people who cannot use rhDNase and the ERG's ICER of £30,100 per QALY gained. There were factors that the Committee agreed would increase uncertainty around the ICERs; those that may increase the ICERs include assumptions about mortality and the long-term effect of mannitol on lung function. Factors that may decrease the ICERs include the possibility of higher rates of pulmonary exacerbations in clinical practice, a rate of adherence reflecting clinical practice, establishing if there is a link between lung function and quality-of-life utilities, and estimating more realistic utility values associated with mannitol use. The Committee agreed that, if mannitol treatment was offered only to patients with a rapid decline in lung function, the ICER would most likely be lower because of this group's lower quality-of-life and lung function, and a greater potential to improve. The Committee concluded that the ICER for mannitol in patients for whom hypertonic saline is not considered appropriate (see section 4.10), who cannot use rhDNase, and whose lung function is rapidly declining would be under £30,000 per QALY gained. It also took into account the severity of the disease and the importance of treatment options for people with cystic fibrosis who have few alternative options. The Committee concluded that mannitol should be recommended as an acceptable use of NHS resources as a treatment option for people with cystic fibrosis who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, whose lung function is rapidly declining, and for whom other osmotic agents are considered inappropriate.\n\nThe Committee discussed whether mannitol should be considered an innovative technology, or if there were any significant and substantial health benefits that were not included in the economic model. It heard from the clinical specialists and the patient expert that the treatment burden is substantially less for an inhaler than for a nebuliser and that mannitol, being a dry powder, represents a step-change in the way cystic fibrosis is managed in the UK. When questioned, the manufacturer stated that the model accurately reflected the utility gain to patients. The Committee concluded that treatment with an inhaler provided practical advantages over treatment with nebulisers, but mannitol as an add-on therapy would not replace the use of nebulisers, and so could not be considered a step-change in treatment.\n\nThe Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The only potential equality issue identified was whether the inhaler used for mannitol inhalation would present a disproportionate burden on patients with physical disabilities. However, the Committee noted the clinical specialists' and patient expert's view that all available treatments are difficult to administer, and that the use mannitol as an add-on therapy to best standard of care would not increase the treatment burden.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA266\n\nAppraisal title: Mannitol dry powder for inhalation for treating cystic fibrosis\n\nSection\n\nKey conclusion\n\nMannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults:\n\n\n\nwho cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and\n\nwhose lung function is rapidly declining (forced expiratory volume in 1 second [FEV1] decline greater than 2% annually) and\n\nfor whom other osmotic agents are not considered appropriate.\n\n\n\n\n\nThe Committee had not been provided with an ICER for the whole population for which mannitol is licensed. The manufacturer made cases for other subgroups, some based on the anticipated, but later amended wording of the marketing authorisation, for example people using rhDNase or people who cannot use rhDNase. However, the Committee concluded that the ICERs for these subgroups were too high for mannitol to be an appropriate use of NHS resources.\n\n\n\nThe Committee agreed that people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function declined rapidly (yearly FEV1% predicted decline of more than 2%) have an unmet clinical need, particularly as there are no other therapies available, and an increased capacity to benefit from treatment with mannitol. Although no ICER was specifically presented for this subgroup, the Committee was able to infer from the other evidence that the ICER for mannitol in this subgroup would be under £30,000 per QALY gained.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from the patient expert and clinical specialists that current treatments are difficult to use and do not encourage adherence. The Committee concluded that cystic fibrosis and its management had a major impact on the quality of life of patients and their carers.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe patient expert explained the difficulties in adhering to current treatments, and felt that using mannitol with an inhaler would be easier than using hypertonic saline with a nebuliser and would be likely to encourage adherence.\n\n\n\nHowever, the Committee concluded that mannitol could not be considered an innovative step-change because it would not replace the use of nebulisers in cystic fibrosis\n\ntreatments.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nClinical specialists explained that after treatment with rhDNase, a patient would be offered either mannitol or hypertonic saline. A treatment pathway survey provided in response to the ACD found that mannitol was unlikely to be used in most patients, and that it would be unlikely to replace hypertonic saline in people with stable cystic fibrosis.\n\n\n\nAdverse reactions\n\nTreatments for cystic fibrosis can increase the incidence of haemoptysis, but haemoptysis is also associated with exacerbations, which occurred less frequently in people taking mannitol compared with people not taking mannitol. The Committee concluded that the treatment of cystic fibrosis can cause a number of moderate and severe adverse reactions, and that it can be difficult to establish the effect of adverse reactions on health-related quality of life.\n\n, 4.20\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe evidence of clinical effectiveness was derived from 2 randomised multinational double-blind controlled trials (DPM-CF-301 and DPM-CF-302). The trials were designed to assess the effectiveness of twice-daily mannitol at a dose of 400 mg compared with mannitol at a sub-therapeutic dose of 50 mg in addition to best supportive care with or without rhDNase. The trials had 26-week double-blind phases, followed by an unblinded phase of 26–52\xa0weeks. The inclusion and exclusion criteria for the 2 trials were similar. Dividing the adult-only intention-to-treat population of 341 into users and non-users of rhDNase, and then into different populations of non-users of rhDNase further reduced the statistical power of the analyses.\n\n, 3.2, 3.3, 4.6\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard from the clinical specialists that best standard of care for cystic fibrosis has a complex treatment pathway, that approximately 98% of patients with cystic fibrosis are registered with cystic fibrosis centres, and that clinicians use the Cystic Fibrosis Trust guidelines as the basis for best standard of care on an individual basis.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted that there were significant concerns about the post-hoc stratification into subgroups by rhDNase use and lung function. It noted that the analysis was underpowered and the small numbers in these analyses increased uncertainty and reduced the statistical power of the trial results. The Committee noted that hypertonic saline was not presented as a comparator, and that mannitol would be unlikely to replace hypertonic saline in people with stable cystic fibrosis.\n\n, 4.5, 4.6, 4.8, 4.10\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe manufacturer provided data for people using rhDNase, and people who cannot use rhDNAse because of ineligibility, intolerance or inadequate response to rhDNase. The Committee concluded that people who cannot use rhDNase may experience greater benefit from mannitol, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness.\n\n\n\nFurthermore, data for people not using rhDNAse (irrespective of the reason) were also provided as part of the manufacturer's response to the ACD. The Committee noted that the subgroup of people not using rhDNase (for unspecified reasons) is clinically not clearly identifiable, and therefore it could not make recommendations for this subgroup.\n\n\n\nThe Committee also considered a subgroup of people with rapidly declining lung function (of greater than 2% per year). The Committee was aware that a group with rapidly declining lung function has higher capacity to benefit from mannitol treatment.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that mannitol is clinically effective in improving both lung function (FEV1) and pulmonary exacerbations in people with cystic fibrosis. The Committee further concluded that there are subgroups of people who may experience greater benefit from mannitol, such as people who cannot use rhDNase, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer developed a Markov health-state transition model, taking into account individual patient pathways over a lifetime horizon, and modelling 2 treatment options: treatment with inhaled mannitol and treatment without inhaled mannitol. The manufacturer did include hypertonic saline as a comparator. The manufacturer did not use clinical-effectiveness data from the trials presented in the submission other than to obtain baseline values and some transition parameters; instead, the manufacturer derived transition parameters from the literature and from its own commissioned studies, incorporating them into the model using regression analysis. The Committee noted that the structure of the original model was not a health-state model, but rather was a model of the cystic fibrosis treatment pathway. The Committee acknowledged the changes to the model made by the manufacturer in their response to the ACD, in light of the ERG's concerns. The Committee concluded that the cost-effectiveness model was complex and may not adequately reflect the clinical trial data.\n\n, 3.20, 4.14\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee was concerned about the manufacturer's assumptions that any improvement in FEV1 would be maintained throughout the lifetime of the patient, and that it would be directly translated into lower morbidity and mortality rates. It was concerned about the limited number of variables incorporated into the model, and that there were other models of cystic fibrosis that had incorporated a greater variety of variables. The Committee concluded that there was substantial uncertainty surrounding the assumption that FEV1% predicted changed with age and that the use of UK data would have been more appropriate, and that this led to uncertainty about the applicability of the model to the UK population with cystic fibrosis.\n\n, 4.15, 4.16, 4.17\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee was also aware that the model was sensitive to the baseline utility, with the ICER increasing as the baseline utility decreased. The Committee noted that adverse events and their effect on quality of life were not incorporated into the model. The Committee was concerned by the use of HUI2 data rather than the EQ-5D. The Committee concluded that it was not convinced that the health-related quality-of-life of patients with cystic fibrosis had been valued with any certainty. The Committee noted that virtually all of the benefit of mannitol was from its modelled extension of life years gained, with very little benefit resulting from improved health-related quality of life.\n\n, 4.22\n\nThe Committee agreed with the manufacturer's statement at the meeting that the model included all potential benefits associated with mannitol treatment, and that no additional health-related benefits had been identified that had not been adequately captured by the economic model.\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee considered the subgroup defined by rapidly declining lung function (greater than 2% per annum) whose condition was unsuitable for treatment with rhDNase. The Committee noted that any increase in lung function would be proportionally greater, and that mannitol was likely to be more clinically effective in this subgroup, which would consequently decrease the ICER.\n\n, 4.28\n\nWhat are the key drivers of cost effectiveness?\n\nFactors that would increase the ICERs include alternative assumptions about mortality and the long-term effect of mannitol on lung function. Factors that could decrease the ICERs included the possibility of higher rates of pulmonary exacerbations seen in clinical practice, a rate of compliance reflecting the trials, establishing if there is a link between lung function and quality-of-life utilities, and estimating more realistic utilities associated with mannitol use.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that if mannitol treatment was offered only to patients with a rapid decline in lung function, the ICER would most likely be lower than in the whole population because of this group's lower quality of life and lung function, and a greater potential to improve. The Committee concluded that the ICER for mannitol in patients for whom hypertonic saline is not considered appropriate, who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function is rapidly declining would be under £30,000 per QALY gained. It also took into account the severity of the disease and the importance of treatment options for people with cystic fibrosis who have few alternative options. The Committee concluded that mannitol should be recommended as an acceptable use of NHS resources as a treatment option in this group.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable\n\n\n\nEnd-of-life considerations\n\nNot applicable\n\n\n\nEqualities considerations and social value judgements\n\nThe only potential equality issue identified was whether the inhaler used for mannitol inhalation would present a disproportionate burden on patients with physical disabilities. However, the Committee noted the clinical specialists' and patient expert's view that all available treatments are difficult to administer, and that the use mannitol as an add-on therapy to best standard of care would not increase the treatment burden.\n\n", 'Recommendations for further research': 'The Committee concluded that a clinical trial is needed to establish the relative effectiveness of mannitol compared with hypertonic saline.', 'Related NICE guidance': 'There is no related guidance for this technology.', 'Review of guidance': 'The guidance on this technology will be considered for review in October 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveNovember 2012', 'Changes after publication': 'February 2014: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta266
d2f521f8af2db6a535e030c7c7d50a5deff046f1	nice	Ivabradine for treating chronic heart failure	Ivabradine for treating chronic heart failure Evidence-based recommendations on ivabradine (Procoralan) for treating chronic heart failure in adults. # Guidance Ivabradine is recommended as an option for treating chronic heart failure for people: with New York Heart Association (NYHA) class II to IV stable chronic heart failure with systolic dysfunction and who are in sinus rhythm with a heart rate of 75 beats per minute (bpm) or more and who are given ivabradine in combination with standard therapy including beta-blocker therapy, angiotensin-converting enzyme (ACE) inhibitors and aldosterone antagonists, or when beta-blocker therapy is contraindicated or not tolerated and with a left ventricular ejection fraction of 35% or less. Ivabradine should only be initiated after a stabilisation period of 4 weeks on optimised standard therapy with ACE inhibitors, beta-blockers and aldosterone antagonists. Ivabradine should be initiated by a heart failure specialist with access to a multidisciplinary heart failure team. Dose titration and monitoring should be carried out by a heart failure specialist, or in primary care by either a GP with a special interest in heart failure or a heart failure specialist nurse.# The technology Ivabradine (Procoralan, Servier Laboratories) is a heart-rate-lowering agent that selectively and specifically inhibits the cardiac pacemaker If current, which controls the spontaneous diastolic depolarisation in the sinus node that regulates the heart rate. Ivabradine is 'indicated in chronic heart failure NYHA class II to IV with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated'. Ivabradine is administered orally at a recommended starting dose of 5 mg twice daily. This dose may be increased after 2 weeks of treatment to 7.5 mg twice daily if the resting heart rate is above 60 bpm, or decreased to 2.5 mg (half of the 5 mg tablet) twice daily if the resting heart rate is below 50 bpm. For full details of dosage see the summary of product characteristics. The summary of product characteristics lists the following adverse reactions for ivabradine: luminous phenomena (phosphenes), bradycardia, atrioventricular first degree, ventricular extrasystoles, blurred vision, headache, dizziness and uncontrolled blood pressure. For full details of adverse reactions and contraindications, see the summary of product characteristics. Ivabradine is available in 5 mg and 7.5 mg tablets at a net price of £40.17 per 56-tablet pack (excluding VAT; 'British national formulary' edition 63). The manufacturer's submission quoted an average monthly cost of £42.10 (excluding VAT) based on the proportion of patients using 2.5 mg (7%) and either 5 mg or 7.5 mg (93%) in the SHIFT study (see section 3.1). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ivabradine and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer conducted a systematic literature search and identified only 1 randomised controlled trial that assessed the effect of ivabradine in people with heart failure, known as SHIFT (systolic heart failure treatment with the If inhibitor ivabradine trial). SHIFT was an international, multicentre, randomised, double-blind, placebo-controlled trial comparing ivabradine with placebo for the treatment of moderate to severe heart failure and left ventricular systolic dysfunction. The trial was carried out in 625 centres in 37 countries and lasted from 12 to 36 months in the active double-blind treatment period, extended to a maximum duration of 52 months. The clinical-effectiveness evidence presented in the manufacturer's submission was based on this trial alone, but results were also provided for the SHIFT patient-reported outcomes (SHIFT-PRO) study. SHIFT-PRO was carried out to evaluate the effects of ivabradine compared with placebo on health-related quality of life in a representative sample of the main trial population. Patients with symptomatic heart failure with a left ventricular ejection fraction of 35% or lower who were in sinus rhythm with a heart rate of 70 bpm or more and were receiving stable background treatment for heart failure were considered eligible for participation in SHIFT. After screening, 6505 patients were randomised to receive either ivabradine or placebo in addition to ongoing optimal therapy (standard care) for heart failure (as assessed by the investigator responsible for the patient). All patients received 5 mg of ivabradine or matching placebo twice daily at day 0. This dose was maintained, or increased to 7.5 mg twice daily or reduced to 2.5 mg twice daily depending on resting heart rate and tolerability. All analyses were based on intention to treat even though a total of 1190 patients died, withdrew consent or were lost to follow-up. The trial groups in SHIFT were well balanced in patient baseline characteristics. The mean age was 60.4 years, 76% of the patients were men and mostly white. Mean heart rate was 79.9 bpm and mean left ventricular ejection fraction was 29%. Heart failure was ischaemic in 68% of the patients and patients were equally distributed between NYHA class II, III or IV. Alcohol consumption and smoking status were also similar between the trial groups, with less than 20% of the patients being current smokers in both groups. The background therapies were also similar in both arms (ACE inhibitors or angiotensin receptor blockers: 91%; diuretics: 84%; beta-blockers: 89%; aldosterone antagonists: 61% and cardiac devices ). Subgroups were predefined in terms of age, sex, beta-blocker intake at randomisation, primary cause of heart failure, NYHA class, presence of diabetes, presence of hypertension and heart rate above and below the median of 77 bpm. The manufacturer stated in its submission that another subgroup was identified after the Committee for Medicinal Products for Human Use recommended identifying the heart rate threshold at which there is a statistically significant mortality benefit. This subgroup consisted of people with a baseline heart rate of 75 bpm or more (n=4150) and was identified post hoc. Data from this subgroup were used to identify the population to be covered by the marketing authorisation. The manufacturer's economic model was also based on this post hoc subgroup. Other post hoc subgroups identified were based on age (75 years or older and 70 years or older). The baseline characteristics of the subgroup with a baseline heart rate of 75 bpm or more (the population covered by the marketing authorisation) were similar to the main trial population. The mean age for this subgroup was 59.6 years and, like the main trial population, they were mostly men (77%) and mostly white. There were no baseline differences between the treatment groups in this population including mean heart rate (84.5 bpm) and distribution of NYHA class. The background therapies received were also similar to the main trial population for both treatment groups (ACE inhibitors or angiotensin receptor blockers: 90%; diuretics: 84%; beta-blockers: 88%; aldosterone antagonists: 62% and cardiac devices). The primary outcome in the SHIFT main trial population was a composite endpoint of first event of cardiovascular death or hospital admission for worsening heart failure. This was carried out using a survival analysis based on time-to-first event estimated by the Kaplan-Meier method. Secondary and other efficacy outcomes included mortality, hospital admission, change in heart rate, change in NYHA class, change in global assessment of heart failure symptoms and efficacy in patients aged 70 years or older (post hoc analysis in the main trial population). In the SHIFT-PRO study (n=5038), which studied a subset of the main SHIFT population, health-related quality of life was estimated using the EuroQol-5 dimensions (EQ-5D) questionnaire and 'Kansas City cardiomyopathy questionnaire' (KCCQ). Analysis in this study was also performed according to the same predefined subgroups specified in the main trial population, with the exception of presence of diabetes and hypertension. An additional subgroup was specified according to whether or not patients had received at least half the target dose of beta-blockers at randomisation. The manufacturer's submission noted that there were no relevant differences in baseline demographics and disease characteristics among the main trial population, the population covered by the marketing authorisation and the population in the SHIFT-PRO study. # Main SHIFT population In the main trial population, the primary outcome of first event of cardiovascular death or hospital admission for worsening heart failure was analysed using a Cox proportional hazards model adjusted for beta-blocker intake at randomisation. The hazard ratio (HR) estimate was 0.82; (95% confidence interval 0.75 to 0.90, p<0.0001), representing a statistically significant relative risk reduction of 18% for ivabradine compared with placebo. This composite endpoint was driven more by the rate of hospital admission for worsening heart failure (HR 0.74; 95% CI 0.66 to 0.83) than by the rate of cardiovascular death (HR 0.91; 95% CI 0.80 to 1.03) because people are often admitted to hospital before they die. Further analysis was carried out by the manufacturer to assess the impact of baseline beta-blocker dose on the efficacy of ivabradine in the main SHIFT population. For the primary composite endpoint, the relative effects of ivabradine compared with placebo for the 5 categories of beta-blocker intake were: HR 0.71; 95% CI 0.55 to 0.93, p=0.012 (no beta-blocker) HR 0.74; 95% CI 0.59 to 0.92, p=0.007 (less than 25% of target dose) HR 0.81; 95% CI 0.68 to 0.98, p=0.029 (25% or more but less than 50% of target dose) HR 0.88; 95% CI 0.72 to 1.07, p=0.193 (50% or more but less than 100% of target dose) and HR 0.99; 95% CI 0.79 to 1.24, p=0.913 (100% or more of target dose). There were similar trends in efficacy for ivabradine compared with placebo across the beta-blocker categories for the component outcomes of hospital admission for worsening heart failure and cardiovascular death. The manufacturer noted that this could be a result of lower doses of beta-blockers being associated with higher heart rate because beta-blockers primarily reduce heart rate. There were no statistically significant differences across the beta-blocker categories. These findings suggest that the efficacy of ivabradine is primarily driven by heart rate and not by beta-blocker dose. # Population covered by the marketing authorisation In the subgroup with a baseline heart rate of 75 bpm or more, the incidence of the primary composite endpoint was statistically significantly lower in the ivabradine group than in the placebo group (26.6% and 32.8% respectively, p<0.0001). The hazard ratio showed a clinically and statistically significant reduction of 24% in the risk of the composite endpoint for ivabradine compared with placebo (HR 0.76; 95% CI 0.68 to 0.85). This was in line with the predefined subgroup analysis on median heart rate, which revealed that baseline heart rate modified the treatment effect of ivabradine. There was a statistically significant improvement in all secondary outcomes for the population covered by the marketing authorisation, unlike for the main SHIFT population in whom some of the secondary outcomes were not statistically significant. There were statistically significant reductions in all mortality outcomes in the ivabradine group compared with placebo as follows: cardiovascular death (HR 0.83; 95% CI 0.71 to 0.97, p=0.0166) heart failure death (HR 0.61; 95% CI 0.46 to 0.81, p=0.0006) all-cause death (HR 0.83; 95% CI 0.72 to 0.96, p=0.0109). Results similarly favoured ivabradine compared with placebo for: hospital admission for cardiovascular problems (HR 0.79; 95% CI 0.71 to 0.88, p<0.0001) worsening heart failure (HR 0.70; 95% CI 0.61 to 0.80, p<0.0001) hospital admission for any cause (HR 0.82; 95% CI 0.75 to 0.90, p<0.0001). In the population covered by the marketing authorisation, heart rate decreased in the ivabradine and placebo groups by 17.4 bpm and 5.7 bpm at day 28 and 14.5 bpm, and 5.8 bpm at the last visit respectively. The manufacturer noted that the greater decrease in heart rate in the population covered by the marketing authorisation was consistent with a higher mean baseline heart rate of 84 bpm in this subgroup compared with 80 bpm in the main trial population. This was confirmed to be in line with previous ivabradine trials, which showed that greater reductions in heart rate are associated with higher resting heart rate. In this subgroup there was a statistically significant improvement in NYHA class in the ivabradine group compared with the placebo group. Using the SHIFT-PRO study data, 3 types of quality of life analyses were performed. The first (main analysis) used '0' as the last post-baseline value for deceased patients, the second (an analysis of surviving patients) used the last post-baseline value for deceased patients, and the third used the change from baseline to month 12 from the main analysis. For the EQ-5D index score measure, quality of life worsened from baseline to the last assessment in the ivabradine group and the placebo group in the main analysis. However, there was an improvement in quality of life from baseline to the last assessment for the analysis of surviving patients in the 2 groups, with a greater improvement in the ivabradine group. The quality of life improvement from baseline to month 12 in both groups was higher in the ivabradine group. The manufacturer suggested that this was because there were fewer deaths during the first 12 months than during the whole study. A mixed regression model was used to estimate quality of life using EQ-5D index scores with UK population tariff values. This showed that quality of life improved in the ivabradine group for the population covered by the marketing authorisation. The KCCQ disease-specific measure was also used and it showed a statistically significant difference of 2.6 (95% CI 0.7 to 4.5, p=0.008) for ivabradine compared with placebo for the 12-month analysis, which was also similar to the main analysis and the analysis of surviving patients. The safety population (n=6492 main trial cohort; n=4141 population covered by the marketing authorisation) was the population who received at least 1 dose of any study treatment. The adverse events that occurred on treatment (between the first study drug intake and last intake plus 2 days) were analysed in this safety population. The following adverse events occurred more frequently with ivabradine than with placebo in the population covered by the marketing authorisation: symptomatic bradycardia (4.1% and 0.7% respectively), atrial fibrillation (7.9% and 6.8% respectively) and phosphenes (2.8% and 0.5% respectively). There were similar results for the main trial population. However, other serious adverse events and fatal events were higher in the placebo group in the 2 populations. The manufacturer noted that the tolerability of ivabradine was not affected by baseline heart rate because there were no differences in the adverse events leading to withdrawal between the main trial population and the population covered by the marketing authorisation. After a request from the ERG during the clarification stage, the manufacturer provided the absolute numbers for the primary composite outcome and key secondary outcomes for the subgroups of the population covered by the marketing authorisation according to their beta-blocker category, age and NYHA class (details of the analyses are in section 3.22). The manufacturer also provided separate scenario analyses of the impact of using a regression model for NYHA progression adjusted for patient baseline characteristics, using updated standard care drug costs and different assumptions for modelling mortality. In addition, the manufacturer provided details of the patients who experienced symptomatic bradycardia and atrial fibrillation, and follow-up data on the reduction in heart rate at various time points for the population covered by the marketing authorisation. ## Evidence Review Group comments – population covered by the marketing authorisation The ERG stated that the literature search conducted by the manufacturer was appropriate, all relevant studies had been identified and that SHIFT, on which the manufacturer's submission was based, was relevant to the decision problem in its analysis. The ERG was satisfied that SHIFT was a well-designed randomised controlled trial with a robust method of randomisation. However, it highlighted that only 12 patients (0.2%) in the study were recruited from the UK, but noted the manufacturer's comment about the difficulties gaining study approval in the UK. The ERG also stated that the low UK patient numbers may have resulted from the difficulty in identifying eligible patients if patients were attending heart failure centres and had good titration of beta-blocker therapy. It also noted that the population covered by the marketing authorisation was younger, included a higher proportion of men and patients with more severe heart failure than a typical UK heart failure patient population, but it recognised that the baseline characteristics of the population covered by the marketing authorisation were similar to those reported for other key heart failure studies. However, the ERG considered that the results of SHIFT were robust and generalisable to a UK population because there was evidence to suggest that the patients in the trial received standard treatments. The ERG noted that the clinical-effectiveness evidence for ivabradine was based on a post hoc subgroup of patients with a resting heart rate of 75 bpm or more without prior stratification based on resting heart rate, but in line with ivabradine's marketing authorisation. Therefore it considered that the evidence presented should be interpreted with a level of caution because there is likely to be an imbalance between the groups in terms of heart rate and potential unknown confounders. However, the ERG acknowledged that the baseline characteristics were well balanced between the treatment groups in the main trial population and the population covered by the marketing authorisation. The ERG was aware that only approximately 26% of the main trial population and the population covered by the marketing authorisation were each treated with the recommended target dose of beta-blocker, and 55.4% of the trial population covered by the marketing authorisation were treated with 50% or more of the recommended dose of beta-blocker despite the recommendations in the SHIFT protocol. It was concerned that the patients who were not treated with the target dose of beta-blocker may not have been optimally treated. The ERG also noted the low use of cardiac devices in SHIFT and considered that this could have resulted from the exclusion of patients with pacemakers from the trial. The ERG noted that the greatest benefit of ivabradine compared with placebo was in reducing heart failure deaths (HR 0.61; 95% CI 0.46 to 0.81, p=0.0006), which supports the observation that the results were generally driven by the cause-specific endpoints of hospital admission for heart failure and heart failure deaths in both populations. The ERG noted that ivabradine was associated with an improvement in NYHA class in the population covered by the marketing authorisation at their last visit compared with their baseline classification and that it had little impact on the proportion of patients with worsening NYHA classification. The ERG noted that treatment-related adverse events occurred more frequently in the ivabradine group (17.8%) than in the placebo group (8.3%) in the main trial population. It felt that this was likely to be the same for the population covered by the marketing authorisation because the most common adverse events were the same as in the main trial population. The ERG highlighted that the reported adverse events (apart from inadequate blood pressure control) were similar to those reported in the BEAUTIFUL trial (10,917 randomised patients), which assessed the effects of ivabradine plus standard care in patients with coronary artery disease and left ventricular systolic dysfunction. The ERG carried out an exploratory analysis of the data provided by the manufacturer after the clarification request on the primary and secondary outcomes of the population covered by the marketing authorisation according to their beta-blocker dosage at randomisation (that is, no beta-blocker, less than 25% of target beta-blocker dose, 25% or more but less than 50% of target beta-blocker dose, 50% or more but less than 100% of target beta-blocker dose and 100% or more of target beta-blocker dose).The ERG highlighted that their exploratory analyses suggest that there is uncertainty around the benefit of ivabradine plus standard care for patients with a resting heart rate of 75 bpm or more and who are receiving at least 25% of beta-blockers. The ERG also explored the efficacy of ivabradine according to NYHA class and in patients aged 70 years or older. It noted that the analysis in the NYHA class IV subgroup was based on small numbers, creating uncertainty about the benefit of ivabradine observed in this subgroup. Because the input data used in the exploratory analyses were marked as academic-in-confidence by the manufacturer, the results have also been marked as confidential and so cannot be shown here. However, the ERG emphasised that these analyses are speculative and based on subgroups of subgroups and should be interpreted with caution. # Cost-effectiveness evidence In a systematic review of the literature the manufacturer did not identify any study on the cost effectiveness of ivabradine for treating chronic heart failure. No cost-effectiveness data were presented for the main SHIFT population, and so the economic evaluation carried out by the manufacturer was based only on the post hoc subgroup of patients from SHIFT with a baseline heart rate of 75 bpm or more. The manufacturer stated that this subgroup reflected the marketing authorisation for ivabradine; that is, people with chronic heart failure NYHA class II to IV with systolic dysfunction, in sinus rhythm and whose heart rate is 75 bpm or more, who are being treated with ivabradine in combination with standard therapy including beta-blockers, or for whom beta-blockers are contraindicated or not tolerated. The manufacturer developed a Markov cohort model consisting of 2 states (alive and dead). The difference in quality of life of patients was captured according to NYHA class in the 'alive' state of the model without modelling the NYHA classes as separate health states. The model has a lifetime time horizon consisting of monthly cycles, includes a half-cycle correction, and both costs and benefits were discounted at 3.5%. The analysis was performed from the perspective of the NHS and personal social services. Standard care was modelled in line with SHIFT because the use of heart failure medications in the trial was higher than current standard care treatment patterns in the UK. The regression equations for mortality, NYHA class distribution, hospital admission and quality of life used in the analysis were based on data from the entire SHIFT cohort rather than developing risk equations based solely on the population covered by the marketing authorisation. This was to avoid breaking randomisation and reducing the predictive power of the risk equations because of smaller sample size. However, the risk equations for mortality, hospital admission and quality of life were adjusted for baseline heart rate to predict estimates for the population covered by the marketing authorisation with a heart rate of 75 bpm or more. The manufacturer estimated the risk of non-cardiovascular death based on age-adjusted and sex-adjusted UK national life table data from the Office for National Statistics rather than SHIFT data because it provided a larger, UK-specific data source. This risk was assumed to be the same across treatment groups and no treatment effect was modelled for this endpoint. The risk of cardiovascular mortality (both heart failure and other non-heart-failure cardiovascular death) for the within-trial period was estimated using a Gompertz parametric survival regression model based on the full SHIFT cohort in the base-case analysis. Survival models based on exponential and Weibull parametric distributions, and as Kaplan-Meier data were included as part of the sensitivity analyses. The cardiovascular mortality risk equation was estimated adjusting for a series of baseline patient characteristics (including age, sex, NYHA class, heart failure duration, body mass index, medical history, baseline use of heart failure medications) to generate different estimates of mortality. The Gompertz distribution was also used to extrapolate cardiovascular mortality beyond the trial period. Mortality was approximately 17% in the standard care group of SHIFT. Because of the uncertainty generated by using a small proportion to extrapolate mortality for the rest of the cohort, the manufacturer considered mortality data from an external data source (CARE-HF data; Cleland 2010) in the sensitivity analyses. The extrapolation assumed that 50% of the cohort would have died after 2000 days (65 months). The distribution of patients in each NYHA class over time was estimated from a generalised ordered regression (a proportional odds model) developed from SHIFT data. It predicted the distribution of NYHA class adjusting for treatment and time covariates but not patient baseline characteristics. By the third year the proportion of patients in class III and IV reduced from 40.2% to 36.9% in the ivabradine arm and from 44% to 40.6% in the standard care arm, whereas those in class II increased from 58.4% to 61.4% and from 54.9% to 58.1% in the ivabradine arm and standard care arm respectively. Because of the lack of any evidence to predict the distribution of patients by NYHA class beyond the trial period, the model assumed that the proportions remained fixed after the trial based on the last observation in the trial at 29 months (although the absolute numbers in each category were expected to vary according to the number of patients alive). The rate of heart failure, cardiovascular and all-cause hospital admission per person month was estimated using a Poisson regression model based on the entire SHIFT cohort and converted into a monthly transition probability in the economic model. The hospital admission endpoints were modelled separately to capture the appropriate resource use for each admission type and to permit sensitivity analysis on the treatment effect of ivabradine. However, the base-case analysis was based on all-cause hospital admission. Admission to hospital after the trial was modelled to be equivalent to the within-trial period and assumed to occur at a constant rate throughout the model irrespective of the ageing population. The treatment effect of ivabradine on cardiovascular mortality (including heart failure death) compared with placebo was estimated as a hazard ratio of 0.90 (95% CI 0.80 to 1.03) from the parametric model to the underlying mortality risk in the standard care group. It was assumed that the treatment effect of ivabradine continues after the trial and is equivalent to that seen in SHIFT. To support this assumption, the manufacturer highlighted that the heart-rate-lowering effect of ivabradine was shown to be maintained throughout SHIFT and also over a 7-year study period for ivabradine in patients with angina. The treatment effect of ivabradine on the rate of admissions to hospital was estimated using a rate ratio of 0.83 (95% CI 0.78 to 0.93) derived from the Poisson regression model. The treatment effect was modelled on all-cause admission because cardiovascular and heart failure admissions were assumed to be implicitly captured in all-cause admission and ivabradine was shown to have a statistically significant effect on all-cause admission in the main trial and populations covered by the marketing authorisation. The length of stay associated with hospital admission was estimated using external data based on expert clinical advice. In the base-case model, the average length of stay was varied according to diagnosis on hospital admission (heart failure: 7.57 days, other cardiovascular: 3.97 days and non-cardiovascular: 5.13 days) and was based on a weighted average of elective and non-elective NHS reference cost data. The utility values used in the model were derived from the SHIFT-PRO study, in which health-related quality of life was captured with the EQ-5D questionnaire. EQ-5D index scores were calculated using UK population tariff values and then analysed using a mixed regression model. Quality of life was modelled to reflect patients' baseline characteristics, severity of the disease over time by NYHA class, rate of hospital admission (which includes serious adverse events) and treatment group. The resulting utility scores by NYHA class without any hospital admission ranged from 0.82 in class I to 0.46 in class IV. Decrease in quality of life because of hospital admission was estimated as decreases in utility of 0.07, 0.03, 0.08 and 0.21 for NYHA class I, II, III and IV respectively. The effect of ivabradine on quality of life was modelled and showed a small utility increase in the ivabradine group compared with the baseline estimates used for the placebo (standard care) group. Treatment-related adverse events were assumed not to have any measurable impact on quality of life and the manufacturer indicated that they had been captured by the treatment covariate in the regression model. Quality of life was assumed to remain the same for each NYHA class in the post-trial period and in the base case and the model estimates were not based on an ageing population. This implies that the utility values for the patients in later cycles were higher than they should be and this was assumed to have favoured ivabradine because additional survival time was associated with greater quality-adjusted life year (QALY) benefits. In the sensitivity analysis, quality of life was adjusted for the increasing age of the modelled cohort by resetting the baseline age for each cycle. The average monthly cost of ivabradine (£42.10; excluding VAT) used in the model was estimated according to the proportion of patients who received 2.5 mg (7%) and either 5 mg or 7.5 mg (93%) in the SHIFT study. The 5 mg and 7.5 mg tablets cost £40.17 per 56-tablet pack (excluding VAT; BNF 63), and the price of the 2.5 mg dose was assumed to be half the price of the 5 mg tablet. Average monthly standard care costs (£9.54) were estimated according to the proportion of patients using each standard care medication in SHIFT. The unit costs of the standard care drugs used such as beta-blockers, ACE inhibitors, diuretics, aldosterone antagonists, angiotensin receptor blockers and cardiac glycosides were also taken from the BNF. The manufacturer assumed that there were no extra costs in administering ivabradine and the standard care drugs. However, additional costs were included for ivabradine therapy titration (1 specialist visit) and an electrocardiogram (ECG). This increased the total monthly cost in the ivabradine group from £52 to £202 for the first month. The hospital admission costs used in the model were estimated using the NHS reference costs for heart failure admissions (general ward: £2308 and cardiac ward: £3295), cardiovascular admissions (general ward: £1942 and cardiac ward: £1730) and non-cardiovascular admissions (general ward: £2644). It was assumed that there was an equal probability of being in a general ward or a cardiac ward. Serious adverse events were captured using these hospital admission endpoints, but non-serious adverse events were not included. The monthly cost of managing heart failure, including physician visits, outpatient procedures and diagnostic tests, was estimated to be £27 from British Heart Foundation statistics. The base-case results of the economic analysis, which was based on the population covered by the marketing authorisation, was estimated by applying individual patient profiles from SHIFT to the risk equations sequentially, one at a time. It showed that the incremental costs and incremental QALYs gained from treating chronic heart failure with ivabradine plus standard care compared with standard care alone were £2376 and 0.28 QALYs respectively. This gave an incremental cost-effectiveness ratio (ICER) of £8498 per QALY gained. The manufacturer highlighted that the deterministic, probabilistic and structural sensitivity analyses were performed using average covariate values in the regression equations to shorten analysis time and that this may have caused some loss in accuracy in the ICER estimates. The base-case ICER using this method was £7743 per QALY gained. The one-way deterministic sensitivity analyses were performed on several model parameters using their 95% confidence intervals. The cost-effectiveness result was most sensitive to changes in cardiovascular mortality risk, with the resulting ICERs ranging from £5655 to £40,638 per QALY gained. The base-case ICER also showed some sensitivity to changes in the rate of hospital admission (£6384 to £10,424 per QALY gained) and treatment effect of ivabradine on quality of life (£6283 to £9253 per QALY gained). Changes in hospital length of stay and ivabradine treatment effect on NYHA class had much less impact on the ICER, £6938 to £8549 and £7232 to £8349 per QALY gained respectively. The manufacturer's probabilistic sensitivity analysis indicated that ivabradine plus standard care would have a more than 95% chance of being cost effective compared with standard care alone if the maximum acceptable ICER was £20,000 per QALY gained. The manufacturer carried out different scenario analyses to manage uncertainties about some of the assumptions in the base-case model. The scenario analyses explored the effect on the ICER of: varying the treatment duration of ivabradine; ivabradine's treatment effect stopping after 5 and 10 years; using alternative models to estimate the risk of cardiovascular mortality; increasing the median length of hospital stay based on the 'National heart failure audit' data; and excluding the costs of the titration visit and the ECG. The manufacturer also carried out other scenario analyses, including: using a within-trial time horizon; using external data to extrapolate cardiovascular mortality and utility values; including age-adjusted utility values; and assuming a 5% change in the distribution of NYHA classes (from I to II, from II to III and from III to IV) in the post-trial period. After a clarification request, the manufacturer also provided a scenario analysis in which a new regression equation was developed to predict NYHA class distribution. This was adjusted for treatment, time covariates and patient baseline characteristics, and drug prices were updated to those in BNF 63. These scenario analyses all gave ICERs below £9000 per QALY gained except for the assumptions of the treatment effect of ivabradine stopping after 5 and 10 years and using the within-trial time horizon, which gave ICERs ranging from £13,964 to £15,200 per QALY gained. The manufacturer carried out several subgroup analyses based on individual patient characteristics from the population covered by the marketing authorisation. These subgroups were based on age, NYHA class, beta-blocker doses, heart failure duration, level of left ventricular ejection fraction, and prior medical history (coronary artery disease and diabetes). The results showed that ivabradine plus standard care was still cost effective when compared with standard care alone. The estimated ICERs for the subgroups were all below £11,000 per QALY gained and ranged from £5197 to £10,427 per QALY gained. The manufacturer also carried out additional subgroup analyses based on a population representative of a UK chronic heart failure patient group. This population was specified as western European men with a median age of 78 years, receiving at least half the target dose of beta-blockers. The ICER generated for this subgroup was £8735 per QALY gained, and the ICER for a UK chronic heart failure patient group taking the target dose of beta-blockers was £9185 per QALY gained. ## Evidence Review Group comments The ERG was satisfied with the manufacturer's modelling approach, which was transparent, used patient-level data and was consistent with other published economic studies on heart failure treatments. The ERG stated that the manufacturer did not carry out an analysis in a patient population with a disease severity reflective of the UK population. However, it agreed with the manufacturer that using values for patient characteristics beyond the SHIFT population range may generate unreliable results. The ERG was satisfied that the standard care treatments used in SHIFT and the economic model reflected UK clinical practice. The ERG accepted the manufacturer's use of Office for National Statistics UK life tables to provide estimates of non-cardiovascular mortality in the base case because this is standard practice in heart failure cost-effectiveness analyses. However, it noted that the risk of non-cardiovascular mortality was higher in SHIFT than in the UK life tables. The ERG noted that there were some uncertainties associated with the regression analyses performed for cardiovascular and heart failure mortality, which limited the potential of ivabradine to reduce the risks of these 2 outcomes. The treatment effect of ivabradine in the regression analysis was not statistically significant for cardiovascular mortality (p=0.38) and was borderline statistically significant (p=0.06) for heart failure mortality (although these results had been statistically significant for the population covered by the marketing authorisation only). By contrast, beta-blockers given at 50% or more of the target dose were associated with a statistically significant reduction in the risk of cardiovascular mortality for ivabradine compared with placebo and beta-blockers at any dose were associated with a statistically significant reduction in the risk of heart failure mortality for ivabradine compared with placebo. Because baseline heart rate was adjusted for in the regression analysis, the ERG thought that the risk reduction of ivabradine and beta-blockers was in addition to the attenuating effect of heart rate. The ERG indicated that the regression model for health-related quality of life in the manufacturer's submission was clinically plausible and the disutility associated with hospital admission was likely to have captured any serious impact of adverse events on quality of life because hospital admission would be the main consequence of serious adverse events. The ERG noted that the impact of age adjustment for health-related quality of life was minimal (it increased the ICER by £216 per QALY gained). Therefore, it accepted the exclusion of age adjustment from the base-case analysis because of the time needed to re-run each cycle to adjust for age throughout the model's time horizon. The ERG was satisfied with the costing approach taken by the manufacturer in the economic analysis. The ERG considered that the manufacturer's base-case ICER of £8498 per QALY gained (incremental costs of £2376 and incremental QALYs of 0.28) was likely to represent the expected cost effectiveness of adding ivabradine to standard care, although the ERG believed it was biased against ivabradine. The ERG was satisfied with the manufacturer's pragmatic approach of conducting the sensitivity analyses using average patient characteristics because of the longer analysis time needed to use individual patient profiles for the base case. It indicated that the reduced level of accuracy with this method was unlikely to alter any conclusions drawn from the evidence presented. The ERG was particularly interested in the cost-effectiveness results for the subgroups of patients at different doses of beta-blockers. It noted that the ICERs for these subgroups and all other subgroups analysed remained below £11,000 per QALY gained. However, the ERG noted that the regression equations used were based on the main trial population of SHIFT or the population covered by the marketing authorisation, rather than the particular subgroups of patients considered. It accepted that breaking randomisation and smaller patient numbers would compromise any analyses based on regression equations developed from subgroups. The ERG highlighted that the hazard ratios estimated from regression equations based on the main trial population of SHIFT or the population covered by the marketing authorisation may over (or under) estimate the effect of ivabradine treatment in particular patient populations. Overall, the ERG considered the modelled results to be conservative because they underestimated the risk of cardiovascular mortality, the rate of hospital admission and the relative effect of treatment with ivabradine plus standard care compared with standard care alone. It stated that the sensitivity and subgroup analyses sufficiently addressed any areas of uncertainty. Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from the NICE website.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ivabradine, having considered evidence on the nature of chronic heart failure and the value placed on the benefits of ivabradine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Committee considered the clinical need for treatment in people with heart failure who are covered by the marketing authorisation of ivabradine. The Committee noted that the clinical specialists indicated that ivabradine is primarily a heart-rate-lowering drug for people with left ventricular systolic dysfunction who are in sinus rhythm and for whom beta-blockers are not suitable. The Committee heard from the clinical specialists that people with chronic heart failure have a poor quality of life. It also noted the comment from the patient experts that chronic heart failure can impact on everyday tasks, with comorbidities increasing the impact of the disease and usually requiring lifestyle changes. The patient experts also stated that ivabradine may provide symptomatic and prognostic benefit in a small number of chronic heart failure patients unable to take beta-blockers. The Committee considered the clinical specialists' comment that it may be difficult to increase beta-blocker dosage for people with low blood pressure, a group who would benefit from ivabradine. It noted that ivabradine is contraindicated in severe hypotension (less than 90/50 mmHg). The Committee recognised the impact of chronic heart failure on quality of life and concluded that there were potential treatment benefits with ivabradine for people who are covered by the marketing authorisation. The Committee considered the generalisability of the SHIFT trial to UK clinical practice. The Committee was aware that the population covered by the marketing authorisation in SHIFT was younger, included a higher proportion of men and people with more severe chronic heart failure than the typical chronic heart failure population in the UK. It also noted that only a few people from the UK were included in the trial and the use of cardiac devices in the trial was low. The clinical specialists and the ERG indicated that the differences in age and severity of chronic heart failure may be caused by patient recruitment from specialist heart failure centres, which is common with randomised trials. The Committee considered the comments from the clinical specialists and the ERG that the results of the trial could be extrapolated to a UK setting because the standard therapies used in SHIFT could be regarded as optimal and were given at similar dosing levels to UK clinical practice. Despite the differences between the trial and the UK population, the Committee concluded that SHIFT was relevant to UK clinical practice. The Committee examined the clinical evidence from SHIFT, which compared ivabradine plus standard care with standard care plus placebo. The Committee noted that it was a well-conducted clinical trial and that the relevant clinical outcomes of mortality and hospital admission were assessed. It also noted that health-related quality of life data were collected in SHIFT-PRO using both generic and disease-specific instruments, and was aware that improved quality of life was an important outcome for chronic heart failure patients and that this is considered to be one of the main aims of managing chronic heart failure. The Committee noted that the Committee for Medicinal Products for Human Use had asked the manufacturer to identify the heart rate threshold at which there was a significant mortality benefit with ivabradine, because this benefit was not observed in the main SHIFT population. So the manufacturer then examined a post hoc subgroup of people with a baseline resting heart rate of 75 bpm or more, and this subgroup formed the population for whom ivabradine has a marketing authorisation. The Committee noted that the results from this subgroup demonstrated a statistically significant reduction in all primary and secondary endpoints assessed. This included cardiovascular death, which reduced by 17% with ivabradine compared with placebo, unlike in the main SHIFT population, in which the 9% reduction in cardiovascular death was not statistically significant. The Committee was aware that baseline resting heart rate was not a stratification factor at randomisation and that this subgroup was identified post hoc, but it was also aware that recommendations could only be made within ivabradine's marketing authorisation. The Committee concluded that SHIFT was well conducted and there was it was plausible biologically that a statistically significant mortality benefit will be observed in the subgroup of people with a baseline resting heart rate of 75 bpm or more, which reflects the marketing authorisation of ivabradine. However they were aware the evidence presented should be interpreted with a level of caution because the subgroup was identified post hoc. The Committee noted that a previous hospital admission for worsening heart failure in the past 12 months was an inclusion criterion for SHIFT. The Committee agreed that this was an important consideration because people with a prior hospital admission in the past 12 months may have more severe chronic heart failure than would be observed in clinical practice, with a higher risk of further hospitalisations, which was the key driver of the clinical and cost-effectiveness estimates. The Committee noted that the marketing authorisation for ivabradine depended on the efficacy of ivabradine in a specific post hoc subgroup with more severe heart failure (with a baseline heart rate of 75 bpm or more) to demonstrate a cardiovascular mortality benefit. The Committee heard from the clinical specialists that prior hospital admission should not be a factor for considering ivabradine treatment because there are no data to prove that the efficacy of ivabradine is limited to the population who have been admitted to hospital in the previous 12 months. The clinical specialists also highlighted that people had to be stabilised for 4 weeks on standard therapy as an entry criterion into the trial. The Committee considered that prior hospital admission did not affect mortality and the marketing authorisation did not make any reference to prior admission status. The Committee was aware that ivabradine was contraindicated for people with unstable heart failure. Therefore when discussing ivabradine, it understood it could only be initiated after prior stabilisation therapy. The Committee concluded that all people for whom treatment with ivabradine is suitable, according to the marketing authorisation, should be able to receive ivabradine regardless of hospital admission status, but that people should be stabilised for 4 weeks on standard therapy first. The Committee considered the adverse event profile associated with ivabradine plus standard care compared with placebo plus standard care. The Committee noted that symptomatic bradycardia, atrial fibrillation and phosphenes occurred more frequently in the ivabradine group compared with the placebo group, although other serious adverse events were higher in the placebo group. It noted the comments from the clinical specialists that phosphenes are recognised adverse effects of ivabradine, which usually resolve in most patients during treatment. The clinical specialists also stated that ivabradine appeared to be much simpler and safer to use compared with most heart failure drugs. The Committee was concerned that an unusually high proportion of people in the population covered by the marketing authorisation who received a beta-blocker were not treated with the target dose because of hypotension, especially because the mean systolic blood pressure in the population covered by the marketing authorisation was 121 mmHg. It also noted that it would be unusual for people with heart failure to have hypotensive symptoms with this level of blood pressure. It noted the ERG's comment that it has been reported that only 3–5% of patients eligible for treatment with beta-blockers are unable to tolerate them because of hypotension or bradycardia. The Committee concluded that ivabradine plus standard care had a manageable adverse event profile in the population covered by the marketing authorisation. The Committee examined the exploratory analysis performed by the ERG on the efficacy of ivabradine according to beta-blocker dose received by the population covered by the marketing authorisation in SHIFT. The Committee noted the impact of the beta-blocker doses on the effectiveness of ivabradine, particularly in terms of cardiovascular mortality. However, the Committee agreed that this analysis was based on subgroups of a subgroup and should be interpreted with caution. The clinical specialists stated that these results further highlight the need for beta-blockers to be used at optimal doses before ivabradine is initiated, because there is good evidence that beta-blockers reduce cardiovascular mortality at optimal doses. They also emphasised that ivabradine would be less effective in people with chronic heart failure who are optimally treated with beta-blockers because both treatments are primarily heart-rate-lowering agents, although beta-blockers are known to have additional effects beyond their heart-rate-lowering properties. The Committee concluded that, given the results of these exploratory analyses, the effectiveness of ivabradine with increasing beta-blocker doses is uncertain. The Committee also discussed the exploratory analysis performed according to NYHA class by the ERG for the population covered by the marketing authorisation. It heard from the clinical specialists that it was debatable whether the NYHA class IV subgroup could be considered to be in a stable condition given the severity of their heart failure and that ivabradine is contraindicated in unstable heart failure. The Committee also heard from the clinical specialists that the benefit observed in this subgroup of people would be expected because they are the population with the greatest risk of cardiovascular mortality. However, the Committee noted that the analysis in this subgroup of people with NYHA class IV heart failure was based on small numbers, which limits the robustness of the results. Therefore the Committee concluded that the effectiveness of ivabradine in people with NYHA class IV heart failure was uncertain because of the small patient numbers in the analysis, which meant that these people could not be considered separately as a subgroup. The Committee discussed the position of ivabradine in the treatment pathway for chronic heart failure, noting that it is indicated in chronic heart failure NYHA class II to IV with systolic dysfunction, for people in sinus rhythm whose heart rate is 75 bpm or more, and in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated. The Committee heard from the clinical specialists that ACE inhibitors, beta-blockers and aldosterone antagonists used routinely for managing chronic heart failure should always be the initial treatments, because there is robust evidence that they are effective in managing chronic heart failure and improving survival. The clinical specialists all agreed that ivabradine is an additional therapy for a subset of people with chronic heart failure who are in sinus rhythm, and not as a replacement for the recommended standard therapies such as ACE inhibitors, beta-blockers and aldosterone antagonists. They suggested that ivabradine should be considered only when patients are still symptomatic after being stabilised on optimal initial standard therapies at maximally tolerated doses, or when beta-blockers are contraindicated or not tolerated. The clinical specialists expressed their concerns that introducing ivabradine earlier than specified in the marketing authorisation would limit efforts to optimise the use of other standard drugs, particularly beta-blockers. They stressed the need for enough time to titrate beta-blockers to optimal doses according to the 'start low, go slow' recommendations in Chronic heart failure (NICE clinical guideline 108). The Committee concluded that ivabradine should be initiated only after standard treatment with ACE inhibitors, beta-blockers and aldosterone antagonists has been optimised. The Committee explored what optimising standard therapy with beta-blockers meant in clinical practice. It heard from clinical specialists that it can take several months to appropriately titrate beta-blockers to the optimal dose for a patient. The Committee was aware that to optimise and ensure adherence to beta-blocker therapy, continuous monitoring and education and support of the patient by members of the heart failure multidisciplinary team are needed. The Committee also noted comments from consultees and commentators that there have been misconceptions that beta-blockers are contraindicated in, for example, the elderly, or in people with non-reversible chronic obstructive pulmonary disease, diabetes mellitus, peripheral vascular disease or erectile dysfunction. It noted that, in line with NICE's guidance on chronic heart failure (NICE clinical guideline 108), these groups of people should receive beta-blockers. The Committee re-emphasised their conclusion in section 4.9 on the importance of optimising beta-blockers before initiating ivabradine. The Committee also considered the comments from consultees and commentators that there is a recent analysis that shows that digoxin may confer benefits similar to ivabradine for patients in sinus rhythm and with heart failure caused by left ventricular systolic dysfunction. However, the Committee noted that digoxin was not included as a comparator in the scope for this appraisal and there was no evidence to support its benefit in this population. The Committee concluded that considering digoxin as a comparator to ivabradine is beyond the scope of this appraisal. The Committee also considered the position of cardiac devices, particularly cardiac resynchronisation therapy, in the treatment pathway for chronic heart failure because the manufacturer proposed positioning ivabradine before them. The clinical specialists were uncertain about this and proposed several different options about the most appropriate choice if people still have symptoms after they are treated with ACE inhibitors, beta-blockers and aldosterone antagonists. The Committee noted that very few patients in SHIFT received cardiac resynchronisation therapy. It therefore considered that more evidence would be useful to determine the position of ivabradine in relation to cardiac devices, particularly cardiac resynchronisation therapy, in the treatment pathway. However, the clinical specialists said that choosing whether to treat with ivabradine or cardiac resynchronisation therapy will depend on clinical need and that ivabradine will only be considered if the person is in sinus rhythm as indicated in ivabradine's marketing authorisation. The Committee was aware that ivabradine is contraindicated in people whose heart rate is dependent on a pacemaker. The Committee recognised that there was some uncertainty about the appropriate choice of treatment when people are eligible for both ivabradine and cardiac resynchronisation therapy, and concluded that the decision will likely be based on the judgement of the treating clinician. The Committee considered the comments from the consultees and commentators that ivabradine should only be given to people with a left ventricular ejection fraction of 35% or less. It noted that the patients in SHIFT had left ventricular systolic dysfunction, which was associated with an ejection fraction of 35% or less, and it was aware that this was an entry criterion for the trial. The Committee was aware that an ejection fraction level was not specified in the marketing authorisation for ivabradine. However, it considered that ivabradine could not be recommended in people with an ejection fraction that is above 35% because there is no evidence of its effectiveness in that group. The Committee discussed how the ejection fraction level will be determined in clinical practice and whether the required tests will be readily available to people who will potentially benefit from ivabradine. It heard that ejection fraction level is usually demonstrated with an echocardiogram and additional tests will not necessarily be required before initiating ivabradine. Therefore, the Committee concluded that ivabradine should only be initiated in people with a left ventricular ejection fraction of 35% or less, normally shown on an echocardiogram. The Committee considered how ivabradine will be prescribed in clinical practice. It heard from clinical specialists that a heart failure specialist in secondary care with access to a multidisciplinary team should initiate ivabradine. The clinical specialists also stated that titration and monitoring of ivabradine could then take place in primary care by a GP with a special interest in heart failure or a heart failure specialist nurse, supported by a multidisciplinary team. They highlighted that this may help ensure the appropriate patients are treated with ivabradine after optimising treatment and stabilising patients on maximally tolerated doses of ACE inhibitors, beta-blockers and aldosterone antagonists. However, the manufacturer anticipated that ivabradine would be prescribed by a clinician experienced in managing chronic heart failure as recommended in the summary of product characteristics. The Committee discussed the emergence of increasing heart failure expertise outside secondary care. It noted that NICE's guideline on chronic heart failure (NICE clinical guideline 108) defined a specialist as a physician with a subspecialty interest in the management of heart failure and who leads a specialist multidisciplinary heart failure team of professionals with appropriate competencies from primary and secondary care. The Committee concluded that ivabradine should be initiated by a heart failure specialist (in line with the NICE clinical guideline) with access to a multidisciplinary heart failure team and dose titration and monitoring should then be carried out by a heart failure specialist or in primary care by either a GP with a special interest in heart failure or a heart failure specialist nurse. # Cost effectiveness The Committee considered the manufacturer's economic model and the ERG's critique of this model. The Committee was aware that the manufacturer had based the economic evaluation on the subgroup of patients with a baseline resting heart rate of 75 bpm or more. The Committee noted that this was the subgroup for whom ivabradine has a UK marketing authorisation. The Committee concluded that the appropriate population for the economic evaluation of ivabradine for treating chronic heart failure had been captured in the model. The Committee discussed the assumptions made by the manufacturer in developing the economic model. The Committee noted the ERG's comment that the manufacturer's model was transparent and made use of patient-level data in the base-case analysis. It agreed with the ERG that the standard care treatments used in the economic model reflected UK clinical practice. The Committee was satisfied that the utility values applied in the model were derived from SHIFT, which was the pivotal trial used in the economic analysis, and considered the approach taken by the manufacturer to obtain the final utility estimates to be plausible and robust. The Committee was also satisfied with the costs used by the manufacturer and that the clinical inputs to the model reflected UK practice. The Committee was aware that the sensitivity analyses conducted by the manufacturer were robust for the base-case estimate, except for the risk of cardiovascular mortality (see section 3.33 and 3.35), and that the ICERs for all the subgroup analyses were below £11,000 per QALY gained. The Committee concluded that the manufacturer's model was robust and the assumptions were realistic and conservative. The Committee considered the uncertainty around the benefit of ivabradine on cardiovascular mortality given that the ICER ranged between approximately £5600 and £40,600 per QALY gained when the risk of cardiovascular mortality was varied using the 95% confidence interval around the mean from the trial data. The Committee noted the ERG's comments that there were uncertainties associated with the regression analyses for cardiovascular and heart failure mortality used in the economic model presented by the manufacturer. The Committee noted that the treatment effect of ivabradine in the regression analysis had a p value of 0.38 for cardiovascular mortality and a p value of 0.06 for heart failure mortality. For the population covered by the marketing authorisation in the clinical effectiveness analysis, the p value for cardiovascular mortality was 0.02, and for heart failure mortality was <0.01. On the other hand, beta-blockers given at 50% or more of the target dose were associated with a statistically significant reduction in the risk of cardiovascular mortality, and beta-blockers at all doses were associated with statistically significant reductions in the risk of heart failure mortality. The Committee considered that this further highlights the importance of optimising beta-blocker therapy before treatment with ivabradine. However, the Committee noted the ERG's comment that the absence of a statistically significant effect with ivabradine in the model may be a result of the adjustment of patient characteristics not accounted for in the clinical analysis. The Committee was also aware that the manufacturer's regression analyses were conservative in favour of placebo, which made the analyses likely to underestimate the risks of cardiovascular and heart failure mortality, and so generated different results from those observed in the population covered by the marketing authorisation of the SHIFT trial. The Committee concluded that the additional treatment effect of ivabradine was uncertain compared with the effect of beta-blocker doses. The Committee considered whether the base-case ICER of approximately £8500 per QALY gained (incremental cost of approximately £2400 and incremental QALY of 0.28) of adding ivabradine to standard care estimated by the manufacturer was the most plausible ICER. The Committee considered that the ICER suggested that ivabradine was cost effective if a threshold of £20,000 per QALY gained was applied. The Committee considered that the effect of ivabradine on the hospital admission endpoints was the key driver of the cost effectiveness of ivabradine plus standard care compared with standard care alone. It noted that ivabradine plus standard care was more effective and cost more than standard care. Additionally it noted that ivabradine was still accruing more QALYs when the confidence interval for the hazard ratio for mortality crossed 1 and favoured standard care alone in the model, which suggested that ivabradine has a large impact in reducing hospital admissions. The Committee agreed that the wide range of sensitivity and subgroup analyses conducted by the manufacturer sufficiently addressed any areas of uncertainty in the economic analysis, including the beta-blocker subgroups, and all produced ICERs below £11,000 per QALY gained. It also considered that the modelled results and most of the model assumptions were conservative and biased against ivabradine. The Committee therefore concluded that the manufacturer's ICER estimate of approximately £8500 per QALY gained was plausible and was likely to represent the expected cost effectiveness of adding ivabradine to standard care for treating chronic heart failure in the population covered by the marketing authorisation. The Committee recognised the novel mode of action of ivabradine as a heart-rate-lowering agent for patients in sinus rhythm for whom beta-blockers are contraindicated or not tolerated. It also considered the manufacturer's comment that ivabradine is the only non-surgical treatment available for people with chronic heart failure whose prognosis remains poor after recommended optimised therapy for chronic heart failure. However, the Committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The Committee therefore concluded that the innovative aspects of ivabradine were already incorporated in the economic model and analyses. The Committee discussed potential equality issues and gave particular consideration to avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity. The Committee noted the potential equality issue raised by the patient experts about the higher prevalence of non-revascularisable coronary artery disease in the Asian population because of the impact of diabetes as a risk factor. It highlighted that higher prevalence rates are not an equality issue that technology appraisal guidance can address. Nevertheless, the Committee did not consider that the wording of the recommendations affected access to treatment by this group. The Committee also noted that older people and women were under-represented in SHIFT. But it considered that the recommendation for ivabradine was not based on sex or age, does not vary according to the sex or age of the patient, and that all patients would benefit from ivabradine. The Committee considered that these were not equality issues under the legislation. The Committee therefore concluded that its recommendations do not have a particular impact on any of the groups whose interests are protected by the legislation and that there is no need to alter or add to its recommendations. Overall the Committee considered the effectiveness of ivabradine in the subgroup of patients with a resting heart rate of 75 bpm or more derived from SHIFT, the generalisability of the trial to UK clinical practice, the adverse event profile of ivabradine, the position of ivabradine in the treatment pathway of chronic heart failure (that is after optimisation on standard care therapy with ACE inhibitors, beta-blockers and aldosterone antagonists) and the way ivabradine will be prescribed in clinical practice. It also considered the robustness of the economic model, the realistic nature of the assumptions used in the model, the plausibility of the base-case ICERs and the range of sensitivity analyses presented by the manufacturer. The Committee noted that there were uncertainties associated with the effectiveness of ivabradine with increasing beta-blocker doses. However, it was convinced of the benefits of adding ivabradine to the standard care therapies for chronic heart failure in the group of people covered by the marketing authorisation. The Committee therefore concluded that ivabradine could be considered a cost-effective use of NHS resources for treating chronic heart failure in people covered by the marketing authorisation. # Summary of Appraisal Committee's key conclusions TA267 Appraisal title: Ivabradine for treating chronic heart failure Section Key conclusion The Committee recommended ivabradine for treating chronic heart failure having concluded that it could be considered a cost-effective use of NHS resources for treating chronic heart failure, but noted that ivabradine should only be initiated after optimal standard therapy with ACE inhibitors, beta-blockers and aldosterone antagonists, and after a stabilisation period on these therapies of 4 weeks. Current practice Clinical need of patients, including the availability of alternative treatments Ivabradine is primarily a heart-rate-lowering drug for people with left ventricular systolic dysfunction who are in sinus rhythm and for whom beta-blockers are not suitable. People with chronic heart failure have a poor quality of life and the condition can impact on everyday tasks, with comorbidities increasing the impact of the disease and usually requiring lifestyle changes. The Committee recognised the impact of chronic heart failure on quality of life and concluded that there were potential treatment benefits with ivabradine for people who are covered by the marketing authorisation. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Ivabradine is a heart-rate-lowering agent that selectively and specifically inhibits the cardiac pacemaker If current, which controls the spontaneous diastolic depolarisation in the sinus node that regulates the heart rate. Ivabradine is primarily a heart-rate-lowering drug for people with left ventricular systolic dysfunction who are in sinus rhythm and for whom beta-blockers are not suitable. The Committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations, and therefore concluded that the innovative aspects of ivabradine were already incorporated in the economic model and analyses. What is the position of the treatment in the pathway of care for the condition? Ivabradine has a marketing authorisation for people 'in chronic heart failure NYHA class II to IV with systolic dysfunction, who are in sinus rhythm and whose heart rate is ≥75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated'. The Committee concluded that ivabradine should be initiated only after optimal treatment with ACE inhibitors, beta-blockers and aldosterone antagonists has been achieved. Adverse reactions Symptomatic bradycardia, atrial fibrillation and phosphenes occurred more frequently in the ivabradine group compared with the placebo group, although other serious adverse events were higher in the placebo group. The Committee concluded that ivabradine plus standard care had a manageable adverse event profile in the population covered by the marketing authorisation. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee noted that SHIFT was a well-conducted clinical trial and that the relevant clinical outcomes of mortality and hospital admission were assessed. Relevance to general clinical practice in the NHS The results of the SHIFT trial could be extrapolated to a UK setting because standard therapies were used in the trial. Therefore, the Committee concluded that SHIFT was relevant to clinical practice in the UK despite the differences between the trial and the UK population. Uncertainties generated by the evidence The Committee concluded that the effectiveness of ivabradine with increasing beta-blocker doses is uncertain, and also that the effectiveness of ivabradine in people with NYHA class IV heart failure was uncertain because of the small patient numbers. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? The Committee concluded that SHIFT was well conducted and that it was biologically plausible that a statistically significant mortality benefit will be observed in the subgroup of people with a baseline resting heart rate of 75 bpm or more, which reflects the marketing authorisation of ivabradine. However they were aware the evidence presented should be interpreted with a level of caution because the subgroup was identified post hoc. The Committee concluded that the effectiveness of ivabradine with increasing beta-blocker doses is uncertain, and also that the effectiveness of ivabradine in people with NYHA class IV heart failure was uncertain because of the small patient numbers, given the results of the exploratory analyses on the efficacy of ivabradine according to the beta-blocker dose received and NYHA class in the population covered by the marketing authorisation in the SHIFT trial. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee noted that the results from the population covered by the marketing authorisation demonstrated a statistically significant reduction in cardiovascular death of 17% with ivabradine compared with placebo, unlike the main SHIFT population, in which there was a non-significant reduction in cardiovascular death of 9%. Evidence for cost effectiveness Availability and nature of evidence The manufacturer developed a Markov cohort model to evaluate the cost effectiveness of ivabradine in combination with standard therapy including beta-blockers, or for whom beta-blockers are contraindicated or not tolerated for treating chronic heart failure. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee considered the uncertainty around the benefit of ivabradine on cardiovascular mortality given that the ICER ranged between approximately £5600 and £40,600 per QALY gained when the risk of cardiovascular mortality was varied using the 95% confidence interval around the mean from the trial data, and concluded that the additional treatment effect of ivabradine was uncertain compared with the effect of beta-blocker doses. Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee was satisfied that the utility values applied in the model were derived from SHIFT, which was the pivotal trial used in the economic analysis, and considered the approach taken by the manufacturer to obtain the final utility estimates to be plausible and robust. The Committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. Are there specific groups of people for whom the technology is particularly cost effective? The Committee was aware that the sensitivity analyses conducted by the manufacturer were robust for the base-case estimate, except for the risk of cardiovascular mortality and the ICERs for all the subgroup analyses were below £11,000 per QALY gained. What are the key drivers of cost effectiveness? The Committee considered that the effect of ivabradine on the hospital admission endpoints was the key driver of the cost effectiveness of ivabradine plus standard care compared with standard care alone. Most likely cost-effectiveness estimate (given as an ICER) The Committee concluded that the manufacturer's ICER estimate of approximately £8500 per QALY gained was plausible and was the most likely cost effectiveness estimate of ivabradine in addition to standard care for treating chronic heart failure in the population covered by the marketing authorisation. Additional factors taken into account Patient access schemes (PPRS) None End-of-life considerations None Equalities considerations and social value judgements The Committee noted the potential equality issue raised by the patient experts about the higher prevalence of non-revascularisable coronary artery disease in the Asian population because of the impact of diabetes as a risk factor. The Committee also noted that older people and women were under-represented in the SHIFT trial. The Committee considered that these were not equality issues under the legislation. It concluded that its recommendations do not have a particular impact on any of the groups whose interests are protected by the legislation and that there is no need to alter or add to its recommendations. # Related NICE guidance Published Chronic heart failure: management of chronic heart failure in adults in primary and secondary care. NICE clinical guideline 108 (2010). Cardiac resynchronisation therapy for the treatment of heart failure. NICE technology appraisal guidance 120 (2007). Under development NICE is developing the following guidance (details available from the NICE website): Implantable cardioverter defibrillators for the treatment of arrhythmias and cardiac resynchronisation therapy for the treatment of heart failure (review of TA95 and TA120). Expected date of publication September 2013.# Review of guidance The guidance on this technology will be considered for review in November 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveNovember 2012# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Ivabradine is recommended as an option for treating chronic heart failure for people:\n\nwith New York Heart Association (NYHA) class II to IV stable chronic heart failure with systolic dysfunction and\n\nwho are in sinus rhythm with a heart rate of 75\xa0beats per minute (bpm) or more and\n\nwho are given ivabradine in combination with standard therapy including beta-blocker therapy, angiotensin-converting enzyme (ACE) inhibitors and aldosterone antagonists, or when beta-blocker therapy is contraindicated or not tolerated and\n\nwith a left ventricular ejection fraction of 35% or less.\n\nIvabradine should only be initiated after a stabilisation period of 4\xa0weeks on optimised standard therapy with ACE inhibitors, beta-blockers and aldosterone antagonists.\n\nIvabradine should be initiated by a heart failure specialist with access to a multidisciplinary heart failure team. Dose titration and monitoring should be carried out by a heart failure specialist, or in primary care by either a GP with a special interest in heart failure or a heart failure specialist nurse.', 'The technology ': "Ivabradine (Procoralan, Servier Laboratories) is a heart-rate-lowering agent that selectively and specifically inhibits the cardiac pacemaker If current, which controls the spontaneous diastolic depolarisation in the sinus node that regulates the heart rate. Ivabradine is 'indicated in chronic heart failure NYHA class II to IV with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥75\xa0bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated'. Ivabradine is administered orally at a recommended starting dose of 5\xa0mg twice daily. This dose may be increased after 2\xa0weeks of treatment to 7.5\xa0mg twice daily if the resting heart rate is above 60\xa0bpm, or decreased to 2.5\xa0mg (half of the 5\xa0mg tablet) twice daily if the resting heart rate is below 50\xa0bpm. For full details of dosage see the summary of product characteristics.\n\nThe summary of product characteristics lists the following adverse reactions for ivabradine: luminous phenomena (phosphenes), bradycardia, atrioventricular first degree, ventricular extrasystoles, blurred vision, headache, dizziness and uncontrolled blood pressure. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nIvabradine is available in 5\xa0mg and 7.5\xa0mg tablets at a net price of £40.17 per 56-tablet pack (excluding VAT; 'British national formulary' [BNF] edition 63). The manufacturer's submission quoted an average monthly cost of £42.10 (excluding VAT) based on the proportion of patients using 2.5\xa0mg (7%) and either 5\xa0mg or 7.5\xa0mg (93%) in the SHIFT study (see section 3.1). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix\xa0A) considered evidence submitted by the manufacturer of ivabradine and a review of this submission by the Evidence Review Group (ERG; appendix\xa0B).\n\nThe manufacturer conducted a systematic literature search and identified only 1\xa0randomised controlled trial that assessed the effect of ivabradine in people with heart failure, known as SHIFT (systolic heart failure treatment with the If inhibitor ivabradine trial). SHIFT was an international, multicentre, randomised, double-blind, placebo-controlled trial comparing ivabradine with placebo for the treatment of moderate to severe heart failure and left ventricular systolic dysfunction. The trial was carried out in 625\xa0centres in 37\xa0countries and lasted from 12 to 36\xa0months in the active double-blind treatment period, extended to a maximum duration of 52\xa0months. The clinical-effectiveness evidence presented in the manufacturer's submission was based on this trial alone, but results were also provided for the SHIFT patient-reported outcomes (SHIFT-PRO) study. SHIFT-PRO was carried out to evaluate the effects of ivabradine compared with placebo on health-related quality of life in a representative sample of the main trial population.\n\nPatients with symptomatic heart failure with a left ventricular ejection fraction of 35% or lower who were in sinus rhythm with a heart rate of 70\xa0bpm or more and were receiving stable background treatment for heart failure were considered eligible for participation in SHIFT. After screening, 6505\xa0patients were randomised to receive either ivabradine or placebo in addition to ongoing optimal therapy (standard care) for heart failure (as assessed by the investigator responsible for the patient). All patients received 5\xa0mg of ivabradine or matching placebo twice daily at day 0. This dose was maintained, or increased to 7.5\xa0mg twice daily or reduced to 2.5\xa0mg twice daily depending on resting heart rate and tolerability. All analyses were based on intention to treat even though a total of 1190\xa0patients died, withdrew consent or were lost to follow-up.\n\nThe trial groups in SHIFT were well balanced in patient baseline characteristics. The mean age was 60.4\xa0years, 76% of the patients were men and mostly white. Mean heart rate was 79.9\xa0bpm and mean left ventricular ejection fraction was 29%. Heart failure was ischaemic in 68% of the patients and patients were equally distributed between NYHA class II, III or IV. Alcohol consumption and smoking status were also similar between the trial groups, with less than 20% of the patients being current smokers in both groups. The background therapies were also similar in both arms (ACE inhibitors or angiotensin receptor blockers: 91%; diuretics: 84%; beta-blockers: 89%; aldosterone antagonists: 61% and cardiac devices [implantable cardioverter defibrillators: 3% and cardiac resynchronisation therapy: 1%]).\n\nSubgroups were predefined in terms of age, sex, beta-blocker intake at randomisation, primary cause of heart failure, NYHA class, presence of diabetes, presence of hypertension and heart rate above and below the median of 77\xa0bpm. The manufacturer stated in its submission that another subgroup was identified after the Committee for Medicinal Products for Human Use recommended identifying the heart rate threshold at which there is a statistically significant mortality benefit. This subgroup consisted of people with a baseline heart rate of 75\xa0bpm or more (n=4150) and was identified post hoc. Data from this subgroup were used to identify the population to be covered by the marketing authorisation. The manufacturer's economic model was also based on this post hoc subgroup. Other post hoc subgroups identified were based on age (75\xa0years or older and 70\xa0years or older).\n\nThe baseline characteristics of the subgroup with a baseline heart rate of 75\xa0bpm or more (the population covered by the marketing authorisation) were similar to the main trial population. The mean age for this subgroup was 59.6\xa0years and, like the main trial population, they were mostly men (77%) and mostly white. There were no baseline differences between the treatment groups in this population including mean heart rate (84.5\xa0bpm) and distribution of NYHA class. The background therapies received were also similar to the main trial population for both treatment groups (ACE inhibitors or angiotensin receptor blockers: 90%; diuretics: 84%; beta-blockers: 88%; aldosterone antagonists: 62% and cardiac devices).\n\nThe primary outcome in the SHIFT main trial population was a composite endpoint of first event of cardiovascular death or hospital admission for worsening heart failure. This was carried out using a survival analysis based on time-to-first event estimated by the Kaplan-Meier method. Secondary and other efficacy outcomes included mortality, hospital admission, change in heart rate, change in NYHA class, change in global assessment of heart failure symptoms and efficacy in patients aged 70\xa0years or older (post hoc analysis in the main trial population).\n\nIn the SHIFT-PRO study (n=5038), which studied a subset of the main SHIFT population, health-related quality of life was estimated using the EuroQol-5 dimensions (EQ-5D) questionnaire and 'Kansas City cardiomyopathy questionnaire' (KCCQ). Analysis in this study was also performed according to the same predefined subgroups specified in the main trial population, with the exception of presence of diabetes and hypertension. An additional subgroup was specified according to whether or not patients had received at least half the target dose of beta-blockers at randomisation. The manufacturer's submission noted that there were no relevant differences in baseline demographics and disease characteristics among the main trial population, the population covered by the marketing authorisation and the population in the SHIFT-PRO study.\n\n# Main SHIFT population\n\nIn the main trial population, the primary outcome of first event of cardiovascular death or hospital admission for worsening heart failure was analysed using a Cox proportional hazards model adjusted for beta-blocker intake at randomisation. The hazard ratio (HR) estimate was 0.82; (95% confidence interval [CI] 0.75 to 0.90, p<0.0001), representing a statistically significant relative risk reduction of 18% for ivabradine compared with placebo. This composite endpoint was driven more by the rate of hospital admission for worsening heart failure (HR\xa00.74; 95% CI\xa00.66 to 0.83) than by the rate of cardiovascular death (HR 0.91; 95% CI\xa00.80 to 1.03) because people are often admitted to hospital before they die.\n\nFurther analysis was carried out by the manufacturer to assess the impact of baseline beta-blocker dose on the efficacy of ivabradine in the main SHIFT population. For the primary composite endpoint, the relative effects of ivabradine compared with placebo for the 5\xa0categories of beta-blocker intake were:\n\nHR\xa00.71; 95% CI\xa00.55 to 0.93, p=0.012 (no beta-blocker)\n\nHR\xa00.74; 95% CI\xa00.59 to 0.92, p=0.007 (less than 25% of target dose)\n\nHR\xa00.81; 95% CI\xa00.68 to 0.98, p=0.029 (25% or more but less than 50% of target dose)\n\nHR\xa00.88; 95% CI\xa00.72 to 1.07, p=0.193 (50% or more but less than 100% of target dose) and\n\nHR\xa00.99; 95% CI\xa00.79 to 1.24, p=0.913 (100% or more of target dose). There were similar trends in efficacy for ivabradine compared with placebo across the beta-blocker categories for the component outcomes of hospital admission for worsening heart failure and cardiovascular death. The manufacturer noted that this could be a result of lower doses of beta-blockers being associated with higher heart rate because beta-blockers primarily reduce heart rate. There were no statistically significant differences across the beta-blocker categories. These findings suggest that the efficacy of ivabradine is primarily driven by heart rate and not by beta-blocker dose.\n\n# Population covered by the marketing authorisation\n\nIn the subgroup with a baseline heart rate of 75\xa0bpm or more, the incidence of the primary composite endpoint was statistically significantly lower in the ivabradine group than in the placebo group (26.6% and 32.8% respectively, p<0.0001). The hazard ratio showed a clinically and statistically significant reduction of 24% in the risk of the composite endpoint for ivabradine compared with placebo (HR\xa00.76; 95% CI\xa00.68 to 0.85). This was in line with the predefined subgroup analysis on median heart rate, which revealed that baseline heart rate modified the treatment effect of ivabradine.\n\nThere was a statistically significant improvement in all secondary outcomes for the population covered by the marketing authorisation, unlike for the main SHIFT population in whom some of the secondary outcomes were not statistically significant. There were statistically significant reductions in all mortality outcomes in the ivabradine group compared with placebo as follows:\n\ncardiovascular death (HR\xa00.83; 95% CI\xa00.71 to 0.97, p=0.0166)\n\nheart failure death (HR\xa00.61; 95% CI\xa00.46 to 0.81, p=0.0006)\n\nall-cause death (HR\xa00.83; 95% CI\xa00.72 to 0.96, p=0.0109). Results similarly favoured ivabradine compared with placebo for:\n\nhospital admission for cardiovascular problems (HR\xa00.79; 95% CI\xa00.71 to 0.88, p<0.0001)\n\nworsening heart failure (HR\xa00.70; 95% CI\xa00.61 to 0.80, p<0.0001)\n\nhospital admission for any cause (HR\xa00.82; 95% CI\xa00.75 to 0.90, p<0.0001).\n\nIn the population covered by the marketing authorisation, heart rate decreased in the ivabradine and placebo groups by 17.4\xa0bpm and 5.7\xa0bpm at day\xa028 and 14.5\xa0bpm, and 5.8\xa0bpm at the last visit respectively. The manufacturer noted that the greater decrease in heart rate in the population covered by the marketing authorisation was consistent with a higher mean baseline heart rate of 84\xa0bpm in this subgroup compared with 80\xa0bpm in the main trial population. This was confirmed to be in line with previous ivabradine trials, which showed that greater reductions in heart rate are associated with higher resting heart rate. In this subgroup there was a statistically significant improvement in NYHA class in the ivabradine group compared with the placebo group.\n\nUsing the SHIFT-PRO study data, 3\xa0types of quality of life analyses were performed. The first (main analysis) used '0' as the last post-baseline value for deceased patients, the second (an analysis of surviving patients) used the last post-baseline value for deceased patients, and the third used the change from baseline to month\xa012 from the main analysis. For the EQ-5D index score measure, quality of life worsened from baseline to the last assessment in the ivabradine group and the placebo group in the main analysis. However, there was an improvement in quality of life from baseline to the last assessment for the analysis of surviving patients in the 2\xa0groups, with a greater improvement in the ivabradine group. The quality of life improvement from baseline to month\xa012 in both groups was higher in the ivabradine group. The manufacturer suggested that this was because there were fewer deaths during the first 12\xa0months than during the whole study.\n\nA mixed regression model was used to estimate quality of life using EQ-5D index scores with UK population tariff values. This showed that quality of life improved in the ivabradine group for the population covered by the marketing authorisation. The KCCQ disease-specific measure was also used and it showed a statistically significant difference of 2.6 (95% CI\xa00.7 to 4.5, p=0.008) for ivabradine compared with placebo for the 12-month analysis, which was also similar to the main analysis and the analysis of surviving patients.\n\nThe safety population (n=6492 main trial cohort; n=4141 population covered by the marketing authorisation) was the population who received at least 1\xa0dose of any study treatment. The adverse events that occurred on treatment (between the first study drug intake and last intake plus 2\xa0days) were analysed in this safety population. The following adverse events occurred more frequently with ivabradine than with placebo in the population covered by the marketing authorisation: symptomatic bradycardia (4.1% and 0.7% respectively), atrial fibrillation (7.9% and 6.8% respectively) and phosphenes (2.8% and 0.5% respectively). There were similar results for the main trial population. However, other serious adverse events and fatal events were higher in the placebo group in the 2\xa0populations. The manufacturer noted that the tolerability of ivabradine was not affected by baseline heart rate because there were no differences in the adverse events leading to withdrawal between the main trial population and the population covered by the marketing authorisation.\n\nAfter a request from the ERG during the clarification stage, the manufacturer provided the absolute numbers for the primary composite outcome and key secondary outcomes for the subgroups of the population covered by the marketing authorisation according to their beta-blocker category, age and NYHA class (details of the analyses are in section 3.22). The manufacturer also provided separate scenario analyses of the impact of using a regression model for NYHA progression adjusted for patient baseline characteristics, using updated standard care drug costs and different assumptions for modelling mortality. In addition, the manufacturer provided details of the patients who experienced symptomatic bradycardia and atrial fibrillation, and follow-up data on the reduction in heart rate at various time points for the population covered by the marketing authorisation.\n\n## Evidence Review Group comments – population covered by the marketing authorisation\n\nThe ERG stated that the literature search conducted by the manufacturer was appropriate, all relevant studies had been identified and that SHIFT, on which the manufacturer's submission was based, was relevant to the decision problem in its analysis. The ERG was satisfied that SHIFT was a well-designed randomised controlled trial with a robust method of randomisation. However, it highlighted that only 12\xa0patients (0.2%) in the study were recruited from the UK, but noted the manufacturer's comment about the difficulties gaining study approval in the UK. The ERG also stated that the low UK patient numbers may have resulted from the difficulty in identifying eligible patients if patients were attending heart failure centres and had good titration of beta-blocker therapy. It also noted that the population covered by the marketing authorisation was younger, included a higher proportion of men and patients with more severe heart failure than a typical UK heart failure patient population, but it recognised that the baseline characteristics of the population covered by the marketing authorisation were similar to those reported for other key heart failure studies. However, the ERG considered that the results of SHIFT were robust and generalisable to a UK population because there was evidence to suggest that the patients in the trial received standard treatments.\n\nThe ERG noted that the clinical-effectiveness evidence for ivabradine was based on a post hoc subgroup of patients with a resting heart rate of 75\xa0bpm or more without prior stratification based on resting heart rate, but in line with ivabradine's marketing authorisation. Therefore it considered that the evidence presented should be interpreted with a level of caution because there is likely to be an imbalance between the groups in terms of heart rate and potential unknown confounders. However, the ERG acknowledged that the baseline characteristics were well balanced between the treatment groups in the main trial population and the population covered by the marketing authorisation.\n\nThe ERG was aware that only approximately 26% of the main trial population and the population covered by the marketing authorisation were each treated with the recommended target dose of beta-blocker, and 55.4% of the trial population covered by the marketing authorisation were treated with 50% or more of the recommended dose of beta-blocker despite the recommendations in the SHIFT protocol. It was concerned that the patients who were not treated with the target dose of beta-blocker may not have been optimally treated. The ERG also noted the low use of cardiac devices in SHIFT and considered that this could have resulted from the exclusion of patients with pacemakers from the trial.\n\nThe ERG noted that the greatest benefit of ivabradine compared with placebo was in reducing heart failure deaths (HR\xa00.61; 95% CI\xa00.46 to 0.81, p=0.0006), which supports the observation that the results were generally driven by the cause-specific endpoints of hospital admission for heart failure and heart failure deaths in both populations. The ERG noted that ivabradine was associated with an improvement in NYHA class in the population covered by the marketing authorisation at their last visit compared with their baseline classification and that it had little impact on the proportion of patients with worsening NYHA classification.\n\nThe ERG noted that treatment-related adverse events occurred more frequently in the ivabradine group (17.8%) than in the placebo group (8.3%) in the main trial population. It felt that this was likely to be the same for the population covered by the marketing authorisation because the most common adverse events were the same as in the main trial population. The ERG highlighted that the reported adverse events (apart from inadequate blood pressure control) were similar to those reported in the BEAUTIFUL trial (10,917 randomised patients), which assessed the effects of ivabradine plus standard care in patients with coronary artery disease and left ventricular systolic dysfunction.\n\nThe ERG carried out an exploratory analysis of the data provided by the manufacturer after the clarification request on the primary and secondary outcomes of the population covered by the marketing authorisation according to their beta-blocker dosage at randomisation (that is, no beta-blocker, less than 25% of target beta-blocker dose, 25% or more but less than 50% of target beta-blocker dose, 50% or more but less than 100% of target beta-blocker dose and 100% or more of target beta-blocker dose).The ERG highlighted that their exploratory analyses suggest that there is uncertainty around the benefit of ivabradine plus standard care for patients with a resting heart rate of 75\xa0bpm or more and who are receiving at least 25% of beta-blockers. The ERG also explored the efficacy of ivabradine according to NYHA class and in patients aged 70\xa0years or older. It noted that the analysis in the NYHA class IV subgroup was based on small numbers, creating uncertainty about the benefit of ivabradine observed in this subgroup. Because the input data used in the exploratory analyses were marked as academic-in-confidence by the manufacturer, the results have also been marked as confidential and so cannot be shown here. However, the ERG emphasised that these analyses are speculative and based on subgroups of subgroups and should be interpreted with caution.\n\n# Cost-effectiveness evidence\n\nIn a systematic review of the literature the manufacturer did not identify any study on the cost effectiveness of ivabradine for treating chronic heart failure. No cost-effectiveness data were presented for the main SHIFT population, and so the economic evaluation carried out by the manufacturer was based only on the post hoc subgroup of patients from SHIFT with a baseline heart rate of 75\xa0bpm or more. The manufacturer stated that this subgroup reflected the marketing authorisation for ivabradine; that is, people with chronic heart failure NYHA class II to IV with systolic dysfunction, in sinus rhythm and whose heart rate is 75\xa0bpm or more, who are being treated with ivabradine in combination with standard therapy including beta-blockers, or for whom beta-blockers are contraindicated or not tolerated.\n\nThe manufacturer developed a Markov cohort model consisting of 2\xa0states (alive and dead). The difference in quality of life of patients was captured according to NYHA class in the 'alive' state of the model without modelling the NYHA classes as separate health states. The model has a lifetime time horizon consisting of monthly cycles, includes a half-cycle correction, and both costs and benefits were discounted at 3.5%. The analysis was performed from the perspective of the NHS and personal social services. Standard care was modelled in line with SHIFT because the use of heart failure medications in the trial was higher than current standard care treatment patterns in the UK. The regression equations for mortality, NYHA class distribution, hospital admission and quality of life used in the analysis were based on data from the entire SHIFT cohort rather than developing risk equations based solely on the population covered by the marketing authorisation. This was to avoid breaking randomisation and reducing the predictive power of the risk equations because of smaller sample size. However, the risk equations for mortality, hospital admission and quality of life were adjusted for baseline heart rate to predict estimates for the population covered by the marketing authorisation with a heart rate of 75\xa0bpm or more.\n\nThe manufacturer estimated the risk of non-cardiovascular death based on age-adjusted and sex-adjusted UK national life table data from the Office for National Statistics rather than SHIFT data because it provided a larger, UK-specific data source. This risk was assumed to be the same across treatment groups and no treatment effect was modelled for this endpoint. The risk of cardiovascular mortality (both heart failure and other non-heart-failure cardiovascular death) for the within-trial period was estimated using a Gompertz parametric survival regression model based on the full SHIFT cohort in the base-case analysis. Survival models based on exponential and Weibull parametric distributions, and as Kaplan-Meier data were included as part of the sensitivity analyses. The cardiovascular mortality risk equation was estimated adjusting for a series of baseline patient characteristics (including age, sex, NYHA class, heart failure duration, body mass index, medical history, baseline use of heart failure medications) to generate different estimates of mortality. The Gompertz distribution was also used to extrapolate cardiovascular mortality beyond the trial period. Mortality was approximately 17% in the standard care group of SHIFT. Because of the uncertainty generated by using a small proportion to extrapolate mortality for the rest of the cohort, the manufacturer considered mortality data from an external data source (CARE-HF data; Cleland 2010) in the sensitivity analyses. The extrapolation assumed that 50% of the cohort would have died after 2000\xa0days (65\xa0months).\n\nThe distribution of patients in each NYHA class over time was estimated from a generalised ordered regression (a proportional odds model) developed from SHIFT data. It predicted the distribution of NYHA class adjusting for treatment and time covariates but not patient baseline characteristics. By the third year the proportion of patients in class III and IV reduced from 40.2% to 36.9% in the ivabradine arm and from 44% to 40.6% in the standard care arm, whereas those in class II increased from 58.4% to 61.4% and from 54.9% to 58.1% in the ivabradine arm and standard care arm respectively. Because of the lack of any evidence to predict the distribution of patients by NYHA class beyond the trial period, the model assumed that the proportions remained fixed after the trial based on the last observation in the trial at 29\xa0months (although the absolute numbers in each category were expected to vary according to the number of patients alive).\n\nThe rate of heart failure, cardiovascular and all-cause hospital admission per person month was estimated using a Poisson regression model based on the entire SHIFT cohort and converted into a monthly transition probability in the economic model. The hospital admission endpoints were modelled separately to capture the appropriate resource use for each admission type and to permit sensitivity analysis on the treatment effect of ivabradine. However, the base-case analysis was based on all-cause hospital admission. Admission to hospital after the trial was modelled to be equivalent to the within-trial period and assumed to occur at a constant rate throughout the model irrespective of the ageing population.\n\nThe treatment effect of ivabradine on cardiovascular mortality (including heart failure death) compared with placebo was estimated as a hazard ratio of 0.90 (95% CI\xa00.80 to 1.03) from the parametric model to the underlying mortality risk in the standard care group. It was assumed that the treatment effect of ivabradine continues after the trial and is equivalent to that seen in SHIFT. To support this assumption, the manufacturer highlighted that the heart-rate-lowering effect of ivabradine was shown to be maintained throughout SHIFT and also over a 7-year study period for ivabradine in patients with angina. The treatment effect of ivabradine on the rate of admissions to hospital was estimated using a rate ratio of 0.83 (95% CI\xa00.78 to 0.93) derived from the Poisson regression model. The treatment effect was modelled on all-cause admission because cardiovascular and heart failure admissions were assumed to be implicitly captured in all-cause admission and ivabradine was shown to have a statistically significant effect on all-cause admission in the main trial and populations covered by the marketing authorisation. The length of stay associated with hospital admission was estimated using external data based on expert clinical advice. In the base-case model, the average length of stay was varied according to diagnosis on hospital admission (heart failure: 7.57\xa0days, other cardiovascular: 3.97\xa0days and non-cardiovascular: 5.13\xa0days) and was based on a weighted average of elective and non-elective NHS reference cost data.\n\nThe utility values used in the model were derived from the SHIFT-PRO study, in which health-related quality of life was captured with the EQ-5D questionnaire. EQ-5D index scores were calculated using UK population tariff values and then analysed using a mixed regression model. Quality of life was modelled to reflect patients' baseline characteristics, severity of the disease over time by NYHA class, rate of hospital admission (which includes serious adverse events) and treatment group. The resulting utility scores by NYHA class without any hospital admission ranged from 0.82 in class\xa0I to 0.46 in class IV. Decrease in quality of life because of hospital admission was estimated as decreases in utility of 0.07, 0.03, 0.08 and 0.21 for NYHA class I, II, III and IV respectively. The effect of ivabradine on quality of life was modelled and showed a small utility increase in the ivabradine group compared with the baseline estimates used for the placebo (standard care) group. Treatment-related adverse events were assumed not to have any measurable impact on quality of life and the manufacturer indicated that they had been captured by the treatment covariate in the regression model. Quality of life was assumed to remain the same for each NYHA class in the post-trial period and in the base case and the model estimates were not based on an ageing population. This implies that the utility values for the patients in later cycles were higher than they should be and this was assumed to have favoured ivabradine because additional survival time was associated with greater quality-adjusted life year (QALY) benefits. In the sensitivity analysis, quality of life was adjusted for the increasing age of the modelled cohort by resetting the baseline age for each cycle.\n\nThe average monthly cost of ivabradine (£42.10; excluding VAT) used in the model was estimated according to the proportion of patients who received 2.5\xa0mg (7%) and either 5\xa0mg or 7.5\xa0mg (93%) in the SHIFT study. The 5\xa0mg and 7.5\xa0mg tablets cost £40.17 per 56-tablet pack (excluding VAT; BNF\xa063), and the price of the 2.5\xa0mg dose was assumed to be half the price of the 5\xa0mg tablet. Average monthly standard care costs (£9.54) were estimated according to the proportion of patients using each standard care medication in SHIFT. The unit costs of the standard care drugs used such as beta-blockers, ACE inhibitors, diuretics, aldosterone antagonists, angiotensin receptor blockers and cardiac glycosides were also taken from the BNF. The manufacturer assumed that there were no extra costs in administering ivabradine and the standard care drugs. However, additional costs were included for ivabradine therapy titration (1\xa0specialist visit) and an electrocardiogram (ECG). This increased the total monthly cost in the ivabradine group from £52 to £202 for the first month.\n\nThe hospital admission costs used in the model were estimated using the NHS reference costs for heart failure admissions (general ward: £2308 and cardiac ward: £3295), cardiovascular admissions (general ward: £1942 and cardiac ward: £1730) and non-cardiovascular admissions (general ward: £2644). It was assumed that there was an equal probability of being in a general ward or a cardiac ward. Serious adverse events were captured using these hospital admission endpoints, but non-serious adverse events were not included. The monthly cost of managing heart failure, including physician visits, outpatient procedures and diagnostic tests, was estimated to be £27 from British Heart Foundation statistics.\n\nThe base-case results of the economic analysis, which was based on the population covered by the marketing authorisation, was estimated by applying individual patient profiles from SHIFT to the risk equations sequentially, one at a time. It showed that the incremental costs and incremental QALYs gained from treating chronic heart failure with ivabradine plus standard care compared with standard care alone were £2376 and 0.28 QALYs respectively. This gave an incremental cost-effectiveness ratio (ICER) of £8498 per QALY gained.\n\nThe manufacturer highlighted that the deterministic, probabilistic and structural sensitivity analyses were performed using average covariate values in the regression equations to shorten analysis time and that this may have caused some loss in accuracy in the ICER estimates. The base-case ICER using this method was £7743 per QALY gained. The one-way deterministic sensitivity analyses were performed on several model parameters using their 95% confidence intervals. The cost-effectiveness result was most sensitive to changes in cardiovascular mortality risk, with the resulting ICERs ranging from £5655 to £40,638 per QALY gained. The base-case ICER also showed some sensitivity to changes in the rate of hospital admission (£6384 to £10,424 per QALY gained) and treatment effect of ivabradine on quality of life (£6283 to £9253 per QALY gained). Changes in hospital length of stay and ivabradine treatment effect on NYHA class had much less impact on the ICER, £6938 to £8549 and £7232 to £8349 per QALY gained respectively.\n\nThe manufacturer's probabilistic sensitivity analysis indicated that ivabradine plus standard care would have a more than 95% chance of being cost effective compared with standard care alone if the maximum acceptable ICER was £20,000 per QALY gained.\n\nThe manufacturer carried out different scenario analyses to manage uncertainties about some of the assumptions in the base-case model. The scenario analyses explored the effect on the ICER of: varying the treatment duration of ivabradine; ivabradine's treatment effect stopping after 5\xa0and 10\xa0years; using alternative models to estimate the risk of cardiovascular mortality; increasing the median length of hospital stay based on the 'National heart failure audit' data; and excluding the costs of the titration visit and the ECG. The manufacturer also carried out other scenario analyses, including: using a within-trial time horizon; using external data to extrapolate cardiovascular mortality and utility values; including age-adjusted utility values; and assuming a 5% change in the distribution of NYHA classes (from I to II, from II to III and from III to IV) in the post-trial period. After a clarification request, the manufacturer also provided a scenario analysis in which a new regression equation was developed to predict NYHA class distribution. This was adjusted for treatment, time covariates and patient baseline characteristics, and drug prices were updated to those in BNF 63. These scenario analyses all gave ICERs below £9000 per QALY gained except for the assumptions of the treatment effect of ivabradine stopping after 5 and 10\xa0years and using the within-trial time horizon, which gave ICERs ranging from £13,964 to £15,200 per QALY gained.\n\nThe manufacturer carried out several subgroup analyses based on individual patient characteristics from the population covered by the marketing authorisation. These subgroups were based on age, NYHA class, beta-blocker doses, heart failure duration, level of left ventricular ejection fraction, and prior medical history (coronary artery disease and diabetes). The results showed that ivabradine plus standard care was still cost effective when compared with standard care alone. The estimated ICERs for the subgroups were all below £11,000 per QALY gained and ranged from £5197 to £10,427 per QALY gained. The manufacturer also carried out additional subgroup analyses based on a population representative of a UK chronic heart failure patient group. This population was specified as western European men with a median age of 78\xa0years, receiving at least half the target dose of beta-blockers. The ICER generated for this subgroup was £8735 per QALY gained, and the ICER for a UK chronic heart failure patient group taking the target dose of beta-blockers was £9185 per QALY gained.\n\n## Evidence Review Group comments\n\nThe ERG was satisfied with the manufacturer's modelling approach, which was transparent, used patient-level data and was consistent with other published economic studies on heart failure treatments. The ERG stated that the manufacturer did not carry out an analysis in a patient population with a disease severity reflective of the UK population. However, it agreed with the manufacturer that using values for patient characteristics beyond the SHIFT population range may generate unreliable results. The ERG was satisfied that the standard care treatments used in SHIFT and the economic model reflected UK clinical practice.\n\nThe ERG accepted the manufacturer's use of Office for National Statistics UK life tables to provide estimates of non-cardiovascular mortality in the base case because this is standard practice in heart failure cost-effectiveness analyses. However, it noted that the risk of non-cardiovascular mortality was higher in SHIFT than in the UK life tables. The ERG noted that there were some uncertainties associated with the regression analyses performed for cardiovascular and heart failure mortality, which limited the potential of ivabradine to reduce the risks of these 2\xa0outcomes. The treatment effect of ivabradine in the regression analysis was not statistically significant for cardiovascular mortality (p=0.38) and was borderline statistically significant (p=0.06) for heart failure mortality (although these results had been statistically significant for the population covered by the marketing authorisation only). By contrast, beta-blockers given at 50% or more of the target dose were associated with a statistically significant reduction in the risk of cardiovascular mortality for ivabradine compared with placebo and beta-blockers at any dose were associated with a statistically significant reduction in the risk of heart failure mortality for ivabradine compared with placebo. Because baseline heart rate was adjusted for in the regression analysis, the ERG thought that the risk reduction of ivabradine and beta-blockers was in addition to the attenuating effect of heart rate.\n\nThe ERG indicated that the regression model for health-related quality of life in the manufacturer's submission was clinically plausible and the disutility associated with hospital admission was likely to have captured any serious impact of adverse events on quality of life because hospital admission would be the main consequence of serious adverse events. The ERG noted that the impact of age adjustment for health-related quality of life was minimal (it increased the ICER by £216 per QALY gained). Therefore, it accepted the exclusion of age adjustment from the base-case analysis because of the time needed to re-run each cycle to adjust for age throughout the model's time horizon. The ERG was satisfied with the costing approach taken by the manufacturer in the economic analysis.\n\nThe ERG considered that the manufacturer's base-case ICER of £8498 per QALY gained (incremental costs of £2376 and incremental QALYs of 0.28) was likely to represent the expected cost effectiveness of adding ivabradine to standard care, although the ERG believed it was biased against ivabradine. The ERG was satisfied with the manufacturer's pragmatic approach of conducting the sensitivity analyses using average patient characteristics because of the longer analysis time needed to use individual patient profiles for the base case. It indicated that the reduced level of accuracy with this method was unlikely to alter any conclusions drawn from the evidence presented. The ERG was particularly interested in the cost-effectiveness results for the subgroups of patients at different doses of beta-blockers. It noted that the ICERs for these subgroups and all other subgroups analysed remained below £11,000 per QALY gained. However, the ERG noted that the regression equations used were based on the main trial population of SHIFT or the population covered by the marketing authorisation, rather than the particular subgroups of patients considered. It accepted that breaking randomisation and smaller patient numbers would compromise any analyses based on regression equations developed from subgroups. The ERG highlighted that the hazard ratios estimated from regression equations based on the main trial population of SHIFT or the population covered by the marketing authorisation may over (or under) estimate the effect of ivabradine treatment in particular patient populations.\n\nOverall, the ERG considered the modelled results to be conservative because they underestimated the risk of cardiovascular mortality, the rate of hospital admission and the relative effect of treatment with ivabradine plus standard care compared with standard care alone. It stated that the sensitivity and subgroup analyses sufficiently addressed any areas of uncertainty.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from the NICE website.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ivabradine, having considered evidence on the nature of chronic heart failure and the value placed on the benefits of ivabradine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee considered the clinical need for treatment in people with heart failure who are covered by the marketing authorisation of ivabradine. The Committee noted that the clinical specialists indicated that ivabradine is primarily a heart-rate-lowering drug for people with left ventricular systolic dysfunction who are in sinus rhythm and for whom beta-blockers are not suitable. The Committee heard from the clinical specialists that people with chronic heart failure have a poor quality of life. It also noted the comment from the patient experts that chronic heart failure can impact on everyday tasks, with comorbidities increasing the impact of the disease and usually requiring lifestyle changes. The patient experts also stated that ivabradine may provide symptomatic and prognostic benefit in a small number of chronic heart failure patients unable to take beta-blockers. The Committee considered the clinical specialists' comment that it may be difficult to increase beta-blocker dosage for people with low blood pressure, a group who would benefit from ivabradine. It noted that ivabradine is contraindicated in severe hypotension (less than 90/50\xa0mmHg). The Committee recognised the impact of chronic heart failure on quality of life and concluded that there were potential treatment benefits with ivabradine for people who are covered by the marketing authorisation.\n\nThe Committee considered the generalisability of the SHIFT trial to UK clinical practice. The Committee was aware that the population covered by the marketing authorisation in SHIFT was younger, included a higher proportion of men and people with more severe chronic heart failure than the typical chronic heart failure population in the UK. It also noted that only a few people from the UK were included in the trial and the use of cardiac devices in the trial was low. The clinical specialists and the ERG indicated that the differences in age and severity of chronic heart failure may be caused by patient recruitment from specialist heart failure centres, which is common with randomised trials. The Committee considered the comments from the clinical specialists and the ERG that the results of the trial could be extrapolated to a UK setting because the standard therapies used in SHIFT could be regarded as optimal and were given at similar dosing levels to UK clinical practice. Despite the differences between the trial and the UK population, the Committee concluded that SHIFT was relevant to UK clinical practice.\n\nThe Committee examined the clinical evidence from SHIFT, which compared ivabradine plus standard care with standard care plus placebo. The Committee noted that it was a well-conducted clinical trial and that the relevant clinical outcomes of mortality and hospital admission were assessed. It also noted that health-related quality of life data were collected in SHIFT-PRO using both generic and disease-specific instruments, and was aware that improved quality of life was an important outcome for chronic heart failure patients and that this is considered to be one of the main aims of managing chronic heart failure. The Committee noted that the Committee for Medicinal Products for Human Use had asked the manufacturer to identify the heart rate threshold at which there was a significant mortality benefit with ivabradine, because this benefit was not observed in the main SHIFT population. So the manufacturer then examined a post hoc subgroup of people with a baseline resting heart rate of 75\xa0bpm or more, and this subgroup formed the population for whom ivabradine has a marketing authorisation. The Committee noted that the results from this subgroup demonstrated a statistically significant reduction in all primary and secondary endpoints assessed. This included cardiovascular death, which reduced by 17% with ivabradine compared with placebo, unlike in the main SHIFT population, in which the 9% reduction in cardiovascular death was not statistically significant. The Committee was aware that baseline resting heart rate was not a stratification factor at randomisation and that this subgroup was identified post hoc, but it was also aware that recommendations could only be made within ivabradine's marketing authorisation. The Committee concluded that SHIFT was well conducted and there was it was plausible biologically that a statistically significant mortality benefit will be observed in the subgroup of people with a baseline resting heart rate of 75\xa0bpm or more, which reflects the marketing authorisation of ivabradine. However they were aware the evidence presented should be interpreted with a level of caution because the subgroup was identified post hoc.\n\nThe Committee noted that a previous hospital admission for worsening heart failure in the past 12\xa0months was an inclusion criterion for SHIFT. The Committee agreed that this was an important consideration because people with a prior hospital admission in the past 12\xa0months may have more severe chronic heart failure than would be observed in clinical practice, with a higher risk of further hospitalisations, which was the key driver of the clinical and cost-effectiveness estimates. The Committee noted that the marketing authorisation for ivabradine depended on the efficacy of ivabradine in a specific post hoc subgroup with more severe heart failure (with a baseline heart rate of 75\xa0bpm or more) to demonstrate a cardiovascular mortality benefit. The Committee heard from the clinical specialists that prior hospital admission should not be a factor for considering ivabradine treatment because there are no data to prove that the efficacy of ivabradine is limited to the population who have been admitted to hospital in the previous 12\xa0months. The clinical specialists also highlighted that people had to be stabilised for 4\xa0weeks on standard therapy as an entry criterion into the trial. The Committee considered that prior hospital admission did not affect mortality and the marketing authorisation did not make any reference to prior admission status. The Committee was aware that ivabradine was contraindicated for people with unstable heart failure. Therefore when discussing ivabradine, it understood it could only be initiated after prior stabilisation therapy. The Committee concluded that all people for whom treatment with ivabradine is suitable, according to the marketing authorisation, should be able to receive ivabradine regardless of hospital admission status, but that people should be stabilised for 4 weeks on standard therapy first.\n\nThe Committee considered the adverse event profile associated with ivabradine plus standard care compared with placebo plus standard care. The Committee noted that symptomatic bradycardia, atrial fibrillation and phosphenes occurred more frequently in the ivabradine group compared with the placebo group, although other serious adverse events were higher in the placebo group. It noted the comments from the clinical specialists that phosphenes are recognised adverse effects of ivabradine, which usually resolve in most patients during treatment. The clinical specialists also stated that ivabradine appeared to be much simpler and safer to use compared with most heart failure drugs. The Committee was concerned that an unusually high proportion of people in the population covered by the marketing authorisation who received a beta-blocker were not treated with the target dose because of hypotension, especially because the mean systolic blood pressure in the population covered by the marketing authorisation was 121\xa0mmHg. It also noted that it would be unusual for people with heart failure to have hypotensive symptoms with this level of blood pressure. It noted the ERG's comment that it has been reported that only 3–5% of patients eligible for treatment with beta-blockers are unable to tolerate them because of hypotension or bradycardia. The Committee concluded that ivabradine plus standard care had a manageable adverse event profile in the population covered by the marketing authorisation.\n\nThe Committee examined the exploratory analysis performed by the ERG on the efficacy of ivabradine according to beta-blocker dose received by the population covered by the marketing authorisation in SHIFT. The Committee noted the impact of the beta-blocker doses on the effectiveness of ivabradine, particularly in terms of cardiovascular mortality. However, the Committee agreed that this analysis was based on subgroups of a subgroup and should be interpreted with caution. The clinical specialists stated that these results further highlight the need for beta-blockers to be used at optimal doses before ivabradine is initiated, because there is good evidence that beta-blockers reduce cardiovascular mortality at optimal doses. They also emphasised that ivabradine would be less effective in people with chronic heart failure who are optimally treated with beta-blockers because both treatments are primarily heart-rate-lowering agents, although beta-blockers are known to have additional effects beyond their heart-rate-lowering properties. The Committee concluded that, given the results of these exploratory analyses, the effectiveness of ivabradine with increasing beta-blocker doses is uncertain.\n\nThe Committee also discussed the exploratory analysis performed according to NYHA class by the ERG for the population covered by the marketing authorisation. It heard from the clinical specialists that it was debatable whether the NYHA class\xa0IV subgroup could be considered to be in a stable condition given the severity of their heart failure and that ivabradine is contraindicated in unstable heart failure. The Committee also heard from the clinical specialists that the benefit observed in this subgroup of people would be expected because they are the population with the greatest risk of cardiovascular mortality. However, the Committee noted that the analysis in this subgroup of people with NYHA class\xa0IV heart failure was based on small numbers, which limits the robustness of the results. Therefore the Committee concluded that the effectiveness of ivabradine in people with NYHA class\xa0IV heart failure was uncertain because of the small patient numbers in the analysis, which meant that these people could not be considered separately as a subgroup.\n\nThe Committee discussed the position of ivabradine in the treatment pathway for chronic heart failure, noting that it is indicated in chronic heart failure NYHA class\xa0II to IV with systolic dysfunction, for people in sinus rhythm whose heart rate is 75\xa0bpm or more, and in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated. The Committee heard from the clinical specialists that ACE inhibitors, beta-blockers and aldosterone antagonists used routinely for managing chronic heart failure should always be the initial treatments, because there is robust evidence that they are effective in managing chronic heart failure and improving survival. The clinical specialists all agreed that ivabradine is an additional therapy for a subset of people with chronic heart failure who are in sinus rhythm, and not as a replacement for the recommended standard therapies such as ACE inhibitors, beta-blockers and aldosterone antagonists. They suggested that ivabradine should be considered only when patients are still symptomatic after being stabilised on optimal initial standard therapies at maximally tolerated doses, or when beta-blockers are contraindicated or not tolerated. The clinical specialists expressed their concerns that introducing ivabradine earlier than specified in the marketing authorisation would limit efforts to optimise the use of other standard drugs, particularly beta-blockers. They stressed the need for enough time to titrate beta-blockers to optimal doses according to the 'start low, go slow' recommendations in Chronic heart failure (NICE clinical guideline 108). The Committee concluded that ivabradine should be initiated only after standard treatment with ACE inhibitors, beta-blockers and aldosterone antagonists has been optimised.\n\nThe Committee explored what optimising standard therapy with beta-blockers meant in clinical practice. It heard from clinical specialists that it can take several months to appropriately titrate beta-blockers to the optimal dose for a patient. The Committee was aware that to optimise and ensure adherence to beta-blocker therapy, continuous monitoring and education and support of the patient by members of the heart failure multidisciplinary team are needed. The Committee also noted comments from consultees and commentators that there have been misconceptions that beta-blockers are contraindicated in, for example, the elderly, or in people with non-reversible chronic obstructive pulmonary disease, diabetes mellitus, peripheral vascular disease or erectile dysfunction. It noted that, in line with NICE's guidance on chronic heart failure (NICE clinical guideline 108), these groups of people should receive beta-blockers. The Committee re-emphasised their conclusion in section 4.9 on the importance of optimising beta-blockers before initiating ivabradine.\n\nThe Committee also considered the comments from consultees and commentators that there is a recent analysis that shows that digoxin may confer benefits similar to ivabradine for patients in sinus rhythm and with heart failure caused by left ventricular systolic dysfunction. However, the Committee noted that digoxin was not included as a comparator in the scope for this appraisal and there was no evidence to support its benefit in this population. The Committee concluded that considering digoxin as a comparator to ivabradine is beyond the scope of this appraisal.\n\nThe Committee also considered the position of cardiac devices, particularly cardiac resynchronisation therapy, in the treatment pathway for chronic heart failure because the manufacturer proposed positioning ivabradine before them. The clinical specialists were uncertain about this and proposed several different options about the most appropriate choice if people still have symptoms after they are treated with ACE inhibitors, beta-blockers and aldosterone antagonists. The Committee noted that very few patients in SHIFT received cardiac resynchronisation therapy. It therefore considered that more evidence would be useful to determine the position of ivabradine in relation to cardiac devices, particularly cardiac resynchronisation therapy, in the treatment pathway. However, the clinical specialists said that choosing whether to treat with ivabradine or cardiac resynchronisation therapy will depend on clinical need and that ivabradine will only be considered if the person is in sinus rhythm as indicated in ivabradine's marketing authorisation. The Committee was aware that ivabradine is contraindicated in people whose heart rate is dependent on a pacemaker. The Committee recognised that there was some uncertainty about the appropriate choice of treatment when people are eligible for both ivabradine and cardiac resynchronisation therapy, and concluded that the decision will likely be based on the judgement of the treating clinician.\n\nThe Committee considered the comments from the consultees and commentators that ivabradine should only be given to people with a left ventricular ejection fraction of 35% or less. It noted that the patients in SHIFT had left ventricular systolic dysfunction, which was associated with an ejection fraction of 35% or less, and it was aware that this was an entry criterion for the trial. The Committee was aware that an ejection fraction level was not specified in the marketing authorisation for ivabradine. However, it considered that ivabradine could not be recommended in people with an ejection fraction that is above 35% because there is no evidence of its effectiveness in that group. The Committee discussed how the ejection fraction level will be determined in clinical practice and whether the required tests will be readily available to people who will potentially benefit from ivabradine. It heard that ejection fraction level is usually demonstrated with an echocardiogram and additional tests will not necessarily be required before initiating ivabradine. Therefore, the Committee concluded that ivabradine should only be initiated in people with a left ventricular ejection fraction of 35% or less, normally shown on an echocardiogram.\n\nThe Committee considered how ivabradine will be prescribed in clinical practice. It heard from clinical specialists that a heart failure specialist in secondary care with access to a multidisciplinary team should initiate ivabradine. The clinical specialists also stated that titration and monitoring of ivabradine could then take place in primary care by a GP with a special interest in heart failure or a heart failure specialist nurse, supported by a multidisciplinary team. They highlighted that this may help ensure the appropriate patients are treated with ivabradine after optimising treatment and stabilising patients on maximally tolerated doses of ACE inhibitors, beta-blockers and aldosterone antagonists. However, the manufacturer anticipated that ivabradine would be prescribed by a clinician experienced in managing chronic heart failure as recommended in the summary of product characteristics. The Committee discussed the emergence of increasing heart failure expertise outside secondary care. It noted that NICE's guideline on chronic heart failure (NICE clinical guideline 108) defined a specialist as a physician with a subspecialty interest in the management of heart failure and who leads a specialist multidisciplinary heart failure team of professionals with appropriate competencies from primary and secondary care. The Committee concluded that ivabradine should be initiated by a heart failure specialist (in line with the NICE clinical guideline) with access to a multidisciplinary heart failure team and dose titration and monitoring should then be carried out by a heart failure specialist or in primary care by either a GP with a special interest in heart failure or a heart failure specialist nurse.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model and the ERG's critique of this model. The Committee was aware that the manufacturer had based the economic evaluation on the subgroup of patients with a baseline resting heart rate of 75\xa0bpm or more. The Committee noted that this was the subgroup for whom ivabradine has a UK marketing authorisation. The Committee concluded that the appropriate population for the economic evaluation of ivabradine for treating chronic heart failure had been captured in the model.\n\nThe Committee discussed the assumptions made by the manufacturer in developing the economic model. The Committee noted the ERG's comment that the manufacturer's model was transparent and made use of patient-level data in the base-case analysis. It agreed with the ERG that the standard care treatments used in the economic model reflected UK clinical practice. The Committee was satisfied that the utility values applied in the model were derived from SHIFT, which was the pivotal trial used in the economic analysis, and considered the approach taken by the manufacturer to obtain the final utility estimates to be plausible and robust. The Committee was also satisfied with the costs used by the manufacturer and that the clinical inputs to the model reflected UK practice. The Committee was aware that the sensitivity analyses conducted by the manufacturer were robust for the base-case estimate, except for the risk of cardiovascular mortality (see section 3.33 and 3.35), and that the ICERs for all the subgroup analyses were below £11,000 per QALY gained. The Committee concluded that the manufacturer's model was robust and the assumptions were realistic and conservative.\n\nThe Committee considered the uncertainty around the benefit of ivabradine on cardiovascular mortality given that the ICER ranged between approximately £5600 and £40,600 per QALY gained when the risk of cardiovascular mortality was varied using the 95% confidence interval around the mean from the trial data. The Committee noted the ERG's comments that there were uncertainties associated with the regression analyses for cardiovascular and heart failure mortality used in the economic model presented by the manufacturer. The Committee noted that the treatment effect of ivabradine in the regression analysis had a p\xa0value of 0.38 for cardiovascular mortality and a p\xa0value of 0.06 for heart failure mortality. For the population covered by the marketing authorisation in the clinical effectiveness analysis, the p\xa0value for cardiovascular mortality was 0.02, and for heart failure mortality was <0.01. On the other hand, beta-blockers given at 50% or more of the target dose were associated with a statistically significant reduction in the risk of cardiovascular mortality, and beta-blockers at all doses were associated with statistically significant reductions in the risk of heart failure mortality. The Committee considered that this further highlights the importance of optimising beta-blocker therapy before treatment with ivabradine. However, the Committee noted the ERG's comment that the absence of a statistically significant effect with ivabradine in the model may be a result of the adjustment of patient characteristics not accounted for in the clinical analysis. The Committee was also aware that the manufacturer's regression analyses were conservative in favour of placebo, which made the analyses likely to underestimate the risks of cardiovascular and heart failure mortality, and so generated different results from those observed in the population covered by the marketing authorisation of the SHIFT trial. The Committee concluded that the additional treatment effect of ivabradine was uncertain compared with the effect of beta-blocker doses.\n\nThe Committee considered whether the base-case ICER of approximately £8500 per QALY gained (incremental cost of approximately £2400 and incremental QALY of 0.28) of adding ivabradine to standard care estimated by the manufacturer was the most plausible ICER. The Committee considered that the ICER suggested that ivabradine was cost effective if a threshold of £20,000 per QALY gained was applied. The Committee considered that the effect of ivabradine on the hospital admission endpoints was the key driver of the cost effectiveness of ivabradine plus standard care compared with standard care alone. It noted that ivabradine plus standard care was more effective and cost more than standard care. Additionally it noted that ivabradine was still accruing more QALYs when the confidence interval for the hazard ratio for mortality crossed 1 and favoured standard care alone in the model, which suggested that ivabradine has a large impact in reducing hospital admissions. The Committee agreed that the wide range of sensitivity and subgroup analyses conducted by the manufacturer sufficiently addressed any areas of uncertainty in the economic analysis, including the beta-blocker subgroups, and all produced ICERs below £11,000 per QALY gained. It also considered that the modelled results and most of the model assumptions were conservative and biased against ivabradine. The Committee therefore concluded that the manufacturer's ICER estimate of approximately £8500 per QALY gained was plausible and was likely to represent the expected cost effectiveness of adding ivabradine to standard care for treating chronic heart failure in the population covered by the marketing authorisation.\n\nThe Committee recognised the novel mode of action of ivabradine as a heart-rate-lowering agent for patients in sinus rhythm for whom beta-blockers are contraindicated or not tolerated. It also considered the manufacturer's comment that ivabradine is the only non-surgical treatment available for people with chronic heart failure whose prognosis remains poor after recommended optimised therapy for chronic heart failure. However, the Committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The Committee therefore concluded that the innovative aspects of ivabradine were already incorporated in the economic model and analyses.\n\nThe Committee discussed potential equality issues and gave particular consideration to avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity. The Committee noted the potential equality issue raised by the patient experts about the higher prevalence of non-revascularisable coronary artery disease in the Asian population because of the impact of diabetes as a risk factor. It highlighted that higher prevalence rates are not an equality issue that technology appraisal guidance can address. Nevertheless, the Committee did not consider that the wording of the recommendations affected access to treatment by this group. The Committee also noted that older people and women were under-represented in SHIFT. But it considered that the recommendation for ivabradine was not based on sex or age, does not vary according to the sex or age of the patient, and that all patients would benefit from ivabradine. The Committee considered that these were not equality issues under the legislation. The Committee therefore concluded that its recommendations do not have a particular impact on any of the groups whose interests are protected by the legislation and that there is no need to alter or add to its recommendations.\n\nOverall the Committee considered the effectiveness of ivabradine in the subgroup of patients with a resting heart rate of 75 bpm or more derived from SHIFT, the generalisability of the trial to UK clinical practice, the adverse event profile of ivabradine, the position of ivabradine in the treatment pathway of chronic heart failure (that is after optimisation on standard care therapy with ACE inhibitors, beta-blockers and aldosterone antagonists) and the way ivabradine will be prescribed in clinical practice. It also considered the robustness of the economic model, the realistic nature of the assumptions used in the model, the plausibility of the base-case ICERs and the range of sensitivity analyses presented by the manufacturer. The Committee noted that there were uncertainties associated with the effectiveness of ivabradine with increasing beta-blocker doses. However, it was convinced of the benefits of adding ivabradine to the standard care therapies for chronic heart failure in the group of people covered by the marketing authorisation. The Committee therefore concluded that ivabradine could be considered a cost-effective use of NHS resources for treating chronic heart failure in people covered by the marketing authorisation.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA267\n\nAppraisal title: Ivabradine for treating chronic heart failure\n\nSection\n\nKey conclusion\n\nThe Committee recommended ivabradine for treating chronic heart failure having concluded that it could be considered a cost-effective use of NHS resources for treating chronic heart failure, but noted that ivabradine should only be initiated after optimal standard therapy with ACE inhibitors, beta-blockers and aldosterone antagonists, and after a stabilisation period on these therapies of 4 weeks.\n\n, 4.9, 4.21\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nIvabradine is primarily a heart-rate-lowering drug for people with left ventricular systolic dysfunction who are in sinus rhythm and for whom beta-blockers are not suitable. People with chronic heart failure have a poor quality of life and the condition can impact on everyday tasks, with comorbidities increasing the impact of the disease and usually requiring lifestyle changes. The Committee recognised the impact of chronic heart failure on quality of life and concluded that there were potential treatment benefits with ivabradine for people who are covered by the marketing authorisation.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nIvabradine is a heart-rate-lowering agent that selectively and specifically inhibits the cardiac pacemaker If current, which controls the spontaneous diastolic depolarisation in the sinus node that regulates the heart rate. Ivabradine is primarily a heart-rate-lowering drug for people with left ventricular systolic dysfunction who are in sinus rhythm and for whom beta-blockers are not suitable.\n\n, 4.2\n\n\n\nThe Committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations, and therefore concluded that the innovative aspects of ivabradine were already incorporated in the economic model and analyses.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nIvabradine has a marketing authorisation for people 'in chronic heart failure NYHA class II to IV with systolic dysfunction, who are in sinus rhythm and whose heart rate is ≥75\xa0bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated'.\n\n\n\nThe Committee concluded that ivabradine should be initiated only after optimal treatment with ACE inhibitors, beta-blockers and aldosterone antagonists has been achieved.\n\n\n\nAdverse reactions\n\nSymptomatic bradycardia, atrial fibrillation and phosphenes occurred more frequently in the ivabradine group compared with the placebo group, although other serious adverse events were higher in the placebo group. The Committee concluded that ivabradine plus standard care had a manageable adverse event profile in the population covered by the marketing authorisation.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted that SHIFT was a well-conducted clinical trial and that the relevant clinical outcomes of mortality and hospital admission were assessed.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe results of the SHIFT trial could be extrapolated to a UK setting because standard therapies were used in the trial. Therefore, the Committee concluded that SHIFT was relevant to clinical practice in the UK despite the differences between the trial and the UK population.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that the effectiveness of ivabradine with increasing beta-blocker doses is uncertain, and also that the effectiveness of ivabradine in people with NYHA class IV heart failure was uncertain because of the small patient numbers.\n\n, 4.8\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee concluded that SHIFT was well conducted and that it was biologically plausible that a statistically significant mortality benefit will be observed in the subgroup of people with a baseline resting heart rate of 75 bpm or more, which reflects the marketing authorisation of ivabradine. However they were aware the evidence presented should be interpreted with a level of caution because the subgroup was identified post hoc.\n\n\n\n\n\nThe Committee concluded that the effectiveness of ivabradine with increasing beta-blocker doses is uncertain, and also that the effectiveness of ivabradine in people with NYHA class IV heart failure was uncertain because of the small patient numbers, given the results of the exploratory analyses on the efficacy of ivabradine according to the beta-blocker dose received and NYHA class in the population covered by the marketing authorisation in the SHIFT trial.\n\n, 4.8\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that the results from the population covered by the marketing authorisation demonstrated a statistically significant reduction in cardiovascular death of 17% with ivabradine compared with placebo, unlike the main SHIFT population, in which there was a non-significant reduction in cardiovascular death of 9%.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer developed a Markov cohort model to evaluate the cost effectiveness of ivabradine in combination with standard therapy including beta-blockers, or for whom beta-blockers are contraindicated or not tolerated for treating chronic heart failure.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered the uncertainty around the benefit of ivabradine on cardiovascular mortality given that the ICER ranged between approximately £5600 and £40,600 per QALY gained when the risk of cardiovascular mortality was varied using the 95% confidence interval around the mean from the trial data, and concluded that the additional treatment effect of ivabradine was uncertain compared with the effect of beta-blocker doses.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee was satisfied that the utility values applied in the model were derived from SHIFT, which was the pivotal trial used in the economic analysis, and considered the approach taken by the manufacturer to obtain the final utility estimates to be plausible and robust.\n\n\n\nThe Committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee was aware that the sensitivity analyses conducted by the manufacturer were robust for the base-case estimate, except for the risk of cardiovascular mortality and the ICERs for all the subgroup analyses were below £11,000 per QALY gained.\n\n\n\n\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee considered that the effect of ivabradine on the hospital admission endpoints was the key driver of the cost effectiveness of ivabradine plus standard care compared with standard care alone.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that the manufacturer's ICER estimate of approximately £8500 per QALY gained was plausible and was the most likely cost effectiveness estimate of ivabradine in addition to standard care for treating chronic heart failure in the population covered by the marketing authorisation.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNone\n\n−\n\nEnd-of-life considerations\n\nNone\n\n−\n\nEqualities considerations and social value judgements\n\nThe Committee noted the potential equality issue raised by the patient experts about the higher prevalence of non-revascularisable coronary artery disease in the Asian population because of the impact of diabetes as a risk factor. The Committee also noted that older people and women were under-represented in the SHIFT trial. The Committee considered that these were not equality issues under the legislation. It concluded that its recommendations do not have a particular impact on any of the groups whose interests are protected by the legislation and that there is no need to alter or add to its recommendations.\n\n", 'Related NICE guidance': 'Published\n\nChronic heart failure: management of chronic heart failure in adults in primary and secondary care. NICE clinical guideline 108 (2010).\n\nCardiac resynchronisation therapy for the treatment of heart failure. NICE technology appraisal guidance 120 (2007).\n\nUnder development\n\nNICE is developing the following guidance (details available from the NICE website):\n\nImplantable cardioverter defibrillators for the treatment of arrhythmias and cardiac resynchronisation therapy for the treatment of heart failure (review of TA95 and TA120). Expected date of publication September 2013.', 'Review of guidance': 'The guidance on this technology will be considered for review in November 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveNovember 2012', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ta267	Evidence-based recommendations on ivabradine (Procoralan) for treating chronic heart failure in adults.
71f67c31c62d34db5e0789670e1b49d60c622d31	nice	Radiofrequency cold ablation for respiratory papillomatosis	Radiofrequency cold ablation for respiratory papillomatosis # Guidance Current evidence on the safety and efficacy of radiofrequency cold ablation for respiratory papillomatosis is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake radiofrequency cold ablation for respiratory papillomatosis should take the following actions: Inform the clinical governance leads in their Trusts. Ensure that patients and their carers or parents understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. NICE encourages further research and data collection on radiofrequency cold ablation for respiratory papillomatosis. In particular, research and data collection should report treatment indication (whether for primary or secondary treatment of respiratory papillomatosis), outcomes related to timing and site of disease recurrence, the need for tracheostomy after the procedure, and longer-term survival. In addition, any effect of the procedure on voice quality should be documented. Clinicians should enter details for all paediatric patients undergoing radiofrequency cold ablation for respiratory papillomatosis onto the Airway Intervention Registry and for adult patients having the procedure into the ENT UK national audit database. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Respiratory papillomatosis is a condition characterised by benign papillomatous (wart-like) growths in the respiratory tract, which can cause voice changes and airway obstruction. It can affect both children and adults. The condition tends to recur after treatment and is then known as recurrent respiratory papillomatosis. Procedures to remove the papillomas surgically include the use of cold steel dissection, suction diathermy, cryotherapy, carbon dioxide (CO2) or other laser ablation, or microdebridement. Any of these may be followed by systemic administration or direct injection of antiviral agents (for example, cidofovir) into the resection sites, with the aim of reducing the frequency of reoperative surgery for recurrent papillomas. Tracheostomy may be needed if significant airway obstruction occurs. # Outline of the procedure Radiofrequency cold ablation involves passing a radiofrequency bipolar electrical current through a medium of normal saline. This produces a plasma field of sodium ions that disrupts intercellular bonds, leading to tissue vaporisation and coagulation. Radiofrequency cold ablation heats tissue to only 60–65°C, which may produce less damage to surrounding structures and postoperative pain than conventional diathermy. The procedure is usually done with the patient under general anaesthesia. Conventional microlaryngoscopy techniques allow introduction of a single-use radiofrequency probe into the lumen of the larynx and trachea. Once the probe tip is in contact with the papilloma, it is activated to produce controlled tissue ablation of individual lesions, together with haemostasis and suction. Steroids and antibiotics may be given after the procedure to reduce inflammation and the risk of infection, respectively. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of 3 adult patients with recurrent papillomas of the nasopharynx, only 1 patient had a recurrent lesion at 4-month follow-up, which was successfully re-excised with endoscopic transnasal radiofrequency cold ablation. A case series of 2 patients reported 'reduced disease recurrence' (no further details provided) in 2 adult patients with juvenile-onset recurrent respiratory papillomatosis who had previously been treated repeatedly by CO2 laser ablation; 1 was treated by radiofrequency cold ablation treatment alone and 1 by radiofrequency cold ablation together with CO2 laser ablation. In a case report of 1 paediatric patient with a large de novo laryngeal papilloma treated by radiofrequency cold ablation alone, there was no sign of recurrence at 18-month follow-up. A case series of 6 adult patients with advanced laryngotracheal recurrent respiratory papillomatosis who had received at least 2 years of treatment by CO2 laser ablation followed by at least 2 years of treatment by radiofrequency cold ablation, reported an increase in the interval between treatments. This was presented as a significant increase (more than 50%) in the interval between treatments in 3 patients when radiofrequency cold ablation was introduced (p=0.03) and a modest increase (less than 25%) in the interval between treatments in the other 3 patients (p value not reported). In another case series of 2 adult patients with extensive and recurrent laryngeal papillomas, 1 patient who presented with severe hoarseness and exertional dyspnoea was found to have a good voice with no exertional dyspnoea at 2-month follow-up (no formal assessment of voice quality reported; no results were presented for the other patient). In the case report of 1 paediatric patient, a dramatic improvement in voice quality was observed (no formal assessment of voice quality reported). The Specialist Advisers listed key efficacy outcomes as reduction in the number or frequency of microlaryngoscopy procedures needed to maintain a safe airway, and achievement of good voice quality. # Safety Minor scarring around the ablated tissues was reported in all patients in a case series of 18 patients (method of assessment of scarring not described). Respiratory papillomas appeared at a new location 4 months after radiofrequency cold ablation in 1 patient in the case series of 18 patients. The procedure was repeated with no further recurrence at 2-month follow-up. The early recurrence raised the possibility of viral seeding (see section 2.4.3). The Specialist Advisers listed theoretical adverse events as laryngeal or airway scarring (with airway stenosis and dysphonia as possible consequences of scarring to the larynx), bleeding and inadequate reduction in the number and size of papillomas, leading to inability to maintain a safe airway. In addition, a Specialist Adviser stated that there is concern about possible seeding of the virus as a result of the procedure.# Further information # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. ISBM: 978-1-4731-2957-3	{'Guidance': "Current evidence on the safety and efficacy of radiofrequency cold ablation for respiratory papillomatosis is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake radiofrequency cold ablation for respiratory papillomatosis should take the following actions:\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers or parents understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nNICE encourages further research and data collection on radiofrequency cold ablation for respiratory papillomatosis. In particular, research and data collection should report treatment indication (whether for primary or secondary treatment of respiratory papillomatosis), outcomes related to timing and site of disease recurrence, the need for tracheostomy after the procedure, and longer-term survival. In addition, any effect of the procedure on voice quality should be documented.\n\nClinicians should enter details for all paediatric patients undergoing radiofrequency cold ablation for respiratory papillomatosis onto the Airway Intervention Registry and for adult patients having the procedure into the ENT UK national audit database.\n\nNICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nRespiratory papillomatosis is a condition characterised by benign papillomatous (wart-like) growths in the respiratory tract, which can cause voice changes and airway obstruction. It can affect both children and adults. The condition tends to recur after treatment and is then known as recurrent respiratory papillomatosis.\n\nProcedures to remove the papillomas surgically include the use of cold steel dissection, suction diathermy, cryotherapy, carbon dioxide (CO2) or other laser ablation, or microdebridement. Any of these may be followed by systemic administration or direct injection of antiviral agents (for example, cidofovir) into the resection sites, with the aim of reducing the frequency of reoperative surgery for recurrent papillomas. Tracheostomy may be needed if significant airway obstruction occurs.\n\n# Outline of the procedure\n\nRadiofrequency cold ablation involves passing a radiofrequency bipolar electrical current through a medium of normal saline. This produces a plasma field of sodium ions that disrupts intercellular bonds, leading to tissue vaporisation and coagulation. Radiofrequency cold ablation heats tissue to only 60–65°C, which may produce less damage to surrounding structures and postoperative pain than conventional diathermy.\n\nThe procedure is usually done with the patient under general anaesthesia. Conventional microlaryngoscopy techniques allow introduction of a single-use radiofrequency probe into the lumen of the larynx and trachea.\n\nOnce the probe tip is in contact with the papilloma, it is activated to produce controlled tissue ablation of individual lesions, together with haemostasis and suction.\n\nSteroids and antibiotics may be given after the procedure to reduce inflammation and the risk of infection, respectively.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 3\xa0adult patients with recurrent papillomas of the nasopharynx, only 1\xa0patient had a recurrent lesion at 4-month follow-up, which was successfully re-excised with endoscopic transnasal radiofrequency cold ablation. A case series of 2\xa0patients reported 'reduced disease recurrence' (no further details provided) in 2\xa0adult patients with juvenile-onset recurrent respiratory papillomatosis who had previously been treated repeatedly by CO2 laser ablation; 1\xa0was treated by radiofrequency cold ablation treatment alone and 1\xa0by radiofrequency cold ablation together with CO2 laser ablation. In a case report of 1\xa0paediatric patient with a large de novo laryngeal papilloma treated by radiofrequency cold ablation alone, there was no sign of recurrence at 18-month follow-up.\n\nA case series of 6\xa0adult patients with advanced laryngotracheal recurrent respiratory papillomatosis who had received at least 2\xa0years of treatment by CO2 laser ablation followed by at least 2\xa0years of treatment by radiofrequency cold ablation, reported an increase in the interval between treatments. This was presented as a significant increase (more than\xa050%) in the interval between treatments in 3\xa0patients when radiofrequency cold ablation was introduced (p=0.03) and a modest increase (less than\xa025%) in the interval between treatments in the other 3\xa0patients (p value not reported).\n\nIn another case series of 2\xa0adult patients with extensive and recurrent laryngeal papillomas, 1\xa0patient who presented with severe hoarseness and exertional dyspnoea was found to have a good voice with no exertional dyspnoea at 2-month follow-up (no formal assessment of voice quality reported; no results were presented for the other patient). In the case report of 1\xa0paediatric patient, a dramatic improvement in voice quality was observed (no formal assessment of voice quality reported).\n\nThe Specialist Advisers listed key efficacy outcomes as reduction in the number or frequency of microlaryngoscopy procedures needed to maintain a safe airway, and achievement of good voice quality.\n\n# Safety\n\nMinor scarring around the ablated tissues was reported in all patients in a case series of 18\xa0patients (method of assessment of scarring not described).\n\nRespiratory papillomas appeared at a new location 4\xa0months after radiofrequency cold ablation in 1\xa0patient in the case series of 18\xa0patients. The procedure was repeated with no further recurrence at 2-month follow-up. The early recurrence raised the possibility of viral seeding (see section\xa02.4.3).\n\nThe Specialist Advisers listed theoretical adverse events as laryngeal or airway scarring (with airway stenosis and dysphonia as possible consequences of scarring to the larynx), bleeding and inadequate reduction in the number and size of papillomas, leading to inability to maintain a safe airway. In addition, a Specialist Adviser stated that there is concern about possible seeding of the virus as a result of the procedure.", 'Further information': '# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nISBM: 978-1-4731-2957-3'}	https://www.nice.org.uk/guidance/ipg434
b4c042e5cc317447272ed4c1aa1287444695365f	nice	Laparoscopic gastric plication for the treatment of severe obesity	Laparoscopic gastric plication for the treatment of severe obesity # Guidance The evidence on laparoscopic gastric plication for severe obesity raises no major safety concerns in the short term. There is inadequate evidence about safety in the long term, specifically with regard to the reversibility of the procedure and how it affects the safety of any further gastric surgery that may be necessary. There is limited evidence of efficacy in the short and medium term but more evidence is needed about the long-term efficacy of the procedure. Therefore, laparoscopic gastric plication for the treatment of severe obesity should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake laparoscopic gastric plication for the treatment of severe obesity should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainties about the procedure's long-term efficacy and about how the procedure may affect the safety of any further gastric surgery that they may need. Clinicians should provide patients with clear written information. In addition, the use of NICE's information for the public is recommended. Laparoscopic gastric plication for severe obesity should only be carried out in units specialising in bariatric surgery that can offer the procedure as one of a range of treatment options. This recommendation is consistent with Obesity: guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children (NICE clinical guideline 43; see section 1.2.6 of the guideline for details on surgical interventions). Clinicians should submit data on all patients undergoing laparoscopic gastric plication for severe obesity to the National Bariatric Surgery Registry. Data should be entered into the register under the 'other' procedure category. Clinicians should also collect and review these data as part of local audit. NICE encourages further research on laparoscopic gastric plication for severe obesity, which should include information about long-term efficacy and safety, and specifically how the procedure influences further gastric surgery. Comparison with alternative procedures would be useful.# The procedure # Indications and current treatments Severe obesity is defined as a body mass index (BMI) of 40 kg/m2 or more, or between 35 kg/m2 and 40 kg/m2 in association with significant comorbidities such as hypertension or diabetes. Weight loss reduces the risk of comorbidities worsening and improves long-term survival. Severe obesity is managed by dietary advice, exercise, lifestyle changes and medication. Bariatric surgery is considered as a treatment option in selected patients who have not lost enough weight using these measures. Surgical procedures for severe obesity aim to help patients to lose weight and to maintain weight loss by restricting the size of the stomach and/or by decreasing the capacity to absorb food. Procedures that reduce the size of the stomach (gastric volume) limit the capacity for food intake by producing a feeling of satiety with a smaller ingested volume of food. They include laparoscopic gastric banding and sleeve gastrectomy. Procedures aimed at decreasing the capacity to absorb food include biliopancreatic diversion and duodenal switch. Patients are also advised to modify their eating behaviour by adhering to an explicit postoperative diet. # Outline of the procedure Laparoscopic gastric plication aims to help patients lose weight by reducing the size of the stomach. It is usually done by plicating the greater curve of the stomach, although anterior plication has also been reported. Because none of the stomach is removed, it is potentially a reversible procedure. The procedure is done with the patient under general anaesthesia, using several (usually 5 or 6) small incisions in the abdomen for the placement of a camera and ports for instruments. Greater curvature plication involves freeing the greater curve of the stomach by dissecting it from the greater omentum and short gastric vessels. Plication is done by folding the gastric wall inward along the greater curvature and securing this fold using rows of running sutures. Modifications of the technique may include a double or triple plication of the greater curve, and this may need extra rows of sutures. Patients are placed on a postoperative diet that typically involves progression from fluids to semi-solid foods, avoiding intake of solid foods for approximately 6 weeks. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 135 patients reported mean excess weight loss of 65% at a mean follow-up of 23 months (the number of patients followed up was not given). The study reported a significantly higher mean excess weight loss of 70% for patients with a BMI of less than 45 kg/m2 (110/135) compared with 56% for patients with a BMI of more than 45 kg/m2 (25/135) (p=0.006). A case series of 100 patients reported mean excess weight loss of 54% after 6 months and 60% after 24 months (72 and 50 patients respectively). The case series of 135 patients reported inadequate excess weight loss (defined as excess weight loss of less than 50%) in 21% (29/135) of patients and failure of the procedure (defined as excess weight loss of less than 30%) in 6% (8/135) of patients at a mean follow-up of 23 months. A case series of 42 patients who had mean excess weight loss of 20% at 1 month follow-up reported no regaining of weight at 18-month follow-up. In the case series of 100 patients, 38 patients had comorbidities such as hypertension, diabetes, low back pain and sleep apnoea. Improvements were reported for 71% (15/21) of patients with low back pain, 61% (8/13) of patients with diabetes, 67% (6/9) of patients with hypertension, and 100% (3/3) of patients with sleep apnoea, 6 months after the operation. A case series of 15 patients reported a significant improvement in the overall quality of life score (Impact of Weight on Quality of Life-Lite ; range 0–100, higher score indicating better quality of life) in 6 patients after greater curvature plication (p=0.009) but not in 9 patients treated by anterior gastric plication (p=0.38) at 12-month follow-up (numerical scores not reported). The Specialist Advisers listed additional key efficacy outcomes as excess weight loss at 3, 5 and 10 years and durability of plication as assessed by endoscopic evaluation or contrast swallow at 12 months. # Safety Partial jejunal necrosis due to portomesenteric thrombosis was reported in 1 patient in the case series of 135 patients 24 days after the procedure. This was treated by small bowel resection at laparotomy. Gastric perforation in the prepyloric area was reported in 1 patient in the case series of 100 patients 3 days after the procedure (repaired at laparotomy). Gastric obstruction due to herniation of the 'gastric fundus between 2 distal fasteners of the suture line' was reported in 1 patient in the case series of 135 patients 14 months after the procedure. This was treated by surgical reduction of the herniated fundus and reinforcement of the suture line using a laparoscopic approach. Micro leak at the suture line was reported in 2 patients in the case series of 135 patients (timing not stated). Both patients were readmitted 7 days after the procedure and were treated conservatively. Gastric leak causing peritonitis was reported in 1 patient in the case series of 120 patients 3 days after the procedure. This was treated laparoscopically by suturing the leak hole, performing looser plication, cleaning the whole peritoneum cavity and antibiotic treatment for 3 weeks. Gastric leak with pain secondary to forceful vomiting was reported in 1 patient in a case series of 100 patients 2 days after the procedure. This was treated by repairing the suture line. Intracapsular liver haematoma with abscess was reported in 1 patient in the case series of 100 patients 6 months after the procedure. This was treated by drainage of the abscess using a laparoscopic approach. Intragastric seroma that resulted in gastric obstruction was reported in 2 patients in the case series of 135 patients 3 months after the procedure. This was treated by revision of plication. Gastrointestinal bleeding was reported in 2 patients in the case series of 135 patients. The patients were readmitted 5 and 30 days after the procedure and were treated conservatively. Non-obstructive jaundice was reported in 2 patients in the case series of 100 patients for more than 2 weeks after the procedure; it 'disappeared spontaneously'. Hypocalcaemia was reported in 1 patient in the case series of 100 patients (no further details reported). Prolonged nausea and vomiting (attributed to mucosal oedema caused by venous stasis) was reported for 2–20 days in 'most' of the 93 patients treated with single plication but only for 'a few hours' in 42 patients treated with multiple plication (exact figures not reported) in the case series of 135 patients who had laparoscopic greater curvature plication. 'Permanent' vomiting and discomfort due to adhesions between liver and stomach was reported in 1 patient in the case series of 100 patients. This resolved after an operation to divide the adhesions 8 months after the procedure. The Specialist Advisers listed an anecdotal event as disruption of plication due to 'broken suture causing weight regain'. They listed theoretical events as bleeding during dissection of omentum from the greater curvature of the stomach, injury to spleen, ischaemia or infarction of the plicated stomach and dysphagia.# Further information Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence, 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "The evidence on laparoscopic gastric plication for severe obesity raises no major safety concerns in the short term. There is inadequate evidence about safety in the long term, specifically with regard to the reversibility of the procedure and how it affects the safety of any further gastric surgery that may be necessary. There is limited evidence of efficacy in the short and medium term but more evidence is needed about the long-term efficacy of the procedure. Therefore, laparoscopic gastric plication for the treatment of severe obesity should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake laparoscopic gastric plication for the treatment of severe obesity should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainties about the procedure's long-term efficacy and about how the procedure may affect the safety of any further gastric surgery that they may need. Clinicians should provide patients with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nLaparoscopic gastric plication for severe obesity should only be carried out in units specialising in bariatric surgery that can offer the procedure as one of a range of treatment options. This recommendation is consistent with Obesity: guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children (NICE clinical guideline\xa043; see section 1.2.6 of the guideline for details on surgical interventions).\n\nClinicians should submit data on all patients undergoing laparoscopic gastric plication for severe obesity to the National Bariatric Surgery Registry. Data should be entered into the register under the 'other' procedure category. Clinicians should also collect and review these data as part of local audit.\n\nNICE encourages further research on laparoscopic gastric plication for severe obesity, which should include information about long-term efficacy and safety, and specifically how the procedure influences further gastric surgery. Comparison with alternative procedures would be useful.", 'The procedure': "# Indications and current treatments\n\nSevere obesity is defined as a body mass index (BMI) of 40\xa0kg/m2\xa0or more, or between 35\xa0kg/m2\xa0and 40\xa0kg/m2\xa0in association with significant comorbidities such as hypertension or diabetes. Weight loss reduces the risk of comorbidities worsening and improves long-term survival.\n\nSevere obesity is managed by dietary advice, exercise, lifestyle changes and medication. Bariatric surgery is considered as a treatment option in selected patients who have not lost enough weight using these measures.\n\nSurgical procedures for severe obesity aim to help patients to lose weight and to maintain weight loss by restricting the size of the stomach and/or by decreasing the capacity to absorb food. Procedures that reduce the size of the stomach (gastric volume) limit the capacity for food intake by producing a feeling of satiety with a smaller ingested volume of food. They include laparoscopic gastric banding and sleeve gastrectomy. Procedures aimed at decreasing the capacity to absorb food include biliopancreatic diversion and duodenal switch. Patients are also advised to modify their eating behaviour by adhering to an explicit postoperative diet.\n\n# Outline of the procedure\n\nLaparoscopic gastric plication aims to help patients lose weight by reducing the size of the stomach. It is usually done by plicating the greater curve of the stomach, although anterior plication has also been reported. Because none of the stomach is removed, it is potentially a reversible procedure.\n\nThe procedure is done with the patient under general anaesthesia, using several (usually 5\xa0or 6) small incisions in the abdomen for the placement of a camera and ports for instruments. Greater curvature plication involves freeing the greater curve of the stomach by dissecting it from the greater omentum and short gastric vessels. Plication is done by folding the gastric wall inward along the greater curvature and securing this fold using rows of running sutures. Modifications of the technique may include a double or triple plication of the greater curve, and this may need extra rows of sutures.\n\nPatients are placed on a postoperative diet that typically involves progression from fluids to semi-solid foods, avoiding intake of solid foods for approximately 6\xa0weeks.\n\nSections 2.3\xa0and 2.4\xa0describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 135\xa0patients reported mean excess weight loss of 65% at a mean follow-up of 23\xa0months (the number of patients followed up was not given). The study reported a significantly higher mean excess weight loss of 70% for patients with a BMI of less than 45\xa0kg/m2\xa0(110/135) compared with 56% for patients with a BMI of more than 45\xa0kg/m2\xa0(25/135) (p=0.006). A case series of 100\xa0patients reported mean excess weight loss of 54% after 6\xa0months and 60% after 24\xa0months (72\xa0and 50\xa0patients respectively).\n\nThe case series of 135\xa0patients reported inadequate excess weight loss (defined as excess weight loss of less than 50%) in 21% (29/135) of patients and failure of the procedure (defined as excess weight loss of less than 30%) in 6% (8/135) of patients at a mean follow-up of 23\xa0months.\n\nA case series of 42\xa0patients who had mean excess weight loss of 20% at 1\xa0month follow-up reported no regaining of weight at 18-month follow-up.\n\nIn the case series of 100\xa0patients, 38\xa0patients had comorbidities such as hypertension, diabetes, low back pain and sleep apnoea. Improvements were reported for 71% (15/21) of patients with low back pain, 61% (8/13) of patients with diabetes, 67% (6/9) of patients with hypertension, and 100% (3/3) of patients with sleep apnoea, 6\xa0months after the operation.\n\nA case series of 15\xa0patients reported a significant improvement in the overall quality of life score (Impact of Weight on Quality of Life-Lite [IWQOL-Lite]; range 0–100, higher score indicating better quality of life) in 6\xa0patients after greater curvature plication (p=0.009) but not in 9\xa0patients treated by anterior gastric plication (p=0.38) at 12-month follow-up (numerical scores not reported).\n\nThe Specialist Advisers listed additional key efficacy outcomes as excess weight loss at 3, 5\xa0and 10\xa0years and durability of plication as assessed by endoscopic evaluation or contrast swallow at 12\xa0months.\n\n# Safety\n\nPartial jejunal necrosis due to portomesenteric thrombosis was reported in 1\xa0patient in the case series of 135\xa0patients 24\xa0days after the procedure. This was treated by small bowel resection at laparotomy.\n\nGastric perforation in the prepyloric area was reported in 1\xa0patient in the case series of 100\xa0patients 3\xa0days after the procedure (repaired at laparotomy).\n\nGastric obstruction due to herniation of the 'gastric fundus between 2\xa0distal fasteners of the suture line' was reported in 1\xa0patient in the case series of 135\xa0patients 14\xa0months after the procedure. This was treated by surgical reduction of the herniated fundus and reinforcement of the suture line using a laparoscopic approach.\n\nMicro leak at the suture line was reported in 2\xa0patients in the case series of 135\xa0patients (timing not stated). Both patients were readmitted 7\xa0days after the procedure and were treated conservatively. Gastric leak causing peritonitis was reported in 1\xa0patient in the case series of 120\xa0patients 3\xa0days after the procedure. This was treated laparoscopically by suturing the leak hole, performing looser plication, cleaning the whole peritoneum cavity and antibiotic treatment for 3\xa0weeks. Gastric leak with pain secondary to forceful vomiting was reported in 1\xa0patient in a case series of 100\xa0patients 2\xa0days after the procedure. This was treated by repairing the suture line.\n\nIntracapsular liver haematoma with abscess was reported in 1\xa0patient in the case series of 100\xa0patients 6\xa0months after the procedure. This was treated by drainage of the abscess using a laparoscopic approach.\n\nIntragastric seroma that resulted in gastric obstruction was reported in 2\xa0patients in the case series of 135\xa0patients 3\xa0months after the procedure. This was treated by revision of plication.\n\nGastrointestinal bleeding was reported in 2\xa0patients in the case series of 135\xa0patients. The patients were readmitted 5\xa0and 30\xa0days after the procedure and were treated conservatively.\n\nNon-obstructive jaundice was reported in 2\xa0patients in the case series of 100\xa0patients for more than 2\xa0weeks after the procedure; it 'disappeared spontaneously'.\n\nHypocalcaemia was reported in 1\xa0patient in the case series of 100\xa0patients (no further details reported).\n\nProlonged nausea and vomiting (attributed to mucosal oedema caused by venous stasis) was reported for 2–20\xa0days in 'most' of the 93\xa0patients treated with single plication but only for 'a few hours' in 42\xa0patients treated with multiple plication (exact figures not reported) in the case series of 135\xa0patients who had laparoscopic greater curvature plication.\n\n'Permanent' vomiting and discomfort due to adhesions between liver and stomach was reported in 1\xa0patient in the case series of 100\xa0patients. This resolved after an operation to divide the adhesions 8\xa0months after the procedure.\n\nThe Specialist Advisers listed an anecdotal event as disruption of plication due to 'broken suture causing weight regain'. They listed theoretical events as bleeding during dissection of omentum from the greater curvature of the stomach, injury to spleen, ischaemia or infarction of the plicated stomach and dysphagia.", 'Further information': 'Information for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence, 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg432
0bdaa79ae49fab87011294571397263c4e2a1d93	nice	Percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease	Percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease # Guidance Current evidence on the efficacy and safety of percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection should be carried out by a vascular multidisciplinary team including a vascular surgeon and a vascular interventional radiologist. The multidisciplinary team should consider carefully whether using percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease is likely to have any benefits over conventional recanalisation by balloon angioplasty (with or without stenting) alone.# The procedure # Indications and current treatments Chronic atherosclerotic peripheral arterial disease commonly causes narrowing or blockage of lower limb arteries. Symptoms include intermittent claudication, ischaemic rest pain, ulceration and gangrene. Cardiovascular risk factor modification is fundamental to the management of peripheral arterial disease. For patients with severely reduced walking distance or critical limb ischaemia, revascularisation procedures such as balloon angioplasty, stenting or surgery (bypass grafts or endarterectomy) can be used. # Outline of the procedure The aim of percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease is to achieve recanalisation when balloon angioplasty and/or stenting alone are considered not to be technically feasible or sufficiently safe. Using local anaesthesia and fluoroscopy, a laser device (with or without a guidewire) is advanced through the artery to the narrowing or blockage. The laser emits pulses of laser light to vaporise the blockage. This is carried out as an adjunct to recanalisation using balloon angioplasty. A stent may then be inserted to treat any stenosis and/or to prevent embolism and restenosis. Several types of laser are available for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial of 116 patients treated by pulsed laser atherectomy plus balloon angioplasty, by continuous-wave laser atherectomy plus balloon angioplasty, or by balloon angioplasty alone, reported that treated arterial segments were patent on angiography at 1-year follow-up in 45%, 36% and 50% of patients respectively (patient numbers and level of significance not stated). A case series of 318 patients (411 lesions) treated by laser atherectomy plus balloon angioplasty reported primary patency (defined as uninterrupted patency with no procedures performed on the treated segment or at its margins) in 34% of patients (patient numbers not reported) at 1-year follow-up. A non-randomised controlled study of 215 patients reported that there was improvement in American Heart Association limb status grade classification of 1 grade in 19% (24/127) of patients, 2 grades in 20% (25/127) of patients, and 3 grades in 10% (13/127) of patients after laser atherectomy plus balloon angioplasty at 36-month follow-up. The non-randomised controlled study of 215 patients reported significantly improved mean ankle brachial index at rest for the 167 patients in whom technical success had been achieved (105 patients treated by laser atherectomy plus balloon angioplasty and in 62 patients treated by balloon angioplasty alone). Pressure indices increased significantly from baseline to 36-month follow-up in both the laser atherectomy plus balloon angioplasty group (0.34±0.16 to 0.55±0.16; p<0.001) and the balloon angioplasty alone group (0.33±0.18 to 0.52±0.13; p<0.001); significance between groups not reported. The Specialist Advisers listed key efficacy outcomes as an increase in arterial diameter and blood flow, tissue healing, symptom relief, improvement in quality of life, amputation-free survival and reintervention rates. # Safety A case series of 40 patients who had laser atherectomy (with or without balloon angioplasty or stenting) reported that 5% (2/40) of patients died within 30 days of the procedure but stated that neither death was related to the revascularisation procedure (no further details reported). Dissection of the arterial wall occurred in 35% (13/37) of patients treated by pulsed laser atherectomy plus balloon angioplasty, in 20% (8/40) of patients treated by continuous-wave laser atherectomy plus balloon angioplasty, and in 15% (6/39) of patients treated by balloon angioplasty alone in the randomised controlled trial of 116 patients (p=0.005). Vessel perforation occurred in 3% (4/127) of patients treated by laser atherectomy plus balloon angioplasty in the non-randomised controlled study of 215 patients (no further details given). Complete or partial embolic occlusion of a proximal lower limb artery was reported in 3% (4/127) of patients treated by laser atherectomy plus balloon angioplasty (3 were symptomatic and were treated by local lysis or dilatation) and in 6% (5/88) of patients treated by balloon angioplasty alone (4 were symptomatic and were treated by local lysis or dilatation) in the non-randomised controlled study of 215 patients at mean 36-month follow-up. Arteriovenous fistula was reported in less than 1% (2/338) of patients in a case series of 338 patients treated by laser atherectomy (alone or plus balloon angioplasty) ('during or after the procedure'; no further details reported). Arteriovenous fistula was reported in 3% (1/40) of patients within 30 days of the procedure in the case series of 40 patients ('treated conservatively'; no further details reported). Pseudoaneurysms at the puncture site were reported in 10 patients in a case series of 312 patients treated by laser atherectomy (with stenting if indicated). These were treated using ultrasound-guided compression. Pseudoaneurysms were reported in 3% (1/40) of patients within 30 days of the procedure in the case series of 40 patients (treated conservatively; no further details reported). Warming of tissues at the treatment site, thought to be caused by direct thermal effect of the laser treatment ('during or after' the procedure), was reported in 64% (215/338) of patients in the case series of 338 patients. In addition to the above, Specialist Advisers stated that the adverse events reported in the literature were access site complications. They considered thermal injury to be a theoretical adverse event. # Other comments The Committee noted that much of the evidence on this procedure is not recent. A limited amount of the older evidence described using laser alone for atherectomy but more recent evidence focused on its use as an adjunct to balloon angioplasty (with or without stenting). This more recent evidence and the advice of specialists underpinned the decision to evaluate laser recanalisation as an adjunctive procedure. While the Committee considered the evidence adequate to recommend normal arrangements for the use of percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting), it remained uncertain about whether its use confers any advantages over balloon angioplasty alone and, if so, in which patients: this underpinned the recommendation in 1.2. The Committee was advised that the application of laser technology in percutaneous atherectomy has evolved during the period covered by the published evidence and may continue to do so.# Further information For related NICE guidance see the NICE website. Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the efficacy and safety of percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection should be carried out by a vascular multidisciplinary team including a vascular surgeon and a vascular interventional radiologist. The multidisciplinary team should consider carefully whether using percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease is likely to have any benefits over conventional recanalisation by balloon angioplasty (with or without stenting) alone.', 'The procedure': "# Indications and current treatments\n\nChronic atherosclerotic peripheral arterial disease commonly causes narrowing or blockage of lower limb arteries. Symptoms include intermittent claudication, ischaemic rest pain, ulceration and gangrene.\n\nCardiovascular risk factor modification is fundamental to the management of peripheral arterial disease. For patients with severely reduced walking distance or critical limb ischaemia, revascularisation procedures such as balloon angioplasty, stenting or surgery (bypass grafts or endarterectomy) can be used.\n\n# Outline of the procedure\n\nThe aim of percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease is to achieve recanalisation when balloon angioplasty and/or stenting alone are considered not to be technically feasible or sufficiently safe.\n\nUsing local anaesthesia and fluoroscopy, a laser device (with or without a guidewire) is advanced through the artery to the narrowing or blockage. The laser emits pulses of laser light to vaporise the blockage. This is carried out as an adjunct to recanalisation using balloon angioplasty. A stent may then be inserted to treat any stenosis and/or to prevent embolism and restenosis.\n\nSeveral types of laser are available for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial of 116\xa0patients treated by pulsed laser atherectomy plus balloon angioplasty, by continuous-wave laser atherectomy plus balloon angioplasty, or by balloon angioplasty alone, reported that treated arterial segments were patent on angiography at 1-year follow-up in 45%, 36% and 50% of patients respectively (patient numbers and level of significance not stated).\n\nA case series of 318\xa0patients (411\xa0lesions) treated by laser atherectomy plus balloon angioplasty reported primary patency (defined as uninterrupted patency with no procedures performed on the treated segment or at its margins) in 34% of patients (patient numbers not reported) at 1-year follow-up.\n\nA non-randomised controlled study of 215\xa0patients reported that there was improvement in American Heart Association limb status grade classification of 1\xa0grade in 19% (24/127) of patients, 2\xa0grades in 20% (25/127) of patients, and 3\xa0grades in 10% (13/127) of patients after laser atherectomy plus balloon angioplasty at 36-month follow-up.\n\nThe non-randomised controlled study of 215\xa0patients reported significantly improved mean ankle brachial index at rest for the 167\xa0patients in whom technical success had been achieved (105\xa0patients treated by laser atherectomy plus balloon angioplasty and in 62\xa0patients treated by balloon angioplasty alone). Pressure indices increased significantly from baseline to 36-month follow-up in both the laser atherectomy plus balloon angioplasty group (0.34±0.16 to 0.55±0.16; p<0.001) and the balloon angioplasty alone group (0.33±0.18 to 0.52±0.13; p<0.001); significance between groups not reported.\n\nThe Specialist Advisers listed key efficacy outcomes as an increase in arterial diameter and blood flow, tissue healing, symptom relief, improvement in quality of life, amputation-free survival and reintervention rates.\n\n# Safety\n\nA case series of 40\xa0patients who had laser atherectomy (with or without balloon angioplasty or stenting) reported that 5% (2/40) of patients died within 30\xa0days of the procedure but stated that neither death was related to the revascularisation procedure (no further details reported).\n\nDissection of the arterial wall occurred in 35% (13/37) of patients treated by pulsed laser atherectomy plus balloon angioplasty, in 20% (8/40) of patients treated by continuous-wave laser atherectomy plus balloon angioplasty, and in 15% (6/39) of patients treated by balloon angioplasty alone in the randomised controlled trial of 116\xa0patients (p=0.005).\n\nVessel perforation occurred in 3% (4/127) of patients treated by laser atherectomy plus balloon angioplasty in the non-randomised controlled study of 215\xa0patients (no further details given).\n\nComplete or partial embolic occlusion of a proximal lower limb artery was reported in 3% (4/127) of patients treated by laser atherectomy plus balloon angioplasty (3\xa0were symptomatic and were treated by local lysis or dilatation) and in 6% (5/88) of patients treated by balloon angioplasty alone (4\xa0were symptomatic and were treated by local lysis or dilatation) in the non-randomised controlled study of 215\xa0patients at mean 36-month follow-up.\n\nArteriovenous fistula was reported in less than 1% (2/338) of patients in a case series of 338\xa0patients treated by laser atherectomy (alone or plus balloon angioplasty) ('during or after the procedure'; no further details reported). Arteriovenous fistula was reported in 3% (1/40) of patients within 30\xa0days of the procedure in the case series of 40\xa0patients ('treated conservatively'; no further details reported).\n\nPseudoaneurysms at the puncture site were reported in 10\xa0patients in a case series of 312\xa0patients treated by laser atherectomy (with stenting if indicated). These were treated using ultrasound-guided compression. Pseudoaneurysms were reported in 3% (1/40) of patients within 30\xa0days of the procedure in the case series of 40\xa0patients (treated conservatively; no further details reported).\n\nWarming of tissues at the treatment site, thought to be caused by direct thermal effect of the laser treatment ('during or after' the procedure), was reported in 64% (215/338) of patients in the case series of 338\xa0patients.\n\nIn addition to the above, Specialist Advisers stated that the adverse events reported in the literature were access site complications. They considered thermal injury to be a theoretical adverse event.\n\n# Other comments\n\nThe Committee noted that much of the evidence on this procedure is not recent. A limited amount of the older evidence described using laser alone for atherectomy but more recent evidence focused on its use as an adjunct to balloon angioplasty (with or without stenting). This more recent evidence and the advice of specialists underpinned the decision to evaluate laser recanalisation as an adjunctive procedure.\n\nWhile the Committee considered the evidence adequate to recommend normal arrangements for the use of percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting), it remained uncertain about whether its use confers any advantages over balloon angioplasty alone and, if so, in which patients: this underpinned the recommendation in 1.2.\n\nThe Committee was advised that the application of laser technology in percutaneous atherectomy has evolved during the period covered by the published evidence and may continue to do so.", 'Further information': 'For related NICE guidance see the NICE website.\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour\n responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact\n NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg433
802e29940f7380476bfec2d97cdbbceada500d43	nice	Depth of anaesthesia monitors – Bispectral Index (BIS), E-Entropy and Narcotrend-Compact M	Depth of anaesthesia monitors – Bispectral Index (BIS), E-Entropy and Narcotrend-Compact M Evidence-based recommendations on 3 electroencephalography (EEG)‑based depth of anaesthesia monitors for assessing a patient’s response to anaesthetic drugs during surgery. The monitors are Bispectral Index (BIS), E‑Entrophy and Narcotrend‑Compact M. # Recommendations The use of electroencephalography (EEG)-based depth of anaesthesia monitors is recommended as an option during any type of general anaesthesia in patients considered at higher risk of adverse outcomes. This includes patients at higher risk of unintended awareness and patients at higher risk of excessively deep anaesthesia. The Bispectral Index (BIS) depth of anaesthesia monitor is therefore recommended as an option in these patients. The use of EEG-based depth of anaesthesia monitors is also recommended as an option in all patients receiving total intravenous anaesthesia. The BIS monitor is therefore recommended as an option in these patients. Although there is greater uncertainty of clinical benefit for the E-Entropy and Narcotrend-Compact M depth of anaesthesia monitors than for the BIS monitor, the Committee concluded that the E-Entropy and Narcotrend-Compact M monitors are broadly equivalent to BIS. These monitors are therefore recommended as options during any type of general anaesthesia in patients considered at higher risk of adverse outcomes. This includes patients at higher risk of unintended awareness and patients at higher risk of excessively deep anaesthesia. The E-Entropy and Narcotrend-Compact M monitors are also recommended as options in patients receiving total intravenous anaesthesia. Anaesthetists using EEG-based depth of anaesthesia monitors should have appropriate training and experience with these monitors and understand the potential limitations of their use in clinical practice. Patients who are considered at higher risk of unintended awareness during general anaesthesia include patients with high opiate or high alcohol use, patients with airway problems, and patients with previous experience of accidental awareness during surgery. The risk of unintended awareness is also raised by the use of concomitant muscle relaxants. Older patients, patients with comorbidities and those undergoing certain types of surgery are also considered at higher risk of unintended awareness. This is because they are at greater risk of haemodynamic instability during surgery. In these patients, lower levels of anaesthetic are often used to prevent adverse effects on the cardiovascular system and these levels can be inadequate. Patients who are considered at higher risk of excessively deep levels of anaesthesia include older patients, patients with liver disease, patients with a high body mass index (BMI), and patients with poor cardiovascular function. Patients receiving total intravenous anaesthesia are not considered at higher risk of adverse outcomes from general anaesthesia than patients receiving inhaled anaesthesia. The use of EEG-based depth of anaesthesia monitors has been recommended in patients receiving total intravenous anaesthesia because it is cost effective and because it is not possible to measure end-tidal anaesthetic concentration in this group.# The technologies The BIS monitor (Covidien), E-Entropy monitor (GE Healthcare) and Narcotrend-Compact M monitor (MT MonitorTechnik) are EEG-based monitors that are used in combination with standard clinical monitoring and clinical skills to indicate the patient's response to anaesthetic drugs (hereafter referred to as depth of anaesthesia) during surgery. Other manufacturers have licensed the BIS (or BISx) technology from Covidien in order to produce BIS modules that are compatible with their own anaesthesia systems.# Clinical need and practice # The problem addressed EEG-based depth of anaesthesia monitors are designed to indicate the probability of consciousness with explicit recall in patients receiving general anaesthetics, and to aid the tailoring of anaesthetic dose to the individual patient to avoid inadequate or excessively deep levels of anaesthesia. Measuring a patient's response to anaesthesia is important clinically because individual variation in response to anaesthetics can occasionally lead to inadequate or excessively deep levels of anaesthesia. An inadequate level of anaesthesia can result in patient awareness during surgery, which can cause post-traumatic stress disorder in some patients. Conversely, an excessively deep level of anaesthesia can result in prolonged recovery and has been linked to an increased risk of postoperative adverse outcomes, including myocardial infarction, stroke and cognitive dysfunction in older patients. The aim of this evaluation is to determine the clinical and cost effectiveness of 3 depth of anaesthesia monitors, in combination with standard clinical monitoring, in patients receiving general anaesthesia. # The condition General anaesthesia is a reversible state of controlled unconsciousness that is achieved with drugs which prevent awareness, pain, recall, distress and movement in patients during surgery. It is estimated that 2.4 million people received general anaesthesia in 2007 in England. Approximately half of those who have a general anaesthetic also receive muscle relaxants. Some common adverse outcomes of general anaesthesia include nausea, headaches and dizziness. Less common adverse outcomes include neurological and cardiovascular morbidity, and unintended patient awareness and recall. Most studies suggest that between 1 and 2 people in 1000 experience awareness or recall during general anaesthesia, with a third of these also experiencing pain. For those who experience awareness during anaesthesia, there can be long-term effects such as clinical depression, anxiety, nightmares, flashbacks and, in some cases, severe post-traumatic stress disorder. Awareness during anaesthesia is more likely during certain types of surgery in which lower levels of anaesthetic are often used. These include cardiac surgery, airway surgery, obstetric surgery or emergency surgery for major trauma. The use of muscle relaxants can also increase the risk of patient awareness because they allow a lower level of anaesthetic to be used. Muscle relaxants also prevent patients from moving. This limits the patient's ability to communicate with the surgical team and means that the anaesthetist has to use other clinical information to judge the patient's state of consciousness. Anaesthetic agents can affect the body's physiology, in particular, the cardiovascular system. Adverse outcomes of excessively deep general anaesthesia include prolonged recovery, particularly in people with a high BMI. In severe cases or in at-risk patient groups (for example, older patients, patients with liver disease, and patients with poor cardiovascular function), excessively deep anaesthesia can result in haemodynamic instability and respiratory complications (which can be fatal without cardiorespiratory support). Inappropriately deep anaesthesia has also been linked to an increased risk of post-operative complications such as myocardial infarction and stroke in older patients. There is some evidence to suggest a link between longer term morbidity (for example, cognitive dysfunction) and mortality, and the depth of anaesthesia. Groups of patients who are considered at higher risk of unintended awareness during general anaesthesia include patients with high opiate or high alcohol use, patients with airway problems, and patients with previous experience of accidental awareness during surgery. The risk of unintended awareness is also raised by the concomitant use of muscle relaxants, particularly with total intravenous anaesthesia. Older patients, patients with comorbidities and those undergoing certain types of surgery are also considered at higher risk of unintended awareness because they are at greater risk of haemodynamic instability during surgery. Therefore, lower levels of anaesthetic are often used to prevent adverse effects on the cardiovascular system, which can result in these patient groups receiving inadequate levels of anaesthesia. # The diagnostic and care pathways Before general anaesthesia, the anaesthetist interviews the patient and reviews the medical records to determine the type and dose of anaesthetic and any monitoring that may be needed. Some patients may receive a premedication before the administration of general anaesthetic. This is to allay anxiety and reduce side effects such as nausea and vomiting. Monitoring devices (for example, to monitor blood pressure and blood oxygen levels) are connected to the patient before general anaesthesia is induced. Monitoring devices are removed after the patient has fully recovered from the effects of the anaesthesia and may be temporarily disconnected when the patient is moved into or out of the operating theatre. In the UK, anaesthesia is usually induced in an anaesthetic room. General anaesthesia is administered intravenously or by inhalation until the patient loses consciousness. Further anaesthetic procedures (for example, intubation of the trachea) may be carried out before moving the patient into the operating theatre. During surgery, other drugs may be given with the general anaesthesia. These may include analgesics, regional anaesthesia, antibiotics, anti-emetic drugs and muscle relaxants. In current NHS clinical practice, a patient's response to anaesthesia during surgery is assessed by clinical observation of signs such as excessive tear formation (lacrimation), sweating, pupillary size and reactivity, and the use of supplementary monitoring devices. These devices include an electrocardiograph (ECG) to measure the speed and rhythm of the heart; a non-invasive blood pressure monitor; a pulse oximeter to detect the pulse and estimate the amount of oxygen in the blood; a device to measure the patient's temperature; a device to monitor end-tidal anaesthetic concentration (for inhaled anaesthesia) and provide a minimum alveolar concentration (MAC) value; a nerve stimulator (if a muscle relaxant is used); and a capnograph to monitor the inhaled and exhaled concentration of carbon dioxide. Additional monitoring equipment such as a cardiac output monitor may be used for some patients or certain types of surgery.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. After surgery, the administration of anaesthetic is stopped, muscle relaxant drugs are reversed (if used) and analgesics are given as appropriate. Patients are extubated (if necessary) before being moved to the recovery room and regaining consciousness. Once they have recovered from the anaesthetic and meet the criteria for discharge after anaesthesia, they can be discharged from recovery to a general ward. When patients do not meet the discharge criteria, they remain in the recovery room until assessed by an anaesthetist. After this assessment, any patient not meeting the discharge criteria is transferred to an appropriate unit such as the high dependency unit.# The diagnostic tests # The interventions ## Bispectral Index The BIS system uses a disposable 4-electrode sensor on the patient's forehead to measure electrical activity in the brain before using a proprietary algorithm to process the EEG data and calculate a number between 0 (absence of brain electrical activity) and 100 (wide awake). This provides a direct measure of the patient's response to anaesthetic drugs. The target range of BIS values during general anaesthesia is 40 to 60; this range indicates a low probability of awareness with recall. The BIS sensors are only compatible with BIS modules. Other manufacturers have licensed the BIS (or BISx) technology in order to produce BIS modules that are compatible with their own anaesthesia systems. The manufacturer estimates that 100% of all UK operating theatres would be compatible with the BIS system. ## E-Entropy The E-Entropy monitor measures irregularity in spontaneous brain and facial muscular activity. It uses a proprietary algorithm to process EEG and frontal electromyography data to produce 2 values that indicate the depth of anaesthesia, response entropy (RE) and state entropy (SE). Highly irregular signals with variation of wavelength and amplitude over time produce high entropy values and may indicate that the patient is awake. More ordered signals with less variation in wavelength and amplitude over time produce low or zero entropy values, indicating suppression of brain electrical activity and a low probability of recall. The RE scale ranges from 0 (no brain activity) to 100 (fully awake) and the SE scale ranges from 0 (no brain activity) to 91 (fully awake). The target range for entropy values is 40 to 60. RE and SE values near 40 indicate a low probability of awareness with recall. E-Entropy is a plug-in module that is compatible with the Ohmeda S/5 Anaesthesia monitor and S/5 Compact Anaesthesia monitor using software L-ANE03(A) and L-CANE03(A), and all subsequent software releases since 2003. It is not compatible with other systems. Brain and facial muscular activity is recorded using a disposable sensor with 3 electrodes that are attached to the patient's forehead and a sensor cable that connects the sensor to the Entropy module. The sensors are not compatible with other systems. The manufacturer estimates that 45% of all UK operating theatres would be compatible with the E-Entropy monitor; for the remaining 55%, investment in new monitoring equipment may be needed for compatibility with the Entropy module. ## Narcotrend-Compact M The Narcotrend-Compact M monitor automatically analyses the raw EEG data using spectral analysis to produce a number of parameters. Multivariate statistical methods using proprietary pattern recognition algorithms are then applied to these parameters to provide an automatically classified EEG. The automatic classification functions were developed from visual classification of EEGs. The EEG classification scale is from stage A (awake) to stage F (very deep hypnosis), with stage E indicating the appropriate depth of anaesthesia for surgery. As a refinement to the A to F scale, an EEG index (100=awake, 0=very deep hypnosis) is also calculated. Generic sensors can be used with Narcotrend-Compact M monitors. # The comparator: standard clinical monitoring The combination of standard clinical observation (of pupillary size and reactivity, excessive tear formation, sweating and patient movement) and measurement of 1 or more clinical markers such as pulse, blood pressure and end-tidal anaesthetic gas concentration (for inhaled anaesthesia) constitutes standard clinical monitoring and is the comparator for this assessment.# Outcomes The Diagnostics Advisory Committee considered evidence from a number of sources but primarily the assessment performed by the External Assessment Group. # How outcomes were assessed The assessment consisted of a systematic review of the evidence on clinical-effectiveness data for the 3 depth of anaesthesia monitors compared with standard clinical monitoring. The outcome measures included consumption of anaesthetic agents, time to extubation, time to discharge from the recovery room, probability of awareness during surgery, patient distress and other sequelae resulting from awareness during surgery, morbidity including post-operative cognitive dysfunction, and mortality. # Clinical effectiveness ## Bispectral Index A Cochrane review on 'Bispectral Index for improving anaesthetic delivery and post-operative recovery' provided a basis for assessing the clinical effectiveness of BIS. It included 31 randomised controlled trials of BIS monitoring compared with standard clinical practice. All of the trials included in the Cochrane review were conducted in adults. The External Assessment Group identified 11 randomised controlled trials that were published after the Cochrane review and compared the clinical effectiveness of the BIS monitor with standard clinical monitoring. Five of these trials were conducted in children aged 2 to 18 years. Two of the trials were conducted in populations with known risk factors for awareness during surgery (for example, patients undergoing cardiac or airway surgery). These 11 trials were used to supplement the Cochrane review. The method of administering general anaesthesia varied across the 11 trials. Five trials used inhaled anaesthetic (predominantly sevoflurane) for both induction and maintenance of general anaesthesia. Three other trials used intravenous anaesthesia (propofol) for both induction and maintenance of general anaesthesia (total intravenous anaesthesia). The remaining 3 trials used both intravenous and inhaled anaesthesia. Two used propofol for the induction of anaesthesia and sevoflurane for the maintenance of anaesthesia. Muscle relaxants were used in 7 of the trials. A total of 6 trials identified by the External Assessment Group reported awareness during surgery as an outcome and 3 of these trials reported this as the primary outcome. The 3 trials that did not report awareness as the primary outcome had no cases of awareness during surgery. These 3 trials were not designed to detect awareness during surgery, and it is likely that the sample sizes were insufficient to detect this uncommon outcome. In the 3 trials that did report awareness as the primary outcome, there were 29 cases of confirmed or possible awareness during surgery with BIS monitoring and 30 cases with the comparators used in the studies. One trial, monitoring inhaled anaesthesia in patients classified as being at high risk of awareness during surgery, reported 19 definite or possible cases of awareness in the group with BIS monitoring (n=2861) compared with 8 definite or possible cases in the group with clinical monitoring, which included a structured protocol with audible alarms for monitoring end-tidal anaesthetic concentration (n=2852). This difference was not statistically significant. The use of structured protocols is not considered part of standard clinical monitoring in the NHS. A second trial, in patients at increased risk of awareness receiving total intravenous anaesthesia, reported 8 cases of confirmed or possible awareness in the group with BIS monitoring (n=2919) compared with 21 cases in the standard clinical monitoring group (n=2309). The lower incidence of confirmed awareness in the group with BIS monitoring was statistically significant. A third trial, monitoring inhaled or intravenous anaesthesia in patients not classified at greater risk, reported 2 cases of awareness during surgery in the group with BIS monitoring (n=67) compared with 1 case in the group with standard clinical monitoring (n=61). Statistical significance was not reported. This trial measured awareness with explicit recall using a modified Brice interview and awareness with implicit recall using a word recognition test. The sample size of this study was small and may have contributed to the inconclusive results. The Cochrane review on BIS included a meta-analysis of awareness during surgery with recall, which included 4 trials in patients at high risk of awareness during surgery. This meta-analysis was updated by the External Assessment Group to include 2 further trials in patients at high risk of awareness during surgery. After the addition of these 2 trials, the odds ratio increased from 0.33 to 0.45, indicating a statistically significant difference between groups favouring BIS. However, there was a large amount of heterogeneity between the trials. Six trials identified by the External Assessment Group reported anaesthetic consumption as an outcome and 2 of these reported it as the primary outcome. Three of the trials showed a statistically significant reduction in the use of inhaled anaesthetic in the group with BIS monitoring compared with the group with standard clinical monitoring. The other 3 trials reported use of intravenous anaesthetic. Two of these trials reported a higher maintenance dose of anaesthetic with BIS monitoring compared with standard clinical monitoring, but there was no statistically significant difference between the 2 groups. The third trial reported a 25.3% reduction in the consumption of intravenous anaesthetic (propofol) with BIS monitoring compared with standard clinical monitoring. No statistical significance was reported in the trial. The Cochrane review of BIS included a meta-analysis of anaesthetic consumption, with separate analyses for inhaled anaesthetic consumption and intravenous anaesthetic consumption. When these meta-analyses were updated by the External Assessment Group, the mean difference (in MAC equivalents) in inhaled anaesthetic consumption was slightly reduced from −0.16 to −0.15 but remained statistically significant. The mean difference in intravenous anaesthetic consumption was also slightly reduced from −1.44 mg/kg/h to −1.33 mg/kg/h but remained statistically significant. Of the 11 trials identified by the External Assessment Group, 5 reported time to extubation as a secondary outcome. All 5 trials showed that time to extubation was reduced by 0.5 to 5 minutes with BIS monitoring compared with standard clinical monitoring. Two of these trials reported statistically significant results. Five trials identified by the External Assessment Group reported the time to discharge from the recovery room as a secondary outcome, and 4 of these trials were conducted in children. All of the trials showed that the time to discharge was shorter by 6.7 to 30 minutes in the group with BIS monitoring than in the group with standard clinical monitoring. These results were reported as statistically significant in all trials. However, the point at which the time to discharge began varied across the trials. One trial reported the time to discharge from the end of surgery and 2 others reported time to discharge from the end of general anaesthesia. In the Cochrane review, 12 trials were included in the meta-analysis of the time to discharge from the recovery room. The mean difference in the Cochrane review was −7.63 minutes in favour of BIS. The External Assessment Group did not update the Cochrane review for this outcome because of heterogeneity between studies. One trial conducted in children receiving inhaled anaesthesia reported post-operative nausea and vomiting as a secondary outcome. There was no significant difference between BIS monitoring and standard clinical monitoring in the number of children with nausea (n=5 and n=6 respectively, p=0.95) or with vomiting (n=2 and n=3 respectively, p=0.88). The Cochrane review did not report post-operative nausea and vomiting. The evidence on long-term cognitive dysfunction following general anaesthesia was limited to 1 study (reported in a conference abstract) of patients over 60 years of age. This study reported a reduction in post-operative cognitive dysfunction at 7 days and 3 months with BIS monitoring, although the difference at 7 days was not statistically significant. ## E-Entropy Seven randomised controlled trials comparing the clinical effectiveness of the E-Entropy monitor with standard clinical monitoring were included in the systematic review conducted by the External Assessment Group. Two of these studies were conducted in children (aged 3 to 12 years). None of the trials was conducted in populations with known risk factors for awareness during surgery. The method of administering general anaesthesia varied across trials. Two trials used inhaled anaesthetic (sevoflurane) and 3 trials used intravenous anaesthetic (propofol), for both induction and maintenance of general anaesthesia. Two trials used intravenous anaesthesia for induction followed by an inhaled anaesthetic for maintenance of general anaesthesia. All but 1 trial used muscle relaxants. There was 1 case of awareness during surgery in the 6 trials that reported this outcome. This occurred in the standard clinical monitoring group. Sample sizes were small in all of the trials, so uncommon events such as awareness during surgery may not have occurred or have been detected. Four trials showed a statistically significant reduction in the consumption of inhaled anaesthetic with E-Entropy monitoring compared with standard clinical monitoring, although 1 of these trials showed no reduction in the total amount of anaesthetic consumed. By contrast, no statistically significant reduction in the consumption of intravenous anaesthetic was found in a trial reporting the consumption of intravenous anaesthetic as a primary outcome. However, 2 trials that reported the consumption of intravenous anaesthesia as a secondary outcome did show lower propofol consumption with E-Entropy monitoring compared with standard clinical monitoring that was statistically significant. Three trials reported time to extubation as a secondary outcome. All showed that time to extubation was shorter by approximately 3 to 4 minutes with E-Entropy monitoring compared with standard clinical monitoring. Two of these trials reported this reduction in time to extubation as statistically significant. Two trials reported that the time to discharge from the operating room to the recovery room was reduced by approximately 3 to 4 minutes with E-Entropy monitoring compared with standard clinical monitoring. Both trials reported that this result was statistically significant. Only 1 trial reported the time to discharge from the recovery room. The group with E-Entropy monitoring was discharged sooner than the group with standard clinical monitoring, but the difference was not statistically significant. One trial conducted in patients receiving intravenous anaesthesia reported post-operative nausea and vomiting as a secondary outcome. There was no statistically significant difference in the number of patients with nausea and vomiting in the group with E-Entropy monitoring and in the group with standard clinical monitoring. ## Narcotrend-Compact M Four randomised controlled trials comparing the clinical effectiveness of the Narcotrend-Compact M monitor with standard clinical monitoring were included in the systematic review conducted by the External Assessment Group. All of these were conducted in adults. None reported risk factors in the study populations for awareness during surgery. The method of administering general anaesthesia varied across trials. Three trials used total intravenous anaesthesia (propofol-remifentanil or propofol-fentanyl) and 1 other trial had a mix of patients receiving intravenous anaesthesia and inhaled anaesthetic (propofol-remifentanil and desflurane-remifentanil) for general anaesthesia. Three trials used muscle relaxants. There were no cases of awareness during surgery in any of the trials reporting the clinical effectiveness of the Narcotrend-Compact M monitor. Of 3 trials that reported consumption of the anaesthetic propofol, 2 showed a statistically significant reduction in consumption with Narcotrend-Compact M monitoring compared with standard clinical monitoring. The third trial showed no difference in propofol consumption between the 2 groups. In 1 trial that reported time to extubation as a primary outcome, no difference was found between the group with Narcotrend-Compact M monitoring and the group with standard clinical monitoring. Two trials that reported time to extubation as a secondary outcome showed a statistically significant reduction of 1.4 to 6 minutes with Narcotrend-Compact M monitoring compared with standard clinical monitoring. Two trials reported a statistically significant reduction in the time to arrival at the recovery room in the group with Narcotrend-Compact M monitoring compared with the group with standard clinical monitoring. # Cost effectiveness A systematic review of the evidence on cost effectiveness for the 3 technologies was undertaken by the External Assessment Group. One study was identified that evaluated the cost effectiveness of standard clinical monitoring in combination with BIS monitoring compared with standard clinical monitoring alone. The cost per patient of BIS monitoring included the cost of the sensors and the monitor. An incidence of awareness during surgery of 0.04% was used for standard clinical monitoring in combination with BIS monitoring and 0.18% was used for standard clinical monitoring alone. The study concluded that the addition of BIS monitoring to standard clinical monitoring was not cost effective. However, the study did not include health-related quality of life and its methodology was of uncertain quality. No studies were identified that included E-Entropy or Narcotrend-Compact M monitoring and met the inclusion criteria for the systematic review on cost effectiveness. An economic model was developed by the External Assessment Group to assess the cost effectiveness of using a monitor to assess the depth of anaesthesia plus standard clinical monitoring compared with standard clinical monitoring alone. The model evaluated costs from the perspective of the NHS and personal social services. Outcomes were expressed as quality-adjusted life years (QALYs). Both costs and outcomes were discounted using a 3.5% annual discount rate. Separate economic analyses were conducted for each of the 3 technologies. No analyses were conducted to directly compare the technologies. A decision tree model was developed to evaluate the outcomes and costs resulting from the use of depth of anaesthesia monitors as opposed to standard clinical monitoring alone. The relevant clinical outcomes included in the model were those associated with excessively deep levels and inadequate levels of general anaesthesia in the general surgical population and the population at high risk of awareness. Specifically, these were the risk of experiencing short-term adverse outcomes (such as post-operative nausea and vomiting) and long-term adverse outcomes (such as post-traumatic stress disorder and post-operative cognitive dysfunction), and the risk of experiencing awareness during surgery. The model was also used to estimate the costs associated with depth of anaesthesia monitoring and the costs of treating short- and long-term adverse outcomes. It was assumed that the costs of monitoring clinical signs such as blood pressure and heart rate were common to all surgery with general anaesthesia with and without depth of anaesthesia monitoring. Therefore, these were not included in the model. The main costs associated with standard clinical monitoring in the model were costs of anaesthesia, costs of adverse outcomes related to anaesthesia and costs of managing long-term sequelae of awareness during surgery. The costs associated with post-operative nausea and vomiting were also included. No impact of short-term adverse outcomes on quality of life was included in the model because, by definition, these are expected to be of short duration. Three separate models were developed, 1 for each monitoring system. However, the model structures were the same, with only the values for the parameters varying. The models used different values for the risks associated with standard clinical monitoring (without a depth of anaesthesia monitor) corresponding to the results in the respective trials. As a result, no direct comparisons of the monitors were performed. For each monitor, 4 analyses were performed; 2 each for the population at general risk of adverse outcomes from anaesthesia and for the population at high risk of adverse outcomes from anaesthesia. For each of the 2 populations, 2 analyses were performed; 1 for patients receiving total intravenous anaesthesia and 1 for a general mix of patients regardless of the type of anaesthesia. Unit costs for depth of anaesthesia monitors included the acquisition cost of the monitor (annual cost assuming a 5-year effective life and converted to an average cost per patient based on assumptions of patient throughput) and recurring costs arising from the single-use sensors. The cost of the monitors varied from £4867 for the BIS monitor to £10,825 (the midpoint of a range of prices for Narcotrend-Compact M). Sensor costs varied more widely, with costs per patient of £14.08 for BIS, £8.68 for E-Entropy and £0.56 for Narcotrend-Compact M. The cost-effectiveness estimates in the following sections were, in most cases, derived using data from BIS monitoring for estimating the impact on awareness during surgery and its sequelae, and for long-term adverse outcomes of anaesthesia overdosing. No robust evidence was identified on the effect of the E-Entropy or Narcotrend-Compact M monitors on awareness during surgery and its sequelae, or for long-term adverse outcomes of anaesthesia overdosing. Therefore, the effect estimates derived from studies using the BIS monitor were applied to E-Entropy and Narcotrend-Compact M in the modelling. ## Patients at high risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia The base-case analysis for patients at high risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia resulted in incremental cost-effectiveness ratios (ICERs) of £21,940, £14,421 and £5681 per QALY gained for BIS, E-Entropy and Narcotrend-Compact M monitoring respectively, compared with standard clinical monitoring alone. Sensitivity analyses showed that the ICERs for BIS, E-Entropy and Narcotrend-Compact M monitoring were sensitive to changes in the probability of awareness during surgery. When the probability of awareness was 0.0006, the ICER for BIS monitoring was £82,903 per QALY gained and, with a probability of 0.0119, the ICER was £8027 per QALY gained compared with standard clinical monitoring alone. The corresponding ICERs for E-Entropy monitoring were £56,429 per QALY gained and £4834 per QALY gained respectively. The corresponding ICERs for Narcotrend-Compact M monitoring were £25,656 per QALY gained and £1123 per QALY gained respectively. The ICER for BIS monitoring was also sensitive to changes in the probability and duration of post-traumatic stress disorder, the effectiveness of the BIS module, the quality-of-life decrement applied to post-traumatic stress disorder and the unit cost of the sensors. In contrast to BIS monitoring, the ICER for E-Entropy monitoring was robust to changes in the unit cost of the sensors. The ICER for E-Entropy monitoring was sensitive to changes in the relative risk of awareness and changes in the quality-of-life decrement applied to post-traumatic stress disorder. The sensitivity analysis for Narcotrend-Compact M monitoring showed that the ICER was robust to most changes in the parameters. However, the ICER was sensitive to changes in the probability of awareness and the decrement applied to post-traumatic stress disorder. ## Patients at general risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia The base-case analysis for patients at general risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia resulted in ICERs of £33,478 and £31,131 per QALY gained for the use of BIS and E-Entropy monitors respectively, compared with standard clinical monitoring alone. Monitoring with the Narcotrend-Compact M monitor dominated standard clinical monitoring in this population (that is, it was more effective and less costly than standard clinical monitoring). As in patients at high risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia, the ICERs for BIS monitoring and E-Entropy monitoring were sensitive to changes in the probability of awareness. When the probability was 0.0023, the ICER for BIS monitoring was £25,778 per QALY gained compared with standard clinical monitoring alone. When the probability was 0.001, the ICER increased to £44,491 per QALY gained. The corresponding ICERs for E-Entropy monitoring were £23,936 and £41,419 per QALY gained respectively. The ICERs were also sensitive to changes in the probability of post-traumatic stress disorder and the quality-of-life decrement applied to post-traumatic stress disorder. The ICER for E-Entropy monitoring was also sensitive to changes in the effectiveness of the E-Entropy module. The sensitivity analysis showed that the ICER for Narcotrend-Compact M monitoring in this general risk population was robust to changes in parameters. Narcotrend-Compact M monitoring dominated standard clinical monitoring by generating improved outcomes at reduced costs. ## Patients at high risk of adverse outcomes from anaesthesia receiving either intravenous or inhaled anaesthesia The base-case analysis for patients at high risk of adverse outcomes from anaesthesia receiving intravenous or inhaled anaesthesia resulted in ICERs of £29,118, £19,367 and £8,033 per QALY gained for the use of BIS, E-Entropy and Narcotrend-Compact M monitors respectively, compared with standard clinical monitoring alone. Sensitivity analyses showed that the ICERs for BIS, E-Entropy and Narcotrend-Compact M monitoring were most sensitive to changes in the probability of awareness. When the probability was 0.0119, the ICER for BIS monitoring compared with standard clinical monitoring alone was £11,591 per QALY gained, rising to £93,139 per QALY gained when the probability was 0.0006. The corresponding ICERs for E-Entropy monitoring were £7290 and £63,483 per QALY gained respectively. The corresponding ICERs for Narcotrend-Compact M monitoring were £2290 and £29,010 per QALY gained respectively. Changes in the relative risk of awareness with the BIS module, probability of developing post-traumatic stress disorder, the duration of post-traumatic stress disorder and the decrement in quality of life applied to post-traumatic stress disorder all led to large variations in the ICER for BIS monitoring, ranging from £22,207 to £61,433 per QALY gained compared with standard clinical monitoring alone. The ICER for E-Entropy monitoring was also sensitive to an increase in the relative risk of awareness with the Entropy module, giving an ICER of £41,635 per QALY gained compared with standard clinical monitoring alone when the odds ratio was increased from 0.45 to 0.81. As in the population receiving total intravenous anaesthesia, the ICER was sensitive to changes in the probability of post-traumatic stress disorder and the decrement in quality of life applied to post-traumatic stress disorder. The ICER for Narcotrend-Compact M monitoring was also sensitive to changes in the effectiveness of the Narcotrend-Compact M monitor, the proportion of patients who develop post-traumatic stress disorder and the quality-of-life decrement applied to post-traumatic stress disorder. ## Patients at general risk of adverse outcomes from anaesthesia receiving either intravenous or inhaled anaesthesia The base-case analysis for patients at general risk of adverse outcomes from anaesthesia receiving intravenous or inhaled anaesthesia resulted in ICERs of £47,882 and £19,000 per QALY gained for the use of BIS and E-Entropy monitors respectively, compared with standard clinical monitoring alone. Monitoring with the Narcotrend-Compact M monitor dominated standard clinical monitoring in this population (that is, it was more effective and less costly than standard clinical monitoring). Sensitivity analysis showed that the ICER for BIS monitoring in this population was sensitive to changes in the probability of awareness with ICERs of £38,163 and £60,911 per QALY gained for probabilities of 0.0023 and 0.001 respectively, compared with standard clinical monitoring alone. The ICER was also sensitive to changes in the relative risk of awareness with the BIS monitor, changes in the probability of developing post-traumatic stress disorder, the duration of post-traumatic stress disorder and the unit costs of the sensors. For E-Entropy monitoring, sensitivity analyses showed that the largest variation in the ICER from the base case of £19,000 per QALY gained was caused by changes in sevoflurane consumption, with ICERs ranging from £6494 to £31,567 per QALY gained, compared with standard clinical monitoring alone. When the probability of awareness was 0.0023 and 0.001 the ICERs were £14,881 and £24,521 per QALY gained respectively, compared with standard clinical monitoring alone. The ICER for E-Entropy monitoring was also sensitive to changes in the probability of post-traumatic stress disorder, the decrement in quality of life applied to post-traumatic stress disorder and changes in the unit cost of the sensors. The sensitivity analysis showed that the ICER for Narcotrend-Compact M monitoring in this population was generally robust to changes in the parameters. However, the ICER was sensitive to a change in the consumption of desflurane (−0.156 to −0.056), resulting in an ICER of £2534 per QALY gained compared with standard clinical monitoring alone. Scenario analyses were performed to investigate the impact of varying the assumed number of patients per monitor per year (1000 patients) in the base-case analyses. These analyses showed that the number of patients per monitor only had a substantial effect on the ICERs at low patient numbers (less than 500 patients). This applied for all 3 monitors.# Considerations The Committee considered the heterogeneity and uncertainty in the studies and the resulting ICERs. It concluded that the large degree of heterogeneity and uncertainty arose mainly from the individual response to anaesthesia, the case mix and the variation in administering anaesthesia in clinical practice. The Committee was advised that population groups considered to be at high risk of adverse events from anaesthesia varied with changes in anaesthesia practice, but that the type of surgery, patient's age, BMI and comorbidities were known risk factors. The Committee was advised that post-traumatic stress disorder following awareness during surgery can be severe and have far-reaching consequences for the patient's quality of life beyond those considered within the health context (for example, marital breakdown and loss of employment). The Committee also noted that people who experience awareness during surgery can become averse to any contact with the healthcare system and may not seek treatment for conditions in the future. This might mean that the impact of awareness and the costs of treating its consequences have been underestimated. The Committee was advised that unintended awareness during surgery in patients who receive muscle relaxants is associated with more severe psychological harm than in patients who do not receive muscle relaxants. The Committee noted that the risk of awareness during surgery in patients receiving inhaled anaesthesia can be reduced using structured anaesthesia protocols such as measuring end-tidal anaesthetic concentration with audible alarms and using MAC values, but the use of such protocols is not possible in patients receiving total intravenous anaesthesia. In patients who are more sensitive to anaesthetic and who are therefore at higher risk of receiving an excess of anaesthetic, such as older patients, the standard levels within such protocols may not be appropriate. The Committee noted that unintended awareness during surgery could still occur with the use of depth of anaesthesia monitors or structured protocols for measuring end-tidal anaesthetic concentration, but that the use of these interventions lowered the risk. The Committee considered that it is uncertain if the depth of anaesthesia monitors reduce the risk of consciousness without recall. The Committee acknowledged that distinguishing between late psychological symptoms and post-traumatic stress disorder was difficult but concluded that the adverse impact on quality of life was the same. The Committee noted that the 2 groups had been separated in the cost-effectiveness analyses, and the costs associated with post-traumatic stress disorder were not applied to the group with late psychological symptoms. Therefore, the Committee concluded that the clinical benefits of monitoring could have been underestimated in the cost-effectiveness analyses. The Committee considered there was uncertainty about the effects of excessively deep levels of anaesthesia. The Committee was advised that there was evidence suggesting an increase in morbidity and mortality associated with excessively deep anaesthesia (for example, an increase in the incidence of stroke or myocardial infarction). They also noted that there was weak evidence showing that excessively deep anaesthesia resulted in post-operative cognitive dysfunction. The Committee noted that these outcomes had not been included in the cost model, and that their absence meant that the clinical benefits of avoiding excessively deep levels of anaesthesia were likely to have been underestimated in the cost-effectiveness analyses. Although the Committee considered that the clinical benefits associated with reducing adverse outcomes from anaesthesia were underestimated in the model, the Committee also discussed the uncertainty about the extent to which depth of anaesthesia monitoring could reduce these adverse effects and the consequent uncertainty about the cost savings. The Committee noted the possibility that the clinical benefits of monitoring may have been overestimated in the cost-effectiveness analyses. The Committee noted that potential cost savings associated with reductions in operating theatre time and recovery time were not included in the model. The Committee considered that incorporating the cost savings associated with these outcomes might improve the cost effectiveness of the monitors, but the time savings were too small to significantly benefit clinical practice. The Committee considered the wide variation in price for the sensors for the 3 monitors (from under £1 to over £14). The Committee noted that there may be technical differences in the sensors, which could affect the accuracy of the monitors, but that there was no evidence of a substantial clinical difference when the sensors are used by anaesthetists well trained in depth of anaesthesia monitoring. The Committee noted anecdotal evidence that the BIS monitor and sensors could be procured locally at a lower cost than that used in the model. The Committee noted that despite many large studies, particularly of the BIS monitor, uncertainties remained about the probability of unintended awareness during surgery and the benefits of avoiding excessively deep levels of anaesthesia and, therefore, the extent to which depth of anaesthesia monitors could reduce adverse outcomes. The Committee considered the value of additional research studies before making its recommendations, but concluded that the size, complexity, cost and time requirements of such studies could unduly delay the uptake by the NHS of what is likely to be a beneficial technology. The Committee concluded that additional research is desirable and should be undertaken by both the manufacturers and clinical researchers to provide additional information about the benefits and costs associated with the use of these technologies. In particular, information is needed about the clinical effectiveness of E-Entropy and Narcotrend-Compact M in reducing unintended awareness during surgery, as is further information about the effectiveness of all 3 monitors in reducing all adverse outcomes of general anaesthesia (including post-operative cognitive dysfunction). The Committee also wished to encourage further research into the clinical implications of accidental awareness during surgery, and the impact of the length and depth of anaesthesia on short- and long-term morbidity and mortality. The Committee noted that the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland have commissioned a National Audit Project (NAP5 – Accidental Awareness during General Anaesthesia ) that will collect data on all reported cases of accidental awareness during general anaesthesia during a 1-year time period. The results of this audit are expected to be published in 2014. The Committee felt that the data from this audit may be of some benefit when this guidance is reviewed. The Committee discussed the potential impact of this guidance on the validity of the audit and concluded that an adverse impact was unlikely. The Committee noted that only literature written in the English language was included in the assessment, and therefore some studies, particularly on the Narcotrend-Compact M monitor, may not have been included in the evidence base. It was also noted that observational studies comparing the different technologies were not included in the evidence base. The Committee noted that the modelling gave base-case ICERs for BIS that were above the usual levels accepted by NICE for the adoption of a technology. The Committee noted the considerable uncertainty in many of the parameters of the model and noted that the ICERs were very sensitive to small changes in the parameters. In addition, the Committee noted that the depth of anaesthesia monitors were relatively low-cost interventions, and it was likely that the clinical benefits of using the monitors were underestimated in the base case, particularly those benefits associated with avoiding excessively deep levels of anaesthesia. The Committee considered that the avoidance of uncommon but catastrophic events for patients was an important factor in accepting a technology with an ICER that appeared to be higher than usually acceptable in the base-case results. The Committee noted that E-Entropy and Narcotrend-Compact M both had ICERs in the acceptable range, but that there was greater uncertainty about their clinical benefit than for the BIS monitor. Notwithstanding the uncertainty in the evidence base, the Committee considered that depth of anaesthesia monitoring is most likely to be cost effective and of clinical benefit in patients receiving total intravenous anaesthesia and in patients considered at higher risk of unintended awareness or of excessively deep levels of general anaesthesia. The Committee considered that anaesthetists using depth of anaesthesia monitors should ensure that they have appropriate experience with these monitors and appreciate the potential pitfalls in their use in clinical practice. The Committee considered it important to note that the use of the monitors might require significant changes to clinical practice to achieve clinical benefit, and the skill and experience of the anaesthetist in using the depth of anaesthesia monitor are highly likely to influence the clinical effectiveness of the technique. The Committee considered possible equality impacts and concluded that the recommendations would be unlikely to disadvantage any groups protected under equalities legislation.# Recommendations for further research The Committee encourages further research as described in section 6.13 but has made no specific research recommendations. This is because, although there is uncertainty about many aspects of depth of anaesthesia monitoring (as described in section 6), the Committee considered that the current evidence base suggests depth of anaesthesia monitoring offers clinical benefits. Given the many complications in undertaking research in this area of anaesthesia, the Committee considered that the current uncertainty in the evidence base does not justify a potentially long delay in the uptake of what is likely to be a beneficial technology to the NHS and, particularly, to patients.	{'Recommendations': 'The use of electroencephalography (EEG)-based depth of anaesthesia monitors is recommended as an option during any type of general anaesthesia in patients considered at higher risk of adverse outcomes. This includes patients at higher risk of unintended awareness and patients at higher risk of excessively deep anaesthesia. The Bispectral Index (BIS) depth of anaesthesia monitor is therefore recommended as an option in these patients.\n\nThe use of EEG-based depth of anaesthesia monitors is also recommended as an option in all patients receiving total intravenous anaesthesia. The BIS monitor is therefore recommended as an option in these patients.\n\nAlthough there is greater uncertainty of clinical benefit for the E-Entropy and Narcotrend-Compact M depth of anaesthesia monitors than for the BIS monitor, the Committee concluded that the E-Entropy and Narcotrend-Compact M monitors are broadly equivalent to BIS. These monitors are therefore recommended as options during any type of general anaesthesia in patients considered at higher risk of adverse outcomes. This includes patients at higher risk of unintended awareness and patients at higher risk of excessively deep anaesthesia. The E-Entropy and Narcotrend-Compact M monitors are also recommended as options in patients receiving total intravenous anaesthesia.\n\nAnaesthetists using EEG-based depth of anaesthesia monitors should have appropriate training and experience with these monitors and understand the potential limitations of their use in clinical practice.\n\nPatients who are considered at higher risk of unintended awareness during general anaesthesia include patients with high opiate or high alcohol use, patients with airway problems, and patients with previous experience of accidental awareness during surgery. The risk of unintended awareness is also raised by the use of concomitant muscle relaxants. Older patients, patients with comorbidities and those undergoing certain types of surgery are also considered at higher risk of unintended awareness. This is because they are at greater risk of haemodynamic instability during surgery. In these patients, lower levels of anaesthetic are often used to prevent adverse effects on the cardiovascular system and these levels can be inadequate.\n\nPatients who are considered at higher risk of excessively deep levels of anaesthesia include older patients, patients with liver disease, patients with a high body mass index (BMI), and patients with poor cardiovascular function.\n\nPatients receiving total intravenous anaesthesia are not considered at higher risk of adverse outcomes from general anaesthesia than patients receiving inhaled anaesthesia. The use of EEG-based depth of anaesthesia monitors has been recommended in patients receiving total intravenous anaesthesia because it is cost effective and because it is not possible to measure end-tidal anaesthetic concentration in this group.', 'The technologies': "The BIS monitor (Covidien), E-Entropy monitor (GE Healthcare) and Narcotrend-Compact M monitor (MT MonitorTechnik) are EEG-based monitors that are used in combination with standard clinical monitoring and clinical skills to indicate the patient's response to anaesthetic drugs (hereafter referred to as depth of anaesthesia) during surgery.\n\nOther manufacturers have licensed the BIS (or BISx) technology from Covidien in order to produce BIS modules that are compatible with their own anaesthesia systems.", 'Clinical need and practice': "# The problem addressed\n\nEEG-based depth of anaesthesia monitors are designed to indicate the probability of consciousness with explicit recall in patients receiving general anaesthetics, and to aid the tailoring of anaesthetic dose to the individual patient to avoid inadequate or excessively deep levels of anaesthesia. Measuring a patient's response to anaesthesia is important clinically because individual variation in response to anaesthetics can occasionally lead to inadequate or excessively deep levels of anaesthesia. An inadequate level of anaesthesia can result in patient awareness during surgery, which can cause post-traumatic stress disorder in some patients. Conversely, an excessively deep level of anaesthesia can result in prolonged recovery and has been linked to an increased risk of postoperative adverse outcomes, including myocardial infarction, stroke and cognitive dysfunction in older patients.\n\nThe aim of this evaluation is to determine the clinical and cost effectiveness of 3 depth of anaesthesia monitors, in combination with standard clinical monitoring, in patients receiving general anaesthesia.\n\n# The condition\n\nGeneral anaesthesia is a reversible state of controlled unconsciousness that is achieved with drugs which prevent awareness, pain, recall, distress and movement in patients during surgery. It is estimated that 2.4\xa0million people received general anaesthesia in 2007 in England. Approximately half of those who have a general anaesthetic also receive muscle relaxants.\n\nSome common adverse outcomes of general anaesthesia include nausea, headaches and dizziness. Less common adverse outcomes include neurological and cardiovascular morbidity, and unintended patient awareness and recall. Most studies suggest that between 1\xa0and 2\xa0people in\xa01000 experience awareness or recall during general anaesthesia, with a third of these also experiencing pain. For those who experience awareness during anaesthesia, there can be long-term effects such as clinical depression, anxiety, nightmares, flashbacks and, in some cases, severe post-traumatic stress disorder.\n\nAwareness during anaesthesia is more likely during certain types of surgery in which lower levels of anaesthetic are often used. These include cardiac surgery, airway surgery, obstetric surgery or emergency surgery for major trauma. The use of muscle relaxants can also increase the risk of patient awareness because they allow a lower level of anaesthetic to be used. Muscle relaxants also prevent patients from moving. This limits the patient's ability to communicate with the surgical team and means that the anaesthetist has to use other clinical information to judge the patient's state of consciousness.\n\nAnaesthetic agents can affect the body's physiology, in particular, the cardiovascular system. Adverse outcomes of excessively deep general anaesthesia include prolonged recovery, particularly in people with a high BMI. In severe cases or in at-risk patient groups (for example, older patients, patients with liver disease, and patients with poor cardiovascular function), excessively deep anaesthesia can result in haemodynamic instability and respiratory complications (which can be fatal without cardiorespiratory support). Inappropriately deep anaesthesia has also been linked to an increased risk of post-operative complications such as myocardial infarction and stroke in older patients. There is some evidence to suggest a link between longer term morbidity (for example, cognitive dysfunction) and mortality, and the depth of anaesthesia.\n\nGroups of patients who are considered at higher risk of unintended awareness during general anaesthesia include patients with high opiate or high alcohol use, patients with airway problems, and patients with previous experience of accidental awareness during surgery. The risk of unintended awareness is also raised by the concomitant use of muscle relaxants, particularly with total intravenous anaesthesia. Older patients, patients with comorbidities and those undergoing certain types of surgery are also considered at higher risk of unintended awareness because they are at greater risk of haemodynamic instability during surgery. Therefore, lower levels of anaesthetic are often used to prevent adverse effects on the cardiovascular system, which can result in these patient groups receiving inadequate levels of anaesthesia.\n\n# The diagnostic and care pathways\n\nBefore general anaesthesia, the anaesthetist interviews the patient and reviews the medical records to determine the type and dose of anaesthetic and any monitoring that may be needed. Some patients may receive a premedication before the administration of general anaesthetic. This is to allay anxiety and reduce side effects such as nausea and vomiting. Monitoring devices (for example, to monitor blood pressure and blood oxygen levels) are connected to the patient before general anaesthesia is induced. Monitoring devices are removed after the patient has fully recovered from the effects of the anaesthesia and may be temporarily disconnected when the patient is moved into or out of the operating theatre.\n\nIn the UK, anaesthesia is usually induced in an anaesthetic room. General anaesthesia is administered intravenously or by inhalation until the patient loses consciousness. Further anaesthetic procedures (for example, intubation of the trachea) may be carried out before moving the patient into the operating theatre.\n\nDuring surgery, other drugs may be given with the general anaesthesia. These may include analgesics, regional anaesthesia, antibiotics, anti-emetic drugs and muscle relaxants. In current NHS clinical practice, a patient's response to anaesthesia during surgery is assessed by clinical observation of signs such as excessive tear formation (lacrimation), sweating, pupillary size and reactivity, and the use of supplementary monitoring devices. These devices include an electrocardiograph (ECG) to measure the speed and rhythm of the heart; a non-invasive blood pressure monitor; a pulse oximeter to detect the pulse and estimate the amount of oxygen in the blood; a device to measure the patient's temperature; a device to monitor end-tidal anaesthetic concentration (for inhaled anaesthesia) and provide a minimum alveolar concentration (MAC) value; a nerve stimulator (if a muscle relaxant is used); and a capnograph to monitor the inhaled and exhaled concentration of carbon dioxide. Additional monitoring equipment such as a cardiac output monitor may be used for some patients or certain types of surgery.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nAfter surgery, the administration of anaesthetic is stopped, muscle relaxant drugs are reversed (if used) and analgesics are given as appropriate. Patients are extubated (if necessary) before being moved to the recovery room and regaining consciousness. Once they have recovered from the anaesthetic and meet the criteria for discharge after anaesthesia, they can be discharged from recovery to a general ward. When patients do not meet the discharge criteria, they remain in the recovery room until assessed by an anaesthetist. After this assessment, any patient not meeting the discharge criteria is transferred to an appropriate unit such as the high dependency unit.", 'The diagnostic tests': "# The interventions\n\n## Bispectral Index\n\nThe BIS system uses a disposable 4-electrode sensor on the patient's forehead to measure electrical activity in the brain before using a proprietary algorithm to process the EEG data and calculate a number between 0 (absence of brain electrical activity) and 100 (wide awake). This provides a direct measure of the patient's response to anaesthetic drugs. The target range of BIS values during general anaesthesia is 40 to 60; this range indicates a low probability of awareness with recall. The BIS sensors are only compatible with BIS modules. Other manufacturers have licensed the BIS (or BISx) technology in order to produce BIS modules that are compatible with their own anaesthesia systems. The manufacturer estimates that 100% of all UK operating theatres would be compatible with the BIS system.\n\n## E-Entropy\n\nThe E-Entropy monitor measures irregularity in spontaneous brain and facial muscular activity. It uses a proprietary algorithm to process EEG and frontal electromyography data to produce 2 values that indicate the depth of anaesthesia, response entropy (RE) and state entropy (SE).\n\nHighly irregular signals with variation of wavelength and amplitude over time produce high entropy values and may indicate that the patient is awake. More ordered signals with less variation in wavelength and amplitude over time produce low or zero entropy values, indicating suppression of brain electrical activity and a low probability of recall. The RE scale ranges from 0 (no brain activity) to 100 (fully awake) and the SE scale ranges from 0 (no brain activity) to 91 (fully awake). The target range for entropy values is 40 to 60. RE and SE values near 40 indicate a low probability of awareness with recall.\n\nE-Entropy is a plug-in module that is compatible with the Ohmeda S/5 Anaesthesia monitor and S/5 Compact Anaesthesia monitor using software L-ANE03(A) and L-CANE03(A), and all subsequent software releases since 2003. It is not compatible with other systems. Brain and facial muscular activity is recorded using a disposable sensor with 3 electrodes that are attached to the patient's forehead and a sensor cable that connects the sensor to the Entropy module. The sensors are not compatible with other systems. The manufacturer estimates that 45% of all UK operating theatres would be compatible with the E-Entropy monitor; for the remaining 55%, investment in new monitoring equipment may be needed for compatibility with the Entropy module.\n\n## Narcotrend-Compact M\n\nThe Narcotrend-Compact M monitor automatically analyses the raw EEG data using spectral analysis to produce a number of parameters. Multivariate statistical methods using proprietary pattern recognition algorithms are then applied to these parameters to provide an automatically classified EEG. The automatic classification functions were developed from visual classification of EEGs. The EEG classification scale is from stage A (awake) to stage F (very deep hypnosis), with stage E indicating the appropriate depth of anaesthesia for surgery. As a refinement to the A to F scale, an EEG index (100=awake, 0=very deep hypnosis) is also calculated. Generic sensors can be used with Narcotrend-Compact M monitors.\n\n# The comparator: standard clinical monitoring\n\nThe combination of standard clinical observation (of pupillary size and reactivity, excessive tear formation, sweating and patient movement) and measurement of 1 or more clinical markers such as pulse, blood pressure and end-tidal anaesthetic gas concentration (for inhaled anaesthesia) constitutes standard clinical monitoring and is the comparator for this assessment.", 'Outcomes': "The Diagnostics Advisory Committee considered evidence from a number of sources but primarily the assessment performed by the External Assessment Group.\n\n# How outcomes were assessed\n\nThe assessment consisted of a systematic review of the evidence on clinical-effectiveness data for the 3 depth of anaesthesia monitors compared with standard clinical monitoring. The outcome measures included consumption of anaesthetic agents, time to extubation, time to discharge from the recovery room, probability of awareness during surgery, patient distress and other sequelae resulting from awareness during surgery, morbidity including post-operative cognitive dysfunction, and mortality.\n\n# Clinical effectiveness\n\n## Bispectral Index\n\nA Cochrane review on 'Bispectral Index for improving anaesthetic delivery and post-operative recovery' provided a basis for assessing the clinical effectiveness of BIS. It included 31 randomised controlled trials of BIS monitoring compared with standard clinical practice. All of the trials included in the Cochrane review were conducted in adults. The External Assessment Group identified 11 randomised controlled trials that were published after the Cochrane review and compared the clinical effectiveness of the BIS monitor with standard clinical monitoring. Five of these trials were conducted in children aged 2\xa0to\xa018\xa0years. Two of the trials were conducted in populations with known risk factors for awareness during surgery (for example, patients undergoing cardiac or airway surgery). These 11 trials were used to supplement the Cochrane review. The method of administering general anaesthesia varied across the 11 trials. Five trials used inhaled anaesthetic (predominantly sevoflurane) for both induction and maintenance of general anaesthesia. Three other trials used intravenous anaesthesia (propofol) for both induction and maintenance of general anaesthesia (total intravenous anaesthesia). The remaining 3 trials used both intravenous and inhaled anaesthesia. Two used propofol for the induction of anaesthesia and sevoflurane for the maintenance of anaesthesia. Muscle relaxants were used in 7 of the trials.\n\nA total of 6 trials identified by the External Assessment Group reported awareness during surgery as an outcome and 3 of these trials reported this as the primary outcome. The 3 trials that did not report awareness as the primary outcome had no cases of awareness during surgery. These 3 trials were not designed to detect awareness during surgery, and it is likely that the sample sizes were insufficient to detect this uncommon outcome. In the 3 trials that did report awareness as the primary outcome, there were 29 cases of confirmed or possible awareness during surgery with BIS monitoring and 30 cases with the comparators used in the studies. One trial, monitoring inhaled anaesthesia in patients classified as being at high risk of awareness during surgery, reported 19 definite or possible cases of awareness in the group with BIS monitoring (n=2861) compared with 8 definite or possible cases in the group with clinical monitoring, which included a structured protocol with audible alarms for monitoring end-tidal anaesthetic concentration (n=2852). This difference was not statistically significant. The use of structured protocols is not considered part of standard clinical monitoring in the NHS. A second trial, in patients at increased risk of awareness receiving total intravenous anaesthesia, reported 8 cases of confirmed or possible awareness in the group with BIS monitoring (n=2919) compared with 21 cases in the standard clinical monitoring group (n=2309). The lower incidence of confirmed awareness in the group with BIS monitoring was statistically significant. A third trial, monitoring inhaled or intravenous anaesthesia in patients not classified at greater risk, reported 2 cases of awareness during surgery in the group with BIS monitoring (n=67) compared with 1 case in the group with standard clinical monitoring (n=61). Statistical significance was not reported. This trial measured awareness with explicit recall using a modified Brice interview and awareness with implicit recall using a word recognition test. The sample size of this study was small and may have contributed to the inconclusive results.\n\nThe Cochrane review on BIS included a meta-analysis of awareness during surgery with recall, which included 4 trials in patients at high risk of awareness during surgery. This meta-analysis was updated by the External Assessment Group to include 2 further trials in patients at high risk of awareness during surgery. After the addition of these 2 trials, the odds ratio increased from 0.33 to 0.45, indicating a statistically significant difference between groups favouring BIS. However, there was a large amount of heterogeneity between the trials.\n\nSix trials identified by the External Assessment Group reported anaesthetic consumption as an outcome and 2 of these reported it as the primary outcome. Three of the trials showed a statistically significant reduction in the use of inhaled anaesthetic in the group with BIS monitoring compared with the group with standard clinical monitoring. The other 3 trials reported use of intravenous anaesthetic. Two of these trials reported a higher maintenance dose of anaesthetic with BIS monitoring compared with standard clinical monitoring, but there was no statistically significant difference between the 2 groups. The third trial reported a 25.3% reduction in the consumption of intravenous anaesthetic (propofol) with BIS monitoring compared with standard clinical monitoring. No statistical significance was reported in the trial.\n\nThe Cochrane review of BIS included a meta-analysis of anaesthetic consumption, with separate analyses for inhaled anaesthetic consumption and intravenous anaesthetic consumption. When these meta-analyses were updated by the External Assessment Group, the mean difference (in MAC equivalents) in inhaled anaesthetic consumption was slightly reduced from −0.16 to −0.15 but remained statistically significant. The mean difference in intravenous anaesthetic consumption was also slightly reduced from −1.44\xa0mg/kg/h to −1.33\xa0mg/kg/h but remained statistically significant.\n\nOf the 11 trials identified by the External Assessment Group, 5 reported time to extubation as a secondary outcome. All 5 trials showed that time to extubation was reduced by 0.5\xa0to\xa05\xa0minutes with BIS monitoring compared with standard clinical monitoring. Two of these trials reported statistically significant results.\n\nFive trials identified by the External Assessment Group reported the time to discharge from the recovery room as a secondary outcome, and 4 of these trials were conducted in children. All of the trials showed that the time to discharge was shorter by 6.7\xa0to\xa030\xa0minutes in the group with BIS monitoring than in the group with standard clinical monitoring. These results were reported as statistically significant in all trials. However, the point at which the time to discharge began varied across the trials. One trial reported the time to discharge from the end of surgery and 2 others reported time to discharge from the end of general anaesthesia.\n\nIn the Cochrane review, 12 trials were included in the meta-analysis of the time to discharge from the recovery room. The mean difference in the Cochrane review was −7.63\xa0minutes in favour of BIS. The External Assessment Group did not update the Cochrane review for this outcome because of heterogeneity between studies.\n\nOne trial conducted in children receiving inhaled anaesthesia reported post-operative nausea and vomiting as a secondary outcome. There was no significant difference between BIS monitoring and standard clinical monitoring in the number of children with nausea (n=5 [10%] and n=6 [11%] respectively, p=0.95) or with vomiting (n=2 [4%] and n=3 [6%] respectively, p=0.88). The Cochrane review did not report post-operative nausea and vomiting.\n\nThe evidence on long-term cognitive dysfunction following general anaesthesia was limited to 1\xa0study (reported in a conference abstract) of patients over 60\xa0years of age. This study reported a reduction in post-operative cognitive dysfunction at 7\xa0days and 3\xa0months with BIS monitoring, although the difference at 7\xa0days was not statistically significant.\n\n## E-Entropy\n\nSeven randomised controlled trials comparing the clinical effectiveness of the E-Entropy monitor with standard clinical monitoring were included in the systematic review conducted by the External Assessment Group. Two of these studies were conducted in children (aged 3\xa0to\xa012\xa0years). None of the trials was conducted in populations with known risk factors for awareness during surgery.\n\nThe method of administering general anaesthesia varied across trials. Two trials used inhaled anaesthetic (sevoflurane) and 3 trials used intravenous anaesthetic (propofol), for both induction and maintenance of general anaesthesia. Two trials used intravenous anaesthesia for induction followed by an inhaled anaesthetic for maintenance of general anaesthesia. All but 1 trial used muscle relaxants.\n\nThere was 1 case of awareness during surgery in the 6 trials that reported this outcome. This occurred in the standard clinical monitoring group. Sample sizes were small in all of the trials, so uncommon events such as awareness during surgery may not have occurred or have been detected.\n\nFour trials showed a statistically significant reduction in the consumption of inhaled anaesthetic with E-Entropy monitoring compared with standard clinical monitoring, although 1 of these trials showed no reduction in the total amount of anaesthetic consumed. By contrast, no statistically significant reduction in the consumption of intravenous anaesthetic was found in a trial reporting the consumption of intravenous anaesthetic as a primary outcome. However, 2 trials that reported the consumption of intravenous anaesthesia as a secondary outcome did show lower propofol consumption with E-Entropy monitoring compared with standard clinical monitoring that was statistically significant.\n\nThree trials reported time to extubation as a secondary outcome. All showed that time to extubation was shorter by approximately 3\xa0to\xa04\xa0minutes with E-Entropy monitoring compared with standard clinical monitoring. Two of these trials reported this reduction in time to extubation as statistically significant. Two trials reported that the time to discharge from the operating room to the recovery room was reduced by approximately 3\xa0to\xa04\xa0minutes with E-Entropy monitoring compared with standard clinical monitoring. Both trials reported that this result was statistically significant. Only 1 trial reported the time to discharge from the recovery room. The group with E-Entropy monitoring was discharged sooner than the group with standard clinical monitoring, but the difference was not statistically significant.\n\nOne trial conducted in patients receiving intravenous anaesthesia reported post-operative nausea and vomiting as a secondary outcome. There was no statistically significant difference in the number of patients with nausea and vomiting in the group with E-Entropy monitoring and in the group with standard clinical monitoring.\n\n## Narcotrend-Compact M\n\nFour randomised controlled trials comparing the clinical effectiveness of the Narcotrend-Compact M monitor with standard clinical monitoring were included in the systematic review conducted by the External Assessment Group. All of these were conducted in adults. None reported risk factors in the study populations for awareness during surgery.\n\nThe method of administering general anaesthesia varied across trials. Three trials used total intravenous anaesthesia (propofol-remifentanil or propofol-fentanyl) and 1 other trial had a mix of patients receiving intravenous anaesthesia and inhaled anaesthetic (propofol-remifentanil and desflurane-remifentanil) for general anaesthesia. Three trials used muscle relaxants.\n\nThere were no cases of awareness during surgery in any of the trials reporting the clinical effectiveness of the Narcotrend-Compact M monitor.\n\nOf 3 trials that reported consumption of the anaesthetic propofol, 2 showed a statistically significant reduction in consumption with Narcotrend-Compact M monitoring compared with standard clinical monitoring. The third trial showed no difference in propofol consumption between the 2 groups.\n\nIn 1 trial that reported time to extubation as a primary outcome, no difference was found between the group with Narcotrend-Compact M monitoring and the group with standard clinical monitoring. Two trials that reported time to extubation as a secondary outcome showed a statistically significant reduction of 1.4\xa0to\xa06\xa0minutes with Narcotrend-Compact M monitoring compared with standard clinical monitoring.\n\nTwo trials reported a statistically significant reduction in the time to arrival at the recovery room in the group with Narcotrend-Compact M monitoring compared with the group with standard clinical monitoring.\n\n# Cost effectiveness\n\nA systematic review of the evidence on cost effectiveness for the 3 technologies was undertaken by the External Assessment Group. One study was identified that evaluated the cost effectiveness of standard clinical monitoring in combination with BIS monitoring compared with standard clinical monitoring alone. The cost per patient of BIS monitoring included the cost of the sensors and the monitor. An incidence of awareness during surgery of 0.04% was used for standard clinical monitoring in combination with BIS monitoring and 0.18% was used for standard clinical monitoring alone. The study concluded that the addition of BIS monitoring to standard clinical monitoring was not cost effective. However, the study did not include health-related quality of life and its methodology was of uncertain quality.\n\nNo studies were identified that included E-Entropy or Narcotrend-Compact M monitoring and met the inclusion criteria for the systematic review on cost effectiveness.\n\nAn economic model was developed by the External Assessment Group to assess the cost effectiveness of using a monitor to assess the depth of anaesthesia plus standard clinical monitoring compared with standard clinical monitoring alone. The model evaluated costs from the perspective of the NHS and personal social services. Outcomes were expressed as quality-adjusted life years (QALYs). Both costs and outcomes were discounted using a 3.5% annual discount rate. Separate economic analyses were conducted for each of the 3 technologies. No analyses were conducted to directly compare the technologies.\n\nA decision tree model was developed to evaluate the outcomes and costs resulting from the use of depth of anaesthesia monitors as opposed to standard clinical monitoring alone. The relevant clinical outcomes included in the model were those associated with excessively deep levels and inadequate levels of general anaesthesia in the general surgical population and the population at high risk of awareness. Specifically, these were the risk of experiencing short-term adverse outcomes (such as post-operative nausea and vomiting) and long-term adverse outcomes (such as post-traumatic stress disorder and post-operative cognitive dysfunction), and the risk of experiencing awareness during surgery.\n\nThe model was also used to estimate the costs associated with depth of anaesthesia monitoring and the costs of treating short- and long-term adverse outcomes. It was assumed that the costs of monitoring clinical signs such as blood pressure and heart rate were common to all surgery with general anaesthesia with and without depth of anaesthesia monitoring. Therefore, these were not included in the model. The main costs associated with standard clinical monitoring in the model were costs of anaesthesia, costs of adverse outcomes related to anaesthesia and costs of managing long-term sequelae of awareness during surgery. The costs associated with post-operative nausea and vomiting were also included. No impact of short-term adverse outcomes on quality of life was included in the model because, by definition, these are expected to be of short duration.\n\nThree separate models were developed, 1 for each monitoring system. However, the model structures were the same, with only the values for the parameters varying. The models used different values for the risks associated with standard clinical monitoring (without a depth of anaesthesia monitor) corresponding to the results in the respective trials. As a result, no direct comparisons of the monitors were performed.\n\nFor each monitor, 4 analyses were performed; 2 each for the population at general risk of adverse outcomes from anaesthesia and for the population at high risk of adverse outcomes from anaesthesia. For each of the 2 populations, 2 analyses were performed; 1 for patients receiving total intravenous anaesthesia and 1 for a general mix of patients regardless of the type of anaesthesia.\n\nUnit costs for depth of anaesthesia monitors included the acquisition cost of the monitor (annual cost assuming a 5-year effective life and converted to an average cost per patient based on assumptions of patient throughput) and recurring costs arising from the single-use sensors. The cost of the monitors varied from £4867 for the BIS monitor to £10,825 (the midpoint of a range of prices for Narcotrend-Compact M). Sensor costs varied more widely, with costs per patient of £14.08 for BIS, £8.68 for E-Entropy and £0.56 for Narcotrend-Compact M.\n\nThe cost-effectiveness estimates in the following sections were, in most cases, derived using data from BIS monitoring for estimating the impact on awareness during surgery and its sequelae, and for long-term adverse outcomes of anaesthesia overdosing. No robust evidence was identified on the effect of the E-Entropy or Narcotrend-Compact M monitors on awareness during surgery and its sequelae, or for long-term adverse outcomes of anaesthesia overdosing. Therefore, the effect estimates derived from studies using the BIS monitor were applied to E-Entropy and Narcotrend-Compact M in the modelling.\n\n## Patients at high risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia\n\nThe base-case analysis for patients at high risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia resulted in incremental cost-effectiveness ratios (ICERs) of £21,940, £14,421 and £5681 per QALY gained for BIS, E-Entropy and Narcotrend-Compact M monitoring respectively, compared with standard clinical monitoring alone.\n\nSensitivity analyses showed that the ICERs for BIS, E-Entropy and Narcotrend-Compact M monitoring were sensitive to changes in the probability of awareness during surgery. When the probability of awareness was 0.0006, the ICER for BIS monitoring was £82,903 per QALY gained and, with a probability of 0.0119, the ICER was £8027 per QALY gained compared with standard clinical monitoring alone. The corresponding ICERs for E-Entropy monitoring were £56,429 per QALY gained and £4834 per QALY gained respectively. The corresponding ICERs for Narcotrend-Compact M monitoring were £25,656 per QALY gained and £1123 per QALY gained respectively.\n\nThe ICER for BIS monitoring was also sensitive to changes in the probability and duration of post-traumatic stress disorder, the effectiveness of the BIS module, the quality-of-life decrement applied to post-traumatic stress disorder and the unit cost of the sensors.\n\nIn contrast to BIS monitoring, the ICER for E-Entropy monitoring was robust to changes in the unit cost of the sensors. The ICER for E-Entropy monitoring was sensitive to changes in the relative risk of awareness and changes in the quality-of-life decrement applied to post-traumatic stress disorder.\n\nThe sensitivity analysis for Narcotrend-Compact M monitoring showed that the ICER was robust to most changes in the parameters. However, the ICER was sensitive to changes in the probability of awareness and the decrement applied to post-traumatic stress disorder.\n\n## Patients at general risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia\n\nThe base-case analysis for patients at general risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia resulted in ICERs of £33,478 and £31,131 per QALY gained for the use of BIS and E-Entropy monitors respectively, compared with standard clinical monitoring alone. Monitoring with the Narcotrend-Compact M monitor dominated standard clinical monitoring in this population (that is, it was more effective and less costly than standard clinical monitoring).\n\nAs in patients at high risk of adverse outcomes from anaesthesia receiving total intravenous anaesthesia, the ICERs for BIS monitoring and E-Entropy monitoring were sensitive to changes in the probability of awareness. When the probability was 0.0023, the ICER for BIS monitoring was £25,778 per QALY gained compared with standard clinical monitoring alone. When the probability was 0.001, the ICER increased to £44,491 per QALY gained. The corresponding ICERs for E-Entropy monitoring were £23,936 and £41,419 per QALY gained respectively. The ICERs were also sensitive to changes in the probability of post-traumatic stress disorder and the quality-of-life decrement applied to post-traumatic stress disorder. The ICER for E-Entropy monitoring was also sensitive to changes in the effectiveness of the E-Entropy module.\n\nThe sensitivity analysis showed that the ICER for Narcotrend-Compact M monitoring in this general risk population was robust to changes in parameters. Narcotrend-Compact M monitoring dominated standard clinical monitoring by generating improved outcomes at reduced costs.\n\n## Patients at high risk of adverse outcomes from anaesthesia receiving either intravenous or inhaled anaesthesia\n\nThe base-case analysis for patients at high risk of adverse outcomes from anaesthesia receiving intravenous or inhaled anaesthesia resulted in ICERs of £29,118, £19,367 and £8,033 per QALY gained for the use of BIS, E-Entropy and Narcotrend-Compact M monitors respectively, compared with standard clinical monitoring alone.\n\nSensitivity analyses showed that the ICERs for BIS, E-Entropy and Narcotrend-Compact M monitoring were most sensitive to changes in the probability of awareness. When the probability was 0.0119, the ICER for BIS monitoring compared with standard clinical monitoring alone was £11,591 per QALY gained, rising to £93,139 per QALY gained when the probability was 0.0006. The corresponding ICERs for E-Entropy monitoring were £7290 and £63,483 per QALY gained respectively. The corresponding ICERs for Narcotrend-Compact M monitoring were £2290 and £29,010 per QALY gained respectively.\n\nChanges in the relative risk of awareness with the BIS module, probability of developing post-traumatic stress disorder, the duration of post-traumatic stress disorder and the decrement in quality of life applied to post-traumatic stress disorder all led to large variations in the ICER for BIS monitoring, ranging from £22,207 to £61,433 per QALY gained compared with standard clinical monitoring alone.\n\nThe ICER for E-Entropy monitoring was also sensitive to an increase in the relative risk of awareness with the Entropy module, giving an ICER of £41,635 per QALY gained compared with standard clinical monitoring alone when the odds ratio was increased from 0.45 to 0.81. As in the population receiving total intravenous anaesthesia, the ICER was sensitive to changes in the probability of post-traumatic stress disorder and the decrement in quality of life applied to post-traumatic stress disorder.\n\nThe ICER for Narcotrend-Compact M monitoring was also sensitive to changes in the effectiveness of the Narcotrend-Compact M monitor, the proportion of patients who develop post-traumatic stress disorder and the quality-of-life decrement applied to post-traumatic stress disorder.\n\n## Patients at general risk of adverse outcomes from anaesthesia receiving either intravenous or inhaled anaesthesia\n\nThe base-case analysis for patients at general risk of adverse outcomes from anaesthesia receiving intravenous or inhaled anaesthesia resulted in ICERs of £47,882 and £19,000 per QALY gained for the use of BIS and E-Entropy monitors respectively, compared with standard clinical monitoring alone. Monitoring with the Narcotrend-Compact M monitor dominated standard clinical monitoring in this population (that is, it was more effective and less costly than standard clinical monitoring).\n\nSensitivity analysis showed that the ICER for BIS monitoring in this population was sensitive to changes in the probability of awareness with ICERs of £38,163 and £60,911 per QALY gained for probabilities of 0.0023 and 0.001 respectively, compared with standard clinical monitoring alone. The ICER was also sensitive to changes in the relative risk of awareness with the BIS monitor, changes in the probability of developing post-traumatic stress disorder, the duration of post-traumatic stress disorder and the unit costs of the sensors.\n\nFor E-Entropy monitoring, sensitivity analyses showed that the largest variation in the ICER from the base case of £19,000 per QALY gained was caused by changes in sevoflurane consumption, with ICERs ranging from £6494 to £31,567 per QALY gained, compared with standard clinical monitoring alone. When the probability of awareness was 0.0023 and 0.001 the ICERs were £14,881 and £24,521 per QALY gained respectively, compared with standard clinical monitoring alone.\n\nThe ICER for E-Entropy monitoring was also sensitive to changes in the probability of post-traumatic stress disorder, the decrement in quality of life applied to post-traumatic stress disorder and changes in the unit cost of the sensors.\n\nThe sensitivity analysis showed that the ICER for Narcotrend-Compact M monitoring in this population was generally robust to changes in the parameters. However, the ICER was sensitive to a change in the consumption of desflurane (−0.156 to −0.056), resulting in an ICER of £2534 per QALY gained compared with standard clinical monitoring alone.\n\nScenario analyses were performed to investigate the impact of varying the assumed number of patients per monitor per year (1000 patients) in the base-case analyses. These analyses showed that the number of patients per monitor only had a substantial effect on the ICERs at low patient numbers (less than 500 patients). This applied for all 3 monitors.", 'Considerations': "The Committee considered the heterogeneity and uncertainty in the studies and the resulting ICERs. It concluded that the large degree of heterogeneity and uncertainty arose mainly from the individual response to anaesthesia, the case mix and the variation in administering anaesthesia in clinical practice.\n\nThe Committee was advised that population groups considered to be at high risk of adverse events from anaesthesia varied with changes in anaesthesia practice, but that the type of surgery, patient's age, BMI and comorbidities were known risk factors.\n\nThe Committee was advised that post-traumatic stress disorder following awareness during surgery can be severe and have far-reaching consequences for the patient's quality of life beyond those considered within the health context (for example, marital breakdown and loss of employment). The Committee also noted that people who experience awareness during surgery can become averse to any contact with the healthcare system and may not seek treatment for conditions in the future. This might mean that the impact of awareness and the costs of treating its consequences have been underestimated.\n\nThe Committee was advised that unintended awareness during surgery in patients who receive muscle relaxants is associated with more severe psychological harm than in patients who do not receive muscle relaxants.\n\nThe Committee noted that the risk of awareness during surgery in patients receiving inhaled anaesthesia can be reduced using structured anaesthesia protocols such as measuring end-tidal anaesthetic concentration with audible alarms and using MAC values, but the use of such protocols is not possible in patients receiving total intravenous anaesthesia. In patients who are more sensitive to anaesthetic and who are therefore at higher risk of receiving an excess of anaesthetic, such as older patients, the standard levels within such protocols may not be appropriate.\n\nThe Committee noted that unintended awareness during surgery could still occur with the use of depth of anaesthesia monitors or structured protocols for measuring end-tidal anaesthetic concentration, but that the use of these interventions lowered the risk. The Committee considered that it is uncertain if the depth of anaesthesia monitors reduce the risk of consciousness without recall.\n\nThe Committee acknowledged that distinguishing between late psychological symptoms and post-traumatic stress disorder was difficult but concluded that the adverse impact on quality of life was the same. The Committee noted that the 2 groups had been separated in the cost-effectiveness analyses, and the costs associated with post-traumatic stress disorder were not applied to the group with late psychological symptoms. Therefore, the Committee concluded that the clinical benefits of monitoring could have been underestimated in the cost-effectiveness analyses.\n\nThe Committee considered there was uncertainty about the effects of excessively deep levels of anaesthesia. The Committee was advised that there was evidence suggesting an increase in morbidity and mortality associated with excessively deep anaesthesia (for example, an increase in the incidence of stroke or myocardial infarction). They also noted that there was weak evidence showing that excessively deep anaesthesia resulted in post-operative cognitive dysfunction. The Committee noted that these outcomes had not been included in the cost model, and that their absence meant that the clinical benefits of avoiding excessively deep levels of anaesthesia were likely to have been underestimated in the cost-effectiveness analyses.\n\nAlthough the Committee considered that the clinical benefits associated with reducing adverse outcomes from anaesthesia were underestimated in the model, the Committee also discussed the uncertainty about the extent to which depth of anaesthesia monitoring could reduce these adverse effects and the consequent uncertainty about the cost savings. The Committee noted the possibility that the clinical benefits of monitoring may have been overestimated in the cost-effectiveness analyses.\n\nThe Committee noted that potential cost savings associated with reductions in operating theatre time and recovery time were not included in the model. The Committee considered that incorporating the cost savings associated with these outcomes might improve the cost effectiveness of the monitors, but the time savings were too small to significantly benefit clinical practice.\n\nThe Committee considered the wide variation in price for the sensors for the 3 monitors (from under £1 to over £14). The Committee noted that there may be technical differences in the sensors, which could affect the accuracy of the monitors, but that there was no evidence of a substantial clinical difference when the sensors are used by anaesthetists well trained in depth of anaesthesia monitoring.\n\nThe Committee noted anecdotal evidence that the BIS monitor and sensors could be procured locally at a lower cost than that used in the model.\n\nThe Committee noted that despite many large studies, particularly of the BIS monitor, uncertainties remained about the probability of unintended awareness during surgery and the benefits of avoiding excessively deep levels of anaesthesia and, therefore, the extent to which depth of anaesthesia monitors could reduce adverse outcomes. The Committee considered the value of additional research studies before making its recommendations, but concluded that the size, complexity, cost and time requirements of such studies could unduly delay the uptake by the NHS of what is likely to be a beneficial technology.\n\nThe Committee concluded that additional research is desirable and should be undertaken by both the manufacturers and clinical researchers to provide additional information about the benefits and costs associated with the use of these technologies. In particular, information is needed about the clinical effectiveness of E-Entropy and Narcotrend-Compact M in reducing unintended awareness during surgery, as is further information about the effectiveness of all 3 monitors in reducing all adverse outcomes of general anaesthesia (including post-operative cognitive dysfunction). The Committee also wished to encourage further research into the clinical implications of accidental awareness during surgery, and the impact of the length and depth of anaesthesia on short- and long-term morbidity and mortality.\n\nThe Committee noted that the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland have commissioned a National Audit Project (NAP5 – Accidental Awareness during General Anaesthesia [AAGA]) that will collect data on all reported cases of accidental awareness during general anaesthesia during a 1-year time period. The results of this audit are expected to be published in 2014. The Committee felt that the data from this audit may be of some benefit when this guidance is reviewed. The Committee discussed the potential impact of this guidance on the validity of the audit and concluded that an adverse impact was unlikely.\n\nThe Committee noted that only literature written in the English language was included in the assessment, and therefore some studies, particularly on the Narcotrend-Compact M monitor, may not have been included in the evidence base. It was also noted that observational studies comparing the different technologies were not included in the evidence base.\n\nThe Committee noted that the modelling gave base-case ICERs for BIS that were above the usual levels accepted by NICE for the adoption of a technology. The Committee noted the considerable uncertainty in many of the parameters of the model and noted that the ICERs were very sensitive to small changes in the parameters. In addition, the Committee noted that the depth of anaesthesia monitors were relatively low-cost interventions, and it was likely that the clinical benefits of using the monitors were underestimated in the base case, particularly those benefits associated with avoiding excessively deep levels of anaesthesia. The Committee considered that the avoidance of uncommon but catastrophic events for patients was an important factor in accepting a technology with an ICER that appeared to be higher than usually acceptable in the base-case results.\n\nThe Committee noted that E-Entropy and Narcotrend-Compact M both had ICERs in the acceptable range, but that there was greater uncertainty about their clinical benefit than for the BIS monitor.\n\nNotwithstanding the uncertainty in the evidence base, the Committee considered that depth of anaesthesia monitoring is most likely to be cost effective and of clinical benefit in patients receiving total intravenous anaesthesia and in patients considered at higher risk of unintended awareness or of excessively deep levels of general anaesthesia.\n\nThe Committee considered that anaesthetists using depth of anaesthesia monitors should ensure that they have appropriate experience with these monitors and appreciate the potential pitfalls in their use in clinical practice. The Committee considered it important to note that the use of the monitors might require significant changes to clinical practice to achieve clinical benefit, and the skill and experience of the anaesthetist in using the depth of anaesthesia monitor are highly likely to influence the clinical effectiveness of the technique.\n\nThe Committee considered possible equality impacts and concluded that the recommendations would be unlikely to disadvantage any groups protected under equalities legislation.", 'Recommendations for further research': 'The Committee encourages further research as described in section 6.13 but has made no specific research recommendations. This is because, although there is uncertainty about many aspects of depth of anaesthesia monitoring (as described in section 6), the Committee considered that the current evidence base suggests depth of anaesthesia monitoring offers clinical benefits. Given the many complications in undertaking research in this area of anaesthesia, the Committee considered that the current uncertainty in the evidence base does not justify a potentially long delay in the uptake of what is likely to be a beneficial technology to the NHS and, particularly, to patients.'}	https://www.nice.org.uk/guidance/dg6	Evidence-based recommendations on 3 electroencephalography (EEG)‑based depth of anaesthesia monitors for assessing a patient’s response to anaesthetic drugs during surgery. The monitors are Bispectral Index (BIS), E‑Entrophy and Narcotrend‑Compact M.
6abc3d7ff2ef9b8b500161e876a3c5f9bf0c3f38	nice	Social and emotional wellbeing: early years	Social and emotional wellbeing: early years This guideline covers supporting the social and emotional wellbeing of vulnerable children under 5 through home visiting, childcare and early education. It aims to optimise care for young children who need extra support because they have or are at risk of social or emotional problems. # Introduction: scope and purpose of this guidance # What is this guidance about? This guidance aims to define how the social and emotional wellbeing of vulnerable children aged under 5 years can be supported through home visiting, childcare and early education. The recommendations cover: strategy, commissioning and review identifying vulnerable children and assessing their needs ante- and postnatal home visiting for vulnerable children and their families early education and childcare delivering services. This guidance does not cover the clinical treatment of emotional and behavioural difficulties or mental health conditions, or the role of child protection services. # Who is this guidance for? The guidance is for all those responsible for ensuring the social and emotional wellbeing of children aged under 5 years. This includes those planning and commissioning children's services in local authorities (including education), the NHS, and the community, voluntary and private sectors. It also includes: GPs, health visitors, midwives, psychologists and other health practitioners, social workers, teachers and those working in all early years settings (including childminders and those working in children's centres and nurseries). The guidance may also be of interest to parents, other family members and the general public. # Why is this guidance being produced? The Department of Health (DH) asked the National Institute for Health and Clinical Excellence (NICE) to produce this guidance. The guidance should be implemented alongside other guidance and regulations (for more details see section 4 on implementation). # How was this guidance developed? The recommendations are based on the best available evidence. They were developed by the Public Health Interventions Advisory Committee (PHIAC). Members of PHIAC are listed in appendix A. The guidance was developed using the NICE public health intervention process. See appendix B for details. Supporting documents used to prepare this document are listed in appendix E. # What evidence is the guidance based on? The evidence that PHIAC considered included: 2 reviews of the evidence on effectiveness, a review of risk factors, economic modelling, the testimony of expert witnesses and commissioned reports. Further detail on the evidence is given in the considerations section (section 3) and appendices B and C. In some cases, the evidence was insufficient and PHIAC has made recommendations for future research. More details of the evidence on which the guidance is based, and NICE's process for developing public health guidance, are on the NICE website. # Status of this guidance The guidance complements, but does not replace, NICE guidance on: child maltreatment; pregnancy and complex social factors; antenatal and postnatal mental health; mental health disorders in children; looked-after children and young people; and the social and emotional wellbeing of children and young people.# Recommendations The evidence statements underpinning the recommendations are listed in appendix C. The Public Health Interventions Advisory Committee (PHIAC) considers that the recommended interventions are cost effective. For the research recommendations and gaps in research, see section 5 and appendix D respectively. The evidence reviews, supporting evidence statements and economic modelling report are available at the NICE website. # Background: social and emotional development A complex range of factors have an impact on social and emotional development. Knowledge of these factors may help encourage investment at a population level in early interventions to support health and wellbeing. This would ensure children (and families) who are most likely to experience the poorest outcomes get the help they need early on in their lives. Knowledge of these factors, aside, practitioners' experience and expertise will be paramount in assessing the needs and risks of individual children and their families. # Home visiting, early education and childcare The recommendations cover home visiting, early education and childcare for vulnerable children. The recommendations: Adopt a 'life course perspective', recognising that disadvantage before birth and in a child's early years can have life-long, negative effects on their health and wellbeing. Focus on the social and emotional wellbeing of vulnerable children as the foundation for their healthy development and to offset the risks relating to disadvantage. This is in line with the overarching goal of children's services, that is, to ensure all children have the best start in life. Aim to ensure universal, as well as more targeted services, provide the additional support all vulnerable children need to ensure their mental and physical health and wellbeing. (Key services include maternity, child health, social care, early education and family welfare.) Should be used in conjunction with local child safeguarding policies and legislation. The term 'vulnerable' is used to describe children who are at risk of, or who are already experiencing, social and emotional problems and who need additional support. See vulnerable children in the glossary for factors likely to increase the risk of problems. # Whose health will benefit? Vulnerable children aged under 5 years and their parents. # Recommendation 1 Strategy, commissioning and review ## Who should take action? All those responsible for planning and commissioning (including joint commissioning) services for children aged under 5 in local authorities, the NHS (primary, secondary and tertiary healthcare) and the voluntary, community and private sectors. This includes: Clinical commissioning groups. Health and wellbeing boards. NHS Commissioning Board (up to 2015). Public health, children's services, education and social services within local authorities. ## What action should they take? Health and wellbeing boards should ensure the social and emotional wellbeing of vulnerable children features in the 'Health and wellbeing strategy', as one of the most effective ways of addressing health inequalities. The resulting plan should include outcomes to ensure healthy child development and 'readiness for school' and to prevent mental health and behavioural problems. (See the Department of Health's Public health outcomes framework indicators for early years.) Directors of public health, directors of children's services and commissioners of maternity care should ensure the social and emotional wellbeing of under-5s is assessed as part of the joint strategic needs assessment. This includes vulnerable children and their families. Population-based models (such as PREview, a set of planning tools published by the Child and Maternity Health Observatory) should be considered as a way of determining need and ensuring resources and services are effectively distributed. Health and wellbeing boards should ensure arrangements are in place for integrated commissioning of universal and targeted services for children aged under 5. This includes services offered by general practice, maternity, health visiting, school nursing and all early years providers. The aim is to ensure: vulnerable children at risk of developing (or who are already showing signs of) social and emotional and behavioural problems are identified as early as possible by universal children and family services targeted, evidence-based and structured interventions (see recommendations 3 and 4) are available to help vulnerable children and their families – these should be monitored against outcomes children and families with multiple needs have access to specialist services, including child safeguarding and mental health services.Also see NICE guidance on: antenatal and postnatal mental health; attention deficit hyperactivity disorder (ADHD); autism spectrum disorder in under 19s; antisocial behaviour and conduct disorders in children and young people; depression in children and young people; looked-after children and young people; pregnancy and complex social factors and child maltreatment: when to suspect maltreatment in under 18s. Local authority scrutiny committees for health and wellbeing should review delivery of plans and programmes designed to improve the social and emotional wellbeing of vulnerable children aged under 5. See guidance on Supporting public health: children, young people and families. # Recommendation 2 Identifying vulnerable children and assessing their needs ## Who should take action? Early years settings (including children's centres and nurseries). Primary schools (independent, maintained, private and voluntary) and school nursing services. The NHS: general practice, health visiting services, maternity services, mental health services (perinatal, child and adolescent and adult) and paediatrics. Voluntary and community sector organisations. Child safeguarding services. Police. Local authority housing departments. ## What action should they take? All health and early years professionals should develop trusting relationships with vulnerable families and adopt a non-judgmental approach, while focusing on the child's needs. They should do this by: identifying the strengths and capabilities of the family, as well as factors that pose a risk to the child's (or children's) social and emotional wellbeing talking about the aspirations and expectations for the child seeking to understand and respond to perceived needs and concerns discussing any risk factors in a sensitive manner to ensure families do not feel criticised, judged or stigmatised (see vulnerable children for factors that may affect a child's social and emotional wellbeing). Health professionals in antenatal and postnatal services should identify factors that may pose a risk to a child's social and emotional wellbeing. This includes factors that could affect the parents' capacity to provide a loving and nurturing environment. For example, they should discuss with the parents any problems they may have in relation to the father or mother's mental health, substance or alcohol misuse, family relationships or circumstances and networks of support. Health visitors, school nurses and early years practitioners should identify factors that may pose a risk to a child's social and emotional wellbeing, as part of an ongoing assessment of their development. They should use the 'Early years foundation stage' assessment process to help identify and share any needs and concerns. Specifically, they should look for risk factors that were not evident at an earlier stage. For an infant or child, this could include: being withdrawn being unresponsive showing signs of behavioural problems delayed speech poor language and communication skills. For parents, this could include indifference to the child or insensitive or harsh behaviour towards them. Family welfare, housing, voluntary services, the police and others who are in contact with a vulnerable child and their family should be aware of factors that pose a risk to the child's social and emotional wellbeing. They should raise any concerns with the family GP or health visitor (working in the context of local safeguarding policies). Health and early years professionals should ensure procedures are in place: to make referrals to specialist services, based on an assessment of need to collect, consistently record and share information as part of the common assessment framework (relevant child and adult datasets should be linked) for integrated team working for continuity of care to avoid multiple assessments. # Recommendation 3 Antenatal and postnatal home visiting for vulnerable children and their families ## Who should take action? Maternity services. Health visiting services. Early years services. ## What action should they take? Health visitors or midwives should offer a series of intensive home visits by an appropriately trained nurse to parents assessed to be in need of additional support (see recommendation 2). The trained nurse should visit families in need of additional support a set number of times over a sustained period of time (sufficient to establish trust and help make positive changes). Activities during each visit should be based on a set curriculum which aims to achieve specified goals in relation to: maternal sensitivity (how sensitive the mother is to her child's needs) the mother–child relationship home learning (including speech, language and communication skills) parenting skills and practice. The nurse should, where possible, focus on developing the father–child relationship as part of an approach that involves the whole family. This includes getting the father involved in any curriculum activities. Health visitors or midwives should regularly check the parents' level of involvement in the intensive home visiting programme. If necessary, they should offer them a break, to reduce the risk that they will stop participating. If the parents do decide to have a break, the nurse should continue to communicate with them on a regular basis. Managers of intensive home-visiting programmes should conduct regular audits to ensure consistency and quality of delivery. Health visitors or midwives should explain to parents that home visits aim to ensure the healthy development of the child (see recommendation 2). They should take into account the parents' first language and make provision for those who do not speak English. They should also be sensitive to a wide range of attitudes, expectations and approaches in relation to parenting. Health visitors or midwives should try to ensure both parents can fully participate in home visits, by taking into account their domestic and working priorities and commitments. They should also try to involve other family members, if appropriate and acceptable to the parents. Health visitors and midwives should consider evidence-based interventions, such as baby massage and video interaction guidance, to improve maternal sensitivity and mother–infant attachment. For example, this approach might be effective when the mother has depression or the infant shows signs of behaviourial difficulties. Health visitors and midwives should encourage parents to participate in other services delivered by children's centres and as part of the Healthy Child Programme. Health visitors and midwives should work in partnership with other early years practitioners to ensure families receive coordinated support. This includes psychologists, therapists, family support workers and other professionals who deliver services provided by children's centres and as part of the Healthy Child Programme. # Recommendation 4 Early education and childcare ## Who should take action? All those involved in providing early education and childcare services. This includes childminders and those working in children's centres, nurseries and primary schools (maintained, private, independent and voluntary). Health visiting services. Local authority children's services. School nursing services. ## What action should they take? Local authority children's services should ensure all vulnerable children can benefit from high quality childcare outside the home on a part- or full-time basis and can take up their entitlement to early childhood education, where appropriate. The aim is to give them the support they need to fulfill their potential. Childcare and education services should: -ffer flexible attendance times, so that parents or carers can take up education, training or employment opportunities address any barriers that may hinder participation by vulnerable children such as geographical access, the cost of transport or a sense of discrimination and stigma be run by well-trained qualified staff, including graduates and qualified teachers be based on an ethos of openness and inclusion. Managers and providers of early education and childcare services should ensure all vulnerable children can benefit from high quality services which aim to enhance their social and emotional wellbeing and build their capacity to learn. Services should: promote the development of positive, interactive relationships between staff and children ensure individual staff get to know, and develop an understanding of, particular children's needs (continuity of care is particularly important for younger children) focus on social and emotional, as well as educational, development. In line with the Department for Education's statutory framework for the early years foundation stage, managers and providers of early education and childcare services should: provide a structured, daily schedule comprising a balance of adult-led and child-initiated activities ensure parents and other family members are fully involved (for example, by contributing to decisions about service provision, or by participating in learning or other activities, as appropriate) ensure the indoor and outdoor environment is spacious, well maintained and pleasant. # Recommendation 5 Delivering services ## Who should take action? Early years settings (including children's centres and nurseries). Primary schools (independent, maintained, private and voluntary) and school nursing services. The NHS: general practice, health visiting services, maternity services, mental health services (perinatal, child and adolescent and adult) and paediatrics. Voluntary and community sector organisations. Child safeguarding services. ## What action should they take? Health and early years providers should put systems in place to deliver integrated universal and targeted services that support vulnerable children's social and emotional wellbeing. This should include systems for sharing information and for multidisciplinary training and development. Health and early years providers should ensure a process is in place to systematically involve parents and families in reviewing services and suggesting how they can be improved. As part of this process, vulnerable parents and families should be asked about their needs and concerns – and their experiences of the services on offer. Health and early years practitioners should be clear about their responsibility for improving the social and emotional wellbeing of vulnerable children and their families. This involves developing and agreeing pathways and referral routes that define how practitioners will work together, as a multidisciplinary team, across different services within a given locality. Health and early years practitioners should be systematic and persistent in their efforts to encourage vulnerable parents to use early years services. (This includes parents who do not use universal services such as primary care.) Activities should include: targeted publicity campaigns making contact by using key workers and referral partners encouraging other parents to help get them involved sending out repeat invitations using local community venues, such as places of worship and play centres to encourage them to participate and to address any concerns about discrimination and stigma home visits by family support workers. Health and early years practitioners should use outreach methods to maintain or improve the participation of vulnerable parents and children in programmes and activities. Parents who may lack confidence or are isolated will require particular encouragement. (This includes those with drug or alcohol problems and those who are experiencing domestic violence.) Health and early years practitioners should work with community and voluntary organisations to help vulnerable parents who may find it difficult to use health and early years services. The difficulties may be due to their social circumstances, language, culture or lifestyle. The NHS Commissioning Board is responsible for commissioning health visiting services up to 2015. From 2015, local authorities will take over this responsibility. It is not clear from current evidence how many home visits are needed. The Family Nurse Partnership, an evidence-based, intensive home visiting programme, provides weekly or fortnightly home visits for 60–90 minutes throughout most stages of the programme (with more in the early stages and less later).# Public health need and practice # Policy Government policy puts a significant emphasis on early intervention services to ensure all children have the best possible start in life. The aim is to address the inequalities in health and life chances that exist between children living in disadvantaged circumstances and those in better-off families. The importance of social and emotional wellbeing in relation to healthy child development is set out in a joint Department for Education and Department of Health publication, 'Supporting families in the foundation years' (2011). The primary aim of the foundation years (years 0–5) is defined as: 'promoting a child's physical, emotional, cognitive and social development so that all children have a fair chance to succeed at school and in later life'. In addition the new 'Statutory framework for the early years foundation stage' (Department for Education 2012a) makes personal, social and emotional development a cornerstone of early years learning and education. Other relevant policy documents and related reviews include: 'Fair society, healthy lives' (Marmot Review Team 2010). 'Healthy child programme: pregnancy and the first five years of life' (DH 2009). 'Healthy lives, healthy people: our strategy for public health in England' (DH 2010a). 'Healthy lives, healthy people: update and way forward' (DH 2011). 'No health without mental health: a cross-government mental health outcomes strategy for people of all ages' (HM Government 2011). 'Support and aspiration: a new approach to special educational needs' (Department for Education 2011a). 'The early years: foundations for life, health and learning' (Tickell 2011). 'The importance of teaching' (Department for Education 2010). # Benefits of social and emotional wellbeing Social and emotional wellbeing is important in its own right, but it also provides the basis for future health and life chances. Poor social and emotional capabilities increase the likelihood of antisocial behaviour and mental health problems, substance misuse, teenage pregnancy, poor educational attainment and involvement in criminal activity. For example, aggressive behaviour at the age of 8 is a predictor of criminal behaviour, arrests, convictions, traffic offences, spouse abuse and punitive treatment of their own children (Farrington et al. 2006). # Factors that impact on social and emotional wellbeing The child's relationship with their mother (or main carer) has a major impact on social and emotional development. In turn, the mother's ability to provide a nurturing relationship is dependent on her own emotional and social wellbeing and intellectual development – and on her living circumstances. The latter includes family environment, social networks and employment status (Shonkoff and Phillips 2000). Most parents living in poor social circumstances provide a loving and nurturing environment, despite many difficulties. However, children living in a disadvantaged family are more likely to be exposed to adverse factors such as parental substance misuse and mental illness, or neglect, abuse and domestic violence. Consequently, they are more likely to experience emotional and behavioural problems that can impact on their development and opportunities in life (Farrington et al. 2006; Shonkoff and Phillips 2000). For example, measures of 'school readiness' show that the poorest 20% of children are more likely to display conduct problems at age 5, compared to children from more affluent backgrounds (Sabates and Dex 2012; Waldfogel and Washbrook 2008). There are less opportunities after the preschool period to close the gap in behavioural, social and educational outcomes (Allen 2011; Field 2010). # Current services Services that support families and children during their early years are generally not well coordinated and integrated either at the strategic or local level (Allen 2011a; Field 2010; Munro 2011; Tickell 2010). The level and quality of early childcare and education services varies, with the most disadvantaged children likely to get the worse provision (Ofsted 2010). In addition, only an estimated 50% of children aged 2 and 2½ years in England are being assessed as part of the Healthy Child Programme – and not all women are being offered antenatal and parenting support services (Care Quality Commission 2010; DH 2010b). The approaches and interventions used to address specific problems (such as abuse, maternal mental health problems and poor parenting) also vary widely and, while some interventions have been proven to be effective and cost effective, others have not. Where evidence-based interventions are used, they are not always being implemented effectively (Allen 2011a; Field 2010). There is limited UK data on the indicators that provide an overall measure of the social and emotional wellbeing of children aged under 5 years. Independent reviews recommend that measures should be developed to assess children's cognitive, physical and emotional development at ages 3 and 5 years (Allen 2011b; Field 2010; Tickell 2011). # Costs Early intervention can provide a good return on investment (Knapp et al. 2011). For example, an evaluation of the US-based Nurse-Family Partnership estimated that the programme made savings by the time the children of high-risk families had reached the age of 15. These savings, which were over five times the cost of the programme itself, resulted from reduced expenditure in the welfare and criminal justice systems, higher tax revenues and improved physical and mental health (Karoly et al. 2005). (The cost effectiveness of the UK Family Nurse Partnership (FNP) model is currently being investigated as part of the FNP trial.) The cost of not intervening to ensure (or improve) the social and emotional wellbeing of children and their families are significant, for both them and wider society (Aked et al. 2009). For example, by the age of 28, the cumulative costs for public services are much higher when supporting someone with a conduct disorder, compared to providing services for someone with no such problems (Scott et al. 2001).# Considerations The Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations. PHIAC focused on local interventions to improve children's social and emotional wellbeing – either directly, or by improving the ability of parents to provide a nurturing and loving family environment. However, such family-based services can only form one component of a broader, multi-agency local strategy within a supportive national policy framework. Other elements may include, for example, policies to improve the social and economic circumstances of disadvantaged children. PHIAC noted that a range of early years child development programmes that were beyond the scope of this guidance are effective. This includes, for example, certain parenting programmes. PHIAC also recognised that these programmes would complement the home visiting, early education and childcare interventions recommended in this guidance. PHIAC was mindful of ongoing policy developments in relation to public health commissioning. It took into account the greater role local government will play in improving and protecting the health and wellbeing of local people. For example, local government will take over responsibility for children's services from the NHS Commissioning Board in 2015. (These services support women in pregnancy and children aged up to 5 years and are delivered as part of the Healthy Child Programme. They include health visiting.) Traditionally, child development policy and practice has focused on physical health and cognitive development. However, a series of independent reviews on early intervention, early education and child protection have underlined the importance of social and emotional wellbeing. (The reviews include Allen ; and Department for Education and DH .) Social and emotional wellbeing forms the basis for healthy child development and 'readiness for school'. It can also help prevent poor health and improve education and employment outcomes in adolescence and throughout adulthood. There is a lack of consensus on how to define and measure young children's social and emotional wellbeing. Much of the evaluation literature concentrates on the consequences of someone lacking mental or social and emotional wellbeing. Evidence on interventions aiming to improve or sustain social and emotional wellbeing is comparatively limited – and the quality varies significantly. There are a small number of high-quality, long-term UK studies. However, the main body of evidence is from the US and it was sometimes difficult to determine how relevant this was for early years services in the UK. Most of the available evidence on early years interventions related to mothers. However, PHIAC recognised the importance of including the father in interventions, where this was possible. Within the guidance, the term 'parent' includes mothers, fathers, carers and foster parents. PHIAC noted that both parents are important to children (whether living in the same household or in a relationship with each other or not). PHIAC noted that programmes to encourage the participation of all parents, at all stages (before birth and throughout the early years) and that support their needs, may benefit their children's social and emotional wellbeing greatly. Independent reviews (Allen 2011; Field 2010) stressed the critical role of the whole family, including fathers and grandparents, in influencing a child's social and emotional wellbeing and subsequent life chances. There is limited evidence on the most effective ways that fathers and grandparents who provide childcare support can promote social and emotional wellbeing. However, PHIAC recognised that an approach that involves the whole family is important. Difficulties with speech, language and communication may contribute significantly to social and emotional wellbeing problems and the resulting behaviour that may ensue. For example, PHIAC noted that, according to one longitudinal study (Silva et al. 1987) 59% of children aged 3 years with language delay had behavioural problems, compared with 14% without language delay. PHIAC also noted that those working with young children and their families have an important role in highlighting the importance of language and communication and in identifying any difficulties in this area. The recommendations build on important national developments to promote and protect the social and emotional wellbeing of children, especially vulnerable children. These developments include: Expansion of the health visitor workforce. The new core purpose of children's centres: 'to improve outcomes for young children and their families with a particular focus on the most disadvantaged, so that children are equipped for life and ready for school, no matter what their background or family circumstances' (Department for Education 2011b). Free early education extended to 40% of infants aged 2 years, starting with those who are from disadvantaged families (Department for Education 2012b). The designation of personal, social and emotional development as 1 of the key themes in the new early years foundation stage (Department for Education 2012a). (This statutory framework sets standards for learning, development and care for children from age 1–5 years for all early years settings). Stronger links between the Healthy Child Programme and early years foundation stage processes of assessment and review to help identify and respond to children with particular needs. Expert testimony relating to the Family Nurse Partnership programme showed that this model can have a positive effect on children's emotional and behavioural development. (The evidence was derived originally from long-term randomised control trials in the US of targeted, intensive interventions.) PHIAC noted that the current UK randomised control trial, based on the same programme, will provide valuable evidence of its effectiveness in this country. It also acknowledged that long-term follow-up and an analysis of the costs and benefits will be crucial. PHIAC was aware of the financial constraints on public sector services and the need to ensure value for money. Members noted that the Allen reviews (2011a; 2011b) set out a strong economic case for early years 'preventive' services. The reviews showed that the greatest cost savings could be achieved by intervening during the early years of life. PHIAC judged that, if effective evidence-based interventions are systematically implemented, then cost savings are likely to be achieved over 3 to 4 years – and also in the longer term. While prevention of child abuse is not the primary focus of this guidance, neglect and abuse are major risks to a child's social and emotional development (as well as to their overall health and wellbeing). PHIAC believes the recommendations should help prevent child abuse. Evidence showed that effective interventions were structured, replicable and auditable. PHIAC also noted that effective interventions require 'high implementation fidelity' with original programmes, that is, they have to be based on the original programme design. PHIAC put an emphasis on arrangements that could be widely and systematically implemented to deliver evidence-based interventions.# Recommendations for research The Public Health Interventions Advisory Committee (PHIAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects. How effective are interventions to promote social and emotional wellbeing among, and reduce the vulnerability of, different groups of vulnerable children aged under 5 years? How can the factors that pose a risk to, or protect, the social and emotional wellbeing of children aged under 5 years be identified and assessed to determine how children can benefit from different interventions? What approaches can be used to ensure fathers and grandparents help protect or improve the social and emotional wellbeing of vulnerable children aged under 5 years? What types of home-based intervention are effective in promoting the social and emotional wellbeing of vulnerable children aged under 5 years without involving the parents? (This could include childcare provided by other family members or childminders.) How can interventions which have been proven effective in other countries be assessed for their cultural relevance to the UK? What measures should be used to assess how transferrable they are? What organisational mechanisms can ensure interventions to improve the social and emotional wellbeing and 'readiness for school' of vulnerable children aged under 5 years are effectively implemented? How do these differ according to the local context? What are the short, medium and long-term economic benefits of interventions aimed at developing the emotional and social skills of vulnerable, preschool children – for the individual, family and wider society? How should these be assessed? What indicators and datasets should be used to measure and predict social and emotional wellbeing over time? Which indicators and datasets can be used to assess the long-term benefits of interventions aimed at improving the social and emotional wellbeing of vulnerable children aged under 5 years? More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.# Glossary # Baby massage techniques Interventions to promote infant massage. Benefits are reported to include improvements in parent and/or child sleep patterns, their interaction and relationship. # Child safeguarding Safeguarding policies and activities aim to ensure children receive safe and effective care, are protected from maltreatment and have their health and development needs met. Legislation and related policies describe how individuals and agencies should work together to safeguard children. # Family Nurse Partnership The Family Nurse Partnership (FNP) is the UK name for the US-developed Nurse-Family Partnership (NFP). The partnership provides an intensive, structured home-visiting programme for young, first-time mothers from a disadvantaged background and their partners. The emphasis is on building a strong relationship between a specially trained (family) nurse and the parents. Support is available from early pregnancy until the child is aged 2 years. The aim is to improve pregnancy outcomes, the child's health and development and the parents' economic self-sufficiency. # Joint strategic needs assessment A joint strategic needs assessment (JSNA) provides a profile of the health and social care needs of a local population. JSNAs are used as the basis for developing joint health and wellbeing strategies. # Readiness for school In the context of this guidance, 'readiness for school' refers to a child's cognitive, social and emotional development. Development during the child's early years may be achieved through interaction with their parents or through the processes of play and learning. # Social and emotional wellbeing Social and emotional wellbeing provides the building block for healthy behaviours and educational attainment. It also helps prevent behavioural problems (including substance misuse) and mental illness. For the purposes of this guidance, the following definitions are used, in line with the Department for Education's Statutory framework for the early years foundation stage: emotional wellbeing – this includes being happy and confident and not anxious or depressed psychological wellbeing – this includes the ability to be autonomous, problem-solve, manage emotions, experience empathy, be resilient and attentive social wellbeing – has good relationships with others and does not have behavioural problems, that is, they are not disruptive, violent or a bully. # Targeted services A targeted service may be distinct from, or an adaptation of, a universal service. For example, a tailored home visiting programme by a nurse, midwife or health visitor may be provided for young parents from a disadvantaged background. This would be separate from the universal home visiting service provided for all new families and might, for example, include longer sessions, goal setting and a range of specific interventions. (See universal services below.) # Universal services Universal services, such as general education and healthcare services, are available to everyone For all children aged up to 5 years, universal provision includes: maternal healthcare, midwife home visits soon after birth and routine health visitor checks. # Video interaction guidance Interactions between a parent or carer and a child are recorded using audio visual equipment. This is later viewed and discussed, typically with a health or social care professional. Parents and carers are given a chance to reflect on their behaviour, with the focus on elements that are successful. The aim is to improve their communications and relationship with their child. # Vulnerable children A number of factors may contribute, to varying degrees, to making a child vulnerable to poor social and emotional wellbeing. In addition, a child's circumstances may vary with time. However, in this guidance vulnerable children include those who are exposed to: parental drug and alcohol problems parental mental health problems family relationship problems, including domestic violence criminality. They may also include those who: are in a single parent family were born to parents aged under 18 years were born to parents who have a low educational attainment were born to parents who are (or were as children) looked after (that is, they have been in the care system) have physical disabilities have speech, language and communication difficulties. These indicators can be used to identify groups of children who are likely to be vulnerable. However, not all of these children will in fact be vulnerable – and others, who do not fall within these groups, could have social and emotional problems.# References Aked J, Steuer N, Lawlor E et al. (2009) Backing the future: why investing in children is good for us all. New economics foundation Allen G (2011a) Early intervention: the next steps. London: The Cabinet Office Allen G (2011b) Early intervention: smart investment, massive savings. London: The Cabinet Office Care Quality Commission (2010) Maternity services survey 2010 Department for Education (2010) The importance of teaching. London: Department for Education Department for Education (2011a) Support and aspiration: a new approach to special educational needs. London: Department for Education Department for Education (2011b) Core purpose of Sure Start children's centres Department for Education, Department of Health (2011) Supporting families in the foundation years. London: Department for Education Department for Education (2012a) Statutory framework for the early years foundation stage Department for Education (2012b) Early education for two-year-olds Department of Health (2009) Healthy child programme: pregnancy and the first five years of life. London: Department of Health Department of Health (2010a) Healthy lives, healthy people: our strategy for public health in England. London: Department of Health Department of Health (2010b) Currency options for the Healthy Child Programme. London: Department of Health Department of Health (2011) Healthy lives, healthy people: update and way forward. London: Department of Health Farrington DP, Coid JW, Harnett AM et al. (2006) Criminal careers up to age 50 and life success up to age 48. Findings from the Cambridge study of delinquent development. London: Home Office Research, Development and Statistics Directorate Field F (2010) The foundation years: preventing poor children becoming poor adults. The report of the independent review on poverty and life chances. London: HM Government HM Government (2011) No health without mental health: a cross-government mental health outcomes strategy for people of all ages. London: HM Government Karoly LA, Kilburn MR, Cannon JS (2005) Early childhood interventions: proven results, future promise. Santa Monica CA: RAND Corporation Knapp M, McDaid D, Parsonage M (2011) Mental health promotion and mental illness prevention: the economic case. London: Department of Health Marmot Review Team (2010) Fair society, healthy lives. London: The Marmot Review Munro E (2011) The Munro review of child protection: final report – a child-centred system. London: Department for Education Ofsted (2010) Ofsted annual report for 2009–10. Manchester: Ofsted Sabates R, Dex S (2012) Multiple risk factors in young children's development Silva P, Williams S, McGee R (1987) A longitudinal study of children with developmental language delay at age three: later intelligence, reading and behaviour problems. Developmental Medicine and Child Neurology 29: 630–40 Shonkoff JP, Phillips DA (2000) From neurons to neighborhoods: the science of early childhood development Scott S, Knapp M, Henderson J et al. (2001) Financial cost of social exclusion: follow up study of antisocial children into adulthood. BMJ 323 (7306): 191 Tickell C (2011) The early years: foundations for life, health and learning. An independent review on the early years foundation stage. London: Department for Education Waldfogel J, Washbrook F (2008) Early years policy. London: Sutton Trust# Appendix B Summary of the methods used to develop this guidance # Introduction The reviews, primary research, commissioned reports and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the Public Health Interventions Advisory Committee (PHIAC) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations. All supporting documents are listed in appendix E and are available at the NICE website. # Guidance development The stages involved in developing public health guidance are outlined below. . Draft scope released for consultation . Stakeholder meeting about the draft scope . Stakeholder comments used to revise the scope . Final scope and responses to comments published on website . Evidence reviews and economic modelling undertaken and submitted to PHIAC . PHIAC produces draft recommendations . Draft guidance (and evidence) released for consultation and for field testing . PHIAC amends recommendations . Final guidance published on website . Responses to comments published on website # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by PHIAC to help develop the recommendations. The overarching questions were: . What are the most effective and cost-effective early education, childcare and home-based interventions for helping improve and maintain the cognitive, social and emotional wellbeing of vulnerable children and their families? . Which progressive early education, childcare and home-based interventions are effective and cost effective in terms of promoting the cognitive, social and emotional wellbeing of vulnerable children and their families at: 0–3 months, 3 months to 1 year, 1–2 years, and other early-life stages? . How can vulnerable children and families who might benefit from early education, childcare and home-based interventions be identified? What factors increase the risk of children experiencing cognitive, social and emotional difficulties? What is the absolute risk posed by these different factors – and in different combinations? . How can home-based interventions reduce a child's vulnerability and build resilience to help achieve positive outcomes? In particular, how can interventions help develop a strong and positive child–parent attachment? . How can early education and childcare interventions reduce vulnerability and build resilience to help achieve positive outcomes and generally prepare children for school? . Which characteristics of an intervention are critical to achieving positive outcomes for vulnerable children and families? . What lessons can be learnt from current UK-based programmes aimed at promoting the social and emotional wellbeing of children under 5? These questions were made more specific for each review (see reviews for further details). # Reviewing the evidence ## Effectiveness reviews Two reviews of effectiveness were conducted. One looked at review-level evidence (review 1), the other focused on primary evaluation studies of UK programmes (review 2). The latter included related qualitative evidence on factors influencing uptake and implementation. A number of databases and websites were searched for review level and evaluation studies from January 2000. See each review for details of the databases searched. Additional methods used to identify evidence were as follows: reference list search of included papers (for reviews 1 and 2) cited reference searches of included studies in the Web of Knowledge, Scopus and Google Scholar additional searches in Medline and the Web of Knowledge for key UK programmes consultation with an expert advisory group. Studies were included in the effectiveness reviews (reviews 1 and 2) if the: populations included vulnerable children aged 0–5 and their families interventions were 'progressive' and were provided at home, within early education or childcare settings and aimed to improve the social and emotional health and cognitive ability of vulnerable under-5s and their families. Studies were excluded if they focused on: tools and methods used to assess the risk and diagnose social and emotional problems or a mental health disorder clinical or pharmacological treatments support provided by specialist child mental health services. See each review for details of the inclusion and exclusion criteria. ## Other reviews Review 3 focused on the risk factors associated with children experiencing social, emotional and cognitive difficulties. The Millennium Cohort database (maintained by the Centre for Longitudinal Studies) was searched for review 3. All records were hand-searched at the title/abstract level to identify relevant publications. See the review for details. ## Selection criteria Studies were included in review 3 if any aspect of a child's social and emotional wellbeing were reported (including behaviour, development and mental health). ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. – Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. ## Summarising the evidence and making evidence statements The review data was summarised in evidence tables (see full reviews). The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope. # Commissioned reports Three expert reports were commissioned. Expert report 1 summarised the evidence from primary evaluation studies on progressive interventions to promote the social and emotional wellbeing of vulnerable children aged under 5 years. The evidence came from the UK, US, the Netherlands and elsewhere. Expert report 2 looked at programmes to promote the social and emotional wellbeing of vulnerable children aged under 5 years. It included the results of applying the 'Evidence2Success' standards of evidence. Expert report 3 looked at the costs and benefits of intervening early with vulnerable children and families to promote their social and emotional wellbeing. # Cost effectiveness There was a review of economic evaluations and an economic modelling exercise. ## Review of economic evaluations A systematic search of key health and medical databases was undertaken for relevant economic evaluation studies. The inclusion and exclusion criteria were the same as for the systematic review of UK interventions (review 1). Included studies were then quality-assessed. ## Economic modelling The economic modelling comprised two parts: an econometric analysis and the development of an economic model. An econometric analysis of longitudinal data was undertaken to: understand the factors determining aspects of social, psychological and cognitive development in early childhood establish a link between early childhood development and adult outcomes predict the effects of childhood interventions on long-term outcomes. An economic model was developed to determine the long-term outcomes of the intervention (home visiting, early education and childcare). It incorporated data from the reviews of effectiveness and the economic evaluation and outputs from the econometric analysis. The results are reported in the economic modelling reports – see appendix E. # Fieldwork Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with commissioners and practitioners who are involved in early years services in local authorities, the NHS and the community, voluntary and private sectors. Parents and carers of vulnerable children aged under 5 were also consulted. The fieldwork comprised: Sixteen discussion groups with commissioners and practitioners. Two were held in each of 8 local authority areas (Barking and Dagenham, Birmingham, Cambridgeshire, Luton, Northamptonshire, Reading, Sheffield and Tower Hamlets). Eight discussion groups involving a total of 41 parents and carers. These were held in 8 local authority areas (Barking and Dagenham, Birmingham, Cambridgeshire, Luton, Northamptonshire, Reading, Sheffield and Tower Hamlets). The main issues arising from the fieldwork are set out in appendix C under fieldwork findings. See also the full fieldwork reports 'The social and emotional wellbeing of vulnerable children (early years): views of professionals' and 'The social and emotional wellbeing of vulnerable children (early years): views of parents and carers'. # How PHIAC formulated the recommendations At its meetings in January 2012, the Public Health Interventions Advisory Committee (PHIAC) considered the evidence, expert reports and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) whether the evidence is applicable to the target groups and context covered by the guidance. PHIAC developed draft recommendations through informal consensus, based on the following criteria: Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. Where possible, recommendations were linked to an evidence statement(s) (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).# Appendix C The evidence # Background This appendix lists the evidence statements from 3 reviews provided by external contractors (see appendix A and appendix E) and links them to the relevant recommendations. See appendix B for the meaning of the (++), (+) and (-) quality assessments referred to in the evidence statements. Appendix C also lists 3 expert reports and their links to the recommendations and sets out a brief summary of findings from the economic analysis. The evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letter(s) in the code refers to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document. Evidence statement 1.1 indicates that the linked statement is numbered 1 in review 1. Evidence statement 2. ES1 indicates that the linked statement is numbered 1 under the heading 'Effectiveness studies' in review 2. Evidence statement 2.PS1 indicates that the linked statement is numbered 1 under the heading 'Process studies' in review 2. Evidence statement 3.1 indicates that the linked statement is numbered 1 in review 3. The 3 reviews are: Review 1: 'Promoting the social and emotional wellbeing of vulnerable preschool children (0–5 years): Systematic review level evidence' Review 2: 'Promoting the social and emotional wellbeing of vulnerable preschool children (0–5 years): UK evidence review' Review 3: ' Summary review of the factors relating to risk of children experiencing social and emotional difficulties and cognitive difficulties' The reviews, expert reports, economic analysis are available at the NICE website. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Where the Public Health Interventions Advisory Committee (PHIAC) has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix. Recommendation 1: evidence statements 1.1, 1.2, 1.4, 2.ES1, 2.ES3; Additional evidence expert report 1, expert report 2; expert testimony: PREview project Recommendation 2: evidence statement 3.1; Additional evidence expert report 1; expert testimony: PREview project Recommendation 3: evidence statements 1.1, 1.2, 1.4, 2.ES1, 2.ES3, 2.PS1, 2.PS2, 2.PS3; Additional evidence expert report 1, expert report 2; expert testimony: Family Nurse Partnership Recommendation 4: evidence statements 1.3, 2.PS1, 2.PS2; Additional evidence expert report 1, expert report 2 Recommendation 5: evidence statements 2.ES3, 2.PS1, 2.PS2, 2.PS4; Additional evidence expert report 1 # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style. The superscript numbers refer to the studies cited beneath each statement. The full references for those studies can be found in the reviews. ## Evidence statement 1.1: Home visits during pregnancy and the post-partum period (0–1 years) There is moderate evidence from six review papers1,3,4,5,6,7 (four , one and one ) suggesting that postpartum home visits interventions may be effective for improving parental outcomes in at-risk families, with one suggesting that nurse-delivered interventions may be more effective than those delivered by para-professionals or lay visitors. One additional (++) review paper2 suggests that there is insufficient evidence regarding the effectiveness of postpartum visits to women with an alcohol or drug problem. These studies were carried out in populations described as: families at risk of dysfunction or child abuse; mothers at risk for postnatal depression; mothers identified as having additional needs; families living in a deprived area; teenage mothers; African-American women; drug users; economically deprived women; socially at-risk women; preterm infants and mothers with maternal risk. In regard to specific outcomes: one of these reviews (-)6 provides evidence for the effectiveness of programmes delivered by nurses on intimate partner violence and reducing child abuse potential in low-income families, ethnic minority families, substance abusing mothers, and families at risk for child abuse. Three reviews (one 7 and two 5,3) provide evidence that interventions may impact on maternal outcomes (such as psychological status, postnatal depression, maternal self-esteem, quality-of-life and contraceptive knowledge and use, interaction with the child and parenting). One (-) study3 suggests that child development outcomes may be improved in preterm infants. Two further reviews provide evidence that postpartum interventions may be effective for parental outcomes in adolescent mothers. One (-) review4 describes positive outcomes such as improved self-confidence and self-esteem following support-education interventions for postpartum adolescent mothers. A second (++) review1 suggests that interventions may have a positive impact on parent outcomes such as improving maternal-child interaction and maternal identity. Coren and Barlow (2009) Doggett et al. (2005) Kearney et al. (2000) Letourneau et al. (2004) McNaughton (2004) Sharps et al. (2008) Shaw et al. (2006) ## Evidence statement 1.2: Home interventions for wider populations (in addition to or not including pregnancy/postpartum) Seven reviews provide evidence 1,2,3,4,5,6,7 (two , four and one ) regarding the effectiveness of home visiting on interventions for at-risk families. Small to medium effects are reported on maternal sensitivity and the home environment, a moderate effect size on parent–child interaction and measures of family wellness, and a small effect size on: attachment security; cognitive development; socio-emotional development; potential abuse; parenting behaviour; parenting attitudes; and maternal lifecourse education. One (+) review3 provides mixed evidence regarding the impact of parenting interventions on childhood behaviour problems. The study populations in the primary papers were described as including: ethnic minority teenage mothers; pregnant and postpartum women who were socially disadvantaged or substance abusers; low birthweight newborns; children with failure to thrive; low socioeconomic status families; low income families; families at risk of abuse or neglect and families considered to be at risk. One (++) review7 concluded that interventions delivered in the home for participants with low SES had lower effect sizes than those with mixed SES levels. A second (++) review2 similarly concluded that interventions with low SES or adolescent populations had lower effect sizes than middle class non-adolescent parents. One review noted that lower effects were found for studies using HOME (Home Observation and Measurement of the Environment) or NCATS (Nursing Child Assessment Teaching Scale) as outcome measures compared with other rating scales or measures. It is unclear how the timing, intensity and other characteristics of inventions influence effectiveness, particularly with respect to levels of risk and needs. One (+) meta-analysis5 reported that characteristics of more successful interventions across all the studies were that: video feedback was included; interventions had less than 16 sessions; interventions did not include personal contact (but provided equipment); interventions started after the age of 6 months. Another (-) review6 concluded that interventions were more successful when of a moderate number of sessions (5–16 versus more than 16) in a limited time period, and were carried out at home either prenatally or after the age of 6 months. Another (++) review7 in contrast concluded that effect sizes were higher for interventions of 13 to 32 visits and lower for interventions of 1 to 12 visits and 33 to 50 visits. Also, that effect sizes were lower for interventions without a component of social support than for those that included social support. One (++) review2 suggested that there may be some reduction in intervention effect over time, and highlighted that the multifaceted nature of interventions provides challenges in ascertaining which element or elements of an intervention are most effective. Bayer et al. (2009) Kendrick et al. (2000) Bernazzani et al. (2001) Sweet and Appelbaum (2004) Bakermans-Kraneburg et al. (2005) Bakermans-Kraneburg et al. (2003) MacLeod and Nelson (2000) ## Evidence statement 1.3: Programmes delivered in educational or centre settings Four reviews provide moderate evidence1,2,3,4 (three and one ) regarding the effectiveness of interventions delivered in an educational or daycare setting. The detail of interventions and distinctions between daycare and childcare were not well defined. Most evidence related to cognitive outcomes. Other outcomes included social competence and child mental health. One (+) review1 found that more than 70% of positive effects reported were regarding cognitive outcomes. Most of the programmes were described as being conducted with economically disadvantaged populations. However, some reviews included both universal and progressive interventions with little detail provided regarding the precise content of the programmes or the population. Most of the programmes had multiple strands –and varied in intensity. Few reviews examined daycare and preschool education without the addition of centre or home-based parenting support. Most of the programmes were for children aged 3 years and above. Positive cognitive effects were reported for some programmes for: vocabulary; letter and word identification; letter knowledge; book knowledge; colour-naming; reduction in number of children kept back a year; increased IQ scores; verbal and 'fluid intelligence' gains; school readiness; improved classroom and personal behaviour (as rated by the teachers); reduced need for special needs education; a reduction in delinquent behaviour; fewer arrests at aged 27. Reported effectiveness however varied across programmes with one review reporting that 53% of the studies demonstrated no effect. Beneficial effects reported on child mental health included reduced anxiety and the ability to externalise behaviour problems. However one (+) review3 highlighted the potential for making difficult behaviours worse. Improvements in social competencies were reported across a number of programmes, including improvements in mother–child interaction and communications. A study of the effective provision of preschool education project found improved self-regulation and positive behaviour if children attended a centre rated as high quality. One (+) review4 of eight daycare interventions in the US concluded that out of home daycare can have beneficial effects in relation to enhancing cognitive development, preventing school failure, improving children's behaviour, and improving maternal education and employment. The authors suggested that the chance of success is higher for interventions if the intervention starts at age 3 three rather than age 4 years. Anderson et al. (2003) Burgher (2010) D'Onise et al. (2010) Zoritch et al. (2009) ## Evidence statement 1.4: Longer-term outcomes of early interventions in adolescence Two good quality (both ) meta-analyses1,2 of outcomes following early developmental prevention programmes provide good evidence of lasting impact in adolescence, particularly as measured by cognitive outcomes. Overall, effect sizes are small to medium. Study populations were described as at risk or disadvantaged with many including a high proportion of participants from African-American backgrounds. Interventions included structured preschool programmes, centre-based developmental daycare, home visitation, family support services and parental education. One (+)review1 reported that the largest effects were seen for educational success during adolescence, reduced social deviance, increased social participation, and cognitive development, with smaller effects for family wellbeing and social-emotional development. It was highlighted that programmes with more than 500 sessions per participant were significantly more effective than those with fewer. The second (+) review2 reported a similar pattern of outcomes. It was noted that programmes with direct teaching components in preschool and those that followed through from preschool to school tended to have the greatest cognitive impacts. Longer programmes tended to produce greater impacts on preschool cognitive outcomes and on social and emotional outcomes at school age. More intense programmes tended to produce greater impact on preschool cognitive outcomes and grade 8 parent-family outcomes. Manning et al. (2010) Nelson and Westhues (2003) ## Evidence statement 2.ES1: Home visiting programmes Evidence from seven studies (eight papers – four and four )1,2,3,4,5,6,7,8 suggests that some home visiting programmes may be effective in directly improving social and emotional wellbeing of vulnerable children. The extent of effect depends partly on the type and nature of intervention being delivered, and the particular outcomes measures. Some outcome measures were indirectly linked to the social and emotional development and cognitive development of the child, concerned with parental support and home environment. Many of the outcomes were self-reported introducing potential biases into the studies. The heterogeneity of interventions across the small number of studies made it difficult to identify clear categories; and difficult to discern clear relationships between particular types of interventions and outcomes. However some distinction was evident. The more structured intensive interventions (with a focus on child-mother interaction) delivered by specifically trained nurses during the first 18 months appears more likely to have positive effects (the 'Family partnership model'). The lower intensity, less structured interventions involving lay providers (Home Start, peer mentoring) are less likely to have positive effect on the social and emotional wellbeing of vulnerable children. Two studies 6,7 (both +) evaluated 'Starting well', an 'intensive home visiting' programme delivered by health professionals and health support workers to socioeconomically deprived parents of newborn children aged up to 24 months (Glasgow). Positive effect on home environment were reported; but methodological limitations meant the studies provided little robust evidence of effectiveness on social and emotional wellbeing. An (++) evaluation2 of Home Start, a volunteer home visitor programme, showed a positive effect on parent–child relationships; but no effect on maternal depression. This programme offered 'unstructured' mainly social support to vulnerable families with newborns consisting of two or more visits over 12 months provided by lay, local volunteer mothers. The (+) study4 of a small scale home visiting (intensive compensatory education) programme showed a positive effect on academic readiness and inhibitory control. This intervention consisted of weekly visits for 12 months delivered to infants aged 3 years by project workers (in an economically disadvantaged area of Wales). The intervention was a parent-delivered education programme aimed at improving school readiness. The (++) evaluation2 of the 'Family partnership model', a home visiting programme consisting of 18 months of weekly visits from a specifically trained health visitor in two UK counties, showed a positive effect on a small number of outcomes, including maternal sensitivity and infant cooperation. The 'Avon premature infant project' was a home visiting programme with parental child developmental education and support (using a counselling model) delivered over 2 years by nurses. The (+) evaluation5 showed that at 5-year follow-up a development advantage was identified, but at 2 years this was not evident. 'Social support and family health' was a home visiting programme delivered by a health visitor providing 'supportive listening', weekly and then monthly over 2 years (in London: Camden and Islington). The (++) evaluation8 reported a possible effect on maternal health. The (++) study3 of a peer mentoring home visiting programme reported negligible effects on social and emotional wellbeing. This programme was delivered by recruited existing mothers twice-monthly during pregnancy and monthly for the following year (in deprived areas in Northern Ireland). Barlow et al. (2007) Barnes et al. (2006; 2009) Cupples et al. (2010) Ford et al. (2009) Johnson et al. (2005) Mackenzie et al. (2004) Shute and Judge (2005) Wiggins et al. (2004) ## Evidence statement 2.ES3: National evaluation of Sure Start Moderate evidence from two studies (reported in four papers: two 1,2 andtwo 3,4) shows that the Sure Start programmes are effective in improving some outcomes among infants aged 9 months and 3 years relating directly and indirectly to the social and emotional development and cognitive development of preschool children (including child positive social behaviour, child independence, better parenting, home learning environment). There was variation in effects between subgroups and over time (evaluation periods). The earlier evaluation findings showed the small and limited effects varied with degree of social deprivation. Children from relatively more socially deprived families (teenage mothers, lone parents, workless households) were adversely affected by living in Sure Start local programme areas. Later evaluation results differed from the earlier findings in that beneficial effects could be generalised to all subgroups, including teenage mothers and workless households. The findings of the impact evaluation study reported the link between implementation (fidelity) and outcomes, and attributed improved outcomes to children being exposed longer to more mature local programmes (see UK process studies: evidence statement 5 below). It is important to note that this evidence relates to the effect of Sure Start local programmes as a whole. Although Sure Start local programmes had common aims set by central government, the types and mix of interventions were not necessarily common between delivery sites. It is likely that interventions included home visiting, early education and daycare, and the education/daycare components were strengthened after the initial phase (although the evaluation was not depended on these being present). There are a broad spectrum of outcome measures but not all of these relate directly to emotional and social wellbeing. Belsky et al. (2006) Melhuish et al. (2008) Melhuish et al. (2008) Melhuish et al. (2005) ## Evidence statement 2.PS1: Engaging families and the take up of early interventions services Moderate evidence from eleven papers1,2,3,4,5,6,7,8,9,10,11 suggests that the uptake of early interventions among vulnerable families is influenced by mothers' perception of benefits, timely provision of information about the interventions, personal circumstances and views, the reputation of the services, recruitment procedures, perceptions about quality of interventions and their physical accessibility. Three papers (two 1,10 and one 11)reported that the perceived benefits for parents in their child attending childcare/early education were described in terms of building networks, providing an opportunity to take a break from parenting and a facilitator for employment Five papers (four 2,3,4,7 and one 9) reported that a perceived lack of need influenced parents' decision not to take up home visiting. In some cases their needs were seen as being fulfilled by support from friends, family, or other services. The 'wrong type of support' was described by one (+) paper3 with parents needing practical support rather than other support. Parental lack of knowledge regarding the content and potential benefits of available services was reported in four papers (three 1,5,8 and one6). One good quality (+) paper4 described how mothers were unclear regarding what a programme offered, with women not understanding or not remembering information. Some women reported that the offer of the programme might have been preferred after the birth of their baby. Two (+) papers3,4 described the influence of personal choice with some women changing their minds or not being interested in a programme, and one (+) paper7 highlighted that needs changed over time. Waiting lists for interventions meant that some women no longer needed the service when it was offered to them. Three papers of mixed quality (one 6 and two 8,5) described the influence of personal circumstances and views in influencing uptake. These included personal and family reasons and perceived cultural and language differences. Personal choice may also be influenced by the confidence levels of parents. Two papers (both )1,5 described how personal time factors could present barriers to uptake; with difficulty fitting the intervention into a personal routine or multiple demands. Four mixed quality papers (two 1,10 and two 6,12) highlighted the importance of marketing, outreach, and recruitment processes for programmes. Studies suggested the use of key workers and targeted publicity, door-knocking, making use of referral partners and ongoing invitations. Two good quality papers (both )1,5 suggested the influence of the reputation of early education programmes in uptake. The reputation and feedback from other parents could be influential, and also a perceived stigma that services were 'for certain groups'. Two good quality papers (both )1,10 described parental worries regarding the cleanliness of venues, staff prying into their personal lives and concerns for their child. The importance of the location of a service was discussed in three papers (two 5,8 and one 6). The papers highlight that the accessibility of a site is important, with settings being visible and accessible to the public through adequate positioning on a busy street and clearly signposted. There was the suggestion that associating the nursery service with nearby schools made the programme appear more 'official' to parents and provided continuity of services. Avis et al. (2007) Barlow et al. (2005) Barnes et al. (2006) Barnes et al. (2009) Coe et al. (2008) Kazimirski et al. (2008) MacPherson et al. (2009) Mori (2009) Murphy et al. (2008) Smith et al. (2009) Toroyan et al. (2004) Tunstill (2005) ## Evidence statement 2.PS2: Parents experience of services and ongoing engagement in early interventions Moderate evidence from thirteen papers 1,2,3,4,5,6,7,8,9,10,11,12,13 suggests that ongoing engagement with early interventions among vulnerable families is influenced by perceived benefits to children, perception of a quality service, timing of the programme, the involvement of parents and personal reasons. Three good quality (all ) papers1,10,12 described that parents who took up the childcare/early education interventions valued the approach, and believed that it was beneficial to their children. Parents continued to use services as they valued how the programme was delivered, structured, and the way information and advice was given in a non-intrusive manner. Perceived benefits for children were the ability of children to mix, play, and learn with other children. Three papers (two 10,12 and one 7) suggested that parental perception of quality of provision influenced ongoing engagement. It was reported that smaller groups are preferable to parents, but if the staff and venue were perceived to be of high quality, maintaining smaller group sizes was of less importance. Three papers (two 10,12 and one 7) suggested that feedback to parents is an important factor in the success of an early education intervention. One (-) paper8 highlighted a need to make parents feel more comfortable with taking part in activities that were designed for parent and child. Three papers (all )1,6,10 suggested that a lack of programme flexibility precluded some parents from engaging with programmes. Some parents indicated that they would value events outside of typical centre hours, with a desire for increased programme flexibility particularly among students and part-time workers. Three papers (all )2,8,13 highlighted that making a large time commitment to in-home support programmes could be a barrier to engagement. One (+) paper5 reported that parents did not like the frequency of visits or fragmented visits. The timing of visits was noted as a problem in one (+) study9 with mothers feeling disrupted by the timing and scheduling of visits. Two studies (one 4 and one 11) reported that flexibility on the part of the visitor to the needs of the client to ensure the service was delivered at a suitable time, was key. One (+) paper5 suggested that a home visitor should be proactive in recognising warning signs of losing a client, offering the family a break from the programme, changing the content delivered, and working with families to meet their needs and achieve goals. Another (+) paper8 highlighted that it made it easier for families to engage in other services once they were taking part in one programme. Four (all ) papers3,4,5,13 described personal reasons for not engaging with a service such as losing interest in the programme, missing too many appointments, moving out of the area, infant illness and other commitments. Avis et al. (2007) Barlow et al. (2005) Barnes et al. (2006) Barnes et al. (2008) Barnes et al. (2009) Coe et al. (2008) Kazimirski et al. (2008) Kirkpatrick et al. (2007) MacPherson et al. (2009) Mori (2009) Murphy et al. (2008) Smith et al. (2009) Wiggins et al. (2004) ## Evidence statement 2.PS3: Home-based interventions and staff-parent relationships Moderate evidence from eight papers1,2,3,4,5,6,7,8 suggests that the nature of the relationship between staff and parents is an important factor influencing the ongoing engagement of vulnerable families in home-based interventions. The importance of building relationships was highlighted in six papers (five 1,3,4,5,6 and one 8) with regular interaction resulting in parents feeling at ease and being able to 'open up', and with home visitors acting as a mentor, friend, and teacher. Women reported that they liked that home visitors did not impose their views, and took an honest, open, humane and egalitarian approach. Some younger women however reportedly viewed a health visitor intervention as somewhat authoritarian, almost like advice from parents and some women were worried about how they may be perceived by home visitors, believing that they were being checked up on, and were concerned about visitors passing judgment on their lifestyle and parenting skills. One (+) paper3 found fathers were pleased with the programme but took a few sessions to become engaged. Support was a theme described in all six papers. Parents reported that having someone there to listen and provide additional support was beneficial, visitors offered assistance in difficult times, allowed parents to vent frustrations, and encouraged parents to develop life skills and confidence. Parents valued the support of a peer home visitor, especially if they had little existing social support, with some women describing how they were reluctant to seek emotional support from family or friends. Barlow et al. (2005) Barnes et al. (2006) Barnes et al. (2008) Barnes et al. (2009) Kirkpatrick et al. (2007) McIntosh et al. (2006) MacPherson et al. (2009) Murphy et al. (2008) ## Evidence statement 2.PS4: Professional roles and practices Evidence from eleven papers1,2,3,4,5,6,7,8,9,10,11 suggests that issues relating to professional roles and working practices impact on service delivery and performance. Staff perceptions of the work being rewarding, the need for skilled staff, clarity about professional roles and inter-agency team working are seen as linked to the success of a programme. Concerns relating to high stress and complex workloads were highlighted, and the need for training and support. Two papers (one 3 and one 6) indicate staff's belief in the programme was related to perceptions that the nature of the work was particularly rewarding. This was noted as a key factor for success. The level of skills among staff was noted as important to the success of programmes in four papers (three rated 3,9,10 one no rating 4). Particular elements were: empowering users and staff; ongoing monitoring; staff keeping families notified of services and the results of any outreach and a supportive and flexible centre manager. Also one (-) paper10 highlighted that clear roles and responsibilities for staff must be in place to avoid the potential for staff to face conflicting management and loyalty pressures between their original home organisation and their new roles. Five papers (three 1,2,8 and two 7,11) described concerns from staff regarding home-based programmes. Stress due to a larger caseload, stress related to the job, fatigue from extended hours of working and the complex nature of issues presented during home visits was described. Three (+) papers5,8,11 described how home visitors harboured frustrations with not being able to reach clients. They, struggled with losing clients they wished they could help, and had to balance the needs of varying clients and had concerns that interventions were too short. One (+) paper1 highlighted the potential for professional roles to be undermined, with concerns apparent regarding role clarity especially when working in mixed teams. While mixed team working was perceived as advantageous in helping at-risk families, there was a blurring of roles and boundaries which created confusion, and in some instances tension within teams. There were mixed views of supervision found in three further studies (two 1,8 and one 7). One reported satisfaction with management, while another described a need for safer working conditions and better management. In one study7 peer mentors reported that at times, they felt unprepared for some of the cultural and ethnic differences that they encountered in the home while visiting mothers, and felt they could not provide adequate support. The need for visitors to be well supported by peers and supervisors was highlighted in one (+) study2. Barnes et al. (2008) Barnes et al. (2009) Kazimirski et al. (2008) Mathers and Sylva (2007) McIntosh et al. (2006) Mori (2009) Murphy et al. (2008) Smith et al. (2009) Toroyan et al. (2004) Tunstill et al. (2005) Wiggins et al. (2004) ## Evidence statement 3.1: How can those vulnerable children and families who might benefit from early education and childcare interventions be identified? It may be possible to identify children and families who might benefit most from early education and childcare interventions by considering the factors which research suggests are likely to increase their risk. The models for predicting future likely child health outcomes could be used at a population level to direct early intervention investment towards those children and families that are most likely to experience the poorest outcomes. However, the model is dependent on the robustness of the longitudinal data sets in identifying all the key risk factors and the availability of local data to map these factors. Certain factors are not well represented, including those relating to parenting and parental mental health problems. The relationship between cultural factors and child outcomes is not well understood. Also, such models cannot be used to predict outcomes at an individual level. The models may inform practitioners about risk factors, however, practitioner knowledge will also be vital in validating the model for use for individual risk-assessment purposes. # Additional evidence Expert report 1: 'Primary study evidence on effectiveness of interventions (home, early education, child care) in promoting social and emotional wellbeing of vulnerable children under 5' Expert report 2: 'Programmes to promote the social and emotional wellbeing of vulnerable children under 5: messages from application of the Evidence2Success standards of evidence' Expert report 3: 'The costs and benefits of early interventions for vulnerable children and families to promote social and emotional wellbeing: economics briefing'. Expert testimony on the Family Nurse Partnership: Kate Billingham, Department of Health Expert testimony on the PREview project: Helen Duncan, Child and Maternal Health Observatory (CHiMAT) and Kate Billingham, Department of Health # Economic modelling The review of cost-effectiveness interventions found little UK evidence. By contrast, the US literature indicates that preschool education and/or home visiting programmes for at-risk populations may be cost effective. Two econometric models were developed to understand what determines aspects of social, psychological and cognitive development (or 'ability') in early childhood. They also aimed to establish a link between early childhood development and adult outcomes. Measures of cognitive and behavioural development were found to have a very important effect on long-term outcomes, as was parental 'investment' in the early years – through its effect on cognitive and behavioural development. The authors noted a number of limitations in the econometric models, however, including reliance on self-report data, limited common variables in the datasets, use of observational data and associated problems with direction of causality. An economic model was used to conduct an economic analysis of interventions to improve the social and emotional wellbeing of infants from a public sector perspective. Seventeen scenarios were modelled, drawing on evidence from the UK and US and reported in review 2. The results were not conclusive. Interventions which improved child cognition could be cost-saving to the public sector, through improved educational outcomes, higher wages and tax revenues. Modelling of the long-term effects of behavioural changes in childhood yielded more modest financial benefits. Improvements in behaviour in childhood improves adult educational outcomes, reduces the probability of being on benefits, being economically inactive or being involved in crime. All these factors yield cost savings for the public sector, but the sums are relatively small compared to the effects of improved cognition. The authors concluded that there is potential for interventions with vulnerable preschool children to be cost effective or cost saving, even without taking into account other potential benefits. (Other benefits might include avoiding child neglect and improving the socioeconomic outcomes for the children's descendants.) A number of limitations were noted including: The limited number of outcomes that can be used to generate financial benefits. Uncertainty introduced by mapping variables across different ages and data sets. The limited nature of the evidence base. The need to estimate the effects of social and emotional wellbeing on long-term outcomes (such as the probability of a criminal conviction, economic activity and unemployment). # Fieldwork findings Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. PHIAC considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B, 'The social and emotional wellbeing of vulnerable children (early years): views of professionals' and 'The social and emotional wellbeing of vulnerable children (early years): views of parents and carers'. ## Views of professionals Fieldwork participants who work with vulnerable children aged under 5 years were very positive about the recommendations and their potential to promote the social and emotional wellbeing of these children. Many stated that the recommendations complement aspects of the Department for Education's Statutory framework for early years foundation stage and government policy for early years services. Participants said the recommendations needed to acknowledge the role of the father and other family members or carers in promoting the social and emotional wellbeing of children under 5. They believed wider, more systematic implementation of the recommendations would be achieved if there was: a clearer definition of what makes a child 'vulnerable' better identification of who should take action clarity about which action points were intended to be targeted or universal. ## Views of parents and carers of children aged under 5 years The guidance was well received by parents and carers. In particular, there was strong support for multidisciplinary working and the need to ensure effective information sharing among services. In addition, they strongly supported the recommendations to provide high quality education and childcare, but stressed the need to promote free education for children aged 2 years. The stigma associated with labelling families as 'vulnerable' was a concern. They accepted that the term (and identified risk factors) may help find children and families in need of help. However, they were concerned that those identified would feel criticised or blamed. Parents and carers also emphasised that practitioners should not assume that all those identified as being part of a high-risk group are vulnerable.# Appendix D Gaps in the evidence The Public Health Interventions Advisory Committee (PHIAC) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below. There is limited UK evidence on the effectiveness of interventions (home visiting, childcare and early education) to improve the social and emotional wellbeing of vulnerable children aged under 5 years. There is limited UK evidence on the cost effectiveness of early interventions to improve the social and emotional wellbeing of vulnerable children aged under 5 years. This includes evidence on the distribution of costs and benefits across all relevant sectors including health, education, social care, welfare and criminal justice. There is a lack of nationally agreed definitions and measures of vulnerability and risk relating to the social and emotional wellbeing of children aged under 5 years. This makes surveillance, planning and evaluation difficult. There is limited evidence on the effectiveness of different methods of delivering early interventions. There is limited evidence on the differential impact of early interventions on the social and emotional wellbeing of particular groups of vulnerable children aged under 5 years and their families. (This includes, for example, the impact on particular minority ethnic groups and on children whose parents have mental health problems.) The Committee made 8 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in section 5.# Appendix E Supporting documents Supporting documents include the following (see supporting evidence). Evidence reviews: Review 1: 'Promoting the social and emotional wellbeing of vulnerable preschool children (0–5 years): Systematic review level evidence' Review 2: 'Promoting the social and emotional wellbeing of vulnerable preschool children (0–5 years): UK evidence review' Review 3: 'Summary review of the factors relating to risk of children experiencing social and emotional difficulties and cognitive difficulties' Economic modelling: 'Economic outcomes of early years programmes and interventions designed to promote cognitive, social and emotional development among vulnerable children and families. Part 1 – econometric analysis of UK longitudinal data sets' 'Economic outcomes of early years programmes and interventions designed to promote cognitive, social and emotional development among vulnerable children and families. Part 2 – economic model'. Commissioned expert reports: Expert report 1: 'Primary study evidence on effectiveness of interventions (home, early education, child care) in promoting social and emotional wellbeing of vulnerable children under 5' Expert report 2: 'Programmes to promote the social and emotional wellbeing of vulnerable children under 5: messages from application of the Evidence2Success standards of evidence' Expert report 3: 'The costs and benefits of early interventions for vulnerable children and families to promote social and emotional wellbeing: economics briefing'. Fieldwork reports: 'The social and emotional wellbeing of vulnerable children (early years): views of professionals' 'The social and emotional wellbeing of vulnerable children (early years): views of parents and carers'.	{'Introduction: scope and purpose of this guidance': "# What is this guidance about?\n\nThis guidance aims to define how the social and emotional wellbeing of vulnerable children aged under 5 years can be supported through home visiting, childcare and early education. The recommendations cover:\n\nstrategy, commissioning and review\n\nidentifying vulnerable children and assessing their needs\n\nante- and postnatal home visiting for vulnerable children and their families\n\nearly education and childcare\n\ndelivering services.\n\nThis guidance does not cover the clinical treatment of emotional and behavioural difficulties or mental health conditions, or the role of child protection services.\n\n# Who is this guidance for?\n\nThe guidance is for all those responsible for ensuring the social and emotional wellbeing of children aged under 5 years. This includes those planning and commissioning children's services in local authorities (including education), the NHS, and the community, voluntary and private sectors. It also includes: GPs, health visitors, midwives, psychologists and other health practitioners, social workers, teachers and those working in all early years settings (including childminders and those working in children's centres and nurseries).\n\nThe guidance may also be of interest to parents, other family members and the general public.\n\n# Why is this guidance being produced?\n\nThe Department of Health (DH) asked the National Institute for Health and Clinical Excellence (NICE) to produce this guidance.\n\nThe guidance should be implemented alongside other guidance and regulations (for more details see section\xa04 on implementation).\n\n# How was this guidance developed?\n\nThe recommendations are based on the best available evidence. They were developed by the Public Health Interventions Advisory Committee (PHIAC). Members of PHIAC are listed in appendix\xa0A.\n\nThe guidance was developed using the NICE public health intervention process. See appendix\xa0B for details.\n\nSupporting documents used to prepare this document are listed in appendix\xa0E.\n\n# What evidence is the guidance based on?\n\nThe evidence that PHIAC considered included: 2 reviews of the evidence on effectiveness, a review of risk factors, economic modelling, the testimony of expert witnesses and commissioned reports. Further detail on the evidence is given in the considerations section (section 3) and appendices B and C.\n\nIn some cases, the evidence was insufficient and PHIAC has made recommendations for future research.\n\nMore details of the evidence on which the guidance is based, and NICE's process for developing public health guidance, are on the NICE website.\n\n# Status of this guidance\n\nThe guidance complements, but does not replace, NICE guidance on: child maltreatment; pregnancy and complex social factors; antenatal and postnatal mental health; mental health disorders in children; looked-after children and young people; and the social and emotional wellbeing of children and young people.", 'Recommendations ': "The evidence statements underpinning the recommendations are listed in appendix\xa0C.\n\nThe Public Health Interventions Advisory Committee (PHIAC) considers that the recommended interventions are cost effective.\n\nFor the research recommendations and gaps in research, see section 5 and appendix\xa0D respectively.\n\nThe evidence reviews, supporting evidence statements and economic modelling report are available at the NICE website.\n\n# Background: social and emotional development\n\nA complex range of factors have an impact on social and emotional development. Knowledge of these factors may help encourage investment at a population level in early interventions to support health and wellbeing. This would ensure children (and families) who are most likely to experience the poorest outcomes get the help they need early on in their lives.\n\nKnowledge of these factors, aside, practitioners' experience and expertise will be paramount in assessing the needs and risks of individual children and their families.\n\n# Home visiting, early education and childcare\n\nThe recommendations cover home visiting, early education and childcare for vulnerable children. The recommendations:\n\nAdopt a 'life course perspective', recognising that disadvantage before birth and in a child's early years can have life-long, negative effects on their health and wellbeing.\n\nFocus on the social and emotional wellbeing of vulnerable children as the foundation for their healthy development and to offset the risks relating to disadvantage. This is in line with the overarching goal of children's services, that is, to ensure all children have the best start in life.\n\nAim to ensure universal, as well as more targeted services, provide the additional support all vulnerable children need to ensure their mental and physical health and wellbeing. (Key services include maternity, child health, social care, early education and family welfare.)\n\nShould be used in conjunction with local child safeguarding policies and legislation.\n\nThe term 'vulnerable' is used to describe children who are at risk of, or who are already experiencing, social and emotional problems and who need additional support. See vulnerable children in the glossary for factors likely to increase the risk of problems.\n\n# Whose health will benefit?\n\nVulnerable children aged under 5 years and their parents.\n\n# Recommendation 1 Strategy, commissioning and review\n\n## Who should take action?\n\nAll those responsible for planning and commissioning (including joint commissioning) services for children aged under 5 in local authorities, the NHS (primary, secondary and tertiary healthcare) and the voluntary, community and private sectors. This includes:\n\nClinical commissioning groups.\n\nHealth and wellbeing boards.\n\nNHS Commissioning Board (up to 2015).\n\nPublic health, children's services, education and social services within local authorities.\n\n## What action should they take?\n\nHealth and wellbeing boards should ensure the social and emotional wellbeing of vulnerable children features in the 'Health and wellbeing strategy', as one of the most effective ways of addressing health inequalities. The resulting plan should include outcomes to ensure healthy child development and 'readiness for school' and to prevent mental health and behavioural problems. (See the Department of Health's Public health outcomes framework indicators for early years.)\n\nDirectors of public health, directors of children's services and commissioners of maternity care should ensure the social and emotional wellbeing of under-5s is assessed as part of the joint strategic needs assessment. This includes vulnerable children and their families. Population-based models (such as PREview, a set of planning tools published by the Child and Maternity Health Observatory) should be considered as a way of determining need and ensuring resources and services are effectively distributed.\n\nHealth and wellbeing boards should ensure arrangements are in place for integrated commissioning of universal and targeted services for children aged under 5. This includes services offered by general practice, maternity, health visiting, school nursing and all early years providers. The aim is to ensure:\n\n\n\nvulnerable children at risk of developing (or who are already showing signs of) social and emotional and behavioural problems are identified as early as possible by universal children and family services\n\ntargeted, evidence-based and structured interventions (see recommendations 3 and 4) are available to help vulnerable children and their families – these should be monitored against outcomes\n\nchildren and families with multiple needs have access to specialist services, including child safeguarding and mental health services.Also see NICE guidance on: antenatal and postnatal mental health; attention deficit hyperactivity disorder (ADHD); autism spectrum disorder in under 19s; antisocial behaviour and conduct disorders in children and young people; depression in children and young people; looked-after children and young people; pregnancy and complex social factors and child maltreatment: when to suspect maltreatment in under 18s.\n\n\n\nLocal authority scrutiny committees for health and wellbeing should review delivery of plans and programmes designed to improve the social and emotional wellbeing of vulnerable children aged under 5. See guidance on Supporting public health: children, young people and families.\n\n# Recommendation 2 Identifying vulnerable children and assessing their needs\n\n## Who should take action?\n\nEarly years settings (including children's centres and nurseries).\n\nPrimary schools (independent, maintained, private and voluntary) and school nursing services.\n\nThe NHS: general practice, health visiting services, maternity services, mental health services (perinatal, child and adolescent and adult) and paediatrics.\n\nVoluntary and community sector organisations.\n\nChild safeguarding services.\n\nPolice.\n\nLocal authority housing departments.\n\n## What action should they take?\n\nAll health and early years professionals should develop trusting relationships with vulnerable families and adopt a non-judgmental approach, while focusing on the child's needs. They should do this by:\n\n\n\nidentifying the strengths and capabilities of the family, as well as factors that pose a risk to the child's (or children's) social and emotional wellbeing\n\ntalking about the aspirations and expectations for the child\n\nseeking to understand and respond to perceived needs and concerns\n\ndiscussing any risk factors in a sensitive manner to ensure families do not feel criticised, judged or stigmatised (see vulnerable children for factors that may affect a child's social and emotional wellbeing).\n\n\n\nHealth professionals in antenatal and postnatal services should identify factors that may pose a risk to a child's social and emotional wellbeing. This includes factors that could affect the parents' capacity to provide a loving and nurturing environment. For example, they should discuss with the parents any problems they may have in relation to the father or mother's mental health, substance or alcohol misuse, family relationships or circumstances and networks of support.\n\nHealth visitors, school nurses and early years practitioners should identify factors that may pose a risk to a child's social and emotional wellbeing, as part of an ongoing assessment of their development. They should use the 'Early years foundation stage' assessment process to help identify and share any needs and concerns. Specifically, they should look for risk factors that were not evident at an earlier stage. For an infant or child, this could include:\n\n\n\nbeing withdrawn\n\nbeing unresponsive\n\nshowing signs of behavioural problems\n\ndelayed speech\n\npoor language and communication skills.\n\n\n\nFor parents, this could include indifference to the child or insensitive or harsh behaviour towards them.\n\nFamily welfare, housing, voluntary services, the police and others who are in contact with a vulnerable child and their family should be aware of factors that pose a risk to the child's social and emotional wellbeing. They should raise any concerns with the family GP or health visitor (working in the context of local safeguarding policies).\n\nHealth and early years professionals should ensure procedures are in place:\n\n\n\nto make referrals to specialist services, based on an assessment of need\n\nto collect, consistently record and share information as part of the common assessment framework (relevant child and adult datasets should be linked)\n\nfor integrated team working\n\nfor continuity of care\n\nto avoid multiple assessments.\n\n\n\n# Recommendation 3 Antenatal and postnatal home visiting for vulnerable children and their families\n\n## Who should take action?\n\nMaternity services.\n\nHealth visiting services.\n\nEarly years services.\n\n## What action should they take?\n\nHealth visitors or midwives should offer a series of intensive home visits by an appropriately trained nurse to parents assessed to be in need of additional support (see recommendation 2).\n\nThe trained nurse should visit families in need of additional support a set number of times over a sustained period of time (sufficient to establish trust and help make positive changes). Activities during each visit should be based on a set curriculum which aims to achieve specified goals in relation to:\n\n\n\nmaternal sensitivity (how sensitive the mother is to her child's needs)\n\nthe mother–child relationship\n\nhome learning (including speech, language and communication skills)\n\nparenting skills and practice.\n\n\n\nThe nurse should, where possible, focus on developing the father–child relationship as part of an approach that involves the whole family. This includes getting the father involved in any curriculum activities.\n\nHealth visitors or midwives should regularly check the parents' level of involvement in the intensive home visiting programme. If necessary, they should offer them a break, to reduce the risk that they will stop participating. If the parents do decide to have a break, the nurse should continue to communicate with them on a regular basis.\n\nManagers of intensive home-visiting programmes should conduct regular audits to ensure consistency and quality of delivery.\n\nHealth visitors or midwives should explain to parents that home visits aim to ensure the healthy development of the child (see recommendation 2). They should take into account the parents' first language and make provision for those who do not speak English. They should also be sensitive to a wide range of attitudes, expectations and approaches in relation to parenting.\n\nHealth visitors or midwives should try to ensure both parents can fully participate in home visits, by taking into account their domestic and working priorities and commitments. They should also try to involve other family members, if appropriate and acceptable to the parents.\n\nHealth visitors and midwives should consider evidence-based interventions, such as baby massage and video interaction guidance, to improve maternal sensitivity and mother–infant attachment. For example, this approach might be effective when the mother has depression or the infant shows signs of behaviourial difficulties.\n\nHealth visitors and midwives should encourage parents to participate in other services delivered by children's centres and as part of the Healthy Child Programme.\n\nHealth visitors and midwives should work in partnership with other early years practitioners to ensure families receive coordinated support. This includes psychologists, therapists, family support workers and other professionals who deliver services provided by children's centres and as part of the Healthy Child Programme.\n\n# Recommendation 4 Early education and childcare\n\n## Who should take action?\n\nAll those involved in providing early education and childcare services. This includes childminders and those working in children's centres, nurseries and primary schools (maintained, private, independent and voluntary).\n\nHealth visiting services.\n\nLocal authority children's services.\n\nSchool nursing services.\n\n## What action should they take?\n\nLocal authority children's services should ensure all vulnerable children can benefit from high quality childcare outside the home on a part- or full-time basis and can take up their entitlement to early childhood education, where appropriate. The aim is to give them the support they need to fulfill their potential. Childcare and education services should:\n\n\n\noffer flexible attendance times, so that parents or carers can take up education, training or employment opportunities\n\naddress any barriers that may hinder participation by vulnerable children such as geographical access, the cost of transport or a sense of discrimination and stigma\n\nbe run by well-trained qualified staff, including graduates and qualified teachers\n\nbe based on an ethos of openness and inclusion.\n\n\n\nManagers and providers of early education and childcare services should ensure all vulnerable children can benefit from high quality services which aim to enhance their social and emotional wellbeing and build their capacity to learn. Services should:\n\n\n\npromote the development of positive, interactive relationships between staff and children\n\nensure individual staff get to know, and develop an understanding of, particular children's needs (continuity of care is particularly important for younger children)\n\nfocus on social and emotional, as well as educational, development.\n\n\n\nIn line with the Department for Education's statutory framework for the early years foundation stage, managers and providers of early education and childcare services should:\n\n\n\nprovide a structured, daily schedule comprising a balance of adult-led and child-initiated activities\n\nensure parents and other family members are fully involved (for example, by contributing to decisions about service provision, or by participating in learning or other activities, as appropriate)\n\nensure the indoor and outdoor environment is spacious, well maintained and pleasant.\n\n\n\n# Recommendation 5 Delivering services\n\n## Who should take action?\n\nEarly years settings (including children's centres and nurseries).\n\nPrimary schools (independent, maintained, private and voluntary) and school nursing services.\n\nThe NHS: general practice, health visiting services, maternity services, mental health services (perinatal, child and adolescent and adult) and paediatrics.\n\nVoluntary and community sector organisations.\n\nChild safeguarding services.\n\n## What action should they take?\n\nHealth and early years providers should put systems in place to deliver integrated universal and targeted services that support vulnerable children's social and emotional wellbeing. This should include systems for sharing information and for multidisciplinary training and development.\n\nHealth and early years providers should ensure a process is in place to systematically involve parents and families in reviewing services and suggesting how they can be improved. As part of this process, vulnerable parents and families should be asked about their needs and concerns – and their experiences of the services on offer.\n\nHealth and early years practitioners should be clear about their responsibility for improving the social and emotional wellbeing of vulnerable children and their families. This involves developing and agreeing pathways and referral routes that define how practitioners will work together, as a multidisciplinary team, across different services within a given locality.\n\nHealth and early years practitioners should be systematic and persistent in their efforts to encourage vulnerable parents to use early years services. (This includes parents who do not use universal services such as primary care.) Activities should include:\n\n\n\ntargeted publicity campaigns\n\nmaking contact by using key workers and referral partners\n\nencouraging other parents to help get them involved\n\nsending out repeat invitations\n\nusing local community venues, such as places of worship and play centres to encourage them to participate and to address any concerns about discrimination and stigma\n\nhome visits by family support workers.\n\n\n\nHealth and early years practitioners should use outreach methods to maintain or improve the participation of vulnerable parents and children in programmes and activities. Parents who may lack confidence or are isolated will require particular encouragement. (This includes those with drug or alcohol problems and those who are experiencing domestic violence.)\n\nHealth and early years practitioners should work with community and voluntary organisations to help vulnerable parents who may find it difficult to use health and early years services. The difficulties may be due to their social circumstances, language, culture or lifestyle.\n\n The NHS Commissioning Board is responsible for commissioning health visiting services up to 2015. From 2015, local authorities will take over this responsibility.\n\n It is not clear from current evidence how many home visits are needed. The Family Nurse Partnership, an evidence-based, intensive home visiting programme, provides weekly or fortnightly home visits for 60–90\xa0minutes throughout most stages of the programme (with more in the early stages and less later).", 'Public health need and practice': "# Policy\n\nGovernment policy puts a significant emphasis on early intervention services to ensure all children have the best possible start in life. The aim is to address the inequalities in health and life chances that exist between children living in disadvantaged circumstances and those in better-off families.\n\nThe importance of social and emotional wellbeing in relation to healthy child development is set out in a joint Department for Education and Department of Health publication, 'Supporting families in the foundation years' (2011). The primary aim of the foundation years (years 0–5) is defined as: 'promoting a child's physical, emotional, cognitive and social development so that all children have a fair chance to succeed at school and in later life'.\n\nIn addition the new 'Statutory framework for the early years foundation stage' (Department for Education 2012a) makes personal, social and emotional development a cornerstone of early years learning and education.\n\nOther relevant policy documents and related reviews include:\n\n'Fair society, healthy lives' (Marmot Review Team 2010).\n\n'Healthy child programme: pregnancy and the first five years of life' (DH 2009).\n\n'Healthy lives, healthy people: our strategy for public health in England' (DH 2010a).\n\n'Healthy lives, healthy people: update and way forward' (DH 2011).\n\n'No health without mental health: a cross-government mental health outcomes strategy for people of all ages' (HM Government 2011).\n\n'Support and aspiration: a new approach to special educational needs' (Department for Education 2011a).\n\n'The early years: foundations for life, health and learning' (Tickell 2011).\n\n'The importance of teaching' (Department for Education 2010).\n\n# Benefits of social and emotional wellbeing\n\nSocial and emotional wellbeing is important in its own right, but it also provides the basis for future health and life chances.\n\nPoor social and emotional capabilities increase the likelihood of antisocial behaviour and mental health problems, substance misuse, teenage pregnancy, poor educational attainment and involvement in criminal activity. For example, aggressive behaviour at the age of 8 is a predictor of criminal behaviour, arrests, convictions, traffic offences, spouse abuse and punitive treatment of their own children (Farrington et al. 2006).\n\n# Factors that impact on social and emotional wellbeing\n\nThe child's relationship with their mother (or main carer) has a major impact on social and emotional development. In turn, the mother's ability to provide a nurturing relationship is dependent on her own emotional and social wellbeing and intellectual development – and on her living circumstances. The latter includes family environment, social networks and employment status (Shonkoff and Phillips 2000).\n\nMost parents living in poor social circumstances provide a loving and nurturing environment, despite many difficulties. However, children living in a disadvantaged family are more likely to be exposed to adverse factors such as parental substance misuse and mental illness, or neglect, abuse and domestic violence. Consequently, they are more likely to experience emotional and behavioural problems that can impact on their development and opportunities in life (Farrington et al. 2006; Shonkoff and Phillips 2000).\n\nFor example, measures of 'school readiness' show that the poorest 20% of children are more likely to display conduct problems at age 5, compared to children from more affluent backgrounds (Sabates and Dex 2012; Waldfogel and Washbrook 2008).\n\nThere are less opportunities after the preschool period to close the gap in behavioural, social and educational outcomes (Allen 2011; Field 2010).\n\n# Current services\n\nServices that support families and children during their early years are generally not well coordinated and integrated either at the strategic or local level (Allen 2011a; Field 2010; Munro 2011; Tickell 2010).\n\nThe level and quality of early childcare and education services varies, with the most disadvantaged children likely to get the worse provision (Ofsted 2010). In addition, only an estimated 50% of children aged 2 and 2½ years in England are being assessed as part of the Healthy Child Programme – and not all women are being offered antenatal and parenting support services (Care Quality Commission 2010; DH 2010b).\n\nThe approaches and interventions used to address specific problems (such as abuse, maternal mental health problems and poor parenting) also vary widely and, while some interventions have been proven to be effective and cost effective, others have not. Where evidence-based interventions are used, they are not always being implemented effectively (Allen 2011a; Field 2010).\n\nThere is limited UK data on the indicators that provide an overall measure of the social and emotional wellbeing of children aged under 5 years. Independent reviews recommend that measures should be developed to assess children's cognitive, physical and emotional development at ages 3 and 5 years (Allen 2011b; Field 2010; Tickell 2011).\n\n# Costs\n\nEarly intervention can provide a good return on investment (Knapp et al. 2011). For example, an evaluation of the US-based Nurse-Family Partnership estimated that the programme made savings by the time the children of high-risk families had reached the age of 15. These savings, which were over five times the cost of the programme itself, resulted from reduced expenditure in the welfare and criminal justice systems, higher tax revenues and improved physical and mental health (Karoly et al. 2005). (The cost effectiveness of the UK Family Nurse Partnership (FNP) model is currently being investigated as part of the FNP trial.)\n\nThe cost of not intervening to ensure (or improve) the social and emotional wellbeing of children and their families are significant, for both them and wider society (Aked et al. 2009). For example, by the age of 28, the cumulative costs for public services are much higher when supporting someone with a conduct disorder, compared to providing services for someone with no such problems (Scott et al. 2001).", 'Considerations': "The Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations.\n\nPHIAC focused on local interventions to improve children's social and emotional wellbeing – either directly, or by improving the ability of parents to provide a nurturing and loving family environment. However, such family-based services can only form one component of a broader, multi-agency local strategy within a supportive national policy framework. Other elements may include, for example, policies to improve the social and economic circumstances of disadvantaged children.\n\nPHIAC noted that a range of early years child development programmes that were beyond the scope of this guidance are effective. This includes, for example, certain parenting programmes. PHIAC also recognised that these programmes would complement the home visiting, early education and childcare interventions recommended in this guidance.\n\nPHIAC was mindful of ongoing policy developments in relation to public health commissioning. It took into account the greater role local government will play in improving and protecting the health and wellbeing of local people. For example, local government will take over responsibility for children's services from the NHS Commissioning Board in 2015. (These services support women in pregnancy and children aged up to 5\xa0years and are delivered as part of the Healthy Child Programme. They include health visiting.)\n\nTraditionally, child development policy and practice has focused on physical health and cognitive development. However, a series of independent reviews on early intervention, early education and child protection have underlined the importance of social and emotional wellbeing. (The reviews include Allen [2011a; 2011b]; and Department for Education and DH .) Social and emotional wellbeing forms the basis for healthy child development and 'readiness for school'. It can also help prevent poor health and improve education and employment outcomes in adolescence and throughout adulthood.\n\nThere is a lack of consensus on how to define and measure young children's social and emotional wellbeing. Much of the evaluation literature concentrates on the consequences of someone lacking mental or social and emotional wellbeing. Evidence on interventions aiming to improve or sustain social and emotional wellbeing is comparatively limited – and the quality varies significantly. There are a small number of high-quality, long-term UK studies. However, the main body of evidence is from the US and it was sometimes difficult to determine how relevant this was for early years services in the UK.\n\nMost of the available evidence on early years interventions related to mothers. However, PHIAC recognised the importance of including the father in interventions, where this was possible.\n\nWithin the guidance, the term 'parent' includes mothers, fathers, carers and foster parents. PHIAC noted that both parents are important to children (whether living in the same household or in a relationship with each other or not). PHIAC noted that programmes to encourage the participation of all parents, at all stages (before birth and throughout the early years) and that support their needs, may benefit their children's social and emotional wellbeing greatly.\n\nIndependent reviews (Allen 2011; Field 2010) stressed the critical role of the whole family, including fathers and grandparents, in influencing a child's social and emotional wellbeing and subsequent life chances. There is limited evidence on the most effective ways that fathers and grandparents who provide childcare support can promote social and emotional wellbeing. However, PHIAC recognised that an approach that involves the whole family is important.\n\nDifficulties with speech, language and communication may contribute significantly to social and emotional wellbeing problems and the resulting behaviour that may ensue. For example, PHIAC noted that, according to one longitudinal study (Silva et al. 1987) 59% of children aged 3 years with language delay had behavioural problems, compared with 14% without language delay. PHIAC also noted that those working with young children and their families have an important role in highlighting the importance of language and communication and in identifying any difficulties in this area.\n\nThe recommendations build on important national developments to promote and protect the social and emotional wellbeing of children, especially vulnerable children. These developments include:\n\nExpansion of the health visitor workforce.\n\nThe new core purpose of children's centres: 'to improve outcomes for young children and their families with a particular focus on the most disadvantaged, so that children are equipped for life and ready for school, no matter what their background or family circumstances' (Department for Education 2011b).\n\nFree early education extended to 40% of infants aged 2 years, starting with those who are from disadvantaged families (Department for Education 2012b).\n\nThe designation of personal, social and emotional development as 1 of the key themes in the new early years foundation stage (Department for Education 2012a). (This statutory framework sets standards for learning, development and care for children from age 1–5 years for all early years settings).\n\nStronger links between the Healthy Child Programme and early years foundation stage processes of assessment and review to help identify and respond to children with particular needs.\n\nExpert testimony relating to the Family Nurse Partnership programme showed that this model can have a positive effect on children's emotional and behavioural development. (The evidence was derived originally from long-term randomised control trials [RCTs] in the US of targeted, intensive interventions.) PHIAC noted that the current UK randomised control trial, based on the same programme, will provide valuable evidence of its effectiveness in this country. It also acknowledged that long-term follow-up and an analysis of the costs and benefits will be crucial.\n\nPHIAC was aware of the financial constraints on public sector services and the need to ensure value for money. Members noted that the Allen reviews (2011a; 2011b) set out a strong economic case for early years 'preventive' services. The reviews showed that the greatest cost savings could be achieved by intervening during the early years of life.\n\nPHIAC judged that, if effective evidence-based interventions are systematically implemented, then cost savings are likely to be achieved over 3 to 4 years – and also in the longer term.\n\nWhile prevention of child abuse is not the primary focus of this guidance, neglect and abuse are major risks to a child's social and emotional development (as well as to their overall health and wellbeing). PHIAC believes the recommendations should help prevent child abuse.\n\nEvidence showed that effective interventions were structured, replicable and auditable. PHIAC also noted that effective interventions require 'high implementation fidelity' with original programmes, that is, they have to be based on the original programme design.\n\nPHIAC put an emphasis on arrangements that could be widely and systematically implemented to deliver evidence-based interventions.", 'Recommendations for research': "The Public Health Interventions Advisory Committee (PHIAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects.\n\nHow effective are interventions to promote social and emotional wellbeing among, and reduce the vulnerability of, different groups of vulnerable children aged under 5 years?\n\nHow can the factors that pose a risk to, or protect, the social and emotional wellbeing of children aged under 5 years be identified and assessed to determine how children can benefit from different interventions?\n\nWhat approaches can be used to ensure fathers and grandparents help protect or improve the social and emotional wellbeing of vulnerable children aged under 5 years?\n\nWhat types of home-based intervention are effective in promoting the social and emotional wellbeing of vulnerable children aged under 5 years without involving the parents? (This could include childcare provided by other family members or childminders.)\n\nHow can interventions which have been proven effective in other countries be assessed for their cultural relevance to the UK? What measures should be used to assess how transferrable they are?\n\nWhat organisational mechanisms can ensure interventions to improve the social and emotional wellbeing and 'readiness for school' of vulnerable children aged under 5 years are effectively implemented? How do these differ according to the local context?\n\nWhat are the short, medium and long-term economic benefits of interventions aimed at developing the emotional and social skills of vulnerable, preschool children – for the individual, family and wider society? How should these be assessed?\n\nWhat indicators and datasets should be used to measure and predict social and emotional wellbeing over time? Which indicators and datasets can be used to assess the long-term benefits of interventions aimed at improving the social and emotional wellbeing of vulnerable children aged under 5 years?\n\nMore detail on the gaps in the evidence identified during development of this guidance is provided in appendix\xa0D.", 'Glossary ': "# Baby massage techniques\n\nInterventions to promote infant massage. Benefits are reported to include improvements in parent and/or child sleep patterns, their interaction and relationship.\n\n# Child safeguarding\n\nSafeguarding policies and activities aim to ensure children receive safe and effective care, are protected from maltreatment and have their health and development needs met. Legislation and related policies describe how individuals and agencies should work together to safeguard children.\n\n# Family Nurse Partnership\n\nThe Family Nurse Partnership (FNP) is the UK name for the US-developed Nurse-Family Partnership (NFP). The partnership provides an intensive, structured home-visiting programme for young, first-time mothers from a disadvantaged background and their partners. The emphasis is on building a strong relationship between a specially trained (family) nurse and the parents. Support is available from early pregnancy until the child is aged 2 years. The aim is to improve pregnancy outcomes, the child's health and development and the parents' economic self-sufficiency.\n\n# Joint strategic needs assessment\n\nA joint strategic needs assessment (JSNA) provides a profile of the health and social care needs of a local population. JSNAs are used as the basis for developing joint health and wellbeing strategies.\n\n# Readiness for school\n\nIn the context of this guidance, 'readiness for school' refers to a child's cognitive, social and emotional development. Development during the child's early years may be achieved through interaction with their parents or through the processes of play and learning.\n\n# Social and emotional wellbeing\n\nSocial and emotional wellbeing provides the building block for healthy behaviours and educational attainment. It also helps prevent behavioural problems (including substance misuse) and mental illness. For the purposes of this guidance, the following definitions are used, in line with the Department for Education's Statutory framework for the early years foundation stage:\n\nemotional wellbeing – this includes being happy and confident and not anxious or depressed\n\npsychological wellbeing – this includes the ability to be autonomous, problem-solve, manage emotions, experience empathy, be resilient and attentive\n\nsocial wellbeing – has good relationships with others and does not have behavioural problems, that is, they are not disruptive, violent or a bully.\n\n# Targeted services\n\nA targeted service may be distinct from, or an adaptation of, a universal service. For example, a tailored home visiting programme by a nurse, midwife or health visitor may be provided for young parents from a disadvantaged background. This would be separate from the universal home visiting service provided for all new families and might, for example, include longer sessions, goal setting and a range of specific interventions. (See universal services below.)\n\n# Universal services\n\nUniversal services, such as general education and healthcare services, are available to everyone For all children aged up to 5 years, universal provision includes: maternal healthcare, midwife home visits soon after birth and routine health visitor checks.\n\n# Video interaction guidance\n\nInteractions between a parent or carer and a child are recorded using audio visual equipment. This is later viewed and discussed, typically with a health or social care professional. Parents and carers are given a chance to reflect on their behaviour, with the focus on elements that are successful. The aim is to improve their communications and relationship with their child.\n\n# Vulnerable children\n\nA number of factors may contribute, to varying degrees, to making a child vulnerable to poor social and emotional wellbeing. In addition, a child's circumstances may vary with time. However, in this guidance vulnerable children include those who are exposed to:\n\nparental drug and alcohol problems\n\nparental mental health problems\n\nfamily relationship problems, including domestic violence\n\ncriminality.\n\nThey may also include those who:\n\nare in a single parent family\n\nwere born to parents aged under 18\xa0years\n\nwere born to parents who have a low educational attainment\n\nwere born to parents who are (or were as children) looked after (that is, they have been in the care system)\n\nhave physical disabilities\n\nhave speech, language and communication difficulties.\n\nThese indicators can be used to identify groups of children who are likely to be vulnerable. However, not all of these children will in fact be vulnerable – and others, who do not fall within these groups, could have social and emotional problems.", 'References': "Aked J, Steuer N, Lawlor E et al. (2009) Backing the future: why investing in children is good for us all. New economics foundation\n\nAllen G (2011a) Early intervention: the next steps. London: The Cabinet Office\n\nAllen G (2011b) Early intervention: smart investment, massive savings. London: The Cabinet Office\n\nCare Quality Commission (2010) Maternity services survey 2010 [online]\n\nDepartment for Education (2010) The importance of teaching. London: Department for Education\n\nDepartment for Education (2011a) Support and aspiration: a new approach to special educational needs. London: Department for Education\n\nDepartment for Education (2011b) Core purpose of Sure Start children's centres [online]\n\nDepartment for Education, Department of Health (2011) Supporting families in the foundation years. London: Department for Education\n\nDepartment for Education (2012a) Statutory framework for the early years foundation stage [online]\n\nDepartment for Education (2012b) Early education for two-year-olds [online]\n\nDepartment of Health (2009) Healthy child programme: pregnancy and the first five years of life. London: Department of Health\n\nDepartment of Health (2010a) Healthy lives, healthy people: our strategy for public health in England. London: Department of Health\n\nDepartment of Health (2010b) Currency options for the Healthy Child Programme. London: Department of Health\n\nDepartment of Health (2011) Healthy lives, healthy people: update and way forward. London: Department of Health\n\nFarrington DP, Coid JW, Harnett AM et al. (2006) Criminal careers up to age 50 and life success up to age 48. Findings from the Cambridge study of delinquent development. London: Home Office Research, Development and Statistics Directorate\n\nField F (2010) The foundation years: preventing poor children becoming poor adults. The report of the independent review on poverty and life chances. London: HM Government\n\nHM Government (2011) No health without mental health: a cross-government mental health outcomes strategy for people of all ages. London: HM Government\n\nKaroly LA, Kilburn MR, Cannon JS (2005) Early childhood interventions: proven results, future promise. Santa Monica CA: RAND Corporation\n\nKnapp M, McDaid D, Parsonage M (2011) Mental health promotion and mental illness prevention: the economic case. London: Department of Health\n\nMarmot Review Team (2010) Fair society, healthy lives. London: The Marmot Review\n\nMunro E (2011) The Munro review of child protection: final report – a child-centred system. London: Department for Education\n\nOfsted (2010) Ofsted annual report for 2009–10. Manchester: Ofsted\n\nSabates R, Dex S (2012) Multiple risk factors in young children's development [online]\n\nSilva P, Williams S, McGee R (1987) A longitudinal study of children with developmental language delay at age three: later intelligence, reading and behaviour problems. Developmental Medicine and Child Neurology 29: 630–40\n\nShonkoff JP, Phillips DA (2000) From neurons to neighborhoods: the science of early childhood development [online]\n\nScott S, Knapp M, Henderson J et al. (2001) Financial cost of social exclusion: follow up study of antisocial children into adulthood. BMJ 323 (7306): 191\n\nTickell C (2011) The early years: foundations for life, health and learning. An independent review on the early years foundation stage. London: Department for Education\n\nWaldfogel J, Washbrook F (2008) Early years policy. London: Sutton Trust", 'Appendix\xa0B Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews, primary research, commissioned reports and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Public Health Interventions Advisory Committee (PHIAC) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix\xa0E and are available at the NICE website.\n\n# Guidance development\n\nThe stages involved in developing public health guidance are outlined below.\n\n. Draft scope released for consultation\n\n. Stakeholder meeting about the draft scope\n\n. Stakeholder comments used to revise the scope\n\n. Final scope and responses to comments published on website\n\n. Evidence reviews and economic modelling undertaken and submitted to PHIAC\n\n. PHIAC produces draft recommendations\n\n. Draft guidance (and evidence) released for consultation and for field testing\n\n. PHIAC amends recommendations\n\n. Final guidance published on website\n\n. Responses to comments published on website\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by PHIAC to help develop the recommendations. The overarching questions were:\n\n. What are the most effective and cost-effective early education, childcare and home-based interventions for helping improve and maintain the cognitive, social and emotional wellbeing of vulnerable children and their families?\n\n. Which progressive early education, childcare and home-based interventions are effective and cost effective in terms of promoting the cognitive, social and emotional wellbeing of vulnerable children and their families at: 0–3 months, 3 months to 1 year, 1–2 years, and other early-life stages?\n\n. How can vulnerable children and families who might benefit from early education, childcare and home-based interventions be identified? What factors increase the risk of children experiencing cognitive, social and emotional difficulties? What is the absolute risk posed by these different factors – and in different combinations?\n\n. How can home-based interventions reduce a child's vulnerability and build resilience to help achieve positive outcomes? In particular, how can interventions help develop a strong and positive child–parent attachment?\n\n. How can early education and childcare interventions reduce vulnerability and build resilience to help achieve positive outcomes and generally prepare children for school?\n\n. Which characteristics of an intervention are critical to achieving positive outcomes for vulnerable children and families?\n\n. What lessons can be learnt from current UK-based programmes aimed at promoting the social and emotional wellbeing of children under 5?\n\nThese questions were made more specific for each review (see reviews for further details).\n\n# Reviewing the evidence\n\n## Effectiveness reviews\n\nTwo reviews of effectiveness were conducted. One looked at review-level evidence (review 1), the other focused on primary evaluation studies of UK programmes (review 2). The latter included related qualitative evidence on factors influencing uptake and implementation.\n\nA number of databases and websites were searched for review level and evaluation studies from January 2000. See each review for details of the databases searched.\n\nAdditional methods used to identify evidence were as follows:\n\nreference list search of included papers (for reviews 1 and 2)\n\ncited reference searches of included studies in the Web of Knowledge, Scopus and Google Scholar\n\nadditional searches in Medline and the Web of Knowledge for key UK programmes\n\nconsultation with an expert advisory group.\n\nStudies were included in the effectiveness reviews (reviews 1 and 2) if the:\n\npopulations included vulnerable children aged 0–5 and their families\n\ninterventions were 'progressive' and\n\nwere provided at home, within early education or childcare settings and\n\naimed to improve the social and emotional health and cognitive ability of vulnerable under-5s and their families.\n\nStudies were excluded if they focused on:\n\ntools and methods used to assess the risk and diagnose social and emotional problems or a mental health disorder\n\nclinical or pharmacological treatments\n\nsupport provided by specialist child mental health services.\n\nSee each review for details of the inclusion and exclusion criteria.\n\n## Other reviews\n\nReview 3 focused on the risk factors associated with children experiencing social, emotional and cognitive difficulties.\n\nThe Millennium Cohort database (maintained by the Centre for Longitudinal Studies) was searched for review 3. All records were hand-searched at the title/abstract level to identify relevant publications. See the review for details.\n\n## Selection criteria\n\nStudies were included in review 3 if any aspect of a child's social and emotional wellbeing were reported (including behaviour, development and mental health).\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix\xa0E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors (see appendix\xa0A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Commissioned reports\n\nThree expert reports were commissioned.\n\nExpert report 1 summarised the evidence from primary evaluation studies on progressive interventions to promote the social and emotional wellbeing of vulnerable children aged under 5 years. The evidence came from the UK, US, the Netherlands and elsewhere.\n\nExpert report 2 looked at programmes to promote the social and emotional wellbeing of vulnerable children aged under 5 years. It included the results of applying the 'Evidence2Success' standards of evidence.\n\nExpert report 3 looked at the costs and benefits of intervening early with vulnerable children and families to promote their social and emotional wellbeing.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and an economic modelling exercise.\n\n## Review of economic evaluations\n\nA systematic search of key health and medical databases was undertaken for relevant economic evaluation studies. The inclusion and exclusion criteria were the same as for the systematic review of UK interventions (review 1). Included studies were then quality-assessed.\n\n## Economic modelling\n\nThe economic modelling comprised two parts: an econometric analysis and the development of an economic model.\n\nAn econometric analysis of longitudinal data was undertaken to:\n\nunderstand the factors determining aspects of social, psychological and cognitive development in early childhood\n\nestablish a link between early childhood development and adult outcomes\n\npredict the effects of childhood interventions on long-term outcomes.\n\nAn economic model was developed to determine the long-term outcomes of the intervention (home visiting, early education and childcare). It incorporated data from the reviews of effectiveness and the economic evaluation and outputs from the econometric analysis.\n\nThe results are reported in the economic modelling reports – see appendix\xa0E.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with commissioners and practitioners who are involved in early years services in local authorities, the NHS and the community, voluntary and private sectors. Parents and carers of vulnerable children aged under 5 were also consulted.\n\nThe fieldwork comprised:\n\nSixteen discussion groups with commissioners and practitioners. Two were held in each of 8 local authority areas (Barking and Dagenham, Birmingham, Cambridgeshire, Luton, Northamptonshire, Reading, Sheffield and Tower Hamlets).\n\nEight discussion groups involving a total of 41 parents and carers. These were held in 8 local authority areas (Barking and Dagenham, Birmingham, Cambridgeshire, Luton, Northamptonshire, Reading, Sheffield and Tower Hamlets).\n\nThe main issues arising from the fieldwork are set out in appendix\xa0C under fieldwork findings. See also the full fieldwork reports 'The social and emotional wellbeing of vulnerable children (early years): views of professionals' and 'The social and emotional wellbeing of vulnerable children (early years): views of parents and carers'.\n\n# How PHIAC formulated the recommendations\n\nAt its meetings in January 2012, the Public Health Interventions Advisory Committee (PHIAC) considered the evidence, expert reports and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nPHIAC developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to an evidence statement(s) (see appendix\xa0C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).", 'Appendix\xa0C The evidence ': "# Background\n\nThis appendix\xa0lists the evidence statements from 3 reviews provided by external contractors (see appendix\xa0A and appendix\xa0E) and links them to the relevant recommendations. See appendix\xa0B for the meaning of the (++), (+) and (-) quality assessments referred to in the evidence statements.\n\nAppendix\xa0C also lists 3 expert reports and their links to the recommendations and sets out a brief summary of findings from the economic analysis.\n\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letter(s) in the code refers to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document.\n\nEvidence statement 1.1 indicates that the linked statement is numbered 1 in review 1. Evidence statement 2. ES1 indicates that the linked statement is numbered 1 under the heading 'Effectiveness studies' in review 2. Evidence statement 2.PS1 indicates that the linked statement is numbered 1 under the heading 'Process studies' in review 2. Evidence statement 3.1 indicates that the linked statement is numbered 1 in review 3.\n\nThe 3 reviews are:\n\nReview 1: 'Promoting the social and emotional wellbeing of vulnerable preschool children (0–5 years): Systematic review level evidence'\n\nReview 2: 'Promoting the social and emotional wellbeing of vulnerable preschool children (0–5 years): UK evidence review'\n\nReview 3: ' Summary review of the factors relating to risk of children experiencing social and emotional difficulties and cognitive difficulties'\n\nThe reviews, expert reports, economic analysis are available at the NICE website. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nWhere the Public Health Interventions Advisory Committee (PHIAC) has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix.\n\nRecommendation 1: evidence statements 1.1, 1.2, 1.4, 2.ES1, 2.ES3; Additional evidence expert report 1, expert report 2; expert testimony: PREview project\n\nRecommendation 2: evidence statement 3.1; Additional evidence expert report 1; expert testimony: PREview project\n\nRecommendation 3: evidence statements 1.1, 1.2, 1.4, 2.ES1, 2.ES3, 2.PS1, 2.PS2, 2.PS3; Additional evidence expert report 1, expert report 2; expert testimony: Family Nurse Partnership\n\nRecommendation 4: evidence statements 1.3, 2.PS1, 2.PS2; Additional evidence expert report 1, expert report 2\n\nRecommendation 5: evidence statements 2.ES3, 2.PS1, 2.PS2, 2.PS4; Additional evidence expert report 1\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style. The superscript numbers refer to the studies cited beneath each statement. The full references for those studies can be found in the reviews.\n\n## Evidence statement 1.1: Home visits during pregnancy and the post-partum period (0–1 years)\n\nThere is moderate evidence from six review papers1,3,4,5,6,7 (four [-], one [+] and one [++]) suggesting that postpartum home visits interventions may be effective for improving parental outcomes in at-risk families, with one suggesting that nurse-delivered interventions may be more effective than those delivered by para-professionals or lay visitors. One additional (++) review paper2 suggests that there is insufficient evidence regarding the effectiveness of postpartum visits to women with an alcohol or drug problem.\n\nThese studies were carried out in populations described as: families at risk of dysfunction or child abuse; mothers at risk for postnatal depression; mothers identified as having additional needs; families living in a deprived area; teenage mothers; African-American women; drug users; economically deprived women; socially at-risk women; preterm infants and mothers with maternal risk.\n\nIn regard to specific outcomes: one of these reviews (-)6 provides evidence for the effectiveness of programmes delivered by nurses on intimate partner violence and reducing child abuse potential in low-income families, ethnic minority families, substance abusing mothers, and families at risk for child abuse.\n\nThree reviews (one [+]7 and two [-]5,3) provide evidence that interventions may impact on maternal outcomes (such as psychological status, postnatal depression, maternal self-esteem, quality-of-life and contraceptive knowledge and use, interaction with the child and parenting). One (-) study3 suggests that child development outcomes may be improved in preterm infants.\n\nTwo further reviews provide evidence that postpartum interventions may be effective for parental outcomes in adolescent mothers. One (-) review4 describes positive outcomes such as improved self-confidence and self-esteem following support-education interventions for postpartum adolescent mothers. A second (++) review1 suggests that interventions may have a positive impact on parent outcomes such as improving maternal-child interaction and maternal identity.\n\nCoren and Barlow (2009)\n\nDoggett et al. (2005)\n\nKearney et al. (2000)\n\nLetourneau et al. (2004)\n\nMcNaughton (2004)\n\nSharps et al. (2008)\n\nShaw et al. (2006)\n\n## Evidence statement 1.2: Home interventions for wider populations (in addition to or not including pregnancy/postpartum)\n\nSeven reviews provide evidence 1,2,3,4,5,6,7 (two [++], four [+] and one [-]) regarding the effectiveness of home visiting on interventions for at-risk families. Small to medium effects are reported on maternal sensitivity and the home environment, a moderate effect size on parent–child interaction and measures of family wellness, and a small effect size on: attachment security; cognitive development; socio-emotional development; potential abuse; parenting behaviour; parenting attitudes; and maternal lifecourse education. One (+) review3 provides mixed evidence regarding the impact of parenting interventions on childhood behaviour problems.\n\nThe study populations in the primary papers were described as including: ethnic minority teenage mothers; pregnant and postpartum women who were socially disadvantaged or substance abusers; low birthweight newborns; children with failure to thrive; low socioeconomic status families; low income families; families at risk of abuse or neglect and families considered to be at risk. One (++) review7 concluded that interventions delivered in the home for participants with low SES had lower effect sizes than those with mixed SES levels. A second (++) review2 similarly concluded that interventions with low SES or adolescent populations had lower effect sizes than middle class non-adolescent parents. One review noted that lower effects were found for studies using HOME (Home Observation and Measurement of the Environment) or NCATS (Nursing Child Assessment Teaching Scale) as outcome measures compared with other rating scales or measures.\n\nIt is unclear how the timing, intensity and other characteristics of inventions influence effectiveness, particularly with respect to levels of risk and needs. One (+) meta-analysis5 reported that characteristics of more successful interventions across all the studies were that: video feedback was included; interventions had less than 16 sessions; interventions did not include personal contact (but provided equipment); interventions started after the age of 6 months. Another (-) review6 concluded that interventions were more successful when of a moderate number of sessions (5–16 versus more than 16) in a limited time period, and were carried out at home either prenatally or after the age of 6 months. Another (++) review7 in contrast concluded that effect sizes were higher for interventions of 13 to 32 visits and lower for interventions of 1 to 12 visits and 33 to 50 visits. Also, that effect sizes were lower for interventions without a component of social support than for those that included social support. One (++) review2 suggested that there may be some reduction in intervention effect over time, and highlighted that the multifaceted nature of interventions provides challenges in ascertaining which element or elements of an intervention are most effective.\n\nBayer et al. (2009)\n\nKendrick et al. (2000)\n\nBernazzani et al. (2001)\n\nSweet and Appelbaum (2004)\n\nBakermans-Kraneburg et al. (2005)\n\nBakermans-Kraneburg et al. (2003)\n\nMacLeod and Nelson (2000)\n\n## Evidence statement 1.3: Programmes delivered in educational or centre settings\n\nFour reviews provide moderate evidence1,2,3,4 (three [+] and one [-]) regarding the effectiveness of interventions delivered in an educational or daycare setting. The detail of interventions and distinctions between daycare and childcare were not well defined.\n\nMost evidence related to cognitive outcomes. Other outcomes included social competence and child mental health. One (+) review1 found that more than 70% of positive effects reported were regarding cognitive outcomes. Most of the programmes were described as being conducted with economically disadvantaged populations. However, some reviews included both universal and progressive interventions with little detail provided regarding the precise content of the programmes or the population.\n\nMost of the programmes had multiple strands –and varied in intensity. Few reviews examined daycare and preschool education without the addition of centre or home-based parenting support. Most of the programmes were for children aged 3 years and above.\n\nPositive cognitive effects were reported for some programmes for: vocabulary; letter and word identification; letter knowledge; book knowledge; colour-naming; reduction in number of children kept back a year; increased IQ scores; verbal and 'fluid intelligence' gains; school readiness; improved classroom and personal behaviour (as rated by the teachers); reduced need for special needs education; a reduction in delinquent behaviour; fewer arrests at aged 27. Reported effectiveness however varied across programmes with one review reporting that 53% of the studies demonstrated no effect.\n\nBeneficial effects reported on child mental health included reduced anxiety and the ability to externalise behaviour problems. However one (+) review3 highlighted the potential for making difficult behaviours worse. Improvements in social competencies were reported across a number of programmes, including improvements in mother–child interaction and communications. A study of the effective provision of preschool education project found improved self-regulation and positive behaviour if children attended a centre rated as high quality. One (+) review4 of eight daycare interventions in the US concluded that out of home daycare can have beneficial effects in relation to enhancing cognitive development, preventing school failure, improving children's behaviour, and improving maternal education and employment. The authors suggested that the chance of success is higher for interventions if the intervention starts at age 3 three rather than age 4 years.\n\nAnderson et al. (2003)\n\nBurgher (2010)\n\nD'Onise et al. (2010)\n\nZoritch et al. (2009)\n\n## Evidence statement 1.4: Longer-term outcomes of early interventions in adolescence\n\nTwo good quality (both [+]) meta-analyses1,2 of outcomes following early developmental prevention programmes provide good evidence of lasting impact in adolescence, particularly as measured by cognitive outcomes. Overall, effect sizes are small to medium. Study populations were described as at risk or disadvantaged with many including a high proportion of participants from African-American backgrounds. Interventions included structured preschool programmes, centre-based developmental daycare, home visitation, family support services and parental education.\n\nOne (+)review1 reported that the largest effects were seen for educational success during adolescence, reduced social deviance, increased social participation, and cognitive development, with smaller effects for family wellbeing and social-emotional development. It was highlighted that programmes with more than 500 sessions per participant were significantly more effective than those with fewer. The second (+) review2 reported a similar pattern of outcomes. It was noted that programmes with direct teaching components in preschool and those that followed through from preschool to school tended to have the greatest cognitive impacts. Longer programmes tended to produce greater impacts on preschool cognitive outcomes and on social and emotional outcomes at school age. More intense programmes tended to produce greater impact on preschool cognitive outcomes and grade 8 parent-family outcomes.\n\nManning et al. (2010)\n\nNelson and Westhues (2003)\n\n## Evidence statement 2.ES1: Home visiting programmes\n\nEvidence from seven studies (eight papers – four [++] and four [+])1,2,3,4,5,6,7,8 suggests that some home visiting programmes may be effective in directly improving social and emotional wellbeing of vulnerable children. The extent of effect depends partly on the type and nature of intervention being delivered, and the particular outcomes measures. Some outcome measures were indirectly linked to the social and emotional development and cognitive development of the child, concerned with parental support and home environment. Many of the outcomes were self-reported introducing potential biases into the studies.\n\nThe heterogeneity of interventions across the small number of studies made it difficult to identify clear categories; and difficult to discern clear relationships between particular types of interventions and outcomes. However some distinction was evident. The more structured intensive interventions (with a focus on child-mother interaction) delivered by specifically trained nurses during the first 18 months appears more likely to have positive effects (the 'Family partnership model'). The lower intensity, less structured interventions involving lay providers (Home Start, peer mentoring) are less likely to have positive effect on the social and emotional wellbeing of vulnerable children.\n\nTwo studies 6,7 (both +) evaluated 'Starting well', an 'intensive home visiting' programme delivered by health professionals and health support workers to socioeconomically deprived parents of newborn children aged up to 24 months (Glasgow). Positive effect on home environment were reported; but methodological limitations meant the studies provided little robust evidence of effectiveness on social and emotional wellbeing.\n\nAn (++) evaluation2 of Home Start, a volunteer home visitor programme, showed a positive effect on parent–child relationships; but no effect on maternal depression. This programme offered 'unstructured' mainly social support to vulnerable families with newborns consisting of two or more visits over 12 months provided by lay, local volunteer mothers.\n\nThe (+) study4 of a small scale home visiting (intensive compensatory education) programme showed a positive effect on academic readiness and inhibitory control. This intervention consisted of weekly visits for 12 months delivered to infants aged 3 years by project workers (in an economically disadvantaged area of Wales). The intervention was a parent-delivered education programme aimed at improving school readiness.\n\nThe (++) evaluation2 of the 'Family partnership model', a home visiting programme consisting of 18 months of weekly visits from a specifically trained health visitor in two UK counties, showed a positive effect on a small number of outcomes, including maternal sensitivity and infant cooperation.\n\nThe 'Avon premature infant project' was a home visiting programme with parental child developmental education and support (using a counselling model) delivered over 2 years by nurses. The (+) evaluation5 showed that at 5-year follow-up a development advantage was identified, but at 2 years this was not evident.\n\n'Social support and family health' was a home visiting programme delivered by a health visitor providing 'supportive listening', weekly and then monthly over 2 years (in London: Camden and Islington). The (++) evaluation8 reported a possible effect on maternal health.\n\nThe (++) study3 of a peer mentoring home visiting programme reported negligible effects on social and emotional wellbeing. This programme was delivered by recruited existing mothers twice-monthly during pregnancy and monthly for the following year (in deprived areas in Northern Ireland).\n\nBarlow et al. (2007)\n\nBarnes et al. (2006; 2009)\n\nCupples et al. (2010)\n\nFord et al. (2009)\n\nJohnson et al. (2005)\n\nMackenzie et al. (2004)\n\nShute and Judge (2005)\n\nWiggins et al. (2004)\n\n## Evidence statement 2.ES3: National evaluation of Sure Start\n\nModerate evidence from two studies (reported in four papers: two [++]1,2 andtwo [+] 3,4) shows that the Sure Start programmes are effective in improving some outcomes among infants aged 9 months and 3 years relating directly and indirectly to the social and emotional development and cognitive development of preschool children (including child positive social behaviour, child independence, better parenting, home learning environment).\n\nThere was variation in effects between subgroups and over time (evaluation periods). The earlier evaluation findings showed the small and limited effects varied with degree of social deprivation. Children from relatively more socially deprived families (teenage mothers, lone parents, workless households) were adversely affected by living in Sure Start local programme areas. Later evaluation results differed from the earlier findings in that beneficial effects could be generalised to all subgroups, including teenage mothers and workless households. The findings of the impact evaluation study reported the link between implementation (fidelity) and outcomes, and attributed improved outcomes to children being exposed longer to more mature local programmes (see UK process studies: evidence statement 5 below).\n\nIt is important to note that this evidence relates to the effect of Sure Start local programmes as a whole. Although Sure Start local programmes had common aims set by central government, the types and mix of interventions were not necessarily common between delivery sites. It is likely that interventions included home visiting, early education and daycare, and the education/daycare components were strengthened after the initial phase (although the evaluation was not depended on these being present). There are a broad spectrum of outcome measures but not all of these relate directly to emotional and social wellbeing.\n\nBelsky et al. (2006)\n\nMelhuish et al. (2008)\n\nMelhuish et al. (2008)\n\nMelhuish et al. (2005)\n\n## Evidence statement 2.PS1: Engaging families and the take up of early interventions services\n\nModerate evidence from eleven papers1,2,3,4,5,6,7,8,9,10,11 suggests that the uptake of early interventions among vulnerable families is influenced by mothers' perception of benefits, timely provision of information about the interventions, personal circumstances and views, the reputation of the services, recruitment procedures, perceptions about quality of interventions and their physical accessibility.\n\nThree papers (two [+]1,10 and one [-]11)reported that the perceived benefits for parents in their child attending childcare/early education were described in terms of building networks, providing an opportunity to take a break from parenting and a facilitator for employment\n\nFive papers (four [+]2,3,4,7 and one [-]9) reported that a perceived lack of need influenced parents' decision not to take up home visiting. In some cases their needs were seen as being fulfilled by support from friends, family, or other services. The 'wrong type of support' was described by one (+) paper3 with parents needing practical support rather than other support.\n\nParental lack of knowledge regarding the content and potential benefits of available services was reported in four papers (three [+]1,5,8 and one[-]6). One good quality (+) paper4 described how mothers were unclear regarding what a programme offered, with women not understanding or not remembering information. Some women reported that the offer of the programme might have been preferred after the birth of their baby.\n\nTwo (+) papers3,4 described the influence of personal choice with some women changing their minds or not being interested in a programme, and one (+) paper7 highlighted that needs changed over time. Waiting lists for interventions meant that some women no longer needed the service when it was offered to them.\n\nThree papers of mixed quality (one [-]6 and two [+]8,5) described the influence of personal circumstances and views in influencing uptake. These included personal and family reasons and perceived cultural and language differences.\n\nPersonal choice may also be influenced by the confidence levels of parents. Two papers (both [+])1,5 described how personal time factors could present barriers to uptake; with difficulty fitting the intervention into a personal routine or multiple demands.\n\nFour mixed quality papers (two [+]1,10 and two [-]6,12) highlighted the importance of marketing, outreach, and recruitment processes for programmes. Studies suggested the use of key workers and targeted publicity, door-knocking, making use of referral partners and ongoing invitations. Two good quality papers (both [+])1,5 suggested the influence of the reputation of early education programmes in uptake. The reputation and feedback from other parents could be influential, and also a perceived stigma that services were 'for certain groups'.\n\nTwo good quality papers (both [+])1,10 described parental worries regarding the cleanliness of venues, staff prying into their personal lives and concerns for their child.\n\nThe importance of the location of a service was discussed in three papers (two [+]5,8 and one [-]6). The papers highlight that the accessibility of a site is important, with settings being visible and accessible to the public through adequate positioning on a busy street and clearly signposted. There was the suggestion that associating the nursery service with nearby schools made the programme appear more 'official' to parents and provided continuity of services.\n\nAvis et al. (2007)\n\nBarlow et al. (2005)\n\nBarnes et al. (2006)\n\nBarnes et al. (2009)\n\nCoe et al. (2008)\n\nKazimirski et al. (2008)\n\nMacPherson et al. (2009)\n\nMori (2009)\n\nMurphy et al. (2008)\n\nSmith et al. (2009)\n\nToroyan et al. (2004)\n\nTunstill (2005)\n\n## Evidence statement 2.PS2: Parents experience of services and ongoing engagement in early interventions\n\nModerate evidence from thirteen papers 1,2,3,4,5,6,7,8,9,10,11,12,13 suggests that ongoing engagement with early interventions among vulnerable families is influenced by perceived benefits to children, perception of a quality service, timing of the programme, the involvement of parents and personal reasons.\n\nThree good quality (all [+]) papers1,10,12 described that parents who took up the childcare/early education interventions valued the approach, and believed that it was beneficial to their children. Parents continued to use services as they valued how the programme was delivered, structured, and the way information and advice was given in a non-intrusive manner. Perceived benefits for children were the ability of children to mix, play, and learn with other children.\n\nThree papers (two [+]10,12 and one [-]7) suggested that parental perception of quality of provision influenced ongoing engagement. It was reported that smaller groups are preferable to parents, but if the staff and venue were perceived to be of high quality, maintaining smaller group sizes was of less importance.\n\nThree papers (two [+]10,12 and one [-]7) suggested that feedback to parents is an important factor in the success of an early education intervention. One (-) paper8 highlighted a need to make parents feel more comfortable with taking part in activities that were designed for parent and child.\n\nThree papers (all [+])1,6,10 suggested that a lack of programme flexibility precluded some parents from engaging with programmes. Some parents indicated that they would value events outside of typical centre hours, with a desire for increased programme flexibility particularly among students and part-time workers.\n\nThree papers (all [+])2,8,13 highlighted that making a large time commitment to in-home support programmes could be a barrier to engagement. One (+) paper5 reported that parents did not like the frequency of visits or fragmented visits. The timing of visits was noted as a problem in one (+) study9 with mothers feeling disrupted by the timing and scheduling of visits. Two studies (one [+]4 and one [-]11) reported that flexibility on the part of the visitor to the needs of the client to ensure the service was delivered at a suitable time, was key.\n\nOne (+) paper5 suggested that a home visitor should be proactive in recognising warning signs of losing a client, offering the family a break from the programme, changing the content delivered, and working with families to meet their needs and achieve goals. Another (+) paper8 highlighted that it made it easier for families to engage in other services once they were taking part in one programme.\n\nFour (all [+]) papers3,4,5,13 described personal reasons for not engaging with a service such as losing interest in the programme, missing too many appointments, moving out of the area, infant illness and other commitments.\n\nAvis et al. (2007)\n\nBarlow et al. (2005)\n\nBarnes et al. (2006)\n\nBarnes et al. (2008)\n\nBarnes et al. (2009)\n\nCoe et al. (2008)\n\nKazimirski et al. (2008)\n\nKirkpatrick et al. (2007)\n\nMacPherson et al. (2009)\n\nMori (2009)\n\nMurphy et al. (2008)\n\nSmith et al. (2009)\n\nWiggins et al. (2004)\n\n## Evidence statement 2.PS3: Home-based interventions and staff-parent relationships\n\nModerate evidence from eight papers1,2,3,4,5,6,7,8 suggests that the nature of the relationship between staff and parents is an important factor influencing the ongoing engagement of vulnerable families in home-based interventions.\n\nThe importance of building relationships was highlighted in six papers (five [+]1,3,4,5,6 and one [-]8) with regular interaction resulting in parents feeling at ease and being able to 'open up', and with home visitors acting as a mentor, friend, and teacher. Women reported that they liked that home visitors did not impose their views, and took an honest, open, humane and egalitarian approach. Some younger women however reportedly viewed a health visitor intervention as somewhat authoritarian, almost like advice from parents and some women were worried about how they may be perceived by home visitors, believing that they were being checked up on, and were concerned about visitors passing judgment on their lifestyle and parenting skills. One (+) paper3 found fathers were pleased with the programme but took a few sessions to become engaged.\n\nSupport was a theme described in all six papers. Parents reported that having someone there to listen and provide additional support was beneficial, visitors offered assistance in difficult times, allowed parents to vent frustrations, and encouraged parents to develop life skills and confidence.\n\nParents valued the support of a peer home visitor, especially if they had little existing social support, with some women describing how they were reluctant to seek emotional support from family or friends.\n\nBarlow et al. (2005)\n\nBarnes et al. (2006)\n\nBarnes et al. (2008)\n\nBarnes et al. (2009)\n\nKirkpatrick et al. (2007)\n\nMcIntosh et al. (2006)\n\nMacPherson et al. (2009)\n\nMurphy et al. (2008)\n\n## Evidence statement 2.PS4: Professional roles and practices\n\nEvidence from eleven papers1,2,3,4,5,6,7,8,9,10,11 suggests that issues relating to professional roles and working practices impact on service delivery and performance. Staff perceptions of the work being rewarding, the need for skilled staff, clarity about professional roles and inter-agency team working are seen as linked to the success of a programme. Concerns relating to high stress and complex workloads were highlighted, and the need for training and support.\n\nTwo papers (one [-]3 and one [+]6) indicate staff's belief in the programme was related to perceptions that the nature of the work was particularly rewarding. This was noted as a key factor for success.\n\nThe level of skills among staff was noted as important to the success of programmes in four papers (three rated [-]3,9,10 one no rating 4). Particular elements were: empowering users and staff; ongoing monitoring; staff keeping families notified of services and the results of any outreach and a supportive and flexible centre manager. Also one (-) paper10 highlighted that clear roles and responsibilities for staff must be in place to avoid the potential for staff to face conflicting management and loyalty pressures between their original home organisation and their new roles.\n\nFive papers (three [+]1,2,8 and two [-]7,11) described concerns from staff regarding home-based programmes. Stress due to a larger caseload, stress related to the job, fatigue from extended hours of working and the complex nature of issues presented during home visits was described.\n\nThree (+) papers5,8,11 described how home visitors harboured frustrations with not being able to reach clients. They, struggled with losing clients they wished they could help, and had to balance the needs of varying clients and had concerns that interventions were too short. One (+) paper1 highlighted the potential for professional roles to be undermined, with concerns apparent regarding role clarity especially when working in mixed teams. While mixed team working was perceived as advantageous in helping at-risk families, there was a blurring of roles and boundaries which created confusion, and in some instances tension within teams.\n\nThere were mixed views of supervision found in three further studies (two [+]1,8 and one [-]7). One reported satisfaction with management, while another described a need for safer working conditions and better management. In one study7 peer mentors reported that at times, they felt unprepared for some of the cultural and ethnic differences that they encountered in the home while visiting mothers, and felt they could not provide adequate support. The need for visitors to be well supported by peers and supervisors was highlighted in one (+) study2.\n\nBarnes et al. (2008)\n\nBarnes et al. (2009)\n\nKazimirski et al. (2008)\n\nMathers and Sylva (2007)\n\nMcIntosh et al. (2006)\n\nMori (2009)\n\nMurphy et al. (2008)\n\nSmith et al. (2009)\n\nToroyan et al. (2004)\n\nTunstill et al. (2005)\n\nWiggins et al. (2004)\n\n## Evidence statement 3.1: How can those vulnerable children and families who might benefit from early education and childcare interventions be identified?\n\nIt may be possible to identify children and families who might benefit most from early education and childcare interventions by considering the factors which research suggests are likely to increase their risk.\n\nThe models for predicting future likely child health outcomes could be used at a population level to direct early intervention investment towards those children and families that are most likely to experience the poorest outcomes. However, the model is dependent on the robustness of the longitudinal data sets in identifying all the key risk factors and the availability of local data to map these factors. Certain factors are not well represented, including those relating to parenting and parental mental health problems. The relationship between cultural factors and child outcomes is not well understood.\n\nAlso, such models cannot be used to predict outcomes at an individual level. The models may inform practitioners about risk factors, however, practitioner knowledge will also be vital in validating the model for use for individual risk-assessment purposes.\n\n# Additional evidence\n\nExpert report 1: 'Primary study evidence on effectiveness of interventions (home, early education, child care) in promoting social and emotional wellbeing of vulnerable children under 5'\n\nExpert report 2: 'Programmes to promote the social and emotional wellbeing of vulnerable children under 5: messages from application of the Evidence2Success standards of evidence'\n\nExpert report 3: 'The costs and benefits of early interventions for vulnerable children and families to promote social and emotional wellbeing: economics briefing'.\n\nExpert testimony on the Family Nurse Partnership: Kate Billingham, Department of Health\n\nExpert testimony on the PREview project: Helen Duncan, Child and Maternal Health Observatory (CHiMAT) and Kate Billingham, Department of Health\n\n# Economic modelling\n\nThe review of cost-effectiveness interventions found little UK evidence. By contrast, the US literature indicates that preschool education and/or home visiting programmes for at-risk populations may be cost effective.\n\nTwo econometric models were developed to understand what determines aspects of social, psychological and cognitive development (or 'ability') in early childhood. They also aimed to establish a link between early childhood development and adult outcomes.\n\nMeasures of cognitive and behavioural development were found to have a very important effect on long-term outcomes, as was parental 'investment' in the early years – through its effect on cognitive and behavioural development.\n\nThe authors noted a number of limitations in the econometric models, however, including reliance on self-report data, limited common variables in the datasets, use of observational data and associated problems with direction of causality.\n\nAn economic model was used to conduct an economic analysis of interventions to improve the social and emotional wellbeing of infants from a public sector perspective. Seventeen scenarios were modelled, drawing on evidence from the UK and US and reported in review 2.\n\nThe results were not conclusive. Interventions which improved child cognition could be cost-saving to the public sector, through improved educational outcomes, higher wages and tax revenues.\n\nModelling of the long-term effects of behavioural changes in childhood yielded more modest financial benefits. Improvements in behaviour in childhood improves adult educational outcomes, reduces the probability of being on benefits, being economically inactive or being involved in crime. All these factors yield cost savings for the public sector, but the sums are relatively small compared to the effects of improved cognition.\n\nThe authors concluded that there is potential for interventions with vulnerable preschool children to be cost effective or cost saving, even without taking into account other potential benefits. (Other benefits might include avoiding child neglect and improving the socioeconomic outcomes for the children's descendants.)\n\nA number of limitations were noted including:\n\nThe limited number of outcomes that can be used to generate financial benefits.\n\nUncertainty introduced by mapping variables across different ages and data sets.\n\nThe limited nature of the evidence base.\n\nThe need to estimate the effects of social and emotional wellbeing on long-term outcomes (such as the probability of a criminal conviction, economic activity and unemployment).\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. PHIAC considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix\xa0B, 'The social and emotional wellbeing of vulnerable children (early years): views of professionals' and 'The social and emotional wellbeing of vulnerable children (early years): views of parents and carers'.\n\n## Views of professionals\n\nFieldwork participants who work with vulnerable children aged under 5\xa0years were very positive about the recommendations and their potential to promote the social and emotional wellbeing of these children. Many stated that the recommendations complement aspects of the Department for Education's Statutory framework for early years foundation stage and government policy for early years services.\n\nParticipants said the recommendations needed to acknowledge the role of the father and other family members or carers in promoting the social and emotional wellbeing of children under\xa05.\n\nThey believed wider, more systematic implementation of the recommendations would be achieved if there was:\n\na clearer definition of what makes a child 'vulnerable'\n\nbetter identification of who should take action\n\nclarity about which action points were intended to be targeted or universal.\n\n## Views of parents and carers of children aged under 5\xa0years\n\nThe guidance was well received by parents and carers. In particular, there was strong support for multidisciplinary working and the need to ensure effective information sharing among services.\n\nIn addition, they strongly supported the recommendations to provide high quality education and childcare, but stressed the need to promote free education for children aged\xa02 years.\n\nThe stigma associated with labelling families as 'vulnerable' was a concern. They accepted that the term (and identified risk factors) may help find children and families in need of help. However, they were concerned that those identified would feel criticised or blamed.\n\nParents and carers also emphasised that practitioners should not assume that all those identified as being part of a high-risk group are vulnerable.", 'Appendix\xa0D Gaps in the evidence': 'The Public Health Interventions Advisory Committee (PHIAC) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below.\n\nThere is limited UK evidence on the effectiveness of interventions (home visiting, childcare and early education) to improve the social and emotional wellbeing of vulnerable children aged under 5 years.\n\nThere is limited UK evidence on the cost effectiveness of early interventions to improve the social and emotional wellbeing of vulnerable children aged under 5 years. This includes evidence on the distribution of costs and benefits across all relevant sectors including health, education, social care, welfare and criminal justice.\n\nThere is a lack of nationally agreed definitions and measures of vulnerability and risk relating to the social and emotional wellbeing of children aged under 5 years. This makes surveillance, planning and evaluation difficult.\n\nThere is limited evidence on the effectiveness of different methods of delivering early interventions.\n\nThere is limited evidence on the differential impact of early interventions on the social and emotional wellbeing of particular groups of vulnerable children aged under 5 years and their families. (This includes, for example, the impact on particular minority ethnic groups and on children whose parents have mental health problems.)\n\nThe Committee made 8 recommendations for research into areas that it believes will be a priority for developing future guidance. These are listed in section 5.', 'Appendix\xa0E Supporting documents': "Supporting documents include the following (see supporting evidence).\n\nEvidence reviews:\n\n\n\nReview 1: 'Promoting the social and emotional wellbeing of vulnerable preschool children (0–5 years): Systematic review level evidence'\n\nReview 2: 'Promoting the social and emotional wellbeing of vulnerable preschool children (0–5 years): UK evidence review'\n\nReview 3: 'Summary review of the factors relating to risk of children experiencing social and emotional difficulties and cognitive difficulties'\n\n\n\nEconomic modelling:\n\n\n\n'Economic outcomes of early years programmes and interventions designed to promote cognitive, social and emotional development among vulnerable children and families. Part 1 – econometric analysis of UK longitudinal data sets'\n\n'Economic outcomes of early years programmes and interventions designed to promote cognitive, social and emotional development among vulnerable children and families. Part 2 – economic model'.\n\n\n\nCommissioned expert reports:\n\n\n\nExpert report 1: 'Primary study evidence on effectiveness of interventions (home, early education, child care) in promoting social and emotional wellbeing of vulnerable children under 5'\n\nExpert report 2: 'Programmes to promote the social and emotional wellbeing of vulnerable children under 5: messages from application of the Evidence2Success standards of evidence'\n\nExpert report 3: 'The costs and benefits of early interventions for vulnerable children and families to promote social and emotional wellbeing: economics briefing'.\n\n\n\nFieldwork reports:\n\n\n\n'The social and emotional wellbeing of vulnerable children (early years): views of professionals'\n\n'The social and emotional wellbeing of vulnerable children (early years): views of parents and carers'.\n\n"}	https://www.nice.org.uk/guidance/ph40	This guideline covers supporting the social and emotional wellbeing of vulnerable children under 5 through home visiting, childcare and early education. It aims to optimise care for young children who need extra support because they have or are at risk of social or emotional problems.

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